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

1118
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Hypothalamus
Anterior
pituitary
Target
tissue
Target
tissue
product
Secondary
target
tissues
Inhibin
Accessory
sex organs
GnRH
regulated by feedback effects of the gonadal hormones (Figures 38–7
and 40-2). Chapters 40 and 41 provide more detailed descriptions of
gonadotropin regulation.
TSH is measured in the diagnosis of thyroid disorders, and
recombinant TSH is used in the evaluation and treatment of welldifferentiated
thyroid cancer, as discussed in Chapter 39.
Physiology of the Gonadotropins
Structure-Function Aspects of the Gonadotropins. The
carbohydrate residues on the gonadotropins influence
their rates of clearance from the circulation, and thus
their serum half-lives, and also play a role in activating
the gonadotropin receptors. Among the gonadotropin β-
subunits, that of hCG is most divergent because it contains
a carboxy-terminal extension of 30 amino acids
and extra carbohydrate residues that prolong its t 1/2
. The
longer t 1/2
of hCG has some clinical relevance for its use
in assisted reproduction technologies (Chapter 66).
LH
FSH
Gonads
Sex
steroids
Other
tissues
Figure 38–7. The hypothalamic-pituitary-gonadal axis. A single
hypothalamic releasing factor, gonadotropin-releasing hormone
(GnRH), controls the synthesis and release of both gonadotropins
(LH and FSH) in males and females. Gonadal steroid hormones
(androgens, estrogens, and progesterone) exert feedback inhibition
at the level of the pituitary and the hypothalamus. The preovulatory
surge of estrogen also can exert a stimulatory effect at
the level of the pituitary and the hypothalamus. Inhibins, a family
of polypeptide hormones produced by the gonads, specifically
inhibit FSH secretion by the pituitary.
Regulation of Gonadotropin Synthesis and Secretion.
The predominant regulator of gonadotropin synthesis
and secretion is the hypothalamic peptide GnRH. It is
a decapeptide with blocked amino and carboxyl termini
(Table 38–3) derived by proteolytic cleavage of a
92–amino acid precursor peptide. A separate gene
encodes a related GnRH peptide, termed GnRH-II
(Millar et al., 2004); its potential functions in reproduction
remain to be defined. GnRH release is pulsatile and
is governed by a neural pulse generator in the hypothalamus,
primarily in the arcuate nucleus, that controls the
frequency and amplitude of GnRH release. The GnRH
pulse generator is active late in fetal life and for ~1 year
after birth but decreases considerably thereafter, presumably
secondarily to CNS inhibition. Shortly before
puberty, CNS inhibition decreases and the amplitude
and frequency of GnRH pulses increase, particularly
during sleep. As puberty progresses, the GnRH pulses
increase further in amplitude and frequency until the
normal adult pattern is established. The intermittent
release of GnRH is crucial for the proper synthesis
and release of the gonadotropins; the continuous
administration of GnRH leads to desensitization and
down-regulation of GnRH receptors on pituitary
gonadotropes and forms the basis for the clinical use of
long-acting GnRH agonists to suppress gonadotropin
secretion, as discussed later.
Molecular and Cellular Bases of GnRH Action. GnRH
signals through a specific GPCR on gonadotropes that
activates G q/11
and stimulates the PLC-IP 3
-Ca 2+ pathway
(Chapter 3), resulting in increased synthesis and
secretion of LH and FSH. Although cyclic AMP is not
the major mediator of GnRH action, binding of GnRH
to its receptor also increases adenylyl cyclase activity.
GnRH receptors also are present in the ovary, testis, and
other sites, where their physiological significance
remains to be determined. The presence of these receptors
on certain tumors has led to investigation of the
role of GnRH analogs in cancer therapy (Engel and
Schally, 2007).
Other Regulators of Gonadotropin Production. Gonadal steroids
regulate gonadotropin production at the level of the pituitary and the
hypothalamus, but effects on the hypothalamus predominate. The
feedback effects of gonadal steroids are dependent on sex, concentration,
and time. In women, low levels of estradiol and progesterone
inhibit gonadotropin production, largely through opioid action on
the neural pulse generator. Higher and more sustained levels of estradiol
have positive feedback effects that ultimately result in the
gonadotropin surge that triggers ovulation. In men, testosterone
inhibits gonadotropin production, in part through direct actions and
in part via its conversion by aromatase to estradiol.