Anovulation is the failure of the ovary to release ova over a period of time generally exceeding 3 months. The normal functioning ovary releases one ovum every 25—28 days. This average time between ovulation events is variable, especially during puberty and the perimenopause period.
Oligomenorrhea is defined as more than 36 days between menstrual cycles or fewer than eight cycles per year. Because menstruation is linked to ovulation, the clinical finding of oligomenorrhea correlates with oligoovulation. This predictable pattern of ovulation and menstruation is regulated by a cyclic change in hormones.
Consequently, the diagnosis of ovulation dysfunction includes the assessment of the hormones and systems involved in ovulation and not just the symptom of amenorrhea. This chapter includes a basic review of the process of ovulation and the primary mechanisms of anovulation. Anovulation is covered using a systems approach. This approach includes hypothalamic and brain, pituitary, ovarian, and systemic based anovulation, synergism of testosterone and estradiol.
Each system review includes diagnosis and treatment options. The process of ovulation To understand anovulation, one must first understand ovulation. Ovulation involves a progression of cellular changes in follicles that occur from fetal life until menopause. Primordial follicles progress to immature follicles and acquired hormone responsiveness by a process that remains unclear.
The number of granulosa cells and theca cells within each follicle increases and a follicular fluid containing hormone products is accumulated in the follicle as it progresses through the growth phase. Follicle stimulating hormone FSH is the primary gonadotropin responsible for this progression.
This allows the follicle to become more sensitive to FSH and grow more rapidly. The larger follicles recruit more theca cells, which produce androstenedione. This androgen passes through the basement membrane and is converted to estradiol by FSH driven aromatization in the increasing number of granulosa cells.
The increasing amount of estradiol produced in turn inhibits the release of FSH from the synergism of testosterone and estradiol. Without FSH, the smaller vitamins for knee and joint health that contain fewer FSH receptors are no longer stimulated to grow and instead regress, leaving the dominant follicle for ovulation. The estradiol produced further stimulates LH release from the pituitary.
When a critical level of LH is reached, ovulation occurs and the follicle rapidly changes to a corpus luteum. Progesterone, produced by the corpus luteum, increases following ovulation and inhibits LH secretion by an effect on the hypothalamus.
Several conditions of anovulation mimic the irregular GnRH pulse pattern seen in prepubescent girls further demonstrating the importance of the cyclic release of GnRH in normal ovulation. Estradiol and progesterone, synergism of testosterone and estradiol, which are produced as the dominant follicle develops, further regulate the release of GnRH. The hormone feedback and regulation of GnRH is mediated by catecholamines and endogenous opioids.
Activin augments the FSH effects on granulosa cells and suppresses androgen synthesis, allowing for follicle growth. Inhibin is produced as the follicle develops and enhances androgen synthesis in theca cells. Theca cells also respond to insulin-like growth factor II that further augments LH action. Disruption at the level of the pituitary causes reduced gonadotropin secretion. Polycystic ovary syndrome can be considered a physiologic state of anovulation that may be caused by disorder in one or synergism of testosterone and estradiol organ systems.
Systemic disease has been shown to affect ovulation as well. This chapter reviews the causes of anovulation and how to treat this common problem. Anovulation can result from disruption at any level in the hypothalamic—pituitary—ovarian HPO axis.
Consequently, categorizing the different mechanisms of anovulation logically follows a systems approach. A systems approach breaks down the causes of anovulation into four categories: It is important to remember that anovulation is affected by the health of the entire patient, therefore, some disorders can involve multiple levels of the HPO axis. Pharmacological studies have shown GnRH release is regulated directly and indirectly by endogenous opioids, catecholamines, and dopamine.
In patients with conditions of elevated endogenous opioids, treatment with naloxone blocks opioid receptors and results in a return of LH levels to normal. CRH is also produced in the amygdala. These neurons project to several limbic structures and have been shown to decrease serotonin and increase beta-endorphin production thereby decreasing GnRH release. High levels of cortisol from the adrenal glands have also been associated with high levels of CRH implicating stress in anovulation.
Stress includes physical, emotional, and nutritional changes. Reproductive status mirrors the physiologic state and the external environment.
CRH has receptors in many different tissues including ovary, endothelium, hypothalamus, and inflammatory tissues. This increases cortisol production in the adrenal glands, synergism of testosterone and estradiol. Cortisol is a glucocorticoid that acts on multiple body systems and reduces LH, estradiol, and progesterone effects. Many of the effects of glucocorticoids and CRH in a stress response involve systematically inhibiting T helper Th1 proinflammatory responses and induction of a Th2 shift.
Techniques are currently being synergism of testosterone and estradiol to reduce stress including acupuncture, yoga, and meditation. Such patients also fail to menstruate after treatment with progesterone demonstrating low estrogen levels correlating to chronic lack of gonadotropin stimulation. Such patients do respond to pulsatile GnRH treatment further identifying the hypothalamus as the main cause for anovulation.
LH pulse frequency is reduced and the interval between pulses is prolonged. This condition represents a state of GnRH resistance similar to insulin resistance. Due to the low estrogen and elevated cortisol levels, patients with FHA are at increased risk of bone loss and systemic disease. Studies have shown the impact of external factors in the environment on menstruation and consequently ovulation. Synergism of testosterone and estradiol changes are likely the result of pheromones influencing the hypothalamus, synergism of testosterone and estradiol.
Further studies note the influence of psychological state on menstruation. In patients with clinical depression, cortisol levels were found to be significantly elevated. Anorexia nervosa is an eating disorder stemming from a disordered body image resulting in malnutrition and severe weight loss, synergism of testosterone and estradiol.
Bone density loss occurs as a result of low estrogen levels. The ovulatory failure in anorexia is due to metabolic changes that occur with weight loss, while the underlying problem is psychological. Gonadotropin levels are reduced in synergism of testosterone and estradiol, as are leptin and estradiol. Leptin levels, which correlate with body fat and nutrition status, have been found to play a role in ovulation and are discussed later in this chapter.
Several findings indicate that anovulation associated with anorexia arises at the level of the hypothalamus. When exogenous GnRH is administered in a physiologic pattern the gonadotropin pulse frequency normalizes and ovulation occurs. Nutritional status and physical activity play a key role in ovulation and treatment. Anovulatory anorexics who weighed the same as ovulating anorexics were found to have higher levels of physical activity.
This syndrome is serious and carries mortal consequences. Bulimia nervosa is another eating disorder associated with anovulation. Bulimia nervosa is defined as binge eating with subsequent compensatory behavior purging and a poor body image.
Fifty per cent of bulimics have amenorrhea. Patients with bulimia are not hypoestrogenic and are at less risk for osteoporosis. However, persistently amenorrheic bulimics do have an elevated risk of endometrial cancer due to continuous estrogen stimulation of the uterus. Estrogen and progesterone effect gonadotropin release indirectly using biogenic amines as intermediaries.
Norepinephrine and epinephrine are responsible for signal transduction between the hypothalamus and the pituitary. Examples of these medications are given in Table 1. These drugs will often cause elevated LH and prolactin. FSH is generally not affected. One additional class of drugs that may affect ovulation is nonsteroidal antiinflammatory drugs NSAIDs. Preovulatory follicles produce prostaglandins in response to the LH surge.
NSAIDs block prostaglandin synthesis thereby preventing ovulation. Hormonal contraception has been associated with amenorrhea and a slow return to fertility after stopping therapy. The post-pill anovulation syndrome is historically defined as a failure to menstruate within 1 year testing and treating arthritis discontinuing hormonal contraception.
Currently there are several different vehicles for administering contraception. Current data support a similar return to fertility between most modalities. The pregnancy rate at 1 year after discontinuing combined oral contraceptive pills COCPs is the same as the pregnancy rate for people not previously taking birth control. Data are not available for continuous use oral contraception, however, synergism of testosterone and estradiol, extrapolating from implantable and intrauterine device data there were no differences in pregnancy rates after discontinuation compared to noncontraception patients.
The only modality that had a lower pregnancy rate at 1 year when compared to noncontraception users is subcutaneous depomedroxyprogesterone. In summary, pregnancy rates 1 year after stopping birth control are the same as pregnancy rates for women who do not use birth control. However, synergism of testosterone and estradiol evaluation workup should be performed in patients who have amenorrhea for more than 3—6 months after discontinuing OCPs, synergism of testosterone and estradiol.
Tumors, inflammation, and degeneration of the hypothalamus can affect ovulatory function. Generally these events will lead to a reduction in gonadotropin release from the pituitary due to the tumor compressing the pituitary stalk. When hormonally active tumors are removed, the symptoms of hormone excess rapidly improve. Hypothalamic hypogonadism can be associated with a genetic syndrome or several single gene mutations.
Follicles are seen in early stages of maturation and successful pregnancy has occurred using gonadotropin therapy. AHC gene mutation results in production of an abnormal DAX1 protein that regulates gonadotropin secretion in the hypothalamus and pituitary. Women with IHH have hypoestrogenism, amenorrhea, and low gonadotropin levels. Leptin mutations and leptin receptor mutations are another cause of IHH.