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Introduction: Genitourinary conditions in women increase in prevalence with age. Androgens are prerequisite hormones of estrogen biosynthesis, are produced in larger amounts than estrogens in women, and decrease throughout adulthood. However, research and treatment for genitourinary complaints have traditionally focused on estrogens to the exclusion of other potential hormonal influences., Aim: To summarize and evaluate the evidence that androgens are important for maintaining genitourinary health in women and that lack of androgenic activity can contribute to the development of symptoms of the genitourinary syndrome of menopause., Methods: The role of androgens in the pathophysiology, diagnosis, and treatment of genitourinary syndrome of menopause was discussed by an international and multidisciplinary panel during a consensus conference organized by the International Society for the Study of Women's Sexual Health. A subgroup further examined publications from the PubMed database, giving preference to clinical studies or to basic science studies in human tissues., Main Outcome Measures: Expert opinion evaluating trophic and functional effects of androgens, their differences from estrogenic effects, and regulation of androgen and estrogen receptor expression in female genitourinary tissues., Results: Androgen receptors have been detected throughout the genitourinary system using immunohistochemical, western blot, ligand binding, and gene expression analyses. Lower circulating testosterone and estradiol concentrations and various genitourinary conditions have been associated with differential expression of androgen and estrogen receptors. Supplementation of androgen and/or estrogen in postmenopausal women (local administration) or in ovariectomized animals (systemic administration) induces tissue-specific responses that include changes in androgen and estrogen receptor expression, cell growth, mucin production, collagen turnover, increased perfusion, and neurotransmitter synthesis., Conclusion: Androgens contribute to the maintenance of genitourinary tissue structure and function. The effects of androgens can be distinct from those of estrogens or can complement estrogenic action. Androgen-mediated processes might be involved in the full or partial resolution of genitourinary syndrome of menopause symptoms in women. Traish AM, Vignozzi L, Simon JA, et al. Role of Androgens in Female Genitourinary Tissue Structure and Function: Implications in the Genitourinary Syndrome of Menopause. Sex Med Rev 2018;6:558-571., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this consensus document is to broaden the perspective on clinical management of genitourinary syndrome of menopause to include androgens., Methods: A modified Delphi method was used to reach consensus among the 14 international panelists representing multiple disciplines and societies., Results: Menopause-related genitourinary symptoms affect over 50% of midlife and older women. These symptoms have a marked impact on sexual functioning, daily activities, emotional well-being, body image, and interpersonal relations. Tissues in the genitourinary system are both androgen and estrogen-dependent. The clitoris, vestibule, including minor and major vestibular glands, urethra, anterior vaginal wall, periurethral tissue, and pelvic floor are androgen-responsive. Historically, treatment of postmenopausal genitourinary symptoms involved both androgens and estrogens. This subsequently gave rise to predominantly estrogen-based therapies. More recently, double-blind, placebo-controlled clinical trials have demonstrated that local vaginal dehydroepiandrosterone improves symptoms in postmenopausal women, including moderate to severe dyspareunia. Limited data suggest that systemic testosterone treatment may improve vaginal epithelial health and blood flow. Open-label studies that have used high doses of intravaginal testosterone in the presence of aromatase inhibitor therapy for breast cancer have resulted in supraphysiological serum testosterone levels, and have been reported to lower vaginal pH, improve the vaginal maturation index, and reduce dyspareunia., Conclusions: Vaginal dehydroepiandrosterone, hypothesized to enhance local production of both androgen and estrogen, is effective for the management of dyspareunia in menopause. Vaginal testosterone offers potential as a treatment for genitourinary syndrome of menopause, but more studies are needed.

Objectives: To investigate the effect of orchiectomy and androgen replacement on the expression of vascular endothelial growth factor (VEGF) in rat penile tissue., Material and Methods: Adult male Sprague-Dawley rats (12 weeks old) were left intact (control) or surgically castrated. Orchiectomized rats were left untreated or received testosterone propionate (TP) for 7 days, beginning 1 or 2 weeks after castration. Erectile function was assessed by measuring intracavernosal pressure in response to cavernous nerve stimulation, and the expression of VEGF protein and mRNA was determined by immunohistochemistry, Western blot analysis, and reverse transcriptase-polymerase chain reaction. Serum testosterone values were measured in each animal by radioimmunoassay., Results: Serum androgen levels decreased significantly in castrated animals, whereas TP injection normalized the serum levels of testosterone. Intracavernosal pressure was significantly decreased in untreated castrated rats (31.3 ± 15.7% at 2 weeks postcastration; 18.6 ± 4.6% at 3 weeks postcastration) compared with intact controls (58.0 ± 11.4% and 58.9 ± 8.2%, respectively). Erectile function was normalized in androgen-replaced rats, irrespective of treatment was initiation 1 or 2 weeks after orchiectomy. The expression of VEGF protein and mRNA was decreased in the corpus cavernosum of castrated animals compared with controls, whereas androgen replacement normalized the expression of VEGF. These results were consistently observed by all 3 methods of assessment., Conclusions: These data suggest that androgen regulates the expression of VEGF in rat penile corpus cavernosum and confirms the importance of androgens in the maintenance of erectile function., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: Androgens are essential for the development and growth of the penis, and they regulate erectile physiology by multiple mechanisms. Our goal is to provide a concise overview of the basic research and how this knowledge can be translated into a new clinical paradigm for patient management. In addition, this new paradigm may serve as a basis for stimulating constructive debate regarding the use of testosterone in men, and to promote new, innovative basic and clinical research to further understand the underlying mechanisms of androgen action in restoring erectile physiology., Methods: A literature review was performed utilizing the US National Library of Medicine's PubMed database., Results: On the basis of evidence derived from laboratory animal studies and clinical data, we postulate that androgen insufficiency disrupts cellular-signaling pathways and produces pathologic alterations in penile tissues, leading to erectile dysfunction. In this review, we discuss androgen-dependent cellular, molecular, and physiologic mechanisms modulating erectile function in the animal model, and the implication of this knowledge in testosterone use in the clinical setting to treat erectile dysfunction. The new clinical paradigm incorporates many of the consensed points of view discussed in traditional consensed algorithms exclusively designed for men with androgen insufficiency. There are, however, novel and innovative differences with this new clinical paradigm. This paradigm represents a fresh effort to provide mandatory and optional management strategies for men with both androgen insufficiency and erectile dysfunction., Conclusions: The new clinical paradigm is evidence-based and represents one of the first attempts to address a logical management plan for men with concomitant hormonal and sexual health concerns.

Androgens are deemed to be critical for the development, growth, and maintenance of penile tissue as well as for erectile function. Androgens are also reported to inhibit differentiation of stroma progenitor cells into adipocytes and promote differentiation into smooth muscle. The objective of this study was to investigate whether androgen deprivation results in accumulation of adipocytes in the corpus cavernosum. Mature, New Zealand white male rabbits were subjected to sham surgery (control) or orchiectomy. Two weeks after surgery, erectile function was assessed by monitoring changes in intracavernosal blood pressure (ICP) in response to pelvic nerve stimulation. All ICP measurements were normalized to the mean systemic arterial blood pressure. In parallel studies, penile cross sections from control and orchiectomized rabbits were fixed and stained with either Masson's trichrome or hematoxylin and eosin to assess smooth muscle and connective tissue content. Alternatively, tissue sections were stained with Toluidine blue to assess accumulation of fat-containing cells. Orchiectomy resulted in loss of erectile function and penile atrophy, associated with reduced trabecular smooth muscle and increased connective tissue content. Most strikingly, tissue from orchiectomized animals exhibited accumulation of fat-containing cells (adipocytes) in the subtunical region of the corpus cavernosum. We hypothesize that androgen deprivation promotes differentiation of progenitor stroma cells into an adipogenic lineage producing fat-containing cells, thus altering erectile function.

The role of steroid hormones in regulating vaginal smooth muscle contractility was investigated. Rabbits were kept intact or ovariectomized. After 2 weeks, animals were continuously infused with vehicle or supraphysiological levels of testosterone (100 microg/day), or estradiol (200 microg/day), for an additional 2 weeks. The distal vaginal tissue was used to assess contractility in organ baths and changes in tissue structure were assessed by histology. Ovariectomized animals infused with vehicle exhibited significant atrophy of the muscularis and decreased epithelial height, resulting in thinning of the vaginal wall. Estradiol infusion increased epithelial height, comparable to that of intact animals, but only partially restored the muscularis layer. In contrast, testosterone infusion completely restored the muscularis layer, but only partially restored the epithelial height. In vaginal tissue strips contracted with norepinephrine and treated with bretylium, electrical field stimulation (EFS) caused frequency-dependent relaxation that was slightly attenuated with vehicle, significantly inhibited with estradiol and significantly enhanced with testosterone. VIP-induced relaxation was slightly attenuated in tissues from vehicle and estradiol-infused groups, but was enhanced in tissues from testosterone-infused animals. Contraction elicited by EFS or exogenous norepinephrine was not significantly altered with ovariectomy or steroid hormone infusion when data were normalized to potassium contraction. However, the tissue from testosterone-infused animals developed significantly greater contractile force to norepinephrine. These observations suggest that steroid hormones may be important regulators of vaginal tissue structure and contractility.

Nitric oxide synthase (NOS) and arginase have been shown to regulate nitric oxide (NO) production reciprocally in genital tissues. In animal models, NO is an important regulator of vaginal blood flow and vaginal wall contractility. In this study, we investigated the modulation of NOS and arginase activities by estrogens and androgens in the proximal and distal rabbit vagina. In intact control animals, total NOS activity was higher in the proximal (528+/-78 pmol/mg protein) than the distal (391+/-44 pmol/mg protein) vagina. However, arginase activity was higher in the distal (206+/-8 nmol/mg protein) than the proximal (64+/-5 nmol/mg protein) vagina. Ovariectomy enhanced NOS activity in the proximal but not distal vagina with concomitant decrease in arginase activity in both the proximal and distal vagina. In ovariectomized rabbits, replacement with 5alpha-dihydrotestosterone (DHT) or Delta5-androstenediol (Adiol) increased NOS activity beyond that observed in ovariectomized rabbits receiving vehicle. In contrast, DHT and Adiol treatment reduced arginase activity more than that of the ovariectomized rabbits receiving vehicle. Testosterone exhibited inconsistent effects on NOS and arginase activity in the distal and proximal vagina. Estradiol replacement in ovariectomized animals reduced NOS activity in the proximal vagina down to levels that were comparable to intact control animals. However, estradiol positively modulated arginase activity in the distal vagina. Western blot analyses indicated that in the proximal vagina, neural NOS protein levels paralleled the changes observed in enzyme activity. These observations suggest that steroid hormones differentially regulate NOS and arginase activities of the proximal and distal regions of the vagina. Although estrogen treatment reduced total NOS activity in proximal vagina, estrogens are known to enhance vaginal blood flow. This paradoxical observation may be explained by differential regulation of n-NOS and e-NOS in the proximal and distal vagina. We suggest that changes in vaginal blood flow and compliance may depend on the endocrine status and the levels of circulating androgens and estrogens.

During our evaluations of women with sexual dysfunction, we have seen many with low interest, arousal, and orgasmic capabilities with associated personal distress and diminished genital sensation and blood flow following sexual stimulation. Laboratory evaluation of these women has revealed normal estrogen but androgen values that were either below or in the lower quartile of the physiologic range. Androgen insufficiency and sexual dysfunction have been the working diagnoses in these women. Although many treatment options currently are available for this syndrome, there are limited data concerning safety and efficacy. The aim of this retrospective, Institutional Review Board (IRB)--approved, single-institution study was to report on the androgen and questionnaire results from a series of patients who underwent androgen replacement therapy with dehydroepiandrosterone for treatment of androgen insufficiency and sexual dysfunction. This study revealed that there was a significant decrease in sexual distress, a significant increase in sexual function in the domains of desire, arousal, lubrication, satisfaction, and orgasm, and a normalization to values within the physiologic range in the following androgens measured: total testosterone, free or bioavAilable testosterone, DHEA, DHEA-S, and androstenedione. Side effects included increased facial hair (11%), weight gain (7%), acne (5%), temporary breast tenderness (1%), loss of head hair (1%) and skin rash (1%). Preliminary results suggest that androgen replacement therapy with dehydroepiandrosterone is a safe and effective treatment for androgen insufficiency and female sexual dysfunction. However, further research is needed, including prospective, multi-institution, placebo-controlled double-blind studies.