Hypothalamic Regulatory Hormones

HYPOTHALAMIC REGULATORY HORMONES

Five peptides isolated from the hypothalamus regulate release of one or more pituitary hormones. In addition, dopamine released from the hypothalamus inhibits pro-lactin production.

Somatostatin

Somatostatin (or somatotropin release–inhibiting fac-tor [SRIF]) occurs primarily as a 14–amino acid pep-tide, although a 28–amino acid form also exists. As with the other hypothalamic peptides, it is formed by prote-olytic cleavage of a larger precursor. Somatostatin, orig-inally isolated from the hypothalamus, is also in many other locations, including the cerebral cortex, brain-stem, spinal cord, gut, urinary system, and skin. Somatostatin inhibits the secretion of many substances in addition to growth hormone (Table 59.1).

Somatostatin has a very brief half-life in serum and is not useful clinically. An 8–amino acid analogue with 2 D-amino acids substituted for the naturally occurring L-amino acids is more stable, and monthly injections of a depot form of this analogue (octreotide, Sandostatin LAR) have several uses. Long-acting octreotide is used to treat acromegaly, as described earlier. It is also used to counteract unpleasant effects caused by overproduc-tion of secreted bioactive substances produced by neu-roendocrine tumors, including hyperinsulinemia from insulinomas and secretions from carcinoid tumors that cause severe diarrhea. Octreotide may also control se-vere diarrhea associated with AIDS that has not re-sponded to other treatments.

Transient side effects, gastrointestinal discomfort and decreased glucose tolerance, usually last only a few weeks after initiation of therapy. The most significant side effect associated with prolonged use of octreotide is formation of gallstones resulting from reduced bile flow.

Thyrotropin-Releasing Hormone

Thyrotropin-releasing hormone, or protirelin, consists of three amino acids. TRH (Relefact TRH) is used for tests to distinguish primary from secondary hypothy-roidism .

Gonadotropin-Releasing Hormone

GnRH (gonadorelin, luteinizing hormone–releasing hormone) is a decapeptide that stimulates production of LH and FSH. It is released in bursts from the hypo-thalamus at regular intervals, about every 2 hours, al-though in women the interval may lengthen in the luteal end of the menstrual cycle. The pituitary gland responds to these regular pulses by producing LH and FSH. The pattern of LH and FSH in cycling women, including the large burst of LH release before ovulation, can be stim-ulated by regular administration of GnRH pulses. The large burst of LH from the pituitary gland appears to be induced by feedback through estradiol and other prod-ucts of the gonads that change the response of the pitu-itary gland to the GnRH pulses rather than by large changes in the amounts of GnRH secreted. The stimu-latory response to GnRH depends on pulsatile adminis-tration and the timing of the pulses. Continual adminis-tration of GnRH does not have the same effects as pulsatile administration; although production of LH and FSH is stimulated initially, it is suppressed within a few days. Part of this desensitization to GnRH is caused by a decrease in the number of pituitary receptors for GnRH; additional postreceptor mechanisms are also important in this complete suppression.

GnRH itself has a short half-life, 7 minutes, if given intravenously. Structural variations of the decapeptide have resulted in more stable analogues with higher affinity for the GnRH receptor; a common modification is to substitute a D-amino acid for the sixth amino acid, glycine, in GnRH.

Gonadotropin Stimulation

When stimulation of gonadotropin production is needed, the pituitary gland is usually capable of re-sponding to appropriately administered GnRH, even in cases of hypogonadotropic hypogonadism, when LH and FSH levels are always low. Therefore, GnRH ther-apy can be substituted for gonadotropin therapy by ad-ministering GnRH (Lutrepulse) pulses intravenously via an indwelling pump. GnRH itself is used, since the short half-life is important to prevent accumulation be-tween pulses. The advantage of this procedure com-pared with intramuscular injections of gonadotropins

for treating infertility is that normal levels of LH and FSH should be maintained because of feedback from the gonads. This should reduce the risk of ovarian hy-perstimulation and multiple births, since the procedure should not result in inappropriately high levels of go-nadotropins (Table 59.2).

Gonadotropin Suppression

Stable potent derivatives of GnRH include leuprolide (Lupron) and goserelin (Zoladex). Because these ago-nists are long acting, they suppress gonadotropin pro-duction after an initial stimulation. In some uses, the ini-tial stimulation of gonadotropin is undesirable; a newer GnRH antagonist, ganirelix (Antagon) inhibits go-nadotropin production without the stimulation and may ultimately replace the long-acting agonists. These com-pounds are formulated so they can be injected monthly or even less frequently.

In men, androgens stimulate growth of prostatic cancer; therefore, a reduction in androgen actions is used for palliative treatment . Estrogen use increases mortality in men primarily as a result of cardiovascular complications, and castration is not pop-ular. Therefore, treatment with GnRH analogues to suppress gonadotropin release is favored. When long-acting agonists are given, signs and symptoms of prosta-tic cancer may increase shortly after initiation of ther-apy because of the initial stimulation of the pituitary gland. These analogues are also used to suppress pu-berty in young children with central precocious puberty.

In women, GnRH agonists are sometimes given along with FSH when stimulating follicles in fertility treatments; this addition prevents premature ovulation caused by the release of pituitary LH. Uterine leiomy-omas and endometriosis regress when gonadotropin se-cretion is decreased. GnRH analogues relieve these conditions, but the relief usually lasts only as long as the analogue is administered, and the condition generally returns within a few months after therapy ceases. 

The main side effects are a result of estradiol deprivation and include hot flashes (sudden intense surface temper-ature elevation and sweating), dry skin and vagina; long-term use may decrease bone density. The addition of estrogen and progesterone can reduce the adverse ef-fects while maintaining gonadotropin suppression. However, there is a continuing need to address the re-cent cancer risk cautions issued for short-term versus long-term use of estrogen–progesterone combinations as hormonal replacement therapy.

Corticotropin-Releasing Hormone

Corticotropin-releasing hormone consists of 41 amino acids; it stimulates ACTH release. It is used for investi-gational purposes.