Agnès Ostertag1, Georgios E Papadakis2,3, Corinne Collet4, Severine Trabado5,6,7, Luigi Maione3,6,7, Nelly Pitteloud2,8, Jerome Bouligand5,6,7, Marie Christine De Vernejoul1, Martine Cohen-Solal1, Jacques Young3,6,7. 1. Department of Rheumatology, Université de Paris and INSERM UMR-U1132 (Biology of bone and cartilage research unit), Hôpital Lariboisière, Paris, France. 2. Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, CH-1011, Lausanne, Switzerland. 3. Department of Reproductive Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France. 4. Service de Biochimie et de Génétique Moléculaire, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, France and INSERM UMR-U1132, UFR Sciences pharmaceutiques et biologiques - Faculté de pharmacie, Université de Paris, France. 5. Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpitaux Universitaires Paris Saclay, Assistance Publique-Hôpitaux de Paris, CHU Bicêtre, France. 6. INSERM UMR-U1185, Fac Med Paris Saclay, Université Paris-Saclay, Le Kremlin Bicêtre, France. 7. University Paris Saclay, Orsay cedex, France. 8. Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Abstract
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. DESIGN: Cross-sectional study. SETTING: One tertiary academic French center. PATIENTS AND CONTROLS: 51 genotyped CHH/KS patients and 40 healthy volunteers were included. Ninety-eight percent of CHH/KS men had received testosterone and/or combined gonadotropins. INTERVENTION(S): High-resolution Peripheral Quantitative Computed Tomography (HR-pQCT), Dual X-ray absorptiometry (DXA) and measurement of serum bone markers. MAIN OUTCOME: Volumetric bone mineral density (vBMD), cortical and trabecular microarchitecture. RESULTS: CHH and controls did not differ for age, BMI, vitamin D and PTH levels. Despite long-term hormonal treatment (10.8 ± 6.8 years), DXA showed lower areal BMD 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 the age of 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.
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. DESIGN: Cross-sectional study. SETTING: One tertiary academic French center. PATIENTS AND CONTROLS: 51 genotyped CHH/KSpatients and 40 healthy volunteers were included. Ninety-eight percent of CHH/KSmen had received testosterone and/or combined gonadotropins. INTERVENTION(S): High-resolution Peripheral Quantitative Computed Tomography (HR-pQCT), Dual X-ray absorptiometry (DXA) and measurement of serum bone markers. MAIN OUTCOME: Volumetric bone mineral density (vBMD), cortical and trabecular microarchitecture. RESULTS:CHH and controls did not differ for age, BMI, vitamin D and PTH levels. Despite long-term hormonal treatment (10.8 ± 6.8 years), DXA showed lower areal BMD 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/KSmen had altered trabecular microarchitecture with a predominant decrease of trabecular thickness. Moreover, CHH/KSmen exhibited lower cortical bone area, whereas total and trabecular areas were higher only at the tibia. Earlier treatment onset (before the age of 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/KSmen 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