Elevated androgens during puberty in female rhesus monkeys lead to increased neuronal drive to the reproductive axis: a possible component of polycystic ovary syndrome

Abstract

Background: Hyperandrogenemia is associated with several clinical disorders in which both reproductive dysfunction and metabolic changes may coexist [i.e. polycystic ovary syndrome (PCOS), obesity and congenital adrenal hyperplasia]. Moreover, there is growing evidence that the elevated levels of circulating androgens in obese girls may lead to an increased neuroendocrine drive to the reproductive axis, similar to that associated with PCOS.

Methods: To test whether androgen exposure in the childhood and adolescent period could lead to pubertal alterations in LH secretory patterns, female rhesus monkeys received subcutaneous testosterone implants prepubertally beginning at 1 year of age, maintaining a 3.7-fold increase (P = 0.001) in circulating testosterone levels over cholesterol-implant controls (n = 6/group) into the post-pubertal period. In early adulthood, pulsatile secretion of LH was measured over 12 h during the early follicular phase of a menstrual cycle, and responsiveness of the pituitary to gonadotrophin-releasing hormone was determined. In addition, ultrasounds were performed to assess ovarian morphology and glucose tolerance testing was performed to assess insulin sensitivity.

Results: The timing of menarche was similar between groups. Testosterone-treated animals had a significantly greater LH pulse frequency during the early follicular phase compared with controls (P = 0.039) when measured at 5 years of age. There was a larger LH response to GnRH when testosterone-treated animals were 4 years of age (P = 0.042), but not when the animals were 5 years old (P = 0.57). No differences were seen in insulin sensitivity or ovarian morphology, and the groups showed similar rates of ovulation in early adulthood.

Conclusions: Exposure to increased levels of androgens over the course of pubertal development appears to trigger physiological changes in the neural drive to the reproductive axis that resemble those of obese hyperandrogenemic girls in early adulthood and are characteristic of PCOS.

Figure 1

Schematic diagram of the experimental timeline indicating ages at which experiments were performed. Note that the timeline does not have a uniform scale.

Figure 2

Body weight across time. Data are expressed as mean ± SEM. ^#Indicates a trend toward a group difference (P = 0.05–0.1). *Indicates a significant difference between groups (P = 0.03).

Figure 3

Pulsatile LH secretion in the six cholesterol-treated animals on D2–3 of the menstrual cycle. E₂ at the time of blood sampling is indicated for each animal. Each experiment is also labeled as occurring during either an ovulatory (Ov) or anovulatory (Non-ov) cycle. *Indicates LH pulse as detected by Pulsar analysis.

Figure 4

Pulsatile LH secretion in the six testosterone-treated animals on D2–3 of the menstrual cycle. E₂ at the time of blood sampling is indicated for each animal. Each experiment is also labeled as occurring during either an ovulatory (Ov) or anovulatory (Non-ov) cycle. *Indicates LH pulse as detected by Pulsar analysis.

Figure 5

LH response to a bolus injection of GnRH at 4 years of age (A) and 5 years of age (B). GnRH (250 ng/kg, i.v.) was infused at time 0. Testosterone-treated animals showed a significantly greater response measured as area under the curve at 4 years of age (P = 0.042) but not at 5 years of age (P = 0.57). Data are expressed as mean ± SEM.