Excess androgens are associated with a characteristic polyfollicular ovarian morphology; however, it is not known to what extent this problem is due to direct androgen action on follicular development vs. interference with gonadotropin release at the level of the pituitary or hypothalamus. To elucidate potential androgen effects on the ovary, we investigated the cellular localization of androgen receptor (AR) messenger ribonucleic acid (mRNA) in rhesus monkey using in situ hybridization. To investigate the regulation of ovarian AR gene expression, we compared the relative abundance of AR transcripts in monkeys during follicular and luteal phases of the menstrual cycle and in monkeys treated with testosterone. To assess potential functional consequences of AR expression in the primate ovary, we compared AR mRNA levels with indexes of follicular cell proliferation and apoptosis in serial sections from individual follicles. AR mRNA expression was most abundant in granulosa cells of healthy preantral and antral follicles in the primate ovary. Theca interna and stromal cells also expressed AR mRNA, but to a lesser degree than granulosa cells. No significant cycle stage effects were noted in AR mRNA levels; however, larger numbers of animals would be necessary to definitively establish a cycle stage effect. AR mRNA level was significantly increased in granulosa cells and was decreased in theca interna and stromal cells of testosterone-treated monkeys. Importantly, granulosa cell AR mRNA abundance was positively correlated with expression of the proliferation-specific antigen Ki-67 (r = 0.91; P < 0.001) and negatively correlated with granulosa cell apoptosis (r = -0.64; P < 0.001). In summary, these data show that primate ovary AR gene expression is most abundant in granulosa cells of healthy growing follicles, where its expression is up-regulated by testosterone. The positive correlation between granulosa AR gene expression and cell proliferation and negative correlation with programmed cell death suggests that androgens stimulate early primate follicle development.

Estrogen protects neurons from a variety of experimental insults in vitro, and is thought to protect from acute and chronic neurodegenerative processes in vivo. Estrogen also enhances higher-level cognitive functions that are centered in the dorsolateral prefrontal cortex (DLPFC) in human and non-human primates. To investigate genomic mechanisms involved in estrogenic effects on the primate brain in vivo, we compared transcription factor mRNA and protein expression in the DLPFC of ovariectomized rhesus monkeys treated with either vehicle or estradiol (E2). c-FOS, E2F1, and general transcription factor IIB (TFIIB) mRNA and protein expression were altered significantly by short-term E2 treatment, as shown by DNA array, in situ hybridization, and immunohistochemical and immunoblot evaluations. C-FOS expression was increased significantly whereas E2F1 and TFIIB levels were decreased in the DLPFC of E2-treated animals. These transcription factors were concentrated in cortical pyramids, as were estrogen receptors alpha and beta. These data indicate that estrogen may have direct as well as indirect effects on neuronal gene expression in the primate prefrontal cortex.

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Fibroblast growth factors (FGF) 1 and 2 are paracrine effectors of proliferation and angiogenesis in many tissues. To elucidate potential roles for these growth factors in uterine plasticity, we used in situ hybridization histochemistry to identify the cellular sources of FGF-1 and -2 production, and immunohistochemistry to identify the cellular and extracellular deposition sites of the peptides in the primate uterus. To evaluate the effects of estradiol on uterine FGFs, uteri from ovariectomized rhesus monkeys treated with estradiol- or vehicle-containing pellets were investigated. FGF-1 and -2 mRNAs were both expressed in uterine epithelial and myometrial cells. Quantitative comparison of their mRNA levels using computerized grain counting showed no significant difference between estradiol- and vehicle-treated animals. FGF-1 immunoreactivity was detected in scattered epithelial, vascular, and myometrial cells in the vehicle-treated animals but found to be significantly more intense and widespread in estradiol-treated animals. In both conditions, FGF-1 immunostaining was predominantly nuclear. FGF-2 immunoreactivity was concentrated extracellularly in the basal lamina of both glandular and surface epithelium and was abundant and diffusely distributed within myometrial and vascular cells in both cytoplasm and nucleus. There was no apparent difference in the pattern or intensity of FGF-2 immunostaining related to estradiol treatment. These data demonstrate that major uterine cell types synthesize both FGF-1 and -2, and that the two peptides are differentially localized in uterine cellular and extracellular compartments and differentially sensitive to regulation by estradiol.