MODULATION OF SEXUAL AND SLEEP FUNCTIONS BY ESTROGEN IN CASTRATED MALE RATS AS A MODEL FOR PROSTATE CANCER PATIENTS ON ANDROGEN DEPRIVATION THERAPY

Abstract

Advanced prostate cancer (PCa) patients are offered androgen deprivation therapy (ADT) to control their cancer’s growth. ADT impairs sexual function and the sleep patterns of ADT patients. Since ADT deprives patients of estrogen, and supplemental estrogen reduces such problems in menopausal women, I studied whether administering estrogen reduces these problems for castrated male rats as a model for PCa patients on ADT. First, I tested how early versus late estradiol treatment after castration influenced rats’ sexual behaviour. Estradiol increases mounting behaviour to comparable levels regardless of when the treatment was started after castration, suggesting that estrogen’s ability to restore male sexual interest is insensitive to a delay since castration. Secondly, to understand the biological basis of these behavioural effects, I examined brain and muscle tissues from the same animals. Specifically, I compared changes in 1) estrogen receptors (ERs) and c-Fos protein (a neuronal activation marker) levels in brain areas controlling sex behavior; 2) ERs levels in pelvic floor muscles, important for erection; and 3) ERs levels in the hippocampus and prefrontal cortex. Prolonged castration increases ER? levels in the preoptic area (POA), a key brain area that regulates mating behaviour, and estradiol treatment reduced these effects. In the POA, mating-induced c-Fos expression was not affected by estradiol regardless of when the treatment began post-castration. Estrogen may upregulate ERs in pelvic floor muscles, and downregulate ERs in the hippocampus and prefrontal cortex, depending on administration time after castration. These findings suggest that mating activates POA neurons, and this activation induces mounting only in the presence of estrogen. Additionally, the duration after castration influences ER autoregulation in the pelvic floor muscles, hippocampus, and prefrontal cortex in response to estradiol. Lastly, I studied how estrogen modulates the sleep-wake behaviour of orchiectomized rats. Estradiol promotes baseline wakefulness during the dark period and prevents castration-induced impairment in sleep recovery after sleep deprivation. These findings suggest that estradiol may positively influence the sleep-wake behaviour of castrated males. Collectively, I demonstrate that estrogen administered to castrated rats improves sexual and sleep functions. It may similarly improve the quality of life of PCa patients on ADT.