Reproductive Phenotypes in Men With Acquired or Congenital Hypogonadotropic Hypogonadism: A Comparative Study

J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2812-e2824. doi: 10.1210/clinem/dgac194.


Context: In men with congenital hypogonadotropic hypogonadism (CHH), gonadotropin deficiency and testicular impairment exist since fetal development and persist throughout life. In a few reported cases of acquired HH (AHH), HH onset occurs mainly post pubertally.

Objective: This work aimed to compare the natural history and reproductive status in large series of CHH and lesional AHH evaluated in a single expert academic center.

Methods: We included 172 controls, 668 male HH patients (CHH: n = 201 [age 16.9 ± 9.0 years], lesional AHH: n = 467 [age 45.6 ± 18.4 years]) caused by hypothalamic and/or pituitary tumors (mainly adenomas and craniopharyngiomas) or infiltrative/traumatic diseases.

Results: At diagnosis, CHH were significantly younger, with 52.9% diagnosed before age 18 years, compared to only 9.6% of AHH patients. Cryptorchidism (21.9% vs 0.3%) and micropenis were more prevalent in CHH than AHH patients. Low testicular volume (TV) was present in 97% of patients with CHH (mean TV: 3.4 ± 2.7 mL) but in only 30% of those with AHH (mean TV: 20.8 ± 5.0 mL). Whereas no men with persistent CHH had spontaneous fertility, 70.4% of AHH men fathered at least one child without medical therapy. Total testosterone was lower both in CHH and AHH patients than in controls. Compared to controls, circulating gonadotropins and testicular peptides (insulin-like factor-3 and inhibin B) were decreased both in CHH and AHH, but were significantly higher in patients with AHH.

Conclusion: In AHH patients, the HH has later onset and is less severe than in CHH and the phenotype can overlap with that of individuals with normal laboratory values. Our data suggest that age at diagnosis is a predictor of the reproductive phenotype in AHH.

Keywords: INSL3; Kallmann syndrome; acquired hypogonadotropic hypogonadism; congenital hypogonadotropic hypogonadism; estradiol; fertility; gonadotropins; inhibin B; testicular volume.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryptorchidism*
  • Gonadotropins
  • Humans
  • Hypogonadism* / diagnosis
  • Male
  • Phenotype
  • Testosterone


  • Gonadotropins
  • Testosterone