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Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age

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Abstract

Background

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.

Results

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).

Conclusions

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.

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Abbreviations

ACTH:

Adrenocorticotrophic hormone

AI:

Adrenal insufficiency

AMH:

Anti-Müllerian hormone

AR:

Androgen receptor

BMI:

Body mass index

C:

Cortisol

CP:

Clinical pregnancies

CRP:

C-reactive protein

DHEA:

Dehyroepiandrosterone

DHEAS:

Dehyroepiandrosterone sulfate

FSH:

Follicle stimulating hormone

FOR:

Functional ovarian reserve

GCs:

Granulosa cells

hMG:

Human menopausal gonadotropin

Ig:

Immunoglobulin

IL-6:

Interleukin 6

IVF:

In vitro fertilization

LB:

Live births

LFOR:

Low functional ovarian reserve

OHSS:

Ovarian hyper-stimulation syndrome

PCO:

Polycystic ovary

PCOS:

Polycystic ovary syndrome

SHBG:

Sex hormone binding globulin

T:

Testosterone

TPO:

Thyroid peroxidase

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Author contributions

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.

Funding

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.

Author information

Authors and Affiliations

  1. The Center for Human Reproduction, New York, NY, 10021, USA

    Norbert Gleicher, Vitaly A. Kushnir, Sarah K. Darmon, Qi Wang, Lin Zhang, David F. Albertini & David H. Barad

  2. The Foundation for Reproductive Medicine, New York, NY, 10020, USA

    Norbert Gleicher & David H. Barad

  3. Stem Cell Biology and Molecular Embryology Laboratory, Rockefeller University, New York, NY, 10016, USA

    Norbert Gleicher & David F. Albertini

  4. Department of Obstetrics and Gynecology, Vienna University School of Medicine, 1090, Vienna, Austria

    Norbert Gleicher

  5. Department of Obstetrics and Gynecology, Wake Forest University, Winston Salem, Winston Salem, NC, 27101, USA

    Vitaly A. Kushnir

Authors
  1. Norbert Gleicher
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  2. Vitaly A. Kushnir
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  3. Sarah K. Darmon
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  7. David H. Barad
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Corresponding author

Correspondence to Norbert Gleicher.

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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.

Appendix

Appendix

Table 5 Comparison of IVF cycle characteristics in women with normal-AMH at age <35 years between low-, normal-T and high-T
Full size table
Table 6 Comparison of IVF cycle characteristics in women with normal-AMH at ages 35–42 years between low-T, normal-T and high-T
Full size table
Table 7 Comparison of patient and IVF cycle characteristics in high-AMH patients at ages 35–42 years with low-T, normal-T, and high-T
Full size table
Table 8 Comparison of patient and IVF cycle characteristics in normal-AMH patients at ages >42 years with low-T, normal-T, and high-T
Full size table
Table 9 Comparison of patient and IVF cycle characteristics in high-AMH patients at age >42 years with low-T, normal-T, and high-T
Full size table

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Gleicher, N., Kushnir, V.A., Darmon, S.K. et al. Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age. Endocrine 59, 661–676 (2018). https://doi.org/10.1007/s12020-017-1498-8

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  • DOI: https://doi.org/10.1007/s12020-017-1498-8

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