Approximately 10% of all couples will seek fertility assessment, and of these, a male factor will be found in up to two-thirds. Fertility assessment may be the first presentation of adult gonadotropin deficiency due to adult-onset or neglected pubertal delay. Missed diagnosis at this stage may have adverse long-term general health consequences (e.g., osteoporosis, sarcopenia, reduced quality of life), and may also immediately expose both the male and female partners, as well as any progeny, to the unnecessary risks of assisted reproduction.

Conventionally, gonadotropin deficiency is treated with androgen replacement therapy to induce and maintain virilization since steroids are cheaper and more easily administered than gonadotropins; however, tesris development, spermatogenesis, and fertility cannot be induced by exogenous testosterone alone, since the resulting inrratesricular testosterone concentrations are two orders of magnitude lower than that achieved with luteinizing hormone (LH) stimulation. Hence, gonadotropin or pulsatile gonadorropin-releasing hormone (GnRH) therapy is required for gonadorropin-deficient men who seek fertility. Since pregnancy is the desired outcome, spermatogenic and tesricular parameters are only surrogate markers of fertility. Nevertheless, sperm output is a critical, quantifiable, and prospecrively quantitative determinate of male fertility.

Although gonadotropin deficiency remains one of the few disorders of male fertility responsive to specific treatment, it accounts for less than 1% of all causes of infertility. Furthermore, affected men seek fertility on few occasions and successful pregnancy typically requires years (rather than months) of treatment. For these reasons, prospective randomized efficacy studies are not feasible, and even retrospective studies in specialized centers require decades to accumulate sparse and incomplete data. Among the larger studies of gonadotropin replacement, only six examined more than 20 men. These six include four multi-center studies where consistency of therapy may not have been maintained. Fertility outcome data following pulsatile gonadotropin-releasing hormone therapy are even sparser.

Important differences in the use and effect of gonadotropin therapy between men and women limit extrapolation. Gonadotropin therapy is typically used pharmacologically for ovarian hyperstimulation in women as part of a nonspecific infertility treatment. Furthermore, the effectiveness and risk of ovarian hyperstimulation syndrome with pharmacological gonadotropin therapy and the physiological variation in gonadotropin and steroid secretion during the menstrual cycle and with age (menopause) has no parallel in men. These important differences limit extrapolation, except when assessing pharmacokinetics, local tolerability, and antigenicity of specific gonadotropin preparations.

This post will therefore highlight studies performed specifically in gonadotropin-deficient men that examined pregnancy outcomes and predictors of fertility; however, since fertility data are so limited, with few studies including it as an important endpoint, other studies will also be included if quantitative spermatogenic data are provided, even if few participants actually sought fertility. The clinical application of this information will be emphasized.

Induction Of Spermatogenesis In Gonadotropin Deficiency

Gonadotropin Therapy

Gonadotropin-Releasing Hormone Therapy

Gonadotropin-Releasing Hormone is secreted by specific neuroendocrine cells located in the arcuate region of the mediobasal hypothalamus into a closed portal system through which it reaches the anterior pituitary gonadorropes, which secrete luteinizing-hormone and follicle-stimulating hormone. Endogenous gonadotropin-releasing hormone is secreted in a pulsatile fashion, typically every 90 to 120 minutes, and this pulsatility is essential to its action. Since small quantities are secreted into a closed system, systemically administered synthetic gonadotropin-releasing hormone (gonadorelin) must be given at much higher doses. Furthermore, long-acting analogues downregulate gonadotropin-releasing hormone action and are not useful in for the treatment of gonadotropin deficiency.

Regimens

Therapeutic studies in men with gonadotropin-releasing hormone deficiency confirm that 5 to 20 µg (25 to 600 ng / kg) per bolus administered every 90 to 120 minutes subcutaneously by portable pump through an indwelling butterfly needle results in physiological luteinizing-hormone and follicle-stimulating hormone response. The needle is usually placed in the abdominal wall and changed every two days. Therapy is monitored by serum luteinizing-hormone, follicle-stimulating hormone, and testosterone usually every two weeks initially, and then every two months. Although intravenous administration produces the most physiologic pulse characteristics and can successfully induce spermatogenesis and pregnancy, subcutaneous administration is more practical for long-term treatment. Intranasal gonadotropin-releasing hormone can maintain already induced spermatogenesis, but the need for frequent dosing every two hours also renders this clinically impractical.

Failure of gonadotropin-releasing hormone therapy may result from anti-GnRH antibody formation, which requires conversion to or supplementation with gonadotropin therapy. Although supplementary human chorionic gonadotropin / hMG treatment may further increase spermatogenesis in men with poor testosterone response to gonadotropin-releasing hormone therapy, it is not possible to determine if modification of gonadotropin-releasing hormone therapy alone would have been sufficient.

Expected Response To Therapy

Predictors Of Response

Nonpredictors Of Response

Choice of Gonadotropin or Pulsatile GNRH Therapy

As indicated by the above discussion, optimal gonadotropin or gonadotropin-releasing hormone therapy results in equivalent pregnancy rates, and spermatogenic and testicular response. As illustrated in Figure, the same relationship between initial testicular volume and treatment duration to induce spermatogenesis exists regardless of whether gonadotropin or pulsatile gonadotropin-releasing hormone therapy is used. Direct comparisons between therapies have been performed in three studies, but none were randomized and one was retrospective. Differences in pregnancy outcome have never been reported and only one of these three studies, recruiting only 18 men who self-selected therapy, found that gonadotropin-releasing hormone therapy was superior to gonadotropin therapy due to significantly faster onset of spermatogenesis and larger final testicular volume. Two separate single- case reports have also reported that pulsatile gonadotropin-releasing hormone can successfully induce spermatogenesis and cause pregnancy after failed gonadotropin therapy. Although there is insufficient data to conclude that gonadotropin-releasing hormone is more effective than gonadotropin therapy, a clinical trial of gonadotropin-releasing hormone after failed gonadotropin therapy may be warranted if feasible.

Cause of Gonadotropin Deficiency

Larger studies have consistently reported that the cause of gonadotropin deficiency is not a significant predictor of spermatogenic endpoints. Smaller studies (fewer than five men) have variably reported hypopituitarism as being advantageous or detrimental. Since hypopituitarism generally occurs postpubertally and is also associated with larger testicular volume, these other confounders must be adjusted for. Similar confounding variables may explain why various hypothalamic causes of gonadotropin deficiency may differ in response to gonadotropin-releasing hormone therapy. It therefore appears unlikely that the cause of gonadotropin deficiency is an important predictor of response if the effect of testicular volume and puberty are first accounted for.

Conclusion

The induction of spermatogenesis with gonadotropin replacement in gonadotropin-deficient men has long been the prototype for successful management of male infertility. Indeed, the effectiveness of urinary gonadotropins in these men has long rendered placebo-controlled studies unethical. Throughout this time, various gonadotropin regimens (subcutaneous vs. intramuscular and urinary vs. recombinant) have been available, differing in cost and convenience, but not in effectiveness.

Methods to improve the effectiveness of treatment have been unsuccessful so far. The superiority of pulsatile gonadotropin-releasing hormone therapy has not been definitively demonstrated, and hence the greater inconvenience is difficult to justify. Furthermore, gonadotropin or gonadotropin-releasing hormone dose escalation eventually becomes ineffective due to a ceiling in response. This fact combined with the unsuccessful attempts to apply these therapies more broadly to other causes of male infertility suggest that, in contrast to ovarian hyperstimulation, hormonal overdrive of spermatogenesis is not feasible. For these reasons, although the commercial availability of longer-acting, more conveniently administered, recombinant gonadotropin analogues are anticipated, effectiveness is unlikely to be improved. Protein- or gene-based treatments to enhance the effect of gonadotropin therapy may eventually be developed. Such research is highly desirable, and resultant therapies may have broad application to other causes of male infertility.

In the meantime, vigilance is required to limit exposure to transmissible prion disease, since decades may elapse between infection and symptoms. The application of quantitative multivariate statistical methods in larger datasets should be encouraged to better quantify clinically useful time-dependent variables and key predictors. Standard therapy needs to be continually reassessed to adjust for more accurate response estimates and advances in assisted reproduction: currently, judicial use of in vitro fertilization or intracytoplasmic sperm injection may be worthwhile if sperm density remains consistently less than 3 million / mL and spermatogenesis or pregnancy has been slow (more than 10 or 20 months, respectively). The role of recombinant luteinizing-hormone, in relation to human chorionic gonadotropin, needs appraisal, particularly in the context of pubertal, and eventually postnatal, tesricular priming. The accumulating evidence supporting the importance of age-appropriate gonadorropin exposure requires formal evaluation.

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