Anovulation

Anovulation is when the ovaries do not release an oocyte during a 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.

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 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, women only notice that there is a problem once they have started trying to conceive.

Temperature charting is a useful way of providing early clues about anovulation, and can help gynaecologists in their diagnosis.

Signs and symptoms

Anovulation is usually associated with specific symptoms. However, it is important to note that they are not necessarily all displayed simultaneously.

Associated conditions

For most women, alteration of

1. oligoovulation
   and/or anovulation
2. excess androgen activity
3. polycystic ovaries (by
   gynecologic ultrasound)^[2]

Hypothalamic causes of HA include functional hypothalamic amenorrhea (FHA) and isolated gonadotropin-releasing hormone (GnRH) deficiency.[3] Laboratory findings of low serum estradiol and low FSH are associated with the decrease in hypothalamic secretion of GnRH.^[3]

A rare form of HA that presents as primary amenorrhea can be due to a congenital deficiency of GnRH knows as idiopathic hypogonadotropic hypogonadism or, Kallmann syndrome if it is associated with anosmia.^[3] Infiltrative disease or tumors affecting the hypothalamus and pituitary can result in HA.^[3]

FHA accounts for around 10–15% of all cases of anovulation. Weight loss or anorexia can lead to FHA by causing a 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.

Primary ovarian insufficiency

POI was previously referred to as premature ovarian failure (POF) and diagnosed when menopause occurred before age 40 but occurs in only 1 percent of all women.

Hyperprolactinemia anovulation makes up 5 to 10 percent of women with anovulation. Hyperprolactinemia inhibits gonadotropin secretion by inhibiting GnRH.[5] Hyperprolactinemia can be confirmed by several measurements of serum prolactin.

Diagnosis

Fertility awareness and LH measurement

Symptoms-based methods of

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.^[2]

Classification and testing

The

Diagnosis of anovulation cause involves hormone level tests, in conjunction with an assessment of associated symptoms. A patient history and physical exam should include history of onset and pattern of oligomenorrhea or amenorrhea, signs of PCOS such as hyperandrogenism and obesity, eating disorders, causes of excessive physical or mental stress, and breast secretions.^[6][7][8] Patients with symptoms of hyperandrogenism, such as hirsutism, can be tested for serum androgen levels as well as serum total testosterone levels.^[6] A 17-hydroprogesterone test may also be conducted if congenital adrenal hyperplasia is suspected. If the differential is broad, hormone serum levels of estradiol, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), anti-Müllerian hormone (AMH), thyroid-stimulating hormone (TSH), and prolactin can be diagnostic since most causes of anovulation are hormonal imbalances.^[7][8][9] Transvaginal ultrasound may also be used to visualize polycystic ovaries.^[6]

Treatments

Treatment should be based on diagnosis of anovulation. Treatment varies based on the 4 most common causes of anovulation: polycystic ovarian syndrome (PCOS), hypogonadotropic hypogonadism (HA), primary ovarian insufficiency (POI), and hyperprolactinemia.^[10]  Importantly, semen analysis should be carried out of the XY partner to exclude severe XY factors before managing anovulatory subfertility.^[10] Overall, in healthy individuals 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.^{[4][non-primary source needed]}

Treatment for polycystic ovarian syndrome (PCOS)

Treatment for management of anovulation due to PCOS is multifaceted, including weight reduction, ovulation induction agents, insulin-sensitizing agents, gonadotrophins and ovarian drilling. In PCOS patients with overweight or obesity, weight loss is first line treatment. Studies show a reduction in weight as little of 5% by caloric restriction and increased physical activity can re-establish spontaneously ovulation and improve response to ovulation induction therapy if initiated.^[11][12] Weight loss also generally results in improved menstrual regularity and pregnancy rates in women with PCOS.^[13]

It is well recognized that insulin resistance can be part of the sequelae of PCOS and if present, contribute to anovulation. Metformin, a biguanide, is a common insulin sensitizer often given to treat women with PCOS.

The main ovulation induction medications include:

• selective estrogen-receptor modulators), as well as letrozole (an aromatase inhibitor.^[10]
• 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.^[16]

Treatment for hypogonadotropic hypogonadism (HA)

In women with hypogonadotropic hypogonadism suspicious for functional hypothalamic amenorrhea, treatment should be centered around weight gain, reducing intensity and frequency of exercise, and stress reduction with psychotherapy or counseling.^[10] Athletes and women with anorexia can have reduced GnRH pulsing due to hypothalamic dysfunction due to increased energy requirements without their needs being met calorically and severely reduced caloric intake, respectively.^[17] If anovulation persists following lifestyle modifications, ovulation can be induced with pulsatile gonadotrophin-releasing hormone (GnRH) or gonadotrophin (FSH & LH) administration.^[10]

Treatment for primary ovarian insufficiency (POI)

For women with POI that desire pregnancy, ovulation induction strategies should be avoided and assisted reproduction, such as in vitro fertilization (IVF) with donor oocytes, should be offered.^[10]

Treatment for hyperprolactinemia

For anovulatory women with hyperprolactinemia without symptoms, they can forgo treatment and continue with close follow up and medical observation.^[10] If symptoms of hyperprolactinemia are present, dopamine agonists, such as bromocriptine, are first line treatment which act by inhibiting production of prolactin by the pituitary and can shrink a prolactin-secretin lesion (i.e. prolactinoma) if present.^[18] In rare cases, endoscopic transnasal transsphenoidal surgery and radiotherapy, may be required to resect and shrink a prolactinoma if greater than 10 mm in size. Importantly, individuals should be able to conceive following normalization of serum prolactin levels and shrinking or removal of the tumor.^[10]

Other treatments