HYPOTHALAMIC PITUITARY GONADAL HORMONAL AXIS
The
hypothalamic pituitary gonadal (HPG) axis plays a fundamental role in
phenotypic gender development during embryogenesis, sexual maturation during
puberty, and endocrine (hormone) and exocrine (oocytes and sperm) function of
the mature ovary and testis. Importantly, gonadal function throughout life,
similar to the adrenal cortex and thyroid, is under the control of the
adenohypophysis (anterior lobe of the pituitary) and hypothalamus.
HORMONE TYPES
Two kinds
of hormones exist in the HPG axis: peptide and steroid. Peptide hormones are
small secretory proteins that act via receptors on the cell surface membrane.
Hormone signals are transduced by one of several second-messenger pathways
involving either cAMP, calcium flux, or tyrosine kinase. Most peptide hormones
induce the phosphorylation of various proteins that alter cell function.
Examples of peptide hormones are luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). In contrast, steroid hormones are derived
from cholesterol and are not stored in secretory granules; consequently,
steroid secretion rates directly reflect production rates. In plasma, these
hormones are usually bound to carrier proteins. Because they are lipophilic,
steroid hormones are generally cell membrane–permeable. After binding to an
intracellular receptor, steroids are translocated to DNA recognition sites
within the nucleus and regulate the transcription of target genes. Examples of reproductive steroid
hormones are estradiol and testosterone.
HORMONAL FEEDBACK LOOPS
Normal
reproduction depends on the cooperation of numerous hormones and thus hormone
signals must be well controlled. Feedback control is the principal mechanism
through which this occurs. With feedback, a hormone can regulate the synthesis
and action of itself or of another hormone. Further coordination is provided by
hormone action at multiple sites and eliciting multiple responses. In the HPG
axis, negative feedback is principally responsible for minimizing hormonal
perturbations and maintaining homeostasis.
HORMONES OF THE HPG AXIS
As the
integrative center of the HPG axis, the hypo- thalamus receives neuronal input
from many brain centers, including the amygdala, thalamus, pons, retina, and
cortex, and it is the pulse generator for the cyclical secretion of pituitary
and gonadal hormones. It is anatomically linked to the pituitary gland by both
a portal vascular system and neuronal pathways. By avoiding the systemic
circulation, the portal vascular system provides a direct mechanism to deliver
hypothalamic hormones to the anterior pituitary. Among the hypothalamic
hormones, the most important for reproduction is gonadotropin-releasing or
LH-releasing hormone (GnRH or LHRH), a 10–amino acid peptide secreted from the
neuronal cell bodies in the preoptic and arcuate nuclei. Currently, the only
known function of GnRH is to stimulate the secretion of LH and FSH from the
anterior pituitary. GnRH has a half-life of approximately 5 to 7 minutes. GnRH
secretion is pulsatile in nature and results from integrated input from a
variety of influences, including stress, exercise, diet, input from higher brain
centers, pituitary gonadotropins, and circulating gonadal hormones.
The
anterior pituitary gland, located within the bony sella turcica, is the site of
action of GnRH. GnRH stimulates the production and release of FSH and LH by a
calcium flux-dependent mechanism. These peptide hormones, named after their
elucidation in the female, are equally important in the male. The sensitivity
of the pituitary gonadotrophs to GnRH varies with patient age and hormonal
status.
LH and
FSH are the primary pituitary hormones that regulate ovarian and testis
function. They are glycoproteins composed of two polypeptide chain subunits,
termed α and β, each coded by a separate gene. The α subunits of each hormone are identical and similar
to that of all other pituitary hormones; biologic and immunologic activity are
conferred by the unique β
subunit. Both subunits are required for endocrine activity. Oligosaccharide
sugars with sialic acid residues are linked to these peptide subunits and may
account for their differences in signal transduction and plasma clearance.
Secretory pulses of LH vary in frequency from 8 to 16 pulses in 24 hours, generally
reflecting GnRH release. Both androgens and estrogens regulate LH secretion
through negative feedback. On average, FSH pulses occur approximately every 1.5
hours. The gonadal protein inhibin inhibits FSH secretion and accounts for the
relative secretory independence of FSH from GnRH secretion. Activin, a
structurally similar gonadal peptide, may act in a paracrine fashion to
increase FSH binding in the ovary and stimulate spermatogenesis in the male,
although serum levels of this substance are difficult to detect.
FSH and
LH are known to act only in the gonads. In the testis, LH stimulates
steroidogenesis within Leydig cells by inducing the mitochondrial conversion of
cholesterol to pregnenolone and testosterone. FSH binds to Sertoli cells and
spermatogonial membranes within the testis and is the major stimulator of
seminiferous tubule growth during development and responds to inhibin secretion
by Sertoli cells. Normal testosterone production in men is approximately 5 g/d,
with secretion occurring in a damped, irregular, pulsatile manner. About 2% of
testosterone is “free” or unbound and considered the biologically active
fraction. The remain- der is almost equally bound to albumin or sex
hormonebinding globulin (SHBG) within the blood. Testosterone is metabolized
into two major active metabolites: dihydrotestosterone (DHT) from the action of
5-reductase, and estradiol through the action of aromatases. DHT is a more
potent androgen than testosterone. In most peripheral tissues, DHT is required
for androgen action, but in the testis and skeletal muscle, conversion to DHT
is not essential for hormonal activity. Testosterone stimulates the growth and
maintenance of the secondary sex organs (prostate, seminal vesicles, penis, and
accessory glands). In addition, testosterone is a potent anabolic steroid with a
variety of extragenital effects. In the brain, it influences libido, male
aggression, mood, and aspects of cognition, including verbal memory and
visual–spatial skills. It is responsible for an increase in muscle strength and
growth and stimulates erythropoietin in the kidney. In bone marrow,
testosterone causes accelerated linear growth and closure of epiphyses. It
helps the liver to produce serum proteins and influences the male external
appearance, including body hair growth and other secondary characteristics.
In the
female, LH stimulates estrogen production from theca interna cells during the
follicular phase of the menstrual cycle. The highest levels of estrogen during
the menstrual cycle occur just prior to ovulation. FSH induces follicular
development through a morphogenic effect on granulosa cells that line the
graafian follicle. Eventually, this stimulation leads to the follicle’s ripening
and ovulation. With ovulation, the follicle is transformed into the corpus
luteum, and the majority of granulosa and theca cells now become luteinized and
produce progesterone simultaneously with estrogen. LH also influences
preovulatory follicular enlargement, induces ovulation, stimulates the
proliferation of the theca cells that secrete progesterone in the latter half
of the menstrual cycle, and supports the development of the corpora lutea for 2
weeks after ovulation. Termed the “hormone of pregnancy,” progesterone supports
endometrial development in early pregnancy, thickens the cervical mucus to
prevent infection, decreases uterine contractility, and inhibits lactation
during pregnancy. It is also necessary for the complete action of ovarian
hormones on the fallopian tubes, uterus, vagina, external genitalia, and
mammary glands. Interestingly, the ovarian estrogens and progesterone do not
have the marked extragenital anabolic effects on muscle, kidney, blood, larynx,
skin, and hair that are found with androgens.
A third
anterior pituitary hormone, prolactin, can also influence the HPG axis.
Prolactin is a large, globular protein that maintains the luteal phase of the
menstrual cycle and induces milk synthesis during pregnancy and lactation in
women. The role of prolactin in men is less clear, but it may promote sexual
gratification after intercourse and induce the refractory period after
ejaculation. It also increases concentration of LH receptors on Leydig cells
and sustains normally high intratesticular testosterone levels. Although low
prolactin levels are not usually pathologic, hyperprolactinemia in either sex abolishes
gonadotropin pulsatility by interfering with GnRH release.
