ABSTRACT
Compound-related effects on the reproductive system are often pivotal in pharmaceutical development. As with other organ systems, a pathologist’s understanding of the physiology, background pathology, and species variations underlying the microscopic presentation of reproductive tissues can be critical to accurate risk assessment. However, the reproductive system has several unique features that require special attention, which includes dependence on hormones from the hypothalamus and pituitary, hormonal feedback, puberty, senescence, cyclicity in the female, stage-aware evaluation of spermatogenesis, and dramatic species differences. This requires the pathologist to be well versed in normal physiology and endocrinology, and in this chapter, we have included more information on normal anatomy, histology, physiology, and endocrinology than is typically provided in pathology textbooks. A rm grasp of the normal state will allow for better characterization of potential reproductive hazards and provide for the best possible risk assessment. In addition, we have considered the male and female reproductive systems together with the mammary gland as many basic concepts track across these organ systems. The reproductive organs cannot be effectively evaluated in isolation. For example, the testes, and spermatogenesis in particular, receive the most attention and are the most common target sites for male reproductive toxicants, but the epididymis and the hypothalamic-pituitary-gonadal (HPG) axis must also be considered. Sometimes they can be the primary site of toxicity, and changes in the testes occur as a secondary consequence. Similarly in the female, changes in the vaginal epithelium must be evaluated in conjunction with an understanding of the reproductive cycle, the HPG axis, and mammary gland. Background pathology and maturity status are confounding factors for identifying toxicity in all species, but especially in the male dog and female nonhuman primate (NHP; unless specied, NHP will refer to cynomologus macaque). Guidance is provided for recognizing and distinguishing these changes from drug-induced changes. Organ weights, sperm parameters, fertility, endocrine measurements, and reproductive cyclicity data are other important endpoints that can be used to evaluate reproductive toxicity and in some cases are more sensitive than histopathology for detecting toxicity. Although these parameters are not generally available to the pathologist from routine toxicity studies, it is important to understand their relevance and application for overall risk assessment.
