Anovulation Pathophysiology

Anovulation is a condition in which the ovaries do not release eggs (ovulate) in the normal cyclic manner. This lack of ovulation results either in pregnancy or in regular menstrual periods. Ovulation failure may be caused by a variety of conditions, ranging from the hypothalamo-pituitary axis which controls egg release via the ovarian cycle, to other endocrine abnormalities, to the ovary itself.

Hypothalamo-Pituitary Causes

Hypothalamo-pituitary causes account for many cases of anovulation. In particular, stress, lack of adequate nutrition or eating disorders, and too rigorous exercise, can result in functional anovulation and amenorrhea (absence of normal menstrual periods). This is suggested by the sudden stoppage of cycles in a woman who is less than 30 years of age, without any known or identifiable disease of the hypothalamo-pituitary axis or any other endocrine gland, such as the thyroid or adrenal gland.

This group of conditions is usually characterized by low normal levels of pituitary gonadotropins and other pituitary hormones, ovarian steroids, and adrenal androgens and cortisol. They typically show a reduced pulsatile secretion of gonadotropins and ovulatory response to externally-administered gonadotropin releasing hormone (GnRH).

The primary dysfunction here is thought to be at hypothalamic level. Associated risk factors could be the abuse of sedatives and hypnotic drugs, unmarried status, life stressors, being severely underweight, having intellectual interests and previous history of irregular cycles. Many factors such as body fat, diet, exercise, stress and other unrecognized influences play a part in determining the regularity of the ovarian cycles, often via the hypothalamo-pituitary pathway.

Eating disorders such as anorexia nervosa and bulimia nervosa are at one extreme of the spectrum of hypothalamic anovulation. They are responsive to gains in body weight with correction of eating patterns, and gonadotropin secretion patterns come back to the adult pattern as they recover or when they are treated with pulsatile GnRH. Young women who lose a lot of weight also show similar changes but to a much lesser degree.

Again, extreme endurance exercise training in females can also be associated with late onset of menstrual periods, disturbances of the luteal phase and amenorrhea.

In addition, eating disorders and osteoporosis are linked with amenorrhea as the female athletic triad. This is especially common in sports which require a slim body and lower body mass, including athletics, gymnastics, and ballet dancing.

An important mediator of disrupted ovulation may be decrease in leptin levels due to dietary alterations, exercise-induced metabolic and hormonal changes, shifts in the body fat distribution and total fat to muscle ratio, and exercise-related stress. Lack of leptin, which is produced in adipose tissue, prevents pulsatile GnRH secretion from the hypothalamus, which is key to normal ovarian function.  Some studies suggest that the disturbance is maximum when women start training in strenuous exercise at a relatively young age, especially if it is not graded in intensity properly.

Stress arising from psychological and social trauma is also associated with anovulatory changes and amenorrhea. These include depression, and gonadotropin levels are low in such women, responding to GnRH but remaining low for a long time if estrogen is administered. Cortisol pulses are high, indicating a stress-related effect on the hypothalamus. Many of these women do have negative experiences in childhood, adolescence or just before the stoppage of normal periods.

Pituitary Causes

Pituitary tumors secreting prolactin may also suppress ovulation. In other women, primary hypothyroidism may lead to hyperprolactinemia. High prolactin levels cause hypothalamic suppression perhaps by dopamine-induced inhibition of pulsatile LH secretion or GnRH secretion.

Pituitary failure, as may occur following a massive postpartum hemorrhage, can lead to anovulation because of the lack of pituitary gonadotropins. Thyroid and adrenal disorders may cause pituitary suppression, and pituitary tumors may also be responsible for lack of gonadotropin secretion.

Ovarian Causes

Polycystic Ovary Syndrome

Polycystic ovary syndrome is a condition affecting approximately 5% of women in the reproductive age group. It may present as chronic anovulation with ovaries containing multiple cysts, hair growth over the face, acne and other signs of high androgens in the blood, and insulin resistance or diabetic tendencies as well as obesity in a significant percentage.

It is characterized by failure of maturation of ovarian follicles, though ovarian development appears to be normal. However, the levels of aromatase enzyme in the granulosa cells which normally surround the maturing egg seem to be lower than normal.

The lack of response to insulin is the root cause of PCOS, according to recent concepts. Insulin resistance leads to the elevated secretion of insulin which in turn acts on insulin-like growth factor-1 (IGF-1) receptors in the ovary. They in turn stimulate androgen synthesis. They also reduce the liver production of sex-hormone binding globulin (SHBG), which means that free androgen levels are raised.

Again, insulin prevents the synthesis of IGF binding protein-1 which means that more IGF is available to act on the ovary. Empirical evidence comes from the fact that reduction of weight even by 5% leads to lowering of insulin and androgen levels.

Granulosa cells also produce much higher levels of anti-Mullerian hormone (AMH) in PCOS than normal. It may be 75 times higher in PCOS with anovulation, and 20 times higher in ovulatory PCOS. It is possible that the reason for such high AMH levels is due to an intrinsic tendency of the theca cells in such women to produce androgens which promote AMH secretion.

The high levels of androgen are converted to estrogen peripherally, outside the ovary. This enhances LH secretion in the hypothalamo-pituitary unit. Too high LH levels and inhibition of FSH causes more androgen to be produced in the theca cells inside the ovary, which perpetuates the vicious cycle. Increased levels of estrogen and androgens increase fat cell number as well, which is responsible for the obesity.

Premature Ovarian Failure

Premature ovarian failure or POF is a condition in which the ovarian follicles undergo atresia before the age of 40 years, resulting in premature menopause. Many causes are known, such as reduced number of germs cells developing during fetal development, faster breakdown of germ cells, or other disorders of germ cell migration. The most important predisposing factor is genetic abnormalities. At present, these account for 15% of all cases of POF.

Other chromosomal anomalies such as Turner’s syndrome (45, XO) and androgen insensitivity syndrome (46, XY) are well-known causes of failed gonadal development, or gonadal dysgenesis. The X chromosome is vital to normal ovarian development. Absence of certain enzymes such as 17-hydroxylase and aromatase is also associated with POF.

Radiotherapy is also an established risk factor for ovarian failure, with 800 rads causing permanent failure in all women, and 400-500 rads producing permanent failure in approximately half of treated women, and a disproportionately higher percentage of older women.

Autoimmune disease is another reason for POF, and may be either primarily seen in the ovary or part of other autoimmune endocrine disorders.

Further Reading

Last Updated: Aug 23, 2018

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