Could an Antibody Test Serve for Simple Diagnosis of PCOS?

AUSTIN, Texas — Detection of an autoantibody directed at a peptide on the gonadotropin-releasing hormone receptor (GnRH) could serve as a diagnostic laboratory test for polycystic ovary syndrome (PCOS), pioneering new research indicates.

The findings were presented May 6 here at the annual meeting of the American Association of Clinical Endocrinologists (AACE) 2017 Annual Scientific & Clinical Congress by Myriam Elkosseifi, MD, an endocrinology fellow at Oklahoma University Health Sciences Center, Oklahoma City.

Currently, the diagnosis of PCOS is typically made using the Rotterdam criteria, which require two of the following three to be present: oligo- or anovulation; clinical and/or biological signs of hyperandrogenism; and detection of polycystic ovaries by ultrasound.

"As of now, it remains a diagnosis of exclusion. No viable laboratory-based assay has been available," Dr Elkosseifi said in her presentation.

As a result, diagnosis and treatment are typically delayed for 2 or more years as women visit multiple medical specialists and undergo numerous tests, thereby increasing healthcare costs. In addition, current hormonal and insulin-sensitizing treatments are imperfect, she noted.

In contrast, an ELISA assay that detects serum autoantibodies directed to the 28-amino acid second extracellular loop of the GnRH receptor "appears to fulfill the need for an inexpensive, sensitive, and specific test to identify subjects with PCOS-activating autoantibodies," she explained.

And, pending validation of the findings with a much larger group of women with PCOS, her team also plans to test a "decoy" peptide that could block the antibodies and possibly even cure the disease.

Groundbreaking Research Representing a Paradigm Shift

Gregory Dodell, MD, assistant clinical professor of medicine, endocrinology, diabetes, and bone disease at the Icahn School of Medicine at Mount Sinai, New York, called the findings "groundbreaking."

"There are so many patients who come into our practices frustrated by years of delay in getting a diagnosis to explain their symptoms….If we had a test, like the one we have for thyroid disease, not only endocrinologists would find that useful but ob-gyns and even primary-care physicians could use it to diagnose the condition earlier and then refer to endocrinologists to let us manage it. It would speed things up," Dr Dodell told Medscape Medical News.

Moreover, he said that the demonstration of an autoimmune etiology for PCOS is intriguing and a departure from the medical community's understanding of the condition: "This is the first time I've heard this.…It's paradigm-shifting."

But Dr Dodell is a bit more skeptical of the potential for a PCOS "cure," noting that "autoimmune disorders are tough to cure. Why would this be any different?"

Is PCOS an Autoimmune Condition?

Previously, Dr Elkosseifi and her colleagues in Oklahoma have demonstrated the presence of autoantibodies against the second extracellular loop of different G-proteins in various other disease states, including postural orthostatic tachycardia syndrome, leading them to hypothesize that such antibodies to the second extracellular loop of the GnRH receptor would be present in PCOS and be of diagnostic and pathogenic value.

After synthesizing the GnRH target peptide, they obtained samples from 32 women with documented PCOS from a reproductive endocrinology and infertility clinic, along with 38 age- and body mass index–matched ovulatory infertile women. Of those, the causes of infertility were tubal in seven, male factor in 12, and unexplained (but PCOS ruled out) in 19.

Using an ELISA assay directed at the target peptide, Dr Elkosseifi and colleagues found a statistically significant difference between the optical densities of the PCOS samples compared with the ovulatory infertile women (0.26 vs 0.17, P < .01).

In addition, the results remained significant in comparisons of the PCOS women with each of the subgroups of other ovulatory infertile women.

The area under the receiver-operator curve was 0.94 (P < .0001), "a pretty accurate test," she noted.

Thus, a GnRH autoantibody level > 0.20 would indicate the presence of PCOS, with a sensitivity of 91% and specificity 87%.

An analysis of antibody activity using intracellular calcium demonstrated a dose-dependent effect, while the addition of the GnRH-specific antagonist cetrorelix blocked the IgG-induced GnRH-receptor activity down to the level seen in the controls. There was no difference in that activity among the controls before and after the addition of cetrorelix. This indicated both specificity and the activating effect of the antibodies, Dr Elkosseifi said.

"It is likely these activating autoantibodies disrupt hypothalamic and pituitary [luteinizing hormone (LH) and follicle-stimulating hormone] signaling and lead to abnormal gonadal signaling in afflicted individuals," she commented.

Future Plans, Including Possible Treatment

As a next step, the Oklahoma group plans to validate the findings in a much larger cohort of more than 800 women with PCOS from a national database. They will also conduct studies of passive transfer of the autoantibody from women with PCOS to mice to assess the effect on their hormonal cycles and LH levels.

The investigators also plan to investigate the effect of an antagonist "decoy peptide" to try to block the antibodies as a possible cure for PCOS.

Moreover, Dr Elkosseifi added, "The variable presence and activity of these autoantibodies in females and in males raises the possibility that they are active in other conditions," including hyperandrogenism, metabolic syndrome, hypogonadotropic hypogonadism, premature pubarche and puberty, and cancers of the ovary, endometrium, breast, and prostate.

Dr Dodell noted that the future studies would need to assess various subtypes of women with PCOS and also correlations between these autoantibody concentrations and levels of LH and symptom severity.

"I think this will be a good diagnostic tool, but as far as treatment we'll have to wait and see. If that works for this as a proof of concept, maybe it could be applied to other conditions."

Dr Elkosseifi and Dr Dodell have no relevant financial relationships; the principal investigator for the study is seeking patents related to the results.

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American Association of Clinical Endocrinologists (AACE) 2017 Annual Scientific & Clinical Congress. May 6, 2017; Austin, Texas. Abstract 1125.

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