Normal

Regulation of the hypothalamic pituitary unit is a complex process involving negative feedback mechanisms in the male. GnRH secreted in a pulsatile manner by neurons with cell bodies in the hypothalamus. GnRH stimulates synthesis and glycosylation of beta subunits of FSH and LH. Inhibin acts on the pituitary gonadotropes to suppress the synthesis and release of FSH but not of LH.

This modulatory effect of inhibin is termed negative feedback. Testosterone from the testes also exerts negative feedback effects on FSH and LH production by negatively modulating production of GnRH in the hypothalamus. Steroid hormones have a much greater inhibitory effect on LH production than on FSH production. Testosterone is thought to act by decreasing GnRH pulse frequency.

It should be remembered that the hormones of the hypothalamic pituitary unit that is GnRH, FSH and LH exist in a dynamic equilibrium with the hormones of the testes that is steroid hormones and inhibin. The male does not have a positive feedback mechanism and is acyclical. GnRH secreted in a pulsatile manner by neurons with cell bodies in the hypothalamus.

GnRH stimulates synthesis and glycosylation of beta subunits of FSH and LH. FSH stimulates the synthesis of inhibin and androgen binding protein in testicular sertoli cells. Stimulation of sertoli cells by FSH results in increased mytosis and spermatogonia with the consequent enhancement of spermatogenesis. FSH however is not absolutely required for initiation or maintenance of spermatogenesis.

LH stimulates interstetial leydig cells to synthesize testosterone. Gonadotropn secretion is inhibited by high concentrations of prolactin termed hyper prolactinemia. Prolactin appears to act directly on GnRH secreting neurons to block either synthesis or secretion of GnRH. Although the inhibition occurs at the level of the hype hypothalamic pituitary unit, the mechanisms are not well-understood.

Individuals with primary or secondary hypothyroidism or with secondary hyperthyroidism due to a TRH secreting hypothalamic tumor also have decreased gonadotropin secretion that is thought to be mediated via increased prolactin due to increased TRH secretion. TRH has been shown to stimulate prolactin secretion by pituitary lactotropes. Inhibin acts on pituitary gonadotropes to suppress the synthesis and release of FSH but not of LH.

Male testosterone. Testosterone acts on unidentified hypothalamic neurons which act on GnRH secreting neurons to inhibit GnRH secretion. Negative modulation of GnRH secretion results in diminished FSH and LH secretion with a greater inhibition of LH secretion. The effect of testosterone on the GnRH pulse oscillator neurons appears to be to decrease GnRH pulse frequency which results in decreased LH and FSH pulse frequency.

GnRH secretion is inhibited by a variety of neurogeneic factors including stress, beta endorphin, a stress related opioid peptide, morphine, alpha adrogenic blockers, and dopaminergic blockers.

 

Stress

Male hypothalamic oligospermia. Stress either physical mental or emotional can inhibit function of the hypothalamic pituitarytesticular axis. Spermatogenesis declines and symptoms of hypogonadism can appear depending on the duration of the stress inducer. Stress causes certain neurons with cell bodies in the cerebral cortex of the brain to secrete increased amounts of inhibitory neurotransmitters such as norepinephrine and beta endorphin and opioid peptide.

The inhibitory neurotransmitters either directly or indirectly act on GnRH secreting neurons in the hypothalamus to inhibit the secretion of GnRH. As a result secretion of GnRH by hypothalamic neurons decreases. Decreased secretion of GnRH results in decreased secretion of FSH and LH. Administration of exogenous GnRH will stimulate secretion of FSH and LH.

Decreased secretion of FSH and LH results in lack of stimulation of spermatogenesis and decreased testicular secretion of testosterone. Administration of FSH alone has little effect.

 

Orchiectomy

 

Male orchiectomy. Removal of the testes, referred to as bilateral orchiectomy in a sexually mature male results in removal of the principal sources of testosterone and inhibin in the circulation. Spermatogenesis ceases, reproductive tissues atrophy and bone mass decreases. The decline in androgens releases the pulse oscillator neurons of hypothalamus from negative feedback as a result secretion of GnRH by hypothalamic GnRH secreting neurons increases.

Administration of exogenous testosterone inhibits secretion of GnRH. Increased GnRH stimulus gonadotropes of the anterior pituitary gland to secrete increased amounts of FSH and LH. The decline in inhibin releases the gonadotropes from inhibition and the gonadotrope secrete increased amounts of FSH. Administration of exogenous inhibin decreases secretion of FSH.

 

Kallman's Syndrome

 

Male Kallman's syndrome. In certain individuals carrying a genetic defect in a gene encoding a cellular adhesion protein in GnRH neurons, these neurons fail to migrate from the olfactory bulb to the hypothalamus during fetal development. These individuals do not have either normal GnRH secretion or a normal sense of smell referred to as anosmia.

These individuals fail to experience normal development of the internal reproductive tract and external genitalia at the time of puberty. They have azoospermia or oligspermia due to lack of gonadotropin to stimulate the testes. The absence of GnRH secreting neurons in the hypothalamus prevents the secretion of GnRH into the hypothalamic hypophyseal portal circulation.

Lack of GnRH results in decreased secretion of FSH and LH. Administration of exogenous GnRH will stimulate the secretion of FSH and LH. Decreased secretion of FSH and LH results in lack of stimulation of spermatogenesis and decrease secretion of androgens. Administration of exogenous androgen results in growth of sex accessory organs.

 

FSH Receptor Defect

 

Male FSH Receptor Defect. Inactivating mutations of the FSH receptor prevents sertoli cells of the seminiferous tubules from responding to FSH. Since the Sertoli cells are principal sources of inhibin, an FSH receptor defect results in functional removal of the principle source of inhibin but not androgens in the circulation. These individuals have low or normal spermatogenesis.

Since androgen secretion is normal, the hypothalamic pulse oscillator neurons function normally. As a result GnRH secretion by the GnRH secreting neurons is expected to be normal. Since GnRH secretion is normal GnRH stimulation of FSH and LH secretion by gonadotropes is normal. Lack of inhibin causes an increase in FSH secretion.

Sertoli cells are unable to respond to FSH. As a result only small amounts of inhibin are synthesised. Spermatogenesis is low or normal.

 

LH Receptor Defect

 

Inactivating mutations of the LH receptor prevent leydig cells of the testes from responding to LH. Since leydig cells require LH to synthesize normal levels of testosterone, an LH receptor defect would result in abnormally low testosterone production and failure of male sexual differentiation during fetal development. These individuals are presumed to have elevated GnRH secretion due to lack of production of testosterone.

These individuals are presumed to have elevated levels of gonadotropins. Testes develop but do not secrete normal male levels of testosterone due to lack of stimulation of leydig cells by LH. Testes would be abnormally small and spermatogenesis would be absent.

 

FSHβ Subunit Defect

 

Male FSH beta subunit defect. Individuals with an inactivating mutation in the gene encoding the beta sub unit of FSH secrete little or no biologically active FSH. These individuals secrete GnRH. These individuals have diminished but not abnormal spermatogenesis. Androgen production is normal so the hypothalamic pulse oscillator neurons function normally.

GnRH secretion is normal the gonadotropes secrete an inactive form of the beta subunit of the FSH, as a result, the pituitary does not secrete active FSH into the circulation. FSH secretion by the pituitary is elevated due to abnormally low levels of inhibin. The lack of FSH stimulation results in lack of stimulation of mytosis in spermatogonia.

Spermatogenesis is normal or low. Sertoli cells make low or no inhibin.

 

Primary Hypothyroidism

 

Male Primary Hypothyroidism. Male patients with chronic severe primary hypothyroidism due to an inability to produce thyroid hormones often experience oligospermia, or low sperm counts. Administrations of thyroid hormones causes resumption of normal spermatogenesis. Lack of thyroid hormone releases the TRH secreting neurons of the hypothalamus from negative feedback inhibition. As a result, TRH secretion increases.

HIgh levels of prolactin inhibit GnRH secretion by GnRH secreting neurons. High levels of TRH stimulate the thyrotropes of the anterior pituitary to secrete increased amounts of TSH. High levels of TRH also stimulate the lactotropes of the anterior pituitary to secrete increased amounts of prolactin. Decreased secretion of GnRH results in decreased secretion of FSH and LH.

Administration of exogenous GnRH will stimulate secretion of FSH and LH. The thyroid gland is unable to synthesize the thyroid hormones T3 and T4. Decreased secretion of LH results in decreased synthesis of testosterone. Decreased secretion of FSH results in decreased secretion of inhibin and decreased mitosis in spermatogonia. Spermatogenesis is abnormally low, referred to as oligospermia.

 

Secondary Hypothyroidism

Male secondary hypothyroidism. Male patients with chronic severe secondary hypothyroidism due to an inability to produce TSH and thyroid hormones can be expected to experience oligospermia or low sperm counts. Administration of thyroid hormones causes resumption of normal spermatogenesis. Lack of thyroid hormone releases the TRH secreting neurons of the hypothalamus from negative feedback inhibition.

As a result TRH secretion increases. High levels of prolactin inhibit GnRH secretion by GnRH secreting neurons. The thyrotropes of the anterior pituitary secrete little or no biologically active TSH. High levels of TRH stimulate the lactotropes of the anterior pituitary to secrete increased amounts of prolactin. Decreased secretion of GnRH results in decreased secretion of FSH and LH.

Administration of exogenous GnRH will stimulate secretion of FSH and LH. Low levels of TSH result in synthesis of low levels of thyroid hormones T3 and T4 by the thyroid gland. Decreased secretion of LH results in decreased synthesis of testosterone. Decreased secretion of FSH results in decreased secretion inhibin and decreased mitosis in spermatogonia.

Spermatogenesis is abnormally low referred to as oligospermia.

 

Secondary Hyperthyroidism

Male secondary hypothyroidism due to a hypothalamic TRH secreting tumor. Male patients with chronic severe secondary hyperthyroidism due to excessive production of TRH secreting hypothalamic tumor often have oligospermia, or low sperm counts. Tumors in the TRH secreting neurons of the hypothalamus secrete high levels of TRH. High levels of prolactin Inhibit GnRH secretion by GnRH secreting neurons.

High levels of TRH stimulate thyrotropes of the anterior pituitary to secrete increased amounts of TSH. High levels of TRH also stimulate the lactotropes of the anterior pituitary to secrete increased amounts of prolactin. Decreased secretion of GnRH results in decreased secretion of FSH and LH. Administration of exogenous GnRH will stimulate secretion of FSH and LH.

High levels of TSH result in synthesis of high levels of thyroid hormones T3 and T4 by the thyroid gland. Decreased secretion of LH results in decreased synthesis of testosterone. Decreased secretion of FSH results in decreased secretion of inhibin and decreased mitosis in spermatogonia. Spermatogenesis is abnormally low, referred to as oligospermia.