Early onset of primary hypogonadism revealed by serum anti-Müllerian hormone determination during infancy and childhood in trisomy 21

Abstract

Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2months-20year). To compare with an adequate control population, we established reference levels for serum anti-Müllerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.

Long-term clinical course in three patients with <i>MAMLD1</i> mutations

“…Indeed, there are no objective clinical indicators for hypogonadism in such a period, and serum T values may overlap between control boys and patients with incomplete/mild testicular dysfunction. In support of this notion, apparently normal serum T values in infancy to early childhood and declined serum T values in later ages have occasionally been reported in patients with incomplete/mild hypogonadism-associated disorders such as Prader-Willi syndrome, Down syndrome, and Klinefelter syndrome [21][22][23]. Second, while Mamld1 knockout male mice have been produced [8], they would not serve as good models to examine the age-dependent deterioration of testicular function.…”

Male hypogonadism: an extended classification based on a developmental, endocrine physiology‐based approach

“…Interestingly, the elevated levels of intratesticular testosterone cannot induce meiosis in the foetal and neonatal testis most probably due to the lack of androgen receptor expression in Sertoli cells at those developmental periods (Berensztein et al, 2006;Chemes et al, 2008;Boukari et al, 2009;Rey et al, 2009). Subsequently, the activity of the axis decreases substantially; however, AMH (Aksglaede et al, 2010;Grinspon et al, 2011) and inhibin B production (Bergadá et al, 1999;Andersson & Skakkebaek, 2001) persists being active. Histologically, seminiferous cords do not have a lumen and are filled with Sertoli cells and spermatogonia that do not enter meiosis, whereas typical Leydig cells soon disappear from the interstitial tissue (Fig.…”

New perspectives in the diagnosis of pediatric male hypogonadism: the importance of AMH as a Sertoli cell marker

“…Serum AMH is transiently low in the first weeks after birth, then increases and peaks at the age of 2-3 years, and remains high until the onset of puberty. Then, AMH decreases, mainly between pubertal Tanner stages 2 and 3, to reach low adult levels (Table 1) (11,12). The onset of AMH expression in fetal life and the maintenance of its basal levels are gonadotropin-independent (13).…”