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  • Review Article
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Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism

Nature Reviews Endocrinology volume 8, pages 172–182 (2012)Cite this article

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Abstract

Congenital hypogonadotropic hypogonadism (CHH) causes pubertal failure and infertility in both women and men due to partial or total secretory failure of the two pituitary gonadotropins lutropin (LH) and follitropin (FSH) during periods of physiological activation of the gonadotropic axis. Men and women with CHH frequently seek treatment for infertility after hypogonadism therapy. Some etiologies, such as autosomal dominant or X-linked Kallmann syndrome, raise the question of hereditary transmission, leading to increasing demands for genetic counseling and monitoring of medically assisted pregnancies. Diagnosis and treatment of newborn boys is, therefore, becoming an increasingly important issue. In male individuals with complete forms of CHH, the antenatal and neonatal gonadotropin deficit leads to formation of a micropenis and cryptorchidism, which could undermine future sexual and reproductive functions. Standard treatments, usually started after the age of puberty, often only partially correct the genital abnormalities and spermatogenesis. The aim of this Review is to examine the possible additional benefits of neonatal gonadotropin therapy in male patients with CHH. Encouraging results of neonatal therapy, together with a few reports of prepubertal treatment, support the use of this novel therapeutic strategy aimed at improving sexual and reproductive functions in adulthood.

Key Points

  • During fetal life, hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins play a key part in the development and growth of the male external genitalia

  • Complete congenital hypogonadotropic hypogonadism (CHH) is associated with penile and testicular hypotrophy and, in many cases, with cryptorchidism

  • Conventional treatment of patients with CHH, with testosterone or gonadotropins, is inadequately effective in terms of adult sexuality and fertility when started after the age of puberty

  • Neonatal treatment corrects genital hypotrophy and improves testicular endocrine function, which might improve the response to treatments intended to induce postpubertal virilization and to restore fertility in men with CHH

  • Long-term studies are needed to assess the effect of this approach on sexuality and fertility before recommending its routine use

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Figure 1: Schematic of the activation of the hypothalamic–pituitary–testicular axis during fetal and postnatal life in humans.
Figure 2: Genital aspect in a young man with Kallmann syndrome, surgically cured cryptorchidism and micropenis a | at presentation, when he was aged 18 years, then b | 6 months and c | 16 months after testosterone enanthate administration (250 mg every 3 weeks, intramuscularly).

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Acknowledgements

This work was supported by grants from Université Paris-Sud (Bonus Qualité Recherche), Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de la Recherche Genopath (ANR KALGENOPATH), Fondation pour la Recherche Médicale (FRM), Programme Hospitalier de Recherche Clinique (PHRC National: Hypo-Protéo) and Agence Française de Lutte contre le Dopage (AFLD).

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  1. Departement de Pédiatrie Endocrinienne, Hôpital Bicêtre–University Paris-Sud, 78 Rue du Général Leclerc, F-94275, Le Kremlin–Bicêtre, France

    Claire Bouvattier

  2.  Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre–University Paris-Sud, 78 Rue du Général Leclerc, F-94275, Le Kremlin–Bicêtre, France

    Luigi Maione & Jacques Young

  3.  Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpital Bicêtre–University Paris-Sud, 78 Rue du Général Leclerc, F-94275, Le Kremlin–Bicêtre, France

    Jérôme Bouligand & Anne Guiochon-Mantel

  4. Département de Génétique et Développement, Institut Cochin, 27 Rue du Faubourg Saint-Jacques, F-75679, cedex 14, Paris, France

    Catherine Dodé

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  1. Claire Bouvattier
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All authors researched the data for the article and provided a substantial contribution to discussions of the content. C. Bouvattier, L. Maione and J. Young contributed equally to writing the article. All authors reviewed and/or edited the manuscript before submission.

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Bouvattier, C., Maione, L., Bouligand, J. et al. Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism. Nat Rev Endocrinol 8, 172–182 (2012). https://doi.org/10.1038/nrendo.2011.164

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