Gonadotropin-Releasing Hormone & Its Analogs

GONADOTROPIN-RELEASING HORMONE & ITS ANALOGS

Gonadotropin-releasing hormone is secreted by neurons in the hypothalamus. It travels through the hypothalamic-pituitary venous portal plexus to the anterior pituitary, where it binds to G protein-coupled receptors on the plasma membranes of gonado-troph cells. Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release LH and FSH.Sustained nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both women and men, resulting in hypogonadism. GnRH ago-nists are used to produce gonadal suppression in men with pros-tate cancer. They are also used in women who are undergoing assisted reproductive technology procedures or who have a gyne-cologic problem that is benefited by ovarian suppression.

Chemistry & Pharmacokinetics

A. Structure

GnRH is a decapeptide found in all mammals. Gonadorelin is an acetate salt of synthetic human GnRH. Synthetic analogs of GnRH include goserelin, histrelin, leuprolide, nafarelin, and triptorelin. These analogs all have D-amino acids at position 6,and all but nafarelin have ethylamide substituted for glycine at position 10. Both modifications make them more potent and longer-lasting than native GnRH and gonadorelin.

B. Pharmacokinetics

Gonadorelin can be administered intravenously or subcutane-ously. GnRH analogs can be administered subcutaneously, intra-muscularly, via nasal spray (nafarelin), or as a subcutaneous implant. The half-life of intravenous gonadorelin is 4 minutes, and the half-lives of subcutaneous and intranasal GnRH analogs are approximately 3 hours. The duration of clinical uses of GnRH agonists varies from a few days for ovulation induction to a num-ber of years for treatment of metastatic prostate cancer. Therefore,preparations have been developed with a range of durations of action from several hours (for daily administration) to 1, 4, 6, or 12 months (depot forms).

Pharmacodynamics

The physiologic actions of GnRH exhibit complex dose-response relationships that change dramatically from the fetal period through the end of puberty. This is not surprising in view of the complex role that GnRH plays in normal reproduction, particu-larly in female reproduction. Pulsatile GnRH release occurs and is responsible for stimulating LH and FSH production during the fetal and neonatal period. Subsequently, from the age of 2 years until the onset of puberty, GnRH secretion falls off and the pitu-itary simultaneously exhibits very low sensitivity to GnRH. Just before puberty, an increase in the frequency and amplitude of GnRH release occurs and then, in early puberty, pituitary sensitiv-ity to GnRH increases, which is due in part to the effect of increas-ing concentrations of gonadal steroids. In females, it usually takes several months to a year after the onset of puberty for the hypo-thalamic-pituitary system to produce an LH surge and ovulation. By the end of puberty, the system is well established so that men-strual cycles proceed at relatively constant intervals. The ampli-tude and frequency of GnRH pulses vary in a regular pattern through the menstrual cycle with the highest amplitudes occur-ring during the luteal phase and the highest frequency occurring late in the follicular phase. Lower pulse frequencies favor FSH secretion, whereas higher pulse frequencies favor LH secretion. Gonadal steroids as well as the peptide hormones activin and inhibin have complex modulatory effects on the gonadotropin response to GnRH.

In the pharmacologic use of GnRH and its analogs, pulsatile intravenous administration of gonadorelin every 1–4 hours stimu-lates FSH and LH secretion. Continuous administration of gona-dorelin or its longer-acting analogs produces a biphasic response. During the first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females; this initial phase is referred to as a flare. After this period, the contin-ued presence of GnRH results in an inhibitory action that mani-fests as a drop in the concentration of gonadotropins and gonadal steroids. The inhibitory action is due to a combination of receptor down-regulation and changes in the signaling pathways activated by GnRH.

Clinical Pharmacology

The GnRH agonists are occasionally used for stimulation of gonadotropin production. They are used far more commonly for suppression of gonadotropin release.

A. Stimulation

Female infertility—In the current era of widespread avail-ability of gonadotropins and assisted reproductive technology, the use of pulsatile GnRH administration to treat infertility is uncom-mon. Although pulsatile GnRH is less likely than gonadotropins

to cause multiple pregnancies and the ovarian hyperstimulation syndrome, the inconvenience and cost associated with continuous use of an intravenous pump and difficulties obtaining native GnRH (gonadorelin) are barriers to pulsatile GnRH. When this approach is used, a portable battery-powered programmable pump and intravenous tubing deliver pulses of gonadorelin every 90 minutes.

Gonadorelin or a GnRH agonist analog can be used to initiate an LH surge and ovulation in women with infertility who are undergoing ovulation induction with gonadotropins. Traditionally, hCG has been used to initiate ovulation in this situation. However, there is some evidence that gonadorelin or a GnRH agonist is less likely than hCG to cause multiple ova to be released and less likely to cause the ovarian hyperstimulation syndrome.

2. Male infertility—It is possible to use pulsatile gonadorelinfor infertility in men with hypothalamic hypogonadotropic hypogonadism. A portable pump infuses gonadorelin intrave-nously every 90 minutes. Serum testosterone levels and semen analyses must be done regularly. At least 3–6 months of pulsatile infusions are required before significant numbers of sperm are seen. As described above, treatment of hypogonadotropic hypogo-nadism is more commonly done with hCG and hMG or their recombinant equivalents. 

3. Diagnosis of LH responsiveness— GnRH can be useful indetermining whether delayed puberty in a hypogonadotropic adolescent is due to constitutional delay or to hypogonadotropic hypogonadism. The LH response (but not the FSH response) to a single dose of GnRH can distinguish between these two condi-tions. Serum LH levels are measured before and at various times after an intravenous or subcutaneous bolus of GnRH. An increase in serum LH with a peak that exceeds 15.6 mIU/mL is normal and suggests impending puberty. An impaired LH response sug-gests hypogonadotropic hypogonadism due to either pituitary or hypothalamic disease, but does not rule out constitutional delay of adolescence.

B. Suppression of Gonadotropin Production

1. Controlled ovarian hyperstimulation—In the con-trolled ovarian hyperstimulation that provides multiple mature oocytes for assisted reproductive technologies such as in vitro fertilization, it is critical to suppress an endogenous LH surge that could prematurely trigger ovulation. This suppression is most commonly achieved by daily subcutaneous injections of leuprolide or daily nasal applications of nafarelin. For leuprolide, treatment is commonly initiated with 1.0 mg daily for about 10 days or until menstrual bleeding occurs. At that point, the dose is reduced to 0.5 mg daily until hCG is administered (Figure 37–3). For nafarelin, the beginning dosage is generally 400 mcg twice a day, which is decreased to 200 mcg when menstrual bleeding occurs. In women who respond poorly to the standard protocol, alternative protocols that use shorter courses and lower doses of GnRH agonists may improve the follicular response to gonadotropins.

2. Endometriosis—Endometriosis is a syndrome of cyclicalabdominal pain in premenopausal women that is due to the pres-ence of estrogen-sensitive endometrium-like tissue outside the uterus. The pain of endometriosis is often reduced by abolishing exposure to the cyclical changes in the concentrations of estrogen and progesterone that are a normal part of the menstrual cycle. The ovarian suppression induced by continuous treatment with a GnRH agonist greatly reduces estrogen and progesterone concen-trations and prevents cyclical changes. The preferred duration of treatment with a GnRH agonist is limited to 6 months because ovarian suppression beyond this period can result in decreased bone density. Leuprolide, goserelin, and nafarelin are approved for this indication. Leuprolide and goserelin are administered as depot preparations that provide 1 or 3 months of continuous GnRH agonist activity. Nafarelin is administered twice daily as a nasal spray at a dose of 0.2 mg per spray. 

3. Uterine leiomyomata (uterine fibroids)—Uterine leio-myomata are benign, estrogen-sensitive, fibrous growths in the uterus that can cause menorrhagia, with associated anemia and pelvic pain. Treatment for 3–6 months with a GnRH agonist reduces fibroid size and, when combined with supplemental iron, improves anemia. Leuprolide, goserelin, and nafarelin are approved for this indication. The doses and routes of administration are similar to those described for treatment of endometriosis. 

4. Prostate cancer—Antiandrogen therapy is the primarymedical therapy for prostate cancer. Combined antiandrogen therapy with continuous GnRH agonist and an androgen receptor antagonist such as flutamide  is as effective as surgical castration in reducing serum testosterone concentrations and effects. Leuprolide, goserelin, histrelin, and triptorelin are approved for this indication. The preferred formulation is one of the long-acting depot forms that provide 1, 3, 4, 6, or 12 months of active drug therapy. During the first 7–10 days of GnRH ana-log therapy, serum testosterone levels increase because of the ago-nist action of the drug; this can precipitate pain in patients with bone metastases, and tumor growth and neurologic symptoms in patients with vertebral metastases. It can also temporarily worsen symptoms of urinary obstruction. Such tumor flares can usually be avoided with the concomitant administration of bicalutamide or one of the other androgen receptor antagonists . Within about 2 weeks, serum testosterone levels fall to the hypo-gonadal range.

5. Central precocious puberty— Continuous administrationof a GnRH agonist is indicated for treatment of central precocious puberty (onset of secondary sex characteristics before 7–8 years in girls or 9 years in boys). Before embarking on treatment with a GnRH agonist, one must confirm central precocious puberty by demonstrating a pubertal gonadotropin response to GnRH or a “test dose” of a GnRH analog. Treatment is typically indicated in a child whose final height would be otherwise significantly com-promised (as evidenced by a significantly advanced bone age) or in whom the development of pubertal secondary sexual characteristicsor menses causes significant emotional distress. While central precocious puberty is most often idiopathic, it is important to rule out central nervous system pathology with MRI imaging of the hypothalamic-pituitary area.

Treatment is most commonly carried out with either a monthly intramuscular depot injection of leuprolide acetate or with a once-yearly implant of histrelin acetate. Daily subcutaneous regimens and multiple daily nasal spray regimens of GnRH agonists are also available. Treatment with a GnRH agonist is generally continued to age 11 in females and age 12 in males.

6. Other—Other clinical uses for the gonadal suppression pro-vided by continuous GnRH agonist treatment include advanced breast and ovarian cancer; thinning of the endometrial lining in preparation for an endometrial ablation procedure in women with dysfunctional uterine bleeding; and treatment of amenorrhea and infertility in women with polycystic ovary disease. Recently pub-lished clinical practice guidelines recommend the use of continu-ous GnRH agonist administration in early pubertal transgender adolescents to block endogenous puberty prior to subsequent treatment with cross-gender gonadal hormones.

Toxicity

Gonadorelin can cause headache, light-headedness, nausea, and flushing. Local swelling often occurs at subcutaneous injection sites. Generalized hypersensitivity dermatitis has occurred after long-term subcutaneous administration. Rare acute hypersensitiv-ity reactions include bronchospasm and anaphylaxis. Sudden pituitary apoplexy and blindness have been reported following administration of GnRH to a patient with a gonadotropin-secret-ing pituitary tumor.

Continuous treatment of women with a GnRH analog (leuprolide, nafarelin, goserelin) causes the typical symptoms of menopause, which include hot flushes, sweats, and headaches. Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur. Ovarian cysts may develop within the first 2 months of therapy and generally resolve after an additional 6 weeks; however, the cysts may persist and require discontinuation of therapy. Reduced bone density and osteoporo-sis may occur with prolonged use, so patients should be monitored with bone densitometry before repeated treatment courses. Depending on the condition being treated with the GnRH ago-nist, it may be possible to ameliorate the signs and symptoms of the hypoestrogenic state without losing clinical efficacy by adding back a small dose of a progestin alone or in combination with a low dose of an estrogen. Contraindications to the use of GnRH agonists in women include pregnancy and breast-feeding.

In men treated with continuous GnRH agonist administra-tion, adverse effects include hot flushes and sweats, edema, gyne-comastia, decreased libido, decreased hematocrit, reduced bone density, asthenia, and injection site reactions. GnRH analog treatment of children is generally well tolerated. However, tem-porary exacerbation of precocious puberty may occur during the first few weeks of therapy. Nafarelin nasal spray may cause or aggravate sinusitis.