Helmy Mohd Mokhtar1, Nelli Giribabu1, Normadiah Kassim2, Sekaran Muniandy3, Naguib Salleh4. 1. Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia. 2. Department of Anatomy, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia. 3. Department of Molecular Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia. 4. Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia. Electronic address: naguib.salleh@yahoo.com.my.
Abstract
OBJECTIVES: Estrogen is known to stimulate uterine fluid and Cl(-) secretion via CFTR. This study investigated testosterone effect on these changes in a rat model. METHODS: Ovariectomized adult female rats received estrogen for five days or estrogen for three days followed by two days peanut oil or testosterone either alone or in the presence of flutamide or finasteride. At the end of treatment, uteri were perfused with perfusate containing CFTRinh-172. The rate of fluid and Cl(-) secretion were determined. Dose-dependent effect of testosterone and effect of forskolin on fluid secretion rate were measured. Animals were sacrificed and uteri were removed for CFTR protein and mRNA expression analyses, histology and cAMP measurement. Morphology of uterus, levels of expression of CFTR protein and mRNA and distribution of CFTR protein were observed. RESULTS: Estrogen causes increase while testosterone causes decrease in uterine fluid and Cl(-) secretions. The effects of estrogen but not testosterone were antagonized by CFTRinh-172. Luminal fluid volume and apical expression of CFTR in the luminal epithelia were highest under estrogen and lowest under testosterone influences. Similar changes were observed in CFTR protein and mRNA expressions. Uterine cAMP level was highest under estrogen and lowest under testosterone influence. Forskolin increases fluid secretion rate in estrogen but not in testosterone-treated animals. Testosterone effects were dose-dependent and were antagonized by flutamide however, not finasteride. CONCLUSIONS: Testosterone inhibition of estrogen-induced uterine fluid and Cl(-) secretion occurs via inhibition of CFTR expression and functional activities. These changes could explain the adverse effects of testosterone on fertility.
OBJECTIVES: Estrogen is known to stimulate uterine fluid and Cl(-) secretion via CFTR. This study investigated testosterone effect on these changes in a rat model. METHODS: Ovariectomized adult female rats received estrogen for five days or estrogen for three days followed by two days peanut oil or testosterone either alone or in the presence of flutamide or finasteride. At the end of treatment, uteri were perfused with perfusate containing CFTRinh-172. The rate of fluid and Cl(-) secretion were determined. Dose-dependent effect of testosterone and effect of forskolin on fluid secretion rate were measured. Animals were sacrificed and uteri were removed for CFTR protein and mRNA expression analyses, histology and cAMP measurement. Morphology of uterus, levels of expression of CFTR protein and mRNA and distribution of CFTR protein were observed. RESULTS: Estrogen causes increase while testosterone causes decrease in uterine fluid and Cl(-) secretions. The effects of estrogen but not testosterone were antagonized by CFTRinh-172. Luminal fluid volume and apical expression of CFTR in the luminal epithelia were highest under estrogen and lowest under testosterone influences. Similar changes were observed in CFTR protein and mRNA expressions. Uterine cAMP level was highest under estrogen and lowest under testosterone influence. Forskolin increases fluid secretion rate in estrogen but not in testosterone-treated animals. Testosterone effects were dose-dependent and were antagonized by flutamide however, not finasteride. CONCLUSIONS:Testosterone inhibition of estrogen-induced uterine fluid and Cl(-) secretion occurs via inhibition of CFTR expression and functional activities. These changes could explain the adverse effects of testosterone on fertility.