OR11-02 Distinctive Neuroendocrine Changes and Menstrual Dysfunction in Early Postmenarchal Daughters of Women With PCOS

PCOS is a complex genetic disease with strong familial aggregation - ~40% of reproductive-age sisters have elevated testosterone (T) levels and other features of the syndrome. Beginning in infancy, daughters of affected women (PCOS-d) have elevated anti-Müllerian hormone (AMH) levels and evidence for global increases in 5α-reductase activity. Peripubertally, PCOS-d have increased T levels. Peripubertal overweight and obesity (OB) girls also have elevated T but not AMH levels. We initiated a prospective study of PCOS-d and OB to test the hypothesis that only PCOS-d are at increased risk to develop PCOS. Herein, we present the baseline assessments in 14 PCOS-d, 14 OB, and 18 lean control girls (LC) aged 11-16 yrs who were enrolled within 2-yrs of menarche. PCOS-d mothers fulfilled NIH criteria, OB and LC mothers had no history of irregular menses or clinical hyperandrogenism. Morning blood sampling was performed for hormone levels. Free T was calculated from total T and SHBG. Ovarian MRI was performed to assess morphology. Data are mean ± SD, α=0.05. By design, age did not differ between the groups, but BMI z-score was higher in OB compared with PCOS-d and LC (1.3±1.1 PCOS-d v 2.0±0.6 OB v 0.1±0.7 LC, P<0.0001). The prevalence of irregular menses (cycles ≤ 21d or ≥ 45d apart) was significantly increased only in PCOS-d (61% PCOS-d, 23% OB, 19% LC, Χ (2) P=0.03). Total T levels did not differ between the groups. SHBG levels were decreased in PCOS-d and OB (23±16 PCOS-d v 30±16 OB v 56±15 LC, nmol/L, P<0.0001), resulting in a trend toward increased free T levels in these groups (0.6±0.3 PCOS-d v 0.6±0.5 OB v 0.4±0.2 LC, ng/dL, P=0.06). DHEAS levels were higher in PCOS-d and OB compared with LC (135±35 PCOS-d v 150±68 OB v 88±46 LC, ug/dL, P=0.05). AMH levels, follicle counts and ovarian volume did not differ. GnRH analog (GnRHa,10 µg/kg SC) stimulation was performed in 9 PCOS-d and 13 OB. Both baseline LH levels (7.6±4.4 PCOS-d v 3.7±2.1 OB, mIU/mL, P=0.01) and LH responses to GnRHa were significantly increased in PCOS-d (LH AUC: 2110±1132 PCOS-d v 1047±808 OB, P=0.01). Baseline FSH and FSH AUC did not differ. Post-GnRHa 17-OHP levels did not differ. Early postmenarchal PCOS-d but not OB have evidence for increased GnRH-mediated LH release, a cardinal feature of PCOS disordered gonadotropin secretion. The increased prevalence of irregular menses in PCOS-d is consistent with this change. In contrast, androgen levels are similarly increased in both groups. These findings align with genomewide association studies implicating gonadotropin secretion and action in PCOS pathogenesis and suggest that neuroendocrine alternations in gonadotropin release are a core causal pathway in PCOS. Moreover, these findings provide further support for our hypothesis that PCOS-d but not OB are at increased risk for PCOS. Longitudinal studies are ongoing to test this hypothesis at 2-yrs postmenarche when the diagnosis of PCOS can be established.