Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age
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A recent report described a new PCOS-like phenotype in lean older infertile women, and was characterized by high age-specific anti-Müllerian hormone (AMH) but hypo- rather than the expected hyper-androgenism. The hypo-androgenism was, furthermore, characterized of, likely, adrenal origin and autoimmune etiology.
Patients and methods
We extracted data on 708 consecutive infertility patients, and separated them into three age-strata, <35, 36–42, and >42 years. In each stratum, we investigated how levels of anti-Müllerian hormone (AMH) and testosterone (T) interrelate between high-AMH (AMH ≥ 75th quantile) and normal AMH (25th–75th quantile) and low-T (total testosterone ≤19.0 ng/dL), normal-T (19.0–29.0 ng/dL) and high-T (>29.0 ng/dL). High-AMH cycles were presumed to reflect PCOS-like patients. Routine in vitro fertilization (IVF) cycle outcomes and clinical phenotypes of patients were then compared between groups with AMH and T as statistical variables.
This hypo-androgenic PCOS-like phenotype already exists in age stratum <35 years. It appears to arise from a lean, at very young ages hyper-androgenic PCOS phenotype that develops in comparison to controls (likely autoimmune-induced) insufficiency of the adrenal zona reticularis (low-T and low-DHEAS) and zona fasciculata (low-C), and is characterized by frequent evidence of autoimmunity. A degree of adrenal insufficiency, thus, concomitantly appears to affect adrenal androgen and, to lesser degrees, glucocorticoid production (mineralocorticoids were not investigated).
Here investigated new PCOS-like phenotype demonstrates features compatible with what under Rotterdam criteria has been referred to as PCOS phenotype-D. If confirmed, the observation that the ontogeny of this phenotype already at young ages is, likely, driven by adrenal autoimmunity, supports the position of the androgen excess and PCOS society that the etiology of phenotype-D differs from that of classical hyper-androgenic PCOS of mostly ovarian etiology.
KeywordsPolycystic ovary syndrome (PCOS) Androgens Hypo-androgenism In vitro fertilization (IVF) Infertility Anti-Müllerian hormone (AMH)
Body mass index
Follicle stimulating hormone
Functional ovarian reserve
Human menopausal gonadotropin
In vitro fertilization
Low functional ovarian reserve
Ovarian hyper-stimulation syndrome
Polycystic ovary syndrome
Sex hormone binding globulin
Study concept: N.G., D.H.B., V.A.K.; Study execution: All authors; Data analysis and statistical evaluation; S.K.D., D.H.B., N.G..; Manuscript preparation: N.G.; Significant manuscript revisions and final manuscript approval: All authors; Study supervision: N.
This work was supported by grants from the Foundation for Reproductive Medicine and intramural support from the Center for Human Reproduction (CHR)—New York. The funders had no role in study design, data collection, and analysis, decision to publish or preparation of the manuscript.
Compliance with ethical standards
Conflict of interest
N.G, and D.H.B, are co-inventors on a number of pending and already awarded U.S. patents claiming therapeutic benefits from androgen supplementation in women with low functional ovarian reserve (LFOR) and relating to the FMR1 gene in a diagnostic function in female fertility. Both receive royalties from Fertility Nutraceuticals, LLC, in which N.G. also holds shares. N.G., D.H.B and V.A.K. also are co-inventors on three pending AMH-related patent applications. All authors received research grants, travel funds and speaker honoraria from Pharma companies, though none in any way related to hear presented materials. The remaining authors declare that they have no conflict of interest.
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