SECTION 34.2
Ovaries
799
Progesterone is required for pregnancy to continue, in part
because it keeps the spiral arteries patent and promotes
maternal blood flow to the placenta. Progesterone is also
involved in the pathogenesis of endometriosis, a condition
in which endometrial tissue grows in ectopic sites (most
commonly in the peritoneal cavity); treatment with dana-
zol, a synthetic androgen that antagonizes progesterone,
reduces growth of the tissue.
Myometrium
Progesterone increases the resting mem-
brane potential of the myometrium and thereby reduces
its contractility. Progesterone antagonizes the effect of es-
trogen by inhibiting synthesis of ER and blocks PGF2a-
induced contraction of the myometrium. Accordingly, the
administration of an antiprogesterone causes a rise in
myometrial ER and increased responsiveness to PGF2a -
induced contractions. There is evidence that myometrial
contractility is promoted by the formation of gap junctions
between muscle cells; progesterone presumably inhibits
gap junction formation and therefore inhibits myometrial
contractions.
Mammary Gland
In the presence of PRL, progesterone
stimulates lobuloalveolar development in the breast of
pubertal girls, but only after the tissue has been stimu-
lated by estrogen. As discussed above, estrogen promotes
the growth of the ducts and induces the synthesis of pro-
gesterone receptors in the tubular epithelium. During the
luteal phase of the menstrual cycle and during pregnancy,
progesterone (in the presence of estrogen and PRL) stimu-
lates maximal proliferative growth of the breast mainly by
alveolar (glandular) growth. In breast cancer cells, proges-
terone reduces the formation of estrogen from androgenic
precursors but increases the production of some of the
autocrine growth factors (e.g., TGF-a).
Central Nervous System
In addition to its inhibitory ef-
fect on GnRH secretion, progesterone causes thermogen-
esis during the menstrual cycle and pregnancy. In a normal
menstrual cycle, the oral basal temperature in most women
increases by about 0.5°F around the time of ovulation and
remains elevated until shortly before the onset of menses.
In pregnant women, the oral basal temperature remains el-
evated to term. An anesthesizing and EEG-altering effect
of progesterone administered to laboratory rodents and
the increase in ventilatory drive (hyperventilation) stimu-
lated by progesterone may also reflect CNS actions of the
steroid.
Immunosuppression and Antiinflammatory Effects
In
addition to its ability to suppress myometrial and endome-
trial prostaglandin formation, progesterone suppresses
T-lymphocyte proliferation, interleukin
- 8
synthesis, and
increases prostaglandin dehydrogenase activity, all of
which contribute to preventing maternal rejection of the
implanting conceptus (an allograft).
Pharmacological Enhancement of Fertility
Female infertility due to inadequate gonadotropin stimu-
lation of the ovary has been successfully treated by two
approaches:
1. Increasing gonadotropin levels by supplying
exogenous gonadotropins, and
2. Increasing gonadotropin levels by stimulating their
release from the pituitary.
Exogenous Gonadotropin Treatment
Women who are
infertile because of a deficiency in gonadotropins are given
exogenous FSH for 7-12 days to promote folliculogen-
esis followed by a single large dose of hCG to induce
ovulation. This has resulted in ovulation in a majority of
patients (~ 90%) and pregnancy in about half. However,
about 17-20% of the patients have multiple births due to
the secretion of more than one follicle.
Stimulation o f Endogenous Gonadotropin Secretion
In women who are infertile because of a neuroendocrine
system that is overly sensitive to negative estrogen feed-
back, an antiestrogen is used to reduce the intensity of the
negative feedback. By reducing the intensity of estrogen
feedback, normal gonadotropin secretion should resume
and lead to ovulation. Clomiphene (50 mg) is taken daily
for 5 days to block the estrogen effect in the neuroen-
docrine system; in a majority of patients (~80%), ovula-
tion occurs about a week later, and about 30-40% of the
women conceive. The incidence of multiple birth by this
method (~
8
%) is higher than in untreated patients (~
1
%)
but lower than with gonadotropin treatment. In some labo-
ratories that conduct
in vitro
fertilization, the two protocols
(exogenous gonadotropins and clomiphene) are combined
for a greater yield of secondary oocytes.
Pharmacological Prevention of Pregnancy
(Female Contraception)
Currently, the most effective method to prevent concep-
tion is by oral steroid hormone treatment (Figure 34-9)
to inhibit or modify the cyclic changes in endogenous
reproductive hormones. Two effective types of oral con-
traceptives are used with proven success: one to prevent
ovulation, the other to prevent implantation.
The most effective means of preventing ovulation is
by the oral administration of ovulation-inducing gonadal
steroid derivatives at dosages that will prevent cyclic
changes in LH and FSH secretion. This method has proven
to be more than 99% effective over the past 40 years
and is currently used by more than 50 million women
worldwide. The treatment protocol is of four different
types, all of which involve the use of synthetic steroid
