Gonadotropin-Releasing Hormone Deficiency in Adults Treatment & Management

Updated: Jan 09, 2017
  • Author: Vaishali Popat, MD, MPH; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Treatment

Medical Care

The choice of therapy depends on the patient's desire to achieve one or more of the following: secondary sex characteristics, fertility, and bone and muscle mass.

Treatment in males

In deciding when and how to provide androgen replacement in males, the patient's age, the potential adverse effects of therapy, and the patient's desire for fertility should be considered. In the prepubertal male who has congenital hypogonadism, androgens stimulate penile growth, body and facial hair growth, bone and muscle development, and voice changes. In addition, androgens stimulate growth hormone production, thus contributing to the adolescent growth spurt.

Because males with androgen deficiency can experience significant social ridicule, starting androgen therapy around age 14-15 years is prudent.

Oral, injectable, transdermal, and implantable (pellets) androgen formulations currently are available for the treatment of males with Kallmann syndrome (KS) and idiopathic hypogonadotropic hypergonadism (IHH). Oral androgen preparations should not be used due to their toxic effects on the liver and adverse effects on lipids.

The injectable long-acting testosterone esters (eg, testosterone enanthate/cypionate) are low-cost, relatively safe, and effective, with a proven 50-year record. The disadvantages include intramuscular injection and a nonphysiologic pattern of testosterone over the dosing interval that in some men can cause wide swings in libido and mood. Research currently is being conducted on longer-acting and sustained-release formulation of testosterone injectables.

Transdermal application avoids first-pass liver metabolism, provides a noninvasive method of replacement, and results in more physiologic serum concentration of testosterone over a daily dosing period. Transdermal patches (scrotal and nonscrotal) and a gel preparation of testosterone are currently available. The most common adverse effect with these formulations is skin reactions at the application site. The gel preparation may be preferred by some patients because it is not visibly apparent and has fewer dermal reactions. However, the gel formulation may result in cross contamination to those in close contact with the patient.

In prepubertal patients, a usual starting dose of 50-75 mg of testosterone injection is used monthly with the expectation of increasing the dose by 50 mg every 4-6 months until sexual maturation has been reached. The troublesome adverse effects of acne and gynecomastia should be monitored closely and the dose adjusted accordingly.

In place of testosterone replacement, injections (200-500 IU alternate d) of human chorionic gonadotropin (hCG) can also be used in the prepubertal male. Although doses should ultimately be based on clinical response and testosterone levels, a twice-weekly dosing regimen of 100-1500 IU or 200-500 IU on alternate days is typical. The advantages of hCG are the normalization of testosterone levels and stimulation of testicular growth. The cost and numerous injections have primarily resulted in reserving hCG for men attempting fertility.

In adult males desiring fertility, a different approach to replacement therapy is employed. Spermatogenesis can be restored with a combination of hCG and human menopausal gonadotropin (hMG, follicle-stimulating hormone [FSH], and luteinizing hormone [LH]), hCG and FSH alone, or gonadotropin-releasing hormone (GnRH) injections. Occasionally, patients may respond to hCG alone. Testicular volumes greater than 3-4 mL can be used to predict those individuals who will respond to hCG. Careful monitoring of testicular size is helpful in gauging the effect of treatment. Those individuals who reach testicular sizes of 12-15 mL usually produce sperm after 12 months of treatment initiation. These hCG-only responsive individuals usually represent the fertile eunuch or patients with late-onset adult IHH.

Most patients with IHH and KS require a combination of hCG and FSH to stimulate sperm production. The starting dose for hCG is 1000 IU, and FSH is 75-150 IU on alternate days with dosage adjusted based on trough testosterone level, testicular growth, sperm production, and avoidance of adverse effects. The most common adverse effect is gynecomastia, which occurs in as many as 30% of patients. This is related to increased estrogen production from several factors, such as hCG induction of testicular aromatase and increase in the peripheral aromatization of testosterone. These monitoring periods should occur every 3 months until an adequate level of replacement is documented. Pregnancy has occurred with counts as low as 2.5 X 106, but 20-40 X 106/mL produces higher pregnancy rates. The median time to induction of spermatogenesis is 6-8 months.

The pulsatile administration of GnRH is an effective alternative to gonadotropin administration. The dose of GnRH ranges from 25-600 ng/kg every 2 hours delivered subcutaneously using a programmable portable infusion pump. As with gonadotropins, the dose and pulse are alternated based on testicular size, testosterone levels, spermatogenesis, and adverse effects. Once the testis has reached 8 mL, regular semen analysis can be obtained. Most patients require as long as 2 years of therapy before they reach maximal gonadal size and sperm production.

GnRh therapy in prepubertal boys to evoke puberty may represent a more physiologic approach because the pulse of GnRH can be altered to mimic the natural process of puberty. Again, the response time appears to be influenced by the initial testicular size; larger testes at the start of therapy result in less time on gonadotropins or GnRH.

Determination of which therapy to use (ie, gonadotropins or GnRH pulses) is related more to preference than science. Therapies appear to be equally effective. The time to full testicular growth and spermatogenesis may be somewhat shorter when using GnRH, although this appears controversial. Some anecdotal evidence suggests that GnRH therapy has proven successful in individuals refractory to gonadotropin treatments. The disadvantage of GnRH, beyond the need to use a pump, is that it is available only at specialized centers pending approval by the Food and Drug Administration (FDA) for this indication.

Treatment in females

In females, as in males, treatment is dictated by the age and fertility desires of the patient. For the woman not currently desiring fertility, estrogen replacement is required to prevent osteoporosis.

The principal estrogen produced by the functioning premenopausal ovary is 17beta-estradiol. Daily serum measurements of estradiol in regularly menstruating women indicate that the mean estradiol levels throughout the menstrual cycle are approximately 104 pg/mL (382 pmol/L). [48] Oral and parenteral preparations (ie, subcutaneous pellets and implants, transdermal patches, vaginal creams and rings) are available for standard hormone replacement therapy in normal postmenopausal women.

Oral estrogens have the disadvantage of the first hepatic passage. Parenteral administration bypasses the intestine, avoids the first pass effect of liver metabolism, and thus prevents the abnormal E2/E1 ratio observed following oral administration. [49, 50] Transdermally administered 17-beta estradiol has been shown to be an effective regimen for preventing bone loss in normal postmenopausal women. [50] The goal is to replace sex hormones in young women by trying to mimic the normal ovarian function.

All women with an intact uterus should receive a cyclical progestin to accompany estradiol replacement. The 12-day administration of medroxyprogesterone acetate (10 mg by mouth daily) per month has been shown to adequately protect the endometrium in continuous hormone replacement therapy. Alternatively, oral micronized progesterone (100 mg by mouth daily for 12-14 days per month) can be used.

Optimal hormone therapy depends on whether the patient has primary or secondary amenorrhea. Young women with primary amenorrhea in whom secondary sex characteristics have failed to develop should initially be exposed to very low doses of estrogen in an attempt to mimic the gradual pubertal maturation process. A typical regimen is as follows: 0.3 mg of conjugated equine estrogens or 25-μg estradiol patch unopposed (ie, no progestogen) daily for 6 months with incremental dose increases at 6-month intervals until the required maintenance dose is achieved. Gradual dose escalation often results in optimal breast development and allows time for the young woman to adjust psychologically to her physical maturation. Cyclical progestogen therapy, given 12-14 days per month, should be instituted toward the end of the second year of treatment.

Barrier methods of contraception should also be provided in the rare event that one of these patients spontaneously ovulates. For the same reason, barrier contraception should also be recommended to women with adult-onset IHH who do not wish to become pregnant.

Women who desire fertility, similar to males, are faced with a much more complicated process. Reports of women with KS achieving a spontaneous pregnancy are rare, with only about 20 described in the literature. The medical treatment strategy is to increase gonadotropin stimulation of the ovaries; 2 pathways (exogenous or endogeneous) are recognized. Exogenous stimulation of the ovaries is accomplished with various preparations of human menopausal gonadotropin composed of FSH with different concentrations of LH. Endogeneous stimulation is accomplished with pulsatile GnRH. Intravenous pulsatile GnRH appears to have advantages over gonadotropins because it can be pulsed to mimic the normal menstrual dynamics. When applied to other IHH conditions, the pregnancy rate, cancellation of cycles, and multiple births rate are improved when compared to gonadotropin therapy.

Reversal of idiopathic hypogonadotropic hypogonadism

Recent reports have shown possible reversal of KS after therapy with hormone replacement. [51, 52] As many as 10% of males with KS have resumption of endogenous androgen production. Men who receive exogenous testosterone rarely have an increase in testicular volume. However, an increase in size reflects the impact of endogenous androgen action. Therefore, assessing reversibility of the condition after a brief discontinuation of hormonal therapy in men who demonstrate an increase in testicular volume is recommended.

In one report, adult-onset IHH was postulated to be a consequence of an altered central set point for estradiol-mediated negative feedback. [53] A 31-year-old man with this condition was treated with low-dose clomiphene citrate (25-50 mg/d) for 4 months with complete reversal of the condition. This method of treatment normalized the endogenous pulsatility of the gonadotropins, testosterone production, and sexual function and, thus, may result in improved fertility in patients with IHH.