Pathogenesis of reproductive and metabolic PCOS traits in a mouse model

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder, however the etiology and pathogenesis of PCOS are poorly understood and current management is symptom based. Defining the pathogenesis of PCOS traits is important for developing early PCOS detection markers and new treatment strategies. Hyperandrogenism is a defining characteristic of PCOS and studies support a role for androgen driven actions in the development of PCOS. Therefore, we aimed to determine the temporal pattern of development of PCOS features in a well characterized dihydrotestosterone (DHT)-induced PCOS mouse model after 2, 4 and 8 weeks of DHT exposure. Following 2 weeks of treatment, DHT induced the key PCOS reproductive features of acyclicity, anovulation and multi-follicular ovaries as well as a decrease in large antral follicle health. DHT treated mice displayed the metabolic PCOS characteristics of increased body weight and exhibited increased visceral adiposity after 8 weeks of DHT treatment. DHT treatment also led to an increase in circulating cholesterol after 2 weeks exposure and had an overall effect on fasting glucose levels, but not triglycerides, aspartate transaminase (AST) and alanine transaminase (ALT) levels or hepatic steatosis. These data reveal that in this experimental PCOS mouse model, acyclicity, anovulation and increased body weight are early features of a developing PCOS phenotype whereas adiposity, impaired glucose tolerance, dyslipidemia and hepatic steatosis are later developing features of PCOS. These findings provide insights into the likely sequence of PCOS trait development and support the addition of body weight criteria to the early diagnosis of PCOS.

ACCUMULATION OF LUTEINIZING HORMONE, OESTRADIOL AND ANDROSTENEDIONE BY SHEEP OVARIAN FOLLICLES IN VIVO

The temporal relationships between the levels of LH in peripheral plasma and in follicular fluid of ovarian follicles in anaesthetized sheep were investigated for a 10-h period after a single i.m. injection of LH releasing hormone (LH-RH; 100 μg). The ovarian secretion rates of oestradiol and androstenedione and the levels of these steroids accumulating in different sized follicles at varying time-intervals after the LH-RH injection were also compared. The data show that the rates at which pituitary LH enters and leaves the intrafollicular fluid-filled spaces are substantially slower than those of peripheral blood. Two hours after LH-RH injection the levels of LH in plasma had increased from 1 to 200 ng/ml, whereas in the follicle the levels remained at approximately 2 ng/ml. Ten hours after the LH-RH injection, the levels of LH in plasma had returned to basal values (∼1·4 ng/ml) but in both small and large follicles the levels of LH (∼20 ng/ml) were comparable to those present in similar sized follicles 4 h earlier. The data also indicate that more than 90% of the oestradiol produced by a large antral follicle (≥5 mm diameter) probably enters the bloodstream without first accumulating within the follicular antrum. Finally it is concluded that the clearance of the small amount of oestradiol which does accumulate in the follicular antrum is negligible compared with the clearance of this hormone from peripheral plasma.