Prenatal testosterone excess programs reproductive and metabolic dysfunction in the female

Padmanabhan, Vasantha; Manikkam, Mohan; Recabarren, Sergio E; Foster, Douglas L.

doi:10.1016/j.mce.2005.11.016

Cited by 106 publications

(79 citation statements)

References 95 publications

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“…Abnormal hormone levels during early development may play a role, as suggested by the high frequency of polycystic ovaries, oligomenorrhea and amenorrhea in female-to-male (FtM) transsexuals. This observation suggests early intrauterine exposure of the female fetus to abnormally high levels of testosterone (83). A recent study did not confirm a significantly increased prevalence of polycystic ovary syndrome.…”

Section: Transsexualitymentioning

confidence: 81%

Sexual differentiation of the human brain in relation to gender identity and sexual orientation

Savić

Garcı́a-Falgueras

Swaab

2010

Sex Differences in the Human Brain, Their Underpinnings and Implications

116

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SummaryDuring the intrauterine period the fetal brain develops in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. In this way, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation are programmed into our brain structures when we are still in the womb. However, since sexual differentiation of the genitals takes place in the first two months of pregnancy and sexual differentiation of the brain starts in the second half of pregnancy, these two processes can be influenced independently, which may result in transsexuality. This also means that in the event of ambiguous sex at birth, the degree of masculinization of the genitals may not reflect the degree of masculinization of the brain. There is no proof that social environment after birth has an effect on gender identity or sexual orientation.KEY WORDS: gender identity, homosexuality, human brain, sexual orientation, sexual differentiation, transsexuality. Sexual organization and activation of the human brainThe process of sexual differentiation of the brain brings about permanent changes in brain structures and functions via interactions of the developing neurons with the environment, understood in its widest sense. The environment of a developing neuron is formed by the surrounding nerve cells and the child's circulating hormones, as well as the hormones, nutrients, medication and other chemical substances from the mother and the environment that enter the fetal circulation via the placenta. All these factors may have a lasting effect on the sexual differentiation of the brain. The testicles and ovaries develop in the sixth week of pregnancy. This occurs under the influence of a cascade of genes, starting with the sex-determining gene on the Y chromosome (SRY). The production of testosterone by a boy's testes is necessary for sexual differentiation of the sexual organs between weeks 6 and 12 of pregnancy. The peripheral conversion of testosterone into dihydrotestosterone is essential for the formation of a boy's penis, prostate and scrotum. Instead, the development of the female sexual organs in the womb is based primarily on the absence of androgens (1). Once the differentiation of the sexual organs into male or female is settled, the next thing that is differentiated is the brain, under the influence, mainly, of sex hormones on the developing brain cells. The changes (permanent) brought about in this stage have organizing effects; later, during puberty, the brain circuits that developed in the womb are activated by sex hormones. This paradigm of sexual differentiation of the brain has been well established, ever since the first paper by Phoenix et al. (2). The fetal brain is protected against the effect of circulating estrogens from the mother by the protein α-fetoprotein, which is produced by the fetus and binds strongly to estrogens but not to testosterone (3,4). However, estrogens do not only reach th...

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Section: Transsexualitymentioning

confidence: 81%

Sexual differentiation of the human brain in relation to gender identity and sexual orientation

Savić

Garcı́a-Falgueras

Swaab

2010

Sex Differences in the Human Brain, Their Underpinnings and Implications

116

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“…Animal models of PCOS (Abbott et al 1998) are a great resource in this regard. In female sheep exposed prenatally to excess testosterone, multiple neuroendocrine, ovarian, and behavioral disorders are evident from birth to adulthood (Padmanabhan et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Pituitary and testis responsiveness of young male sheep exposed to testosterone excess during fetal development

Recabarren¹,

Rojas-García²,

Einspanier³

et al. 2013

Reproduction

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Prenatal exposure to excess testosterone induces reproductive disturbances in both female and male sheep. In females, it alters the hypothalamus-pituitary-ovarian axis. In males, prenatal testosterone excess reduces sperm count and motility. Focusing on males, this study tested whether pituitary LH responsiveness to GNRH is increased in prenatal testosterone-exposed males and whether testicular function is compromised in the testosterone-exposed males. Control males (nZ6) and males born to ewes exposed to twice weekly injections of 30 mg testosterone propionate from days 30 to 90 and of 40 mg testosterone propionate from days 90 to 120 of gestation (nZ6) were studied at 20 and 30 weeks of age. Pituitary and testicular responsiveness was tested by administering a GNRH analog (leuprolide acetate). To complement the analyses, the mRNA expression of LH receptor (LHR) and that of steroidogenic enzymes were determined in testicular tissue. Basal LH and testosterone concentrations were higher in the testosterone-exposed-males. While LH response to the GNRH analog was higher in the testosterone-exposed males than in the control males, testosterone responses did not differ between the treatment groups. The testosterone:LH ratio was higher in the control males than in the testosterone-exposed males of 30 weeks of age, suggestive of reduced Leydig cell sensitivity to LH in the testosterone-exposed males. The expression of LHR mRNA was lower in the testosterone-exposed males, but the mRNA expression of steroidogenic enzymes did not differ between the groups. These findings indicate that prenatal testosterone excess has opposing effects at the pituitary and testicular levels, namely increased pituitary sensitivity to GNRH at the level of pituitary and decreased sensitivity of the testes to LH.

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“…17 It is becoming increasingly evident that inappropriate exposure to sex steroids/steroid mimics has an impact on fetal growth and organ differentiation. 20,21 For instance, fetal exposure to excess prenatal testosterone, an estrogen precursor, from days 30 to 90 of gestation (term 147 days), resulted in intrauterine growth restriction (IUGR) and low birth weight offspring in sheep. [22][23][24] On the contrary, prenatal treatment with dihydrotestosterone, a nonaromatizable androgen, did not reduce birth weight (Padmanabhan V, unpublished).…”

Section: Introductionmentioning

confidence: 99%

Maternal bisphenol-A levels at delivery: a looming problem?

et al. 2008

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Objective: The objective was to determine whether bisphenol-A (BPA) is found in maternal circulation of pregnant women in the US population and is related to gestational length and birth weight.Method: Circulating levels of BPA were quantified by high performance liquid chromatography-tandem mass spectrometry at delivery in 40 southeastern Michigan mothers and correlated with gestational length and birth weight of offspring.Result: Maternal levels of unconjugated BPA ranged between 0.5 and 22.3 ng ml À1 in southeastern Michigan mothers. There was no correlation between BPA concentrations and gestational length or birth weight of offspring.Conclusion: This is the first study to document measurable levels of BPA in maternal blood of the US population. Long-term follow-up studies of offspring are needed to validate or refute concerns over human fetal exposure to synthetic exogenous steroids.

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Prenatal testosterone excess programs reproductive and metabolic dysfunction in the female

Cited by 106 publications

References 95 publications

Sexual differentiation of the human brain in relation to gender identity and sexual orientation

Sexual differentiation of the human brain in relation to gender identity and sexual orientation

Pituitary and testis responsiveness of young male sheep exposed to testosterone excess during fetal development

Maternal bisphenol-A levels at delivery: a looming problem?

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