Extremely high levels of estradiol and testosterone in a case of polycystic ovarian syndrome. Hormone and clinical similarities with the phenotype of the alpha estrogen receptor null mice

A 19-year-old nulliparous hirsute woman was evaluated for the very high serum levels of testosterone (T) and estradiol (E-2) measured in an outside laboratory. Menarche had occurred at 11 years and was followed by regular menses. We confirmed the high levels of T (9-16 ng/ml, nv 0.2-0.8) and E-2 (>1000 pg/ml, nv 30-120). LH and FSH were consistently high (73-118 mU/l and 1829 mU/l, respectively; LH/FSH ratio=4.1-4.7) and responsive to iv GnRH (LH baseline=118 mU/l, 30 min=290; FSH baseline=25 mU/l, 30 min=46). The unstimulated values contrasted with those (LH=12, FSH=8 mU/l) measured in the outside laboratory, suggesting antigenically anomalous gonadotropins. 17-OH-progesterone was normal (0.5 ng/ml). After 1 mg dexamethasone, serum cortisol was normally suppressed (24-->0.4 mu g/dl), T declined minimally (9-->8.6 ng/ml) and E-2 remained high (>1000 pg/ml). An exploratory laparotomy was performed, and two enlarged ovaries with multiple cysts as in a typical polycystic ovarian syndrome (PCOS) were seen. Before the wedge re-section of the ovaries, hormones were assayed in the ovary veins (right ovary: T=30 ng/ml, Pg=17 ng/ml, E-2=>5000 pg/ml; left: T=14 ng/ml, Pg=14 ng/ml, E-2=>5000 pg/ml). Histologically, the follicle cysts showed luteinization of the theca interna; there was no evidence for ovary tumor in either ovary. After 21 days of 35 mu g ethynyl-E-2+2 mg cyproterone acetate (CA), E-2=3,000 pg/ml, T=1.4 ng/ml, LH=10.5 mU/I and FSH=4.1 mU/l. After three cycles of the said therapy (but with 50 mg CA in the first 10 days of each cycle), E-2 was 1600 pg/ml, T 1.7 ng/ml, LH 7.1 and FSH 4.6 mU/l. Based on similarities with the phenotype of the ct estrogen receptor knockout female mice (alpha ERKO), one possible explanation for the puzzling clinical and biochemical picture of our patient is resistance of alpha ER to estrogens. This is the first case of PCOS with extremely high E-2 and T. Thus, the differential diagnosis of high levels of E-2+/-T should include PCOS.