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

1120 Gonadotropin production also is regulated by the inhibins,
which are members of the bone morphogenetic protein family of
secreted signaling proteins. Inhibin A and B are made by granulosa
cells in the ovary and Sertoli cells in the testis in response to the
gonadotropins and local growth factors (Bilezikjian et al., 2006). They
act directly in the pituitary to inhibit FSH secretion without affecting
that of LH. Inhibin A exhibits variation during the menstrual
cycle, suggesting that it acts as a dynamic regulator of FSH secretion.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Molecular and Cellular Bases of Gonadotropin Action.
The actions of LH and hCG on target tissues are mediated
by the LH receptor; those of FSH are mediated by
the FSH receptor. Both of these GPCRs have large glycosylated
extracellular domains that contribute to their
affinity and specificity for their ligands. The FSH and
LH receptors couple to G sa
to activate the adenylyl
cyclase/cyclic AMP pathway. At higher ligand concentrations,
the agonist-occupied gonadotropin receptors
also activate PKC and Ca 2+ signaling pathways via G q
-
mediated effects on PLCβ. Because most, if not all,
actions of the gonadotropins can be mimicked by cyclic
AMP analogs, the precise physiological role of Ca 2+ and
PKC in gonadotropin action remains to be determined.
Physiological Effects of Gonadotropins. In men, LH
acts on testicular Leydig cells to stimulate the de novo
synthesis of androgens, primarily testosterone, from
cholesterol. Testosterone is required for gametogenesis
within the seminiferous tubules and for maintenance of
libido and secondary sexual characteristics (Chapter 41).
FSH acts on the Sertoli cells to stimulate the production
of proteins and nutrients required for sperm
maturation.
In women, the actions of FSH and LH are more
complicated. FSH stimulates the growth of developing
ovarian follicles and induces the expression of LH
receptors on theca and granulosa cells. FSH also regulates
the expression of aromatase in granulosa cells,
thereby stimulating the production of estradiol. LH acts
on the theca cells to stimulate the de novo synthesis of
androstenedione, the major precursor of ovarian estrogens
in premenopausal women (Figure 40-1). LH also
is required for the rupture of the dominant follicle during
ovulation and for the synthesis of progesterone by
the corpus luteum.
CLINICAL DISORDERS OF THE
HYPOTHALAMIC-PITUITARY-GONADAL
AXIS
Clinical disorders of the hypothalamic-pituitary-gonadal
axis can manifest either as alterations in levels and
effects of sex steroids (hyper- or hypogonadism) or as
impaired reproduction. This section focuses on those
conditions that specifically affect the hypothalamicpituitary
components of the axis and those for which
gonadotropins are used diagnostically or therapeutically.
Deficient sex steroid production resulting from
hypothalamic or pituitary defects is termed hypogonadotropic
hypogonadism because circulating levels of
gonadotropins are either low or undetectable (Layman,
2007). Hypogonadotrophic hypogonadism in some
patients results from GnRH receptor mutations; some
of these mutations impair targeting of the GnRH
receptor to the plasma membrane of gonadotropes,
prompting efforts to develop pharmacological strategies
to correct receptor trafficking and restore function
(Conn et al., 2007). Many other disorders can impair
gonadotropin secretion, including pituitary tumors,
other genetic disorders such as Kallmann’s syndrome,
infiltrative processes such as sarcoidosis, and functional
disorders such as exercise-induced amenorrhea.
In contrast, reproductive disorders caused by
processes that directly impair gonadal function are
termed hypergonadotropic because the impaired production
of sex steroids leads to a loss of negative feedback
inhibition, thereby increasing the synthesis and
secretion of gonadotropins.
Precocious Puberty. Puberty normally is a sequential
process requiring several years over which the GnRH
neurons escape CNS inhibition and initiate pulsatile
secretion of GnRH. This stimulates the secretion of
gonadotropins and gonadal steroids, thus directing the
development of secondary sexual characteristics appropriate
for sex. Normally, the initial signs of puberty
(breast development in girls and testes enlargement in
boys) do not occur before age 8 in girls or age 9 in boys;
the initiation of sexual maturation before this time is
termed “precocious.”
Precocious puberty can be divided into processes
that lead to the premature activation of the normal
hypothalamic-pituitary-gonadal axis, termed central or
GnRH-dependent precocious puberty, and processes
that lead to peripheral production of sex steroids in a
GnRH-independent manner (Carel and Léger, 2008).
Specific etiologies of GnRH-dependent precocious
puberty include CNS tumors (including hypothalamic
hamartomas), developmental abnormalities of the CNS,
and encephalitis or other infectious processes; in most
patients and especially in girls, a specific etiology is
never defined, and patients are deemed to have an idiopathic
process. GnRH-independent precocious puberty