Developmental Programming: Impact of Prenatal Testosterone Excess on Pre- and Postnatal Gonadotropin Regulation in Sheep

Department of Pediatrics, the Reproductive Sciences Program, and the Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan 48109-0404, USA.
Biology of Reproduction (Impact Factor: 3.32). 05/2008; 78(4):648-60. DOI: 10.1095/biolreprod.107.063347
Source: PubMed


The goal of this study was to explore mechanisms that mediate hypersecretion of LH and progressive loss of cyclicity in female sheep exposed during fetal life to excess testosterone. Our working hypothesis was that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH (but not FSH) secretion and, thus, hypersecretion of LH in adulthood, and that this results from altered developmental gene expression of GnRH and estradiol (E2) receptors, gonadotropin subunits, and paracrine factors that differentially regulate LH and FSH synthesis. We observed that, relative to controls, females exposed during fetal life to excess testosterone, as well as the nor-aromatizable androgen dihydrotestosterone, exhibited enhanced LH but not FSH responses to intermittent delivery of GnRH boluses under conditions in which endogenous LH (GnRH) pulses were suppressed. Luteinizing hormone hypersecretion was more evident in adults than in prepubertal females, and it was associated with development of acyclicity. Measurement of pituitary mRNA concentrations revealed that prenatal testosterone excess induced developmental changes in gene expression of pituitary GnRH and E2 receptors and paracrine modulators of LH and FSH synthesis in a manner consistent with subsequent amplification of LH release. Together, this series of studies suggests that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH response, leading to LH hypersecretion and acyclicity in adulthood, and that this programming involves developmental changes in expression of pituitary genes involved in LH and FSH release.

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    • "Elevated levels of prenatal androgens such as fetal testosterone (FT) during a critical period are hypothesized to contribute to the etiology of ASC [10] as FT shapes neurological development [11-13]. Prenatal androgens also contribute to the programming of the hypothalamic-pituitary-gonadal (HPG) axis [14,15], and elevated levels of prenatal androgens also contribute to the etiology of polycystic ovary syndrome (PCOS) [16]. The present study further explores the link between ASC and PCOS. "
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    ABSTRACT: Prenatal exposure to increased androgens has been implicated in both polycystic ovary syndrome (PCOS) and autism spectrum conditions (ASC), suggesting that PCOS may be increased among women with ASC. One study suggested elevated steroidopathic symptoms ('steroidopathy') in women with ASC. As the symptoms are not independent, we conducted a latent class analysis (LCA). The objectives of the current study are: (1) to test if these findings replicate in a larger sample; and (2) to use LCA to uncover affected clusters of women with ASC. We tested two groups of women, screened using the Autism Spectrum Quotient - Group 1: n = 415 women with ASC (mean age 36.39 +/- 11.98 years); and Group 2: n = 415 controls (mean age 39.96 +/- 11.92 years). All participants completed the Testosterone-related Medical Questionnaire online. A multiple-group LCA was used to identify differences in latent class structure between women with ASC and controls. There were significant differences in frequency of steroid-related conditions and symptoms between women with ASC and controls. A two-class semi-constrained model best fit the data. Based on response patterns, we identified the classes as 'Typical' and 'Steroidopathic'. The prevalence of the 'Steroidopathic' class was significantly increased within the ASC group (DeltaG2 = 15, df =1, P = 0.0001). In particular, we confirmed higher frequencies of epilepsy, amenorrhea, dysmenorrhea, severe acne, gender dysphoria, and transsexualism, and differences in sexual preference in women with ASC. Women with ASC are at increased risk for symptoms and conditions linked to steroids. LCA revealed this steroidopathy despite the apparent underdiagnosis of PCOS.
    Molecular Autism 04/2014; 5(1):27. DOI:10.1186/2040-2392-5-27 · 5.41 Impact Factor
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    • "Since it is not known when or where the pathology actually begins, several different hypotheses are presented. Prenatal androgenization represents an established hypothesis of PCOS etiology and is based on animal models including monkeys, sheep, and rodents where prenatal androgenization inflicts several features of PCOS in the offspring [16] [17] [18] [19]. However, in humans, although increased levels of androgens have been found in pregnant PCOS women [20], only one study has found increased levels of testosterone in umbilical vein blood in infants of PCOS mothers although these levels were measured by immunoassays and not mass spectrometry [21]. "
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    ABSTRACT: Polycystic ovary syndrome (PCOS), the most common endocrine disorder among women of reproductive age, is characterized by the coexistence of hyperandrogenism, ovulatory dysfunction, and polycystic ovaries (PCO). PCOS also represents the largest part of female oligoovulatory infertility, and the management of ovulatory and menstrual dysfunction, comprises a third of the high costs of PCOS treatment. Current pharmacological and surgical treatments for reproductive symptoms are effective, however, associated with negative side effects, such as cardiovascular complications and multiple pregnancies. For menstrual irregularities and ovulation induction in women with PCOS, acupuncture has indicated beneficial effects. This review will focus on the results from randomized controlled acupuncture trials for regulation of menstrual dysfunction and for inducing ovulation in women with PCOS although there are uncontrolled trials with nonetheless interesting results. Animal experimental studies will be further discussed when they can provide a more mechanistic explanatory view.
    Evidence-based Complementary and Alternative Medicine 09/2013; 2013(1):762615. DOI:10.1155/2013/762615 · 1.88 Impact Factor
    • "Fifteen days after CIDR insertion, a jugular catheter was placed and blood samples were procured for 6 h at 24 min intervals to assess baseline levels. On the following day, all animals were primed by administering 2 ng/kg of GnRH (L7134, Sigma-Aldrich) i.v. at 90 min intervals for a total of 17 injections (Manikkam et al., 2008). GnRH administration of 2 ng/kg has been shown to produce peak GnRH levels of ~ 6 pg/min/ml (Sharma et al., 2012). "
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    ABSTRACT: Bisphenol-A (BPA), a polymer used in plastics manufacturing, and methochychlor (MXC) a pesticide, are endocrine disrupting compounds with estrogenic and anti-androgenic properties. Prenatal BPA or MXC treatment induces reproductive defects in sheep with BPA causing prepubertal luteinizing hormone (LH) hypersecretion and dampening of periovulatory LH surges and MXC lengthening follicular phase and delaying the LH surge. In this study, we addressed the underlying neuroendocrine defects by testing the following hypotheses: 1) prenatal BPA but not MXC reduces sensitivity to estradiol and progesterone negative feedback, 2) prenatal BPA but not MXC increases pituitary responsiveness to gonadotropin releasing hormone (GnRH), and 3) prenatal BPA dampens LH surge response to estradiol positive feedback challenge while prenatal MXC delays the timing of the LH surge. Pregnant sheep were treated with either 1) 5 mg/kg/day BPA (produces approximately twice the level found in human circulation, n=8), 2) 5 mg/kg/day MXC (lowest observed effect level stated in the EPA National Toxicology Program's Report; n=6), or 3) vehicle (cotton seed oil: C: n=6) from days 30 to 90 of gestation. Female offspring of these ewes were ovariectomized at 21 months of age and tested for progesterone negative, estradiol negative, estradiol positive feedback sensitivities and pituitary responsiveness to GnRH. Results revealed that sensitivity to all 3 feedbacks as well as pituitary responsiveness to GnRH were not altered by either of the prenatal treatments. These findings suggest that the postpubertal reproductive defects seen in these animals may have stemmed from ovarian defects and the steroidal signals emanating from them.
    Toxicology and Applied Pharmacology 02/2013; 268(3). DOI:10.1016/j.taap.2013.02.011 · 3.71 Impact Factor
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