Pregnancy Protects Hyperandrogenemic Female Rats From Postmenopausal Hypertension

Abstract

Polycystic ovary syndrome, the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenemia, obesity, insulin resistance, and elevated blood pressure. However, few studies have focused on the consequences of pregnancy on postmenopausal cardiovascular disease and hypertension in polycystic ovary syndrome women. In hyperandrogenemic female (HAF) rats, the hypothesis was tested that previous pregnancy protects against age-related hypertension. Rats were implanted with dihydrotestosterone (7.5 mg/90 days, beginning at 4 weeks and continued throughout life) or placebo pellets (controls), became pregnant at 10 to 15 weeks, and pups were weaned at postnatal day 21. Dams and virgins were then aged to 10 months (still estrous cycling) or 16 months (postcycling). Although numbers of offspring per litter were similar for HAF and control dams, birth weights were lower in HAF offspring. At 10 months of age, there were no differences in blood pressure, proteinuria, nitrate/nitrite excretion, or body composition in previously pregnant HAF versus virgin HAF. However, by 16 months of age, despite no differences in dihydrotestosterone, fat mass/or lean mass/body weight, previously pregnant HAF had significantly lower blood pressure and proteinuria, higher nitrate/nitrite excretion, with increased intrarenal mRNA expression of endothelin B receptor and eNOS (endothelial nitric oxide synthase), and decreased ACE (angiotensin-converting enzyme), AT1aR (angiotensin 1a receptor), and endothelin A receptor than virgin HAF. Thus, pregnancy protects HAF rats against age-related hypertension, and the mechanism(s) may be due to differential regulation of the nitric oxide, endothelin, and renin-angiotensin systems. These data suggest that polycystic ovary syndrome women who have experienced uncomplicated pregnancy may be protected from postmenopausal hypertension.

Cardiometabolic consequences of maternal hyperandrogenemia in male offspring

“…HAF rats have elevated blood pressure prior to pregnancy (Yanes et al, 2011), as has also be reported in PCOS women (Christakou & Diamanti-Kandarakis, 2008). We have also shown that the higher body weights prepregnancy in HAF rats remain so 48 h postpartum, but comparisons of percentage weight gains per body weight from pre to post-pregnancy are similar between the control and HAF dams (Shawky et al, 2020). The numbers of pups per litter were also similar between HAF and control pregnancies (Shawky et al, 2020).…”

“…As mentioned above, we have shown previously that the numbers of pups per litter were similar between control and HAF offspring, but the birth weights of male and female HAF offspring were lower than those for control offspring (Shawky et al, 2020). As shown in Figure 1A, body weights remained lower in HAF males until PND 4, when they became similar to body weight in controls, and remained similar up to 8 weeks of age (Figure 1b,c).…”

“…Pregnancy occurred typically between 10 and 14 weeks of age, thus pellets were re‐implanted during pregnancy/lactation in all rats (16 weeks of age). Pups were weighed within 12 h of birth (Shawky et al, 2020). The numbers of pups per litter were similar between control and HAF dams, and the offspring body weights were lower for both male and female HAF offspring compared to those in control offspring (Shawky et al, 2020).…”

“…Pups were weighed within 12 h of birth (Shawky et al, 2020). The numbers of pups per litter were similar between control and HAF dams, and the offspring body weights were lower for both male and female HAF offspring compared to those in control offspring (Shawky et al, 2020). Both control and HAF offspring were culled at 48 h after birth to 8 pups/ litter (4 males and 4 females).…”

“…In order to study the consequences of maternal hyperandrogenemia on body composition and cardiovascular complications later in life in male offspring, we use the hyperandrogenemic female (HAF) rat as a model (Dalmasso, Maranon, Patil, Bui, et al, 2016;Yanes et al, 2011). We showed previously that pregnancy occurs in approximately 60% of HAF rats, and that their offspring are born small for gestational age (Shawky et al, 2020). Unlike studies in animal models of PCOS and pregnancy in which androgens are given only in late pregnancy, the HAF dams are implanted with dihydrotestosterone pellets at 4-5 weeks of age such that the dams have elevated levels of androgens before, during and after their pregnancies, as PCOS women have (Falbo et al, 2010).…”