Gonadorelin

Gonadotropin-releasing hormone (GnRH), a decapeptide secreted by the hypothalamus, regulates the production and release of gonadotropins by the pituitary. Recently, synthetic analogs of GnRH have become commercially available for the treatment of endometriosis, infertility, prostate cancer, precocious puberty and hirsutism. [1] By exogenous administration of these agonists, the pituitary-gonadal axis can be manipulated to achieve a desired effect. The GnRH agonists are capable of either arousing or suppressing the activity of the gonadal pathway, depending on the means of administration. [2]

Chemistry

Several GnRH agonist analogs have been discovered, all of which are more potent than naturally occurring GnRH. The basic structure of the three analogs is similar, differing only at two sites (Table 1). [1,3] Each of the analogs has an ethylamide group substituted for the carboxy-terminal glycine moiety of GnRH, which promotes greater receptor affinity to the

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compound. The analogs also have a substitution for the glycine at position 6. The larger and more hydrophobic the substitution, the greater the potency of the drug.

Of the analogs available, only leuprolide (Lupron) and nafarelin (Synarel) have been approved for use in the United States. Gonadorelin acetate ( Lutrepulse), which has also been approved for use in the United States, is not actually an analog of GnRH; instead, it as a synthetic formulation of the neurohormone itself.

Mechanism of Action

The anterior pituitary gland secretes six major hormones. Of these, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play an important role in the pituitary-gonadal axis. Synthesis and release of these hormones is tightly controlled by the secretion of neurohormonal releasing factors from the hypothalamus and by direct feedback from existing plasma levels of the hormones themselves. The hypothalamus, which lies below the thalamus and posterior to the optic chiasm, is the source of these neurohormonal releasing factors.

GnRH is one of several neurohormonal releasing factors that travel by way of a unique portal vascular system to the anterior pituitary, where they exert their effects on the hormone-producing cells (Figure 1). Despite the extremely small concentrations of the neurohormones produced, the hypophyseal portal system is able to accurately deliver a significant concentration of the neurohormones to the anterior pituitary without "wasting" much to the peripheral circulation. The neurohormones can produce either stimulatory or inhibitory regulation on the target anterior pituitary cells.

Under normal physiologic conditions, the releasing factors are secreted from the hypothalamus is discrete pulsatile bursts. For GnRH, these pulses usually occur every two to six hours. [3,4] If GnRH is administered exogenously in a cyclically pulsed schedule, it can induce the pituitary to secrete increased amounts of LH and FSH.

If GnRH is made available to the anterior pituitary in a continuous drip or a depot injection, an initial surge (up-regulation) in the levels of LH and FSH will be followed rapidly by a sharp decline in concentration (down-regulation). LH and FSH levels then remain depressed until GnRH is available on an intermittent schedule. This activity is the result of the continuous availability of releasing factors that saturate the receptor sites of the neurohormone in the anterior pituitary gland and, in turn, lead to desensitization and down-regulation in the maintenance and control of the hypothalamic-pituitary axis.

In women, LH is predominantly responsible for ovulation, while FSH develops maturing follicles and induces enzymes to

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convert androgens to estrogens. In men, LH increases production of testosterone by interstitial Leydig cells in the testes. FSH, in conjunction with testosterone, is required for spermatogenesis.

A GnRH agonist can be used to stimulate or inhibit LH and FSH production and thereby serve as either an infertility aid or a contraceptive. [5,6] The dosing schedule is the key to the drug's action.

Pharmacokinetics

The half-life of GnRH has been estimated as approximately two to four minutes. GnRH circulates within the hypophyseal portal system almost completely unbound to a carrier protein but is highly susceptible to degradation by circulating proteins in the blood, which explains the difference between the physiologically significant concentration of hormone in the portal system and the nearly undetectable concentration of hormone in peripheral serum. Nafarelin and leuprolide have a half-life of approximately three hours--much longer than that of GnRH.

The bioavailability of gonadorelin, leuprolide and nafarelin is relatively similar. They exhibit equal bioavailability patterns in intravenous and subcutaneous preparations. All of these formulations are poorly absorbed via oral, vaginal or rectal routes. Nafarelin is also available as an intranasal spray. Although the bioavailability of the nasally administered preparation is only one-fifth that of the subcutaneously administered preparation, the preparations have an equal biologic effectiveness, as measured by LH and FSH response. Although it is much more amenable to long-term outpatient use, the intranasally administered aerosol spray is absorbed in a highly variable fashion. Several factors, such as nasal congestion, administration technique and low ambient temperatures (which may cause nasal constriction), affect the degree of absorption.

Adverse Reactions

Although GnRH is a naturally occurring neurohormone, it has some side effects. Since all of the GnRH agonists have a similar structure and mechanism of action, they share the same adverse reactions. The most common effects are flushing, headache, nausea and vomiting.[1] Most of the effects of the drugs are secondary to the hypoestrogenic state they induce. Phlebitis, anaphylactic reactions, abdominal cramping and gynecomastia have also been observed. Bone loss is a major concern in patients who are treated for long periods. [4] Patients receiving nafarelin therapy should be advised to discontinue the drug after six months because of the risk of long-term bone loss. Up to 10 percent of patients treated with the aerosol nafarelin spray have reported nasal irritation. [7]

Clinical Uses

Although gonadorelin, leuprolide and nafarelin share the same mechanism of action and are structurally similar, they differ in their indications for use. They are used interchangeably for many nonapproved applications. As use of these drugs increases, their cost, ease of administration and potency will become important considerations in the choice of a particular GnRH agonist. Uses, modes of administration, adverse reactions, doses, treatment duration and cost of the agents are summarized in Table 2.

GONADORELIN

Gonadorelin is identical to naturally occurring GnRH. It is administered either subcutaneously or intravenously, usually in a pulsatile fashion using an infusion pump. It has been found to be effective in inducing ovulation in patients who are refractory to clomiphene (Clomid) and bromocriptine (Parlodel). [4,6] The frequency of spontaneous abortion and multiple birth with gonadorelin therapy is similar to that occurring with clomiphene treatment, 20 percent and 7 percent, respectively.

Gonadorelin is also indicated for diagnostic testing of hypogonadal patients. [4] After gonadorelin is administered, the plasma LH level is monitored over the next two hours. A rise in the LH level indicates primary hypothalamic dysfunction; a stationary LH level indicates a hypopituitary state or end-organ dysfunction.

LEUPROLIDE

Leuprolide is, at present, indicated only for the palliative treatment of prostate cancer that is unresponsive to other treatments, such as orchiectomy or estrogen therapy. [1] Since the goal of therapy is to greatly reduce the concentration of testosterone, leuprolide is given in a continuous fashion.

Compared with the thromboembolic events associated with estrogen treatment and the stress of orchiectomy, the side effects of leuprolide are benign and few. Furthermore, the Leuprolide Study Group found that leuprolide treatment is almost identical to estrogen therapy in terms of one-year survival rates and response rates. [8] After approximately two to four weeks, levels of testosterone and alkaline phosphatase in leuprolide-treated patients are similar to those in castrated patients.

NAFARELIN

Because nafarelin can be administered intranasally, it is much more amenable to outpatient use. Like gonadorelin, it can also be used for diagnostic testing of the hypogonadal patient. [5] Its other indication is the treatment of endometriosis. It appears to be as effective as danazol (Danocrine) in the treatment of endometriosis. [3,4,9] Many investigators are now using nafarelin in conjunction with low-dose danazol and achieving better results than with either therapy alone. Both danazol and nafarelin only control the symptoms of endometriosis, not the disease. Fifty percent of patients who had complete relief of symptoms with nafarelin noted return of their symptoms within six months of cessation of therapy. [4] Nafarelin has been limited to six months of continuous administration because of its tendency to produce osteopenia in some patients.

Nafarelin has also been used for the treatment of hirsutism due to polycystic ovary syndrome. [1,9] Although not officially approved for this use, nafarelin appears to be a reasonable choice of therapy, since polycystic ovary syndrome causes a state of relative hyperandrogenemia. Long-term treatment is required, however, and early termination of the therapy results in the reappearance of signs and symptoms. Estrogens must be administered concurrently to prevent the development of osteoporosis.

Precocious puberty was an untreatable disorder until the development of GnRH agonists. Nafarelin has been shown to successfully treat this disorder by down-regulating and deactivating the prematurely active pituitary-gonadal axis and, therefore, blocking the release of LH and FSH. [4,9] Osteopenia does not occur with long-term nafarelin treatment in children. Instead, nafarelin stops premature growth and prevents the devastating growth defects that arise from early closure of the epiphyseal plates.

Other nonapproved indications for nafarelin include treatment of prostate cancer, uterine fibroids, infertility and contraception. [4] When administered in a pulsatile fashion to a preovulatory woman, nafarelin helps additional follicles develop to full maturity. It also blocks premature luteal surges, helping to assure that ovulation occurs on schedule. Continuous administration of the drug completely inhibits the luteal surge and actually abolishes ovulation. Once the drug is withdrawn, normal menstrual function resumes without side effects.

Final Comment

Vast strides have been made in neuroendocrinology over the past decade. By exogenous manipulation of the hypopituitary-gonadal axis, hormonal excesses or deficiencies can be controlled with new agents that have few side effects. Additionally, some studies have found GnRH receptors in solid tumors. Certain solid tumors, notably pancreatic, pituitary, breast and ovarian, may thus respond to treatment with GnRH agonists. [4] However, these studies are preliminary and must be repeated. The future of GnRH analogs appears promising as they are used with increasing frequency for diseases that currently have no optimal treatments.

REFERENCES

[1] Facts and comparisons. St. Louis: Facts and Comparisons Div., J.B. Lippincott Co., 1991: 115j-p.

[2] Heber D, Bhasin S, Steiner B, Swerdloff RS. The stimulatory and down-regulatory effects of a gonadotropin-releasing hormone agonist in man. J Clin Endocrinol Metab 1984;58:1084-8.

[3] Kurel AK, Murad F. Adenohypophyseal hormones and related substances. In: Gilman AG, ed. The Pharmacological basis of therapeutics. New York: Pergamon Press, 1991:1334-60.

[4] Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogues. N Engl J Med 1991; 324:93-103.

[5] Rosenfield RL, Burstein S, Cuttler L, et al. Use of nafarelin for testing pituitary-ovarian function. J Reprod Med 1989; 34 (12 Suppl): 1044-50.

[6] Martin MC. Gonadotropin releasing hormone agonists and the induction or augmentation of ovulation. J Reprod Med 1989; 34 (12 Suppl):1034-8.

[7] Chan RL, Henzl MR, LePage ME, et al. Absorption and metabolism of nafarelin, a potent agonist of gonadotropin-releasing hormone. Clin Pharm Ther 1988; 44:275-82.

[8] Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med 1984;311:1281-6.

[9] Jaffe RB. Nafarelin in gynecologic use. A symposium. J Reprod Med 1989; 34 (12 Suppl):1017-20.

JOSEPH. PACE, M.D. is a second-year resident in internal medicine at Hahnemann University School of Medicine, where he also earned his medical degree.

JEFFREY L. MILLER, M.D. is associate professor of medicine and assistant director of the Division of Endocrinology and Metabolism at Hahnemann University School of Medicine. Dr. Miller earned his medical degree at the University of Witwatersrand, Johannesburg, South Africa. He completed a residency in internal medicine and a fellowship in endocrinology and metabolism at the University of Cape Town, South Africa.

LESLIE I. ROSE, M.D. is professor of medicine and chief of the Division of Endocrinology and Metabolism at Hahnemann University School of Medicine, Philadelphia. Dr. Rose graduated from George Washington University School of Medicine and Health Sciences, Washington, D.C., where he also completed a residency in internal medicine. He served a fellowship in endocrinology and metabolism at Harvard Medical School, Boston.

COPYRIGHT 1991 American Academy of Family Physicians
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