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 hypothalamus at regular intervals, about every 2 hours, although 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 stimulated 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 products of the gonads that change the response of the pituitary gland to the GnRH pulses rather than by large changes in the amounts of GnRH secreted. The stimulatory response to GnRH depends on pulsatile administration and the timing of the pulses. Continual administration 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 responding to appropriately administered GnRH, even in cases of hypogonadotropic hypogonadism, when LH and FSH levels are always low. Therefore, GnRH therapy can be substituted for gonadotropin therapy by administering GnRH (Lutrepulse) pulses intravenously via an indwelling pump. GnRH itself is used, since the short half-life is important to prevent accumulation between pulses. The advantage of this procedure compared 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 hyperstimulation and multiple births, since the procedure should not result in inappropriately high levels of gonadotropins (Table 59.2).

Gonadotropin Suppression

Stable potent derivatives of GnRH include leuprolide (Lupron) and goserelin (Zoladex). Because these agonists are long acting, they suppress gonadotropin production after an initial stimulation. In some uses, the initial 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 compounds 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 (see Chapter 63). Estrogen use increases mortality in men primarily as a result of cardiovascular complications, and castration is not popular. 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 therapy because of the initial stimulation of the pituitary gland. These analogues are also used to suppress puberty 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 secretion 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

100 Pregnancy Tips

100 Pregnancy Tips

Prior to planning pregnancy, you should learn more about the things involved in getting pregnant. It involves carrying a baby inside you for nine months, caring for a child for a number of years, and many more. Consider these things, so that you can properly assess if you are ready for pregnancy. Get all these very important tips about pregnancy that you need to know.

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