Hormone Replacement Therapy (HRT) is a special kind of supplementing therapy for women with hormones that lost during menopausal time or transition periods. To relieve the symptoms associated with hormonal deficiency menopause, conventional HRT includes an estrogen and progesterone component to mimic hormones created by the human ovary.

Estrogen therapies are numerous, and include those indigenous to the human ovary, for example, estradiol and estriol. Other estrogenic compounds include conjugated equine estrogen (CEE), the most commonly prescribed estrogen in the United States.

Indications and Treatment of Hormone Replacement Therapy

FDA indications, according to the Physicians Desk Reference. The indications for menopausal issues include:

  • Treatment of vasomotor symptoms of menopause
  • Treatment of genitourinary syndrome of menopause ( previously known as vaginal and vulvar atrophy)
  • Prevention of osteoporosis
  •  Amenorrhea, either primary or secondary
  •  Assisted reproductive technology treatment
  •  Endometrial hyperplasia
  •  Dysfunctional uterine bleeding
Several strategies are used to treat hormone-sensitive breast cancer:
  • Blocking ovarian function: Because the ovaries are the main source of estrogen in premenopausal women, estrogen levels in these women can be reduced by eliminating or suppressing ovarian function. Blocking ovarian function is called ovarian ablation. Ovarian ablation can be done surgically in an operation to remove the ovaries (called oophorectomy) or by treatment with radiation. This type of ovarian ablation is usually permanent. Alternatively, ovarian function can be suppressed temporarily by treatment with drugs called gonadotropin-releasing hormone (GnRH) agonists, which are also known as luteinizing hormone-releasing hormone (LHRH) agonists. By mimicking GnRH, these medicines interfere with signals that stimulate the ovaries to produce estrogen.
  • Blocking estrogen production: Drugs called aromatase inhibitors are used to block the activity of an enzyme called aromatase, which the body uses to make estrogen in the ovaries and in other tissues. Aromatase inhibitors are used primarily in postmenopausal women because the ovaries in premenopausal women produce too much aromatase for the inhibitors to block effectively. However, these drugs can be used in premenopausal women if they are given together with a drug that suppresses ovarian function. Examples of aromatase inhibitors approved by the FDA are anastrozole (Arimidex) and letrozole (Femara), both of which temporarily inactivate aromatase, and exemestane (Aromasin), which permanently inactivates aromatase.
  • Blocking estrogen’s effects: Several types of drugs interfere with estrogen’s ability to stimulate the growth of breast cancer cells:
  • Selective estrogen receptor modulators (SERMs) bind to estrogen receptors, preventing estrogen from binding. Examples of SERMs approved by the FDA for the treatment of breast cancer are tamoxifen (Nolvadex) and toremifene (Fareston).
  • Other antiestrogen drugs, such as fulvestrant (Faslodex), work in a somewhat different way to block estrogen’s effects. Like SERMs, fulvestrant binds to the estrogen receptor and functions as an estrogen blocker. However, unlike SERMs, fulvestrant does not mimic estrogen. For this reason, it is called a pure antiestrogen. In addition, when fulvestrant binds to the estrogen receptor, the receptor is targeted for destruction.

How is hormone therapy used to treat breast cancer?

There are three main ways that hormone therapy is used to treat hormone-sensitive breast cancer:

  • Adjuvant therapy for early-stage breast cancer: Tamoxifen is FDA approved for adjuvant hormone treatment of premenopausal and postmenopausal women (and men) with ER-positive early-stage breast cancer, and the aromatase inhibitors anastrozole, letrozole, and exemestane are approved for this use in postmenopausal women. Research has shown that women who receive at least 5 years of adjuvant therapy with tamoxifen after having surgery for early-stage ER-positive breast cancer have reduced risks of breast cancer recurrence, including a new breast cancer in the other breast, and reduced risk of death at 15 years [rx]. Until recently, most women who received adjuvant hormone therapy to reduce the chance of a breast cancer recurrence took tamoxifen every day for 5 years. However, with the introduction of newer hormone therapies (i.e., the aromatase inhibitors), some of which have been compared with tamoxifen in clinical trials, additional approaches to hormone therapy have become common [rx–rx, rx].
  • Treatment of advanced or metastatic breast cancer: Several types of hormone therapy are approved to treat metastatic or recurrent hormone-sensitive breast cancer. Hormone therapy is also a treatment option for ER-positive breast cancer that has come back in the breast, chest wall, or nearby lymph nodes after treatment (also called a locoregional recurrence). Two SERMs, tamoxifen and toremifene, are approved to treat metastatic breast cancer. The antiestrogen fulvestrant is approved for postmenopausal women with metastatic ER-positive breast cancer that has spread after treatment with other antiestrogens [rx]. Fulvestrant is also approved for postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer who have not previously been treated with hormone therapy [rx]. In addition, it may be used in premenopausal women who have had ovarian ablation. The aromatase inhibitors anastrozole and letrozole are approved to be given to postmenopausal women as initial therapy for metastatic or locally advanced hormone-sensitive breast cancer [rx, rx]. Both of these drugs and the aromatase inhibitor exemestane are also approved to treat postmenopausal women with advanced breast cancer whose disease has worsened after treatment with tamoxifen [rx]. Men with advanced breast cancer who are treated with an aromatase inhibitor also receive a GnRH agonist.
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Some women with advanced breast cancer are treated with a combination of hormone therapy and one of several targeted therapies:
  • Palbociclib (Ibrance) – is approved for use in combination with letrozole as initial therapy for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women. Palbociclib inhibits two cyclin-dependent kinases (CDK4 and CDK6) that appear to promote the growth of hormone-receptor-positive breast cancer cells [rx]. Palbociclib is also approved to be used in combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer whose cancer has gotten worse after treatment with another hormone therapy [rx].
  • Abemaciclib (Verzenio) – another CDK4 and CDK6 inhibitor, is approved to be used in combination with fulvestrant for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer whose disease has progressed after treatment with hormone therapy [rx]. Abemaciclib is also approved to be used alone for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer whose disease got worse after treatment with hormone therapy and previous chemotherapy given for metastatic disease [rx].
  • Ribociclib (Kisqali) – another CDK4/6 inhibitor, is approved to be used in combination with an aromatase inhibitor in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer that has not been treated with hormone therapy [rx, rx]. Ribociclib is also approved to be used in combination with fulvestrant in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer who have not been treated with hormone therapy or whose disease got worse during treatment with hormone therapy [rx].
  • Lapatinib (Tykerb) –  is approved to be used in combination with letrozole to treat hormone receptor-positive, HER2-positive metastatic breast cancer in postmenopausal women for whom hormone therapy is indicated. It is a small-molecule inhibitor of the HER2 and EGFR tyrosine kinases.
  • Alpelisib (Piqray) – is approved to treat breast cancer that is HR-positive and HER2 negative and has a mutation in the PIK3CA gene. It is used with fulvestrant to treat postmenopausal women, and men, whose breast cancer is advanced or metastatic and has gotten worse during or after treatment with hormone therapy [rx].
  • Neoadjuvant treatment of breast cancer: The use of hormone therapy to treat breast cancer to reduce tumor size before surgery (neoadjuvant therapy) has been studied in clinical trials [rx]. These trials have shown that neoadjuvant hormone therapy—in particular, with aromatase inhibitors—can be effective in reducing the size of breast tumors in postmenopausal women, but it is not yet clear how effective it is in premenopausal women.  Hormone therapy is sometimes used for the neoadjuvant treatment of HR-positive breast cancer in postmenopausal women who cannot tolerate chemotherapy or when surgery needs to be delayed.
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Contraindications of Hormone Replacement Therapy

Contraindications for oral or transdermal estrogen-based therapies include:

  • Known, suspected or history of breast cancer
  • Known or suspected history of other estrogen-based cancer, i.e., uterine cancer. Women who have had a hysterectomy and have no remaining evidence of disease are still candidates for HRT
  • Active deep venous thrombosis (DVT) or a history of DVT or pulmonary embolism (PE)
  • History of blood clotting disorder, the most common being Factor V Leiden mutation carriers
  • Active or history of arterial thrombotic diseases such as myocardial infarction or stroke
  • Chronic liver disease or dysfunction

These contraindications do not apply to transvaginal based estrogen therapies, as the serum concentration of estrogen from this route is extremely low. The North American Menopause Society (NAMS) has recommended that the black-box warning that applies to conventional HRT not be applied to transvaginal estrogen treatments.

Dosage and Administration of Hormone Replacement Therapy

There are numerous estrogen and progestogen choices, and they may be administrated orally or transdermally either through cream, patch, vaginal inserts, or subdermal pellets. Each route of administration has unique benefits and risks.

  • Oral Estrogen – Any estrogen administered orally results in increased activated protein-C resistance, increasing the risk of a blood clot. Oral estradiol also induces the hepatic formation of matrix metalloprotease 9, which decreases the formation and rupture of atherosclerotic plaque.
  • Transdermal Estrogen – Bypasses the hepatic metabolism that produces activated protein-C resistance, and the risk for blood clotting is negated. Progestin administration is usually via the oral route, although a few are available in combination with estrogen in patch forms. Progesterone is available in an oral form that can also be used vaginally for non-FDA-approved uses.

Specialized pharmacies make compounded estrogen and progesterone creams, sublingual troches, and vaginal inserts, but these are not FDA approved and are not be included in this article.

What are the side effects of Hormone Replacement Therapy?

When studying the potential adverse effects of HRT, the most referenced information in the United States comes from the Women’s Health Initiative (WHI).

  • WHI Trial – This was a multifaceted trial, including two double-blind, placebo-controlled, randomized trials of postmenopausal hormone therapy. The first arm included CEE at 0.625 mg per day with medroxyprogesterone acetate (MPA) 2.5 mg per day. The second arm studied patients who had prior hysterectomies and treated with CEE 0.625 mg only.
  • HRT and the Breast – The CEE/MPA arm was discontinued earlier than expected due to an increased incidence of invasive breast cancer of 24% (HR=1.24). The CEE only arm was not discontinued early, completed in 2004, and extended follow up of patients has continued for 11.8 years. CEE use for 5 to 9 years is associated with a statistically significant reduction in breast cancer by 23% (HR=0.77). Those in the CEE arm also had decreased mortality from breast cancer by 63% compared to those not on CEE, and 38% fewer died from all other causes after breast cancer was diagnosed.
  • HRT and the Heart – In the WHI CEE/MPA arm, the overall incidence of coronary heart disease (CHD) increased by 24% over five years of use, with the most substantial elevation in risk within the first year, with an increase of 81% (HR=1.81). This evidence requires cautious interpretation due to the following:
  • HRT and Risk of Stroke – Stroke incidence increased in both arms of the WHI trial by 31% in the CEE/MPA arm, and 39% in the CEE arm. Studies using oral estradiol are conflicted, showing a similar stroke risk, but the incidence of fatal stroke is unchanged.
  • HRT and the Risk of Venous Thromboembolism (VTE) – VTE, comprised of deep venous thrombosis and pulmonary embolism, was increased by 2-fold (HR= 2.06) in the WHI CEE/MPA arm. Transdermal estradiol does not confer the same thromboembolic risk, as is evidenced by numerous European studies. The ESTHER study from France showed an overall risk of 0.9 for a blood clot, which is a decreased risk. Subsequent studies looking at other transdermal estradiol doses and routes confirm these findings, with at least a null effect for blood-clotting risk. [rx].
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Tamoxifen

  • Risk of blood clots, especially in the lungs and legs
  • Stroke
  • Cataracts
  • Endometrial cancer and uterine sarcoma
  • Bone loss in premenopausal women, but no increased risk of fracture
  • Mood swings, depression, and loss of libido
  • In men: headaches, nausea, vomiting, skin rash, impotence, and loss of libido

Raloxifene

  • Risk of blood clots, especially in the lungs and legs
  • Stroke in certain subgroups

Ovarian suppression

  • Bone loss
  • Mood swings, depression, and loss of libido

Aromatase inhibitors

  • Risk of heart attack, angina, heart failure, and hypercholesterolemia
  • Bone loss
  • Joint pain
  • Mood swings and depression

Fulvestrant

  • Gastrointestinal symptoms, including nausea, vomiting, and constipation
  • Weakness and fatigue
  • Pain, including bone pain, back pain, musculoskeletal pain, joint pain, and in the extremities 
  • Headache
  • Hot flashes
  • Breathing problems, including painful breathing, shortness of breath, and cough
  • Loss of appetite

Can other drugs interfere with Hormone Replacement Therapy

  • Certain drugs, including several commonly prescribed antidepressants (those in the category called selective serotonin reuptake inhibitors or SSRIs), inhibit an enzyme called CYP2D6. This enzyme plays a critical role in the body’s use of tamoxifen because CYP2D6 metabolizes, or breaks down, tamoxifen into molecules, or metabolites, that are much more active than tamoxifen itself.
  • The possibility that SSRIs might, by inhibiting CYP2D6, slow the metabolism of tamoxifen and reduce its effectiveness is a concern given that as many as one-fourth of breast cancer patients experience clinical depression and may be treated with SSRIs. In addition, SSRIs are sometimes used to treat hot flashes caused by hormone therapy.
  • Many experts suggest that patients who are taking antidepressants along with tamoxifen should discuss treatment options with their doctors. For example, doctors may recommend switching from an SSRI that is a potent inhibitor of CYP2D6, such as paroxetine hydrochloride (Paxil), to one that is a weaker inhibitor, such as sertraline (Zoloft), or that has no inhibitory activity, such as venlafaxine (Effexor) or citalopram (Celexa). Or they may suggest that their postmenopausal patients take an aromatase inhibitor instead of tamoxifen.

Other medications that inhibit CYP2D6 include the following:

  • Quinidine, which is used to treat abnormal heart rhythms
  • Diphenhydramine, which is an antihistamine
  • Cimetidine, which is used to reduce stomach acid

People who are prescribed tamoxifen should discuss the use of all other medications with their doctors.

References

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