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

The gonadotropins (LH and FSH) regulate the
growth and maturation of the graafian follicle in the
ovary and the ovarian production of estrogen and progesterone,
which exert feedback regulation on the pituitary
and hypothalamus.
Because the release of GnRH is intermittent, LH
and FSH secretion is pulsatile. The pulse frequency is
determined by the neural “clock” (Figure 40–2), termed
the hypothalamic GnRH pulse generator (Knobil,
1981), but the amount of gonadotropin released in each
pulse (i.e., the pulse amplitude) is largely controlled by
the actions of estrogens and progesterone on the pituitary.
The intermittent, pulsatile nature of hormone
release is essential for the maintenance of normal ovulatory
menstrual cycles because constant infusion of
GnRH results in a cessation of gonadotropin release
and ovarian steroid production (Chapter 38). The neuropeptide
kisspeptin-1, which is released from the
hypothalamic anteroventral periventricular nucleus and
the arcuate nucleus, may regulate GnRH pulsatility
through its G protein-coupled receptor, GPR54,
expressed in GnRH neurons. Inactivating mutations in
GPR54 have been associated with hypogonadotropic
hypogonadism (Seminara, 2006).
Although the precise mechanism that regulates the timing of
GnRH release (i.e., pulse frequency) is unclear, hypothalamic cells
appear to have an intrinsic ability to release GnRH episodically. The
overall pattern of GnRH release likely is regulated by the interplay
of intrinsic mechanism(s) and extrinsic synaptic inputs from opioid,
catecholamine, and GABAergic neurons (Figure 40–2). Ovarian
steroids, primarily progesterone, regulate the frequency of GnRH
release, but the cellular and molecular mechanisms of this regulation
are not well established. Some GnRH cells have immunoreactive
steroid receptors. Some nerve cells that synapse with GnRH
neurons also contain steroid receptors, and neighboring glial cells
may contain estrogen and progesterone receptors. Steroids may thus
directly and indirectly modulate GnRH neuronal function.
At puberty the pulse generator is activated and establishes
cyclic profiles of pituitary and ovarian hormones. Although the
mechanism of activation is not entirely established, it may involve
increases in circulating insulin-like growth factor (IGF)-1 and leptin
levels, the latter acting to inhibit neuropeptide Y (NPY) in the arcuate
nucleus to relieve an inhibitory effect on GnRH neurons.
Figure 40–3 provides a schematic diagram of the
profiles of gonadotropin and gonadal steroid levels
in the menstrual cycle. The “average” plasma levels
of LH throughout the cycle are shown in panel A of
Figure 40–3; inserts illustrate the pulsatile patterns of
LH during the proliferative and secretory phases in
more detail. The average LH levels are similar throughout
the early (follicular) and late (luteal) phases of the
cycle, but the frequency and amplitude of the LH
pulses are quite different in the two phases. This characteristic
pattern of hormone secretions results from
complex positive and negative feedback mechanisms
(Hotchkiss and Knobil, 1994).
In the early follicular phase of the cycle, (1) the pulse generator
produces bursts of neuronal activity with a frequency of about
one per hour that correspond with pulses of GnRH secretion, (2)
these cause a corresponding pulsatile release of LH and FSH from
pituitary gonadotropes, and (3) FSH in particular causes the graafian
follicle to mature and secrete estrogen. The effects of estrogens on
the pituitary are inhibitory at this time and cause the amount of LH
and FSH released from the pituitary to decline (i.e., the amplitude of
the LH pulse decreases), so gonadotropin levels gradually fall, as
seen in Figure 40–3. Inhibin, produced by the ovary, also exerts a
negative feedback to selectively decrease serum FSH at this time
(Chapter 38). Activin and follistatin, two other peptides released
from the ovary, may also regulate FSH production and secretion to
a lesser extent, although their levels do not vary appreciably during
the menstrual cycle.
At mid-cycle, serum estradiol rises above a threshold level of
150-200 pg/mL for ~36 hours. This sustained elevation of estrogen
no longer inhibits gonadotropin release but exerts a brief positive
feedback effect on the pituitary to trigger the preovulatory surge of
LH and FSH. This effect primarily involves a change in pituitary
responsiveness to GnRH. In some species, estrogens may also exert
a positive effect on hypothalamic neurons that contributes to a midcycle
“surge” of GnRH release; this is not yet established in humans.
Progesterone may contribute to the mid-cycle LH surge.
The mid-cycle surge in gonadotropins stimulates follicular
rupture and ovulation within 1-2 days. The ruptured follicle then
develops into the corpus luteum, which produces large amounts of
progesterone and lesser amounts of estrogen under the influence of
LH during the second half of the cycle. In the absence of pregnancy,
the corpus luteum ceases to function, steroid levels drop, and menstruation
occurs. When steroid levels drop, the pulse generator
reverts to a firing pattern characteristic of the follicular phase, the
entire system then resets, and a new ovarian cycle occurs.
Regulation of the frequency and amplitude of gonadotropin
secretions by steroids may be summarized as follows: Estrogens act
primarily on the pituitary to control the amplitude of gonadotropin
pulses, and they may also contribute to the amplitude of GnRH
pulses secreted by the hypothalamus.
In the follicular phase of the cycle, estrogens inhibit
gonadotropin release but then have a brief mid-cycle stimulatory
action that increases the amount released and causes the LH surge.
Progesterone, acting on the hypothalamus, exerts the predominant
control of the frequency of LH release. It decreases the firing rate of
the hypothalamic pulse generator, an action thought to be mediated
largely via inhibitory opioid neurons (containing progesterone receptors)
that synapse with GnRH neurons. Progesterone also exerts a
direct effect on the pituitary to oppose the inhibitory actions of estrogens
and thus enhance the amount of LH released (i.e., to increase
the amplitude of the LH pulses). These steroid feedback effects, coupled
with the intrinsic activity of the hypothalamic GnRH pulse generator,
lead to relatively frequent LH pulses of small amplitude in
the follicular phase of the cycle, and less frequent pulses of larger
amplitude in the luteal phase. Studies in knockout mice indicate that
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CHAPTER 40
ESTROGENS AND PROGESTINS