Background Polycystic ovary syndrome (PCOS), a syndrome of hyperandrogenism, polycystic ovaries, and oligo-anovulation, is a major cause of infertility in American women. Observational studies suggest that women first develop PCOS in adolescence. Recent studies show that testosterone (T) levels are elevated in prepubertal obese girls in comparison with normal weight age and puberty-matched controls and this trend continues throughout puberty. Although insulin resistance is a common finding in PCOS and is implicated in the pathogenesis of PCOS, the causal role of T in the development of PCOS is less clear.
Purpose of Study The long-term goal of our study is to determine whether raised peripubertal T levels in female macaques lead to the hypothalamic-pituitary-ovarian sequelae of PCOS. During the first phase of the study presented here our goals are threefold: to obtain normative data for peripubertal T levels in female macaques, to choose a raised T target range, and to devise a method for raising the T levels.
Methods Used Sera obtained from five female macaques starting at prepuberty (age 12 months) and through menarche (average age 29 months) were used to determine normative T data. The commercially available RIA T assay DSL-4100 was used. We used surgically placed Silastic tube implants to raise T levels to target range in eight experimental animals. Six control animals were implanted with cholesterol-containing Silastic implants.
Summary of Results The mean peripubertal T in female macaques was 0.36 ± 0.16 ng/mL. Since obese peripubertal adolescent girls have T levels 3 to 4 times the normal-weight controls, we chose a target T range of 0.12 to 0.16 ng/mL. Subcutaneously placed Silastic implants containing 5 mm of T:cholesterol (1:12 or 1:15) are used to achieve the target T range. Monkeys are phlebotomized weekly and the frequency of implant change (on average every 6 weeks) is determined by the serum T levels.
Conclusions Peripubertal female macaques have a low circulating level of T, which can be raised reliably to a narrow target range with surgically placed Silastic tubes and close monitoring of resultant circulating T levels. We will maintain the raised T levels throughout puberty as we compare the T-treated animals' ovarian changes (menstrual/ovarian follicles) and hypothalamic-pituitary parameters (LH pulse and response to GnRH/progesterone) with those in control animals.
This work is supported by the following NIH grants: HD18185, DK007674-13, and RR00163.
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