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Background: 5α-reductase inhibitors (5α-RIs) (finasteride and dutasteride) have been proven useful in treatment of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). However, these inhibitors exert undesirable sexual side effects and, in some cases, these effects are persistent. There is considerable disagreement with regard to whether the adverse side effects resolve with continuous treatment., Aim: To investigate the long-term adverse effects of finasteride treatment in men with BPH on erectile function and to compare these adverse effects in men treated with the α1-adrenergic receptor blocker, tamsolusin., Methods: In this retrospective registry study, a cohort of 470 men aged between 47 and 68 years (mean 57.78±4.81) were treated with finasteride (5 mg/day). A second cohort of 230 men aged between 52 and 72 years (mean 62.62±4.65) were treated with tamsulosin (0.4 mg). All men were followed up for 45 months. At intervals of 3 months and at each visit, plasma testosterone (T) levels and the international index of erectile function (IIEF-EF) questionnaire scores were determined., Results: Long-term treatment with finasteride therapy is associated with worsening of erectile dysfunction (ED) as shown by the significant decrease in the IIEF-EF scores in men treated with finasteride. No worsening of ED was observed in men treated with tamsulosin. The increase in ED due to finasteride did not resolve with continued treatment with finasteride. Most importantly, long-term finasteride therapy resulted in reduction in total T levels, contributing to a state of hypogonadism. On the contrary, no changes in T levels were noted in men treated with tamsolusin., Conclusion: Our findings suggest that in men with BPH, long-term finasteride therapy but not tamsulosin results in worsening of ED and reduces total T concentrations. Clinicians are urged to discuss the impact of 5α-RIs therapy on sexual function with their patients before commencing this therapy.

5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease.

Aim: Altered expression of connexin 43 (Cx43) has been postulated to be involved in the development and progression of various diseases including erectile dysfunction (ED). The aim of this study was to determine whether distribution and density of the gap junction protein Cx43 are altered in human corpus cavernosum (HCC) tissue samples derived from diabetic or hypogonadal patients with ED compared to those from normal subjects., Methods: HCC tissue sections derived from normal, diabetic and hypogonadal subjects were fixed in 4% formaldehyde, embedded in paraffin and immunostained with a monoclonal mouse anti-rat Cx43 antibody. Cx43 density was expressed as the cumulative number of gap junction plaques per unit area of tissue corrected for number of 4',6-diamidino-2-phenylindole, dihydrochloride-labeled smooth muscle cells (dots per unit area corrected for number of cells)., Results: The distribution of Cx43 plaques in smooth muscle was not affected in tissues derived from diabetic or hypogonadal subjects with ED compared with those from normal subjects. However, the number of Cx43 plaques was significantly reduced in HCC tissues derived from diabetic or hypogonadal subjects (73 ± 8% and 68 ± 11% of normal, respectively), indicating reduced Cx43 gap junctions in diabetic and hypogonadal subjects with ED., Conclusions: Cx43 density in the HCC was diminished in tissue samples derived from diabetic or hypogonadal patients with ED compared to tissue samples from normal non-diabetic subjects. This marked decrease in Cx43 gap junction channels may contribute to attenuated gap junction function and to diminished erectile physiology.

Over the past 60 years, androgen deprivation therapy has been the mainstay of treatment of metastatic prostate cancer. However, research findings suggest that androgen deprivation therapy inflicts serious adverse effects on overall health and reduces the quality of life. Among the adverse effects known to date are insulin resistance, diabetes, metabolic syndrome fatigue, erectile dysfunction, and cardiovascular disease. In this clinical perspective, we discuss the relationship between induced androgen deficiency and a host of pathologies in the course of treatment with androgen deprivation therapy for prostate cancer patients.

Among the major physiological functions of steroid hormones is regulation of carbohydrate, fat, and protein metabolism. Mitochondria, through oxidative phosphorylation, play a critical role in modulating a host of complex cellular metabolic pathways to produce chemical energy to meet the metabolic demand for cellular function. Thus, androgens may regulate cellular metabolism and energy production by increased mitochondrial numbers, activation of respiratory chain components, and increased transcription of mitochondrial-encoded respiratory chain genes that code for enzymes responsible for oxidative phosphorylation. Androgen deficiency is associated with increased insulin resistance, type 2 diabetes (T2DM), metabolic syndrome, obesity, and increased overall mortality. One common link among all these pathologies is mitochondrial dysfunction. Contemporary evidence exists suggesting that testosterone deficiency (TD) contributes to mitochondrial dysfunction, including structural alterations and reduced expression and activities of metabolic enzymes. Here, we postulate that TD contributes to symptoms of fatigue, insulin resistance, T2DM, cardiovascular risk, and metabolic syndrome through a common mechanism involving impairment of mitochondrial function.

Advancement in basic and clinical research has provided considerable evidence suggesting a key role of androgens in the physiology and pathophysiology of sexual function. Evidence from clinical studies in men and women with androgen deficiency support a role of androgens in maintaining sexual function in men and women and are integral in maintaining sexual health. Preclinical studies utilizing male animal models demonstrated a role of androgens in maintenance of: (i) penile tissue structural integrity, (ii) penile trabecular smooth muscle growth and function, (iii) integrity of penile nerve fiber network, (iv) signaling pathways in the corpora cavernosa, (v) myogenic and adipogenic differentiation in the corpora cavernosa, (vi) physiological penile response to stimuli, and (vii) facilitating corporeal hemodynamics. These findings strongly suggest a role for androgen in the physiology of penile erection. In addition, clinical studies in hypogonadal men with erectile dysfunction treated with testosterone provided invaluable information on restoring erectile function and improving ejaculatory function. Similarly, clinical studies in surgically or naturally postmenopausal women with androgen deficiency suggested that androgens are important for maintaining sexual desire and testosterone treatment was shown to improve sexual desire, arousal and orgasm. Furthermore, studies in female animal models demonstrated that androgens maintain the integrity of vaginal nerve fiber network, muscularis volume, and enhance genital blood flow and mucification. Based on the biochemical, physiological and clinical findings from human and animal studies, we suggest that androgens are integral for maintaining sexual function and play a critical role in maintaining sexual health in men and women.

The objective of this review was to examine data from preclinical, clinical and epidemiological studies to evaluate if testosterone (T) poses increased risk of breast cancer in women. Appraisal of the existing literature produced several lines of evidence arguing against increased breast cancer risk with T. These include: (i) Data from breast tumor cell lines treated with androgens did not corroborate the notion that T increases breast cancer risk. On the contrary, androgens appear to be protective, as they inhibit tumor cell growth. (ii) Many of the epidemiological studies claiming an association between T and breast cancer did not adjust for estrogen levels. Studies adjusted for estrogen levels reported no association between T and breast cancer. (iii) Data from clinical studies with exogenous androgen treatment of women with endocrine and sexual disorders did not show any increase in incidence of breast cancer. (iv) Women afflicted with polycystic ovary disease, who exhibit high levels of androgens do not show increased risk of breast cancer compared to the general population. (v) Female to male transsexuals, who receive supraphysiological doses of T for long time periods prior to surgical procedures, do not report increased risk of breast cancer. (vi) Finally, women with hormone responsive primary breast cancer are treated with aromatase inhibitors, which block conversion of androgens to estrogens, thus elevating androgen levels. These women do not experience increased incidence of contralateral breast cancer nor do they experience increased tumor growth. In conclusion, the evidence available strongly suggests that T does not increase breast cancer risk in women.