Important implication of stress-response-mechanism in ovarian dysfunction and IVF pregnancy loss: a novel method to detect its dysfunction by circadian rhythm of salivary cortisol

Abstract

OBJECTIVE: Stress causes infertility and ovarian dysfunction. Stress response is controlled by hypothalamo-pituitary-adrenocortical (HPA) axis and sympathoadrenal system (SAS). We analyzed the association of HPA axis and SAS with various types of ovarian dysfunction and IVF outcomes. DESIGN: A retrospective study. MATERIALS AND METHODS: In study 1, 157 women with ovarian dysfunction according to abnormalities in basal body temperature and 7 normal volunteers were studied. The patients were classified to 8 groups: PCOS, 49 women; PCOS with habitual abortion, 7; low body weight, 10; elevated FSH, 24; elevated PRL, 6; endometriosis, 10; high age, 4; and idiopathic, 47. HPA axis was analyzed by the circadian rhythm of salivary cortisol and dexamethasone suppression test (DST) on cycle days 3-7. The circadian rhythm was classified into normal (N) type and 4 abnormal types: low-morning (LM), plateau (P), V-shaped (V), and flat (F) types. SAS was analyzed by measuring plasma catecholamines. In study 2, the rates of pregnancy and abortion were compared between patients with normal and abnorml HPA axis in 178 IVF cycles. RESULTS: Study 1: The incidence of abnormal circadian rhythm in salivary cortisol was significantly higher in women with ovarian dysfunction than in normal volunteers (48% vs. 0%) The incidence was high in PCOS with habitual abortion (86%), low body weight (60%) and PCOS (53%), and moderate in elevated PRL (50%), idiopathic (47%) and elevated FSH (42%), and low in endometriosis (30%) and high age (0%). DST was worsened in types N, LM, P, V and F in this order. The incidence of elevated catecholamines was prominently high in PCOS with habitual abortion (86%), compared with other groups of ovarian dysfunction (0%-27%) and normal volunteers (0%). Study 2: IVF pregnancy rates were similar in N, LM, P, V and F types, but abortion rate was significantly higher in V and F types than in N, LM and P types (50% vs. 19%). Abortion rate was significantly higher with abnormal DST than with normal DST (50% vs. 21.4%). CONCLUSIONS: Abnormal HPA axis was identified by the circadian rhythm of salivary cortisol in half of women with ovarian dysfunction, especially more frequently in PCOS and low body weight. Abnormal HPA axis and SAS were prominently frequent in PCOS with habitual abortion, and also were associated with abortion in IVF. Stress-response-mechanism is closely related to ovarian function and maintenance of pregnancy, and its normalization may work as a novel treatment of infertility and pregnancy loss.