Anovulation

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.

This is the most common cause of anovulation and is thought to account for about 70% of all cases. About half the women with hormonal imbalances do not produce enough follicles to ensure the development of an ovule, possibly due to poor hormonal secretions from the pituitary gland or the hypothalamus. The pituitary gland controls most other hormonal glands in the human body. Therefore, any pituitary malfunctioning affects other glands under its influence, including the ovaries. This occurs in around 10% of cases. The mammary glands are also controlled by the pituitary gland, so lactation can also be affected. The pituitary gland is controlled by the hypothalamus. In 10% of cases, alterations in the chemical signals from the hypothalamus can easily seriously affect the ovaries.

There are other hormonal anomalies with no direct link to the ones mentioned above that can affect ovulation. For instance, women with hyper or hypo-thyroidism sometimes have ovulation problems. Thyroid dysfunction can halt ovulation by upsetting the balance of the body’s natural reproductive hormones. Polycystic ovary syndrome (also known as Stein-Leventhal syndrome) and hyperprolactinemia can also cause anovulatory cycles through hormonal imbalances.[1][2]

This accounts for around 10–15% of all cases of anovulation. The ovaries can stop working in about 5% of cases. This may be because the ovaries do not contain eggs. However, a complete blockage of the ovaries is rarely a cause of infertility. Blocked ovaries can start functioning again without a clear medical explanation. In some cases, the egg may have matured properly, but the follicle may have failed to burst (or the follicle may have burst without releasing the egg). This is called luteinised unruptured follicle syndrome (LUFS). Physical damage to the ovaries, or ovaries with multiple cysts, may affect their ability to function. This is called ovarian dystrophy. Patients who are suffering from Stein-Leventhal syndrome (also referred to as polycystic ovary syndrome, or PCOS) can also suffer from anovulation.[3] Up to 90% of cases of anovulation are caused by PCOS; this syndrome is usually hereditary.[4][5]

Weight loss or anorexia can also cause hormonal imbalance, leading to irregular ovulation (dysovulation). It is possible that this mechanism evolved to protect the mother’s health. A pregnancy where the mother is weak could pose a risk to the baby’s and mother’s health. On the other hand, excess weight can also create ovarian dysfunctions. Dr Barbieri of Harvard Medical School has indicated that cases of anovulation are quite frequent in women with a BMI (body mass index) over 27 ^kg/_m2.[6][7][8] Unfortunately, not only does excess weight have a negative impact on ovulation itself,[9] but also on treatment efficacy and outcomes of ART (assisted reproductive technique).[10][11]

Symptoms-based methods of fertility awareness may be used to detect ovulation or to determine that cycles are anovulatory. Charting of the menstrual cycle may be done by hand, or with the aid of various fertility monitors. Records of one of the primary fertility awareness signs—basal body temperature—can detect ovulation by identifying the shift in temperature which takes place after ovulation. It is said to be the most reliable way of confirming whether ovulation has occurred.[12]

Women may also use ovulation predictor kits (OPKs) which detect the increase in luteinizing hormone (LH) levels that usually indicates imminent ovulation. For some women, these devices do not detect the LH surge, or high levels of LH are a poor predictor of ovulation; this is particularly common in women with PCOS. In such cases, OPKs and those fertility monitors which are based on LH may show false results, with an increased number of false positives or false negatives. Dr Freundl from the University of Heidelberg suggests that tests which use LH as a reference often lack sensitivity and specificity.[13]

The World Health Organization criteria for classification of anovulation include the determination of oligomenorrhea (menstrual cycle >35 days) or amenorrea (menstrual cycle > 6 months) in combination with concentration of prolactin, follicle stimulating hormone (FSH) and estradiol (E2). The patients are classified as WHO1 (15%) - hypo-gonadotropic, hypo-estrogenic, WHO2 (80%) - normo-gonadotropic, normo-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.[14]

In women with polycystic ovary syndrome with anovulation, weight loss generally results in improved menstrual regularity, ovulation, and pregnancy rates.[16]

In otherwise healthy women with anovulation, ovulatory disorders may be favorably influenced by a healthy diet such as a higher consumption of monounsaturated fats rather than trans fats, vegetable rather than animal protein sources, high fat dairy, multivitamins, and iron from plants and supplements.[15]

The main alternatives for ovulation induction medications are:

• Antiestrogen, causing an inhibition of the negative feedback of estrogen on the pituitary gland, resulting in an increase in secretion of follicle-stimulating hormone. Medications in use for this effect are mainly clomifene citrate and tamoxifen (both being selective estrogen-receptor modulators), as well as letrozole (an aromatase inhibitor.[17]
• Follicle-stimulating hormone (FSH), directly stimulating the ovaries. In women with anovulation, it may be an alternative after 7 - 12 attempted cycles of pituitary feedback regimens (as evidenced by clomifene citrate), since the latter ones are less expensive and more easy to control.[18]

The standard procedure of in vitro fertilization includes controlled ovarian hyperstimulation with gonadotropins, but in larger doses, with the intention to induce development of supernumerary follicles. This is followed by transvaginal oocyte retrieval, co-incubation and then embryo transfer of a safe number of follicles, which in international guidelines is no more than two.[19]

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.[20] 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.[21] Following this study, the ESHRE/ASRM-sponsored Consensus workshop do not recommend metformin for ovulation stimulation.[22] Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene.[23]