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.
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.