Ovarian Lifecycle

Normal Events

Ovulation Detection

Ovulation Dysfunction
  • Ovarian Dysfunction
  • Pituitary Dysfunction
  • Hypothalamic &
      CNS Dysfunction

    ¬ Polycystic Syndrome
    ¬ Anorexia Nervosa

Clinical Evaluation

Treatment Options

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The central nervous system (CNS) - hypothalamic causes for ovulatory dysfunctions include:

(1) Polycystic ovary syndrome (PCOS)
PCOS is a complex disorder of ovulation involving the CNS-hypothalamus, the pituitary gland, the adrenal glands and the ovaries. It is not clear which of these organ systems initiates the disorder. The goal for the treatment of PCOS ideally would be to treat or to prevent the initiating event. This goal has not been realized to date, and so modern management most often is directed at the restoration of ovulation with medication or surgery.

The basis for anovulation with this syndrome is hormonal. There is (1) an increase in the hypothalamic GnRH pulse frequency and amplitude, (2) a continuously elevated pituitary LH concentration (with an exaggerated LH secretion and a normal FSH secretion in response to GnRH, resulting in an increase in the circulating LH:FSH ratio to about 3:1), (3) increased circulating adrenal and ovarian androgen concentrations (testosterone, androstenedione and dehydroepiandrosterone sulfate [DHEAS]) in at least half the women, (4) decreased sex hormone binding globulin (liver protein which normally binds sex steroids such as estrogen to result in decreased bioactivity) so that bioactive forms of estrogen are increased (increased estrogen results in a decrease in FSH and may increase GnRH pulsatility to further increase LH, either of which may further elevate the LH:FSH ratio), and (5) increased ovarian inhibin secretion (inhibin specifically inhibits FSH secretion) to further suppress FSH and enhance the LH:FSH ratio. The elevation of LH and the relative abundance of LH with respect to FSH result in follicular growth that either becomes arrested in early to mid development or results in atresia (deterioration). Consequently, the ovaries become polycystic with numerous partially matured follicles.

(2) “Functional hypothalamic amenorrhea”
This refers to women with an absence of menstrual flow with no identifiable cause. The hypothalamic GnRH pulse frequency and amplitude is generally abnormal, with an absence of LH pulsatility or a reduction in LH pulse frequency. The mechanism is not clear but most likely is due to abnormal neurotransmitter regulation of GnRH. Suppression of GnRH pulsatility results in a reduction or total suppression of LH pulsatility. Infertility specialists can distinguish 2 degrees of severity, “hypothalamic pituitary dysfunction” referring to abnormalities that allow for enough ovarian follicular development and consequent estrogen production to maintain growth of the uterine lining (thought to be an estrogen level of greater than 40 pg/mL) and “hypothalamic pituitary failure” referring to abnormalities that do not allow for estrogen production by the ovarian follicles (so there would be no withdrawal flow if a progesterone challenge is given).

(3) Structural lesions
Structural lesions may mechanically interfere with the ability of hypothalamic releasing hormones (GnRH) to arrive at and act on the pituitary gland. These lesions include tumors (craniopharyngiomas are the most common associated tumor) and granulomas (tumors resulting from infection with tuberculosis or sarcoidosis). Radiologic imaging is suggested to rule out anatomic lesions in women with both low circulating estrogen and low circulating FSH concentrations.

(4) Stress
The mechanism is not entirely clear. Stress may alter CNS neurotransmitters such as opioids. Elevated opioid activity in the hypothalamus suppresses GnRH release. Suppressed GnRH will then lead to decreased FSH and LH.

An intense emotional experience is often identifiable, such as a woman leaving her family to go away to college or a death in the family. Once the intensity of the stress is decreased the menstrual cycle generally returns to its prior regularity.

(5) Strenuous exercise
Extreme exercise, especially running and swimming, may result in a loss of menstrual function. A number of studies have compared women athletes who have regular menstrual intervals with those who have no menses. The major difference found in runners related to the number of miles ran rather than any other physical parameter (such as age, weight, lean body mass). Similarly, the distance used in training for swimmers is most closely correlated to the degree of ovulatory dysfunction.

The mechanism for the suppression of FSH, LH and ovulation has not been clearly established. It may involve opioids since administration of an opioid antagonist (such as naloxone, which counteracts the action of opioids) to swimmers with ovulatory dysfunctions can result in an increase in circulating LH (whereas if given to swimmers without an apparent ovulatory dysfunction there is no change in LH).

(6) Sudden weight loss and malnutrition
The mechanism is not entirely clear. It seems to involve GnRH and the hypothalamus while sparing the pituitary gland. Most likely malnutrition affects ovulation via the brain’s neurotransmitters which are responsible for regulating GnRH secretion. Starvation diets or binge dieting can also result in ovulatory dysfunctions even in women who are not underweight.

A particularly dangerous illness associated with extreme forms of weight loss is “anorexia nervosa.” Anorexia nervosa results in death in up to 15% of afflicted women. Anorexia nervosa is associated with multiple medical problems. A physician (and the woman potentially affected by it) should attempt to establish the diagnosis of anorexia nervosa early on in its clinical course and direct these patients (themselves) into potentially life sparing treatment directions.

Weight loss usually is associated with ovulatory dysfunction until the woman increases her weight to about 85% of ideal body weight. Ideal body weight is roughly 100 pounds for the first 5 feet and 5 pounds for every inch taller (so that a 5 foot 4 inch woman ideally weighs about 120 pounds).

(7) Medication or illicit drug abuse
Almost any mind altering drug can interfere with ovulation. Some of the drugs act by altering neurotransmitter function, which also affects GnRH (typically suppressing it).

Available Case Reports:

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