Category Archive Endocrinology

Diagnosis of Adrenal Insufficiency

The clinical diagnosis of adrenal insufficiency can be confirmed by demonstrating inappropriately low cortisol secretion, determining whether the cortisol deficiency is secondary or primary and, hence, dependent or independent of ACTH deficiency, and detecting the cause of the disorder.

• Basal morning serum cortisol concentrations – The diagnosis of adrenal insufficiency depends upon the demonstration of inappropriately low cortisol secretion. Serum cortisol concentrations are normally highest in the early morning hours (06:00h – 08:00h), ranging between 10 – 20 mcg/dL (275 – 555 nmol/L) than at other times of the day. Serum cortisol concentrations determined at 08:00h of less than 3 µg/dL (80 nmol/L) are strongly suggestive of adrenal insufficiency, while values below 10 µg/dL (275 nmol/L) make the diagnosis likely. Simultaneous measurements of cortisol and ACTH concentrations confirm in most cases the diagnosis of primary adrenal insufficiency.
• Morning salivary cortisol concentrations – Adrenal insufficiency is excluded when salivary cortisol concentration at 08:00his higher than 5.8 ng/mL (16 nmol/L), whereas the diagnosis, is more possible for values lower than 1.8 ng/mL (5 nmol/L).
• Urinary free cortisol (UFC) – Basal urinary cortisol and 17-hydroxycorticosteroid excretion is low in patients with severe adrenal insufficiency, but may below-normal in patients with partial adrenal insufficiency. Generally, baseline urinary measurements are not recommended for the diagnosis of adrenal insufficiency.
• Basal plasma ACTH, renin, and aldosterone concentrations – Basal plasma ACTH concentration at 08:00h, when determined simultaneously with the measurement of basal serum cortisol concentration, may both confirm the diagnosis of adrenal insufficiency and establish the cause. The normal values of basal 08:00h plasma ACTH concentrations range between 20-52 pg/mL (4.5-12 pmol/L). In primary adrenal insufficiency, the 08:00h plasma ACTH concentration is elevated and is coupled with increased concentration or activity of plasma renin, low aldosterone concentrations, hyperkalemia and hyponatremia. In the cases of secondary or tertiary adrenal insufficiency, plasma ACTH concentrations are low or low normal, associated with normal values of plasma concentrations of renin and aldosterone.
• Standard dose ACTH stimulation test – Adrenal insufficiency is usually diagnosed by the standard-dose ACTH test, which determines the ability of the adrenal glands to respond to 250 mcg intravenous or intramuscular administration of ACTH(1-24) by measurement of serum cortisol concentrations at 0, 30 and 60 min following stimulation. The test is defined as normal if peak cortisol concentration is higher than 18–20 mcg/dL (500–550 nmol/L), thereby excluding the diagnosis of primary adrenal insufficiency and almost all cases of secondary adrenal insufficiency. However, if secondary adrenal insufficiency is of recent onset, the adrenal glands will have not yet atrophied, and will still be capable of responding to ACTH stimulation normally. In these cases, a low-dose ACTH stimulation test or an insulin-induced hypoglycemia test may be required to confirm the diagnosis.
• Low-Dose ACTH stimulation test This test theoretically provides a more sensitive index of adrenocortical responsiveness because it results in physiologic plasma ACTH concentrations. This test should be performed at 14:00h when the endogenous secretion of ACTH is at its lowest. The results might not be valid if it is performed at another time. At 14:00h, a blood sample is collected for the determination of basal cortisol concentrations. The low dose of ACTH(1-24) (500 nanograms ACTH(1-24)/1.73 m² ) is then administered as an intravenous bolus. In normal subjects, this dose results in a peak plasma ACTH concentration about twice that of insulin-induced hypoglycemia. Subsequently, blood samples are collected at +10 min, +15 min, +20 min, +25 min, +30 min, +35 min, +40 min, and +45 min after stimulation for determination of serum cortisol concentrations. A value of 18 µg/dL (500 nmol/L) or more at any time during the test is indicative of normal adrenal function. The advantage of this test is that it can detect partial adrenal insufficiency that may be missed by the standard-dose test. The low-dose test is also preferred in patients with secondary or tertiary adrenal insufficiency.
• Prolonged ACTH Stimulation Tests – Prolonged stimulation with exogenous administration of ACTH helps differentiate between primary and secondary or tertiary adrenal insufficiency. In secondary or tertiary adrenal insufficiency, the adrenal glands display cortisol secretory capacity following prolonged stimulation with ACTH, whereas in primary adrenal insufficiency, the adrenal glands are partially or completely destroyed and do not respond to ACTH. The prolonged ACTH test consists of the intravenous administration of 250 μg of ACTH as an infusion over eight hours (8-hour test) or over 24 hours on two (or three) consecutive days (two-day test), and the measurement of serum cortisol, and 24-hour urinary cortisol and 17-hydroxycorticoid (17-OHCS) concentrations before and after the infusion.
• Insulin-induced hypoglycemia test – This test provides an alternative choice for confirmation of the diagnosis when secondary adrenal insufficiency is suspected. The insulin tolerance test helps in the investigation of the integrity of the HPA axis and has the ability to assess growth hormone reserve. Insulin, at a dose of 0.1-0.15 U/kg, is administered to induce hypoglycemia, and measurements of cortisol concentrations are determined at 30 min intervals for at least 120 min. This test is contraindicated in patients with cardiovascular disease or a history of seizures and requires a high degree of supervision.
• Corticotropin-releasing hormone (CRH) test – This test is used to differentiate between secondary and tertiary adrenal insufficiency. It consists of intravenous administration of CRH (1 mcg/kg up to a maximum of 100 mcg) and determination of serum cortisol and plasma ACTH concentrations at 0, 15, 30, 45, 60, 90, and 120 min following stimulation. Patients with secondary adrenal insufficiency demonstrate little or no ACTH response, whereas patients with tertiary adrenal insufficiency show an exaggerated and prolonged response of ACTH to CRH stimulation, which is not followed by an appropriate cortisol response.
• Autoantibody screen – Adrenocortical antibodies or antibodies against 21-hydroxylase can be detected in more than 90% of patients with recent-onset autoimmune adrenalitis. Furthermore, antibodies that react against other enzymes involved in steroidogenesis and anti-steroid-producing cell antibodies are present in some patients.
• Very long-chain fatty acids – To exclude adrenoleukodystrophy, plasma very-long-chain fatty acids should be determined in male patients with isolated Addison’s disease and negative autoantibodies.
• Imaging – Patients without any associated autoimmune disease and negative autoantibody screen should undergo computed tomography (CT) scan of the adrenal glands. In cases of tuberculous adrenalitis, the CT scan shows initially hyperplasia of the adrenal glands and subsequently spotty calcifications during the late stages of the disease. Bilateral adrenal lymphoma, adrenal metastases or adrenal infiltration (sarcoidosis, amyloidosis, hemochromatosis) may also be detected by CT scan. If central adrenal insufficiency is suspected, a magnetic resonance imaging (MRI) scan of the hypothalamus and pituitary gland should be performed. This may detect any potential disease process, such as craniopharyngiomas, pituitary adenomas, meningiomas, metastases, and infiltration by Langerhans cell histiocytosis, sarcoidosis, or other granulomatous diseases. It should be noted that imaging is not required when adrenal cortex autoantibodies are detected.

Treatment of Adrenal Insufficiency

Treatment of Chronic Primary Adrenal Insufficiency

1. Glucocorticoid replacement (one of the given regimens)

• Hydrocortisone 15 to 25 mg orally in two or three divided doses (the largest dose is taken early in the  morning; typically 10 mg upon awakening in the morning, 5 mg early afternoon, 2.5 mg late afternoon), or
• Prednisone 5 mg (2.5 to 7.5 mg) orally at bedtime, or
• Dexamethasone 0.75 mg (0.25 to 0.75 mg) orally at bedtime
• Monitor clinical symptoms and morning plasma ACTH as needed.

2. Mineralocorticoid replacement

• Fludrocortisone 0.1 mg (range: 0.05 to 0.2 mg) orally. Hydrocortisone 20 mg and prednisone 50 mg provide a mineralocorticoid effect that is almost equivalent to 0.1 mg of fludrocortisone. Therefore, fludrocortisone replacement (if needed) must be decreased accordingly. Dexamethasone, however, lacks a mineralocorticoid effect and would require a full dose of fludrocortisone.
• Liberal salt intake.
• Monitor supine and standing blood pressure as well as pulse, edema, serum potassium, and plasma renin activity

3. Androgen replacement

• Dehydroepiandrosterone (DHEA) initially 25 to 50 mg orally (only in women for psychological well-being, if needed, after optimal glucocorticoid and mineralocorticoid replacement).

4. Patient education

• Educate the patient about the illness, how to manage stresses, and inject dexamethasone or other glucocorticoids intramuscularly or subcutaneously.

5. Emergency precautions

• Patients should have a medical alert bracelet/necklace, an emergency medical information card on their phone or inside their wallet, and prefilled syringes containing 4 mg of dexamethasone 1 mL saline.

6. Treatment of minor febrile illness or stress

• Increase glucocorticoid dose two to three times for the few days of illness. Do not change the mineralocorticoid dose (3×3 rule).
• The patient should contact the clinician if the condition worsens or persists for more than three days.
• No extra dose is required for most uncomplicated, outpatient dental procedures under local anesthesia.
• Glucocorticoid supplement for surgical stress:
• Minor: hydrocortisone 25 mg IV (or equivalent) on the day of the procedure
• Moderate: hydrocortisone 50 to 75 mg IV (or equivalent) on day of surgery and postoperative day 1
• Major: hydrocortisone 100 to 150 mg IV (or equivalent) in two or three divided doses on the day of surgery and postoperative days 1 and 2

7. Emergency treatment of severe stress or trauma

• Each patient should have an injectable as well as vials of sterile 0.9% normal saline and syringes.

Treatment of Adrenal Crisis

Measures to stabilize the patient

• Intravenous access with one or two large-gauge needles
• Laboratory analysis, including serum electrolytes, glucose, and routine measurement of plasma cortisol and ACTH.
• Infusion of 2 to 3 liters of isotonic saline or 5% dextrose in isotonic saline as urgently as possible. Periodic hemodynamic monitoring and measurement of serum electrolytes.
• Give hydrocortisone (100 mg intravenous bolus), followed by 50 mg intravenously every 6 hours (or 200 mg/24 hours as a continuous intravenous infusion for the first 24 hours). If hydrocortisone is unavailable, alternatives include prednisolone, prednisone, and dexamethasone.
• Correct any ongoing electrolyte abnormalities. Hyponatremia is often corrected by cortisol and volume repletion.

Subacute measures after stabilization of the patient

• Intravenous isotonic saline infusion at a slower rate for the next 24 to 48 hours.
• Diagnosis and treatment of possible infectious precipitating causes of the adrenal crisis.
• If the patient does not have known adrenal insufficiency, a short ACTH stimulation test should establish the diagnosis and determine its type and cause.
• 4. Tapering of parenteral glucocorticoid over 1 to 3 days to the oral glucocorticoid maintenance dose, if there are no ongoing contraindications.
• Initiating mineralocorticoid replacement with fludrocortisone, 0.1 mg by mouth daily after stopping the saline infusion.

Treatment By specific condition

Adrenal insufficiency is one of the most life-threatening disorders. Treatment should be administered to the patients as soon as the diagnosis is established, or even sooner if an adrenal crisis occurs.

• Treatment of Chronic Adrenal Insufficiency – One of the most important aspects of the management of chronic primary adrenal insufficiency is patient and family education. Patients should understand the reason for life-long replacement therapy, the need to increase the dose of glucocorticoid during minor or major stress, and to inject hydrocortisone, methylprednisolone, or dexamethasone in emergencies.
• Emergency precautions – Patients should wear a medical alert (Medic Alert) bracelet or necklace and carry the Emergency Medical Information Card, which should provide information on the diagnosis, the medications, and daily doses, and the physician involved in the patient’s management. Patients should also have supplies of dexamethasone sodium phosphate and should be educated about how and when to administer them.
• Glucocorticoid replacement therapy – Patients with adrenal insufficiency should be treated with hydrocortisone, the natural glucocorticoid, or cortisone acetate if hydrocortisone is not available. The hydrocortisone daily dose is 10-12 mg per meter square body surface area and can be administered in two to three divided doses with one-half to two-thirds of the total daily dose being given in the morning. Small reductions of bone mineral density (BMD) probably due to higher than recommended doses, as well as impaired quality of life were observed in patients treated with hydrocortisone. A longer-acting synthetic glucocorticoid, such as prednisone, prednisolone, or dexamethasone, should be avoided because their longer duration of action may produce manifestations of chronic glucocorticoid excess, such as loss of lean body mass and bone density, and gain of visceral fat. Recently, preparations of hydrocortisone that lead to both delayed and sustained release of this compound have been developed and are under clinical investigation. These formulations maintain stable cortisol concentrations during 24 hours and physiologic circadian rhythmicity with the cortisol peak occurring during the early morning after oral intake of the preparation at bedtime. Furthermore, a novel once-daily (OD) dual-release hydrocortisone tablet has been developed to maintain more physiologic circadian-based serum cortisol concentrations. Compared to the conventional treatment, the OD dual-release hydrocortisone improved glucose metabolism, cardiovascular risk factors, and quality of life. Regardless of the type of formulation used, glucocorticoid replacement should be monitored clinically, evaluating weight gain/loss, arterial blood pressure, annualized growth velocity, and presence of Cushing features.
• Glucocorticoid replacement during minor illness or surgery – During minor illness or surgical procedures, glucocorticoids should be given at a dosage up to three times the usual maintenance dosage for up to three days. Depending on the nature and severity of the illness, additional treatment may be required.
• Glucocorticoid replacement during major illness or surgery – During major illness or surgery, high doses of glucocorticoid analogs (10 times the daily production rate) are required to avoid an adrenal crisis. A continuous infusion of 10 mg of hydrocortisone per hour or the equivalent amount of dexamethasone or prednisolone eliminates the possibility of glucocorticoid deficiency. This dose can be halved on the second postoperative day, and the maintenance dose can be resumed on the third postoperative day.
• Mineralocorticoid replacement therapy – Mineralocorticoid replacement therapy is required to prevent intravascular volume depletion, hyponatremia, and hyperkalemia. For these purposes, fludrocortisone (9-alpha-fluorohydrocortisone) in a dose of 0.05 – 0.2 mg daily should be taken in the morning. The dose of fludrocortisone is titrated individually based on the findings of clinical examination (mainly the body weight and arterial blood pressure) and the levels of plasma renin activity. Patients receiving prednisone or dexamethasone may require higher doses of fludrocortisone to lower their plasma renin activity to the upper normal range, while patients receiving hydrocortisone, which has some mineralocorticoid activity, may require lower doses. The mineralocorticoid dose may have to be increased in the summer, particularly if patients are exposed to temperatures above 29ºC (85ºF). If patients receiving mineralocorticoid replacement develop hypertension, the dose of fludrocortisone should be reduced accordingly. In case of uncontrolled blood pressure, patients should be encouraged to continue fludrocortisone and initiate antihypertensive therapy, such as angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, or dihydropyridine calcium blockers.
• Androgen replacement – In women, the adrenal cortex is the primary source of androgen in the form of dehydroepiandrosterone and dehydroepiandrosterone sulfate. Treatment with DHEA enhances mood and general well-being both in adult patients and in children and adolescents with adrenal insufficiency. A single oral morning dose of DHEA of 25-50 mg may be sufficient to maintain normal serum androgen concentrations in premenopausal women with primary adrenal insufficiency, who present with decreased libido, anxiety, depression, and low energy levels. If symptoms are still present during a period of 6 months, patients are advised to discontinue DHEA replacement. Naturally, women should be encouraged to report any side effects of androgen therapy. Finally, DHEA replacement should be monitored by determining serum DHEA concentrations in the morning before the patient receives her daily DHEA dose.
• Treatment of adrenal crisis – The aim of initial management in an adrenal crisis is to treat hypotension, hyponatremia, and hyperkalemia, and to reverse glucocorticoid deficiency. Treatment should be started with immediate administration of 100 mg hydrocortisone i.v. and rapid rehydration with normal saline infusion under continuous cardiac monitoring, followed by 100–200 mg hydrocortisone in glucose 5% per 24-hour continuous iv infusion; alternatively, hydrocortisone could be administered iv or im at a dose of 50-100 mg every 6 hours depending on body surface area and age. With daily hydrocortisone doses of 50 mg or more, mineralocorticoids in patients with primary adrenal insufficiency can be discontinued or reduced because this dose is equivalent to 0.1 mg fludrocortisone. Once the patient’s condition is stable and the diagnosis has been confirmed, parenteral glucocorticoid therapy should be tapered over 3-4 days and converted to an oral maintenance dose. Patients with primary adrenal insufficiency require life-long glucocorticoid and mineralocorticoid replacement therapy.
• Treatment of chronic secondary and tertiary adrenal insufficiency – In chronic secondary or tertiary adrenal insufficiency, glucocorticoid replacement is similar to that in primary adrenal insufficiency, however, measurement of plasma ACTH concentrations cannot be used to titrate the optimal glucocorticoid dose. Mineralocorticoid replacement is rarely required, while replacement of other anterior pituitary deficits might be necessary.

• https://www.ncbi.nlm.nih.gov/books/NBK26/
• https://www.ncbi.nlm.nih.gov/books/NBK482264/
• https://www.ncbi.nlm.nih.gov/books/NBK537260/
• https://www.ncbi.nlm.nih.gov/books/NBK278945/
• https://www.ncbi.nlm.nih.gov/books/NBK441832/
• https://www.ncbi.nlm.nih.gov/books/NBK278929/
• https://www.ncbi.nlm.nih.gov/books/NBK278929/
• https://www.ncbi.nlm.nih.gov/books/NBK470339/
• https://en.wikipedia.org/wiki/Adrenal_gland
• https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency

Graves’ disease is an autoimmune disorder that causes hyperthyroidism or overactive thyroid. With this disease, your immune system attacks the thyroid and causes it to make more thyroid hormone than your body needs. The thyroid is a small, butterfly-shaped gland in the front of your neck. Thyroid hormones control how your body uses energy, so they affect nearly every organ in your body—even the way your heartbeats.

Graves’ disease is the most common cause of hyperthyroidism. It is a disorder with systemic manifestations that primarily affect the heart, skeletal muscle, eyes, skin, bone, and liver. Failure to diagnose Graves’ disease in a timely manner can predispose to thyroid storm which carries high morbidity and mortality. Clinicians ought to be aware of systemic manifestations of Graves’ disease and the different modalities available for treatment. Early diagnosis and management of Graves’ disease can also prevent severe cardiac complications such as atrial flutter, atrial fibrillation, and high output cardiac failure. This activity reviews the evaluation and treatment of Graves’ disease and highlights the role of the interprofessional team in reducing morbidity and improving care for affected patients.

Graves’ disease is an autoimmune disease that primarily affects the thyroid gland. It may also affect multiple other organs including eyes and skin. It is the most common cause of hyperthyroidism.[rx] In this chapter, we attempt to review different aspects of Graves’ disease.

Causes of Graves’ Disease

Like all autoimmune diseases, it occurs more commonly in patients with a positive family history. It is more common in monozygotic twins than in dizygotic twins. It is precipitated by environmental factors like stress, smoking, infection, iodine exposure, and postpartum, as well as after highly active antiretroviral therapy (HAART) due to immune reconstitution.[rx]

Genetics

A genetic predisposition for Graves’ disease is seen, with some people more prone to develop TSH receptor activating antibodies due to a genetic cause. Human leukocyte antigen DR (especially DR3) appears to play a role.^[10] To date, no clear genetic defect has been found to point to a single-gene cause.

Genes believed to be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22, and cytotoxic T-lymphocyte–associated antigen 4, among others.^[rx]

Infectious trigger

Since Graves’ disease is an autoimmune disease that appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies that cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry.^[rx]

The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor^[rx] and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals. In the 1990s, it was suggested that Y. enterocolitis may be associated with Graves’ disease.^[rx] More recently, the role for Y. enterocolitis has been disputed.^[rx]

Epstein–Barr virus (EBV) is another potential trigger.^[rx]

Pathophysiology

Graves’ disease is caused by thyroid-stimulating immunoglobulin (TSI), also known as a thyroid-stimulating antibody (TSAb). B lymphocytes primarily synthesize Thyroid stimulating immunoglobulin within the thyroid cells, but it can also be synthesized in lymph nodes and bone marrow. B lymphocytes are stimulated by T lymphocytes which get sensitized by antigen in the thyroid gland. Thyroid-stimulating immunoglobulin binds with thyroid-stimulating hormone (TSH) receptor on the thyroid cell membrane and stimulates the action of the thyroid-stimulating hormone. It stimulates both, thyroid hormone synthesis and thyroid gland growth, causing hyperthyroidism and thyromegaly.[rx]

Several environmental factors including pregnancy (mainly postpartum), iodine excess, infections, emotional stress, smoking, and interferon alfa trigger immune responses on susceptible genes to eventually cause Graves’ disease.

Graves’ orbitopathy (ophthalmopathy) is caused by inflammation, cellular proliferation, and increased growth of extraocular muscles and retro-orbital connective and adipose tissues due to the actions of thyroid-stimulating antibodies and cytokines released by cytotoxic T lymphocytes (killer cells). These cytokines and thyroid-stimulating antibodies activate periorbital fibroblasts and preadipocytes, causing the synthesis of excess hydrophilic glycosaminoglycans (GAG) and retro-orbital fat growth. Glycosaminoglycans cause muscle swelling by trapping water. These changes give rise to proptosis, diplopia, congestion, and periorbital edema. If left untreated, it eventually leads to irreversible fibrosis of the muscles.[rx]

Pathogenesis of other rare manifestations of Graves disease like pretibial myxedema and thyroid acropachy are poorly understood and are believed to be due to cytokines-mediated stimulation of fibroblasts. Many symptoms of hyperthyroidism like tachycardia, sweating, tremors, lid lag, and stare are thought to be related to increased sensitivity to catecholamine.

Symptoms

Common signs and symptoms of Graves’ disease include:

• Anxiety and irritability
• A fine tremor of the hands or fingers
• Heat sensitivity and an increase in perspiration or warm, moist skin
• Weight loss, despite normal eating habits
• Enlargement of the thyroid gland (goiter)
• Change in menstrual cycles
• Erectile dysfunction or reduced libido
• Frequent bowel movements
• Bulging eyes (Graves’ ophthalmopathy)
• Fatigue
• Thick, red skin usually on the shins or tops of the feet (Graves’ dermopathy)
• Rapid or irregular heartbeat (palpitations)
• Sleep disturbance

Additional Symptoms

• Goitre (enlarged thyroid). If the thyroid grows large enough, it may compress the recurrent laryngeal nerve, producing vocal cord paralysis, dysphonia, and even respiratory stridor. Compression of the sympathetic chain may result in Horner’s syndrome.
• Graves’ ophthalmopathy (protrusion of one or both eyes)
• Pretibial myxedema
• Cardiovascular features may include hypertension, and heart rate that may be rapid or irregular in character; these may be perceived as palpitations. Less common findings include left ventricular hypertrophy, premature atrial and ventricular contractions, atrial fibrillation, congestive heart failure, angina, myocardial infarction, systemic embolization, death from cardiovascular collapse and resistance to some drug effects (digoxin, coumadin).
• Hyperreflexia, with a rapid relaxation phase.
• A distinctly excessive reaction to all sorts of stimuli.
• A marked increase in fatigability, or asthenia, is often prominent. This increased weariness may be combined with hyperactivity; patients remark that they are impelled to incessant activity, which, however, causes great fatigue.
• Insomnia
• Tremor (usually fine shaking; tremor of the outstretched fingers). In a small study of newly diagnosed hyperthyroid patients, tremor was observed in 76% of them. Some studies lay the cause for hyperthyroid tremor with a heightened beta-adrenergic state, others suggest an increased metabolism of dopamine.
• Weight loss despite normal or increased appetite. Some patients (especially younger ones) gain weight due to excessive appetite stimulation that exceeds the weigh loss effect.
• Increased appetite.
• Weakness or muscle weakness (especially in the large muscles of the arms and legs). This latter occurs in 60 to 80 percent of patients with untreated hyperthyroidism. Muscle weakness is rarely the chief complaint. The likelihood and degree of muscle weakness is correlated with the duration and severity of the hyperthyroid state, and become more likely after the age of 40. Muscle strength returns gradually over several months after the hyperthyroidism has been treated.
• Muscle degeneration
• Shortness of breath
• Increased sweating
• Heat intolerance
• Warm and moist skin
• Thin and fine hair
• Redness of the elbows is frequently present. It is probably the result of the combination of increased activity, an exposed part, and a hyperirritable vasomotor system.
• Chronic sinus infections
• Brittle nails
• Plummer’s nail
• Abnormal breast enlargement in men
• Gastrointestinal symptoms. This includes increased bowel movements, but malabsorption is unusual.
• Augmented calcium levels in the blood (by as much as 25% – known as hypercalcemia). This can cause stomach upset, excessive urination, and impaired kidney function.
• Diabetes may be activated or intensified, and its control worsened. The diabetes is ameliorated or may disappear when the thyrotoxicosis is treated
• Evidence of mild or severe liver disease may be found.
• Reproductive symptoms in men may include reduced free testosterone (due to the elevation of testosterone-estrogen binding globulin level), diminished libido, erectile dysfunction and (reversible) impaired sperm production with lower mean sperm density, a high incidence of sperm abnormalities, and reduced mobility of the sperm cells. Women may experience infrequent menstruation or irregular and scant menstrual flow along with difficulty conceiving, infertility, and recurrent miscarriage.
• Neurological seizures, neuropathy from nerve entrapment by lesions of pretibial myxedema, and hypokalemic periodic paralysis may occur. Athetoid, choreia, and corticospinal tract damage are rare. An acute thyrotoxic encephalopathy is very rare.

Diagnosis of Graves’ Disease

Most patients with Graves disease present with classic signs and symptoms of hyperthyroidism. Initial presentation of Graves disease with only Graves orbitopathy or pretibial myxedema is rare. Presentation depends on the age of onset, severity, and duration of hyperthyroidism. In the elderly population, symptoms may be subtle or masked, and they may present with non-specific signs and symptoms like fatigue, weight loss, and new-onset atrial fibrillation. Atypical presentation of hyperthyroidism in elderly is also referred as apathetic thyrotoxicosis.

In younger patients, common presentations include heat intolerance, sweating, fatigue, weight loss, palpitation, hyper defecation, and tremors. Other features include insomnia, anxiety, nervousness, hyperkinesia, dyspnea, muscle weakness, pruritus, polyuria, oligomenorrhea or amenorrhea in the female, loss of libido, and neck fullness. Eye symptoms include lids swelling, ocular pain, conjunctival redness, double vision. Palpable goiter is more common in the younger population, age younger than 60 years.  Up to 10 % of patients may have weight gain.[rx]

Physical signs of hyperthyroidism include tachycardia, systolic hypertension with increased pulse pressure, signs of heart failure (like edema, rales, jugular venous distension, tachypnea), atrial fibrillation, fine tremors, hyperkinesia, hyperreflexia, warm and moist skin, palmar erythema and onycholysis, hair loss, diffuse palpable goiter with thyroid bruit and altered mental status.

Signs of extrathyroidal manifestations of Graves’ disease include ophthalmopathy like eyelid retraction, proptosis, periorbital edema, chemosis, scleral injection, exposure keratitis. Thyroid dermopathy causes marked thickening of the skin, mainly over tibia which is rare, seen in 2% to 3% of cases.[rx] The thickened skin has peau d’orange appearance and is difficult to pinch. Bone involvement includes subperiosteal bone formation and swelling in the metacarpal bones which is called osteopathy or thyroid acropachy. Onycholysis (Plummer nails) and clubbing are very rare.

Evaluation

Diagnosis of Graves disease starts with a thorough history and physical examination. History should include a family history of Graves’ disease. [rx][rx]

• Blood tests. Blood tests can help your doctor determine your levels of thyroid-stimulating hormone (TSH) — the pituitary hormone that normally stimulates the thyroid gland — and your levels of thyroid hormones. People with Graves’ disease usually have lower than normal levels of TSH and higher levels of thyroid hormones.Your doctor may order another lab test to measure the levels of the antibody known to cause Graves’ disease. It’s usually not needed to diagnose the disease, but results that don’t show antibodies might suggest another cause of hyperthyroidism.
• Radioactive iodine uptake. Your body needs iodine to make thyroid hormones. By giving you a small amount of radioactive iodine and later measuring the amount of it in your thyroid gland with a specialized scanning camera, your doctor can determine the rate at which your thyroid gland takes up iodine. The amount of radioactive iodine taken up by the thyroid gland helps determine if Graves’ disease or another condition is the cause of the hyperthyroidism. This test may be combined with a radioactive iodine scan to show a visual image of the uptake pattern.
• Ultrasound. Ultrasound uses high-frequency sound waves to produce images of structures inside the body. It can show if the thyroid gland is enlarged. It’s most useful in people who can’t undergo radioactive iodine uptake, such as pregnant women.
• Imaging tests. If the diagnosis of Graves’ disease isn’t clear from a clinical assessment, your doctor may order special imaging tests, such as a CT scan or MRI.
• Thyroid function tests to diagnose hyperthyroidism – The initial test for diagnosis of hyperthyroidism is the thyroid-stimulating hormone (TSH) test. If TSH is suppressed, one needs to order Free T4 (FT4) and Free T3 (FT3). If free hormone assays are not available, total T4 (Thyroxine) and total T3 (Triiodothyronine) can be ordered. Suppressed TSH with high FT4 or FT3 or both will confirm the diagnosis of hyperthyroidism. In subclinical hyperthyroidism, only TSH is suppressed, but FT4 and FT3 are normal.
• Tests to differentiate Graves from other causes of hyperthyroidism – Graves’s diagnosis can be obvious with a careful history and physical examination. Features suggestive of Graves disease include a positive family history of Graves disease, the presence of orbitopathy, diffusely enlarged thyroid with or without bruit, and pretibial myxedema.

Measurement of TSH receptor antibody (TRAb) –  There are two available assays, the thyroid-stimulating immunoglobulin (TSI) and thyrotropin-binding inhibiting (TBI) immunoglobulin or thyrotropin-binding inhibitory immunoglobulin (TBII). Measurement of TRAb with third-generation assay has sensitivity and specificity of 97% and 99% for the diagnosis of Graves disease.[rx] TRAb measurement is indicated in the following conditions:

• Hyperthyroidism during pregnancy when thyroid uptake scan is contraindicated
• Pregnant women with h/o Graves disease to determine possible fetal and neonatal hyperthyroidism as these antibodies cross the placenta
• Patients with possible Graves’ orbitopathy without biochemical hyperthyroidism
• Patients with recent h/o large iodine load where thyroid uptake scan cannot be reliable, e.g., recent amiodarone use, recent imaging studies with iodinated contrast
• To determine the prognosis of hyperthyroidism who are being treated.

 Radioactive iodine uptake scan with I-123 or I-131:  In Graves disease, the uptake will be high and diffuse whereas, in a toxic nodule, the uptake will be focal known as a hot nodule. Toxic multinodular goiter will have heterogeneous uptake. The radioactive iodine uptake in subacute or silent thyroiditis, factitious hyperthyroidism, and recent iodine load will be low.

Thyroid Ultrasonogram with Doppler: The thyroid gland in Graves disease is usually hypervascular. T3/T4 ratio greater than20 (ng/mcg) or FT3/FT4 ratio greater than 0.3 (SI unit) suggests Graves disease and can be used to differentiate Graves’ disease from thyroiditis induced thyrotoxicosis.

Other Tests – CT or MRI of orbits can be performed to diagnose Graves orbitopathy in patients who present with orbitopathy without hyperthyroidism. Patients with hyperthyroidism can have microcytic anemia, thrombocytopenia, bilirubinemia, high transaminases, hypercalcemia, high alkaline phosphatase, low LDL and HDL cholesterol.

Treatment of Graves’ Disease

Treatment for Graves’ disease depends on its presentation. Treatment consists of rapid symptoms control and reduction of thyroid hormone secretion.

A beta-adrenergic blocker should be started for symptomatic patients, specifically for patients with a heart rate of more than 90 beats/min, patients with a history of cardiovascular disease, and elderly patients. Atenolol 25 mg to 50 mg orally once daily may be considered the preferred beta-blocker due to its convenience of daily dosing, and it is cardioselective (beta-1 selective). Some prescribers recommend Propranolol 10 mg to 40 mg orally every six to eight hours, due to its potential effect to block peripheral conversion of T4 to T3. If a beta-blocker after that, calcium channel blockers like diltiazem and verapamil can be used to control heart rate.[rx][rx][rx]

There are three options to reduce thyroid hormone synthesis. These options are:

• Antithyroid drugs block thyroid hormone synthesis and release
• Radioactive iodine (RAI) treatment of the thyroid gland
• Total or subtotal thyroidectomy.

All three options have pros and cons, and there is no consensus on which one is the best option. It is very important to discuss all three options in detail with the patients and make an individualized decision.

Anti-thyroid Drugs (Thionamides)

Methimazole (MMI) and propylthiouracil (PTU) are two anti-thyroid drugs available in the USA. Outside USA, carbimazole, a derivative of methimazole that is rapidly metabolized to methimazole, is also available. These thioamides inhibit Thyroid Peroxidase (TPO) mediated iodination of thyroglobulin in the thyroid gland, blocking the synthesis of T4 and T3. To some extent, Propylthiouracil also blocks the peripheral conversion of T4 to T3.

In nonpregnant patients, methimazole is the drug of choice due to its less frequent side effects (especially hepatotoxicity), once-daily dosing, and more rapid achievement of normal thyroid function. During the first trimester of pregnancy, propylthiouracil must be used due to its less teratogenic side effects. We can start methimazole from the second trimester of pregnancy. American Thyroid Association (ATA) recommends propylthiouracil for patients with thyroid storm and for patients with minor reactions to methimazole therapy who refuses surgery or RAIA.

Before starting ethionamide treatment, patients should be informed about possible side effects including allergic reactions, neutropenia, and hepatotoxicity. A complete blood count with differentials and liver function tests should be obtained. Ethionamide should not be started if the baseline transaminase level is more than five times the upper limit of normal or if absolute neutrophil count (ANC) is less than 1000/ml.

Dosage: Initiate methimazole 5 mg to 10 mg oral daily if FT4 is 1 to 1.5 times the upper limit of normal (ULN), 10 mg to 20 mg oral daily if FT4 is 1.5 to 2 times ULN, 30 mg to 40 mg oral daily if FT4 is more than two to three times ULN.  Start PTU 50 mg t0 150 mg orally three times daily based on the severity of hyperthyroidism. Once thyroid function improves, the thioamide dose can be tapered and continued at maintenance doses once TFTs become euthyroid. Methimazole is usually maintained at 5 mg to 10 mg daily, and propylthiouracil is maintained at 50 mg two to three times a day.

Adverse effects: Minor side-effects include pruritus and rash (3% to 6%), and major side effects include hepatocellular injury (2.7% propylthiouracil, 0.4% Methimazole), agranulocytosis (0.7%, ANC  less than 500/ml), and vasculitis (rarely lupus and pANCA-positive small vessel vasculitis; more with propylthiouracil than methimazole). Rarely hypoglycemia has been reported with methimazole therapy.

Follow-up and monitoring: Monitor thyroid function tests (TFTs) every four to six weeks for the ethionamide dose adjustment. Once TFTs improve, we can reduce the ethionamide dose by 30% to 50% until a maintenance dose is achieved. Once on a maintenance dose, TFTs can be checked every three months for up to 18 months, thereafter every six months is acceptable. Monitor for adverse effects and perform blood tests as needed based on clinical information. Stop the thioamide if the transaminase level is more than three times of ULN.  Routine monitoring of liver function tests and complete blood count is not necessary. Thionamides can be continued for minor cutaneous reactions with or without concurrent use of antihistamines, but if the problem persists, alternative treatment options including surgery or RAI therapy should be considered.

Duration of treatment: For patients on long-term, thionamide therapy who are on maintenance doses, we can consider stopping the therapy after 12 to 8 months, if TSH and TRAb levels normalize during follow-up. If patients remain clinically and biochemically euthyroid, we can repeat TFTs every two to three months during the first six months after stopping the treatment, then every four to six months for another six months, then every six to 12 months. If TSH remains normal for one year without treatment, annual monitoring with TSH is enough.

RAI Therapy

It is preferred for non-pregnant adult patients older than 21 years, patients not planning to get pregnant within the next six to 12 months after treatment, patients with risky comorbid conditions for surgery, and patients with contraindications for thioamides. It is contraindicated during pregnancy, lactation, coexisting thyroid cancer, in patients with moderate to severe Graves orbitopathy, and for individuals who cannot follow radiation safety guidelines.

Preparation: Beta-adrenergic blockade and pretreatment with methimazole (propylthiouracil pretreatment has a high failure rate for RAI treatment) should be considered for patients with an increased risk of complications from hyperthyroidism and patients with very high thyroid hormone levels. If methimazole is started, it should be stopped three to five days before RAI treatment. It can be restarted for high-risk patients three to seven days after treatment. A pregnancy test is required before RAI treatment.

Dosage: I-131 is administered as a capsule or liquid. The I-131 dose can be calculated or one may use a fixed-dose. The calculated dose is based on thyroid volume, uptake of RAI, and local factors. A fixed-dose can be 10 to 25 mCi of I-131. The patient should be provided with a written radiation safety precautions after RAI treatment to avoid exposure to household members or community members, especially children, and pregnant women.

Follow-up and monitoring: TFTs should be monitored every four to six weeks for six months or until the patient becomes hypothyroid. Once the patient is on a stable levothyroxine dose, TFTs can be repeated every six to 12 months. If hyperthyroidism persists after six months of RAI therapy, it can be considered a treatment failure, and repeat treatment with RAI may be needed.[rx]

Thyroidectomy

Thyroidectomy is preferred for patients with very large goiter (more than 80 grams), anterior neck compressive symptoms, co-existing suspicious thyroid cancer, large thyroid nodules (greater than 4 cm), cold nodules, co-existing parathyroid adenoma, very high TRAb, and moderate to severe Graves orbitopathy.

Preparation: 

• Use thioamides to achieve a near or complete euthyroid state before surgery
• Use Beta-blockers as needed
• Use potassium iodide, five to seven drops of Lugol’s solution, or one to two drops of SSKI, mixed in water or juices three times a day, starting seven to ten days before surgery to reduce vascularity
• Assess calcium and Vitamin D levels and replace if needed

Post-op follow-up:

Thionamides should be stopped after surgery and beta-blockers should be weaned off. Levothyroxine is started at 1.6 micrograms per kg body weight, and the dose is adjusted based on TSH level every six to eight weeks.[rx][rx]

Other Adjunct Treatment for Graves Hyperthyroidism

Iodinated contrast agents, sodium iodate, and iopanoic acid inhibit the peripheral conversion of T4 to T3. They are used with methimazole but not as a solo agent as they can cause resistant hyperthyroidism. They are not available in the United States. Iodide (SSKI drops) can be used for mild hyperthyroidism especially after RAI treatment. Glucocorticoid, cholestyramine, lithium, carnitine are other agents that have also been tried. Rituximab may induce remission in patients with Graves disease, but it is costly. 

Treatment of Graves Orbitopathy (GO)

Rapid achievement of euthyroid level should be sought in patients with Graves orbitopathy. Patients should be advised to quit smoking if they do.  Treatment depends on the severity of orbitopathy. For patients with mild orbitopathy who undergo RAI treatment, prednisone 0.4 mg/kg/day to 0.5 mg/kg/day should be started one to three days after treatment and continued for one month. It should be tapered slowly over two months. Mild active Graves orbitopathy should be treated with artificial tears, and glucocorticoid therapy can be considered. Elevation of the head during sleep reduces orbital congestion. Selenium treatment has doubtful benefits. Prompt ophthalmology referral should be considered for all cases of Graves orbitopathy.

Treatment of moderate to severe active Graves orbitopathy requires up to 100 mg of oral prednisone daily for one to two weeks, then tapered over six to 12 weeks or intravenous (IV) methylprednisolone 500 mg/wk for six weeks followed by 250 mg/wk for six weeks. Other options include orbital irradiation, rituximab, and emergency orbital decompression.[13]

Treatment of inactive Graves orbitopathy involves interval close clinical monitoring, elective orbital decompression, strabismus repair and eyelid repair depending upon severity.

Treatment of Dermopathy and Acropachy

Graves dermopathy usually does not need treatment. If treatment is considered, topical high potency glucocorticoid with occlusive dressing can be considered. Rituximab treatment to reduce B-cell may be beneficial, but it remains experimental. There is no treatment available for acropachy.

• https://www.ncbi.nlm.nih.gov/books/NBK28/
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• https://en.wikipedia.org/wiki/Thyroid_hormones
• https://en.wikipedia.org/wiki/Parathyroid_gland
• https://www.nhs.uk/conditions/underactive-thyroid-hypothyroidism/

Secondary Hyperparathyroidism/Primary hyperparathyroidism is a relatively common disorder that can cause significant renal and skeletal complications. Surgery remains the definitive treatment. However, alternative therapies may be appropriate for select patients. A basic knowledge of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism. This activity reviews the evaluation and management of primary hyperparathyroidism and highlights the role of the interprofessional team in the management of patients with this disorder.

Primary hyperparathyroidism is a relatively common disorder that may cause significant renal and skeletal complications, although most patients diagnosed in recent decades have mild degrees of hypercalcemia and are often asymptomatic. Surgery remains the definitive treatment. However, conservative observation or medical therapy may be appropriate for selected patients.[rx] A basic understanding of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism.

Types

Primary hyperparathyroidism

Primary hyperparathyroidism occurs because of some problem with one or more of the four parathyroid glands:

• A noncancerous growth (adenoma) on a gland is the most common cause.
• Enlargement (hyperplasia) of two or more parathyroid glands accounts for most other cases.
• A cancerous tumor is a very rare cause of primary hyperparathyroidism.

Primary hyperparathyroidism usually occurs randomly, but some people inherit a gene that causes the disorder.

Secondary hyperparathyroidism

Secondary hyperparathyroidism is the result of another condition that lowers calcium levels. This causes your parathyroid glands to overwork to compensate for the calcium loss. Factors that may contribute to secondary hyperparathyroidism include:

• Severe calcium deficiency. Your body may not get enough calcium from your diet, often because your digestive system doesn’t absorb the calcium from it.
• Severe vitamin D deficiency. Vitamin D helps maintain appropriate calcium levels in the blood. It also helps your digestive system absorb calcium from your food. Your body produces vitamin D when your skin is exposed to sunlight. You also consume some vitamin D in food. If you don’t get enough vitamin D, then calcium levels may drop.
• Chronic kidney failure. Your kidneys convert vitamin D into a form that your body can use. If your kidneys work poorly, usable vitamin D may decline and calcium levels drop, causing parathyroid hormone levels to go up. Chronic kidney failure is the most common cause of secondary hyperparathyroidism. Some medical treatments, such as vitamin D, bisphosphonates and cinacalcet, will lower PTH levels. In some people with long-term end-stage kidney disease, the parathyroid glands enlarge and begin to release PTH on their own, and PTH doesn’t go down with medical treatment. This is called tertiary hyperparathyroidism, and people with this condition may require surgery to remove parathyroid tissue.

Pathophysiology

Normal Calcium Homeostasis

Under physiologic circumstances, the concentration of calcium in the extracellular fluid is maintained within a very narrow range. Normal calcium homeostasis is dependent upon a complex set of hormonal regulatory mechanisms that include the effects of parathyroid hormone, vitamin D metabolites, and calcitonin on calcium transport in bone, kidney, and the gastrointestinal tract.

Approximately 50% of total serum calcium is protein-bound, principally to albumin. Forty-five percent is ionized, while a small proportion is complexed to anions such as phosphate and citrate. It is only the ionized calcium that is biologically active, yet most laboratories report total serum calcium levels. Measurements of ionized calcium are available. However, an approximate correction of serum calcium can be made by adjusting for differences in the serum albumin level.

Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin)

Caution must be exercised in evaluating normal total serum calcium levels in patients with hypoalbuminemia. Such patients may have elevated ionized calcium levels and are truly hypercalcemic. Conversely, the ionized calcium is often normal when there is a low total calcium concentration in the presence of hypoalbuminemia.

Parathyroid Hormone

Secretion of parathyroid hormone is inversely related to the concentration of ionized calcium in the extracellular fluid. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor whose activity varies with changes in the types of serum calcium. As the calcium concentration in the extracellular fluid increases, this receptor is activated and parathyroid cells decrease secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases and parathyroid hormone secretion increases as calcium levels decline. Mutations that inactivate the CaSR are the etiology of familial hypocalciuric hypercalcemia (FHH), an autosomal dominant disorder characterized by increased parathyroid hormone secretion, hypercalcemia, and hypocalciuria.

Parathyroid hormone activates the parathyroid hormone receptor increasing the resorption of calcium and phosphorus from bone, enhancing the distal tubular resorption of calcium, and decreasing the renal tubular resorption of phosphorus. Also, the parathyroid hormone plays an essential role in vitamin D metabolism, activating the vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihydroxyvitamin D.

Causes of Primary Hyperparathyroidism

PTH-dependent Causes of Hypercalcemia

• Primary Hyperparathyroidism
  • Single adenoma
  • Multigland disease
    • Familial causes of hyperparathyroidism
      • Multiple endocrine neoplasia Type 1
      • Multiple endocrine neoplasia Type 2
      • Familial hyperparathyroidism
      • Hyperparathyroidism-jaw tumor syndrome
  • Parathyroid carcinoma
• Familial hypocalciuric hypercalcemia, autosomal dominant inactivating mutations of the calcium-sensing receptor
• Adverse effect of treatment with lithium

PTH Independent Causes of Hypercalcemia

• Malignancy
• Granulomatous diseases
• Hyperthyroidism
• Thiazide therapy
• Vitamin D intoxication
• Milk-alkali syndrome
• Adrenal insufficiency
• Vitamin A intoxication
• Genetic associations include:

In all cases, the disease is idiopathic but is thought to involve the inactivation of tumor suppressor genes (Menin gene in MEN1) or involve gain of function mutations (RET proto-oncogene MEN 2a).

Recently, it was demonstrated that liquidators of the Chernobyl power plant are faced with a substantial risk of primary hyperparathyroidism, possibly caused by radioactive strontium isotopes.^[rx]

What are the symptoms of primary hyperparathyroidism?

The signs and symptoms of primary hyperparathyroidism are those of hypercalcemia. They are classically summarized by “stones, bones, abdominal groans, thrones, and psychiatric overtones”.

• “Stones” refers to kidney stones, nephrocalcinosis, and diabetes insipidus (polyuria and polydipsia). These can ultimately lead to kidney failure.
• “Bones” refers to bone-related complications. The classic bone disease in hyperparathyroidism is osteitis fibrosa cystica, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosis, osteomalacia, and arthritis.
• “Abdominal groans” refers to gastrointestinal symptoms of constipation, indigestion, nausea, and vomiting. Hypercalcemia can lead to peptic ulcers and acute pancreatitis. Peptic ulcers can be an effect of increased gastric acid secretion by hypercalcemia.
• “Thrones” refers to polyuria and constipation
• “Psychiatric overtones” refer to effects on the central nervous system. Symptoms include lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma.

These are the most common symptoms of primary hyperparathyroidism. However, each person may experience symptoms differently. Symptoms of too much calcium in the blood may include:

• Constipation
• Frequent urination
• Increased thirst
• Joint pain
• Kidney pain (due to the presence of kidney stones)
• Lethargy and fatigue
• Loss of appetite
• Muscle weakness

Other serious symptoms may include:

• Abdominal pain
• Depression
• Memory loss
• Nausea
• Vomiting

The symptoms of primary hyperparathyroidism may look like other medical problems. Always talk with your healthcare provider for a diagnosis.

Diagnosis of Primary Hyperparathyroidism

In past decades most patients were diagnosed when they had complaints of nephrolithiasis, bone pain, or bone deformity. Now, most patients with primary hyperparathyroidism are asymptomatic, diagnosed when hypercalcemia is incidentally discovered on a chemistry profile. Patients should be asked about any history of kidney stones, bone pain, myalgias or muscle weakness, symptoms of depression, use of thiazide diuretics, calcium products, vitamin D supplements, or other symptoms associated with the multiples etiologies of hypercalcemia.[rx] A familial syndrome should be considered when primary hyperparathyroidism is diagnosed at an early age, or there is a family history of hypercalcemia, pituitary adenomas, pancreatic islet cell tumors, pheochromocytomas, or medullary thyroid cancer.

The physical examination of a patient with primary hyperparathyroidism is usually normal. However, the physical examination can be helpful in finding abnormalities that could suggest other etiologies of hypercalcemia. Parathyroid adenomas are rarely palpable on physical examination, but the presence of a large, firm mass in the neck of a patient with hypercalcemia should raise suspicion of parathyroid carcinoma.

Evaluation

Patients with primary hyperparathyroidism and other causes of PTH-dependent hypercalcemia often have frankly elevated levels of PTH, while some will have values that fall within the reference range for the general population. A normal PTH in the presence of hypercalcemia is considered inappropriate and still consistent with PTH-dependent hypercalcemia. PTH levels should be very low in those patients with PTH-independent hypercalcemia.

A comprehensive clinical evaluation complemented by routine laboratory and radiologic studies should be sufficient to establish a diagnosis of primary hyperparathyroidism in a patient with persistent hypercalcemia and an elevated serum level of parathyroid hormone. It is uncommon for clinically occult malignancies to cause hypercalcemia. Most patients with malignancy-associated hypercalcemia are known to have cancer, or cancer is readily detectable on initial evaluation, and PTH levels will be suppressed.

A review of previous medical records can often be of significant value in establishing the cause of hypercalcemia. Most patients with hyperparathyroidism have persistent or intermittent hypercalcemia for many years before a definitive diagnosis is established. Very few diseases, other than hyperparathyroidism, will allow a healthy-appearing individual to be hypercalcemic for more than a few years without becoming clinically obvious.[rx]

Bone mineral density test

Dual-energy x-ray absorptiometry, also called a DXA or DEXA scan uses low-dose x-rays to measure bone density. During the test, you will lie on a padded table while a technician moves the scanner over your body. A bone expert or radiologist will read the scan.

During a DXA scan, you will lie on a padded table while a technician moves the scanner over your body.

Kidney imaging tests

Doctors may use one of the following imaging tests to look for kidney stones.

Ultrasound. Ultrasound uses a device called a transducer that bounces safe, painless sound waves off organs to create an image of their structure. A specially trained technician does the procedure. A radiologist reads the images, which can show kidney stones.

Abdominal x-ray. An abdominal x-ray is a picture of the abdomen that uses low levels of radiation and is recorded on film or on a computer. During an abdominal x-ray, you lie on a table or stand up. A technician positions the x-ray machine close to your abdomen and asks you to hold your breath so the picture won’t be blurry. A radiologist reads the x-ray, which can show the location of kidney stones in the urinary tract. Not all stones are visible on an abdominal x-ray.

Computed tomography (CT) scans. CT scans use a combination of x-rays and computer technology to create images of your urinary tract. CT scans sometimes use a contrast medium—a dye or other substance that makes structures inside your body easier to see. A contrast medium isn’t usually needed to see kidney stones. For the scan, you’ll lie on a table that slides into a tunnel-shaped machine that takes the x-rays. A radiologist reads the images, which can show the size and location of a kidney stone.

Vitamin D blood test – Health care professionals test for vitamin D levels because low levels are common in people with primary hyperparathyroidism. In patients with primary hyperparathyroidism, the low vitamin D level can further stimulate the parathyroid glands to make even more parathyroid hormone. Also, a very low vitamin D level may cause a secondary form of hyperparathyroidism, which resolves when vitamin D levels are returned to normal.

List of tests for primary hyperparathyroidism: 

• Total calcium
• Albumin
• Calculation of the “corrected” serum calcium. Approximately 50% of total serum calcium is protein-bound, principally to albumin and only free or ionized fraction is biologically active. Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin) (calcium measured in mg/dL; albumin measured in g/dL)
• Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium
• Parathyroid hormone
• Phosphorus
• BUN and creatinine
• Alkaline phosphatase
• 25-hydroxyvitamin D
• Urine calcium and creatinine
• Imaging to screen for renal calcifications or urolithiasis
• Bone densitometry (DXA) including measurement at the distal 1/3 radius
• EKG
• Genetic testing in selected individuals if there is suspicion of a genetic syndrome
• Parathyroid scan and neck ultrasound. These tests are not considered diagnostic because there can be false-negative results. They should not be ordered when there are no plans for surgery. They should be ordered when there are plans for surgery to assist the surgeon as a “roadmap” in localizing the enlarged parathyroid gland.

The need for other studies such as PTHrP levels, serum or urine protein electrophoresis, 1,25-dihydroxy vitamin D levels, thyroid tests, bone scans, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia.[rx]

Treatment of Primary Hyperparathyroidism

Drugs

Medications to treat hyperparathyroidism include the following:

• Calcimimetics. A calcimimetic is a drug that mimics calcium circulating in the blood. The drug may trick the parathyroid glands into releasing less parathyroid hormone. This drug is sold as a cinacalcet (Sensipar). Some doctors may prescribe cinacalcet to treat primary hyperparathyroidism, particularly if surgery hasn’t successfully cured the disorder or a person isn’t a good surgery candidate. The most commonly reported side effects of cinacalcet are joint and muscle pain, diarrhea, nausea, and respiratory infection.
• Hormone replacement therapy. For women who have gone through menopause and have signs of osteoporosis, hormone replacement therapy may help bones retain calcium. This treatment doesn’t address the underlying problems with the parathyroid glands. Prolonged use of hormone replacement therapy can increase the risk of blood clots and breast cancer. Work with your doctor to evaluate the risks and benefits to help you decide what’s best for you. Some common side effects of hormone replacement therapy include breast pain and tenderness, dizziness, and headaches.
• Bisphosphonates. Bisphosphonates also prevent the loss of calcium from bones and may lessen osteoporosis caused by hyperparathyroidism. Some side effects associated with bisphosphonates include low blood pressure, fever and vomiting. This treatment doesn’t address the underlying problems with the parathyroid glands

Surgery remains the definitive treatment for primary hyperparathyroidism, but non-operative surveillance may be the appropriate option for some, particularly for patients who are elderly with mild hypercalcemia and no significant complications. Medical treatment with bisphosphonates or cinacalcet can be useful in selected patients. The decision of whether to recommend surgery is based on age, the degree of hypercalcemia, and the presence or absence of complications due to hyperparathyroidism. Surgery is the treatment of choice for those with recurrent kidney stones.

Since 1990, several workshops have been convened to develop guidelines to assist physicians in the management of asymptomatic hyperparathyroidism. Surgical and medical experts, internationally recognized for their experience in managing patients with hyperparathyroidism, reviewed the evidence-based medical literature and a consensus of their opinions was disseminated to the medical community. The most recent guidelines were published in 2014.[rx]

The current guidelines state that surgery should be recommended for asymptomatic primary hyperparathyroidism when:[rx]

• Serum calcium is more than 1 mg/dL greater than the upper limit of normal
• Age younger than 50 years
• Osteoporosis
• GFR less than 60 mL/min
• Urine calcium greater than 400 mg/24 hours
• Evidence of renal calcification or stones

Left untreated, many patients with primary hyperparathyroidism have progressive loss of cortical bone while successful surgery leads to a substantial increase in bone mineral density, an effect that can persist for up to 15 years.

For patients where observation is the selected course of action, periodic monitoring with measurement of serum and urine calcium, renal function, and bone densitometry is required. If there is worsening hypercalcemia or the development of complications, then surgery should be recommended.[rx]

Medical Treatment

Some patients who are not surgical candidates may benefit from medical management of primary hyperparathyroidism.

• Bisphosphonates can increase bone mineral density in those with osteoporosis or osteopenia.
• Agonists to the calcium-sensing receptor, such as cinacalcet will lower PTH and calcium levels. However, they do not increase bone density.[rx]

Surgery

Surgery to remove the overactive parathyroid gland or glands is the only sure way to cure primary hyperparathyroidism. Doctors recommend surgery for people with clear symptoms or complications of the disease. In people without symptoms, doctors follow the above guidelines to identify who might benefit from parathyroid surgery.² Surgery can lead to improved bone density and can lower the chance of forming kidney stones.

When performed by experienced surgeons, surgery almost always cures primary hyperparathyroidism.

Surgeons often use imaging tests before surgery to locate the overactive gland or glands to be removed. The tests used most often are sestamibi, ultrasound, and CT scans. In a sestamibi scan, you will get an injection, or shot, of a small amount of radioactive dye in your vein. The overactive parathyroid gland or glands then absorb the dye. The surgeon can see where the dye has been absorbed by using a special camera.

Surgeons use two main types of operations to remove the overactive gland or glands.

Minimally invasive parathyroidectomy. Also called focused parathyroidectomy, surgeons use this type of surgery when they think only one of the parathyroid glands is overactive. Guided by a tumor-imaging test, your surgeon will make a small incision, or cut, in your neck to remove the gland. The small incision means you will probably have less pain and a faster recovery than people who have more invasive surgery. You can go home the same day. Your doctor may use regional or general anesthesia during the surgery.

Bilateral neck exploration. This type of surgery uses a larger incision that lets the surgeon find and look at all four parathyroid glands and remove the overactive ones. If you have bilateral neck exploration, you will probably have general anesthesia and may need to stay in the hospital overnight.

Monitoring

Some people who have mild primary hyperparathyroidism may not need surgery right away, or even any surgery, and can be safely monitored.

You may want to talk with your doctor about long-term monitoring if you

• don’t have symptoms
• have only slightly high blood calcium levels
• have normal kidneys and bone density

Long-term monitoring should include regular doctor visits, a yearly blood test to measure calcium levels and check your kidney function, and a bone density test every 1 to 2 years.

If you and your doctor choose long-term monitoring, you should

• drink plenty of water so you don’t get dehydrated
• get regular physical activity External link to help keep your bones strong
• avoid certain diuretics, such as thiazides

Next steps

Tips to help you get the most from a visit to your healthcare provider:

• Know the reason for your visit and what you want to happen.
• Before your visit, write down questions you want to be answered.
• Bring someone with you to help you ask questions and remember what your healthcare provider tells you.
• At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also, write down any new instructions your provider gives you.
• Know why a new medicine or treatment is prescribed, and how it will help you. Also, know what the side effects are.
• Ask if your condition can be treated in other ways.
• Know why a test or procedure is recommended and what the results could mean.
• Know what to expect if you do not take the medicine or have the test or procedure.
• If you have a follow-up appointment, write down the date, time, and purpose for that visit.
• Know how you can contact your healthcare provider if you have questions.

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• https://www.ncbi.nlm.nih.gov/books/NBK537039/
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• https://www.ncbi.nlm.nih.gov/books/NBK537039/
• https://www.ncbi.nlm.nih.gov/books/NBK279388/
• https://www.ncbi.nlm.nih.gov/books/NBK551659/
• https://www.ncbi.nlm.nih.gov/books/NBK241/
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• https://www.ncbi.nlm.nih.gov/books/NBK519566/
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• https://www.ncbi.nlm.nih.gov/books/NBK249/
• https://www.ncbi.nlm.nih.gov/books/NBK470452/
• https://www.ncbi.nlm.nih.gov/books/NBK537053/
• https://www.ncbi.nlm.nih.gov/books/NBK285550/
• https://www.ncbi.nlm.nih.gov/books/NBK244/
• https://www.ncbi.nlm.nih.gov/books/NBK448195/
• https://www.ncbi.nlm.nih.gov/books/NBK499940/
• https://www.ncbi.nlm.nih.gov/books/NBK546596/
• https://www.ncbi.nlm.nih.gov/books/NBK537203/
• https://www.ncbi.nlm.nih.gov/books/NBK507870/
• https://www.ncbi.nlm.nih.gov/books/NBK519038/
• https://www.ncbi.nlm.nih.gov/books/NBK278923/
• https://www.ncbi.nlm.nih.gov/books/NBK278923/
• https://en.wikipedia.org/wiki/Thyroid
• https://en.wikipedia.org/wiki/Thyroid_hormones
• https://en.wikipedia.org/wiki/Parathyroid_gland
• https://www.nhs.uk/conditions/underactive-thyroid-hypothyroidism/

Primary hyperparathyroidism is a relatively common disorder that can cause significant renal and skeletal complications. Surgery remains the definitive treatment. However, alternative therapies may be appropriate for select patients. A basic knowledge of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism. This activity reviews the evaluation and management of primary hyperparathyroidism and highlights the role of the interprofessional team in the management of patients with this disorder.

Primary hyperparathyroidism is a relatively common disorder that may cause significant renal and skeletal complications, although most patients diagnosed in recent decades have mild degrees of hypercalcemia and are often asymptomatic. Surgery remains the definitive treatment. However, conservative observation or medical therapy may be appropriate for selected patients.[rx] A basic understanding of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism.

Types

Primary hyperparathyroidism

Primary hyperparathyroidism occurs because of some problem with one or more of the four parathyroid glands:

• A noncancerous growth (adenoma) on a gland is the most common cause.
• Enlargement (hyperplasia) of two or more parathyroid glands accounts for most other cases.
• A cancerous tumor is a very rare cause of primary hyperparathyroidism.

Primary hyperparathyroidism usually occurs randomly, but some people inherit a gene that causes the disorder.

Secondary hyperparathyroidism

Secondary hyperparathyroidism is the result of another condition that lowers calcium levels. This causes your parathyroid glands to overwork to compensate for the calcium loss. Factors that may contribute to secondary hyperparathyroidism include:

• Severe calcium deficiency. Your body may not get enough calcium from your diet, often because your digestive system doesn’t absorb the calcium from it.
• Severe vitamin D deficiency. Vitamin D helps maintain appropriate calcium levels in the blood. It also helps your digestive system absorb calcium from your food. Your body produces vitamin D when your skin is exposed to sunlight. You also consume some vitamin D in food. If you don’t get enough vitamin D, then calcium levels may drop.
• Chronic kidney failure. Your kidneys convert vitamin D into a form that your body can use. If your kidneys work poorly, usable vitamin D may decline and calcium levels drop, causing parathyroid hormone levels to go up. Chronic kidney failure is the most common cause of secondary hyperparathyroidism. Some medical treatments, such as vitamin D, bisphosphonates and cinacalcet, will lower PTH levels. In some people with long-term end-stage kidney disease, the parathyroid glands enlarge and begin to release PTH on their own, and PTH doesn’t go down with medical treatment. This is called tertiary hyperparathyroidism, and people with this condition may require surgery to remove parathyroid tissue.

Pathophysiology

Normal Calcium Homeostasis

Under physiologic circumstances, the concentration of calcium in the extracellular fluid is maintained within a very narrow range. Normal calcium homeostasis is dependent upon a complex set of hormonal regulatory mechanisms that include the effects of parathyroid hormone, vitamin D metabolites, and calcitonin on calcium transport in bone, kidney, and the gastrointestinal tract.

Approximately 50% of total serum calcium is protein-bound, principally to albumin. Forty-five percent is ionized, while a small proportion is complexed to anions such as phosphate and citrate. It is only the ionized calcium that is biologically active, yet most laboratories report total serum calcium levels. Measurements of ionized calcium are available. However, an approximate correction of serum calcium can be made by adjusting for differences in the serum albumin level.

Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin)

Caution must be exercised in evaluating normal total serum calcium levels in patients with hypoalbuminemia. Such patients may have elevated ionized calcium levels and are truly hypercalcemic. Conversely, the ionized calcium is often normal when there is a low total calcium concentration in the presence of hypoalbuminemia.

Parathyroid Hormone

Secretion of parathyroid hormone is inversely related to the concentration of ionized calcium in the extracellular fluid. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor whose activity varies with changes in the types of serum calcium. As the calcium concentration in the extracellular fluid increases, this receptor is activated and parathyroid cells decrease secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases and parathyroid hormone secretion increases as calcium levels decline. Mutations that inactivate the CaSR are the etiology of familial hypocalciuric hypercalcemia (FHH), an autosomal dominant disorder characterized by increased parathyroid hormone secretion, hypercalcemia, and hypocalciuria.

Parathyroid hormone activates the parathyroid hormone receptor increasing the resorption of calcium and phosphorus from bone, enhancing the distal tubular resorption of calcium, and decreasing the renal tubular resorption of phosphorus. Also, the parathyroid hormone plays an essential role in vitamin D metabolism, activating the vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihydroxyvitamin D.

Causes of Primary Hyperparathyroidism

PTH-dependent Causes of Hypercalcemia

• Primary Hyperparathyroidism
  • Single adenoma
  • Multigland disease
    • Familial causes of hyperparathyroidism
      • Multiple endocrine neoplasia Type 1
      • Multiple endocrine neoplasia Type 2
      • Familial hyperparathyroidism
      • Hyperparathyroidism-jaw tumor syndrome
  • Parathyroid carcinoma
• Familial hypocalciuric hypercalcemia, autosomal dominant inactivating mutations of the calcium-sensing receptor
• Adverse effect of treatment with lithium

PTH Independent Causes of Hypercalcemia

• Malignancy
• Granulomatous diseases
• Hyperthyroidism
• Thiazide therapy
• Vitamin D intoxication
• Milk-alkali syndrome
• Adrenal insufficiency
• Vitamin A intoxication
• Genetic associations include:

In all cases, the disease is idiopathic but is thought to involve the inactivation of tumor suppressor genes (Menin gene in MEN1) or involve gain of function mutations (RET proto-oncogene MEN 2a).

Recently, it was demonstrated that liquidators of the Chernobyl power plant are faced with a substantial risk of primary hyperparathyroidism, possibly caused by radioactive strontium isotopes.^[rx]

What are the symptoms of primary hyperparathyroidism?

The signs and symptoms of primary hyperparathyroidism are those of hypercalcemia. They are classically summarized by “stones, bones, abdominal groans, thrones, and psychiatric overtones”.

• “Stones” refers to kidney stones, nephrocalcinosis, and diabetes insipidus (polyuria and polydipsia). These can ultimately lead to kidney failure.
• “Bones” refers to bone-related complications. The classic bone disease in hyperparathyroidism is osteitis fibrosa cystica, which results in pain and sometimes pathological fractures. Other bone diseases associated with hyperparathyroidism are osteoporosis, osteomalacia, and arthritis.
• “Abdominal groans” refers to gastrointestinal symptoms of constipation, indigestion, nausea, and vomiting. Hypercalcemia can lead to peptic ulcers and acute pancreatitis. Peptic ulcers can be an effect of increased gastric acid secretion by hypercalcemia.
• “Thrones” refers to polyuria and constipation
• “Psychiatric overtones” refer to effects on the central nervous system. Symptoms include lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma.

These are the most common symptoms of primary hyperparathyroidism. However, each person may experience symptoms differently. Symptoms of too much calcium in the blood may include:

• Constipation
• Frequent urination
• Increased thirst
• Joint pain
• Kidney pain (due to the presence of kidney stones)
• Lethargy and fatigue
• Loss of appetite
• Muscle weakness

Other serious symptoms may include:

• Abdominal pain
• Depression
• Memory loss
• Nausea
• Vomiting

The symptoms of primary hyperparathyroidism may look like other medical problems. Always talk with your healthcare provider for a diagnosis.

Diagnosis of Primary Hyperparathyroidism

In past decades most patients were diagnosed when they had complaints of nephrolithiasis, bone pain, or bone deformity. Now, most patients with primary hyperparathyroidism are asymptomatic, diagnosed when hypercalcemia is incidentally discovered on a chemistry profile. Patients should be asked about any history of kidney stones, bone pain, myalgias or muscle weakness, symptoms of depression, use of thiazide diuretics, calcium products, vitamin D supplements, or other symptoms associated with the multiples etiologies of hypercalcemia.[rx] A familial syndrome should be considered when primary hyperparathyroidism is diagnosed at an early age, or there is a family history of hypercalcemia, pituitary adenomas, pancreatic islet cell tumors, pheochromocytomas, or medullary thyroid cancer.

The physical examination of a patient with primary hyperparathyroidism is usually normal. However, the physical examination can be helpful in finding abnormalities that could suggest other etiologies of hypercalcemia. Parathyroid adenomas are rarely palpable on physical examination, but the presence of a large, firm mass in the neck of a patient with hypercalcemia should raise suspicion of parathyroid carcinoma.

Evaluation

Patients with primary hyperparathyroidism and other causes of PTH-dependent hypercalcemia often have frankly elevated levels of PTH, while some will have values that fall within the reference range for the general population. A normal PTH in the presence of hypercalcemia is considered inappropriate and still consistent with PTH-dependent hypercalcemia. PTH levels should be very low in those patients with PTH-independent hypercalcemia.

A comprehensive clinical evaluation complemented by routine laboratory and radiologic studies should be sufficient to establish a diagnosis of primary hyperparathyroidism in a patient with persistent hypercalcemia and an elevated serum level of parathyroid hormone. It is uncommon for clinically occult malignancies to cause hypercalcemia. Most patients with malignancy-associated hypercalcemia are known to have cancer, or cancer is readily detectable on initial evaluation, and PTH levels will be suppressed.

A review of previous medical records can often be of significant value in establishing the cause of hypercalcemia. Most patients with hyperparathyroidism have persistent or intermittent hypercalcemia for many years before a definitive diagnosis is established. Very few diseases, other than hyperparathyroidism, will allow a healthy-appearing individual to be hypercalcemic for more than a few years without becoming clinically obvious.[rx]

Bone mineral density test

Dual-energy x-ray absorptiometry, also called a DXA or DEXA scan uses low-dose x-rays to measure bone density. During the test, you will lie on a padded table while a technician moves the scanner over your body. A bone expert or radiologist will read the scan.

During a DXA scan, you will lie on a padded table while a technician moves the scanner over your body.

Kidney imaging tests

Doctors may use one of the following imaging tests to look for kidney stones.

Ultrasound. Ultrasound uses a device called a transducer that bounces safe, painless sound waves off organs to create an image of their structure. A specially trained technician does the procedure. A radiologist reads the images, which can show kidney stones.

Abdominal x-ray. An abdominal x-ray is a picture of the abdomen that uses low levels of radiation and is recorded on film or on a computer. During an abdominal x-ray, you lie on a table or stand up. A technician positions the x-ray machine close to your abdomen and asks you to hold your breath so the picture won’t be blurry. A radiologist reads the x-ray, which can show the location of kidney stones in the urinary tract. Not all stones are visible on an abdominal x-ray.

Computed tomography (CT) scans. CT scans use a combination of x-rays and computer technology to create images of your urinary tract. CT scans sometimes use a contrast medium—a dye or other substance that makes structures inside your body easier to see. A contrast medium isn’t usually needed to see kidney stones. For the scan, you’ll lie on a table that slides into a tunnel-shaped machine that takes the x-rays. A radiologist reads the images, which can show the size and location of a kidney stone.

Vitamin D blood test – Health care professionals test for vitamin D levels because low levels are common in people with primary hyperparathyroidism. In patients with primary hyperparathyroidism, the low vitamin D level can further stimulate the parathyroid glands to make even more parathyroid hormone. Also, a very low vitamin D level may cause a secondary form of hyperparathyroidism, which resolves when vitamin D levels are returned to normal.

List of tests for primary hyperparathyroidism: 

• Total calcium
• Albumin
• Calculation of the “corrected” serum calcium. Approximately 50% of total serum calcium is protein-bound, principally to albumin and only free or ionized fraction is biologically active. Corrected calcium = Measured calcium + 0.8 x (4.0 – albumin) (calcium measured in mg/dL; albumin measured in g/dL)
• Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium
• Parathyroid hormone
• Phosphorus
• BUN and creatinine
• Alkaline phosphatase
• 25-hydroxyvitamin D
• Urine calcium and creatinine
• Imaging to screen for renal calcifications or urolithiasis
• Bone densitometry (DXA) including measurement at the distal 1/3 radius
• EKG
• Genetic testing in selected individuals if there is suspicion of a genetic syndrome
• Parathyroid scan and neck ultrasound. These tests are not considered diagnostic because there can be false-negative results. They should not be ordered when there are no plans for surgery. They should be ordered when there are plans for surgery to assist the surgeon as a “roadmap” in localizing the enlarged parathyroid gland.

The need for other studies such as PTHrP levels, serum or urine protein electrophoresis, 1,25-dihydroxy vitamin D levels, thyroid tests, bone scans, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia.[rx]

Treatment of Primary Hyperparathyroidism

Drugs

Medications to treat hyperparathyroidism include the following:

• Calcimimetics. A calcimimetic is a drug that mimics calcium circulating in the blood. The drug may trick the parathyroid glands into releasing less parathyroid hormone. This drug is sold as a cinacalcet (Sensipar). Some doctors may prescribe cinacalcet to treat primary hyperparathyroidism, particularly if surgery hasn’t successfully cured the disorder or a person isn’t a good surgery candidate. The most commonly reported side effects of cinacalcet are joint and muscle pain, diarrhea, nausea, and respiratory infection.
• Hormone replacement therapy. For women who have gone through menopause and have signs of osteoporosis, hormone replacement therapy may help bones retain calcium. This treatment doesn’t address the underlying problems with the parathyroid glands. Prolonged use of hormone replacement therapy can increase the risk of blood clots and breast cancer. Work with your doctor to evaluate the risks and benefits to help you decide what’s best for you. Some common side effects of hormone replacement therapy include breast pain and tenderness, dizziness, and headaches.
• Bisphosphonates. Bisphosphonates also prevent the loss of calcium from bones and may lessen osteoporosis caused by hyperparathyroidism. Some side effects associated with bisphosphonates include low blood pressure, fever and vomiting. This treatment doesn’t address the underlying problems with the parathyroid glands

Surgery remains the definitive treatment for primary hyperparathyroidism, but non-operative surveillance may be the appropriate option for some, particularly for patients who are elderly with mild hypercalcemia and no significant complications. Medical treatment with bisphosphonates or cinacalcet can be useful in selected patients. The decision of whether to recommend surgery is based on age, the degree of hypercalcemia, and the presence or absence of complications due to hyperparathyroidism. Surgery is the treatment of choice for those with recurrent kidney stones.

Since 1990, several workshops have been convened to develop guidelines to assist physicians in the management of asymptomatic hyperparathyroidism. Surgical and medical experts, internationally recognized for their experience in managing patients with hyperparathyroidism, reviewed the evidence-based medical literature and a consensus of their opinions was disseminated to the medical community. The most recent guidelines were published in 2014.[rx]

The current guidelines state that surgery should be recommended for asymptomatic primary hyperparathyroidism when:[rx]

• Serum calcium is more than 1 mg/dL greater than the upper limit of normal
• Age younger than 50 years
• Osteoporosis
• GFR less than 60 mL/min
• Urine calcium greater than 400 mg/24 hours
• Evidence of renal calcification or stones

Left untreated, many patients with primary hyperparathyroidism have progressive loss of cortical bone while successful surgery leads to a substantial increase in bone mineral density, an effect that can persist for up to 15 years.

For patients where observation is the selected course of action, periodic monitoring with measurement of serum and urine calcium, renal function, and bone densitometry is required. If there is worsening hypercalcemia or the development of complications, then surgery should be recommended.[rx]

Medical Treatment

Some patients who are not surgical candidates may benefit from medical management of primary hyperparathyroidism.

• Bisphosphonates can increase bone mineral density in those with osteoporosis or osteopenia.
• Agonists to the calcium-sensing receptor, such as cinacalcet will lower PTH and calcium levels. However, they do not increase bone density.[rx]

Surgery

Surgery to remove the overactive parathyroid gland or glands is the only sure way to cure primary hyperparathyroidism. Doctors recommend surgery for people with clear symptoms or complications of the disease. In people without symptoms, doctors follow the above guidelines to identify who might benefit from parathyroid surgery.² Surgery can lead to improved bone density and can lower the chance of forming kidney stones.

When performed by experienced surgeons, surgery almost always cures primary hyperparathyroidism.

Surgeons often use imaging tests before surgery to locate the overactive gland or glands to be removed. The tests used most often are sestamibi, ultrasound, and CT scans. In a sestamibi scan, you will get an injection, or shot, of a small amount of radioactive dye in your vein. The overactive parathyroid gland or glands then absorb the dye. The surgeon can see where the dye has been absorbed by using a special camera.

Surgeons use two main types of operations to remove the overactive gland or glands.

Minimally invasive parathyroidectomy. Also called focused parathyroidectomy, surgeons use this type of surgery when they think only one of the parathyroid glands is overactive. Guided by a tumor-imaging test, your surgeon will make a small incision, or cut, in your neck to remove the gland. The small incision means you will probably have less pain and a faster recovery than people who have more invasive surgery. You can go home the same day. Your doctor may use regional or general anesthesia during the surgery.

Bilateral neck exploration. This type of surgery uses a larger incision that lets the surgeon find and look at all four parathyroid glands and remove the overactive ones. If you have bilateral neck exploration, you will probably have general anesthesia and may need to stay in the hospital overnight.

Monitoring

Some people who have mild primary hyperparathyroidism may not need surgery right away, or even any surgery, and can be safely monitored.

You may want to talk with your doctor about long-term monitoring if you

• don’t have symptoms
• have only slightly high blood calcium levels
• have normal kidneys and bone density

Long-term monitoring should include regular doctor visits, a yearly blood test to measure calcium levels and check your kidney function, and a bone density test every 1 to 2 years.

If you and your doctor choose long-term monitoring, you should

• drink plenty of water so you don’t get dehydrated
• get regular physical activity External link to help keep your bones strong
• avoid certain diuretics, such as thiazides

Next steps

Tips to help you get the most from a visit to your healthcare provider:

• Know the reason for your visit and what you want to happen.
• Before your visit, write down questions you want to be answered.
• Bring someone with you to help you ask questions and remember what your healthcare provider tells you.
• At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also, write down any new instructions your provider gives you.
• Know why a new medicine or treatment is prescribed, and how it will help you. Also, know what the side effects are.
• Ask if your condition can be treated in other ways.
• Know why a test or procedure is recommended and what the results could mean.
• Know what to expect if you do not take the medicine or have the test or procedure.
• If you have a follow-up appointment, write down the date, time, and purpose for that visit.
• Know how you can contact your healthcare provider if you have questions.

• https://www.ncbi.nlm.nih.gov/books/NBK28/
• https://www.ncbi.nlm.nih.gov/books/NBK537039/
• https://www.ncbi.nlm.nih.gov/books/NBK500006/
• https://www.ncbi.nlm.nih.gov/books/NBK537039/
• https://www.ncbi.nlm.nih.gov/books/NBK279388/
• https://www.ncbi.nlm.nih.gov/books/NBK551659/
• https://www.ncbi.nlm.nih.gov/books/NBK241/
• https://www.ncbi.nlm.nih.gov/books/NBK221541/
• https://www.ncbi.nlm.nih.gov/books/NBK519566/
• https://www.ncbi.nlm.nih.gov/books/NBK499850/
• https://www.ncbi.nlm.nih.gov/books/NBK482216/
• https://www.ncbi.nlm.nih.gov/books/NBK536970/
• https://www.ncbi.nlm.nih.gov/books/NBK285545/
• https://www.ncbi.nlm.nih.gov/books/NBK249/
• https://www.ncbi.nlm.nih.gov/books/NBK470452/
• https://www.ncbi.nlm.nih.gov/books/NBK537053/
• https://www.ncbi.nlm.nih.gov/books/NBK285550/
• https://www.ncbi.nlm.nih.gov/books/NBK244/
• https://www.ncbi.nlm.nih.gov/books/NBK448195/
• https://www.ncbi.nlm.nih.gov/books/NBK499940/
• https://www.ncbi.nlm.nih.gov/books/NBK546596/
• https://www.ncbi.nlm.nih.gov/books/NBK537203/
• https://www.ncbi.nlm.nih.gov/books/NBK507870/
• https://www.ncbi.nlm.nih.gov/books/NBK519038/
• https://www.ncbi.nlm.nih.gov/books/NBK278923/
• https://www.ncbi.nlm.nih.gov/books/NBK278923/
• https://en.wikipedia.org/wiki/Thyroid
• https://en.wikipedia.org/wiki/Thyroid_hormones
• https://en.wikipedia.org/wiki/Parathyroid_gland
• https://www.nhs.uk/conditions/underactive-thyroid-hypothyroidism/

What are the symptoms of thyroid in females?/Thyroid hormone is made by the thyroid gland, a butterfly-shaped endocrine gland normally located in the lower front of the neck. Thyroid hormone is released into the blood where it is carried to all the tissues in the body. It helps the body controlling metabolism, growth, and many other body functions use energy, stay warm, and keeps the brain, heart, muscles, and other organs working as they should. The thyroid gland, anterior pituitary gland, and hypothalamus comprise a self-regulatory circuit called the hypothalamic-pituitary-thyroid axis. The main hormones produced by the thyroid gland are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) from the hypothalamus, thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 work in synchronous harmony to maintain proper feedback mechanism and homeostasis. Hypothyroidism, caused by an underactive thyroid gland, typically manifests as bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism caused by increased thyroid gland function manifests as weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness.

Iodine is an essential trace element absorbed in the small intestine. It is an integral part of T3 and T4. Sources of iodine include iodized table salt, seafood, seaweed, and vegetables. Decreased iodine intake can cause iodine deficiency and decreased thyroid hormone synthesis. Iodine deficiency can cause cretinism, goiter, myxedema coma, and hypothyroidism. [rx][rx][rx]

The thyroid gland produces three hormones:

• Triiodothyronine, also known as T3
• Tetraiodothyronine also called thyroxine or T4
• Calcitonin

Strictly speaking, only T3 and T4 are proper thyroid hormones. They are made in what are known as the follicular epithelial cells of the thyroid.

Size

The thyroid gland is 2 inches (5 centimeters) wide and it weighs between 20 and 60 grams (0.7 to 2.1 ounces), according to the U.S. National Library of Medicine. The gland stretches across the front of the neck, below the voice box. Like a butterfly, it has two wings called lobes that stretch around the windpipe. The wings are connected by a small piece called the isthmus.

Cellular

Regulation of thyroid hormone starts at the hypothalamus. The hypothalamus releases thyrotropin-releasing hormone (TRH) into the hypothalamic-hypophyseal portal system to the anterior pituitary gland. TRH stimulates thyrotropin cells in the anterior pituitary to the release of thyroid-stimulating hormone (TSH). TRH is a peptide hormone created by the cell bodies in the periventricular nucleus (PVN) of the hypothalamus. These cell bodies project their neurosecretory neurons down to the hypophyseal portal circulation, where TRH can concentrate before reaching the anterior pituitary.

TRH is a tropic hormone, meaning that it indirectly affects cells by stimulating other endocrine glands first. It binds to the TRH receptors on the anterior pituitary gland, causing a signal cascade mediated by a G-protein coupled receptor. Activation of Gq protein leads to the activation of phosphoinositide-specific phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-P(PIP) into inositol 1,4,5-triphosphate (IP) and 1,2-diacylglycerol (DAG). These second messengers mobilize intracellular calcium stores and activate protein kinase C, leading to downstream gene activation and transcription of TSH. TRH also has a nootropic effect on the pituitary gland through the hypothalamic-pituitary-prolactin axis. As a nootropic hormone, TRH directly stimulates lactotropic cells in the anterior pituitary to produce prolactin. Other substances like serotonin, gonadotropin-releasing hormone, and estrogen can also stimulate prolactin release. Prolactin can cause breast tissue growth and lactation. [rx]

TSH is released into the blood and binds to the thyroid-releasing hormone receptor (TSH-R) on the basolateral aspect of the thyroid follicular cell. The TSH-R is a Gs-protein coupled receptor, and its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP.  The increased cAMP activates protein kinase A (PKA). PKA phosphorylates different proteins to modify their functions.

The five steps of thyroid synthesis are below

• Synthesis of Thyroglobulin – Thyrocytes in the thyroid follicles produce a protein called thyroglobulin (TG). TG does not contain any iodine, and it is a precursor protein stored in the lumen of follicles. It is produced in the rough endoplasmic reticulum. Golgi apparatus pack it into the vesicles, and then it enters the follicular lumen through exocytosis.
• Iodide uptake – Protein kinase A phosphorylation causes increased activity of basolateral Na+-I- symporters, driven by Na+-K+-ATPase, to bring iodide from the circulation into the thyrocytes. Iodide then diffuses from the basolateral side to the apex of the cell, where it is transported into the colloid through the Pendrin transporter.
• Iodination of thyroglobulin – Protein kinase A also phosphorylates and activates the enzyme thyroid peroxidase (TPO). TPO has three functions: oxidation, organification, and coupling reaction.
  • Oxidation – TPO uses hydrogen peroxide to oxidize iodide (I-) to iodine (I2). NADPH-oxidase, an apical enzyme, generates hydrogen peroxide for TPO.
  • Organification – TPO links tyrosine residues of thyroglobulin protein with I2. It generates monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT has a single tyrosine residue with iodine, and DIT has two tyrosine residues with iodine.
  • Coupling reaction – TPO combines iodinated tyrosine residues to make triiodothyronine (T3) and tetraiodothyronine (T4). MIT and DIT join to form T3, and two DIT molecules form T4.
• Storage – thyroid hormones are bound to thyroglobulin for stored in the follicular lumen.
• Release – thyroid hormones are released into the fenestrated capillary network by thyrocytes in the following steps:
  • Thyrocytes uptake iodinated thyroglobulin via endocytosis
  • Lysosome fuse with the endosome containing iodinated thyroglobulin
  • Proteolytic enzymes in the endolysosome cleave thyroglobulin into MIT, DIT, T3, and T4.
  • T3 (20%) and T4 (80%) are released into the fenestrated capillaries via MCT8 transporter. [rx]
  • Deiodinase enzymes remove iodine molecules from DIT and MIT. Iodine can be salvaged and redistributed to an intracellular iodide pool. [rx][rx][rx][rx]
    

Organ Systems Involved

Thyroid hormone affects virtually every organ system in the body, including the heart, CNS, autonomic nervous system, bone, GI, and metabolism. In general, when the thyroid hormone binds to its intranuclear receptor, it activates the genes for increasing metabolic rate and thermogenesis. Increasing metabolic rate involves increased oxygen and energy consumption.

• Heart – thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.
• Lungs – thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion.
• Skeletal muscles – thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions.
• Metabolism – thyroid hormone increases the basal metabolic rate. It increases the gene expression of Na+/K+ ATPase in different tissues leading to increased oxygen consumption, respiration rate, and body temperature. Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Thyroid hormones stimulate the metabolism of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses. Thyroid hormones do not change the blood glucose level, but they can cause increased glucose reabsorption, gluconeogenesis, glycogen synthesis, and glucose oxidation.
• Growth during childhood – In children, thyroid hormones act synergistically with growth hormones to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts. Thyroid hormone also helps with brain maturation by axonal growth and the formation of the myelin sheath.[rx]

Functions

The physiological effects of thyroid hormones are listed below

• Increases the basal metabolic rate
• Depending on the metabolic status it can induce lipolysis or lipid synthesis
• Stimulate the metabolism of carbohydrates
• Anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses
• Permissive effect on catecholamines
• In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth
• The impact of thyroid hormone in CNS is important. During the prenatal period, it is needed for the maturation of the brain. In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness.
• Thyroid hormone affects fertility, ovulation, and menstruation
• Regulate the rate at which calories are burned, affecting weight loss or weight gain.
• Can slow down or speed up the heartbeat.
• Can raise or lower body temperature.
• Influence the rate at which food moves through the digestive tract.
• Control the way muscles contract.
• Control the rate at which dying cells are replaced.

Mechanism

Thyroid hormones are lipophilic and circulate bound to the transport proteins. Only a fraction (~0.2%) of the thyroid hormone (free T4) is unbound and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) of the T4, and transthyretin transports thyroxine and retinol. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Receptors for T3 bind are already bound to the DNA in the nucleus before the ligand binding. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of transcription factors leading to the activation of certain genes and cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile. [rx]

Thyroid receptors are transcription factors that can bind to both T3 and T4. However, they have a much higher affinity for T3. As a result, T4 is relatively inactive. Deiodinases convert T4 to active T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I, II, and III. Type I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and thyroid glands. Type III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 convert T4 to active form T3, and DIO3 converts T4 into inactive form rT3. [rx]

Clinical Significance

Symptoms of Hypothyroidism

Generalized decreased basal metabolic rate can present as apathy, slowed cognition, skin dryness, alopecia, increased low-density lipoproteins, and increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting with apathy and slowed cognition. Hypothyroidism can decrease sympathetic activity leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and decreased cardiac output because of decreased transcription of sarcolemmal genes.

Hyperprolactinemia can be caused by hypothyroidism. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates prolactin and TSH release. Prolactin release can suppress testosterone, LH, FSH, and GnRH release. Prolactin can also cause breast tissue growth.

Patients with hypothyroidism may present with myxedema caused by decreased clearance of complex glycosaminoglycans and hyaluronic acids from the reticular layer of the dermis. Initially, the nonpitting edema is pretibial. As the state of hypothyroidism continues, patients can develop generalized edema.

• Feeling cold when other people do not
• Constipation
• Muscle weakness
• Weight gain, even though you are not eating more food
• Joint or muscle pain
• Feeling sad or depressed
• Feeling very tired
• Pale, dry skin
• Dry, thinning hair
• Slow heart rate
• Less sweating than usual
• A puffy face
• A hoarse voice
• More than usual menstrual bleeding

Symptoms related to decreased metabolic rate:

• Bradycardia
• Fatigue
• Cold intolerance
• Weight gain
• Poor appetite
• Hair loss
• Cold and dry skin
• Constipation
• Myopathy, stiffness, cramps, entrapment syndromes
• Delayed deep tendon reflex relaxation

Symptoms from generalized myxedema:

• Myxedematous heart disease
• Puffy appearance with doughy skin texture
• Hoarse voice with difficulty articulate words
• Pretibial and periorbital edema

Symptoms of hyperprolactinemia:

• Amenorrhea or menorrhagia
• Galactorrhea
• Erectile dysfunction, infertility in men
• Decreased libido

Other symptoms:

• Depression
• Impaired concentration and memory
• Goiter
• Hypertension

Congenital hypothyroidism:

• Umbilical hernia
• Hypotonia
• Prolonged neonatal jaundice
• Poor feeding, absence of thirst (adipsia)
• Decreased activity
• Pot-belly, puffy-face, protuberant tongue
• Poor brain development

Symptoms of Hyperthyroidism

Generalized hypermetabolism from hyperthyroidism causes increased Na+/K+-ATPase to promote thermogenesis. There is increased catecholamine secretion and, beta-adrenergic receptors are also upregulated in various tissues. As a result of the hyperadrenergic state, peripheral vascular resistance is decreased. In the heart, hyperthyroidism causes a decreased amount of phospholamban, a protein that normally decreases the affinity of calcium-ATPase for calcium in the sarcoplasmic reticulum. As a result of decreased phospholamban, there is increased Ca+ movement between the sarcoplasmic reticulum and cytosol, leading to increased contractility. Increased beta-receptors on the heart also leads to increased cardiac output.

General

• Heat intolerance
• Weight loss
• Increased appetite
• Increased sweating from cutaneous blood flow increase
• Weakness
• Fatigue
• Onycholysis (separation of nails from nail beds)
• Pretibial myxedema
• Weight loss, even if you eat the same or more food (most but not all people lose weight)
• Eating more than usual
• Rapid or irregular heartbeat or pounding of your heart
• Feeling nervous or anxious
• Feeling irritable
• Trouble sleeping
• Trembling in your hands and fingers
• Increased sweating
• Feeling hot when other people do not
• Muscle weakness
• Diarrhea or more bowel movements than normal
• Fewer and lighter menstrual periods than normal
• Changes in your eyes can include bulging of the eyes, redness, or irritation

Eyes

• Lid lag (when looking down, sclera visible above cornea)
• Lid retraction (when looking straight, sclera visible above the cornea)
• Graves ophthalmopathy

Goiter

• Diffuse, smooth, non-tender goiter
• The audible bruit can be heard at the superior poles

Cardiovascular

• Tachycardia (can be masked by patients taking beta-blockers)
• Palpitations
• An irregular pulse from atrial fibrillation
• Hypertension
• Widened pulse pressure because systolic pressure increases and diastolic pressure decreases
• Heart failure (elderly patients)
• Chest pain
• Abnormal heart rhythms

Musculoskeletal

• Fine tremors of the outstretched fingers. Face, tongue, and head can also be involved. Tremors respond well to treatment with beta-blockers.
• Myopathy affecting proximal muscles. Serum creatine kinase levels can be normal
• Osteoporosis caused by the direct effects of T3. Elderly patients can present with fractures.

Neuropsychiatric system

• Restlessness
• Anxiety
• Depression
• Emotional instability
• Insomnia
• Tremoulousness
• Hyperreflexia

Conditions associated with hypothyroidism

• Iodine deficiency [rx]
• Cretinism [rx]
• Wolff-Chaikoff effect [rx]
• Subacute thyroiditis [rx]
• Postpartum thyroiditis [rx]
• Riedel thyroiditis [rx]
• Hashimoto thyroiditis [rx]
• Drug-induced [rx]

Conditions associated with hyperthyroidism

• Graves disease [rx]
• Iodine excess [rx]
• Struma ovarii [rx]
• Thyrotropic pituitary adenoma [rx]
• Job-Basedow phenomenon [rx]
• Drug-induced: amiodarone, lithium [rx]
• Thyrotoxicosis and thyroid storm [rx]
• Toxic multinodular goiter [rx]
• Thyroid adenoma [rx]

Antithyroid drugs that work in the thyroid gland [rx]

• Perchlorate – inhibits Na+/I- symporter – blocks iodide uptake
• Thionamides – inhibits TPO – block thyroid hormone synthesis
• Iodide > 5mg – inhibits Na+/I- symporter and TPO – blocks iodide uptake and thyroid hormone synthesis
• Lithium – inhibits thyroid hormone release (off-label use for thyroid storm)

Antithyroid drugs work in peripheral tissue – all these drugs inhibit the deiodinase enzymes. Deiodinase enzymes normally convert T4 into the active form T3. These drugs inhibit the conversion of T4 to T3 and reduce its activity.

• Propylthiouracil (ethionamide)
• Dexamethasone
• Amiodarone
• Propranolol

• https://www.ncbi.nlm.nih.gov/books/NBK538498/
• https://www.ncbi.nlm.nih.gov/books/NBK541112/
• https://www.ncbi.nlm.nih.gov/books/NBK22/
• https://www.ncbi.nlm.nih.gov/books/NBK20/
• https://www.ncbi.nlm.nih.gov/books/NBK482141/
• https://www.ncbi.nlm.nih.gov/books/NBK539692/
• https://www.ncbi.nlm.nih.gov/books/NBK537039/
• https://www.ncbi.nlm.nih.gov/books/NBK535380/
• https://www.ncbi.nlm.nih.gov/books/NBK537038/
• https://www.ncbi.nlm.nih.gov/books/NBK499850/
• https://www.ncbi.nlm.nih.gov/books/NBK537260/
• https://www.ncbi.nlm.nih.gov/books/NBK28/
• https://www.ncbi.nlm.nih.gov/books/NBK538260/
• https://www.ncbi.nlm.nih.gov/books/NBK500006/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206851/
• https://www.ncbi.nlm.nih.gov/books/NBK279388/
• https://en.wikipedia.org/wiki/Hormone
• https://en.wikipedia.org/wiki/Thyroid_hormones
• https://medlineplus.gov/hormones.html
• https://www.webmd.com/menopause/guide/which-type-of-estrogen-hormone-therapy-is-right-for-you
• https://www.medicalnewstoday.com/articles/277177
• https://www.cancer.org/cancer/thyroid-cancer/treating/thyroid-hormone-therapy.html
• https://www.webmd.com/women/picture-of-the-thyroid
• https://www.womenshealth.gov/a-z-topics/thyroid-disease
• https://www.thyroid.org/thyroid-hormone-treatment/
• https://www.nhs.uk/conditions/underactive-thyroid-hypothyroidism/symptoms/

What is the main function of the thyroid hormone? Thyroid hormone is made by the thyroid gland, a butterfly-shaped endocrine gland normally located in the lower front of the neck. Thyroid hormone is released into the blood where it is carried to all the tissues in the body. It helps the body controlling metabolism, growth, and many other body functions use energy, stay warm, and keeps the brain, heart, muscles, and other organs working as they should. The thyroid gland, anterior pituitary gland, and hypothalamus comprise a self-regulatory circuit called the hypothalamic-pituitary-thyroid axis. The main hormones produced by the thyroid gland are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) from the hypothalamus, thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 work in synchronous harmony to maintain proper feedback mechanism and homeostasis. Hypothyroidism, caused by an underactive thyroid gland, typically manifests as bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism caused by increased thyroid gland function manifests as weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness.

Iodine is an essential trace element absorbed in the small intestine. It is an integral part of T3 and T4. Sources of iodine include iodized table salt, seafood, seaweed, and vegetables. Decreased iodine intake can cause iodine deficiency and decreased thyroid hormone synthesis. Iodine deficiency can cause cretinism, goiter, myxedema coma, and hypothyroidism. [rx][rx][rx]

The thyroid gland produces three hormones:

• Triiodothyronine, also known as T3
• Tetraiodothyronine also called thyroxine or T4
• Calcitonin

Strictly speaking, only T3 and T4 are proper thyroid hormones. They are made in what are known as the follicular epithelial cells of the thyroid.

Size

The thyroid gland is 2 inches (5 centimeters) wide and it weighs between 20 and 60 grams (0.7 to 2.1 ounces), according to the U.S. National Library of Medicine. The gland stretches across the front of the neck, below the voice box. Like a butterfly, it has two wings called lobes that stretch around the windpipe. The wings are connected by a small piece called the isthmus.

Cellular

Regulation of thyroid hormone starts at the hypothalamus. The hypothalamus releases thyrotropin-releasing hormone (TRH) into the hypothalamic-hypophyseal portal system to the anterior pituitary gland. TRH stimulates thyrotropin cells in the anterior pituitary to the release of thyroid-stimulating hormone (TSH). TRH is a peptide hormone created by the cell bodies in the periventricular nucleus (PVN) of the hypothalamus. These cell bodies project their neurosecretory neurons down to the hypophyseal portal circulation, where TRH can concentrate before reaching the anterior pituitary.

TRH is a tropic hormone, meaning that it indirectly affects cells by stimulating other endocrine glands first. It binds to the TRH receptors on the anterior pituitary gland, causing a signal cascade mediated by a G-protein coupled receptor. Activation of Gq protein leads to the activation of phosphoinositide-specific phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-P(PIP) into inositol 1,4,5-triphosphate (IP) and 1,2-diacylglycerol (DAG). These second messengers mobilize intracellular calcium stores and activate protein kinase C, leading to downstream gene activation and transcription of TSH. TRH also has a nootropic effect on the pituitary gland through the hypothalamic-pituitary-prolactin axis. As a nootropic hormone, TRH directly stimulates lactotropic cells in the anterior pituitary to produce prolactin. Other substances like serotonin, gonadotropin-releasing hormone, and estrogen can also stimulate prolactin release. Prolactin can cause breast tissue growth and lactation. [rx]

TSH is released into the blood and binds to the thyroid-releasing hormone receptor (TSH-R) on the basolateral aspect of the thyroid follicular cell. The TSH-R is a Gs-protein coupled receptor, and its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP.  The increased cAMP activates protein kinase A (PKA). PKA phosphorylates different proteins to modify their functions.

The five steps of thyroid synthesis are below

• Synthesis of Thyroglobulin – Thyrocytes in the thyroid follicles produce a protein called thyroglobulin (TG). TG does not contain any iodine, and it is a precursor protein stored in the lumen of follicles. It is produced in the rough endoplasmic reticulum. Golgi apparatus pack it into the vesicles, and then it enters the follicular lumen through exocytosis.
• Iodide uptake – Protein kinase A phosphorylation causes increased activity of basolateral Na+-I- symporters, driven by Na+-K+-ATPase, to bring iodide from the circulation into the thyrocytes. Iodide then diffuses from the basolateral side to the apex of the cell, where it is transported into the colloid through the Pendrin transporter.
• Iodination of thyroglobulin – Protein kinase A also phosphorylates and activates the enzyme thyroid peroxidase (TPO). TPO has three functions: oxidation, organification, and coupling reaction.
  • Oxidation – TPO uses hydrogen peroxide to oxidize iodide (I-) to iodine (I2). NADPH-oxidase, an apical enzyme, generates hydrogen peroxide for TPO.
  • Organification – TPO links tyrosine residues of thyroglobulin protein with I2. It generates monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT has a single tyrosine residue with iodine, and DIT has two tyrosine residues with iodine.
  • Coupling reaction – TPO combines iodinated tyrosine residues to make triiodothyronine (T3) and tetraiodothyronine (T4). MIT and DIT join to form T3, and two DIT molecules form T4.
• Storage – thyroid hormones are bound to thyroglobulin for stored in the follicular lumen.
• Release – thyroid hormones are released into the fenestrated capillary network by thyrocytes in the following steps:
  • Thyrocytes uptake iodinated thyroglobulin via endocytosis
  • Lysosome fuse with the endosome containing iodinated thyroglobulin
  • Proteolytic enzymes in the endolysosome cleave thyroglobulin into MIT, DIT, T3, and T4.
  • T3 (20%) and T4 (80%) are released into the fenestrated capillaries via MCT8 transporter. [rx]
  • Deiodinase enzymes remove iodine molecules from DIT and MIT. Iodine can be salvaged and redistributed to an intracellular iodide pool. [rx][rx][rx][rx]
    

Organ Systems Involved

Thyroid hormone affects virtually every organ system in the body, including the heart, CNS, autonomic nervous system, bone, GI, and metabolism. In general, when the thyroid hormone binds to its intranuclear receptor, it activates the genes for increasing metabolic rate and thermogenesis. Increasing metabolic rate involves increased oxygen and energy consumption.

• Heart – thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.
• Lungs – thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion.
• Skeletal muscles – thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions.
• Metabolism – thyroid hormone increases the basal metabolic rate. It increases the gene expression of Na+/K+ ATPase in different tissues leading to increased oxygen consumption, respiration rate, and body temperature. Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Thyroid hormones stimulate the metabolism of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses. Thyroid hormones do not change the blood glucose level, but they can cause increased glucose reabsorption, gluconeogenesis, glycogen synthesis, and glucose oxidation.
• Growth during childhood – In children, thyroid hormones act synergistically with growth hormones to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts. Thyroid hormone also helps with brain maturation by axonal growth and the formation of the myelin sheath.[rx]

Functions

The physiological effects of thyroid hormones are listed below

• Increases the basal metabolic rate
• Depending on the metabolic status it can induce lipolysis or lipid synthesis
• Stimulate the metabolism of carbohydrates
• Anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses
• Permissive effect on catecholamines
• In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth
• The impact of thyroid hormone in CNS is important. During the prenatal period, it is needed for the maturation of the brain. In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness.
• Thyroid hormone affects fertility, ovulation, and menstruation
• Regulate the rate at which calories are burned, affecting weight loss or weight gain.
• Can slow down or speed up the heartbeat.
• Can raise or lower body temperature.
• Influence the rate at which food moves through the digestive tract.
• Control the way muscles contract.
• Control the rate at which dying cells are replaced.

Mechanism

Thyroid hormones are lipophilic and circulate bound to the transport proteins. Only a fraction (~0.2%) of the thyroid hormone (free T4) is unbound and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) of the T4, and transthyretin transports thyroxine and retinol. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Receptors for T3 bind are already bound to the DNA in the nucleus before the ligand binding. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of transcription factors leading to the activation of certain genes and cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile. [rx]

Thyroid receptors are transcription factors that can bind to both T3 and T4. However, they have a much higher affinity for T3. As a result, T4 is relatively inactive. Deiodinases convert T4 to active T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I, II, and III. Type I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and thyroid glands. Type III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 convert T4 to active form T3, and DIO3 converts T4 into inactive form rT3. [rx]

Clinical Significance

Symptoms of Hypothyroidism

Generalized decreased basal metabolic rate can present as apathy, slowed cognition, skin dryness, alopecia, increased low-density lipoproteins, and increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting with apathy and slowed cognition. Hypothyroidism can decrease sympathetic activity leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and decreased cardiac output because of decreased transcription of sarcolemmal genes.

Hyperprolactinemia can be caused by hypothyroidism. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates prolactin and TSH release. Prolactin release can suppress testosterone, LH, FSH, and GnRH release. Prolactin can also cause breast tissue growth.

Patients with hypothyroidism may present with myxedema caused by decreased clearance of complex glycosaminoglycans and hyaluronic acids from the reticular layer of the dermis. Initially, the nonpitting edema is pretibial. As the state of hypothyroidism continues, patients can develop generalized edema.

• Feeling cold when other people do not
• Constipation
• Muscle weakness
• Weight gain, even though you are not eating more food
• Joint or muscle pain
• Feeling sad or depressed
• Feeling very tired
• Pale, dry skin
• Dry, thinning hair
• Slow heart rate
• Less sweating than usual
• A puffy face
• A hoarse voice
• More than usual menstrual bleeding

Symptoms related to decreased metabolic rate:

• Bradycardia
• Fatigue
• Cold intolerance
• Weight gain
• Poor appetite
• Hair loss
• Cold and dry skin
• Constipation
• Myopathy, stiffness, cramps, entrapment syndromes
• Delayed deep tendon reflex relaxation

Symptoms from generalized myxedema:

• Myxedematous heart disease
• Puffy appearance with doughy skin texture
• Hoarse voice with difficulty articulate words
• Pretibial and periorbital edema

Symptoms of hyperprolactinemia:

• Amenorrhea or menorrhagia
• Galactorrhea
• Erectile dysfunction, infertility in men
• Decreased libido

Other symptoms:

• Depression
• Impaired concentration and memory
• Goiter
• Hypertension

Congenital hypothyroidism:

• Umbilical hernia
• Hypotonia
• Prolonged neonatal jaundice
• Poor feeding, absence of thirst (adipsia)
• Decreased activity
• Pot-belly, puffy-face, protuberant tongue
• Poor brain development

Symptoms of Hyperthyroidism

Generalized hypermetabolism from hyperthyroidism causes increased Na+/K+-ATPase to promote thermogenesis. There is increased catecholamine secretion and, beta-adrenergic receptors are also upregulated in various tissues. As a result of the hyperadrenergic state, peripheral vascular resistance is decreased. In the heart, hyperthyroidism causes a decreased amount of phospholamban, a protein that normally decreases the affinity of calcium-ATPase for calcium in the sarcoplasmic reticulum. As a result of decreased phospholamban, there is increased Ca+ movement between the sarcoplasmic reticulum and cytosol, leading to increased contractility. Increased beta-receptors on the heart also leads to increased cardiac output.

General

• Heat intolerance
• Weight loss
• Increased appetite
• Increased sweating from cutaneous blood flow increase
• Weakness
• Fatigue
• Onycholysis (separation of nails from nail beds)
• Pretibial myxedema
• Weight loss, even if you eat the same or more food (most but not all people lose weight)
• Eating more than usual
• Rapid or irregular heartbeat or pounding of your heart
• Feeling nervous or anxious
• Feeling irritable
• Trouble sleeping
• Trembling in your hands and fingers
• Increased sweating
• Feeling hot when other people do not
• Muscle weakness
• Diarrhea or more bowel movements than normal
• Fewer and lighter menstrual periods than normal
• Changes in your eyes can include bulging of the eyes, redness, or irritation

Eyes

• Lid lag (when looking down, sclera visible above cornea)
• Lid retraction (when looking straight, sclera visible above the cornea)
• Graves ophthalmopathy

Goiter

• Diffuse, smooth, non-tender goiter
• The audible bruit can be heard at the superior poles

Cardiovascular

• Tachycardia (can be masked by patients taking beta-blockers)
• Palpitations
• An irregular pulse from atrial fibrillation
• Hypertension
• Widened pulse pressure because systolic pressure increases and diastolic pressure decreases
• Heart failure (elderly patients)
• Chest pain
• Abnormal heart rhythms

Musculoskeletal

• Fine tremors of the outstretched fingers. Face, tongue, and head can also be involved. Tremors respond well to treatment with beta-blockers.
• Myopathy affecting proximal muscles. Serum creatine kinase levels can be normal
• Osteoporosis caused by the direct effects of T3. Elderly patients can present with fractures.

Neuropsychiatric system

• Restlessness
• Anxiety
• Depression
• Emotional instability
• Insomnia
• Tremoulousness
• Hyperreflexia

Conditions associated with hypothyroidism

• Iodine deficiency [rx]
• Cretinism [rx]
• Wolff-Chaikoff effect [rx]
• Subacute thyroiditis [rx]
• Postpartum thyroiditis [rx]
• Riedel thyroiditis [rx]
• Hashimoto thyroiditis [rx]
• Drug-induced [rx]

Conditions associated with hyperthyroidism

• Graves disease [rx]
• Iodine excess [rx]
• Struma ovarii [rx]
• Thyrotropic pituitary adenoma [rx]
• Job-Basedow phenomenon [rx]
• Drug-induced: amiodarone, lithium [rx]
• Thyrotoxicosis and thyroid storm [rx]
• Toxic multinodular goiter [rx]
• Thyroid adenoma [rx]

Antithyroid drugs that work in the thyroid gland [rx]

• Perchlorate – inhibits Na+/I- symporter – blocks iodide uptake
• Thionamides – inhibits TPO – block thyroid hormone synthesis
• Iodide > 5mg – inhibits Na+/I- symporter and TPO – blocks iodide uptake and thyroid hormone synthesis
• Lithium – inhibits thyroid hormone release (off-label use for thyroid storm)

Antithyroid drugs work in peripheral tissue – all these drugs inhibit the deiodinase enzymes. Deiodinase enzymes normally convert T4 into the active form T3. These drugs inhibit the conversion of T4 to T3 and reduce its activity.

• Propylthiouracil (ethionamide)
• Dexamethasone
• Amiodarone
• Propranolol

• https://www.ncbi.nlm.nih.gov/books/NBK538498/
• https://www.ncbi.nlm.nih.gov/books/NBK541112/
• https://www.ncbi.nlm.nih.gov/books/NBK22/
• https://www.ncbi.nlm.nih.gov/books/NBK20/
• https://www.ncbi.nlm.nih.gov/books/NBK482141/
• https://www.ncbi.nlm.nih.gov/books/NBK539692/
• https://www.ncbi.nlm.nih.gov/books/NBK537039/
• https://www.ncbi.nlm.nih.gov/books/NBK535380/
• https://www.ncbi.nlm.nih.gov/books/NBK537038/
• https://www.ncbi.nlm.nih.gov/books/NBK499850/
• https://www.ncbi.nlm.nih.gov/books/NBK537260/
• https://www.ncbi.nlm.nih.gov/books/NBK28/
• https://www.ncbi.nlm.nih.gov/books/NBK538260/
• https://www.ncbi.nlm.nih.gov/books/NBK500006/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206851/
• https://www.ncbi.nlm.nih.gov/books/NBK279388/
• https://en.wikipedia.org/wiki/Hormone
• https://en.wikipedia.org/wiki/Thyroid_hormones
• https://medlineplus.gov/hormones.html
• https://www.webmd.com/menopause/guide/which-type-of-estrogen-hormone-therapy-is-right-for-you
• https://www.medicalnewstoday.com/articles/277177
• https://www.cancer.org/cancer/thyroid-cancer/treating/thyroid-hormone-therapy.html
• https://www.webmd.com/women/picture-of-the-thyroid
• https://www.womenshealth.gov/a-z-topics/thyroid-disease
• https://www.thyroid.org/thyroid-hormone-treatment/
• https://www.nhs.uk/conditions/underactive-thyroid-hypothyroidism/symptoms/

Thyroid hormone is made by the thyroid gland, a butterfly-shaped endocrine gland normally located in the lower front of the neck. Thyroid hormone is released into the blood where it is carried to all the tissues in the body. It helps the body controlling metabolism, growth, and many other body functions use energy, stay warm, and keeps the brain, heart, muscles, and other organs working as they should. The thyroid gland, anterior pituitary gland, and hypothalamus comprise a self-regulatory circuit called the hypothalamic-pituitary-thyroid axis. The main hormones produced by the thyroid gland are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) from the hypothalamus, thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 work in synchronous harmony to maintain proper feedback mechanism and homeostasis. Hypothyroidism, caused by an underactive thyroid gland, typically manifests as bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism caused by increased thyroid gland function manifests as weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness.

Iodine is an essential trace element absorbed in the small intestine. It is an integral part of T3 and T4. Sources of iodine include iodized table salt, seafood, seaweed, and vegetables. Decreased iodine intake can cause iodine deficiency and decreased thyroid hormone synthesis. Iodine deficiency can cause cretinism, goiter, myxedema coma, and hypothyroidism. [rx][rx][rx]

The thyroid gland produces three hormones:

• Triiodothyronine, also known as T3
• Tetraiodothyronine also called thyroxine or T4
• Calcitonin

Strictly speaking, only T3 and T4 are proper thyroid hormones. They are made in what are known as the follicular epithelial cells of the thyroid.

Size

The thyroid gland is 2 inches (5 centimeters) wide and it weighs between 20 and 60 grams (0.7 to 2.1 ounces), according to the U.S. National Library of Medicine. The gland stretches across the front of the neck, below the voice box. Like a butterfly, it has two wings called lobes that stretch around the windpipe. The wings are connected by a small piece called the isthmus.

Cellular

Regulation of thyroid hormone starts at the hypothalamus. The hypothalamus releases thyrotropin-releasing hormone (TRH) into the hypothalamic-hypophyseal portal system to the anterior pituitary gland. TRH stimulates thyrotropin cells in the anterior pituitary to the release of thyroid-stimulating hormone (TSH). TRH is a peptide hormone created by the cell bodies in the periventricular nucleus (PVN) of the hypothalamus. These cell bodies project their neurosecretory neurons down to the hypophyseal portal circulation, where TRH can concentrate before reaching the anterior pituitary.

TRH is a tropic hormone, meaning that it indirectly affects cells by stimulating other endocrine glands first. It binds to the TRH receptors on the anterior pituitary gland, causing a signal cascade mediated by a G-protein coupled receptor. Activation of Gq protein leads to the activation of phosphoinositide-specific phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol 4,5-P(PIP) into inositol 1,4,5-triphosphate (IP) and 1,2-diacylglycerol (DAG). These second messengers mobilize intracellular calcium stores and activate protein kinase C, leading to downstream gene activation and transcription of TSH. TRH also has a nootropic effect on the pituitary gland through the hypothalamic-pituitary-prolactin axis. As a nootropic hormone, TRH directly stimulates lactotropic cells in the anterior pituitary to produce prolactin. Other substances like serotonin, gonadotropin-releasing hormone, and estrogen can also stimulate prolactin release. Prolactin can cause breast tissue growth and lactation. [rx]

TSH is released into the blood and binds to the thyroid-releasing hormone receptor (TSH-R) on the basolateral aspect of the thyroid follicular cell. The TSH-R is a Gs-protein coupled receptor, and its activation leads to the activation of adenylyl cyclase and intracellular levels of cAMP.  The increased cAMP activates protein kinase A (PKA). PKA phosphorylates different proteins to modify their functions.

The five steps of thyroid synthesis are below

• Synthesis of Thyroglobulin – Thyrocytes in the thyroid follicles produce a protein called thyroglobulin (TG). TG does not contain any iodine, and it is a precursor protein stored in the lumen of follicles. It is produced in the rough endoplasmic reticulum. Golgi apparatus pack it into the vesicles, and then it enters the follicular lumen through exocytosis.
• Iodide uptake – Protein kinase A phosphorylation causes increased activity of basolateral Na+-I- symporters, driven by Na+-K+-ATPase, to bring iodide from the circulation into the thyrocytes. Iodide then diffuses from the basolateral side to the apex of the cell, where it is transported into the colloid through the Pendrin transporter.
• Iodination of thyroglobulin – Protein kinase A also phosphorylates and activates the enzyme thyroid peroxidase (TPO). TPO has three functions: oxidation, organification, and coupling reaction.
  • Oxidation – TPO uses hydrogen peroxide to oxidize iodide (I-) to iodine (I2). NADPH-oxidase, an apical enzyme, generates hydrogen peroxide for TPO.
  • Organification – TPO links tyrosine residues of thyroglobulin protein with I2. It generates monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT has a single tyrosine residue with iodine, and DIT has two tyrosine residues with iodine.
  • Coupling reaction – TPO combines iodinated tyrosine residues to make triiodothyronine (T3) and tetraiodothyronine (T4). MIT and DIT join to form T3, and two DIT molecules form T4.
• Storage – thyroid hormones are bound to thyroglobulin for stored in the follicular lumen.
• Release – thyroid hormones are released into the fenestrated capillary network by thyrocytes in the following steps:
  • Thyrocytes uptake iodinated thyroglobulin via endocytosis
  • Lysosome fuse with the endosome containing iodinated thyroglobulin
  • Proteolytic enzymes in the endolysosome cleave thyroglobulin into MIT, DIT, T3, and T4.
  • T3 (20%) and T4 (80%) are released into the fenestrated capillaries via MCT8 transporter. [rx]
  • Deiodinase enzymes remove iodine molecules from DIT and MIT. Iodine can be salvaged and redistributed to an intracellular iodide pool. [rx][rx][rx][rx]
    

Organ Systems Involved

Thyroid hormone affects virtually every organ system in the body, including the heart, CNS, autonomic nervous system, bone, GI, and metabolism. In general, when the thyroid hormone binds to its intranuclear receptor, it activates the genes for increasing metabolic rate and thermogenesis. Increasing metabolic rate involves increased oxygen and energy consumption.

• Heart – thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility.
• Lungs – thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion.
• Skeletal muscles – thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions.
• Metabolism – thyroid hormone increases the basal metabolic rate. It increases the gene expression of Na+/K+ ATPase in different tissues leading to increased oxygen consumption, respiration rate, and body temperature. Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Thyroid hormones stimulate the metabolism of carbohydrates and anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses. Thyroid hormones do not change the blood glucose level, but they can cause increased glucose reabsorption, gluconeogenesis, glycogen synthesis, and glucose oxidation.
• Growth during childhood – In children, thyroid hormones act synergistically with growth hormones to stimulate bone growth. It induces chondrocytes, osteoblasts, and osteoclasts. Thyroid hormone also helps with brain maturation by axonal growth and the formation of the myelin sheath.[rx]

Functions

The physiological effects of thyroid hormones are listed below

• Increases the basal metabolic rate
• Depending on the metabolic status it can induce lipolysis or lipid synthesis
• Stimulate the metabolism of carbohydrates
• Anabolism of proteins. Thyroid hormones can also induce catabolism of proteins in high doses
• Permissive effect on catecholamines
• In children, thyroid hormones act synergistically with growth hormone to stimulate bone growth
• The impact of thyroid hormone in CNS is important. During the prenatal period, it is needed for the maturation of the brain. In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness.
• Thyroid hormone affects fertility, ovulation, and menstruation
• Regulate the rate at which calories are burned, affecting weight loss or weight gain.
• Can slow down or speed up the heartbeat.
• Can raise or lower body temperature.
• Influence the rate at which food moves through the digestive tract.
• Control the way muscles contract.
• Control the rate at which dying cells are replaced.

Mechanism

Thyroid hormones are lipophilic and circulate bound to the transport proteins. Only a fraction (~0.2%) of the thyroid hormone (free T4) is unbound and active. Transporter proteins include thyroxine-binding globulin (TBG), transthyretin, and albumin. TBG transports the majority (two-thirds) of the T4, and transthyretin transports thyroxine and retinol. When it reaches its target site, T3 and T4 can dissociate from their binding protein to enter cells either by diffusion or carrier-mediated transport. Receptors for T3 bind are already bound to the DNA in the nucleus before the ligand binding. T3 or T4 then bind to nuclear alpha or beta receptors in the respective tissue and cause activation of transcription factors leading to the activation of certain genes and cell-specific responses. Thyroid hormones are degraded in the liver via sulfation and glucuronidation and excreted in the bile. [rx]

Thyroid receptors are transcription factors that can bind to both T3 and T4. However, they have a much higher affinity for T3. As a result, T4 is relatively inactive. Deiodinases convert T4 to active T3 or inactive reverse T3 (rT3). There are three types of deiodinases: type I, II, and III. Type I (DIO1) and II (DIO2) are located in the liver, kidneys, muscles, and thyroid glands. Type III (DIO3) deiodinases are located in the CNS and placenta. DIO1 and DIO2 convert T4 to active form T3, and DIO3 converts T4 into inactive form rT3. [rx]

Clinical Significance

Symptoms of Hypothyroidism

Generalized decreased basal metabolic rate can present as apathy, slowed cognition, skin dryness, alopecia, increased low-density lipoproteins, and increased triglycerides. Hypothyroidism must be ruled out in psychiatry patients presenting with apathy and slowed cognition. Hypothyroidism can decrease sympathetic activity leading to decreased sweating, bradycardia, and constipation. Patients can present with myopathy and decreased cardiac output because of decreased transcription of sarcolemmal genes.

Hyperprolactinemia can be caused by hypothyroidism. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates prolactin and TSH release. Prolactin release can suppress testosterone, LH, FSH, and GnRH release. Prolactin can also cause breast tissue growth.

Patients with hypothyroidism may present with myxedema caused by decreased clearance of complex glycosaminoglycans and hyaluronic acids from the reticular layer of the dermis. Initially, the nonpitting edema is pretibial. As the state of hypothyroidism continues, patients can develop generalized edema.

• Feeling cold when other people do not
• Constipation
• Muscle weakness
• Weight gain, even though you are not eating more food
• Joint or muscle pain
• Feeling sad or depressed
• Feeling very tired
• Pale, dry skin
• Dry, thinning hair
• Slow heart rate
• Less sweating than usual
• A puffy face
• A hoarse voice
• More than usual menstrual bleeding

Symptoms related to decreased metabolic rate:

• Bradycardia
• Fatigue
• Cold intolerance
• Weight gain
• Poor appetite
• Hair loss
• Cold and dry skin
• Constipation
• Myopathy, stiffness, cramps, entrapment syndromes
• Delayed deep tendon reflex relaxation

Symptoms from generalized myxedema:

• Myxedematous heart disease
• Puffy appearance with doughy skin texture
• Hoarse voice with difficulty articulate words
• Pretibial and periorbital edema

Symptoms of hyperprolactinemia:

• Amenorrhea or menorrhagia
• Galactorrhea
• Erectile dysfunction, infertility in men
• Decreased libido

Other symptoms:

• Depression
• Impaired concentration and memory
• Goiter
• Hypertension

Congenital hypothyroidism:

• Umbilical hernia
• Hypotonia
• Prolonged neonatal jaundice
• Poor feeding, absence of thirst (adipsia)
• Decreased activity
• Pot-belly, puffy-face, protuberant tongue
• Poor brain development

Symptoms of Hyperthyroidism

Generalized hypermetabolism from hyperthyroidism causes increased Na+/K+-ATPase to promote thermogenesis. There is increased catecholamine secretion and, beta-adrenergic receptors are also upregulated in various tissues. As a result of the hyperadrenergic state, peripheral vascular resistance is decreased. In the heart, hyperthyroidism causes a decreased amount of phospholamban, a protein that normally decreases the affinity of calcium-ATPase for calcium in the sarcoplasmic reticulum. As a result of decreased phospholamban, there is increased Ca+ movement between the sarcoplasmic reticulum and cytosol, leading to increased contractility. Increased beta-receptors on the heart also leads to increased cardiac output.

General

• Heat intolerance
• Weight loss
• Increased appetite
• Increased sweating from cutaneous blood flow increase
• Weakness
• Fatigue
• Onycholysis (separation of nails from nail beds)
• Pretibial myxedema
• Weight loss, even if you eat the same or more food (most but not all people lose weight)
• Eating more than usual
• Rapid or irregular heartbeat or pounding of your heart
• Feeling nervous or anxious
• Feeling irritable
• Trouble sleeping
• Trembling in your hands and fingers
• Increased sweating
• Feeling hot when other people do not
• Muscle weakness
• Diarrhea or more bowel movements than normal
• Fewer and lighter menstrual periods than normal
• Changes in your eyes can include bulging of the eyes, redness, or irritation

Eyes

• Lid lag (when looking down, sclera visible above cornea)
• Lid retraction (when looking straight, sclera visible above the cornea)
• Graves ophthalmopathy

Goiter

• Diffuse, smooth, non-tender goiter
• The audible bruit can be heard at the superior poles

Cardiovascular

• Tachycardia (can be masked by patients taking beta-blockers)
• Palpitations
• An irregular pulse from atrial fibrillation
• Hypertension
• Widened pulse pressure because systolic pressure increases and diastolic pressure decreases
• Heart failure (elderly patients)
• Chest pain
• Abnormal heart rhythms

Musculoskeletal

• Fine tremors of the outstretched fingers. Face, tongue, and head can also be involved. Tremors respond well to treatment with beta-blockers.
• Myopathy affecting proximal muscles. Serum creatine kinase levels can be normal
• Osteoporosis caused by the direct effects of T3. Elderly patients can present with fractures.

Neuropsychiatric system

• Restlessness
• Anxiety
• Depression
• Emotional instability
• Insomnia
• Tremoulousness
• Hyperreflexia

Conditions associated with hypothyroidism

• Iodine deficiency [rx]
• Cretinism [rx]
• Wolff-Chaikoff effect [rx]
• Subacute thyroiditis [rx]
• Postpartum thyroiditis [rx]
• Riedel thyroiditis [rx]
• Hashimoto thyroiditis [rx]
• Drug-induced [rx]

Conditions associated with hyperthyroidism

• Graves disease [rx]
• Iodine excess [rx]
• Struma ovarii [rx]
• Thyrotropic pituitary adenoma [rx]
• Job-Basedow phenomenon [rx]
• Drug-induced: amiodarone, lithium [rx]
• Thyrotoxicosis and thyroid storm [rx]
• Toxic multinodular goiter [rx]
• Thyroid adenoma [rx]

Antithyroid drugs that work in the thyroid gland [rx]

• Perchlorate – inhibits Na+/I- symporter – blocks iodide uptake
• Thionamides – inhibits TPO – block thyroid hormone synthesis
• Iodide > 5mg – inhibits Na+/I- symporter and TPO – blocks iodide uptake and thyroid hormone synthesis
• Lithium – inhibits thyroid hormone release (off-label use for thyroid storm)

Antithyroid drugs work in peripheral tissue – all these drugs inhibit the deiodinase enzymes. Deiodinase enzymes normally convert T4 into the active form T3. These drugs inhibit the conversion of T4 to T3 and reduce its activity.

• Propylthiouracil (ethionamide)
• Dexamethasone
• Amiodarone
• Propranolol

• https://www.ncbi.nlm.nih.gov/books/NBK538498/
• https://www.ncbi.nlm.nih.gov/books/NBK541112/
• https://www.ncbi.nlm.nih.gov/books/NBK22/
• https://www.ncbi.nlm.nih.gov/books/NBK20/
• https://www.ncbi.nlm.nih.gov/books/NBK482141/
• https://www.ncbi.nlm.nih.gov/books/NBK539692/
• https://www.ncbi.nlm.nih.gov/books/NBK537039/
• https://www.ncbi.nlm.nih.gov/books/NBK535380/
• https://www.ncbi.nlm.nih.gov/books/NBK537038/
• https://www.ncbi.nlm.nih.gov/books/NBK499850/
• https://www.ncbi.nlm.nih.gov/books/NBK537260/
• https://www.ncbi.nlm.nih.gov/books/NBK28/
• https://www.ncbi.nlm.nih.gov/books/NBK538260/
• https://www.ncbi.nlm.nih.gov/books/NBK500006/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206851/
• https://www.ncbi.nlm.nih.gov/books/NBK279388/
• https://en.wikipedia.org/wiki/Hormone
• https://en.wikipedia.org/wiki/Thyroid_hormones
• https://medlineplus.gov/hormones.html
• https://www.webmd.com/menopause/guide/which-type-of-estrogen-hormone-therapy-is-right-for-you
• https://www.medicalnewstoday.com/articles/277177
• https://www.cancer.org/cancer/thyroid-cancer/treating/thyroid-hormone-therapy.html
• https://www.webmd.com/women/picture-of-the-thyroid
• https://www.womenshealth.gov/a-z-topics/thyroid-disease
• https://www.thyroid.org/thyroid-hormone-treatment/
• https://www.nhs.uk/conditions/underactive-thyroid-hypothyroidism/symptoms/

Low Estrogen Symptoms/Estrogen Hormone is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen or estradiol is the most common form of estrogen hormone for FDA-approved treatment as hormone replacement therapy (HRT) in the management of symptoms associated with menopause. Furthermore, this activity will highlight the mechanism of action, adverse event profile, off-label uses, administration and dosing, monitoring, and relevant interactions pertinent for members of the interprofessional team.

Types of Estrogen Hormone

There are different types of estrogen:

• Estrone – This type of estrogen is present in the body after menopause. It is a weaker form of estrogen and one that the body can convert to other forms of estrogen, as necessary.
• Estradiol – Both males and females produce estradiol, and it is the most common type of estrogen in females during their reproductive years. Too much estradiol may result in acne, loss of sex drive, osteoporosis, and depression. Very high levels can increase the risk of uterine and breast cancer. However, low levels can result in weight gain and cardiovascular disease.
• Estriol – levels of estriol rise during pregnancy, as it helps the uterus grow and prepares the body for delivery. Estriol levels peak just before birth.

Normal estrogen levels in women

According to Mayo Medical Laboratories, the following estrone and estradiol levels are considered normal for women:

Mechanism of Action

Estrogen enters the systemic circulation as a free hormone or protein-bound, either as sex hormone-binding globulin (SHBG) or albumin. Non-protein-bound estrogen has the property to diffuse into cells freely with no regulation. The initiation of cellular physiological response to estrogen begins in the cell cytoplasm with the binding of estrogen to either alpha-estrogen receptor or beta-estrogen receptor. The activated estrogen-estrogen receptor complex then crosses into the nucleus of cells to induce transcription of DNA by binding to nucleotide sequences known as estrogen response elements (ERE) to enact a physiological response. Estrogen hormone levels in the body are regulated by the negative feedback effect of estrogen on the hypothalamus and pituitary gland. An example of negative feedback can be observed during the menstrual cycle. Estrogen metabolic activity primarily takes place within the liver hepatocytes CYP3A4 and excreted from the body in the urine.[rx][rx][rx]

The effects of estrogen on various systems of the body are described below

• Breast – Estrogen is responsible for the development of mammary gland tissue and parenchymal and stromal changes in breast tissue at puberty in females. Estrogen is also responsible for the development of mammary ducts during puberty, and during pregnancy, functions to secrete breast milk in postpartum lactation.
• Uterus – In the uterus, estrogen helps to proliferate endometrial cells in the follicular phase of the menstrual cycle, thickening the endometrial lining in preparation for pregnancy.
• Contraception – Ethinyl estradiol, an ingredient of OCPs, functions to suppress the hypothalamus release of gonadotropin-releasing hormone (GnRH) and pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in preventing ovulation during the menstrual cycle.
• Vagina – Estrogen supports the proliferation of epithelial mucosa cells of the vagina and the vulva. In the absence of estrogen, the vaginal and vulvar mucosal epithelium becomes thin and presents with symptoms of dryness known as vulvovaginal atrophy.[rx]
• Bone – During puberty, estrogen aids in the development of long bones and fusion of the epiphyseal growth plates.[rx] Estrogen protects bones by inactivating osteoclast activity, preventing osteoporosis in both estrogen-deficient and postmenopausal women.[rx]
• Cardiovascular – Estrogen affects plasma lipids by increasing high-density lipoproteins (HDL) and triglyceride levels while decreasing low-density lipoproteins (LDL) and total plasma cholesterol and reduce the risk of coronary artery disease in early use in postmenopausal women.[rx]

Indications of Estrogen Hormone

Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen is often referred to in the following structures as either estrone, estradiol, and estriol.

• According to early studies, estrogen as hormone replacement therapy for postmenopausal women showed promising benefits of decreased risk of osteoporosis, coronary arterial disease, and mortality.[rx] Later studies conducted by the Women’s Health Initiative concluded that risk was greater than the benefit of hormone replacement therapy in postmenopausal women.
• The Women’s Health Initiative ended clinical studies prematurely because of participants in the study developed an increased risk of breast cancer and coronary artery disease.[rx] Newer studies contradict the finding of the Women’s Health Initiative, with evidence of the improved quality of life and reduced risk of coronary artery disease and osteoporosis in women when women start estrogen hormone replacement therapy at the onset of menopause.[rx]
• The FDA approves of estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use with the purpose of having increase absorption and effectiveness by alteration of the estrogen chemical structure for topical or oral administration. Synthetic steroid estrogens include Ethinyl estradiol, estradiol valerate, estropipate, conjugate esterified estrogen, and quinestrol. Ethinyl estradiol is a commonly used synthetic estrogen to prevent pregnancy as a component of the oral contraceptive pill approved by the FDA.[rx] Some nonsteroidal synthetic estrogens include dienestrol, diethylstilbestrol, benzestrol, methestrol, and hexestrol.
• Conjugated estrogen therapy is indicated in the treatment of moderate to severe vasomotor symptoms due to menopause.
• Conjugated estrogen therapy is indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
• Conjugated estrogen therapy is indicated in the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
• Conjugated estrogen therapy is indicated in the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
• Conjugated estrogen therapy is indicated in the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
• The FDA approves of estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use with the purpose of having increase absorption and effectiveness by alteration of the estrogen chemical structure for topical or oral administration.

Clinically, the use of estrogen includes the following FDA-approved indications

• Primary ovarian insufficiency
• Female hypogonadism
• Symptoms associated with menopause including vulvovaginal atrophy, dyspareunia, hot flashes and night sweats, and prevention of osteoporosis
• Oral contraceptive pill (OCP) to prevent pregnancy
• Moderate acne vulgaris
• Prostate cancer with advanced forms of metastasis

Estrogen/synthetic estrogen has the following non-FDA-approved indication for polycystic ovarian syndrome for the relief of symptoms of hyperandrogenism and amenorrhea.[rx]

Contraindications of Estrogen Hormone

The following are contraindications for the use of natural estrogen and synthetic estrogen derivatives:

• Estrogen hormone receptor sensitive malignancies including breast cancer, ovarian cancer, and endometrial cancers
• Coronary arterial disease
• History of thromboembolism or thrombophlebitis
• History of hypercoagulable disease (Factor V Leiden syndrome, Protein C or Protein S deficiencies and metastatic disease)
• History of ischemic stroke
• Migraine headaches
• Seizure disorder
• History of dementia or neurocognitive disorders
• Hypertension
• Uterine leiomyomas
• Endometriosis
• Urinary incontinence
• Hyperlipidemia
• Gallbladder disease
• Liver disease
• History of tobacco use
• Estradiol use in pregnancy is classified as pregnancy risk factor category X, and the use of esterified estrogens are contraindicated for use during pregnancy

Dosage of Estrogen Hormone

Estrogen hormone therapy may be prescribed in the following combinations as either estrogen-only medication or estrogen and hormone combination medication to treat symptoms of menopause, prevention of osteoporosis, prevention of pregnancy, hypoestrogenism, and metastatic breast and advance prostate cancers.

Available Estrogen Preparations

Oral

• Estrogen: Conjugated may be prescribed in the dosage of 0.3-mg, 0.625-mg, 0.9-mg, and 1.25-mg tablets
• Estradiol may be prescribed in the dosage of 0.5-mg, 1-mg, and 2-mg tablets
• Norethindrone/Ethinyl estradiol 1.5 mg/30 mcg tablets for oral contraception

Vaginal Ring

• Combination estrogen-etonogestrel/ethinyl estradiol hormone vaginal ring for contraception: 0.12 mg/0.015 mg per day.
• Estradiol only vaginal ring for vulvovaginal atrophy: 7.5 mcg per day

Intramuscular Injection

• Estradiol valerate administered as an intramuscular injection in the dosage of 10 mg per mL, 20 mg per mL, and 40 mg per mL for vasomotor symptoms of menopause, vulvovaginal atrophy,  and hypoestrogenism. Recommendations for advanced prostate cancer palliative treatment is more than 30-mg intramuscular injection.
• Estradiol cypionate administered as an intramuscular injection in the dosage of 5 mg per mL for treatment of moderate-to-severe symptoms of menopause.

Transdermal

Available as a topical cream, topical spray, vaginal cream, vaginal tablet insert, and transdermal patch

• Estradiol topical gel (0.006%): 0.52 mg per pump
• Estradiol topical spray applied to the inner surface of the forearm: 1.53 mg per actuation
• Estradiol hemihydrate tablet for vaginal insert may be prescribed at the following dosage: 10-mcg, 25-mcg tablet
• Estrogen, conjugated vaginal cream: 0.625 mg per gram applied intravaginally
• Estradiol transdermal patches may be prescribed at the following dosage: 0.025 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day.

Estrogen Treatment: Pills

• What are they? Oral medication is the most common form of ERT. Examples are conjugated Estrogens (Premarin), estradiol (Estrace), and Estratab. Follow your doctor’s instructions for dosing. Most estrogen pills are taken once a day without food. Some have more complicated dosing schedules.
• Pros. Like other types of estrogen therapy, estrogen pills can reduce or resolve troublesome symptoms of menopause. They can also lower the risk of osteoporosis. While there are newer ways of getting ERT, oral estrogen medicines are the best-studied type of estrogen therapy.
• Cons. The risks of this type of estrogen therapy have been well-publicized. On its own, estrogen causes a slight increase in the risk of strokes, blood clots, and other problems. When combined with the hormone progestin, the risks of breast cancer and heart attack may rise as well. Oral estrogen-like any estrogen therapy — can also cause side effects. These include painful and swollen breasts, vaginal discharge, headache, and nausea.
  Because oral estrogen can be hard on the liver, people with liver damage should not take it. Instead, they should choose a different way of getting estrogen.

Side Effects of Estrogen Hormone

• Natural estrogen and synthetic estrogen may cause the following common adverse effects: breast tenderness, nausea, vomiting, bloating, stomach cramps, headaches, weight gain, hyperpigmentation of the skin, hair loss, vaginal itching, abnormal uterine bleeding also known as breakthrough bleeding, and anaphylaxis.
• Weight gain may be a reported adverse effect of the oral contraceptive pill (OCP) containing Ethinyl estradiol, but studies conducted on short-term and long-term use of OCPs resulted in no weight gain association.[rx][rx]
• More severe side effects of estrogen include hypertension, cerebrovascular accident, myocardial infarction, venous thromboembolism, pulmonary embolism, exacerbation of epilepsy, irritability, exacerbation of asthma, galactorrhea and nipple discharge, hypocalcemia, gallbladder disease, hepatic hemangioma and adenoma, pancreatitis, breast hypertrophy, endometrial hyperplasia, vaginitis, vulvovaginal candidiasis (intravaginal preparations), enlargement of uterine fibroids, and risk of cervical cancer and breast cancer.

Tell your doctor right away if you have any serious side effects, including mental, mood changes (such as depression, memory loss), breast lumps, unusual vaginal bleeding (such as spotting, breakthrough bleeding, prolonged, recurrent bleeding), increased or new vaginal irritation, itching, odor, discharge, severe stomach, abdominal pain, persistent nausea, vomiting, yellowing eyes, skin, dark urine, swelling hands, ankles, feet, increased thirst, urination.

Box Warnings

The use of estrogen without progestins increased the risk of endometrial cancer. The use of estrogen with and without progestins resulted in an increased risk of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years old) and an increased risk of invasive breast cancer in postmenopausal women (50 to 79 years old) with oral conjugated estrogens with medroxyprogesterone by studies established by the Women’s Health Initiative. The use of oral conjugated estrogens plus medroxyprogesterone acetate increased the risk of developing dementia in postmenopausal women older than 65 years of age have been established by the Women’s Health Initiative Memory Study.[rx][rx]

US Preventive Services Task Force (USPSTF) Score: D

Using estrogen-alone or combined estrogen and progestin use to prevent a chronic condition in postmenopausal women with or without a uterus is not recommended by the US Preventive Services Task Force (USPSTF).[rx]

Drug Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Some products that may interact with this drug include: aromatase inhibitors (such as anastrozole, exemestane, letrozole), fulvestrant, ospemifene, raloxifene, tamoxifen, toremifene, tranexamic acid.

This medication may interfere with certain laboratory tests (including metyrapone test), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

Why is estrogen important?

Estrogen helps bring about the physical changes that turn a girl into a woman. This time of life is called puberty. These changes include:

• Growth of the breasts
• Growth of pubic and underarm hair
• Start of menstrual cycles

Estrogen helps control the menstrual cycle and is important for childbearing.

Estrogen also has other functions

• Keeps cholesterol in control
• Protects bone health for both women and men
• Affects your brain (including mood), bones, heart, skin, and other tissues

How does estrogen work?

The ovaries, which produce a woman’s eggs, are the main source of estrogen from your body. Your adrenal glands, located at the top of each kidney, make small amounts of this hormone, so does fat tissue. Estrogen moves through your blood and acts everywhere in your body.

What can go wrong with estrogen levels?

• For many reasons, your body can make too little or too much estrogen. Or, you can take in too much estrogen, such as through birth control pills or estrogen replacement therapy. You might want to keep track of your symptoms (changes you feel) by writing them down each day. Bring this symptom journal to your doctor.

Estrogen and your menstrual cycle

• Your estrogen levels change throughout the month. They are highest in the middle of your menstrual cycle and lowest during your period. Estrogen levels drop at menopause.
• How do you know what your estrogen level is? You will need to give a blood or urine sample to test your estrogen. Ask your doctor what your test results mean.

Low Estrogen

Women

The most common reason for low estrogen in women is menopause or surgical removal of the ovaries. Symptoms of low estrogen include:

• Menstrual periods that are less frequent or that stop
• Hot flashes (suddenly feeling very warm) and/or night sweats
• Trouble sleeping
• Dryness and thinning of the vagina
• Low sexual desire
• Mood swings
• Dry skin

Some women get menstrual migraines, a bad headache right before their menstrual period, because of the drop in estrogen.

Men – Low estrogen in men can cause excess belly fat and low sexual desire.

High Estrogen in Women

Excess estrogen can lead to these problems, among others:

• Weight gain, mainly in your waist, hips, and thighs
• Menstrual problems, such as light or heavy bleeding
• Worsening of premenstrual syndrome
• Fibrocystic breasts (non-cancerous breast lumps)
• Fibroids (noncancerous tumors) in the uterus
• Fatigue
• Loss of sex drive
• Feeling depressed or anxious
• bloating
• swelling and tenderness in your breasts
• fibrocystic lumps in your breasts
• decreased sex drive
• irregular menstrual periods
• increased symptoms of premenstrual syndrome (PMS)
• mood swings
• headaches
• anxiety and panic attacks
• weight gain
• hair loss
• cold hands or feet
• trouble sleeping
• sleepiness or fatigue
• memory problems

Men. High estrogen in men can cause

• Infertility – Estrogen is partly responsible for creating healthy sperm. When estrogen levels are high, sperm levels may fall and lead to fertility issues.
• Gynecomastia – Estrogen may stimulate breast tissue growth. Men with too much estrogen may develop gynecomastia, a condition which leads to larger breasts.
• Erectile dysfunction (ED) – Men with high levels of estrogen may have difficulty getting or maintaining an erection.
• Enlarged breasts (gynecomastia)
• Poor erections
• Infertility

Monitoring

Prior to the initiation of the use of estrogen, screening should be conduct towards the patient’s risk of breast cancer, endometrial cancer, the risk of cardiovascular disease including stroke, venous thrombosis, and myocardial infarction. Patients should also be screened for hypertension before starting estrogen therapy, and patients should be continued to be monitored for the development of hypertension while taking estrogen. Routine women’s wellness exams including mammography and pap smear should be continued during the use of hormone replacement therapy with estrogen. Smoking cessation should be encouraged before the start and duration of use of OCPs due to tobacco use having an increased risk of venous thrombosis.[rx]

The Endocrine Society recommends monitoring patients’ improvement of postmenopausal symptoms while taking estrogen as hormone replacement therapy at the following intervals: first 1 to 3 months of the start of therapy, then re-evaluated at 6 to 12 months of therapy, then annually after the first year.[rx]

• https://www.ncbi.nlm.nih.gov/books/NBK538498/
• https://www.ncbi.nlm.nih.gov/books/NBK541112/
• https://www.ncbi.nlm.nih.gov/books/NBK22/
• https://www.ncbi.nlm.nih.gov/books/NBK20/
• https://www.ncbi.nlm.nih.gov/books/NBK482141/
• https://www.ncbi.nlm.nih.gov/books/NBK539692/
• https://www.ncbi.nlm.nih.gov/books/NBK537039/
• https://www.ncbi.nlm.nih.gov/books/NBK535380/
• https://www.ncbi.nlm.nih.gov/books/NBK537038/
• https://www.ncbi.nlm.nih.gov/books/NBK499850/
• https://www.ncbi.nlm.nih.gov/books/NBK537260/
• https://www.ncbi.nlm.nih.gov/books/NBK28/
• https://www.ncbi.nlm.nih.gov/books/NBK538260/
• https://en.wikipedia.org/wiki/Hormone
• https://medlineplus.gov/hormones.html
• https://www.webmd.com/menopause/guide/which-type-of-estrogen-hormone-therapy-is-right-for-you
• https://www.medicalnewstoday.com/articles/277177

Estrogen Pills/Estrogen Hormone is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen or estradiol is the most common form of estrogen hormone for FDA-approved treatment as hormone replacement therapy (HRT) in the management of symptoms associated with menopause. Furthermore, this activity will highlight the mechanism of action, adverse event profile, off-label uses, administration and dosing, monitoring, and relevant interactions pertinent for members of the interprofessional team.

Types of Estrogen Hormone

There are different types of estrogen:

• Estrone – This type of estrogen is present in the body after menopause. It is a weaker form of estrogen and one that the body can convert to other forms of estrogen, as necessary.
• Estradiol – Both males and females produce estradiol, and it is the most common type of estrogen in females during their reproductive years. Too much estradiol may result in acne, loss of sex drive, osteoporosis, and depression. Very high levels can increase the risk of uterine and breast cancer. However, low levels can result in weight gain and cardiovascular disease.
• Estriol – levels of estriol rise during pregnancy, as it helps the uterus grow and prepares the body for delivery. Estriol levels peak just before birth.

Normal estrogen levels in women

According to Mayo Medical Laboratories, the following estrone and estradiol levels are considered normal for women:

Mechanism of Action

Estrogen enters the systemic circulation as a free hormone or protein-bound, either as sex hormone-binding globulin (SHBG) or albumin. Non-protein-bound estrogen has the property to diffuse into cells freely with no regulation. The initiation of cellular physiological response to estrogen begins in the cell cytoplasm with the binding of estrogen to either alpha-estrogen receptor or beta-estrogen receptor. The activated estrogen-estrogen receptor complex then crosses into the nucleus of cells to induce transcription of DNA by binding to nucleotide sequences known as estrogen response elements (ERE) to enact a physiological response. Estrogen hormone levels in the body are regulated by the negative feedback effect of estrogen on the hypothalamus and pituitary gland. An example of negative feedback can be observed during the menstrual cycle. Estrogen metabolic activity primarily takes place within the liver hepatocytes CYP3A4 and excreted from the body in the urine.[rx][rx][rx]

The effects of estrogen on various systems of the body are described below

• Breast – Estrogen is responsible for the development of mammary gland tissue and parenchymal and stromal changes in breast tissue at puberty in females. Estrogen is also responsible for the development of mammary ducts during puberty, and during pregnancy, functions to secrete breast milk in postpartum lactation.
• Uterus – In the uterus, estrogen helps to proliferate endometrial cells in the follicular phase of the menstrual cycle, thickening the endometrial lining in preparation for pregnancy.
• Contraception – Ethinyl estradiol, an ingredient of OCPs, functions to suppress the hypothalamus release of gonadotropin-releasing hormone (GnRH) and pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in preventing ovulation during the menstrual cycle.
• Vagina – Estrogen supports the proliferation of epithelial mucosa cells of the vagina and the vulva. In the absence of estrogen, the vaginal and vulvar mucosal epithelium becomes thin and presents with symptoms of dryness known as vulvovaginal atrophy.[rx]
• Bone – During puberty, estrogen aids in the development of long bones and fusion of the epiphyseal growth plates.[rx] Estrogen protects bones by inactivating osteoclast activity, preventing osteoporosis in both estrogen-deficient and postmenopausal women.[rx]
• Cardiovascular – Estrogen affects plasma lipids by increasing high-density lipoproteins (HDL) and triglyceride levels while decreasing low-density lipoproteins (LDL) and total plasma cholesterol and reduce the risk of coronary artery disease in early use in postmenopausal women.[rx]

Indications of Estrogen Hormone

Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for the development of female sexual characteristics. Estrogen is often referred to in the following structures as either estrone, estradiol, and estriol.

• According to early studies, estrogen as hormone replacement therapy for postmenopausal women showed promising benefits of decreased risk of osteoporosis, coronary arterial disease, and mortality.[rx] Later studies conducted by the Women’s Health Initiative concluded that risk was greater than the benefit of hormone replacement therapy in postmenopausal women.
• The Women’s Health Initiative ended clinical studies prematurely because of participants in the study developed an increased risk of breast cancer and coronary artery disease.[rx] Newer studies contradict the finding of the Women’s Health Initiative, with evidence of the improved quality of life and reduced risk of coronary artery disease and osteoporosis in women when women start estrogen hormone replacement therapy at the onset of menopause.[rx]
• The FDA approves of estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use with the purpose of having increase absorption and effectiveness by alteration of the estrogen chemical structure for topical or oral administration. Synthetic steroid estrogens include Ethinyl estradiol, estradiol valerate, estropipate, conjugate esterified estrogen, and quinestrol. Ethinyl estradiol is a commonly used synthetic estrogen to prevent pregnancy as a component of the oral contraceptive pill approved by the FDA.[rx] Some nonsteroidal synthetic estrogens include dienestrol, diethylstilbestrol, benzestrol, methestrol, and hexestrol.
• Conjugated estrogen therapy is indicated in the treatment of moderate to severe vasomotor symptoms due to menopause.
• Conjugated estrogen therapy is indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
• Conjugated estrogen therapy is indicated in the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
• Conjugated estrogen therapy is indicated in the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
• Conjugated estrogen therapy is indicated in the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
• The FDA approves of estrogen for hormone replacement therapy in the treatment of symptoms of menopause. Synthetic estrogen is also available for clinical use with the purpose of having increase absorption and effectiveness by alteration of the estrogen chemical structure for topical or oral administration.

Clinically, the use of estrogen includes the following FDA-approved indications

• Primary ovarian insufficiency
• Female hypogonadism
• Symptoms associated with menopause including vulvovaginal atrophy, dyspareunia, hot flashes and night sweats, and prevention of osteoporosis
• Oral contraceptive pill (OCP) to prevent pregnancy
• Moderate acne vulgaris
• Prostate cancer with advanced forms of metastasis

Estrogen/synthetic estrogen has the following non-FDA-approved indication for polycystic ovarian syndrome for the relief of symptoms of hyperandrogenism and amenorrhea.[rx]

Contraindications of Estrogen Hormone

The following are contraindications for the use of natural estrogen and synthetic estrogen derivatives:

• Estrogen hormone receptor sensitive malignancies including breast cancer, ovarian cancer, and endometrial cancers
• Coronary arterial disease
• History of thromboembolism or thrombophlebitis
• History of hypercoagulable disease (Factor V Leiden syndrome, Protein C or Protein S deficiencies and metastatic disease)
• History of ischemic stroke
• Migraine headaches
• Seizure disorder
• History of dementia or neurocognitive disorders
• Hypertension
• Uterine leiomyomas
• Endometriosis
• Urinary incontinence
• Hyperlipidemia
• Gallbladder disease
• Liver disease
• History of tobacco use
• Estradiol use in pregnancy is classified as pregnancy risk factor category X, and the use of esterified estrogens are contraindicated for use during pregnancy

Dosage of Estrogen Hormone

Estrogen hormone therapy may be prescribed in the following combinations as either estrogen-only medication or estrogen and hormone combination medication to treat symptoms of menopause, prevention of osteoporosis, prevention of pregnancy, hypoestrogenism, and metastatic breast and advance prostate cancers.

Available Estrogen Preparations

Oral

• Estrogen: Conjugated may be prescribed in the dosage of 0.3-mg, 0.625-mg, 0.9-mg, and 1.25-mg tablets
• Estradiol may be prescribed in the dosage of 0.5-mg, 1-mg, and 2-mg tablets
• Norethindrone/Ethinyl estradiol 1.5 mg/30 mcg tablets for oral contraception

Vaginal Ring

• Combination estrogen-etonogestrel/ethinyl estradiol hormone vaginal ring for contraception: 0.12 mg/0.015 mg per day.
• Estradiol only vaginal ring for vulvovaginal atrophy: 7.5 mcg per day

Intramuscular Injection

• Estradiol valerate administered as an intramuscular injection in the dosage of 10 mg per mL, 20 mg per mL, and 40 mg per mL for vasomotor symptoms of menopause, vulvovaginal atrophy,  and hypoestrogenism. Recommendations for advanced prostate cancer palliative treatment is more than 30-mg intramuscular injection.
• Estradiol cypionate administered as an intramuscular injection in the dosage of 5 mg per mL for treatment of moderate-to-severe symptoms of menopause.

Transdermal

Available as a topical cream, topical spray, vaginal cream, vaginal tablet insert, and transdermal patch

• Estradiol topical gel (0.006%): 0.52 mg per pump
• Estradiol topical spray applied to the inner surface of the forearm: 1.53 mg per actuation
• Estradiol hemihydrate tablet for vaginal insert may be prescribed at the following dosage: 10-mcg, 25-mcg tablet
• Estrogen, conjugated vaginal cream: 0.625 mg per gram applied intravaginally
• Estradiol transdermal patches may be prescribed at the following dosage: 0.025 mg, 0.05 mg, 0.075 mg, or 0.1 mg per day.

Estrogen Treatment: Pills

• What are they? Oral medication is the most common form of ERT. Examples are conjugated Estrogens (Premarin), estradiol (Estrace), and Estratab. Follow your doctor’s instructions for dosing. Most estrogen pills are taken once a day without food. Some have more complicated dosing schedules.
• Pros. Like other types of estrogen therapy, estrogen pills can reduce or resolve troublesome symptoms of menopause. They can also lower the risk of osteoporosis. While there are newer ways of getting ERT, oral estrogen medicines are the best-studied type of estrogen therapy.
• Cons. The risks of this type of estrogen therapy have been well-publicized. On its own, estrogen causes a slight increase in the risk of strokes, blood clots, and other problems. When combined with the hormone progestin, the risks of breast cancer and heart attack may rise as well. Oral estrogen-like any estrogen therapy — can also cause side effects. These include painful and swollen breasts, vaginal discharge, headache, and nausea.
  Because oral estrogen can be hard on the liver, people with liver damage should not take it. Instead, they should choose a different way of getting estrogen.

Side Effects of Estrogen Hormone

• Natural estrogen and synthetic estrogen may cause the following common adverse effects: breast tenderness, nausea, vomiting, bloating, stomach cramps, headaches, weight gain, hyperpigmentation of the skin, hair loss, vaginal itching, abnormal uterine bleeding also known as breakthrough bleeding, and anaphylaxis.
• Weight gain may be a reported adverse effect of the oral contraceptive pill (OCP) containing Ethinyl estradiol, but studies conducted on short-term and long-term use of OCPs resulted in no weight gain association.[rx][rx]
• More severe side effects of estrogen include hypertension, cerebrovascular accident, myocardial infarction, venous thromboembolism, pulmonary embolism, exacerbation of epilepsy, irritability, exacerbation of asthma, galactorrhea and nipple discharge, hypocalcemia, gallbladder disease, hepatic hemangioma and adenoma, pancreatitis, breast hypertrophy, endometrial hyperplasia, vaginitis, vulvovaginal candidiasis (intravaginal preparations), enlargement of uterine fibroids, and risk of cervical cancer and breast cancer.

Tell your doctor right away if you have any serious side effects, including mental, mood changes (such as depression, memory loss), breast lumps, unusual vaginal bleeding (such as spotting, breakthrough bleeding, prolonged, recurrent bleeding), increased or new vaginal irritation, itching, odor, discharge, severe stomach, abdominal pain, persistent nausea, vomiting, yellowing eyes, skin, dark urine, swelling hands, ankles, feet, increased thirst, urination.

Box Warnings

The use of estrogen without progestins increased the risk of endometrial cancer. The use of estrogen with and without progestins resulted in an increased risk of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years old) and an increased risk of invasive breast cancer in postmenopausal women (50 to 79 years old) with oral conjugated estrogens with medroxyprogesterone by studies established by the Women’s Health Initiative. The use of oral conjugated estrogens plus medroxyprogesterone acetate increased the risk of developing dementia in postmenopausal women older than 65 years of age have been established by the Women’s Health Initiative Memory Study.[rx][rx]

US Preventive Services Task Force (USPSTF) Score: D

Using estrogen-alone or combined estrogen and progestin use to prevent a chronic condition in postmenopausal women with or without a uterus is not recommended by the US Preventive Services Task Force (USPSTF).[rx]

Drug Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Some products that may interact with this drug include: aromatase inhibitors (such as anastrozole, exemestane, letrozole), fulvestrant, ospemifene, raloxifene, tamoxifen, toremifene, tranexamic acid.

This medication may interfere with certain laboratory tests (including metyrapone test), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

Why is estrogen important?

Estrogen helps bring about the physical changes that turn a girl into a woman. This time of life is called puberty. These changes include:

• Growth of the breasts
• Growth of pubic and underarm hair
• Start of menstrual cycles

Estrogen helps control the menstrual cycle and is important for childbearing.

Estrogen also has other functions

• Keeps cholesterol in control
• Protects bone health for both women and men
• Affects your brain (including mood), bones, heart, skin, and other tissues

How does estrogen work?

The ovaries, which produce a woman’s eggs, are the main source of estrogen from your body. Your adrenal glands, located at the top of each kidney, make small amounts of this hormone, so does fat tissue. Estrogen moves through your blood and acts everywhere in your body.

What can go wrong with estrogen levels?

• For many reasons, your body can make too little or too much estrogen. Or, you can take in too much estrogen, such as through birth control pills or estrogen replacement therapy. You might want to keep track of your symptoms (changes you feel) by writing them down each day. Bring this symptom journal to your doctor.

Estrogen and your menstrual cycle

• Your estrogen levels change throughout the month. They are highest in the middle of your menstrual cycle and lowest during your period. Estrogen levels drop at menopause.
• How do you know what your estrogen level is? You will need to give a blood or urine sample to test your estrogen. Ask your doctor what your test results mean.

Low Estrogen

Women

The most common reason for low estrogen in women is menopause or surgical removal of the ovaries. Symptoms of low estrogen include:

• Menstrual periods that are less frequent or that stop
• Hot flashes (suddenly feeling very warm) and/or night sweats
• Trouble sleeping
• Dryness and thinning of the vagina
• Low sexual desire
• Mood swings
• Dry skin

Some women get menstrual migraines, a bad headache right before their menstrual period, because of the drop in estrogen.

Men – Low estrogen in men can cause excess belly fat and low sexual desire.

High Estrogen in Women

Excess estrogen can lead to these problems, among others:

• Weight gain, mainly in your waist, hips, and thighs
• Menstrual problems, such as light or heavy bleeding
• Worsening of premenstrual syndrome
• Fibrocystic breasts (non-cancerous breast lumps)
• Fibroids (noncancerous tumors) in the uterus
• Fatigue
• Loss of sex drive
• Feeling depressed or anxious
• bloating
• swelling and tenderness in your breasts
• fibrocystic lumps in your breasts
• decreased sex drive
• irregular menstrual periods
• increased symptoms of premenstrual syndrome (PMS)
• mood swings
• headaches
• anxiety and panic attacks
• weight gain
• hair loss
• cold hands or feet
• trouble sleeping
• sleepiness or fatigue
• memory problems

Men. High estrogen in men can cause

• Infertility – Estrogen is partly responsible for creating healthy sperm. When estrogen levels are high, sperm levels may fall and lead to fertility issues.
• Gynecomastia – Estrogen may stimulate breast tissue growth. Men with too much estrogen may develop gynecomastia, a condition which leads to larger breasts.
• Erectile dysfunction (ED) – Men with high levels of estrogen may have difficulty getting or maintaining an erection.
• Enlarged breasts (gynecomastia)
• Poor erections
• Infertility

Monitoring

Prior to the initiation of the use of estrogen, screening should be conduct towards the patient’s risk of breast cancer, endometrial cancer, the risk of cardiovascular disease including stroke, venous thrombosis, and myocardial infarction. Patients should also be screened for hypertension before starting estrogen therapy, and patients should be continued to be monitored for the development of hypertension while taking estrogen. Routine women’s wellness exams including mammography and pap smear should be continued during the use of hormone replacement therapy with estrogen. Smoking cessation should be encouraged before the start and duration of use of OCPs due to tobacco use having an increased risk of venous thrombosis.[rx]

The Endocrine Society recommends monitoring patients’ improvement of postmenopausal symptoms while taking estrogen as hormone replacement therapy at the following intervals: first 1 to 3 months of the start of therapy, then re-evaluated at 6 to 12 months of therapy, then annually after the first year.[rx]

• https://www.ncbi.nlm.nih.gov/books/NBK538498/
• https://www.ncbi.nlm.nih.gov/books/NBK541112/
• https://www.ncbi.nlm.nih.gov/books/NBK22/
• https://www.ncbi.nlm.nih.gov/books/NBK20/
• https://www.ncbi.nlm.nih.gov/books/NBK482141/
• https://www.ncbi.nlm.nih.gov/books/NBK539692/
• https://www.ncbi.nlm.nih.gov/books/NBK537039/
• https://www.ncbi.nlm.nih.gov/books/NBK535380/
• https://www.ncbi.nlm.nih.gov/books/NBK537038/
• https://www.ncbi.nlm.nih.gov/books/NBK499850/
• https://www.ncbi.nlm.nih.gov/books/NBK537260/
• https://www.ncbi.nlm.nih.gov/books/NBK28/
• https://www.ncbi.nlm.nih.gov/books/NBK538260/
• https://en.wikipedia.org/wiki/Hormone
• https://medlineplus.gov/hormones.html
• https://www.webmd.com/menopause/guide/which-type-of-estrogen-hormone-therapy-is-right-for-you
• https://www.medicalnewstoday.com/articles/277177