Growth factors and cytokines in the reproductive tract of women: Physiology and pathophysiology

Abstract The remarkably coordinated changes that occur in the female reproductive system during the menstrual cycle are unparalleled by any other integrated organ system in the body. The predictable and precise cyclic changes in this system set the stage for ovulation of generally a single oocyte from the ovary, its fertilization, nourishment, and transport in the oviduct, and implantation in the endometrium (Figure 1). In the absence of implantation, the ovarian corpus luteum undergoes regression, and the endometrium is shed as the menses. These events occur prior to a repeat performance in each organ in a subsequent cycle, with the single-minded goal of successfully establishing a pregnancy. In women, dysfunctions in ovarian follicle development, oocyte maturation, the process of ovulation, ovum pickup by and transport of gametes and an embryo through the Fallopian tubes, and nonreceptivity of the endometrium to implantation all have a common endpoint of unsuccessfully establishing a pregnancy. Seekers of contraception have exploited several of these possibilities, however, to couples desiring fertility, abnormalities in one or more of these processes (as well as in the male partner) can pose formidable barriers to achieving their goals. In addition to an impact on fertility, dysfunction in the female reproductive system can lead to other sequelae. Anovulation, resulting in no progesterone to oppose the effects of estradiol, predisposes women to dysfunctional uterine bleeding, endometrial hyperplasia, and/or endometrial cancer. Blocked Fallopian tubes can result in severe lower abdominal pain, and poorly developed endometrium can result in abnormal uterine bleeding and repetitive miscarriage. Endometriosis is a benign gynecologic condition in which endometrial tissue is found outside of its normal location, mainly on the ovaries and in the cul de sac. It responds to changes in circulating steroids and is associated with severe dysmenorrhea (pain with menses) and infertility. Another member of the system, the uterine myometrium (Figure 1), is most commonly thought of as an active participant in the process of labor and as a structural bystander in the nonpregnant state, aside from its potential contributions to dysmenorrhea. However, benign smooth muscle tumors of this compartment of the female reproductive tract, called leiomyomas or “fibroids,” often impair fertility and have other side-effects that are detrimental to women's health, including discomfort, excessive uterine bleeding and repetitive miscarriage. These unwelcome intruders comprise a leading cause of hysterectomy in women of reproductive age. Clearly, mechanisms regulating the processes at work for normal reproductive function are critical to continuation of the species and for the well-being of women. These processes involve auto- para- and/or juxtacrine interactions of growth modulators. This chapter reviews what is currently known about growth factors and cytokines in normal ovarian follicle development as well as in abnormal development (in polycystic ovarian syndrome [PCOS]), in oviductal function, in endometrial development, implantation, and endometrial shedding, in endometriosis, and in the growth of uterine leiomyomas. Our information is at best incomplete, which prompts us to propose models for the potential roles of growth factors and related peptides in the pathogenesis of these processes. Some systems have been more extensively studied than others due to tissue availability. Most systems have also been extensively studied in animal models, although some do not have natural homologues in most animals (e.g., PCOS, endometriosis, and uterine fibroids). Where appropriate we have made reference to animal models, although the primary focus of the chapter is on growth modulators in the human female reproductive system in health and disease.