Compromised Volumetric Bone Density and Microarchitecture in Men With Congenital Hypogonadotropic Hypogonadism

J Clin Endocrinol Metab. 2021 Aug 18;106(9):e3312-e3326. doi: 10.1210/clinem/dgab169.


Context: Men with congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) have both low circulating testosterone and estradiol levels. Whether bone structure is affected remains unknown.

Objective: To characterize bone geometry, volumetric density and microarchitecture in CHH/KS.

Methods: This cross-sectional study, conducted at a single French tertiary academic medical center, included 51 genotyped CHH/KS patients and 40 healthy volunteers. Among CHH/KS men, 98% had received testosterone and/or combined gonadotropins. High-resolution peripheral quantitative computed tomography (HR-pQCT), dual-energy x-ray absorptiometry (DXA), and measurement of serum bone markers were used to determine volumetric bone mineral density (vBMD) and cortical and trabecular microarchitecture.

Results: CHH and controls did not differ for age, body mass index, and levels of vitamin D and PTH. Despite long-term hormonal treatment (10.8 ± 6.8 years), DXA showed lower areal bone mineral density (aBMD) in CHH/KS at lumbar spine, total hip, femoral neck, and distal radius. Consistent with persistently higher serum bone markers, HR-pQCT revealed lower cortical and trabecular vBMD as well as cortical thickness at the tibia and the radius. CHH/KS men had altered trabecular microarchitecture with a predominant decrease of trabecular thickness. Moreover, CHH/KS men exhibited lower cortical bone area, whereas total and trabecular areas were higher only at the tibia. Earlier treatment onset (before age 19 years) conferred a significant advantage for trabecular bone volume/tissue volume and trabecular vBMD at the tibia.

Conclusion: Both vBMD and bone microarchitecture remain impaired in CHH/KS men despite long-term hormonal treatment. Treatment initiation during adolescence is associated with enhanced trabecular outcomes, highlighting the importance of early diagnosis.

Keywords: Congenital hypogonadotropic hypogonadism; HR-pQCT; Kallmann syndrome; androgen replacement therapy; bone microarchitecture; bone mineral density; exome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorptiometry, Photon
  • Adolescent
  • Adult
  • Bone Density*
  • Bone and Bones / pathology*
  • Cross-Sectional Studies
  • Early Diagnosis
  • Estradiol / blood
  • Genotype
  • Gonadotropins / deficiency*
  • Hormone Replacement Therapy
  • Humans
  • Hypogonadism / congenital
  • Hypogonadism / drug therapy
  • Hypogonadism / pathology*
  • Kallmann Syndrome / pathology
  • Male
  • Middle Aged
  • Testosterone / blood
  • Tomography, X-Ray Computed
  • Young Adult


  • Gonadotropins
  • Testosterone
  • Estradiol