Growth Factors and the Development and Function of the Reproductive Organs

Linda C. Giudice, M.D., Ph.D. Marco Conti, M.D.

Together with well established endocrine regulations that involve the hypothalamic-pituitary-gonadal axis, investigation spanning the last two decades has solidified the concept that additional layers of local controls are essential for gonadal function. In both the female and male gonads, these regulations rely on local secretion of growth factors functioning in a short and medium range within the gonad itself. These regulations support the dialogue between somatic and germ cells that begins when the bipotential gonadal primordium is colonized by primordial germ cells. This function continues at the time of formation of follicles and seminiferous tubules, as well as in the adult, where it is essential for the production of fully functional male and female gametes. Paracrine regulations involving growth factors are equally important after fertilization, when the embryo begins its interaction with the uterus at the time of implantation.

The present issue provides an overview of how growth factor signaling is implicated at different stages of the life cycle of the male and female gonads. Given the broadness of the field and page constraints, this compendium could not be a comprehensive review of all growth factors involved in reproduction. Instead, we have elected to focus on areas where regulatory circuits involving growth factors are more advanced, those that have most recently emerged, and those that have the greatest impact on reproduction. The reader is directed to several excellent reviews focusing on other aspects that could not be covered here, for instance, the role of local growth factors in spermatogonial stem cell regulation and generation of the niche,[1] Leydig cell–Sertoli cell crosstalk,[2] growth factors involved in reproductive tract development,[3] and paracrine interactions during blastocyst implantation into the maternal decidua.[4] [5]

During gonadal development, formation of the seminiferous cord and primordial follicles depends on a well-orchestrated exchange of signals encoded by the growth factors released. Migration of cells from the adjacent mesonephron also depends on the local signal originating from the primordial gonad. Cool and Capel have summarized how these signals are required at the time when the development of the female or male gonad is determined. A comprehensive review of the role of different growth factors in the organization of the mouse testis is also included.

In the female, the number of follicles present in the ovary is established at midgestation in humans or at birth in rodents, and ample evidence indicates that the size of this reservoir determines the reproductive lifespan of a female. Any genetic disruption or endocrine manipulation affecting this pool causes rapid exhaustion of follicle reserve, thus shortening the reproductive lifespan of the female. Thus knowledge of the mechanisms establishing the primordial follicle pool is an indispensable background to understanding human pathologies of infertility and eventually for devising suitable therapies. In articles by Trombly et al, and by Dissen et al, the role of transforming growth factor and the neurotrophin families of growth factors in the formation of the primordial follicles is summarized. Together with cell autonomous genetic programs, these paracrine/autocrine regulations are critical for the normal reproductive life of a female.

Whereas formation of the seminiferous tubules does not require the presence of germ cells, follicle formation is mostly orchestrated by the oocyte. Thus oocyte–granulosa cell interactions are critical for the aggregation and growth of a healthy follicle. This concept is supported by numerous studies demonstrating how oocyte signals modify the function of granulosa cells. GDF-9 (growth differentiation factor 9), BMP-15 (bone morphogenetic protein 15), and FGF-9 (fibroblast growth factor 9) are examples of the expanding list of growth factors that convey the oocyte messages to the somatic cells. Using the regulation of intermediate metabolism in somatic cells as an example, Su and colleagues have reviewed the mechanisms underlying this oocyte–somatic cell crosstalk, as well as the growth factors involved. In addition to signals from the oocytes, differentiation of granulosa cells depends on local release of members of the insulin-like growth factor (IGF) growth factor family. These growth factors are essential for growth of the follicle and steroidogenesis. The complexity of this IGF growth factor system is reviewed in the article by Kwintkiewicz and Giudice. They review the role of the IGF system in follicle growth, selection, atresia, cellular differentiation, steroidogenesis, oocyte maturation, cumulus expansion, and follicle dynamics, along with recent data on the effects of environmental contaminants on IGF actions in the ovary. In addition, these authors have reviewed data on how this system contributes to the resistance to follicle-stimulating hormone in patients with polycystic ovary syndrome and how the IGF system is compromised by environmental endocrine disruptors.

When the ovarian follicle has reached the final stages of maturation and is ready for ovulation, the luteinizing hormone (LH) surge acts as a trigger for activation of genetic programs required for terminal differentiation of somatic cells and for the rapid structural changes of the follicle wall that culminate in rupture and ovulation. At the same time, the LH signal reaching the oocyte promotes nuclear and cytoplasm maturation. Both events are essential for production of a fertilizable egg and embryo development. It is now recognized that the LH surge is associated with production of growth factors involved in all of the events just described. The article by Hsieh et al reviews the evidence on the involvement of the epidermal growth factor network in rodents and human follicles at the time of ovulation.

In addition to their role in gametogenesis and gamete–somatic cell interactions, growth factors play critical roles in uterine receptivity and implantation. Guzeloglu-Kayisli and colleagues provide an overview of the different families of growth factors and cytokines during implantation. Chennazhi and Nayak have reviewed the role that vascular endothelial growth factor plays in the regulation of angiogenesis in the endometrium, focusing mostly on primate models. The secretion of interferons by the trophoblast and the essential role of this endocrine/paracrine regulator during implantation are summarized in the article by Bazer and colleagues.

We believe that this collection of articles underscores the importance of paracrine/autocrine regulation supported by growth factors in the development and function of the gonads and in the process of implantation, both critical in preserving fertility. From the articles an underlying theme emerges—namely, that signaling modules involving growth factors are used over and over at different times during the lifecycle of the male and female gonads and during the process of implantation. Although this makes it more challenging to fully dissect their role in gonadal function and embryo–decidual interactions, this multitude of functions opens new avenues for pharmacological intervention for enhancing fertility and contraception. With the discovery of the role of these growth factors, the repertoire of potential targets to manipulate fertility is greatly increased. Some of these growth factor–mediated pathways may be used in the future to support follicle growth or to sensitize the gonads to gonadotropins, to promote or inhibit endometrial–embryo interactions, and as biomarkers of gonadal function and uterine receptivity.

REFERENCES

• 1 Spradling A, Drummond-Barbosa D, Kai T. Stem cells find their niche.  Nature. 2001;  414 98-104
• 2 Saunders P T. Germ cell-somatic cell interactions during spermatogenesis.  Reprod Suppl. 2003;  61 91-101
• 3 Kobayashi A, Behringer R R. Developmental genetics of the female reproductive tract in mammals.  Nat Rev Genet. 2003;  4 969-980
• 4 Wang H, Dey S K. Roadmap to embryo implantation: clues from mouse models.  Nat Rev Genet. 2006;  7 185-199
• 5 Aghajanova L, Hamilton A E, Giudice L C. Uterine receptivity to human embryonic implantation: histology, biomarkers, and transcriptomics.  Semin Cell Dev Biol. 2008;  19 204-211