The importance of adrenal hypoandrogenism in infertile women with low functional ovarian reserve: a case study of associated adrenal insufficiency.
BACKGROUND
Low testosterone (T), whether due to ovarian and/or adrenal insufficiency, usually results in poor follicle maturation at small growing follicle stages. The consequence is a phenotype of low functional ovarian reserve (LFOR), characterized by poor granulosa cell mass, low anti-Müllerian hormone and estradiol but rising follicle stimulating hormone. Such hypoandrogenism can be of ovarian and/or adrenal origin. Dehydroepiandrosterone sulfate (DHEAS) is exclusively produced by adrenals and, therefore, reflects adrenal androgen production in the zona reticularis. We here determined in a case study of infertile women with LFOR the presence of adrenal hypoandrogenism, its effects on ovarian function, and the possibility of presence of concomitant adrenal insufficiency (AI), thus reflecting insufficiency of all three adrenal cortical zonae.


METHODS
We searched our center's anonymized electronic research database for women with LFOR, who were also characterized by peripheral adrenal hypoandrogenemia (total testosterone < 16.9 ng/dL) and low DHEAS (<76.0 μg/dL). Among 225 women with LFOR, we identified 29 (12.9 %). The adrenal function of so identified women were further investigated with morning cortisol and ACTH levels and/or standard ACTH stimulation tests. We also determined the prevalence of classical AI (insufficiency glucocorticoid production by zona fasciculata) in hypoandrogenic women with LFOR, and impact of adrenal hypoandrogenism on ovaries.


RESULTS
Among 14/28 women with adrenal hypoandrogenism due to insufficiency of the zona reticularis available for follow up, 4 (28.6 %) also demonstrated previously unrecognized classical primary, secondary or tertiary AI due to insufficiency of the zona fasciculata. An additional patient with presenting diagnosis of seemingly primary ovarian insufficiency (POI), demonstrated extremely low T and DHEAS levels, a diagnosis of Addison's disease, and was on glucocorticoid but not androgen supplementation. As her dramatic improvement in ovarian function criteria after androgen supplementation confirmed, her correct diagnosis, therefore, was actually secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism.


CONCLUSIONS
Women with LFOR, characterized by low T and DHEAS, are also at risk for AI, while women with AI may be at risk for adrenal induced hypoandrogenism and, therefore, SOI. A currently undetermined percentage of POI patients actually are, likely, affected by SOI, a for prognostic reasons highly significant difference in diagnosis.
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA. ykizawa@thechr.com.|The Foundation for Reproductive Medicine, New York, NY, USA. ykizawa@thechr.com.|Stem Cell Biology and Molecular Embryology Laboratory, The Rockefeller University, New York, NY, USA. ykizawa@thechr.com.
Norbert
N
Gleicher
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.|Department of Obstetrics and Gynecology, Wake Forest University, Winston-Salem, NC, 27106, USA.
Vitaly A
VA
Kushnir
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.|Vienna University School of Medicine, Vienna, Austria.
Andrea
A
Weghofer
The Center for Human Reproduction, 21 East 69th Street, New York, NY, 10021, USA.|The Foundation for Reproductive Medicine, New York, NY, USA.|Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
David H
DH
Barad
D000309:Adrenal Insufficiency / Q000150:complications / Q000175:diagnosis*; D000328:Adult; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000150:complications*; D065851:Ovarian Reserve; D016649:Primary Ovarian Insufficiency / Q000175:diagnosis*; D012189:Retrospective Studies