418 SECTION IVEndocrine & Reproductive Physiology
Female Secondary Sex Characteristics
The body changes that develop in girls at puberty—in addition
to enlargement of breasts, uterus, and vagina—are due in part to
estrogens, which are the “feminizing hormones,” and in part
simply to the absence of testicular androgens. Women have nar-
row shoulders and broad hips, thighs that converge, and arms
that diverge (wide carrying angle). This body configuration,
plus the female distribution of fat in the breasts and buttocks, is
seen also in castrate males. In women, the larynx retains its pre-
pubertal proportions and the voice stays high-pitched. Women
have less body hair and more scalp hair, and the pubic hair gen-
erally has a characteristic flat-topped pattern (female escutch-
eon). However, growth of pubic and axillary hair in both sexes
is due primarily to androgens rather than estrogens.
Other Actions
Normal women retain salt and water and gain weight just be-
fore menstruation. Estrogens cause some degree of salt and
water retention. However, aldosterone secretion is slightly ele-
vated in the luteal phase, and this also contributes to the pre-
menstrual fluid retention.
Estrogens are said to make sebaceous gland secretions more
fluid and thus to counter the effect of testosterone and inhibit
formation of comedones (“black-heads”) and acne. The liver
palms, spider angiomas, and slight breast enlargement seen in
advanced liver disease are due to increased circulating estro-
gens. The increase appears to be due to decreased hepatic
metabolism of androstenedione, making more of this andro-
gen available for conversion to estrogens.
Estrogens have a significant plasma cholesterol-lowering
action, and they rapidly produce vasodilation by increasing
the local production of NO. Their action on bone is discussed
in Chapter 23.
Mechanism of Action
There are two principal types of nuclear estrogen receptors:
estrogen receptor α (ERα) encoded by a gene on chromosome
6; and estrogen receptor β (ERβ), encoded by a gene on chro-
mosome 14. Both are members of the nuclear receptor super-
family (see Chapter 2). After binding estrogen, they form
homodimers and bind to DNA, altering its transcription.
Some tissues contain one type or the other, but overlap also
occurs, with some tissues containing both ERα and ERβ. ERα
is found primarily in the uterus, kidneys, liver, and heart,
whereas ERβ is found primarily in the ovaries, prostate, lungs,
gastrointestinal tract, hemopoietic system, and central ner-
vous system (CNS). They also form heterodimers with ERα
binding to ERβ. Male and female mice in which the gene for
ERα has been knocked out are sterile, develop osteoporosis,
and continue to grow because their epiphyses do not close.
ERβ female knockouts are infertile, but ERβ male knockouts
are fertile even though they have hyperplastic prostates and
loss of fat. Both receptors exist in isoforms and, like thyroid re-
ceptors, can bind to various activating and stimulating factors.
In some situations, ERβ can inhibit ERα transcription. Thus,
their actions are complex, multiple, and varied.
Most of the effects of estrogens are genomic, that is, due to
actions on the nucleus, but some are so rapid that it is difficult
to believe they are mediated via production of mRNAs. These
include effects on neuronal discharge in the brain and, possi-
bly, feedback effects on gonadotropin secretion. Evidence is
accumulating that these effects are mediated by cell mem-
brane receptors that appear to be structurally related to the
nuclear receptors and produce their effects by intracellular
mitogen-activated protein kinase pathways. Similar rapid
effects of progesterone, testosterone, glucocorticoids, aldos-
terone, and 1,25-dihydroxycholecalciferol may also be pro-
duced by membrane receptors.Synthetic and Environmental Estrogens
The ethinyl derivative of estradiol is a potent estrogen and,
unlike the naturally occurring estrogens, is relatively active
when given by mouth because it is resistant to hepatic metab-
olism. The activity of the naturally occurring hormones is low
when they are administered by mouth because the portal
venous drainage of the intestine carries them to the liver,
where they are inactivated before they can reach the general
circulation. Some nonsteroidal substances and a few com-
pounds found in plants have estrogenic activity. The plant es-
trogens are rarely a problem in human nutrition, but they
may cause undesirable effects in farm animals. Dioxins,
which are found in the environment and are produced by a
variety of industrial processes, can activate estrogen response
elements on genes. However, they have been reported to have
antiestrogenic as well as estrogenic effects, and their role, if
any, in the production of human disease remains a matter of
disagreement and debate.
Because natural estrogens have undesirable as well as desir-
able effects (for example, they preserve bone in osteoporosis
but can cause uterine and breast cancer), there has been an
active search for “tailor-made” estrogens that have selective
effects in humans. Two compounds, tamoxifen and ralox-
ifene, show promise in this regard. Neither combats the
symptoms of menopause, but both have the bone-preserving
effects of estradiol. In addition, tamoxifen does not stimulate
the breast, and raloxifene does not stimulate the breast or
uterus. The way the effects of these selective estrogen receptor
modulators (SERMs) are brought about is related to the com-
plexity of the estrogen receptors and hence to differences in
the way receptor–ligand complexes they form bind to DNA.Chemistry, Biosynthesis, &
Metabolism of Progesterone
Progesterone is a C 21 steroid (Figure 25–29) secreted by the
corpus luteum, the placenta, and (in small amounts) the folli-
cle. It is an important intermediate in steroid biosynthesis in
all tissues that secrete steroid hormones, and small amounts
apparently enter the circulation from the testes and adrenal