The latter mechanism is believed to involve the formation
of catecholestrogen (
2
-hydroxyestradiol) after uptake by
the median eminence, which, because of its abundance,
competes with hypothalamic norepinephrine for inactiva-
tion by catechol-O-methyltransferase (COMT). This inac-
tivation results in a higher norepinephrine content in the
median eminence, which favors GnRH release.
The large bolus of LH released (preovulatory LH surge)
in response to positive feedback by estradiol induces ovu-
lation in about
1
day, probably by stimulation of produc-
tion of granulosa plasminogen activator, which leads to
formation of plasmin, an enzyme that may be responsible
for the digestion of the basal lamina and, consequently, for
the rupture of the follicle (ovulation).
Hormonal Control of Luteal Function
After ovulation, the granulosa cells proliferate in response
to the preovulatory LH surge, and the theca interna cells
and perifollicular blood vessels invade the cavity of the
collapsed follicle. Under the influence of LH, the granu-
losa and invasive theca cells differentiate into luteal cells,
which are characterized by their high lipid content. These
luteal cells are steroidogenic and produce large amounts
of progesterone and moderate amounts of estradiol. The
ruptured follicle thus becomes the corpus luteum. Morpho-
genesis of the corpus luteum is not complete until about
1
or 4 days after ovulation, and luteal production of pro-
gesterone and estradiol gradually increases to a maximum
about
6
or 7 days after ovulation. Thus, there is an inter-
val of about 3 days after ovulation during which levels of
circulating estradiol are reduced (Figure 34-4), and this in-
terval is required for proper transport of the ovum through
the fallopian tube into the uterus. Exposure to high levels
of estrogen during this interval would lead to expulsion of
the ovum or to blockage of ovum transport. The rise in lev-
els of progesterone and of estradiol during the first week of
the luteal phase is required for the endometrium to become
secretory in preparation for implantation and pregnancy.
The corpus luteum has a life span of about 12 days; it
can synthesize steroids autonomously without extraovar-
ian hormonal stimulation. Although the corpus luteum has
receptors for LH, release of LH (and FSH) during the luteal
phase is strongly inhibited by the potent negative feedback
effect of progesterone and estradiol. Thus, if fertilization
and implantation do not occur, the corpus luteum degen-
erates (luteolysis), and its production of progesterone and
estradiol rapidly declines (Figure 34-4). Withdrawal of
progesterone and estradiol during luteolysis results in de-
terioration of the endometrium and its shedding (men-
struation). If fertilization and implantation occur, secre-
tion of chorionic gonadotropin (hCG) (Chapter 31) by the
792
implanting blastocyst stimulates the corpus luteum to con-
tinue producing progesterone, and luteolysis is prevented.
The regularity of the menstrual cycle in women of re-
productive age can be affected by anatomical defects of
the uterus or vagina, or by functional or structural defects
in the hypothalamic-pituitary-ovarian axis that affect hor-
monal secretions. Complete cessation of menses (for more
than
6
months) is known as
amenorrhea
and a reduction in
the frequency is known as
oligomenorrhea.
Physiologic
states of amenorrhea include prepuberty, pregnancy, lac-
tation, and postmenopause. A common pathologic cause
of amenorrhea can result from a reduction in the secre-
tion of GnRH from the hypothalamic neurons into the
hypothalamic-hypophyseal portal system with a corre-
sponding reduction in the secretion of FSH and LH from
the pituitary. Decreased GnRH can occur due to weight
loss, anorexia nervosa, excessive exercise, debilitating
diseases, or psychological trauma.
Pregnancy
Human Chorionic Gonadotropin (hCG)
After fertilization of the ootid in the fallopian tube,
the zygote develops into a blastocyst by the time it en-
ters the uterine cavity (about 4 days after ovulation). By
the seventh day after ovulation, the blastocyst is com-
pletely embedded in the endometrium, and its outer tro-
phoblast has differentiated into an inner, mitotically ac-
tive cytotrophoblast and an outer, nonmitotic syncytiotro-
phoblast. The syncytiotrophoblast begins producing hCG
from about the eighth day after ovulation, and it con-
tinues producing increasing amounts of hCG until maxi-
mal levels are attained at about
6 - 8
weeks of pregnancy.
hCG stimulates the corpus luteum to continue producing
progesterone from about the eighth day after ovulation
and thus protects the corpus luteum from luteolysis. As
mentioned above, hCG promotes expression of the male
genotype in the fetus by stimulating testosterone produc-
tion by fetal Leydig cells from about the eighth week of
pregnancy. Moreover, hCG may be the stimulus for the
initial development of the fetal zone of the adrenal cor-
tex, which appears at about the sixth week. Lastly, and
perhaps most importantly, hCG stimulates steroidogen-
esis in syncytiotrophoblasts at 4—5 weeks of pregnancy
by inducing CYP11A (side chain cleavage enzyme),
3/3-hydroxysteroid dehydrogenase (3/J-HSDH/iso), and
CYP 19 (aromatase). These enzymes are critical for main-
tenance of pregnancy because the placenta assumes the
role of the ovaries as the major generator of progesterone
and estrogen after the sixth week of pregnancy.
The implantation of the fertilized ovum at a site other
than the endometrium is known as
ectopic pregnancy.
chapter
34
Endocrine Metabolism V: Reproductive System
