Effects of acute hCG stimulation on serum INSL3 and 25-OH vitamin D in Klinefelter syndrome

Daniele Santi; Richard Ivell; Ravinder Anand-Ivell; Luca De Toni; Flaminia Fanelli; Marco Mezzullo; Carla Pelusi; Uberto Pagotto; Serena Belli; Antonio R M Granata; Laura Roli; Vincenzo Rochira; Tommaso Trenti; Alberto Ferlin; Manuela Simoni

doi:10.1111/andr.12851

Diagnostics · Hormone Testing

Effects of acute hCG stimulation on serum INSL3 and 25-OH vitamin D in Klinefelter syndrome

Santi D, Ivell R, Anand-Ivell R, De Toni L, Fanelli F, Mezzullo M, Pelusi C, Pagotto U, Belli S, Granata ARM, Roli L, Rochira V, Trenti T, Ferlin A, Simoni M

Published November 2020 Andrology

DOI 10.1111/andr.12851 PMID 32593193

RRM Academy Synopsis

A single hCG dose did not raise INSL3 or vitamin D in Klinefelter men

One hCG injection raised neither INSL3 nor vitamin D in either group of men. This retrospective analysis of a prospective trial compared 11 men with Klinefelter syndrome and 11 age-matched healthy men over five days. INSL3, a hormone made by testicular Leydig cells, was lower at baseline among the men with Klinefelter syndrome.

Key Findings

At baseline, INSL3 was lower in 11 men with Klinefelter syndrome than in 11 healthy controls (p=0.007).
Testosterone was lower in the Klinefelter group (p=0.004). The testosterone-to-INSL3 ratio (p=0.251) and the 17-hydroxyprogesterone-to-INSL3 ratio (p=0.282) did not differ between groups.
Baseline vitamin D did not differ between groups (p=0.064) and was below the normal range in both. One hCG injection did not significantly change INSL3 or vitamin D in either group.
A small INSL3 increase at visits 1 and 2 appeared in two men with Klinefelter syndrome and four controls.
Among controls, higher body mass index and larger waist circumference went with lower INSL3 (Rho -0.750, p=0.020 for each).

Interpretation

The study is a retrospective analysis of stored blood samples from a prospective case-control trial, with 11 men per group aged 18 to 45. Not every sample held enough serum for INSL3 testing at every time point. Participants with Klinefelter syndrome had a non-mosaic 47,XXY karyotype and no past androgen replacement. The trial tested a single hCG dose. The authors did not measure testosterone inside the testis and report that INSL3 testing has no clear clinical use in Klinefelter syndrome yet. The body mass index and waist findings are correlations in a small control group.

RRM Context

Restorative reproductive medicine evaluates the male partner and seeks the cause of a hormone finding before treatment. Low blood testosterone in Klinefelter syndrome may reflect faulty steroid production. Low release of testosterone into the blood is another possible source. Here, steroid output adjusted for INSL3 suggested that the Leydig cells in these men kept their ability to make steroids.

Our editorial summary of this paper, not the article's abstract.

Abstract

Background

It has recently been suggested that the hypergonadotropic hypogonadism characterizing Klinefelter syndrome (KS) might not be due to a steroidogenic dysfunction per se, but mainly to an altered testosterone (T) secretion into the bloodstream. However, the Leydig cell functionality remains incompletely studied in KS, and new markers should be considered. Previous data indicated that chronic hCG stimulation influences the production of both insulin-like peptide 3 (INSL3) and 25-hydroxy-vitamin D (25-VD) in eugonadal men.

Aim

To evaluate INSL3 and 25-VD serum levels, as markers of Leydig cell functionality, in association with sex steroids, after an acute hCG test in a group of KS patients and healthy volunteers.

Methods

A retrospective analysis of a prospective case-control clinical trial was carried out. KS patients (n = 11) and age-matched healthy controls (n = 11) provided a basal blood sample (V0) immediately followed by a single intramuscular injection of hCG 5000 IU. Blood samples were taken in the following five days (V1-V5).

Results

At baseline, INSL3 was lower in KS patients compared with controls (P = .007). When adjusted for INSL3 levels, the production of steroids was similar between KS patients and controls. 25-VD was in the insufficient range both in KS patients and in controls and was not different (P = .064). Acute hCG stimulation increased neither INSL3 nor 25-VD in both KS patients and controls. In controls, an inverse correlation was detected between INSL3 levels and body mass index (P = .020) and waist circumference (P = .020).

Conclusions

INSL3 secretion is independent from steroidogenesis, and its production is mostly not influenced by acute hCG stimulation both in KS men and in controls. INSL3 serum levels should be considered as a marker of Leydig cell differentiation and numbers rather than steroidogenesis. 25-VD serum levels are also not increased by a single acute hCG administration, which was not able to restore the normal concentrations of 25-VD.

Topics

Diagnostics Hormone Testing Serum Panels

Diagnostics › Hormone Testing › Serum Panels

Daniele Santi, Richard Ivell, Ravinder Anand-Ivell, Luca De Toni, Flaminia Fanelli, Marco Mezzullo, Carla Pelusi, Uberto Pagotto, Serena Belli, Antonio R M Granata, Laura Roli, Vincenzo Rochira, Tommaso Trenti, Alberto Ferlin, Manuela Simoni

D Santi, Rick Ivell, Dick Ivell, Rich Ivell, R Ivell, R Anand-Ivell, L Toni, F Fanelli, M Mezzullo, C Pelusi, U Pagotto, S Belli, A Granata, L Roli, V Rochira, T Trenti, A Ferlin, M Simoni

PMID 32593193 32593193 DOI 10.1111/andr.12851 10.1111/andr.12851 Santi et al. 2020, Santi 2020

Effects of acute hCG stimulation on serum INSL3 and 25-OH vitamin D in Klinefelter syndrome

A single hCG dose did not raise INSL3 or vitamin D in Klinefelter men

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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