HYPERINSULINEMIA AND HUMAN CHORIONIC-GONADOTROPIN SYNERGISTICALLY PROMOTE THE GROWTH OF OVARIAN FOLLICULAR CYSTS IN RATS

Tonically elevated serum luteinizing hormone (LH) and hyperinsulinemia are prominent features of polycystic ovary syndrome (PCO) in women, but the relative roles of LH and insulin in the pathogenesis of PCO is still unknown. The present study was undertaken to determine the effect(s) hyperinsulinemia might have on the induction of follicular cysts by LH/human chorionic gonadotropin (hCG) in the rat. Beginning on day 85 of age, adult female rats were given one of the following in vivo treatments: (1) vehicle alone; (2) a high-fat diet to control for the effects of weight-gain; (3) up to 6 U insulin per day; (4) 50 μg gonadotropin-releasing hormone (GnRH) antagonist (GnRHant) per day; (5) 1.5 IU hCG twice daily; (6) insulin + hCG; (7) insulin + GnRHant; (8) hCG + GnRHant; or (9) hCG + insulin + GnRHant. After 22 days of treatment, animals were killed on day 23, trunk blood was collected, and ovaries were excised for histological study. Regular cycles, assessed by vaginal smears, ceased after 10 days for most animals in treatment groups receiving hCG, but continued in all other treatment groups. All the animals in each hCG-treated group developed either unilateral or bilateral cystic ovaries, while no animals in the groups not receiving hCG developed follicular cysts. More animals from each group treated with both hCG and insulin possessed bilateral ovarian cysts than did rats treated with hCG alone: 80% and 60%, respectively. Mean ovarian product ([MOP] OP = ovarian length × width, mm2 was greater for animals that received hCG + insulin than for animals that received hCG alone (46.6 ± 5.1 and 32.5 ± 2.1, respectively; P < .01). Animals treated with hCG + GnRHant ± insulin displayed more follicular cysts than animals treated with hCG ± insulin (7.9 ± 1.3 and 4.5 ± 1.27 cysts/rat, respectively; P < .05). In addition, only rats that received hCG + insulin + GnRHant possessed a greater mean follicular cyst volume than rats that received hCG alone (2.18 ± 0.58 and 1.0 ± .19 mm3, respectively; P < .05). Rats treated with insulin had elevated plasma insulin concentrations (range, 100 to 340 μIU/mL), while all other treatment groups had plasma insulin values similar to those of control rats (∼50 μIU/mL). Plasma estradiol concentrations were elevated only for animals treated with hCG alone (201 ± 17 pg/mL compared with 144 ± 30 pg/mL for all other treatment groups, P < .05). Plasma estrone concentrations were elevated only for rats treated with insulin (139 ± 11 compared with 95 ± 9 pg/mL for all other treatment groups; P < .02). Androstenedione concentrations were elevated for rats that received hCG when compared with values for other treatment groups (13.4 ± 1.0 and 10.7 ± 0.4 ng/mL, respectively; P < .05). However, treatment with both hCG and insulin failed to elevate plasma androstenedione values further (14.8 ± 1.1 ng/mL). These data indicate that while unabated LH-like stimulation is sufficient to induce ovarian follicular cysts in intact rats, hyperinsulinemia enhances follicular cyst development in this species by increasing the volume of the induced cysts and thus increasing ovarian size. © 1992.