Abstract
Congenital hypogonadotrophic hypogonadism (CHH) is a rare but important etiology of pubertal failure and infertility, resulting from impaired gonadotrophin-releasing hormone secretion or action. Despite the availability of effective hormonal therapies, the majority of men with CHH experience unsatisfactory outcomes, including chronic psychosocial and reproductive sequelae. Early detection and timely interventions are crucial to address the gaps in medical care and improve the outlook for these patients. In this paper, we review the clinical implications of missing minipuberty in CHH and therapeutic strategies that can modify the course of disease, as well as explore a targeted approach to identifying affected male infants by integrating clinical and biochemical data in the early postnatal months.
Highlights
Congenital hypogonadotrophic hypogonadism (CHH) is a rare genetic condition characterized by reproductive disorder due to deficiency in secretion or action of gonadotrophin-releasing hormone (GnRH)
The genetic defects underpinning CHH broadly fall into two principle groups, comprising (a) those causing neurodevelopmental defects of GnRH neuron migration frequently associated with non-reproductive defects, anosmia/hyposmia from olfactory axon misrouting (i.e., Kallmann syndrome–KS), and (b) those causing pure neuroendocrine impairment of GnRH secretion or action
In the first published report of a boy with CHH and micropenis who received short-term recombinant human luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from age 7.9–13.7 months, the penile length successfully increased by 50% and the testicular volume nearly tripled by the end of treatment [65]
Summary
Congenital hypogonadotrophic hypogonadism (CHH) is a rare genetic condition characterized by reproductive disorder due to deficiency in secretion or action of gonadotrophin-releasing hormone (GnRH). Pulsatile GnRH secretion in the neonatal period appears to be paramount for the normal development of male genitalia, with a far-reaching impact on male reproductive phenotype and fertility potential later in adult life Another important clinical implication of minipuberty is that it potentially provides a window-of-opportunity to facilitate detection of children with congenital GnRH deficiency, who would demonstrate abnormally low FSH, LH, and T levels if measured, thereby offering the advantage of a definitive prepubertal diagnosis and sign-posting them to pre-planned pubertal-induction with sex hormones at median age of pubertalonset, rather than expectative management. Definitive evidence is currently lacking, the prospect of early childhood hormonal intervention in CHH boys in augmenting sexual and reproductive function in adult life is worth serious consideration, and hopefully will provide impetus for larger clinical trials
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