Consequence of evolutionary loss of seasonal breeding by humans for prostate cancer chemoprevention.

Abstract

During mammalian evolution, circulating levels of gonadotropins [i.e., luteinizing hormone (LH) and follicle-stimulating hormone (FSH)] acquired regulation by environmental (e.g., light, temperature, water, food, predators, etc.), and social (e.g., sound, sight, aggression, crowding, etc.) inputs that determine the level of testosterone production and secretion by the testis and systemic levels in the blood. This regulation became coordinated by interaction between the retinohypothalamic-pineal and the hypothalamic-pituitary neural axes, which resulted in androgen levels and its ligand-dependent transducing receptor being the master downstream determinant of male reproduction. A major factor in this selection of androgen levels relates to the unique danger of mammalian reproduction for survival of the individual. During mammalian evolution, breeding needed for survival of the species became episodically (i.e., seasonally) timed by androgen levels. Seasonal breeding has great reproductive advantage in restricting energy requirements for reproduction and limiting dangers associated with procreation (i.e., survival of the species) at the expense of suppression of the flight instinct (i.e., survival of the individual) to the minimal time frame of the breeding season. Human males evolved away from strict seasonal breeding by chronically maintaining androgen levels, enabling human males to reproduce year-round and worldwide, rather than "locking" them into specific indigenous breeding ranges, like other mammals. The price for the reproductive "freedom" that arises from the loss of seasonal breeding is an increased probability of developing prostate cancer as a result of chronically maintaining a hyperplastic state in the prostate. In human males, this results in the loss of episodic pruning of genetically-mutated prostate cancer precursors that normally occurs during seasonal breeding. Instead, the continuous androgen-dependent stimulation of the growth of such precursors occurs during prostate carcinogenesis. This review provides the rationale for the development of a therapeutic approach using PSA-activated prodrugs to selectively deplete prostate-specific AR protein for chemoprevention of prostate cancer.