ESTROGENS AND PROGESTINS IN FEMALES
gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the
release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from
the anterior pituitary. FSH and LH regulate the production of estrogen and
progesterone by the ovary. Ovarian estrogen and progesterone secretion proceed
in a cyclical manner. It is this cyclical release of estrogen and progesterone
that determines the regular hormonal changes in the uterus, vagina, and cervix
as-sociated with the menstrual cycle. Cyclical changes in blood levels of
estrogen and progesterone, together with FSH and LH, modulate the development
of ova, ovulation, and the corpus luteum in the ovary.
During the first, or follicular, phase of the menstrual
cycle, estradiol blood levels rise slowly and then fall quite rapidly.
Estradiol blood levels peak around mid-cycle (days 12–14). The midcycle
estrogen peak is thought to be important in triggering a midcycle surge of LH
and FSH secretion. Estrogens have a biphasic ef-fect on LH and FSH release,
with high levels of estro-gen at midcycle triggering LH and FSH release;
subse-quently they suppress LH and FSH secretion. This suppression is mediated
by inhibition of GnRH release from the hypothalamus.
The luteal phase of the menstrual cycle follows the LH and FSH surge
(days 14–28). The brief elevation of the LH level stimulates production of the
ovarian cor-pus luteum. The high levels of estradiol and the FSH surge at
midcycle inhibit estradiol biosynthesis by the ovarian granulosa cells. As a
consequence, during the luteal phase, estrogen production is reduced and
andro-gens produced by the ovarian thecal cells accumulate. Androgens, together
with low levels of FSH, stimulate the production of progesterone by the
granulosa cells in the corpus luteum. The menstrual cycle ends about 14 days
later with the regression of the corpus luteum and a concomitant fall in
estrogen and progesterone pro-duction. The triggering mechanism for this
regression may involve both estrogens and prostaglandins. In the event that
pregnancy occurs, human chorionic go-nadotropin secretion by the embryo
maintains the cor-pus luteum through stimulation of progesterone and es-trogen
During the follicular phase
of the menstrual cycle, one or more follicles are prepared for ovulation. FSH
and estrogens are the most important hormones for this de-velopmental process.
Complete follicular maturation cannot occur in the absence of LH. Rupture of a
mature follicle follows the midcycle peak of LH and FSH by about 24 hours. In
humans, usually one mature ovum is released per cycle. During the luteal phase
of the men-strual cycle and under the influence of LH, the ovarian granulosa
cells of the corpus luteum become vacuolated and accumulate a yellow pigment
The lining of the uterus,
that is, the endometrium, is crit-ical for implantation of the fertilized ovum.
The en-dometrium consists of a layer of epithelial cells overly-ing a layer of
vascularized stromal cells. Under the influence of estrogen and progesterone,
the endome-trium undergoes cyclical changes that prepare it for the
implantation of a fertilized ovum. The follicular phase of the menstrual cycle
also may be called the prolifera-tive
phase when referring to changes that occur in the uterus. Estrogens induce endometrial cell division and growth.
During the luteal phase, when
the uterus is exposed to high concentrations of progesterone and moderate
estradiol levels, the mitotic activity in the endometrial cells is suppressed.
The action of progesterone on the endometrium converts it from a proliferative
state to a secretory state. The epithelial cell structure assumes a more
glandular appearance. Vascularization of the stroma increases, and some stromal
cells begin to look like the decidual cells of early pregnancy. Estrogens and
progesterone are key hormones in the maintenance of pregnancy. Estriol is
produced in high concentrations by the placenta in pregnant women.
Cervical mucus is secreted by
the endocervical glands and is regulated by estrogens and progestins. Under the
influence of high levels of estrogen or pro-gesterone, the physicochemical
composition of cervical mucus may reduce sperm motility and provide a barrier
When implantation of the ovum
does not occur, es-trogen and progesterone levels fall and menstrual bleeding
ensues. The endometrial lining, but for a single layer of epithelial cells, is
Estrogens cause the growth of
the uterus, fallopian tubes, and vagina. Stimulation of proliferation of the
vaginal epithelium is checked by the cyclical exposure to progesterone during
the luteal phase in the mature female. Estrogens also are responsible for the
expres-sion of female secondary sex characteristics during pu-berty. These
include breast enlargement, the distribu-tion of body hair, body contours as
determined by subcutaneous fat deposition, and skin texture. During
development, estrogens stimulate proliferation of the ductal epithelial cells
in breast tissue. Progesterone me-diates lobuloalveolar development at the ends
of these mammary ducts. In women, cyclical changes in the breast cell
proliferation occur during the menstrual cy-cle, with the highest levels of
proliferation occurring during the luteal phase, when circulating levels of
both estrogen and progesterone are high. This has led to the idea that
progesterone, as well as estrogens, exerts mi-totic effects in adult human
breast tissue. The effects of estrogens and progesterone on breast development
are most noticeable during puberty and pregnancy.
Estrogens can stimulate the
release of growth hor-mone and exert a positive effect on nitrogen balance.
These effects contribute to the growth spurt during pu-berty. Closure of the
bone epiphyses signaling the end of long bone growth is also estrogen mediated.
Bone remodeling occurs
throughout adult life. Osteoblasts are the bone cells that are responsible for
increasing bone mass. Bone loss occurs through the ac-tivity of other bone
cells, called osteoclasts. Normal bone remodeling takes place when there is a
balance between osteoblast and osteoclast activities. Estrogens maintain bone
mass by inhibiting bone resorption by the osteoclasts. Estrogens inhibit the
production of cy-tokines by peripheral blood cells and the osteoblasts that
stimulate osteoclast activity. In postmenopausal women, declining estrogen
levels give rise to a net in-crease in osteoclast activity and loss of bone
mass re-sulting in the serious condition osteoporosis. Also, pro-gestins
antagonize loss of bone.
The high levels of estrogens
and progesterone associ-ated with pregnancy may alter liver function and
glu-cose metabolism. High circulating levels of estrogen can cause mild glucose
intolerance. Estrogens increase the synthesis of many liver proteins, including
transferrin, SHBG, corticosteroid-binding globulin, thyroid-binding globulin,
and proteins involved in blood clotting.
Estrogens lower serum
cholesterol levels by stimulating the formation of high-density lipoproteins
and reducing low-density lipoproteins. Reductions in serum albumin and
antithrombin III synthesis can occur in the pres-ence of elevated female sex
In males, estrogens stimulate
the growth of the stro-mal cells in the accessory sex organs.