Diagnosis of Male Central Hypogonadism During Childhood

Abstract

The diagnosis of male central (or hypogonadotropic) hypogonadism, typically based on low LH and testosterone levels, is challenging during childhood since both hormones are physiologically low from the 6 th month until the onset of puberty. Conversely, FSH and anti-Müllerian hormone (AMH), which show higher circulating levels during infancy and childhood, are not used as biomarkers for the condition. We report the case of a 7-year-old boy with a history of bilateral cryptorchidism, who showed repeatedly low FSH and AMH serum levels during prepuberty. Unfortunately, the diagnosis could not be ascertained until he presented with delayed puberty at the age of 14 years. A GnRH test showed impaired LH and FSH response. By then, his growth and bone mineralization were partially impaired. Gene panel sequencing identified a variant in exon 15 of FGFR1, affecting the tyrosine kinase domain of the receptor, involved in GnRH neuron migration and olfactory bulb morphogenesis. Testosterone replacement was started, which resulted in the development of secondary sexual characteristics and partial improvement of bone mineral density. This case illustrates the difficulty in making the diagnosis of central hypogonadism in boys during childhood based on classical criteria, and how serum FSH and AMH assessment may be helpful to suspect it before the age of puberty, and confirm it using next-generation sequencing. The possibility of making an early diagnosis of central hypogonadism may be useful for a timely start of hormone replacement therapy, and to avoid delays that could affect growth and bone health as well as psychosocial adjustment.

Delayed Puberty Due to a WDR11 Truncation at Its N-Terminal Domain Leading to a Mild Form of Ciliopathy Presenting With Dissociated Central Hypogonadism: Case Report

“…Less frequently, only one cell population (Leydig, Sertoli, or germ cells) is primarily affected, resulting in a dissociated hypogonadism (30). Boys with failure to enter puberty due to central hypogonadism obviously show a deficiency in the LH-Leydig cell axis, while the FSH-Sertoli cell axis is usually overlooked (31,32). The existence of microorchidism prompts the suspicion of concomitant FSH insufficiency, since this gonadotropin is critical for Sertoli cell proliferation, and Sertoli cells are the main component of the testes before pubertal onset (31).…”

AMH Regulation by Steroids in the Mammalian Testis: Underlying Mechanisms and Clinical Implications

“…The continuous effect of high FSH levels on Sertoli cells for almost one year (the last 6 months of fetal life plus the 3-6 months of postnatal life induces a progressive increase in serum AMH ( 57 ), which peaks at 5-6 months of age ( 58 ). This explains why serum AMH levels are low, in coincidence with small testicular size, in boys with congenital central (hypogonadotrophic) hypogonadism ( 45 , 59 ) and increase after FSH treatment ( 60 , 61 ). The underlying molecular mechanisms include the classical cyclic AMP-dependent pathway triggered by the FSH receptor coupled to the Gαs protein ( 16 ), which activates SOX9 ( 62 ) and SF1 ( 62 ) acting on the proximal AMH promoter, but also NFκB and AP2, which bind to response elements lying approximately 2 kb upstream of the AMH start site ( 62 ).…”

“…In patients with 46,XX DSD, serum AMH above the female range indicates the existence of functional testicular tissue suggesting the diagnosis of ovotesticular or testicular DSD, in contrast with other forms of XX virilization, such as aromatase deficiency, congenital adrenal hyperplasia of androgen-secreting tumors, which present with serum AMH in the female range ( 42 ). In normally virilized boys, low serum AMH is seen in patients with primary ( 24 , 43 , 44 ) or central hypogonadism ( 45 ). Conversely, high AMH is suggestive of Sertoli cell tumors ( 46 ), excessive signaling downstream the FSH receptor pathway like in McCune-Albright syndrome ( 47 ), or hyperestrogenism ( 19 ).…”

Recent advancement in the treatment of boys and adolescents with hypogonadism

“…When the condition is of central origin, the FSH insufficiency results in reduced Sertoli cell numbers, leading to microorchidism and low serum AMH and inhibin B. 11,14,15 If congenital hypogonadism goes unnoticed during the first 3 to 6 months of postnatal life, androgen insufficiency cannot be detected during childhood, and low Sertoli cell biomarkers 3,4,[16][17][18] and genetic tests 19,20 are more helpful for the diagnosis (Figure 1). At the age of puberty, lack of pubertal signs prompts the assessment.…”