Estrogens, androgens, and the hormonal modulation of female primate sexual motivation in rhesus monkeys Open Access

Cappelletti, Maurand Madilyn (2016)

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Ovarian steroids modulate female sexual motivation in human and nonhuman primates. Estrogens decrease following menopause, and many postmenopausal women experience decreased sexual desire. High-dose estrogen therapies increase sexual desire in postmenopausal women, but may increase women's risk of breast and uterine cancers. Estradiol para-quinol (DHED), a biologically inactive metabolite of estradiol, is converted to estradiol only in the brain, and thus may represent a brain-specific estrogen therapy. Because of cancer concerns, postmenopausal women are prescribed low-dose estrogen therapies, which do not increase sexual desire. Supraphysiological levels of testosterone improve the effectiveness of low-dose estrogen therapies; however, the mechanism by which testosterone increases women's sexual desire remains unknown. Testosterone may increase women's sexual desire via its aromatization to estradiol, or by binding sex hormone binding globulin (SHBG) and liberating SHBG-bound estradiol. Unlike testosterone, dihydrotestosterone (DHT) cannot be aromatized. The present dissertation investigated the roles of estrogens and androgens in the hormonal modulation of female primate sexual motivation. Study One investigated the effects of estradiol, DHED, and DHT on serum estradiol and female sexual initiation in group-housed ovariectomized rhesus monkeys. DHED treatment did not increase serum estradiol, suggesting that DHED is not converted to estradiol in the periphery. Neither DHED nor DHT treatment increased female sexual initiation; however, estradiol, the positive control, also did not increase female sexual initiation, suggesting that contextual factors inhibited female response to hormonal treatment. The social groups containing the study subjects were unstable, with high levels of conflict, throughout the study. The effects of estradiol on female sexual initiation were thus likely inhibited by group instability. Future studies should investigate the effects of DHED and DHT on female sexual initiation under stable social conditions. Study Two investigated changes in serum free estradiol following an acute DHT injection in estradiol-treated ovariectomized rhesus monkeys. Although preliminary, results indicated that free estradiol temporarily increased after an acute DHT injection, consistent with the hypothesis that DHT preferentially binds SHBG and liberates SHBG-bound estradiol. Collectively, the behavioral results of this dissertation indicate that the relationship between hormones and female primate sexual behavior is highly sensitive to social context.

Table of Contents

1. Introduction. 1

1.1. Hormones and women's sexual desire. 1

1.2. Studies of hormone therapies for low libido in postmenopausal women. 3

1.3. DHED: a brain-specific estrogen. 10

1.4. Mechanisms by which androgens may influence women's sexual desire. 14

1.5. Hormones and female primate sexual behavior. 17

2. Specific Aims. 22

3. Study One: The effects of estradiol (E2), estradiol para-quinol (DHED), and dihydrotestosterone (DHT) on female sexual initiation in rhesus monkeys. 26

3.1. Methods. 26

3.1.1. Subjects and housing. 26

3.1.2. Experimental design. 28

3.1.3. Behavioral testing. 31

3.1.4. Blood sampling. 34

3.1.5. Group stability. 35

3.1.6. Statistical analyses. 36

3.2. Results. 39

3.2.1. Hormonal data. 39

3.2.2. Behavioral data. 40

3.2.3. Analysis of behavioral means. 41

3.2.4. Reanalysis of behavioral means. 42

3.2.5. Individual subjects. 44

3.2.6. Male behavior. 45

3.2.7. Wounding data. 45

3.3. Discussion. 46

4. Study Two: Dynamic changes in free estradiol following an acute injection of dihydrotestosterone (DHT) in estradiol-treated female rhesus monkeys. 59

4.1. Methods. 59

4.1.1. Subjects and housing. 59

4.1.2. Experimental design. 60

4.1.3. First hormone assay run. 61

4.1.4. Second hormone assay run. 63

4.1.5. Statistical analyses. 64

4.2. Results. 65

4.2.1. First hormone assay run data. 65

4.2.2. Second hormone assay run data. 65

4.3. Discussion. 66

5. Limitations. 69

6. Conclusions. 70

References. 75

Appendix 1: Validation of estradiol benzoate dosage. 95

Appendix 2: Abandoned treatment paradigm. 96

Appendix 3: Behavioral ethogram. 100

Figures. 104

Tables. 124

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