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Polycystic ovary syndrome (PCOS) is a common condition with reproductive and metabolic features. Recent studies confirmed that women with PCOS have multiple genetic allelic variants that are independently associated with hyperandrogenism, gonadotropin regulation, timing of menopause, depression, and metabolic disturbances, including insulin resistance [1]. Of note, the data cited above showed that not all women with PCOS possess the full complement of the 14 genetic variants identified. Genetic heterogeneity results in clinical heterogeneity. We have long recognized that there is a spectrum of clinical presentation, with some women having a more pronounced reproductive phenotype and others presenting primarily with metabolic features. Despite variation related to PCOS genotype and phenotype, however, two long-recognized pathogenic themes remain the same: excess androgen exposure and insulin resistance. Since androgens and insulin modulate of brain architecture and function, it is not surprising that PCOS is associated with a brain phenotype, but also one that presents variably. Building on the notion that the brain is a target of hormones of all classes, in this chapter we characterize the brain phenotype in PCOS and explore the evidence that the brain phenotype is the result of androgen exposure that not only predisposes to anovulation and obesity but also has the potential to skew gender identity and sexual orientation.

Endometriosis is a common gynecological syndrome associated with pain and infertility and characterized by the growth of hormone-responsive endometrial tissue outside the uterine cavity. Three major subtypes of ectopic endometriotic implants are currently recognized, based on their anatomic location: (1) attached to the peritoneal surface, (2) encapsulated within the ovary, or (3) infiltrating the connective tissues of the rectovaginal septum. However, more widely dispersed lesions have been described in the pleura, the cutaneous skin, and even the lacrimal duct [1]. The high prevalence of endometriosis is broadly recognized, and recent population-based estimates put its overall frequency among reproductive-age women at around 11% [2]. This disease is accompanied by pelvic pain in millions of women worldwide, resulting in work absenteeism, social isolation, and high costs of medical and surgical therapies. In the United States, endometriosis is the third commonest indication for hysterectomy, a procedure that can be particularly devastating in women under age 30, because they are likely to experience residual somatic symptoms and a severe psychological sense of loss.

The cornerstone of female reproduction is the hypothalamic-pituitary-ovarian (HPO) axis. This term is incomplete in that it omits reference to the uterus and endometrium, which are clearly critical to the most important step in reproduction, namely, implantation. Implantation requires that the endometrium become receptive to a healthy blastocyst. Thus, folliculogenesis must result not only in ovulation but also in the secretion of estradiol and progesterone in a pattern that prepares the endometrium for implantation. While implantation failure can be defined as absent hCG production after ovulation that is signaled by menstrual bleeding, the definition also encompasses transient hCG production that is not sustained, which is often called “chemical” pregnancy.