DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1182 with the fetal adrenal glands, and thereafter the corpus luteum is
not essential to continued gestation. Estrogen and progesterone continue
to be secreted in large amounts by the placenta up to the time
of delivery.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
PHYSIOLOGICAL AND
PHARMACOLOGICAL ACTIONS
Neuroendocrine Actions. As discussed earlier in this
chapter, progesterone produced in the luteal phase of
the cycle has several physiological effects including
decreasing the frequency of GnRH pulses. This progesterone-mediated
decrease in GnRH pulse frequency
is critical for suppressing gonadotropin
release and resetting the hypothalamic-pituitarygonadal
axis to transition from the luteal back to the
follicular phase. Furthermore, GnRH suppression is the
major mechanism of action of progestin-containing
contraceptives.
Reproductive Tract. Progesterone decreases estrogendriven
endometrial proliferation and leads to the development
of a secretory endometrium (Figure 40–3), and
the abrupt decline in progesterone at the end of the
cycle is the main determinant of the onset of menstruation.
If the duration of the luteal phase is artificially
lengthened, either by sustaining luteal function or by
treatment with progesterone, decidual changes in the
endometrial stroma similar to those seen in early pregnancy
can be induced. Under normal circumstances,
estrogen antecedes and accompanies progesterone in its
action on the endometrium and is essential to the development
of the normal menstrual pattern.
Progesterone also influences the endocervical glands, and the
abundant watery secretion of the estrogen-stimulated structures is
changed to a scant viscid material. As noted previously, these and other
effects of progestins decrease penetration of the cervix by sperm.
The estrogen-induced maturation of the human vaginal
epithelium is modified toward the condition of pregnancy by the
action of progesterone, a change that can be detected in cytological
alterations in the vaginal smear. If the quantity of estrogen concurrently
acting is known to be adequate, or if it is assured by giving
estrogen, the cytological response to a progestin can be used to evaluate
its progestational potency.
Progesterone is very important for the maintenance of pregnancy.
Progesterone suppresses menstruation and uterine contractility,
but other effects also may be important. These effects to maintain
pregnancy led to the historical use of progestins to prevent threatened
abortion. However, such treatment is of questionable benefit,
probably because spontaneous abortion infrequently results from
diminished progesterone.
Mammary Gland. Development of the mammary gland
requires both estrogen and progesterone. During
pregnancy and to a minor degree during the luteal phase
of the cycle, progesterone, acting with estrogen, brings
about a proliferation of the acini of the mammary gland.
Toward the end of pregnancy, the acini fill with secretions
and the vasculature of the gland notably increases;
however, only after the levels of estrogen and progesterone
decrease at parturition does lactation begin.
During the normal menstrual cycle, mitotic activity in the
breast epithelium is very low in the follicular phase and then peaks in
the luteal phase. This pattern is due to progesterone, which triggers a
single round of mitotic activity in the mammary epithelium. This
effect is transient because continued exposure to the hormone is rapidly
followed by arrest of growth of the epithelial cells. Importantly,
progesterone may be responsible for the increased risk of breast cancer
associated with estrogen-progestin use in postmenopausal
women, although controlled studies with only progestin have not been
performed (Anderson et al., 2004; Rossouw et al., 2002).
Central Nervous System Effects. During a normal menstrual
cycle, an increase in basal body temperature of
~0.6°C (1°F) may be noted at mid-cycle; this correlates
with ovulation. This increase is due to progesterone, but
the exact mechanism of this effect is unknown.
Progesterone also increases the ventilatory response of
the respiratory centers to carbon dioxide and leads to
reduced arterial and alveolar PCO 2
in the luteal phase of
the menstrual cycle and during pregnancy. Progesterone
also may have depressant and hypnotic actions in the
CNS, possibly accounting for reports of drowsiness after
hormone administration. This potential untoward effect
may be abrogated by giving progesterone preparations at
bedtime, which may even help some patients sleep.
Metabolic Effects. Progestins have numerous metabolic
actions. Progesterone itself increases basal insulin levels
and the rise in insulin after carbohydrate ingestion,
but it does not normally alter glucose tolerance.
However, long-term administration of more potent progestins,
such as norgestrel, may decrease glucose tolerance.
Progesterone stimulates lipoprotein lipase activity
and seems to enhance fat deposition. Progesterone and
analogs such as MPA have been reported to increase
LDL and cause either no effects or modest reductions
in serum HDL levels. The 19-norprogestins may have
more pronounced effects on plasma lipids because of
their androgenic activity.
In this regard, a large prospective study has shown that MPA
decreases the favorable HDL increase caused by conjugated estrogens
during postmenopausal hormone replacement, but it does not
significantly affect the beneficial effect of estrogens to lower LDL.
In contrast, micronized progesterone does not significantly alter beneficial
estrogen effects on either HDL or LDL profiles (Writing