Excessive Ovarian Production of Nerve Growth Factor Facilitates Development of Cystic Ovarian Morphology in Mice and Is a Feature of Polycystic Ovarian Syndrome in Humans

Abstract

Although ovarian nerve growth factor (NGF) facilitates follicular development and ovulation, an excess of the neurotrophin in the rodent ovary reduces ovulatory capacity and causes development of precystic follicles. Here we show that ovarian NGF production is enhanced in patients with polycystic ovarian syndrome (PCOS) and that transgenically driven overproduction of NGF targeted to the ovary results in cystic morphology, when accompanied by elevated LH levels. NGF levels are increased in the follicular fluid from PCOS ovaries and in the culture medium of granulosa cells from PCOS patients, as compared with non-PCOS patients. Ovaries from transgenic mice carrying the NGF gene targeted to thecal-interstitial cells by the 17alpha-hydroxylase gene promoter produce more NGF than wild-type (WT) ovaries and are hyperinnervated by sympathetic nerves. Antral follicle growth is arrested resulting in accumulation of intermediate size follicles, many of which are apoptotic. Peripubertal transgenic mice respond to a gonadotropin challenge with a greater increase in plasma 17-hydroxyprogesterone, estradiol, and testosterone levels than WT controls. Transgenic mice also exhibit a reduced ovulatory response, delayed puberty, and reduced fertility, as assessed by a prolonged interval between litters, and a reduced number of pups per litter. Sustained, but mild, elevation of plasma LH levels results in a heightened incidence of ovarian follicular cysts in transgenic mice as compared with WT controls. These results suggest that overproduction of ovarian NGF is a component of polycystic ovarian morphology in both humans and rodents and that a persistent elevation in plasma LH levels is required for the morphological abnormalities to appear.

Balanced levels of nerve growth factor are required for normal pregnancy progression

“…A variety of pleiotropic effects of the NGF pathway, including the control of ovarian function, inflammation and angiogenesis, are most likely to influence the outcome of pregnancy (Tometten et al 2005). In particular, decreased progesterone levels in diestrus and an impaired response to hCG-like activity have been observed upon NGF overexpression in the ovaries of mice (Dissen et al 2009). However, results from our mouse studies revealed no overt defects in progesterone levels and luteal structure, suggesting that the disruption of pregnancy caused by the deregulation of NGF levels does not result from alterations in ovarian physiology.…”

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence

“…Additional studies in this rat model showed an association between the development of follicular cysts and chronic increased production of nerve growth factor in the ovary [122], a hallmark of sympathetic hyperactivity. The association between the neurotrophins and PCOS was strengthened by the finding that ovarian nerve growth factor production is increased in PCOS women [123]. …”

Brown adipose tissue transplantation ameliorates polycystic ovary syndrome

“…3D and Table S2). Previous studies demonstrated that ovarian sympathetic tone was increased in women with PCOS (26,27). Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of norepinephrine (NE), and expression of TH in the ovary is highly restricted to sympathetic nerves.…”