The Role of Growth Hormone on Ovarian Functioning and Ovarian Angiogenesis

Abstract

Although not yet well-understood, today it is clear that Growth Hormone (GH) exerts a relevant role in the regulation of ovulation and fertility; in fact, fertility is lower in women with GH deficiency (GHD), and GH receptors (GHR) and GH mRNA have been found in the ovary since the onset of follicular development in humans. However, despite the strong evidence of GH in the regulation of fertility, many aspects of GH actions at this level are still not well-established, and it is likely that some controversial data depend on the species analyzed, the dose of the hormone and the duration of use of GH. Folliculogenesis, ovulation, and corpus luteum formation and maintenance are processes that are critically dependent on angiogenesis. In the ovary, new blood vessel formation facilitates oxygen, nutrients, and hormone substrate delivery, and also secures transfer of different hormones to targeted cells. Some growth factors and hormones overlap their actions in order to control the angiogenic process for fertility. However, we still know very little about the factors that play a critical role in the vascular changes that occur during folliculogenesis or luteal regression. To promote and maintain the production of VEGF-A in granulosa cells, the effects of local factors such as IGF-I and steroids are needed; that VEGF-A-inducing effect cannot be induced by luteinizing hormone (LH) or chorionic gonadotropin (CG) alone. As a result of the influences that GH exerts on the hypothalamic-pituitary-gonadal axis, facilitating the release of gonadotropins, and given the relationship between GH and local ovarian factors such as VEGF-A, FGF-2, IGF-1, or production of sex steroids, we assume that GH has to be a necessary factor in ovarian angiogenesis, as it happens in other vascular beds. In this review we will discuss the actions of GH in the ovary, most of them likely due to the local production of the hormone and its mediators.

Why Should Growth Hormone (GH) Be Considered a Promising Therapeutic Agent for Arteriogenesis? Insights from the GHAS Trial

“…MSCs also can differentiate into ECs in the presence of the vascular endothelial growth factor A (VEGF-A) [61,62], a factor that plays many roles in cell differentiation, proliferation, and angiogenesis. The relationships between GH and VEGF-A are not well known, but GH plays a pivotal role among the factors that regulate VEGF family expression in humans [63]. In addition, GH regulates the expression of different genes involved in Notch-1 signaling, at least at the ovarian level [63], and two Notch-1 ligands-delta-like protein Dl14 and Jagged 1-that directly regulate angiogenesis in the endothelium [64,65].…”

“…The relationships between GH and VEGF-A are not well known, but GH plays a pivotal role among the factors that regulate VEGF family expression in humans [63]. In addition, GH regulates the expression of different genes involved in Notch-1 signaling, at least at the ovarian level [63], and two Notch-1 ligands-delta-like protein Dl14 and Jagged 1-that directly regulate angiogenesis in the endothelium [64,65]. Therefore, given the relationships existing between Notch-1, VEGF-A, Notch-1, and GH, it is presumable that the differentiation of MSCs into ECs for neovascularization and endothelium repair may involve the participation of GH (for a more detailed explanation, see Figure 9 in reference [61]).…”

Why Should Growth Hormone (GH) Be Considered a Promising Therapeutic Agent for Arteriogenesis? Insights from the GHAS Trial

“…of interest to indicate that MSCs differentiate to ECs in the presence of the vascular endothelial growth factor A (VEGF-A) [77,78], a factor that plays many roles in cell differentiation, proliferation and angiogenesis. The relationships between GH and VEGF-A are not well known, but GH plays a pivotal role among the factors that regulate VEGF family expression in humans [79]. On the other side, GH regulates the expression of different genes involved in Notch-1 signaling, at least at the ovarian level [79], and two Notch-1 ligands, delta-like protein Dl14 and Jagged 1 regulate angiogenesis directly in the endothelium [80,81], but besides it there is a strong relationship between VEGF-A and Notch-1 signaling.…”

“…The relationships between GH and VEGF-A are not well known, but GH plays a pivotal role among the factors that regulate VEGF family expression in humans [79]. On the other side, GH regulates the expression of different genes involved in Notch-1 signaling, at least at the ovarian level [79], and two Notch-1 ligands, delta-like protein Dl14 and Jagged 1 regulate angiogenesis directly in the endothelium [80,81], but besides it there is a strong relationship between VEGF-A and Notch-1 signaling. Therefore, given the relationships existing between Notch-1 and VEGF-A, and Notch-1 and GH, it is presumable that the differentiation of MSCs to ECs, neovascularization and endothelium repair, may involve the participation of GH, Notch-1 and VEGF-A [for a more detailed explanation, see Figure 9 in reference 79].…”

“…With independence of the cardiovascular system, one of the most interesting location of GHR is in the endothelium of vessels of endometrium, where GH seems to have an important action in the creation and maintenance of vessels during every sexual cycle in females [97]. This fact is extraordinarily important, since it represents one of the key aspect that supports the role of GH in arteriogenesis, mimicking the physiologic process that takes place in fertile women [79].…”