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

Gregory Dissen, Cecilia Garcia-Rudaz, Alfonso Paredes, Christine Mayer, Artur Mayerhofer, Sergio Ojeda

    Research output: Contribution to journalArticle

    70 Citations (Scopus)

    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 17α-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.

    Original languageEnglish (US)
    Pages (from-to)2906-2914
    Number of pages9
    JournalEndocrinology
    Volume150
    Issue number6
    DOIs
    StatePublished - Jun 2009

    Fingerprint

    Polycystic Ovary Syndrome
    Nerve Growth Factor
    Ovary
    Transgenic Mice
    Rodentia
    Follicular Cyst
    Delayed Puberty
    17-alpha-Hydroxyprogesterone
    Follicular Fluid
    Ovarian Cysts
    Granulosa Cells
    Nerve Growth Factors
    Mixed Function Oxygenases
    Ovulation
    Gonadotropins
    Genes
    Fertility
    Culture Media
    Testosterone
    Estradiol

    ASJC Scopus subject areas

    • Endocrinology

    Cite this

    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. / Dissen, Gregory; Garcia-Rudaz, Cecilia; Paredes, Alfonso; Mayer, Christine; Mayerhofer, Artur; Ojeda, Sergio.

    In: Endocrinology, Vol. 150, No. 6, 06.2009, p. 2906-2914.

    Research output: Contribution to journalArticle

    Dissen, Gregory ; Garcia-Rudaz, Cecilia ; Paredes, Alfonso ; Mayer, Christine ; Mayerhofer, Artur ; Ojeda, Sergio. / 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. In: Endocrinology. 2009 ; Vol. 150, No. 6. pp. 2906-2914.
    @article{23c7fbaffeb14845ad7aa363f9405916,
    title = "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 17α-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.",
    author = "Gregory Dissen and Cecilia Garcia-Rudaz and Alfonso Paredes and Christine Mayer and Artur Mayerhofer and Sergio Ojeda",
    year = "2009",
    month = "6",
    doi = "10.1210/en.2008-1575",
    language = "English (US)",
    volume = "150",
    pages = "2906--2914",
    journal = "Endocrinology",
    issn = "0013-7227",
    publisher = "The Endocrine Society",
    number = "6",

    }

    TY - JOUR

    T1 - 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

    AU - Dissen, Gregory

    AU - Garcia-Rudaz, Cecilia

    AU - Paredes, Alfonso

    AU - Mayer, Christine

    AU - Mayerhofer, Artur

    AU - Ojeda, Sergio

    PY - 2009/6

    Y1 - 2009/6

    N2 - 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 17α-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.

    AB - 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 17α-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.

    UR - http://www.scopus.com/inward/record.url?scp=66649126063&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=66649126063&partnerID=8YFLogxK

    U2 - 10.1210/en.2008-1575

    DO - 10.1210/en.2008-1575

    M3 - Article

    VL - 150

    SP - 2906

    EP - 2914

    JO - Endocrinology

    JF - Endocrinology

    SN - 0013-7227

    IS - 6

    ER -