Date

May 2012

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Behavioral Neuroscience

Institution

Oregon Health & Science University

Abstract

Hyperandrogenemia (HA) is associated with several clinical disorders in reproductive-aged women. The most common disorder associated with HA is polycystic ovary syndrome (PCOS), which affects 4-8% of women and is characterized by elevated androgens and ovarian dysfunction. Other features associated with PCOS include neuroendocrine alterations such as increased frequency of pulsatile luteinizing hormone (LH) secretion, increased LH response to gonadotropin-releasing hormone (GnRH), and decreased sensitivity to progesterone negative feedback. Additionally, women with PCOS frequently are obese and have decreased insulin sensitivity compared with healthy women. The overall goal of this dissertation was to examine whether symptoms of PCOS would develop in female monkeys that were treated with low doses of testosterone (T), which were designed to mimic the circulating levels of T seen in women with PCOS, beginning just prior to puberty. To examine neuroendocrine function in these monkeys, pulsatile LH secretion, the LH response to GnRH, and sensitivity to progesterone negative feedback were assessed after the animals had gone through puberty and had been exposed to elevated T for 3 years. Additionally, ultrasounds were performed to assess ovarian function, and glucose tolerance testing and metabolic testing were performed to assess metabolic function. It was found that T treatment led to increased central drive to the reproductive axis, as evidenced by faster LH pulse frequency during the early follicular phase in the T-treated animals in addition to a larger LH response to exogenous GnRH. However, T treatment for 4 years did not result in any ovarian or metabolic changes that were indicative of a PCOS phenotype. After these initial assessments were made, the monkeys were fed a high-calorie, high-fat diet typical of Western cultures (Western style diet; WSD) that resulted in increased adiposity in order to mimic the high prevalence of overweight and obesity in women with PCOS. Neuroendocrine, ovarian, and metabolic functions were assessed in the same manner as before the WSD. The frequency of pulsatile LH secretion measured during the early follicular phase increased in the control animals, such that T-treated and control animals both had approximately hourly LH pulses. It was also found that after 14 months on the WSD, all animals had peripheral compartmentalization of ovarian follicles, which is similar to the polycystic ovary phenotype in women with PCOS. Moreover, the T-treated animals had decreased insulin sensitivity compared with control animals after one year on the WSD, even when controlling for weight. These data indicate that T treatment, in combination with the WSD, leads to neuroendocrine, ovarian, and metabolic features that are typically seen in PCOS. Behavior was also examined in these animals to assess whether mild HA would lead to changes in aggression or anxiety (i.e., behavioral inhibition). No group differences were found in aggression, but the T-treated animals showed slightly less inhibited behavior, which may represent a greater degree of impulsivity, as they were more active than control animals when presented with a potentially threatening stimulus in a novel environment. This indicates that while low T might not increase aggression in female monkeys, it does lead to a decrease in behavioral inhibition, a common form of anxious behavior. Interestingly, there was also a strong correlation between decreased behavioral inhibition (being active in a novel environment) and weight gain on the WSD, suggesting that impulsive behavior may play an important role in determining who will become obese when a highly palatable diet is made available.

Identifier

doi:10.6083/M4VM4992

School

School of Medicine

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