3) 多嚢胞性卵巣症候群とアンドロゲン : 疾患モデルが意味するもの(シンポジウム3:生殖「多嚢胞性卵巣症候群(PCOS)の病因・病態と管理」,第65回日本産科婦人科学会・学術講演会)

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  • 馬場,剛
    札幌医科大学医学部産婦人科学教室

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  • The relationship between polycystic ovary syndrome and excess androgen exposure : What does biological models of PCOS suggest?

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Polycystic ovary syndrome (PCOS) is a heterogeneous group of disorders affecting 5-10% of women of reproductive age. It is characterized by ovulatory disorders, signs of hyperandrogenism and polycystic ovarian morphology (PCOM). There are several diagnostic criteria for PCOS that have been set by major clinical societies. According to these criteria, PCOS can be diagnosed after the exclusion of related disorders such as androgen-secreting neoplasms and nonclassical congenital adrenal hyperplasia. That is, excess androgens are thought to cause PCOS. Although the pathogenesis is not entirely understood, hypotheses for the etiology of PCOS include genetic abnormalities, insulin resistance, excess fetal/juvenile androgen exposure, fetal growth restriction and hypothalamic abnormalities. Previous studies indicate that female animals and women exposed to excess androgens during the fetal/juvenile periods show ovulatory disorders, hyperandrogenism and PCOM as adults: similar symptoms to PCOS. The excess androgen exposure hypothesis tends to dominate current thinking among endocrinologists. However, it is obvious that there are differences in effects between the extrinsic administration of androgens and intrinsic hypersecretion. We investigated the impact of extrinsic androgen excess on ovarian morphology and evaluated different effects between intrinsic and extrinsic androgens. We examined the differences in ovarian morphology and the levels of various sex steroid and pituitary hormones between age-matched female controls and female-to-male transsexual (FTM-TS) individuals. First, we assessed 128 FTM-TS persons without prior androgen treatment (untreated group) and 50 FTM-TS persons using androgen (self-administration group) for symptoms of PCOS. Among 128 FTM-TS persons without prior androgen treatment, 21 (16.4%; Japan Society of Obstetrics and Gynecology; JSOG 2007), 22 (17.2%; NIH 1990) and 41 (32.0%; Rotterdam 2003) subjects were diagno sed as having PCOS based on the set criteria. Hyperandrogenemia was seen in 49 (38.3%) subjects. PCOM was determined in 36.7% of the untreated group and in 18.6% of the androgen-treated group. Thus, FTM-TS persons have a high prevalence of PCOS and hyperandrogenemia. However, PCOM can disappear even after androgen administration. Second, we counted various stages of follicles in ovaries from 11 FTM-TS persons undergoing testosterone therapy (testosterone enanthate 125mg biweekly for more than 17 months) and 10 female controls. Compared with the controls, the FTM-TS group had a significantly thicker cortex (P=0.0001) and more ovarian stromal hyperplasia (P=0.003). The numbers of growing follicles were similar; however, more atretic follicles were seen in the FTMTS subjects than that in the control group (P=0.01). These findings indicate that excessive extrinsic androgen exposure to women of reproductive age cause an ovarian morphology that is dissimilar to PCOS and might not be a factor in the pathogenesis of PCOS. We then conducted an experiment using 30 immature (3-week-old) Sprague Dawley rats that were injected with dehydroepiandrosterone (DHEA) (6mg/100g body weight/0.2mL sesame oil) for 7, 15 or 30 days. Control rats were injected with 0.2mL of sesame oil each evening for the corresponding length of time. The next day after the last administration of DHEA, rats were killed and resected ovaries were examined to determine the numbers of follicles at each developmental stage and expression of anti-Miillerian hormone (AMH) using immunostaining. In the 7-days group, the number of follicles at each developmental stage and the AMH expression were similar. In the 15-day groups, total number of follicles (P=0.041) and AMH expression in the DHEA group were significantly greater than in the control group. Macroscopic findings indicated that DHEA administration for 15 days made the ovaries polycystic. In the 30-day groups, the proportions of primary (P=0.0002) and atretic (P=0.03) follicles in the DHEA group were significantly greater than in the control; conversely, the proportion of intermediary follicles (early pre-antral, late preantral, and early antral follicle) in the DHEA group was significantly lower (P=<0.0001) than in the control. These results suggest that excess androgen has dual nature. That is, androgen transiently suppresses natural decrease of follicle number and makes PCOM, however, long-term androgen exposure arrests follicle growth at the stage of primary follicle, and makes ovaries atretic. We then studied the effect of intrinsic androgen on ovarian morphology using 16 patients with epilepsy who had been taking valproate started before puberty, 32 patients with PCOS using pioglitazone, and 14 patients with PCOS treated by laparoscopic ovarian drilling (LOD). Fifteen out of 16 patients using valproat e fulfilled the PCOS criteria (JSOG 2007) and had high levels of androstenedione. Notably, reversible changes were shown in one subject after cessation of the drug. Among patients taking pioglitazone or undergoing LOD, treatments significantly decreased the levels of androstenedione and AMH related to PCOM. Our results suggest that hypersecretion of androstenedione before puberty may cause PCOS-like symptoms, and the PCOM may be associated with the effects of androstenedione. Our data suggest that exposure to extrinsic androgen in reproductive-aged women does not cause PCOS-like phenomena. However, intrinsic androgen hypersecretion before puberty might cause reversible PCOS-like symptoms. In addition, the symptoms of PCOS can be modified by decreasing androgen and AMH levels. Judging from these findings, we speculate that excess androgen exposure early in life might cause epigenetic modifications in putative genes predisposing to PCOS. Further studies are needed to elucidate this hypothesis.

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