In prepubertal patients with hypogonadism, treatment is directed at initiating pubertal development at the appropriate age. Age of therapy initiation takes into account the patient's psychosocial needs, current growth, and growth potential. Treatment entails hormonal replacement therapy with sex steroids, ie,estrogen for females and testosterone for males.

Introduction of sex steroids in such cases startswith the use ofsmall, escalating doses over a period of a couple of years. In females, introduction of puberty can begin with administration of small doses of estrogen given either orally or transdermally. One traditional regimen uses conjugated estrogen startingat doses as low as 0.15 mg daily and titrating upwards in 6-12 month intervals to typically 0.625 mg daily, at which point menses can be induced with the introduction of a progestin. Alternatively, transdermal 17-estradiol (0.08 to 0.12 mcg estradiol/kg) can be used.

In boys, introduction of puberty is achieved with the use of testosterone, administered intramuscularly or transdermally (in the form of a patch or gel). A typical regimen involves testosterone enanthate injections 50 mg monthly, titrating up to 200-250 mg every 2 weeks, which is a typical adult replacement dose. Adult testosterone dose can be adjusted to maintain serum testosterone concentrations in the normal adult range.

Therapy with sexsteroid replacement ensures development of secondary sexual characteristics and maintenance of normal sexual function. In patients with hypergonadotropic hypogonadism, fertility is not possible. However, patients with hypogonadotropic hypogonadism have fertilitypotential,although therapy with sex steroids does not confer fertility or stimulate testicular growth in men.An alternative for men with hypogonadotropic hypogonadism has been treatment with pulsatile LHRH or hCG, either of which can stimulate testicular growth and spermatogenesis.

Because such treatment is more complex than testosterone replacement, and because treatment with testosterone does not interfere with later therapy to induce fertility, most male patients with hypogonadotropic hypogonadism prefer to initiate and maintain virilization with testosterone.At a time when fertility is desired, it may be induced with either pulsatile LHRH or (more commonly) with a schedule of injections of hCG and FSH. Similarly, fertility can be achieved in females with pulsatile LHRH or exogenous gonadotropin. Such therapy results in ovulation in 95% of women.

A phase III, multicenter, open-label, single-arm trial by Nieschlag et al indicated that corifollitropin-alfa therapy combined with hCG treatment can significantly increase testicular volume and induce spermatogenesis in adult males with hypogonadotropic hypogonadism whose azoospermia could not be cured by hCG treatment alone. Patients in the study who remained azoospermic, though with normalized testosterone levels, after 16 weeks of hCG treatment underwent 52 weeks of twice-weekly hCG therapy along with every-other-week corifollitropin-alfa treatment (150 g). Mean testicular volume in these patients rose from 8.6 mL to 17.8 mL, while spermatogenesis was induced in more than 75% of subjects. [9]

The use of oral testosterone preparations, such as 17-alkylated androgens (eg, methyltestosterone), is discouraged because of liver toxicity. However, oral testosterone undecanoate is available in some countriesand is now approved in the United States. Intramuscular testosterone is available as testosterone enanthate or cypionate. Transdermal testosterone can be administered either in the form of a patch or gel. A nasal testosterone replacement therapy has been approved by the US Food and Drug Administration (FDA) for adult males with conditions such as primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired) resulting from a deficiency or absence of endogenous testosterone. [10] The recommended dosage is 33 mg/day in three divided doses. The drug has not been approved for males younger than 18 years.

For older men with testosterone deficiency, a review by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) found that the evidence concerning the risk of serious cardiovascular side effects from the use of testosterone in men with hypogonadism was inconsistent. [11, 12] The PRAC determined that the benefits of testosterone outweigh its risks but stressed that testosterone-containing medicines should be used only when lack of testosterone has been confirmed by signs and symptoms, as well as by laboratory tests. However,a literature review by Albert and Morley indicated that testosterone supplementation in males aged 65 years or older may increase the risk of cardiovascular events, particularly during the first year of treatment, althoughintramuscular testosterone seemed to carry less risk than other forms. [13]

On the other hand,a study by Traish et al suggested that long-term testosterone therapy in men with hypogonadism significantly reduces cardiovascular diseaserelated mortality. Patients in the studys testosterone-treated group (n=360) underwent therapy for up to 10 years, with median follow-up being 7 years. The investigators found no cardiovascular eventrelated deaths in the treated patients, compared with 19 such deaths in the group that received no testosterone therapy (n=296). According to the study, mortality in the testosterone-treated patients was reduced by an estimated 66-92%. [14]

The latest Endocrine Society clinical practice guidelines suggest testosterone therapy for men receiving high doses of glucocorticoids who also have low testosterone levels, to promote bone health. The guidelines also suggest such therapy in human immunodeficiency virus (HIV)infected men with low testosterone levels, to maintain lean bone mass and muscle strength.

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Hypogonadism Treatment & Management: Approach ...

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