Autoimmunity to the Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone Receptor (LHR) in Polycystic Ovarian Syndrome

Hanna A Schniewind,Waldemar B Minich,Julia Münzker,Lisa-Marie Sattler,Barbara Obermayer-Pietsch,Lutz Schomburg,Christoph W Haudum

doi:10.3390/ijms222413667

Abstract

Hyperandrogenemia and ovulatory dysfunction are hallmarks of polycystic ovary syndrome (PCOS), pointing to a deranged hypothalamus-pituitary-ovarian (HPO) axis. An autoimmune etiology of PCOS is suspected in a subset of patients due to the relatively high concordance of PCOS with common autoimmune diseases. For this reason, we tested the hypothesis that natural autoantibodies (aAb) to the follicle-stimulating hormone receptor (FSHR) or luteinizing hormone receptor (LHR) are prevalent in PCOS. To this end, new luminometric assays for quantifying aAb to the FSHR (FSHR-aAb) or LHR (LHR-aAb) were developed using full-length recombinant human receptors as fusion proteins with luciferase as reporter. Prevalence of FSHR-aAb and LHR-aAb was determined in serum samples from healthy controls and PCOS patients. Steroid hormone profiles were compared between patients with and without FSHR-aAb or LHR-aAb. Signal linearity and detection ranges were characterized and both methods passed basic performance quality checks. The analysis revealed a relatively low prevalence, with 4 out of 430 samples positive for FSHR-aAb in the control versus 11 out of 550 samples in the PCOS group, i.e., 0.9% versus 2.0%, respectively. Similarly, there were only 5 samples positive for LHR-aAb in the control versus 2 samples in the PCOS group, i.e., 1.2% versus 0.4%, respectively. Samples positive for FSHR-aAb displayed steroid hormones in the typical range of PCOS patients, whereas the two samples positive for LHR-aAb showed relatively elevated free testosterone in relation to total testosterone concentrations with unclear significance. We conclude that the FSHR and LHR constitute potential autoantigens in human subjects. However, the prevalence of specific autoantibodies to these receptors is relatively low, both in control subjects and in women with PCOS. It is therefore unlikely that autoimmunity to the LHR or FSHR constitutes a frequent cause of hyperandrogenemia or ovulatory dysfunction in PCOS.

Highlights

Polycystic ovarian syndrome (PCOS) constitutes a common endocrine disorder affecting approximately 8–13% of adult European women, with the prevalence varying widely among different populations throughout the world [1]
The definition of PCOS includes morphological along with endocrine and symptomatic parameters, and the disease is currently diagnosed according to the Rotterdam criteria based on hyperandrogenemia, oligo-/anovulatory infertility, and/or polycystic ovary morphology [3]
This study describes two newly developed autoantibody assays for two human G-protein coupled receptors (GPCR), a first characterization of their key performance parameters, and a parallel application of these assays to test their potential suitability to aid PCOS diagnosis and improve our understanding of the disease

Summary

Introduction

Polycystic ovarian syndrome (PCOS) constitutes a common endocrine disorder affecting approximately 8–13% of adult European women, with the prevalence varying widely among different populations throughout the world [1]. Several lines of research are currently being pursued in the search for novel informative parameters to help identify the disease early, support treatment, and stratify the patients These include molecular analyses testing for associated gene variants and genetic alterations, metabolome and proteome analyses from different matrices, immunological approaches to identify alterations in cells of the immune system and circulating autoantibodies, or microbiome analyses [6,7,8,9]. Based on the currently available results, a purely genetic or environmental origin of PCOS is unlikely, and no single genetic biomarkers, environmental triggers, or common circulating disease-specific autoantibodies have been identified so far [7]. This notion again underlines the complexity of the disease, despite the observation that PCOS often runs in families. These numbers are considerably higher than the prevalence of 9.1–9.9% in the general female population [20], and further support the hypothesis of a relevant autoimmune component in a subgroup of patients with PCOS [21,22]

Methods

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Discussion

Conclusion