Introduction Androgens induce increases in blood pressure (BP) and risk of cardiovascular diseases (CVDs) in females, as seen in polycystic ovary syndrome females. However, it is not clear whether treatment with gender‐affirming hormone therapy in trans‐men have an impact on their BP or risk of CVD. Therefore, the present study was undertaken to test the hypothesis that chronic androgen supplements (starting post pubertal) in a rodent model of transgender men, will increase BP and promote metabolic dysfunction. Methods Female SD rats were implanted with testosterone propionate (TP, 7.5 mg in 5 mm silastic tubes, replaced every 3 wks, n = 10) starting at 7 wks of age (post‐puberty) and compared to controls (empty silastic implants, n = 10). Rats were weighed weekly. Radiotelemetry transmitters were implanted at 13 wks of age (n = 5‐6/group) and mean arterial pressure (MAP) was measured at 15, 21 and 25 wks of age. Body composition was determined at 15, 21 and 23 wks of age and proteinuria was determined at 15 and 21 wks of age (n = 4/group). Serum testosterone was measured by LC/MS at 15 wks of age (n = 4/group). Oral glucose tolerance test was performed at 11 and 22 wks of age (n = 4/group). Results TP supplements increased serum testosterone at 15 wks of age by 30‐fold compared to female controls (6.4 ± 1.5 vs 0.2 ± 0.05 ng/ml, respectively; p<0.005). Body weight (BW) increased significantly in TP group compared to controls by 10 wks of age (241 ± 4 g vs 220 ± 2 g, respectively; p<0.05) and was sustained through 26 wks of age (311 ± 7 g vs 276 ± 5 g, respectively; p<0.05). Fat mass and fat mass/BW were similar between TP and controls. Lean mass was significantly higher in TP group compared to controls at 15, 21 and 23 wks of age (254 ± 7, 268 ± 12 and 273 ± 12 g vs 218 ± 6, 227 ± 5 and 229 ± 5 g, respectively; p<0.01); however, when factored for BW, there were no differences between TP and controls. Proteinuria was significantly higher in TP group compared to controls at 15 wks of age (4.9 ± 1.2 vs 2.1 ± 0.3 mg/24 h, respectively, p<0.05) and 21 wks of age (7.6 ± 1.1 vs 2.4 ± 0.5 mg/24 h, respectively, p<0.005). Importantly, MAP was increased significantly in TP group at 15 wks of age (112 ± 3 vs 106 ± 4 mmHg, p<0.05), 21 wks of age (114 ± 3 vs 105 ± 2 mmHg; p<0.05) and 24 wks of age (115 ± 3 vs 104 ± 2 mmHg, p<0.05), compared to controls, respectively. Oral glucose tolerance test at 11 and 22 wks of age was similar between groups. Conclusion Testosterone used in a form of sex‐affirming therapy in female rats induced increases in BP that are independent of adiposity or Insulin resistance and maybe associated to renal injury. Future studies should determine whether these changes are sustained with aging, and the mechanisms responsible for the increase in BP in the female‐to‐male trans‐sex model.
Background: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and polycystic ovaries. Renal injury, increased central adiposity and higher circulating levels of the adipokine leptin are common characteristics of PCOS. Leptin has direct renal fibrotic, hypertrophic, and albuminuric effects and can cause renal mitochondrial dysfunction and oxidative stress leading to chronic kidney disease development. Despite increased circulating leptin level in both lean and obese PCOS women, its role in PCOS-mediated renal damage remains unknown. In a well-characterized mouse model of PCOS, we aimed to test the hypothesis that hyperandrogenemia increases central adiposity leading to hyperleptinemia, which via leptin receptors induces intrarenal mitochondrial oxidative stress and dysfunction causing renal injury. Methods: Three-week-old peripubertal female mice were implanted with Silastic tubes filled with the non-aromatizable androgen dihydrotestosterone (DHT, 8 mg) or vehicle for 12 weeks. Eight weeks post-Silastic tubes implantation, the animals were treated with the leptin receptor antagonist (LepR-Ant) pegylated leptin (2 mg/kg, ip, 3x/week) for 4 weeks. Body weight, fat mass (EchoMRI), kidney weight (gravimetry), plasma leptin (ELISA), the glomerular filtration rate (GFR, transcutaneous fluorescence), as well as the renal injury markers urinary albumin to creatinine ratio (UACR, clinical chemistry analyzer), NGAL, and KIM1 (ELISA) were measured. Freshly isolated kidney mitochondria were used to measure mitochondrial reactive oxygen species (mtROS) by Amplex Red assay. Moreover, mitochondrial complex I and complex II-driven respiration and complex IV activity were assessed using Oroboros Fluorespirometer. Results: DHT significantly (p<0.05) increased body weight (31.6 ± 2.3 vs. 23.6 ± 0.5 g), fat mass (3.5 ± 0.6 vs. 1.9 ± 0.4 g), kidney weight (365.6 ± 13.1 vs. 257.1 ± 3.7 mg), leptin (3.7-fold), UACR (1013.3 ± 56.4 vs. 658.9 ± 103.6 μg albumin/g creatinine), NGAL (6-fold), and KIM1 (3.7-fold). Moreover, PCOS mice had significantly (p<0.05) lower GFR (1067.2 ± 59.9 vs. 1335.6 ± 60.3 uL/min/100g body weight), higher mtROS driven by complexes I (3.8 ± 0.8 vs. 2.0 ± 0.3 % electron leak) and III (8.0 ± 1.8 vs. 3.7 ± 0.9 % electron leak), as well as lower complexes I, II, and IV respiration (43-71%). The LepR-Ant had no effect on kidney weight or GFR; however, it abolished DHT-induced increases in body weight and fat mass. Excitingly, the LepR-Ant inhibited mtROS generation and completely restored complex I and II respiration, which was associated with a significant reduction in the urinary renal injury markers UACR, NGAL, and KIM-1 levels (40-60%, p<0.05). Conclusion and significance: Our findings suggest that leptin via its receptor activation plays a significant role in the renal outcomes in PCOS by inducing mitochondrial dysfunction. Leptin receptor blockade could be a novel therapeutic approach to ameliorate renal injury in PCOS. Supported by NIH grants NIGMS P20GM121334 to KSE, LLYC, and DGR, NIGMS P20GM104357, NHLBI P01HL51971, and American Heart Association Predoctoral Fellowship 903804 (A.M.H.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Introduction: Early pre-pubertal exposure to androgens induces an increase in blood pressure (BP) and renal injury in females, as seen in polycystic ovary syndrome females. However, it is not clear whether treatment with gender-affirming hormonal therapy (GAHT) in trans-men have an impact on their BP and renal health as adults and with aging. Therefore, the present study was undertaken to test the hypothesis that chronic androgen supplements (starting post-pubertal, model of GAHT) in female-to-male trans-sex rats will increase BP and promote renal injury that are exaggerated with aging. Methods: Female SD rats were implanted with testosterone propionate-filled silastic implants (TP, 7.5 mg/10 mm silastic tube/rat, replaced every 3 wks) starting at 7 wks of age (post-pubertal) until 17 months (mos) of age and compared to controls (CON, empty silastic implants). Serum testosterone was measured by LC/MS at 3 mos of age (n=4/grp). Radiotelemetry transmitters were implanted and mean arterial pressure (MAP) was measured at 3 and 17 mos of age (n=3-6/grp). Body composition was determined at 3 and 17 mos of age (n=3-4/grp). Proteinuria was determined at 3, 5 and 7 mos of age (n=4/grp). Serum and urinary creatinine (Cr) were measured at 7 mos of age and Cr clearance was calculated (n=4/grp). Urinary kidney injury molecule-1 (Kim-1) was measured at 12 mos of age (n=3-4/grp). Results: TP had significantly higher serum testosterone compared to CON (6.4 ± 1.5 vs 0.2 ± 0.05 ng/ml; p<0.05). Despite the similar fat mass, lean mass was significantly higher in TP compared to CON starting at 3 mos of age (253.9 ± 6.7 vs 217.7 ± 5.8 g; p<0.05), until 17 mos of age (325.7 ± 15.1 vs 253.5 ± 3.9 g; p<0.05). Proteinuria was significantly higher in TP compared to CON at 5 and 7 mos of age (7.6 ± 1.1 vs 2.4 ± 0.5 mg/24 h and 10.1 ± 1.6 vs 2.4 ± 0.4 mg/24 h, respectively, p<0.05). Cr clearance was significantly lower (0.24 ± 0.03 vs 0.32 ± 0.02 ml/min/100 g, p<0.05) and urinary Kim-1 was significantly higher (6.3 ± 1.5 vs 3.5 ± 0.2 ng/24 h, p<0.05) in TP compared to CON. Importantly, MAP was significantly higher in TP compared to CON starting at 3 mos of age (112 ± 3 vs 106 ± 4 mmHg, p<0.05), with further increases at 17 mos of age (133 ± 1 vs 117 ± 6 mmHg, p<0.05). Conclusion: Post-pubertal testosterone in female sex promotes renal injury and increases BP, independent of adiposity. Aging promotes further increases in BP, suggesting increased risk of cardiovascular diseases. Future studies should determine the mechanisms behind the increase in BP in the female-to-male trans-sex model. P20GM121334, AHA Career Development Award 938320, P20GM104357, R01HL135089, P01HL051971 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Background SARS‐CoV‐2, the causative agent of COVID‐19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including the transmembrane serine protease TMPRSS2. Androgen action in target tissues may partially mediate entry of SAR‐CoV‐2 and male patients have been shown to suffer increased severity and mortality compared with females. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive‐age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic dysfunctions, both being risk factors associated with severe COVID‐19 pathology. The purpose of this study is to investigate the role of hyperandrogenism in a female mouse model of PCOS and to characterize the differences in host machinery required for SARS‐CoV‐2 viral entry in multiple tissues that are affected by COVID‐19 in humans. Methods Female mice were treated with dihydrotestosterone (DHT, 8 mg) s.c. for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method and the oral glucose tolerance test was performed with an oral glucose load (2g glucose per kg lean mass weight). mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT‐qPCR, Western‐blot, and ELISA in tissues, serum, and urine. All differences are considered significant p<0.05. Results DHT treatment increased body weight, fat and lean mass. DHT treated females showed altered glucose homeostasis, having increased fasting glucose (201.10 ± 11.11 vs. 152.80 ± 9.23 mg/dL, p<0.05) and an increased area under the curve (209.2 ± 11.0 vs. 160.8 ± 3.5 mg.min/dL, p<0.05) by OGTT. The small intestine was shown to have the greatest relative Ace2 mRNA expression compared with the other tissues. Ace2 mRNA was upregulated in DHT‐treated animals in the lung (1.24‐fold), cecum (4.4‐fold), left ventricle (1.54‐fold), and kidney (2.37‐fold), and was downregulated in DHT‐treated animals in the brain (0.68‐fold) and colon (0.37‐fold). ACE2 protein expression was increased in the small intestine (1.98‐fold), left ventricle (1.30‐fold), and kidney (1.32‐fold). The SARS‐CoV‐2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney, and protein TMPRSS2 was increased in the small intestine (1.38‐fold). ACE2 sheddase Adam17 mRNA was upregulated in the kidney by DHT, which corresponded with increased urinary ACE2 in DHT‐treated mice (14.13±3.33 vs. 0.55±0.19 pg/ng creatinine, p<0.05). Conclusions Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID‐19. The differences observed in androgen‐treated mice highlight that several mechanisms involved in SARS‐CoV‐2entry may be altered in women with PCOS and translate to the reduced protection of specific target organs known to be susceptible to COVID‐19 injury.
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