Steroid Receptors and Mammalian Penile Development: An Unexpected Role for Progesterone Receptor?

Institute for the Study and Treatment of Hypospadias, Department of Urology, School of Medicine, University of California, San Francisco, 94143, USA.
The Journal of Urology (Impact Factor: 4.47). 09/2006; 176(2):728-33. DOI: 10.1016/j.juro.2006.03.078
Source: PubMed


We investigated the role of steroid receptors in normal and abnormal genital tubercle development in males and females. We hypothesized that progesterone receptor expression might be involved in abnormal development in both sexes.
We examined the effects of medroxyprogesterone acetate on steroid receptor mRNA expression and assessed the involvement of androgen receptor in the action of medroxyprogesterone acetate on genital tubercle development using androgen receptor deficient (Tfm) mice.
Quantitative reverse transcriptase polymerase chain reaction and morphological results demonstrated a pattern of virilized females and feminized males in medroxyprogesterone acetate exposed embryos. Progesterone receptor was the only steroid receptor examined that did not differ between medroxyprogesterone acetate treated males and vehicle treated females. At the morphological level in utero exposure to medroxyprogesterone acetate from gestational days 12 to 17 feminized male genital tubercles, producing a more proximal urethral opening. Female fetuses exposed for the same period exhibited virilized genitalia, with a more distal urethral opening. We also exposed Tfm mice to medroxyprogesterone acetate to assess the role of androgen receptor in the activity of medroxyprogesterone acetate. These medroxyprogesterone acetate exposed mice did not differ morphologically from vehicle treated Tfm mice, indicating that medroxyprogesterone acetate requires androgen receptor to elicit genital tubercle abnormalities.
The increase of progesterone receptor mRNA expression in males and the decrease in females as a result of exposure to medroxyprogesterone acetate, which also causes urethral abnormalities in both sexes, suggests a previously unidentified role for progesterone receptor, possibly interacting with androgen receptor, in anomalous genital tubercle development.

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    • "BPS as well as BPF led to the greatest changes in efficacy on 17␣-OH progesterone and progesterone levels, respectively. Administration of a synthetic progestagen in utero has been associated with virilization of female mice and feminization in male mice (Willingham et al., 2006). Thus, these data indicate that the five analogues, especially BPS and BPF, may have effects which are not prominent for BPA on this endpoint. "
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    ABSTRACT: Background: Bisphenol A (BPA) is a chemical with widespread human exposure suspected of causing low-dose effects. Thus a need for developing alternatives to BPA exists. Structural analogues of BPA have already been detected in foods and humans. Due to the structural analogy of the alternatives there is a risk of effects similar to BPA.Objectives: The aim was to elucidate and compare the hazards of BPB, BPE, BPF, BPS and 4-cumylphenol (HPP) to BPA.Methods: In vitro studies on steroidogenesis, receptor activity, and biomarkers of effect, as well as QSAR modeling.Results: All test compounds caused the same qualitative effects on estrogen receptor and androgen receptor activity, and most of the alternatives exhibited potencies within the same range as BPA. Hormone profiles for the compounds indicated a specific mechanism of action on steroidogenesis generally leading to decreased androgen, and increased estrogen and progestagen levels. Differential effects on corticosteroid synthesis were observed suggesting a compound specific mechanism. Overall BPS was less estrogenic and antiandrogenic than BPA, but BPS showed the largest efficacy on 17α-OH progesterone. Finally there were indications of DNA damage, carcinogenicity, oxidative stress, effects on metabolism and skin sensitization of one or more of the test compounds.Conclusions: Interference with the endocrine system was the predominant effect of the test compounds. A substitution of BPA with these structural analogues should be carried out with caution.
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    ABSTRACT: In fetal mice genital tubercles the ontogenetic expression of progesterone receptors and the effect of in utero estrogen and testosterone exposure were investigated. To evaluate ontogenetic progesterone receptor expression genital tubercles from untreated fetuses at gestational days 12, 14, 16 and 18, and newborn pups were prepared for real-time reverse transcriptase-polymerase chain reaction or immunohistochemistry. To evaluate estrogen and testosterone effects pregnant dams were gavaged once daily with corn oil (vehicle), ethinyl estradiol or testosterone propionate from gestational days 12 through 17. At gestational day 19 the genital tubercles of delivered fetuses were harvested for morphological examination and then pooled for real-time reverse transcriptase-polymerase chain reaction. Progesterone receptor protein was first detected at gestational day 12 in the urethral plate and mesenchyma. At later stages staining intensity increased with a greater progesterone receptor signal, especially in the urethra. Progesterone receptor mRNA expression showed different increasing patterns in each sex until birth. However, no difference was noted between male and female genital tubercles in terms of the distribution and quantity of progesterone receptor expression. In utero ethinyl estradiol led to 8.2, 9.7 and 5.2-fold increases in progesterone receptor mRNA in females and in males with and without hypospadias, respectively. Testosterone propionate significantly decreased progesterone receptor mRNA levels in females and males. Progesterone receptors are expressed in developing genital tubercles, suggesting a direct role of progesterone in normal genital tubercle patterning. Their increasing expression until birth also implies increasing sensitivity of the genital tubercles to the effects of estrogenic and progestogenic endocrine disruptors during fetal life. Ethinyl estradiol and testosterone propionate lead to opposing effects on progesterone receptor expression, in addition to their opposing morphological effects on the genital tubercles. These findings expand our knowledge of genital tubercle morphogenesis and provide important information for understanding the effects of endocrine disruptors.
    No preview · Article · Sep 2007 · The Journal of Urology
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