AACE Guildlines:
Gonadal Stimulation in Hypogonadotropic Hypogonadism
Because gonadotropin or GnRH therapy is effective only in hypogonadotropic hypogonadism, this diagnosis must be firmly established before consideration of therapy. Although these agents may also be used to induce puberty in boys and to treat androgen deficiency in hypogonadotropic hypogonadism, the major use of these preparations is in the initiation and maintenance of spermatogenesis in hypogonadotropic men who desire fertility.
Gonadotropin Therapy in Androgen Deficiency
It is known that hCG binds to Leydig cell LH receptors and stimulates the production of testosterone. Peripubertal boys with hypogonadotropic hypogonadism and delayed puberty can be treated with hCG instead of testosterone to induce pubertal development. The initial regimen of hCG is usually 1,000 to 2,000 IU administered intramuscularly two to three times a week. The clinical response is monitored and testosterone levels are measured about every 2 to 3 months. Dosage adjustments of hCG may be needed to determine an optimal schedule. Increasing doses of hCG may reduce testicular stimulation by down-regulating the end-organ; thus, a more optimal result may occur with less frequent or reduced dosing. The half-life of hCG is long.Gonadotropin Therapy for Induction of Spermatogenesis
Male patients with onset of hypogonadotropic hypogonadism before completion of pubertal development may have testes smaller than 5 mL. These patients usually require therapy with both hCG and human menopausal gonadotropin (or FSH) to induce spermatogenesis. Men with partial gonadotropin deficiency, or who have previously (peripubertally) been stimulated with hCG, may initiate and maintain production of sperm with HCG only. Men with postpubertal-acquired hypogonadotropic hypogonadism and who have previously had normal production of sperm can also generally initiate and maintain production of sperm with hCG therapy only. Fertility may be possible at sperm counts much lower than what would otherwise be considered fertile. Counts of less than 1 million/mL may be associated with pregnancies under these circumstances. It is imperative that the female partner undergo assessment for optimal fertility before or concurrently with consideration of therapy in the man.
Therapy with hCG is generally begun at 1,000 to 2,000 IU intramuscularly two to three times a week, and testosterone levels should be monitored monthly to determine whether any therapeutic adjustments are needed to normalize the levels. It may take 2 to 3 months to achieve normal levels of testosterone. When normal levels of testosterone are produced, examinations should be conducted monthly to determine whether any testicular growth has occurred. Sperm counts should also be conducted monthly during a 1-year period. Because of the high cost of human menopausal gonadotropin (or FSH) preparations, hCG should be the initial therapy of choice for at least 6 to 12 months. Use of hCG, in the absence of exogenous FSH, can often complete spermatogenesis in men with partial gonadotropin deficiency. In general, the response to hCG can be predicted on the basis of the initial testicular volume—the greater the initial testicular volume, the greater the chance of responding to hCG only.
If spermatogenesis has not been initiated by the end of 6 to12 months of therapy with hCG or LH, administration of an FSH-containing preparation is initiated in a dosage of 75 IU intramuscularly three times a week along with the hCG injections. After 6 months, if sperm are not present or are present in very low numbers (<100,000 per mL), the human menopausal gonadotropin (or FSH) dosage can be increased to 150 IU intramuscularly three times a week for another 6 months. If pregnancy occurs, the patient’s regimen can be switched to only hCG to allow continued spermatogenesis for subsequent potential pregnancies. After delivery, if no further pregnancies are desired, the patient can be switched to testosterone therapy if desired, or long-term hCG therapy can be continued in conjunction with appropriate contraceptive measures, if needed. Rarely, antibodies against hCG may arise and prevent any response to therapy; in such a case, human LH may be effective. Recombinant LH has recently become available and may be of use in selected patients.
Gonadotropin-releasing Hormone (GnRH) Therapy
In patients with an otherwise intact pituitary gland and hypogonadotropic hypogonadism, synthetic gonadotropin-releasing hormone (GnRH) can be given in a pulsatile fashion subcutaneously through a pump every 2 hours. GnRH therapy is monitored by measuring LH, FSH, and testosterone levels every 2 weeks until levels are in the normal range, at which point monitoring can be adjusted to every 2 months. GnRH can be used to initiate pubertal development, maintain virilization and sexual function, and initiate and maintain spermatogenesis. In most patients, these effects may take from 3 to 15 months to achieve sperm production. As with gonadotropin therapy, fertility can be achieved with very low sperm counts—often in the range of 1 million/mL. GnRH may be more effective than gonadotropin stimulation in increasing testicular size and initiating spermatogenesis in many patients with hypogonadotropic hypogonadism.
Other Treatment Considerations
Antiestrogen Therapy in Oligospermia
Currently, the guideline authors do not recommend the general use of clomiphene citrate or tamoxifen for treatment of oligospermia in male patients.
Assisted Reproductive Technology
The ability to perform in vitro fertilization with intracytoplasmic sperm injection directly into the egg has revolutionized the approach to male subfertility. A single sperm or immature form retrieved from the testicle is sufficient to fertilize an egg and provide a reasonable chance at pregnancy. In vitro fertilization with intracytoplasmic sperm injection may be a viable option in many men with hypogonadism who cannot otherwise be induced to produce enough sperm to result in pregnancy as well as in the presence of a female factor that may further make pregnancy by the couple difficult or impossible. The procedure is expensive and seldom covered by health insurance; therefore, this technology will generally not replace conventional gonadal stimulation protocols. Intrauterine insemination may also be a low-cost option in suitable women when the man has mild to moderate oligospermia.
Pituitary Tumors
Patients with acquired hypogonadotropic hypogonadism may require assessment for a possible pituitary tumor with appropriate pituitary imaging studies, such as MRI, and determination of a prolactin level. Depending on the presence or absence of a tumor, other hormonal testing may be indicated, including thyroid and adrenal function tests. Further evaluation and treatment options would depend on what hormonal deficits are present, the size and site of the tumor, the operability of the tumor, and the patient’s preferences in specific circumstances.
If a prolactinoma is present, therapy would be directed toward correcting this problem before initiation of other therapy. Medical therapy with bromocriptine, pergolide, or cabergoline may effectively reduce prolactin levels sufficiently to allow gonadal function to resume or allow stimulation with gonadotropins. Even when prolactin levels cannot be normalized, hCG therapy alone or in conjunction with human menopausal gonadotropin (or FSH) therapy may stimulate spermatogenesis in treated prolactinomas and result in pregnancies.
Surgical therapy should especially be considered for significant pituitary tumors that are not prolactin-secreting microadenomas. Surgical treatment may also be an option in prolactin-secreting microadenomas if patients have severe side effects from medications or prefer this approach after being appropriately informed of the risks and benefits of medical versus surgical management.
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