Excessive ovarian nerve growth factor production induces a polycystic ovary syndrome-like condition in mice
thesis
posted on 2017-03-14, 22:41 authored by Jenny WilsonPolycystic
ovary syndrome (PCOS) is the most common endocrine disorder affecting women of
reproductive age, with a prevalence of 6-19%. This heterogeneous disorder is
characterized by reproductive abnormalities including hyperandrogenaemia,
menstrual disorders, infertility and polycystic ovary morphology as well as
cardiometabolic conditions such as visceral adiposity, insulin resistance (IR),
hyperinsulinemia, type 2 diabetes mellitus, hypertension and premature
atherosclerosis. Despite decades of research, the aetiology of PCOS remains
elusive.
Previous findings of increased catecholaminergic nerve fibre density in the ovaries of PCOS patients as well as increased muscle sympathetic nerve activity in PCOS women compared to control women raised the possibility that altered sympathetic innervation may contribute to the development of PCOS. Furthermore, the findings of increased nerve growth factor (NGF) content in human PCOS ovaries, a hallmark of sympathetic hyperactivity, suggests a contribution of excess NGF, to PCOS. These findings led the Ojeda research group to generate transgenic mice overexpressing NGF in the ovary (17NF mice). These mice exhibited enhanced sympathetic input to the ovary. as well as a number of reproductive alterations including delayed puberty and reduced fertility. Moreover, peripubertal 17NF mice exhibited an accumulation of antral follicles in basal conditions in the ovary, as well as cystic ovarian morphology and hyperandrogenemia when treated with gonadotropins. This thesis aimed to further these findings by examining ovarian morphology in early postnatal life as well as adulthood in 17NF mice. Interestingly 17NF mice exhibited in a consistently reduced number of primordial follicles from early postnatal life through to adulthood. Additionally, an increased number of antral follicles and ovarian cysts as well as increased circulating testosterone and estradiol levels was observed in mature 17NF mice compared to WT mice.
Furthermore, 17NF mice were found to exhibit increased circulating NGF levels as well as increased interscapular brown adipose tissue thermogenesis, a marker of central sympathetic outflow. This suggests that overproduction of ovarian NGF not only increased ovarian sympathetic innervation but also lead to enhanced central sympathetic outflow, which could have detrimental consequences on glucose homeostasis and cardiovascular functions. Indeed, a number of cardiometabolic alterations were observed in 17NF mice including increased body weight, increased visceral fat mass, IR, and systolic dysfunction, as well as cardiac remodeling evidenced by LV dilation and collagen degradation. Finally, this thesis also sought to elucidate the effect of exposure to diet induced obesity (DIO) on the development of PCOS in 17NF mice. Surprisingly, 17NF DIO mice gained weight at variable rates compared to WT DIO mice, initially gaining rate at a slower rate and then switching to a higher rate of weight gain. Additionally, 17NF DIO mice exhibited a slightly lesser degree of glucose intolerance compared to WT DIO mice.
Collectively, these results suggest that overproduction of ovarian NGF is sufficient to cause reproductive, metabolic and cardiovascular alterations characteristic of PCOS and support the hypothesis that sympathetic hyperactivity plays a pathological role in the development and/or progression of PCOS. Furthermore, exposure to DIO concomitant with excess ovarian NGF did not seem to exacerbate metabolic alterations of 17NF mice.
Previous findings of increased catecholaminergic nerve fibre density in the ovaries of PCOS patients as well as increased muscle sympathetic nerve activity in PCOS women compared to control women raised the possibility that altered sympathetic innervation may contribute to the development of PCOS. Furthermore, the findings of increased nerve growth factor (NGF) content in human PCOS ovaries, a hallmark of sympathetic hyperactivity, suggests a contribution of excess NGF, to PCOS. These findings led the Ojeda research group to generate transgenic mice overexpressing NGF in the ovary (17NF mice). These mice exhibited enhanced sympathetic input to the ovary. as well as a number of reproductive alterations including delayed puberty and reduced fertility. Moreover, peripubertal 17NF mice exhibited an accumulation of antral follicles in basal conditions in the ovary, as well as cystic ovarian morphology and hyperandrogenemia when treated with gonadotropins. This thesis aimed to further these findings by examining ovarian morphology in early postnatal life as well as adulthood in 17NF mice. Interestingly 17NF mice exhibited in a consistently reduced number of primordial follicles from early postnatal life through to adulthood. Additionally, an increased number of antral follicles and ovarian cysts as well as increased circulating testosterone and estradiol levels was observed in mature 17NF mice compared to WT mice.
Furthermore, 17NF mice were found to exhibit increased circulating NGF levels as well as increased interscapular brown adipose tissue thermogenesis, a marker of central sympathetic outflow. This suggests that overproduction of ovarian NGF not only increased ovarian sympathetic innervation but also lead to enhanced central sympathetic outflow, which could have detrimental consequences on glucose homeostasis and cardiovascular functions. Indeed, a number of cardiometabolic alterations were observed in 17NF mice including increased body weight, increased visceral fat mass, IR, and systolic dysfunction, as well as cardiac remodeling evidenced by LV dilation and collagen degradation. Finally, this thesis also sought to elucidate the effect of exposure to diet induced obesity (DIO) on the development of PCOS in 17NF mice. Surprisingly, 17NF DIO mice gained weight at variable rates compared to WT DIO mice, initially gaining rate at a slower rate and then switching to a higher rate of weight gain. Additionally, 17NF DIO mice exhibited a slightly lesser degree of glucose intolerance compared to WT DIO mice.
Collectively, these results suggest that overproduction of ovarian NGF is sufficient to cause reproductive, metabolic and cardiovascular alterations characteristic of PCOS and support the hypothesis that sympathetic hyperactivity plays a pathological role in the development and/or progression of PCOS. Furthermore, exposure to DIO concomitant with excess ovarian NGF did not seem to exacerbate metabolic alterations of 17NF mice.
