Induction of fertility in men with secondary hypogonadism
- Peter J Snyder, MD
Peter J Snyder, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Male Reproductive Endocrinology
- Professor of Medicine
- University of Pennsylvania School of Medicine
Sperm production cannot be stimulated in men who are infertile as a result of primary hypogonadism due to damage to the seminiferous tubules. On the other hand, sperm production can usually be stimulated to a level sufficient to restore fertility in men who are infertile as a result of secondary hypogonadism, ie, due to damage to the pituitary or hypothalamus. Men who have pituitary disease can be treated with gonadotropins, while those with hypothalamic disease can be treated with gonadotropins or gonadotropin-releasing hormone (GnRH). (See "Causes of secondary hypogonadism in males".)
Which patients are likely to respond? — The diagnosis of secondary hypogonadism must be firmly established before therapy is begun, since only patients whose infertility is due to this disorder will respond. We recommend treatment with gonadotropins for most men who have secondary hypogonadism due to either hypothalamic or pituitary disease who wish to become fertile (see "Clinical features and diagnosis of male hypogonadism"). Gonadotropin treatment will not increase the sperm count in men who have idiopathic oligospermia, in which a subnormal sperm count is associated with a normal serum testosterone concentration .
Several factors enhance the likelihood that the sperm count will be increased, and increased sooner after gonadotropin administration:
●Development of hypogonadism after puberty rather than before. In one study, as an example, all six men whose hypogonadism occurred postpubertally experienced an increase in total sperm count from less than one million to above 40 million per ejaculate when treated with human chorionic gonadotropin (hCG) (see 'Initial treatment: hCG' below). In comparison, only one of eight men whose hypogonadism occurred prepubertally (but without cryptorchidism) had a similar response .
●Partial hypogonadism, rather than complete, as judged by testes that are not as small [3-6], and serum concentrations of follicle-stimulating hormone (FSH), inhibin B, and testosterone that are not as low .
- Knuth UA, Hönigl W, Bals-Pratsch M, et al. Treatment of severe oligospermia with human chorionic gonadotropin/human menopausal gonadotropin: a placebo-controlled, double blind trial. J Clin Endocrinol Metab 1987; 65:1081.
- Finkel DM, Phillips JL, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med 1985; 313:651.
- Burris AS, Rodbard HW, Winters SJ, Sherins RJ. Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab 1988; 66:1144.
- Büchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol 1998; 139:298.
- Miyagawa Y, Tsujimura A, Matsumiya K, et al. Outcome of gonadotropin therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers: a 30-year retrospective study. J Urol 2005; 173:2072.
- Liu PY, Baker HW, Jayadev V, et al. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab 2009; 94:801.
- McLachlan RI, Finkel DM, Bremner WJ, Snyder PJ. Serum inhibin concentrations before and during gonadotropin treatment in men with hypogonadotropic hypogonadism: physiological and clinical implications. J Clin Endocrinol Metab 1990; 70:1414.
- Ley SB, Leonard JM. Male hypogonadotropic hypogonadism: factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens. J Clin Endocrinol Metab 1985; 61:746.
- Rastrelli G, Corona G, Mannucci E, Maggi M. Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study. Andrology 2014; 2:794.
- Zorn B, Pfeifer M, Virant-Klun I, Meden-Vrtovec H. Intracytoplasmic sperm injection as a complement to gonadotrophin treatment in infertile men with hypogonadotrophic hypogonadism. Int J Androl 2005; 28:202.
- Schaison G, Young J, Pholsena M, et al. Failure of combined follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1993; 77:1545.
- Saal W, Glowania HJ, Hengst W, Happ J. Pharmacodynamics and pharmacokinetics after subcutaneous and intramuscular injection of human chorionic gonadotropin. Fertil Steril 1991; 56:225.
- Claustrat B, David L, Faure A, Francois R. Development of anti-human chorionic gonadotropin antibodies in patients with hypogonadotropic hypogonadism. A study of four patients. J Clin Endocrinol Metab 1983; 57:1041.
- Thau RB, Goldstein M, Yamamoto Y, et al. Failure of gonadotropin therapy secondary to chorionic gonadotropin-induced antibodies. J Clin Endocrinol Metab 1988; 66:862.
- Warne DW, Decosterd G, Okada H, et al. A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin. Fertil Steril 2009; 92:594.
- Burris AS, Clark RV, Vantman DJ, Sherins RJ. A low sperm concentration does not preclude fertility in men with isolated hypogonadotropic hypogonadism after gonadotropin therapy. Fertil Steril 1988; 50:343.
- Farhat R, Al-zidjali F, Alzahrani AS. Outcome of gonadotropin therapy for male infertility due to hypogonadotrophic hypogonadism. Pituitary 2010; 13:105.
- Resorlu B, Abdulmajed MI, Kara C, et al. Is intracytoplasmic sperm injection essential for the treatment of hypogonadotrophic hypogonadism? A comparison between idiopathic and secondary hypogonadotrophic hypogonadism. Hum Fertil (Camb) 2009; 12:204.
- Liu L, Banks SM, Barnes KM, Sherins RJ. Two-year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1988; 67:1140.
- Kliesch S, Behre HM, Nieschlag E. High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic hypogonadal men. Eur J Endocrinol 1994; 131:347.
- Spratt DI, Finkelstein JS, O'Dea LS, et al. Long-term administration of gonadotropin-releasing hormone in men with idiopathic hypogonadotropic hypogonadism. A model for studies of the hormone's physiologic effects. Ann Intern Med 1986; 105:848.
- Pitteloud N, Hayes FJ, Dwyer A, et al. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2002; 87:4128.
- Whitten SJ, Nangia AK, Kolettis PN. Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate. Fertil Steril 2006; 86:1664.
- PRETREATMENT EVALUATION
- Which patients are likely to respond?
- GONADOTROPIN THERAPY
- Initial treatment: hCG
- - Dosing and regimen
- - Monitoring
- Adding FSH
- - Recombinant human FSH
- Clinical outcomes
- - Sperm concentration
- - Timing of response
- - Pregnancy not achieved
- - Pregnancy achieved
- ROLE OF PULSATILE GNRH
- CLOMIPHENE CITRATE
- SUMMARY AND RECOMMENDATIONS