of testosterone within the seminiferous tubules is not met,
and spermatogenesis ceases as a result.
Progestins
A synthetic progestin,
medroxyproges-
terone acetate (Provera), has been used for male contra-
ceptive trials alone or in combination with nandrolone
(a synthetic androgen). When given once monthly for 2-3
months, the combined treatment caused azoospermia in
about one-half of the subjects.
Synthetic GnRH Agonists
Synthetic derivatives of
GnRH with more biological activity than the native hor-
mone have been used for the suppression of spermatoge-
nesis after
2
or more weeks of treatment that downregu-
lated GnRH receptors in the anterior pituitary. However, in
most trials there was no uniform induction of azoospermia,
probably because the reduction of LH and testosterone
secretion was incomplete.
Gossypol
Gossypol is a naphthaphenol present in crude
cottonseed oil that causes infertility in those who consume
it regularly, as was found to be the case during the 1950s.
Oral consumption of this agent for one month caused a
reduction in sperm count and immobilization of sperma-
tozoa, the result of the drug on the seminiferous tubule and
epididymis that affected both spermatogenesis and sperm
maturation. Leydig cell function was not affected. Aside
from symptomatic hypokalemia, the disadvantage of this
contraceptive is that its effect is not completely reversible
after cessation of treatment.
Androgen Antagonists
Cyproterone acetate and flu-
tamide have been shown to be ineffective in reducing fertil-
ity in men, primarily because their effects on the neuroen-
docrine system override any intratesticular effects they
may exert. Thus, the increase in LH and FSH caused by
these antiandrogens stimulates increased testosterone pro-
duction by the Leydig cells leading to a compensatory in-
crease in intratesticular androgen. Both spironolactone (a
mineralocorticoid receptor antagonist) and cimetidine (an
H
2
blocker) interfere with androgen effects in the testes,
and may cause a reduction in sperm count in those who
are treated with either drug on a chronic basis. However,
the effect is mild and completely reversible.
790
34.2 Ovaries
Menstrual Cycle
The menstrual cycle consists of the
follicular phase
and
the
luteal phase,
each lasting about 2 weeks. The follicu-
lar phase is a period of ovarian follicular growth (follicu-
logenesis) that results in ovulation (release of secondary
oocyte). This phase is dominated by estrogen produced by
the growing follicle itself. During the follicular phase, the
uterine endometrium is stimulated by estrogen to prolifer-
ate and to synthesize cytosolic receptors for progesterone.
Follicular production of estrogen depends on FSH and
LH. The luteal phase is progesterone-dominated. The fol-
licle that ruptures at ovulation becomes the corpus luteum,
which produces progesterone and estradiol. During this
period, the uterine endometrium becomes secretory under
the influence of progesterone. About 5 days into the luteal
phase, the endometrium is ready to accept a blastocyst
for implantation; in the absence of fertilization, however,
the corpus luteum degenerates after about
1 2
days, steroid
production ends, and the endometrium deteriorates (men-
struation). The first day of menstruation is the first day of
the menstrual cycle.
Endocrine Control of Folliculogenesis
Two types of endocrine cells are associated with the ovar-
ian follicle. One is the granulosa cell, which resides within
the follicle and is encased by the basal lamina. Like the
Sertoli cell in the testes, the granulosa cell is perfused by
plasma transudate, not blood, and possesses FSH-sensitive
aromatase activity; thus, FSH stimulates the formation
of estrogen by the granulosa cell. Unlike Sertoli cells,
however, granulosa cells proliferate in response to estro-
gen, and this proliferation is inhibited by androgens. The
nonendocrine function of granulosa cells is to promote
growth of oocytes by conditioning the follicular fluid.
The other type of follicular cell with endocrine function is
the theca interna cell. Such cells are positioned along the
outer border of the basal lamina; thus, they are located out-
side the follicle and are perfused by blood. Theca interna
cells, like Leydig cells of the testes, respond to LH with an-
drogen production from cholesterol. Unlike Leydig cells,
they produce mainly androstenedione, although some
testosterone is also produced. Theca interna cells provide
androgens for estrogen production by granulosa cells.
Hormonal Control of Follicle Growth
During the follicular phase, the ovarian follicle (preantral
follicle) grows by pronounced proliferation of granulosa
cells. During the second half of the follicular phase, the
follicle accumulates fluid, which leads to formation of an
antrum (antral follicle).
In the preantral follicle, LH stimulates the interna cells
to produce androgens (mainly androstenedione), which
diffuse through the basal lamina into the granulosa cell
compartment. The granulosa cells, under the influence
of FSH, aromatize the androgens into estrogens (mainly
estradiol), which act directly on the granulosa cells to stim-
ulate proliferation. This causes the follicle to grow and
chapter
34
Endocrine Metabolism V: Reproductive System
