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Female Offspring of Hyperandrogenemic Female (HAF) Rat Model Exhibit Insulin Resistance and Increased Blood Pressure With Aging
Author(s) -
Shawky Noha M.,
Vinson Ruth M.,
Zuchowski Yvonne P.,
Reckelhoff Jane F.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03023
Subject(s) - offspring , medicine , endocrinology , polycystic ovary , blood pressure , placebo , insulin resistance , ovulation , litter , insulin , biology , hormone , pregnancy , genetics , alternative medicine , pathology , agronomy
Background Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia, oligo/an‐ovulation and polycystic ovaries. It is also associated with metabolic dysfunction and elevated blood pressure (BP). Whether daughters born to PCOS mothers exhibit a PCOS phenotype is controversial. In addition, whether daughters of PCOS women develop metabolic dysfunction and elevated BP with aging has not been reported. Objectives The present study aimed to test the hypothesis that aging causes an increase in MAP and metabolic dysfunction in female offspring of HAF rats (model of PCOS). Methods Hyperandrogenemia was induced in Sprague Dawley (SD) females by implantation of 5α‐dihydrotestosterone pellets (DHT; 7.5 mg/90 days, subcutaneously) starting at 4 weeks of age. Rats were mated with SD males, and allowed to deliver and lactate. Female offspring (F1 HAF ) were weighed at birth, left untreated and studied at 4–6 (adult) or 16–18 (aging) months of age. Control dams were implanted with placebo pellets subcutaneously, allowed to mate, deliver and suckle their offspring (F1 Placebo ). Results Despite the similar litter size, body weight (BW) at birth was significantly lower in female F1 HAF compared to F1 Placebo (6.0 ± 0.1 vs 6.5 ± 0.1 g, n=13–15). As adults (4–6 months), BW, fat and lean masses, proteinuria and mean arterial pressure (MAP, radiotelemetry) of female F1 HAF were not different compared to F1 Placebo . With aging, female F1 HAF rats showed increased MAP compared to F1 Placebo (109 ± 1 versus 96 ± 1 mmHg, n=3–4). Fasting blood glucose was not different between groups (91 ± 3 vs 90 ± 2 mg/dl), but female F1 HAF rats showed significant hyperinsulinemia (0.90 ± 0.05 vs 0.78 ± 0.03 ng/ml, p ≤ 0.05) and insulin resistance ( HOMA‐IR index; 3.3 ± 0.2 vs 2.8 ± 0.1, p ≤ 0.05, (n = 5–6)). Despite the insulin resistance, lean mass (248.4 ± 8.5 vs 241.2 ± 3.9 g) and fat mass (41.2 ± 7.9 vs 39.7 ± 1.8 g) by Echo MRI, in addition to body weight (307.5 ± 16.2 vs 298.1 ± 6.4 g; (n = 2–4)) were also not different between groups. Conclusion Adult female offspring of hyperandrogenemic females do not show a PCOS phenotype (e.g. no hypertension, insulin resistance, metabolic phenotype), whereas with aging, they develop hypertension, hyperinsulinemia and insulin resistance with no changes in fasting glucose, lean/fat mass or body weight. These data suggest that women whose mothers had PCOS may be at increased risk for hypertension and metabolic dysfunction with aging, although the mechanisms for the hypertension are not clear. Support or Funding Information R01HL135089, P01HL051971, P20GM121334, P20GM104357