Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ∼50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRH-synthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ∼10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

Testosterone Deficiency in Men: Systematic Review and Standard Operating Procedures for Diagnosis and Treatment

From the Division of Endocrinology, the Hospital for Sick Children, and the Departments of Pediatrics and Physiology, University of Toronto — both in Toronto (M.R.P.); and the Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London (L.D.). Address reprint requests to Dr. Palmert at the Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada, or at mark.palmert@sickkids.ca; or to Dr. Dunkel at the Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Sq., London EC1M 6BQ, United Kingdom, or at l.dunkel@ qmul.ac.uk.

Clinical practice. Delayed puberty.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1743-6109.2010.01780.x

Endocrine Aspects of Male Sexual Dysfunctions

The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (∼10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development.

Clinical Management of Congenital Hypogonadotropic Hypogonadism

Background: The induction of spermatogenesis and fertility with gonadotropin therapy in gonadotropin-deficient men varies in rate and extent. Understanding the predictors of response would inform clinical practice but requires multivariate analyses in sufficiently large clinical cohorts that are suitably detailed and frequently assessed. Design, Setting, and Participants: A total of 75 men, with 72 desiring fertility, was treated at two academic andrology centers for a total of 116 courses of therapy from 1981–2008. Outcomes: Semen analysis and testicular examination were performed every 3 months. Results: A total of 38 men became fathers, including five through assisted reproduction. The median time to achieve first sperm was 7.1 months [95% confidence interval (CI) 6.3–10.1]) and for conception was 28.2 months (95% CI 21.6–38.5). The median sperm concentration at conception for unassisted pregnancies was 8.0 m/ml (95% CI 0.2–59.5). Multivariate correlated time-to-event analyses show that larger testis v...

H. W. Gordon Baker

Papers

Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome.