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A form of secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism as new infertility diagnosis

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Abstract

Background

Mediated via the androgen receptor on granulosa cells, models of small growing follicle stages demonstrate dependence on testosterone. Androgen deficiency reduces ovarian response to follicle stimulation hormone (FSH), granulosa cell mass and estradiol (E2) production falls and FSH, therefore, rises. Though potentially of adrenal and/or ovarian origin, androgen deficiency in association with female infertility is almost universally primarily of adrenal origin, raising the possibility that women with presumptive diagnosis of primary ovarian insufficiency (POI), also called primary ovarian failure (POF) may actually suffer from secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism that leads to follicular arrest at small-growing follicle stages.

Methods

This retrospective cohort study was performed in a private, academically affiliated infertility center in New York City. We searched the center’s anonymized electronic research data bank for consecutive patients who presented with a diagnosis of POI, defined by age <41 year, FSH > 40.0 mIU/mL, amenorrhea for at least 6 month, and low testosterone (T), defined as total T (TT) in the lowest age-specific quartile of normal range. This study did not include patients with oophoritis. Since dehydroepiandrosterone sulfate (DHEAS) is the only androgen almost exclusively produce by adrenals, adrenal hypoandrogenism was defined by DHEAS < 100ug/dL. Thirteen of 78 presumed POI women (16.67%) qualified and represented the original study population. POI patients are usually treated with third-party egg donation; 6/13, however, rejected egg donation for personal or religious reasons and insisted on undergoing at least one last IVF cycle attempt (final study population). In preparation, they were supplemented with DHEA 25 mg TID and CoQ10 333 mg TID for at least 6 weeks prior to ovarian stimulation for IVF with FSH and human menopausal gonadotropins (hMG). Since POI patients are expected to be resistant to ovarian stimulation, primary outcome for the study was ovarian response, while secondary outcome was pregnancy/delivery.

Results

Though POI/POF patients usually are completely unresponsive to ovarian stimulation, to our surprise, 5/6 (83.3%) patients demonstrated an objective follicle response. In addition, 2/6 (33.3%) conceived spontaneously between IVF cycles, while on DHEA and CoQ10 supplementation and delivered healthy offspring. One of those is currently in treatment for a second child.

Conclusions

This preliminary report suggests that a surprising portion of young women below age 41, tagged with a diagnosis of POI/POF, due to adrenal hypoandrogenism actually suffer from a form of SOI, at least in some cases amenable to treatment by androgen supplementation. Since true POI/POF usually requires third-party egg donation, correct differentiation between POI and SOI in such women appears of great importance and may warrant a trial stimulation after androgen pre-supplementation for at least 6 weeks.

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Author contributions

Concept and design: Gleicher, Barad, Albertini Acquisition, analysis or interpretation of data: All authors. Drafting of manuscript: Gleicher. Critical revision of manuscript for important intellectual content: All authors. Data retrieval: Darmon Statistical analysis: n/a Obtained funding: Gleicher Administrative, technical or material support: Gleicher Supervision: Gleicher.

Financial support

This study was supported by intramural funds of CHR and the Foundation for Reproductive Medicine

Author information

Authors and Affiliations

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

    Norbert Gleicher, Sarah Darmon, Emanuela Molinari, Lin Zhang, Jianjun Hu, David F. Albertini & David H. Barad

  2. The Foundation for Reproductive Medicine, New York, NY, 10022, 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, 1009, Vienna, Austria

    Norbert Gleicher

Authors
  1. Norbert Gleicher
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  2. Sarah Darmon
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  3. Emanuela Molinari
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  4. Lin Zhang
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  5. Jianjun Hu
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  6. David F. Albertini
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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

Drs. Gleicher and Barad are listed as co-inventors on a number of U.S. patents. Some of these patents relate to pre-supplementation of hypo-androgenic infertile women with androgens, such as DHEA and testosterone and, therefore, relate to the subject of this manuscript. N.G., D.F.A, and D.H.B. have received research support, travel funds and speaker honoraria from a number of pharmaceutical and medical device companies, though none related to here presented subjects and manuscript. Dr. Gleicher is a shareholder in Fertility Nutraceuticals, LLC. Drs. Gleicher and Barad receive royalty payments from Fertility Nutraceuticals LLC. That company’s over-the-counter products (DHEA and CoQ10) were used in this study.

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APPENDIX

APPENDIX

Table 4 Evidence for immune system hyperactivity in study patients
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Gleicher, N., Darmon, S., Molinari, E. et al. A form of secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism as new infertility diagnosis. Endocrine 72, 260–267 (2021). https://doi.org/10.1007/s12020-020-02512-0

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