The role of the AR in areas relevant to the sexual dysfunction in PFS

Libido, erectile function, and penile structural maintenance

Male libido and sexual desire is primarily androgen-mediated and strictly testosterone dependent. Considerable evidence supports libido loss as the clearest symptom of hypogonadism ​(Santi et al., 2018)​. Evidence regarding the role of other hormones is less clear ​(Corona et al., 2016)​. Male-typical behaviour requires AR signaling in adults, and AR inactivation in male mice causes a complete loss of male sexual behaviour alongside a significant reduction in aggression ​(Sato et al., 2004)​.

Phosphorylated endothelial nitric oxide synthase (eNOS) has a key facilitative role in physiological penile erection following initiation by neuronal nitric oxide synthase (nNOS) ​(Burnett, 2004)​. In human aortic endothelium cells, T rapidly induces eNOS activation and production of nitric oxide through AR-dependent induction of PI3-kinase/Akt signaling ​(Yu et al., 2010)​. Additionally, AR inactivation in mice demonstrates a dramatic reduction in nNOS expression in the hypothalamus, suggesting AR regulation of this neurotransmitter and its sexually relevant functions ​(Sato et al., 2004)​. A particularly common and important symptom of PFS is the loss of nocturnal and morning erections. This is a central mechanism of unconscious sexual arousability ​(Santi et al., 2018)​. Inactivation of the noradrenergic cells in the locus coeruleus in the brain stem, a site expressive of the AR, is a testosterone-dependant process ​(Bancroft, 2005)​ that results in nocturnal penile tumescence.

Androgens are crucial to maintain male reproductive physiology and erectile function and are critical to the integrity and maintenance of the tunica albuginea, cavernous endothelium, cavernosal smooth muscle, and nerve structure and function ​(A. Traish & Kim, 2005; A. M. Traish, 2008; Zhang et al., 2013)​. Tissue integrity and structure is vital to venoocclusive function, and structural alteration will result in dysfunction that is both difficult to diagnose and challenging to treat ​(A. M. Traish, 2008)​. Castration of adult male rats significantly decreases penile length, girth, smooth muscle content and endothelial nitric oxide synthase activity, and this is reversible with testosterone administration ​(Halmenschlager et al., 2017; Hofer et al., 2015; Huh et al., 2018; A. M. Traish, 2008)​. Immunohistochemical study of stromal and endothelial human corpus cavernosum cells biopsied from potent males aged between 19 and 63 revealed age-independent high expression of the AR (74.9%) and low expression of ERa (11%). Cultured endothelial cells exposed to T or DHT showed dose-dependent and significant increases in cellular metabolic activity than control groups with or without growth medium, while similar concentrations of estradiol or progesterone had no respective effect compared with controls ​(Schultheiss et al., 2003)​. This comparably reflects the testosterone-stimulated increase in proliferation reported in fetal smooth muscle cells ​(Crescioli et al., 2003)​, suggesting that peripheral androgen receptor function is important for maintenance of physiology and function of the endothelium in the adult human male penis. The significant expression of AR in penile tissue suggests its vulnerability to a proposed loss of function and potential toxic gain of function conferred by site-specific AR overexpression. This is of particular relevance to the progressive and often rapid penile atrophy after cessation of the drug experienced by some PFS patients that can occur after only one dose ​(Garreton et al., 2016)​. It is particularly relevant that PFS patients reporting this can have normal serum androgen levels ​(Irwig, 2014)​, or frequently relatively high – or intraindividually increased – levels of T.

In addition to venous leakage, clinical findings of calcification and atherosclerosis upon penile ultrasound are anecdotally reported findings following urological evaluation of PFS patients with atrophic changes to the penis. AR signaling is increasingly appreciated as involved in calcification and atherosclerotic lesions, in line with the well-appreciated heightened risk of cardiovascular disease in males, as recently reviewed by Takov et al ​(Takov et al., 2018)​. Vascular smooth muscle cells (VSMCs) provide structural integrity of blood vessels and control diameter via regulation of contraction and vasodilation ​(Metz et al., 2011)​. Zhu et al. reported significant expression of the AR in VSMCs and the presence of AR in calcified aortic and femoral artery tissue. In vitro investigation revealed striking induction of pro-calcificatory effects by both testosterone and DHT, and the lack of aromatase expression in these cells indicated direct mediation by AR signaling ​(Zhu et al., 2016)​. Arterial calcification and atherosclerosis has been associated with long term anabolic steroid abuse, hyperandrogenemia in women with polycystic ovary syndrome and postmenopausal women administered testosterone ​(Christian et al., 2003; Hak et al., 2007; Santora et al., 2006)​. However, in addition to pro-calcificatory effects, investigations have revealed that androgen induction of AR-mediated processes are atheroprotective ​(Son et al., 2010; Yu et al., 2010)​, further suggesting appropriate AR-mediated signaling is necessary for vascular health.

Testosterone treatment of rats during urethral wound healing increases myofibroblast proliferation and collagen deposition, and Hofer et al. speculate this may contribute to spongiofibrosis and stricture development ​(Hofer et al., 2015)​. Finasteride has recently been suggested as a potential therapy in myocardial infarction. Evidence of increased DHT and androgen-responsive gene expression in mouse models of myocardial infarction was reported, and treatment with finasteride markedly improved cardiac function and reduced fibroblast collagen secretion ​(Froese et al., 2018)​. Interestingly, prominent collagen deposition is reported in the corpus cavernosum of rats treated with either finasteride or dutasteride ​(Sahin Kilic et al., 2018)​, reflecting androgen deprivation and hypogonadism ​(El-Sakka, 2011; A. Traish & Kim, 2005)​, possibly indicative of a similar histopathological effect of both reduced or increased androgen signaling.

Hypospadias, a congenital penile deformation associated with prenatal endocrine disruption ​(Wolf et al., 1999)​ and decreased androgen signaling ​(Aschim et al., 2004)​, is associated with altered expression of the AR ​(Vottero et al., 2011)​. Loss of AR expression is not correlated to severity ​(Celayir, 2018)​. Interestingly, Qiao et al. reported that AR was significantly upregulated in the preputial skin of boys with severe hypospadias compared with boys without hypospadias or boys with mild hypospadias, the latter demonstrating a more moderate elevation in AR expression ​(Qiao et al., 2012)​.

Sperm count, motility, and semen consistency

AR dysregulation is a plausible causative factor for well-reported changes to sperm count, motility, semen consistency and ejaculate volume in PFS. AR action in the male reproductive system is functionally critical to sperm differentiation, maturation and survival. Targeted AR knockout in mice causes azoospermia and infertility ​(Krutskikh et al., 2011)​. The AR has been recently shown to be critical across the spermatogenesis and maturation processes. Androgen blockade inhibits differentiation to spermatocytes. In vitro cell culture and in vivo confirmations revealed that promyelocytic leukemia zinc-finger, an important gene in differentiation of spermatogonial stem cells. AR in Sertoli cells indirectly regulates β1 integrin via GATA2 and WT-1, and β1 integrin further binds to E-cadherin to regulate the fate of spermatogonial stem cells. DHT treatment of AR-overexpressing Sertoli cells demonstrated AR indirectly down-regulates WT-1, a key gene in spermatogenesis, via GATA2 ​(J. Wang et al., 2019)​. WT-1 is critical to spermatogenesis and deficiency is associated with male infertility ​(X. N. Wang et al., 2013)​. The human epididymis is a complex tubular structure in which spermatozoa functionally develop and reach maturity, serving as conduit to the vas deferens from the testis ​(Cornwall, 2008)​. AR is prominently expressed throughout the epididymis ​(SAR et al., 1990; Zhou et al., 2002)​, and the importance of the AR in this tissue is well established ​(Robaire & Hamzeh, 2011)​. The critical influence of the AR in human epidydimal cells has been confirmed by next generation deep sequencing protocols ​(Browne et al., 2019)​. The AR has been identified to regulate a functional transcriptional network of about 200 genes in the human caput epididymis epithelium and is therefore critically implicated in sperm maturation and fertility maintenance in men ​(Yang et al., 2018)​. The vas deferens fluid microenvironment is crucial to sperm transport and survival in the organ. In rats, vas deferens lumen size, fluid volume and osmolality have been demonstrated to be under the regulation of the AR, as was the expression of aquaporin isoforms AQP-1, AQP-2 and AQP-9. Testosterone was shown to increase water secretion and osmolality in this organ through the AR and was interrupted by Finasteride or Flutamide ​(Ramli et al., 2018)​.

Post-Orgasm illness and increased refractory period

Both a significantly increased refractory period and a post-orgasm modulation of symptoms is widely reported in PFS. Male accessory sex organs are responsive to prolactin. Post-orgasm increases in prolactin are implicated in sex organ maintenance and functionality, whereas constant levels would prove deleterious ​(Hernandez et al., 2006)​. Prolactin administration has been observed to induce a dose-related increase of AR expression levels beyond levels explainable by organ weight increases in the testes, prostate and epididymis in male rats ​(BARAÑAO et al., 1982)​.

In male rats, AR mRNA levels in the ventral prostate were determined after consecutive ejaculations by Hernandez et al. AR, with a concurrent steady increase in AR mRNA, was significantly increased after one ejaculation (100% increase; p < 0.05). Levels were further highly increased after two and three ejaculations (200% and 300% increases respectively) to a total of 800%, returning to precopulatory levels rapidly after the fourth ejaculation. Interestingly, a rapid and significant copulation-induced induced increase in androgen receptor protein precedes higher expression of mRNA or serum elevation of testosterone, suggesting rapid regulatory processes. Additionally, testosterone reaching its maximal increase did not arrest the continual increase of AR mRNA, suggesting the existence of a balance of both gene transcription and stabilization in regards to AR-mRNA levels ​(Hernandez et al., 2007)​.

The paracrine influence of oxytocin ​(H. Nicholson, 1996)​, which systemically increases at orgasm ​(Ivell et al., 1997; OGAWA et al., 1980; Thackare et al., 2006)​, may be influential in the commonly reported modulation of PFS symptoms following orgasm, which can include severe multi-symptom worsening usually lasting a number of days. Administration of oxytocin to rats has been shown to increase testicular and epididymal weight, with a significant increase in 5alpha reductase activity in these organs (P < 0.005 and P < 0.01 respectively). In vitro homogenates incubated with oxytocin additionally showed significant increases in 5alpha reductase activity at low concentrations (10 pg/0.3-mg protein) ​(H. D. Nicholson & Jenkin, 1994)​. Oxytocin at physiological levels positively regulates the activity of type I and II 5alpha reductases in human prostate epithelial cells ​(S.J. Assinder, 2007)​ and in LNCAP cell lines ​(Stephen J. Assinder et al., 2015)​. These results occurred at the level of post-translational protein activity and do not appear to regulate gene expression. Oxytocin is considered to be a potent growth inducer in prostate cancer ​(Xu et al., 2017)​. We hypothesise the increase in 5alpha-reductase activity and increased androgen receptor expression may explain a significant and widely anecdotally reported impact of orgasm on PFS symptoms.

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