The
Pituitary Gland And Gonadotropins
There are three lobes to the pituitary gland (hypophysis): the anterior
lobe, the posterior lobe and the pars intermedia, a small
intermediate structure lying between the anterior and posterior lobe that is
actually a subdivision of the anterior lobe.
The pituitary is connected to the brain via a small branch of tissue
known as the pituitary stalk or infundibulum. The posterior pituitary serves
mainly as a storage site for two hormones produced in the hypothalamus:
oxytocin and arginine vasopressin (also known as anti- diuretic hormone, ADH).
In contrast, the anterior pituitary produces tropic hormones under the
regulatory control of the hypothalamus. This control is mediated by neuroendocrine
signals from the hypothalamus that travel through rich vascular connections
surrounding the pituitary stalk. Blood flowing through this highly vascular
plexus delivers signals to the anterior pituitary gland, regulating production
and release of its protein products.
There are five cell types in the anterior pituitary that are associated
with tropic hormone production: gonadotropes, lactotropes, somatotropes,
thyrotropes and corticotropes. These specific cells are responsible for
production and secretion of: follicle-stimulating hormone (FSH) and luteinizing
hormone (LH); prolactin; growth hormone; thyroid-stimulating
hormone (TSH); and adrenocorticotropic hormone (ACTH), respectively.
The thyrotropes and gonadotropes closely resemble each other histologically
because their secretory products, LH, FSH and TSH, are all glycoprotein
hormones that stain with carbohydrate-sensitive reagents. LH and FSH are produced
by a single cell type, allowing coupled secretion and regulation by a single
releasing factor.
Control of pituitary gland activity comes largely from the hypothalamus
with important direct modulation by feedback mechanisms. The hypothalamic
nuclei associated with reproduction include the supraoptic, paraventricular,
arcuate, ventromedial and suprachiasmatic nuclei. Neurons in two less
well-defined areas, the medial anterior hypothalamus and the medial preoptic
areas, are also involved. The magnocellular (large) neurons that originate in
the supraoptic and paraventricular nuclei project into the posterior pituitary
and produce the hormones vasopressin and oxytocin. The parvocellular (small)
neurons found in the paraventricular, arcuate and ventromedial nuclei and the
periventricular and medial preoptic areas produce regulatory peptides that
control the tropic hormones produced by the anterior pituitary.
Those cells in the hypothalamic nuclei that regulate the pituitary have
several functions. They receive signals from higher centers in the brain,
generate neural signals of their own and have neuroendocrine capabilities. The
higher areas of the brain that connect to the hypothalamic nuclei involved with
reproduction are the locus ceruleus, the medulla and pons, the midbrain raphe,
the olfactory bulb, the limbic system (amygdala and hippocampus), the piriform
cortex and the retina. Endogenous opioids also influence hypothalamic function.
The neuroendocrine signals generated within the hypothalamus are
mediated by peptide-releasing factors that travel through the
hypothalamic–pituitary portal system to their site of action in the pituitary
gland. Gonadotropin-releasing hormone (GnRH) is the key tropic hormone
for regulating gonadotrope cell function and hence, reproduction. A key neural
signal in human reproduction arises from what is known as the GnRH pulse
generator. The mechanism by which pulsatile GnRH release controls
gonadotropin synthesis and secretion remains poorly defined. At baseline, GnRH
secretes from the hypothalamus in pulses at a frequency of approximately one
pulse per hour. GnRH pulse frequency is most rapid in the follicular phase,
slightly slower in the early luteal phase and slowest in the late luteal phase
of the female menstrual cycle. In general, rapid pulse frequencies favor LH
secretion and slower pulse frequencies favor FSH release. The relationship between pulse
frequency and LH and FSH secretion appears to exist in both women and men.
Continuous GnRH release inhibits gonadotrope function. This is the basis for
the downregulating activities of long-acting exogenous GnRH agonists and
antagonists.
Thyrotropin-releasing hormone (TRH) and prolactin inhibitory
factor (PIF) also have roles in reproductive regulation. Those hypothalamic
neuroendocrine peptides that control growth hormone (GH) and ACTH secretion are
less directly related to reproduction.
Structure of LH and FSH
LH, FSH and TSH are structurally similar. They are formed by two
distinct, noncovalently bound protein subunits called α and β. The
pregnancy-specific gonadotropin, human chorionic gonadotropin (hCG), is a
fourth glycoprotein formed of α and β chains. The α subunit for all four
hormones is identical. The β subunit of each hormone differs, conferring
functional specificity on each αβ dimer (Fig. 1.1a and b). The β chains for LH
and hCG are the most similar with 82% homology. Carbohydrate side chains on
both the α and β chains of LH, hCG and FSH add to structural specificity. The
carbo- hydrate chains also influence metabolic clearance rates for the glycoprotein
hormones. This effect is most dramatic with the hCG molecule. The β chain of
hCG has a 24 amino acid extension at its C terminus that contains four O-linked
polysaccharides. This sugar-laden “tail” dramatically slows the clearance of
hCG. By prolonging its half-life, the effects of small amounts of this
glycoprotein are dramatically enhanced. This characteristic is very important
in early pregnancy recognition and maintenance (Chapters 16 and 18).
Regulation of FSH and LH
The biosynthesis and secretion of FSH and LH are tightly controlled
within the reproductive cycle. There are multiple ways in which FSH and LH can
be regulated, including alterations in gene transcription, mRNA stabilization,
rate of protein subunit synthesis, posttranslational glycosylation and changes
in the number of gonadotropin- secreting cells.
Gonadal steroids exert negative feedback control over FSH and LH
synthesis and secretion. Estrogen, androgen and progesterone receptors are
present in the gonadotropin-secreting cells of the pituitary and in some
neurons in the hypothalamus. In the pituitary, the gonadal steroids appear to
affect the transcription rate of the genes coding for FSH-β, LH-β and the
common α subunit. While there is some evidence that steroids can act at the
level of the hypothalamic pulse generator, gonadal steroid hormone receptors do
not appear to be present in the GnRH-containing cells of the arcuate nucleus.
There is one important exception to the generally inhibitory effect of
gonadal steroids on gonadotrope function. In certain situations, estrogen
exerts positive feedback on gonadotropin secretion. This is critical to produce
the midcycle LH surge in women (Chapter 14) and requires a sustained (>48 h)
elevation in circulating estradiol. Estrogen-induced stimulation involves both
increased gonadotropin gene expression in the pituitary and alterations in GnRH
pulse frequency in the hypothalamus.
Inhibin and activin are closely related peptides produced
by the ovary, testes, pituitary gland and placenta that influence gonadotrope
function. As suggested by their names, inhibin decreases gonadotrope function
and activin stimulates it. Inhibin and activin are formed from common α and β
subunits. Inhibin is formed of one α subunit linked to either of two highly
homologous β subunits to form inhibin A (αβA) or inhibin B (αβB).
Activin is composed of three combinations of the β subunits: activin A (βAβA),
activin AB (βAβB) and activin B (βBβB).
Activin is a member of the transforming growth factor β (TGF-β) superfamily of
growth and differentiation factors that include TGF-β, Müllerian-inhibiting
substance (MIS) and bone morphogenic proteins. Follistatin is
structurally unrelated to either inhibin or activin. It is a highly
glycosylated pituitary peptide that inhibits gonadotrope function but at
one-third the potency of inhibin. All three of these peptides have their major
influence on the expression of the FSH-β gene. Of these peptides, inhibin
appears to be the most biologically important regulator of the FSH gene,
directly suppressing its activity. The other two peptides appear to act within
the pituitary cells through locally released second messengers or autocrine
peptides. Activin B stimulates FSH release. Activins also affect the gonads directly
by increasing the activity of the aromatase enzyme in the ovary and stimulating
proliferation of spermatogonia in the testes.
Mechanism of action of gonadotropins There are distinct FSH and LH
receptors. The latter also bind the closely related hCG molecule. Receptors
for both glycoprotein hormones FSH and LH are located in the plasma membranes
of the granulosa cells in the ovary and the Sertoli cells in the testes.
Ovarian thecal cells and testicular Leydig cells only display LH receptors. In
addition to regulating steroidogenesis and gametogenesis, gonadotropins
regulate expression of their own receptors in a dose-dependent fashion. FSH
also induces LH/hCG receptor formation in granulosa and Sertoli cells.
Although gonadotropin receptors are normally present in very low
concentrations on the cell surface, they have high specificity and affinity for
their ligands. The interactions between the glycoprotein dimer and its receptor
lead to conformational changes in the receptor. This then activates a
membrane-associated G protein-coupled signaling system. Although the G
protein-coupled cAMP pathway is the principal mediator of both FSH and LH
receptor activity, activation of the protein kinase C system can also occur.
In addition to activating specific intracellular signaling processes,
binding of the gonadotropin to its receptor also initiates a regulatory
function termed desensitization. Desensitization reduces the cell’s
responsiveness to ongoing stimulation. In the first phase of desensitization,
the gonadotropin receptor becomes “uncoupled” from its down- stream activity so
that it no longer activates adenylate cyclase. In the second, slower phase of
desensitization, the degradation rate for the receptors is increased. This
latter process is called “downregulation.” Both are involved in the activities
of GnRH agonists and antagonists.
