growth. Estrogen also stimulates production of lactogenic
receptors in mammary ductal cells and acts on the anterior
pituitary to stimulate prolactin secretion. In the presence
of prolactin or hPL, progesterone acts on the estrogen-
conditioned mammary gland to promote differentiation
of the terminal ductal buds into alveoli and, consequently,
into lobules. Synthesis and secretion of milk occur in these
lobules. Lactogenesis begins during the third trimester of
pregnancy and involves synthesis of the milk-specific pro-
teins casein, lactalbumin, and lactoglobulin. The primary
regulator of lactogenesis is prolactin, although the par-
ticipation of additional hormones is needed (i.e., insulin,
cortisol, thyroid hormone). Lactation involves release of
milk into the alveolar lumen. Lactation is inhibited by
estrogen and, thus, is held in check by the high levels of
estrogen during pregnancy; the withdrawal of estrogen
after birth triggers lactation. When lactation is unwanted
by the mother, a large amount of estrogen is administered
at the time of labor. Lactation is maintained by prolactin,
the release of which is triggered when the mother’s nipple
is stimulated (neuroendocrine reflex). Prolactin does
not stimulate the actual release of milk from the nipple
(milk let-down or milk ejection); this is brought about
by oxytocin released in response to suckling. Oxytocin
acts on myoepithelial cells, contractile cells that surround
the alveoli and ducts, and causes them to contract and
squeeze out the milk.
Mothers who nurse their infants have frequent prolactin
surges in response to suckling. During the initial
of lactation, the response amplitude of prolactin is high,
LH and LSH levels are suppressed, and ovarian steroido-
genesis is reduced. These effects are due to the antigo-
nadotropic action of elevated levels of prolactin. They have
been explained by reduced GnRH secretion by the hy-
pothalamus. This condition, which is common during the
months of lactation and usually does not persist be-
yond 9 months, is referred to as lactational amenorrhea. It
resembles the gonadal quiescence of hyperprolactinemia.
Biological Effects of Estrogens
The biological effects of estrogen are many. Estrogen is the
major determinant of female reproductive function, bone
maintenance, and cardioprotection. Its effect on the brain
includes reproductive behavior and function, learning, and
memory. The mechanism of action of estrogen in the im-
provement of cognitive function is not understood, but it
is thought that estrogen delays the onset of Alzheimer’s
disease. Estrogen is also a male hormone and has impor-
tant actions in the male urogenital tract and skeleton. The
key role of estrogen in the normal bone metabolism of
both sexes is illustrated in two human syndromes, namely,
defects in aromatase and estrogen receptor (ER). The latter
is required for the conversion of testosterone to estrogen.
Men and women with
aromatase deficiency
suffer from
osteoporosis, incomplete epiphyseal fusion and continued
linear growth in adulthood, and lack of sexual develop-
ment. Treatment with estrogen in the aromatase- deficient
patient increases bone mineral density and the epiphyseal
closure. A mutation in the ER-« gene can cause severe os-
teoporosis with unclosed epiphyses and continued linear
growth in males. An undesirable property of estrogen is its
potential carcinogenicity. Estrogen exposure increases the
risk of breast and endometrial cancer. Exposure to high-
potency estrogens (e.g., diethylstilbestrol) during embry-
onic and neonatal development results in abnormalities of
the reproductive tract and in increased incidence of repro-
ductive tract tumors. The antiestrogenic action of selective
estrogen response modifiers (e.g., tamoxifen) is used in the
treatment of breast cancer (discussed later).
The diverse actions of estrogen and its differential ef-
fects in tissues are mediated by ER-a and ER-/T The ERs
perdominantly found in the cell nucleus are transcription
factors whose action is similar to that of other steroid hor-
mones (Chapter 30). In the target cells, ER is in the inactive
state bound to heat-shock proteins. Estrogen binding to ER
releases the associated proteins and facilitates formation of
ligand-bound receptors. Receptor dimers bind to the cog-
nate DNA response elements. The overall complex, with
the recruitment of coactivators and other transcription fac-
tors, becomes an active transcriptional complex capable of
gene expression.
The dimerization of ER can involve either homo- or
heterodimers—(ER-a)2, (ER-/3)2, or ER-a/
expanding the physiological specificity and action of es-
trogen in the target tissue. Breast tumors that contain
ER are treated with selective estrogen response modifiers
(SERMs). Current assays for ER in breast tumors only
identify ER-a, but ER-a- negative, ER-/3- positive tumors
may also respond to SERM therapy.
Estradiol and FSH stimulate proliferation of
granulosa cells in recruited follicles and promote their se-
cretory function. Estradiol, with FSH, transforms the basal
subpopulation of granulosa cells (next to the basal lam-
ina) into LH-responsive granulosa cells by inducing the
synthesis of LH receptor sites. These intraovarian effects
of estradiol require high levels of the hormone locally,
which are normally achieved because of the autocrine ac-
tion of these effects. Estradiol also exerts a paracrine ef-
fect in the ovary, inhibiting CYP17 (both 17a-hydroxylase
and 17,20-lyase) activity in theca interna cells during their
luteinization. In the corpus luteum, estradiol may be the
cause of luteolysis in a nonfertile cycle, although the in-
volvement of intraluteal PGF2(/, is also implicated.
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