Male Offspring of Hyperandrogenemic Female (HAF) Rats Develop Hypertension Beginning at 16 Weeks of Age
Authors: Zuchowski Yvonne P. , Dalmasso Carolina , Shawky Noha M. , Vinson Ruth M. , Reckelhoff Jane F. 
Published: April 2020

Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women. It is characterized by hyperandrogenemia, oligo/anovulation, and polycystic ovaries. Children born to women with PCOS often have intrauterine growth restriction (IUGR) or are small for gestational age. This present study was conducted to test the hypothesis that maternal hyperandrogenemia will affect blood pressure (mean arterial pressure (MAP)) in male offspring.

Hyperandrogenemia was produced by implantation of 5α‐dihydrotestosterone pellets (DHT; 7.5 mg/90 days, sc) in SD female rats at 4 wks of age (hyperandrogenemic females (HAF)). Control females received placebo pellets. Females were mated with SD males at 10–12 wks of age. Approximately 60% of HAF rats became pregnant, compared to 100% of controls. At 48 hrs, offspring were weighed and measured, and litters were culled to 4 males and 4 females. DHT and control dams were allowed to nurse offspring for 3 wks. Offspring (F1) were left untreated and studied at 4–6 mos (adult) and ≥16 mos (aging).

Despite similar litter sizes (n=10–12±2 for HAF and control dams; p=NS), male offspring from HAF dams (F1HAF) weighed significantly less than offspring from control dams (F1contr.): (male F1HAF vs. F1contr: (PN 12 hrs :6.4±0.1 vs. 7.0±0.2g; n=13–15; p<0.05; PN 48 hrs: 7.4±0.3 vs. 8.1±0.1 g; n=13–15; p<0.05). Male F1HAF were also significantly shorter in length (6.2±0.6 vs. 6.8±0.2 cm; n= 15–18, p<0.05) and had smaller head circumference (4.4±0.1 vs. 4.6±0.1 cm; n=12–15) at 48hrs than male F1contr. At 16 wks, fat mass (normalized to BW) was significantly higher in male F1HAF than F1contr (0.07±0.01 vs. 0.06±0.01; p<0.05). MAP (radiotelemetry) was significantly elevated in adult male F1HAF compared to F1contr (121± 3 vs. 113 ± 3 mmHg; n=4–5/grp, p<0.05). DHT levels were significantly lower in male F1HAF than F1contr (57.4±34.9 vs 136.4±55.7 ng/ml; n=7–11/grp; p<0.01). With aging, male F1HAF had higher levels of proinflammatory cytokines than did male F1contr (by Bioplex; n=3–7/grp; all p<0.05): IL‐17a (149.5±39 vs. 32.1±5 pg/ml; p<0.05), IL‐1α (426±159 vs. 138±33 pg/ml), IL‐1β (122.6±36 vs. 36±6 pg/ml), and PAI‐1 (1690±386 vs. 590±63 pg/ml).

Male offspring of HAF dams are born with IUGR compared to offspring of control females. As adults, male offspring of HAF dams have lower levels of androgens, increased fat mass, and develop hypertension. With aging, HAF male offspring have higher levels of inflammation than control offspring. These data are important since physicians rarely ask their middle‐aged, hypertensive, overweight male patients with androgen deficiencies if their mothers had PCOS during their pregnancy. With this knowledge, physicians may not only be able to predict which men will suffer from these complications, but may also provide the best therapeutic options for these men.

Support or Funding Information

Studies were supported by NIH R01HL135089, R01HL66072, P01HL05971, P20GM121334