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Serum insulin-like factor 3 quantification by LC–MS/MS in male patients with hypogonadotropic hypogonadism and Klinefelter syndrome

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Abstract

Purpose

Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC–MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS).

Methods

This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC–MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n = 96; KS: n = 71) or untreated (HH: n = 7; KS: n = 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated.

Results

In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p = 0.01).

Conclusions

The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear.

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Data availability

Restrictions apply to some or all the availability of data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.

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Funding

The study was funded by the Absalon Foundation (M.L.L.), Innovation Fund Denmark (14–2013–4), and The ReproUnion collaboration (J.A., A.J.U.), co-financed by The European Union, Interreg V ÖKS (NYPS-ID 20200407).

Author information

Authors and Affiliations

  1. Dept. of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Trine Holm Johannsen, Marie Lindhardt Ljubicic, Jørgen Holm Petersen, Jakob Albrethsen & Anders Juul

  2. International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Trine Holm Johannsen, Marie Lindhardt Ljubicic, Jørgen Holm Petersen, Jakob Albrethsen & Anders Juul

  3. Paris-Saclay University and Assistance Publique-Hôpitaux de Paris, Department of Reproductive Endocrinology, Bicêtre Hospital, Le Kremlin-Bicêtre, France

    Jacques Young

  4. Molecular Genetics, Pharmacogenomics, and Hormonology, Inserm U1185, Université Paris-Saclay, Assistance Publique Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France

    Séverine Trabado

  5. Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark

    Jørgen Holm Petersen

  6. Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark

    Allan Linneberg

  7. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Allan Linneberg

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  1. Trine Holm Johannsen
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  2. Marie Lindhardt Ljubicic
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  3. Jacques Young
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  4. Séverine Trabado
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  6. Allan Linneberg
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Corresponding author

Correspondence to Trine Holm Johannsen.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

Denmark: The study was approved by the ethics committees of the Capital Region of Denmark (H-KA20060011). All patient samples were taken as part of the clinical follow-up. Access to Danish patient data was approved by the Danish Patient Safety Authority (no. 3–3013–1376/1/) and the Danish Data Protection Agency (no. 2015–235, I-Suite no. 04204). In Denmark, the permission for INSL3 measurements was approved as part of a quality assurance project at Rigshospitalet, University Hospital of Copenhagen (approval no. 20012618). France: The study was approved by Assistance Publique-Hôpitaux de Paris and the institutional review boards at Bicêtre teaching hospital (Comité de Protection des Personnes Ile de France, Hôpital Bicêtre, Programme Hospitalier de Recherche Clinique [PHRC-2009, Hypoproteo].

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France: All participants gave written informed consent according to the French Bioethics Law and the Declaration of Helsinki.

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Johannsen, T.H., Ljubicic, M.L., Young, J. et al. Serum insulin-like factor 3 quantification by LC–MS/MS in male patients with hypogonadotropic hypogonadism and Klinefelter syndrome. Endocrine 71, 578–585 (2021). https://doi.org/10.1007/s12020-021-02609-0

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