Monthly case report: “Unexplained infertility” turns out to be hypoandrogenic PCOS

History: A 29-year-old woman, never pregnant, presented with a history of primary infertility of ca. 24 months duration. She reported a first menses at age 14, and remained regular in a 26-28-day cycle even once she came off oral contraceptives, ca. 2 years earlier. Her medical history was negative except for a diagnosis of Hashimoto’s thyroiditis at age 22. She received thyroxin supplementation of 0.075µg.

She had been receiving fertility treatment at another center over the preceding 8-9 months with a diagnosis of unexplained infertility. Treatment consisted of 3 clomiphen citrate/ insemination cycles, followed by 2 IVF cycles. Both IVF cycles were characterized by very large oocyte numbers but, in comparison, also by relatively few oocytes.

Review of her medical records revealed a BMI of 23, normal FSH and estradiol levels, and AMH of 5.8ng/mL. Her TSH was normal and she still demonstrated mild positivity in thyroid peroxidase and thyroglobulin antibodies.

Discussion: Upon presentation, this patient was by the treating physician immediately suspected of being a hypoandrogenic polycystic ovary syndrome (H-PCOS). This newly described PCOS phenotype is, likely the equivalent or a subgroup of the Phenotype D PCOS under Rotterdam Criteria. It was recently described (Gleicher et al., J Steroid Biochem and Molec Biol 2017;, and is characterized by exclusively appearing in lean women with mostly regular menses, at youngest ages (20s) by hyper-androgenemia (and sometimes mild hyper-cortisolemia), which after going through a period of normal androgen levels in the early mid-30s usually converts to hypo-androgenemia (and mild hypo-cortisolemia). Hypo-androgenism gets worse with advancing age. Hypo-androgenemia is characterized by low testosterone levels, particularly low dehydroepiandrosterone-sulfate (DHEAS) (of adrenal origin) and relatively high sex hormone binding globulin (SHBG). The phenotype is also characterized by a high degree of associated autoimmunity, especially thyroid autoimmunity (ca. 40% positive TPO-antibodies).

Resolution: After laboratory work-up, this patient, indeed, was confirmed in the diagnosis of H-PCOS. She was advised that her presentation, including the relatively small number of retrieved eggs in comparison to on ultrasound seen follicles, was typical. She was also advised that this condition is believed to reflect an autoimmune-induced insufficiency of her adrenal glands, primarily affecting the zona reticularis, which produces androgens. Low androgens, in turn, inhibited her normal follicular maturation in the ovaries and, therefore, produced fewer oocytes and poor quality oocytes. The recommended treatment was androgen supplementation for at least 6-8 weeks, which was given to her via oral DHEA supplementation.

She did not conceive in her 1st fresh IVF cycle at CHR (day-3 transfer) but conceived in her first subsequent frozen-thawed cycle and has a normally progressing singleton pregnancy. The number of retrieved oocytes almost doubled in comparison to her earlier two IVF cycles.

This is a part of the March 2017 VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.