Experimental Induction of Reduced Ovarian Reserve in a Nonhuman Primate Model (Macaca fascicularis)

摘要

Chronic diseases including coronary heart disease and osteoporosis represent a substantial health burden to postmenopausal women, yet the initiation of these conditions and their relationships with reproductive aging remain poorly understood. This situation is due, in part, to the lack of animal models reflecting ovarian and hormonal characteristics of peri- and postmenopausal women. Ovaries of women approaching menopause are nearly depleted of primordial follicles but retain a pool of larger developing follicles and androgen-producing stroma, a condition known as reduced ovarian reserve (ROR). The long-term goal of the research presented here was to create a monkey model of reproductive aging, beginning with ROR and progressing to perimenopause and finally postmenopause. Here we sought to develop a method to reduce primordial follicles in cynomolgus monkeys (Macaca fascicularis) and document hormonal changes associated with follicle reduction or ROR. At 30 d after surgical placement of a biodegradable fiber containing approximately 200 mg of 4-vinlycyclohexene diepoxide (VCD) next to one ovary in each of 8 monkeys, primordial follicles were reduced by approximately 70%, with a corresponding decrease (83%) in antimullerian hormone (AMH, a serum marker of ovarian follicle numbers). At 4 mo after VCD-treatment of both ovaries in 29 monkeys (approximately 200 mg VCD per ovary), AMH was reduced 56% from baseline, testosterone was unchanged, and follicular phase estradiol was slightly increased. These data indicate that VCD treatment markedly reduced primordial follicles while preserving larger estradiol- and testosterone-producing follicles and ovarian stroma, a condition that mimics ROR in women.