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      Effects of Sex Hormones on Vascular Reactivity in Boys With Hypospadias

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          Abstract

          Background

          Arteries from boys with hypospadias demonstrate hypercontractility and impaired vasorelaxation. The role of sex hormones in these responses in unclear.

          Aims

          We compared effects of sex steroids on vascular reactivity in healthy boys and boys with hypospadias.

          Methods

          Excess foreskin tissue was obtained from 11 boys undergoing hypospadias repair (cases) and 12 undergoing routine circumcision (controls) (median age [range], 1.5 [1.2-2.7] years) and small resistance arteries were isolated. Vessels were mounted on wire myographs and vascular reactivity was assessed in the absence/presence of 17β-estradiol, dihydrotestosterone (DHT), and testosterone.

          Results

          In controls, testosterone and 17β-estradiol increased contraction (percent of maximum contraction [Emax]: 83.74 basal vs 125.4 after testosterone, P < .0002; and 83.74 vs 110.2 after estradiol, P = .02). 17β-estradiol reduced vasorelaxation in arteries from controls (Emax: 10.6 vs 15.6 to acetylcholine, P < .0001; and Emax: 14.6 vs 20.5 to sodium nitroprusside, P < .0001). In hypospadias, testosterone (Emax: 137.9 vs 107.2, P = .01) and 17β-estradiol (Emax: 156.9 vs 23.6, P < .0001) reduced contraction. Androgens, but not 17β-estradiol, increased endothelium-dependent and endothelium-independent vasorelaxation in cases (Emax: 77.3 vs 51.7 with testosterone, P = .02; and vs 48.2 with DHT to acetylcholine, P = .0001; Emax: 43.0 vs 39.5 with testosterone, P = .02; and 39.6 vs 37.5 with DHT to sodium nitroprusside, P = .04).

          Conclusion

          In healthy boys, testosterone and 17β-estradiol promote a vasoconstrictor phenotype, whereas in boys with hypospadias, these sex hormones reduce vasoconstriction, with androgens promoting vasorelaxation. Differences in baseline artery function may therefore be sex hormone-independent and the impact of early-life variations in androgen exposure on vascular function needs further study.

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          Most cited references47

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          Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.

          Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation.
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            Androgen action in the masculinization programming window and development of male reproductive organs.

            We have shown previously that deficient androgen action within a masculinization programming window (MPW; e15.5-e18.5 in rats) is important in the origin of male reproductive disorders and in programming male reproductive organ size, but that androgen action postnatally may be important to achieve this size. To further investigate importance of the MPW, we used two rat models, in which foetal androgen production or action was impaired during the MPW by exposing in utero to either di(n-butyl) phthalate (DBP) or to flutamide. Reduced anogenital distance (AGD) was used as a monitor of androgen production/action during the MPW. Offspring were evaluated in early puberty (Pnd25) to establish if reproductive organ size was altered. The testes, penis, ventral prostate (VP) and seminal vesicles (SV) were weighed and penis length measured. Both DBP and flutamide exposure in the MPW significantly reduced penis, VP and SV size along with AGD at Pnd25; AGD and organ size were highly correlated. In DBP-, but not flutamide-, exposed animals, testis weight was also reduced and correlated with AGD. Intratesticular testosterone was also measured in control and DBP-exposed males during (e17.5) or after (e21.5) the MPW and related to AGD at e21.5. To evaluate the importance of postnatal androgen action in reproductive organ growth, the effect of combinations of prenatal and postnatal maternal treatments on AGD and penis size at Pnd25 was evaluated. In prenatally DBP-exposed animals, further postnatal exposure to either DBP or flutamide significantly reduced AGD and penis size in comparison with prenatal DBP exposure alone. In comparison, rats exposed postnatally to testosterone propionate after prenatal vehicle-exposure showed considerable increase in these parameters vs. controls. In conclusion, we show that the size of all male reproductive organs is programmed by androgen exposure in the MPW, but that growth towards this size is dependent on androgen action postnatally.
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              Vascular actions of estrogens: functional implications.

              The impact of estrogen exposure in preventing or treating cardiovascular disease is controversial. But it is clear that estrogen has important effects on vascular physiology and pathophysiology, with potential therapeutic implications. Therefore, the goal of this review is to summarize, using an integrated approach, current knowledge of the vascular effects of estrogen, both in humans and in experimental animals. Aspects of estrogen synthesis and receptors, as well as general mechanisms of estrogenic action are reviewed with an emphasis on issues particularly relevant to the vascular system. Recent understanding of the impact of estrogen on mitochondrial function suggests that the longer lifespan of women compared with men may depend in part on the ability of estrogen to decrease production of reactive oxygen species in mitochondria. Mechanisms by which estrogen increases endothelial vasodilator function, promotes angiogenesis, and modulates autonomic function are summarized. Key aspects of the relevant pathophysiology of inflammation, atherosclerosis, stroke, migraine, and thrombosis are reviewed concerning current knowledge of estrogenic effects. A number of emerging concepts are addressed throughout. These include the importance of estrogenic formulation and route of administration and the impact of genetic polymorphisms, either in estrogen receptors or in enzymes responsible for estrogen metabolism, on responsiveness to hormone treatment. The importance of local metabolism of estrogenic precursors and the impact of timing for initiation of treatment and its duration are also considered. Although consensus opinions are emphasized, controversial views are presented to stimulate future research.
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                Author and article information

                Contributors
                Journal
                J Clin Endocrinol Metab
                J Clin Endocrinol Metab
                jcem
                The Journal of Clinical Endocrinology and Metabolism
                Oxford University Press (US )
                0021-972X
                1945-7197
                February 2024
                06 September 2023
                06 September 2023
                : 109
                : 2
                : e735-e744
                Affiliations
                Institute of Cardiovascular and Medical Sciences, British Heart Foundation Center for Research Excellence, University of Glasgow , 126 University Avenue, Glasgow G12 8TA, UK
                Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Royal Hospital for Children , 1345 Govan Road, Glasgow G51 4TF, UK
                Institute of Cardiovascular and Medical Sciences, British Heart Foundation Center for Research Excellence, University of Glasgow , 126 University Avenue, Glasgow G12 8TA, UK
                Research Institute of McGill University Health Center, McGill University , 1001 Boul Décarie, Montréal, QC H4A 3J1, Canada
                Institute of Cardiovascular and Medical Sciences, British Heart Foundation Center for Research Excellence, University of Glasgow , 126 University Avenue, Glasgow G12 8TA, UK
                Institute of Cardiovascular and Medical Sciences, British Heart Foundation Center for Research Excellence, University of Glasgow , 126 University Avenue, Glasgow G12 8TA, UK
                Department of Pediatric Surgery, Royal Hospital for Children, Royal Hospital for Children , 1345 Govan Road, Glasgow G51 4TF, Scotland, UK
                Department of Pediatric Surgery, Royal Hospital for Children, Royal Hospital for Children , 1345 Govan Road, Glasgow G51 4TF, Scotland, UK
                Department of Pediatric Surgery, Royal Hospital for Children, Royal Hospital for Children , 1345 Govan Road, Glasgow G51 4TF, Scotland, UK
                Department of Pediatric Surgery, Royal Hospital for Children, Royal Hospital for Children , 1345 Govan Road, Glasgow G51 4TF, Scotland, UK
                Department of Pediatric Surgery, Royal Hospital for Children, Royal Hospital for Children , 1345 Govan Road, Glasgow G51 4TF, Scotland, UK
                Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Royal Hospital for Children , 1345 Govan Road, Glasgow G51 4TF, UK
                Department of Clinical Biochemistry, Queen Elizabeth University Hospital , Glasgow G51 4TF, Scotland, UK
                Institute of Cardiovascular and Medical Sciences, British Heart Foundation Center for Research Excellence, University of Glasgow , 126 University Avenue, Glasgow G12 8TA, UK
                Institute of Cardiovascular and Medical Sciences, British Heart Foundation Center for Research Excellence, University of Glasgow , 126 University Avenue, Glasgow G12 8TA, UK
                Research Institute of McGill University Health Center, McGill University , 1001 Boul Décarie, Montréal, QC H4A 3J1, Canada
                Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Royal Hospital for Children , 1345 Govan Road, Glasgow G51 4TF, UK
                Author notes
                Correspondence: S. Faisal Ahmed, MD, FRCPCH, Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Office Block, Royal Hospital for Children, 1345 Govan Road, Glasgow G51 4TF, UK. Email: faisal.ahmed@ 123456glasgow.ac.uk .
                Author information
                https://orcid.org/0000-0003-2662-1684
                https://orcid.org/0000-0001-5296-0423
                https://orcid.org/0000-0003-0670-0887
                https://orcid.org/0000-0003-0689-5549
                Article
                dgad525
                10.1210/clinem/dgad525
                10795938
                37672642
                bb52c524-4843-4d24-8686-eae1a9c682b6
                © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 11 January 2023
                : 30 August 2023
                : 18 September 2023
                Page count
                Pages: 10
                Categories
                Clinical Research Article
                AcademicSubjects/MED00250

                Endocrinology & Diabetes
                testosterone,vessel,estrogen,dihydrotestosterone,androgen
                Endocrinology & Diabetes
                testosterone, vessel, estrogen, dihydrotestosterone, androgen

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