Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats

Abstract

Elevated maternal testosterone levels are shown to cause fetal growth restriction, eventually culminating in sex-specific adult-onset hypertension that is more pronounced in males than females. In this study, we tested whether utero- and feto-placental disturbances underlie fetal growth restriction and if these changes vary in male and female placentas. Pregnant Sprague-Dawley rats were injected with vehicle (n=16) or testosterone propionate (0.5 mg/Kg/day from gestation day 15–19; n=16). On gestation day 20, we quantified uterine artery blood flow using microultrasound, visualized placental arterial network using x-ray microcomputed tomography, determined fetoplacental hypoxia using pimonidazole and hypoxia-inducible factor-1α, and used Affymetrix array to determine changes in placental expression of genes involved in vascular development. Plasma testosterone levels increased 2-fold in testosterone-injected rats. Placental and fetal weights were lower in rats with elevated testosterone. Uterine artery blood flow was lower and resistance index was higher in testosterone group. Radial and spiral artery diameter and length, number of fetoplacental arterial branches, and umbilical artery diameter were reduced in the testosterone group. In addition, markers of hypoxia in the placentas and fetuses were elevated in the testosterone group. The magnitude of changes in placental vasculature and hypoxia were greater in males than females and were associated with sex-specific alteration of unique sets of genes involved in angiogenesis and blood vessel morphogenesis. The results demonstrate that elevated testosterone during gestation induces a decrease in uterine arterial blood flow and fetal sex-related uteroplacental vascular changes, which may set the stage for subsequent sex differences in adult-onset diseases.

Maternal Vascular Physiology in Preeclampsia

“…94 Pregnant rats with hypertension, vascular dysfunction, and proteinuria because of testosterone treatment had reduced radial artery diameter and length, diminished uterine blood flow, and elevated markers of hypoxia in placental tissues. 97 Reduced placental perfusion in eNOS knockout mice was associated with a 30% reduction in uterine and radial arteries. 98 This model does not exhibit gestational hypertension and proteinuria but shows systemic vascular dysfunction and placental hypoxia, 98 which are also features of preeclampsia.…”

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

“…1 -5 In the case of gestational hyperandrogenemia, polycystic ovary syndrome (PCOS), gestational luteoma 6 , or hyperreactio luteinalis, 7 the fetus may also be exposed to high levels of testosterone from the maternal circulation. 8 , 9 Hyperandrogenism during pregnancy causes fetal virilization, 10 , 11 intrauterine growth restriction, 12 and low birth weight. 13 These prenatal complications positively correlate with the development in adulthood of hyperinsulinemia 14 , 15 and metabolic disorders such as obesity, 16 , 17 hypertension, 18 and PCOS.…”

“…23 , 24 During this period, testosterone peaks between days 17–19. 25 , 26 Excess prenatal androgens (PNA) during this period induce a hypertensive phenotype in adulthood that is characterized by impaired blood flow in the vascular endothelium 12 , increased blood volume 27 , and increased blood pressure in adult females and males. 28 , 29 However, the mechanism by which androgens induce this hypertension is not clear.…”

Elevated androgen levels induce hyperinsulinemia through increase in Ins1 transcription in pancreatic beta cells in female rats†

“…The aim of the present study was to elucidate potential mechanisms involved in beta cell alterations in a previously described rat model of PCOS that exhibits metabolic as well as reproductive features of PCOS (24)(25)(26). We used this model to elucidate (1) whether androgen excess plays an underlying role in altering beta cell structure and insulin secretion, (2) investigate the molecular mechanism by which androgens transcriptionally modulate insulin expression and secretion, and (3) determine whether regulation of insulin action in skeletal muscles play a role in mediating glucose intolerance.…”