Anovulation is when the ovaries do not release an oocyte during the menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility. Ovulation happens when an ovary releases an egg in preparation for pregnancy. In some menstrual cycles, an egg does not mature, and a woman does not ovulate. This is known as anovulation. Anovulation may cause irregular menstrual cycles or no periods at all.
In addition to the alteration of menstrual periods and infertility, chronic anovulation can cause or exacerbate other long term problems, such as hyperandrogenism or osteopenia. It plays a central role in the multiple imbalances and dysfunctions of polycystic ovary syndrome. During the first two years after menarche, 50% of the menstrual cycles could be anovulatory cycles.
It is in fact possible to restore ovulation using an appropriate medication, and ovulation is successfully restored in approximately 90% of cases. The first step is the diagnosis of anovulation. The identification of anovulation is not easy; contrary to what is commonly believed, women undergoing anovulation still have (more or less) regular periods. In general, patients only notice that there is a problem once they have started trying to conceive
Anovulation occurs when an egg does not release or ovulate, from a woman’s ovaries. Chronic anovulation is a common cause of infertility. According to the National Institutes of Health, these conditions account for almost 30 percent of female infertility.
Anovulation is typical, although not always, coupled with irregular or lack of menstruation. However, with anovulatory cycles, there may be bleeding, which a woman may mistake for normal menstruation, although this would only rarely occur on a regular, monthly basis.
How ovulation works
Ovulation begins to happen when the hypothalamus (a gland in the brain) secretes gonadotropin-releasing hormone (GnRH), which then causes the pituitary gland (another gland in the brain) to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
FSH stimulates the woman’s eggs (follicles) that then make the hormone estrogen, which builds the uterine lining. Next comes the release of LH (“LH surge”), which serves to release the egg from the ovary and into the fallopian tube.
At this point, fertilization by the male’s sperm must take place within 12-24 hours, or the egg will no longer be viable. If fertilization occurs, the embryo will reach the uterus and attach to the wall of the uterus in about five days after ovulation, establishing a pregnancy.
Ovulatory disorders make up 25% of the known causes of female infertility. Oligo-ovulation or anovulation results in infertility because no oocyte will be released monthly. In the absence of an oocyte, there is no opportunity for fertilization and pregnancy. To help with treatment and further classification, the World Health Organization subdivided ovulatory disorders into four classes:
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Hypogonadotropic hypogonadal anovulation: i.e., hypothalamic amenorrhea
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Normogonadotropic normoestrogenic anovulation: i.e., polycystic ovarian syndrome (PCOS)
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Hypergonadotropic hypoestrogenic anovulation: i.e., premature ovarian failure
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Hyperprolactinemic anovulation: i.e., pituitary adenoma
Hypothalamic amenorrhea or functional hypothalamic amenorrhea (FHA) is associated with eating disorders and excessive exercise, which results in a decrease in hypothalamic GnRH secretion.[rx] The decreased caloric intake, associated weight loss, or excessive exercise leads to elevated cortisol, which causes a suppression of GnRH.[rx] The decreased or absent pulsatility of GnRH results in a decrease in the release of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), from the anterior pituitary gland. These two deficiencies result in abnormal follicle growth, anovulation, and low estrogen levels.[rx] The FSH and LH will have variations ranging from normal to low, but the ratio of the hormones will resemble that of a prepubertal female, with FSH higher than LH.[rx]
Anovulation Disorders are divided into 3 groups by the World Health Organization
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Group I Disorders – Hypothalamic failure leading to Hypogonadotropic hypogonadism which is responsible for 10% of anovulation cases.
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Examples: Kallmann Syndrome, Panhypopituitarism from apoplexy, autoimmune destruction, adenoma interference, or infections. Postpartum hemorrhage (Sheehan Syndrome) or head trauma can also cause hypothalamic failure that is irreversible or transient.[rx]
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Group II Disorders – HPO axis dysfunction which is responsible for 85% of anovulatory cases.
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The most common cause of female infertility in the United States is ovulatory dysfunction, in which a variety of hormonal factors interfere with the complex sequence of hormonal events required to trigger ovulation. Problems can occur at any point in this pathway (hypothalamus, pituitary, ovary) and can lead to failure to ovulate. The most common cause of chronic ovulatory dysfunction in the United States is Polycystic Ovarian Syndrome, or PCOS, which interferes with ovulation at multiple points.[rx]
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Polycystic Ovarian Syndrome – is considered an endocrinopathy that is the etiology for anovulatory infertility (i.e. >90% of cases). PCOS is characterized by irregular menstrual cycles secondary to anovulatory bleeding caused by friable hyperplastic endometrial tissue, hyperandrogenism, and it is associated with various metabolic derangements (i.e. hyperinsulinemia).[rx]
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It is understood, hyperandrogenism is the result of the balance-derangement between Androgen hormone levels and LH/FSH levels. The exact mechanism for how this is caused is not entirely understood, but research supports the thought that peripheral conversion of estrogen into androgens by adipose tissue is one mechanism for elevating serum androgen levels and depleting estrogen.[rx]
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Hyperinsulinemia secondary to insulin resistance is thought to play a role in PCOS. During puberty, it is common for a degree of Insulin resistance to be seen resulting from Insulin-growth factor-1 (IGF-1). This process is considered largely normal if IR is confined to glucose metabolism. In women with PCOS, IR affects multi-systems including the liver resulting in decreased sex-hormone-binding globulin (SHBG) synthesis. Reduced SHBG levels contribute to the elevation of free androgens, further deranging the hormone balance. [rx]
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Immature Hypothalamic-pituitary-ovarian Axis
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Anovulation that presents with irregular menstruation in adolescent females as a result of an immature hypothalamic-pituitary-ovarian axis can be a common, expected finding. An anovulatory pattern of menstruation can be seen during the first year after the onset of menarche and persist till 18 years-of-age. The HPO axis is believed to have reached maturation. Persistent irregularities should be further evaluated for “non-functional” causes of inoculation. [rx][rx][rx]
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Group III Disorders: Ovarian insufficiency or failure suggesting the premature depletion of oocytes as a result of genetic, iatrogenic, or acquired causes.
The World Health Organization criteria for the classification of anovulation include the determination of oligomenorrhea (menstrual cycle >35 days) or amenorrhea (menstrual cycle > 6 months) in combination with a concentration of prolactin, follicle-stimulating hormone (FSH), and estradiol (E2). The patients are classified as WHO1 (15%) – hypo-gonadotropic, hypo-estrogenic, WHO2 (80%) – normal-gonadotropic, normal-estrogenic, and WHO3 (5%) – hyper-gonadotropic, hypo-estrogenic. The vast majority of anovulation patients belong to the WHO2 group and demonstrate very heterogeneous symptoms ranging from anovulation, obesity, biochemical or clinical hyperandrogenism and insulin resistance.[rx]
Causes of Anovulation
If the ovulation process is interrupted, this results in anovulation. Ovulation is a complex process, which involves many glands and organs and for chemicals to be sequentially released. So there are many different things that can cause anovulation.
Some common causes of anovulation follow.
- Obesity – A high BMI, or body mass index, can cause a chemical imbalance to occur when there is an excess of androgens such as testosterone.
- Stress – Excessive stress or anxiety can cause GnRH, LH, and FSH to become imbalanced.
- Low body weight and/or excessive exercise – A low BMI or regular intense physical exercise can negatively impact the woman’s pituitary gland. This may cause the pituitary gland to not produce enough LH and FSH.
- Abnormalities of TSH and/or prolactin – Thyroid-stimulating hormone (TSH) and prolactin are two hormones released by the brain. Imbalances in either one of these can interfere with ovulation.
- Polycystic ovary syndrome (PCOS) – PCOS is a common disorder that affects about 1 in 10 women of childbearing age in the United States and can result in anovulation. It is considered the most common hormonal imbalance for women of reproductive age. PCOS causes the woman’s body to make an excess of male hormones, including testosterone. With those high levels of androgens (male hormones), the ovaries’ follicles containing the eggs remain small. This syndrome is marked by small, typically painless, cysts on the ovaries. Other symptoms may include acne and hirsutism, or excessive hair growth, particularly around the upper lip and chin.
- First and last periods – Anovulation and abnormal bleeding often occur when a girl first begins her menstruation. It also can occur during perimenopause, when a woman is in her mid-40s and approaching the menopause. During both of these transitional periods, anovulatory cycles are caused by hormonal imbalances.
Causes of anovulation suitable for ovulation induction treatment
| Hypothalamic |
| Low concentration of gonadotrophin-releasing hormone (hypogonadotropic hypogonadism) |
| Weight or exercise-related amenorrhoea |
| Kallman’s syndrome |
| Stress |
| Idiopathic |
| Pituitary |
| Hyperprolactinemia |
| Pituitary failure (hypogonadotropic hypogonadism) |
| Sheehan’s syndrome |
| Craniopharyngioma or hypophysectomy |
| Cerebral radiotherapy |
| Ovarian |
| Polycystic ovaries |
| Other endocrine |
| Hypothyroidism |
| Congenital adrenal hyperplasia |
Symptoms of Anovulation
Anovulation is usually associated with specific symptoms. However, it is important to note that they are not necessarily all displayed simultaneously. Amenorrhea (absence of menstruation) occurs in about 20% of women with ovulatory dysfunction. Infrequent and light menstruation occurs in about 40% of women with ovulatory dysfunction. Another potential symptom is irregular menstruation, where five or more menstrual cycles a year are five or more days shorter or longer than the length of the average cycle. The absence of mastodynia (breast pain or tenderness) occurs in about 20% of women with ovulatory problems. Also possible is increased body mass and facial hair, which is relatively easy to treat, and is often associated with PCOS, or polycystic ovary syndrome.
Associated conditions
For most women, alteration of menstrual periods is the principal indication of chronic anovulation. Ovulatory menstrual periods tend to be regular and predictable in terms of cycle length, duration and heaviness of bleeding, and other symptoms. Ovulatory periods are often accompanied by midcycle symptoms such as mittelschmerz or premenstrual symptoms. In contrast, anovulation usually manifests itself as irregularity of menstrual periods, that is, unpredictable variability of intervals, duration, or bleeding. Anovulation can also cause cessation of periods (secondary amenorrhea) or excessive bleeding (dysfunctional uterine bleeding). Mittelschmerz and premenstrual symptoms tend to be absent or reduced when a woman is anovulatory.
Becoming aware of the signs of ovulation (and monitoring your menstrual and ovulation cycles accordingly) can alert you to symptoms of ovulation dysfunction, which include:
- Irregular menstruation
- Excessive or light menstruation
- Lack of menstruation
- Lack of cervical mucus
- Irregular basal body temperature (BBT)
Diagnosis of Anovulation
Investigations for anovulation
| Investigation | When done | Interpretation |
|---|---|---|
| Progesterone | The mid-luteal phase of the cycle (for example, day 21 of the 28-day cycle or day 28 of 35-day cycle) | >30 nmol/l confirms ovulation; if 10-30 nmol/l check when sample taken in relation to cycle length |
| Follicle-stimulating hormone | Early follicular phase | >10 IU/l indicates reduced ovarian reserve; >40 IU/l indicates ovarian failure; <5 IU/l may indicate pituitary or hypothalamic problem |
| Luteinizing hormone | Early follicular phase | >10 IU/l indicates polycystic ovaries; <5 IU/l may indicate pituitary or hypothalamic problem |
| Testosterone | Any time in the cycle | >2.4 nmol/l indicates polycystic ovaries >5 nmol/l suggests congenital adrenal hyperplasia; check DHEAS and 17-OHP |
| Prolactin | Any time in cycle (but not after exercise or stress) | >1000 IU/l indicates pituitary adenoma; needs repeating |
| Thyroid-stimulating hormone | Any time in the cycle if a woman has symptoms or signs of hypothyroidism or has hyperprolactinemia | High thyroid-stimulating hormone indicates hypothyroidism |
| Transvaginal ultrasound scan | Oligomenorrhoea or amenorrhoea; raised luteinizing hormone or testosterone | Identifies polycystic ovaries |
| MRI/CT of pituitary | abcboxtIf two prolactin levels >1000 IU/l | Identifies macroadenomas |
| Karyotype | Primary amenorrhoea and premature menopause | Identifies karyotypic abnormalities—for example, Turner’s syndrome (45,X), translocations, and androgen insensitivity syndrome (46,XY) |
| Body mass index | Oligomenorrhoea or amenorrhoea | Body mass index >30 suggests polycystic ovary syndrome; body mass index <20 suggests hypogonadotropic hypogonadism |
CT=computed tomogram; DHEAS=dihydroepiandrosterone sulfate; MRI=magnetic resonance imaging scan; 17-OHP=17-hydroxyprogesterone
Treatment of Anovulation
Lifestyle changes
Lifestyle modifications can be the first step for overcoming anovulation.
- For women struggling with obesity or a high BMI, we recommend they make changes to be at a healthier weight. This can be very difficult in women with anovulation, and support such as nutritional counseling may be helpful.
- For women with a low BMI (very low body weight), nutritional counseling can also help.
- For those where significant exercise is the cause of the anovulation, modifying those habits is optimal.
- Similarly, in women with high stress help with stress management may be beneficial.
Change of weight
Women with polycystic ovary syndrome who are obese (BMI > 30Kg/m2) should be advised to lose weight[rx,rx]. Together with exercise weight loss (even as little as 5% of body mass) reduces insulin and free androgen levels[rx], resulting in improved menstrual regularity, ovulation, and pregnancy rates. If a woman is obese when she is pregnant she is more likely to miscarry. Women who are underweight (BMI < 18Kg/m2) should be encouraged to gain weight, and no infertility treatment should be offered until their body mass has returned to the lower limits of normal.
Hyperprolactinemia
Bromocryptine is safe and commonly used. Treatment should start with a dose of 1,25mg (taken with food) at night for the first fortnight and then increased to 2,5mg for another fortnight. The prolactin level should be checked, and if the level is below 1000 IU/L, the dose should be maintained. The side effects of bromocriptine (postural hypotension, nausea, vertigo, and headache) can make it unacceptable to the patient. Cabergoline and quinazoline are newer long-acting dopamine agonists with fewer side effects. Once prolactin levels have returned to below 1000 IU/L the woman.s periods should return and 70-80% of women will ovulate[rx].
Hypothyroidism
In hypothyroidism thyrotropin-releasing hormone (TRH) may stimulate prolactin secretion in addition to TSH from the anterior pituitary. Correction of hypothyroidism with thyroxine replacement allows thyroid-stimulating hormone and prolactin levels to return to normal, releasing the suppression to gonadotropin secretion and ovulation[rx].
Medical induction
Pulsatile gonadotropin-releasing hormone
Treatment with a gonadotropin-releasing hormone that is started in a specialized hospital setting may be suitable for women who have a purely hypothalamic cause for their amenorrhoea, for example, women with recovered weight related to amenorrhoea but who are still not ovulating. The woman wears a small mechanical syringe pump that can deliver a pulse of gonadotropin-releasing hormone subcutaneously every 90 minutes, and this usually leads to unifollicular ovulation. Local reactions may occur at the injection site. Conception rates are similar to those of the normal population at around 20-30% per cycle and 80-90% after 12months of use[rx].
Antiestrogen treatment: clomiphene citrate
It is now >40 years ago that Greenblatt et al first reported a new compound, the anti-estrogen MRL-41, capable of inducing ovulation for anovulatory women[rx]. Later to become as clomiphene citrate (CC) this compound has had a remarkably sustained career as the first-line treatment for women with absent or irregular ovulation due to hypothalamic-pituitary dysfunction associated with normal basal levels of endogenous estradiol (WHO II). The vast majority of these patients probably some 80% are now known to be oligo- or anovulatory due to polycystic ovary syndrome. Until the introduction of CC the only plausible treatment for these patients who wished to conceive was bilateral wedge resection of the ovaries[rx–rx].
Clomiphene contains an unequal mixture of two isomers as their citrate salts, clomiphene, and clomiphene. Zuclomiphene is much the more potent of the two for induction of ovulation, accounts for 38% of the total drug content of one tablet, and has a much longer half-life than enclomiphene, being detectable in plasma one month following its administration. Rostami-Hodjegan et al[rx] have suggested that wide variability in the metabolism of the zuclomiphene component contributes to variability in response to the drug.
Clomiphene citrate is capable of inducing a discharge of FSH from the anterior pituitary and this is often enough to reset the cycle of events leading to ovulation into motion. The release of even small amounts of FSH into the system will often induce ovulation and pregnancy in a proportion of eu-estrogenic anovulatory women. This is achieved indirectly, through the action of CC, a non-steroidal compound closely resembling an estrogen, in blocking hypothalamic estrogen receptors, signaling a lack of circulating estrogen to the hypothalamus and inducing a change in the pattern of pulsatile release of GnRH[rx,rx].
CC is given orally in a dose of 50-250mg per day for 5 days from day 2,3,4 or 5 of spontaneous or induced bleeding, starting with the lowest dose and increasing the dose in increments of 50mg/day per cycle until an anovulatory cycle is achieved. The starting day of treatment, whether on day 2 or through day 5 of the cycle, does not influence the result[rx].
Antioestrogen treatment: Clomifene
Clomifene acts by blocking oestrogen receptors in the pituitary leading to an increased production of follicle stimulating hormone, which then stimulates development of one or more dominant follicles. These drugs can be used only in conditions in which the hypothalamic-pituitary axis is functioning—for example, polycystic ovary syndrome. Ovulation induction with clomifene should be undertaken only in circumstances that allow access to ovarian ultrasound monitoring, because of the risk of multiple follicle development and the small but real risk of ovarian hyperstimulation syndrome (Royal College of Obstetricans and Gynaecologists’ guidelines, No 3). Seventy per cent of women with polycystic ovary syndrome will ovulate in response to clomifene, with a conception rate of 40-60% at six months. The incidence of twins is around 10%, and triplets 1%.
Gonadotropins
Patients remaining anovulatory [CC-resistant anovulation (CRA)] and patients failing to conceive during CC treatment [CC failure to conceive (CCF)] are generally treated with exogenous gonadotropins[rx]. Recently, it has become more accepted to treat CRA patients with a combination of CC and an insulin sensitizer before treatment with exogenous gonadotropins is started. Individual differences in the daily amount of FSH required to induce ongoing follicle growth and ovulation (the FSH response dose) have been suggested to be the main factor of hyper-responsiveness and severe complications during FSH ovulation induction‘[rx].
Metformin
Increasingly, studies report that metformin at doses of 1500 mg a day (in a similar way to weight loss) may improve menstrual regularity by reducing insulin and free testosterone concentrations in both lean and obese women with polycystic ovary syndrome who are not ovulating. However, caution is needed because metformin is not licensed for this indication, and the results of convincing trials are still awaited.
Follicle-stimulating hormone injections
Treatment with follicle-stimulating hormone is used in women with hypothalamic-pituitary causes of anovulation, and for women with polycystic ovary syndrome who have failed to respond to or conceive using clomifene. As the most serious complications of this therapy are ovarian hyperstimulation syndrome and high order multiple pregnancies, it is essential that this treatment is monitored by reproductive specialists with access to ultrasonography and tertiary care facilities.
Insulin sensitizers
The presumed central role of insulin resistance in hyperandrogenism in PCOS-rx] is the reason that insulin sensitizers were introduced in ovulation induction[rx]. Lowering insulin resistance might reduce ovarian dysfunction and improve ovarian responsiveness to FSH[rx]. This effect might be more evident in overweight and insulin-resistant PCOS patients [rx], although conflicting results have been reported. Clinically, metformin has been shown to be effective as an adjuvant of CC in CRA patients[rx]. The efficacy of metformin as first-line ovulation induction is still uncertain, as is its additional role as pretreatment or co-treatment in FSH ovulation induction. Only small studies have been performed, and this indicates that metformin cotreatment could improve ovarian response during FSH ovulation induction in anovulatory infertility patients[rx–rx]. It is suggested that metformin co-treatment in gonadotropin induction of ovulation reduces the amount of FSH needed, significantly shortens the stimulation period, and produces more non-follicular cycles.
Aromatase inhibitors
Aromatase inhibitors are a new group of drugs to join the arsenal of fertility treatments. They are orally administered, easy to use, and relatively inexpensive, with minor side effects. Anastrazole and letrozole are third-generation aromatase inhibitors that have been used for ovulatory disorders and for superovulation. To date, letrozole has been studied much more extensively than anastrozole. The data on letrozole suggests that it can be used to replace CC as the first-line treatment for women with ovulatory disorders.[rx–rx]. For superovulation, there is a trend for higher pregnancy rates with letrozole than with CC. When letrozole is added to gonadotropin regimens, it leads to less gonadotropin requirement and a pregnancy rate that is comparable to that with gonadotropin treatment. The role of aromatase inhibitors in assisted reproductive technologies remains to be seen. The ideal dose of letrozole is unknown; however, it seems that the dose of 5mg daily for five days is the most effective[rx].
Laparoscopic electrocoagulation of the ovaries (LEO)
Bilateral electrocoagulation of the ovarian surface is performed by laparoscopy. This induces endocrine changes[rx] and restoration of ovulation in most patients for one or more menstrual cycles [rx]. Similar pregnancy rates have been reported during the first year after laparoscopic electrocoagulation of the ovaries compared with gonadotropic ovulation induction[rx].
Other treatments
Bromocriptine acts in a completely different manner to the other treatments mentioned above. It does not induce ovulation but reduces the production of prolactin by the pituitary.[rx] Bromocriptine is only prescribed in cases of overproduction of prolactin (hyperprolactinemia).
Corticosteroids (usually found in anti-inflammatory drugs) can be used to treat anovulation if it is caused by an overproduction of male hormones by the adrenal glands. Corticosteroids are usually used to reduce the production of testosterone.
Several studies indicate that in some cases, a simple change in lifestyle could help patients suffering from anovulation. Consulting a nutritionist, for example, could help a young woman suffering from anorexia to put on some weight, which might restart her menstrual cycle. Conversely, a young overweight woman who manages to lose weight could also relieve the problem of anovulation (losing just 5% of body mass could be enough to restart ovulation). However, it is widely acknowledged by doctors that it is usually very difficult for PCOS patients to lose weight.
Previously, metformin was recommended as treatment for anovulation in polycystic ovary syndrome, but in the largest trial to date, comparing clomiphene with metformin, clomiphene was more effective than metformin alone.[rx] Following this study, the ESHRE/ASRM-sponsored Consensus workshop do not recommend metformin for ovulation stimulation.[rx] Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene.[rx]
References