640
Chapter 17
A small amount of estrogen usually persists in plasma
beyond menopause, mainly from the peripheral conversion
of adrenal androgens to estrogen by aromatase, but the level
is inadequate to maintain estrogen-dependent tissues. The
breasts and genital organs gradually atrophy to a large degree.
Thinning and dryness of the vaginal epithelium can cause
sexual intercourse to be painful. Because estrogen is a potent
bone-protective hormone, signifi
cant decreases in bone mass
may occur (
osteoporosis
). This results in an increased risk of
bone fractures in postmenopausal women. The
hot fl
ashes
so
typical of menopause are periodic sudden feelings of warmth,
dilation of the skin arterioles, and marked sweating. In addi-
tion, the incidence of cardiovascular disease increases after
menopause. Women have much less coronary artery disease
than men until after menopause, when the incidence becomes
similar in both sexes, a pattern that is due to the protec-
tive effects of estrogen: estrogen exerts benefi cial actions on
plasma cholesterol and also exerts multiple direct protective
actions on vessel walls. Recent studies, however, have ques-
tioned the long-term protective effects of estrogen in the pre-
vention of heart disease.
Many of the symptoms associated with menopause as
well as the development of osteoporosis can be reduced by the
administration of estrogen. Recent studies also indicate that
estrogen use may reduce the risk of developing Alzheimer’s
disease and may also be useful in the treatment of this disease.
The desirability of administering estrogen to postmeno-
pausal women is controversial, however, because estrogen
administration increases the risk of developing uterine endome-
trial cancer and breast cancer. The increased risk of endometrial
cancer can be reduced by the administration of a progestogen
along with estrogen, but the progestogen does not infl uence
the risk of breast cancer. The progestogen only slightly lessens
estrogen’s protective effect against coronary artery disease.
Relevant to the question of hormone replacement ther-
apy (as well as to the hormonal treatment of breast and uterine
cancer) is the development of drugs (for example,
tamoxifen
)
that exert some proestrogenic and some antiestrogenic effects.
These drugs are collectively termed
selective estrogen receptor
modulators
(
SERMs
)
because they activate estrogen receptors
in certain tissues but not in others; moreover, in these latter tis-
sues SERMs act as estrogen antagonists. Obviously, the ideal
would be to have a SERM that has the pro-estrogenic effects of
protecting against osteoporosis, heart attacks, and Alzheimer’s
disease, but opposes the development of breast and uterine
cancers. What makes this type of SERM possible? One impor-
tant contributor is that there are two distinct forms of estrogen
receptors, which are affected differentially by different SERMs.
Dysmenorrhea, pregnancy sickness, infertility, and
postmenopausal osteoporosis have already been discussed.
There are several other clinical conditions that further
illustrate important physiological principles related to
reproduction.
Amenorrhea
Amenorrhea
is defi ned as a failure to have a normal
menstruation for approximately six months. The two general
types are primary amenorrhea (the failure to have a normal
menarche) and secondary amenorrhea (the loss of previously
normal menstrual cycles).
There are many reasons why a girl may fail to initiate
normal menarche. It is generally believed that a phenotypic
female who does not have the onset of menses by age 16
should be evaluated. One cause of amenorrhea, the androgen
insensitivity syndrome (testicular feminization) was discussed
in Section A of this chapter. Other possible causes of primary
amenorrhea are ovarian enzyme defects and lack of normal
pituitary function.
The most common cause of secondary amenorrhea is
pregnancy. Menstrual cycles cease after normal implantation
of the blastocyst due primarily to hCG-induced increases
in estrogen and progesterone production from the corpus
luteum, which suppress maternal pituitary gonadotropin
secretion. Another cause of secondary amenorrhea is
hyperprolactinemia
,
which occurs for similar reasons in
women as in men (discussed in the previous section). Tumors
ADDITIONAL CLINICAL EXAMPLES
of the lactotrophs of the pituitary hypersecrete prolactin,
which suppresses LH and FSH secretion. Thus, menstrual
cycles cannot continue since gonadotropin levels are low.
This is often accompanied by
galactorrhea
—inappropriate
milk production—because prolactin stimulates the mammary
gland. Hyperprolactinemia can be treated with dopamine
agonists because prolactin is primarily under the inhibitory
control of hypothalamic dopamine.
Excessive exercise and
anorexia nervosa
(self-imposed
starvation) can cause primary or secondary amenorrhea.
There are a variety of theories for why this is so. One
unifying theory is that the brain can sense a loss of body fat,
possibly via decreased leptin levels, and that this leads the
hypothalamus to cease GnRH pulses. From a teleological
view, this makes sense because pregnant women must supply
a large caloric input to the developing fetus and a lack of
body fat would indicate inadequate caloric capacity. The
prepubertal appearance of female gymnasts who have minimal
body fat indicates hypogonadism and probably amenorrhea,
which can persist for many years after menarche would
normally take place.
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia
is caused by adrenal
androgen overproduction in the fetus. It is almost always
caused by a partial defect in the ability of the fetal adrenal
gland to synthesize cortisol due to a mutation in an enzyme
in the cortisol synthetic pathway (
Figure 17–34
). The
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