The central nervous system (CNS)-hypothalamic causes for ovulatory
* (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 results
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
* (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 in
athletes 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 additional inch (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).