PFS: Manifestation of a Post-Androgen Deprivation Syndrome following exposure to substances with antiandrogenic effects

Endocrine disruption

“Endocrine disruption” refers to a specific toxicity whereby natural and/or anthropogenic chemicals cause adverse health effects by disrupting the endogenous hormone system. An endocrine disruptor is defined by the World Health Organisation as “an exogenous substance or mixture that alters the function(s) of the endocrine system and consequently causes adverse effects in an intact organism, or its progeny, or (sub) populations”. Potential endocrine disruptors can act on hormone receptors directly or interfere with proteins mediating hormonal delivery to target tissues and cells. They may act at low doses, exhibit non-monotonic dose-response relationships, cause tissue specific effects and differing endpoints ​(Bergman et al., 2012)​. There is broad potential for pharmaco/toxicodynamic influences from EDCs including alteration of receptor expression and interruption of the critical and complex feedback mechanisms regulating the endocrine system ​(Lagarde et al., 2015)​. It has been estimated that, in the EU, the cost associated with disease and disability reasonably attributable to EDC exposure is €157 billion, 1.23% of the European Union’s gross domestic product ​(Trasande et al., 2015)​. Health risks related to exposure to endocrine disruptors are typically underestimated and poorly characterised ​(Fucic et al., 2018)​.

There is now scientific consensus that, as well as disruptive effects during developmental windows, interference with the role of hormones during maintenance of physiological function in adult life can cause adverse effects ​(Solecki et al., 2016)​. An adverse effect in this context constitutes “a change in morphology, physiology, growth, reproduction, development or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increased susceptibility to the harmful effects of other environmental influences” ​(Bergman et al., 2012)​. In this context, anthropogenic chemicals can represent pervasive environmental stressors ​(Latchney et al., 2017)​, and the marked sensitivity to endocrine-affecting substances common in PFS patients appears to us to be a manifestation of this increased susceptibility. Changes to the epigenome that can persist indefinitely after exposure to pharmaceutical products is an increasing area of consideration ​(Csoka & Szyf, 2009)​. Recent publications centring on epigenetics increasingly appreciate Finasteride in the context of endocrine disruptors, with respect to both PFS ​(Traish, 2018)​ and in broader animal studies. Finasteride induces hypospadias and a permanent reduction in anogenital distance in adult male rats exposed during late gestation ​(Bowman et al., 2003)​. This effect on LABC weight is consistent with the effects of other antiandrogens such as flutamide, procymidone, vinclozolin, and linuron ​(McIntyre, 2001, 2002; Ostby et al., 1999; Wolf et al., 1999)​.

Despite the “clear endocrine disrupting activity” of 5-alpha reductase inhibitors, there is a paucity of information regarding the impact of non-clinical 5-alpha reductase inhibition ​(Patisaul & Belcher, 2017)​. Even with sole consideration of the known effects of very low doses of finasteride on development, the strong persistence of the drug in the environment and high photostability raises serious concerns about its widespread availability ​(Sammartino et al., 2013)​. The profound and devastating changes to physiological health manifesting as PFS in an adult subpopulation of fertile age following exposure to as little as 0.2mg of Finasteride should add significant and urgent public health concerns regarding its environmental toxicity as an EDC.

“PFS” following therapeutic use and cessation of other substances?

Importantly, patients are increasingly presenting to us suffering what is ostensibly clinically “post-finasteride syndrome” following use of drugs and substances including Isotretinoin, Serenoa repens (saw palmetto) extract, SSRI antidepressants, topical ketoconazole, topical minoxidil, and high-dose phenolic compounds marketed as health supplements including quercetin and milk thistle extract.

It is recognised that the syndrome termed Post-SSRI Sexual Dysfunction (PSSD) and PFS may share an etiological link. With focus on neurological symptoms, Giatti et al. presented a hypothesis that the impairment of overlapping signals of neuroactive steroids, dopamine and serotonin as potentially underlying the condition(s) ​(Giatti et al., 2018)​. In another consideration of the potential for a single syndrome underlying these presentations, Healy et al. analysed 300 patient responses to structured questions provided by and submitted to rxisk.org, an independent drug safety website. The cohort was comprised of patients suffering persistent sexual dysfunction following use of 5-ARIs, Isotretinoin and Serotonin Reuptake Inhibitors, with treatment duration ranging from a single dose to over 16 years. Overlap was seen in symptoms including ED, Libido loss, genital anaesthesia, difficulty achieving orgasm, pleasureless orgasm, premature ejaculation, emotional blunting, loss of nocturnal erections, penile or testicular pain, reduction of penis size, decreased testosterone, watery ejaculate, testicular atrophy, and other skin numbness. Across drug groups, the sexual dysfunction became markedly worse or even began after cessation of treatment in many instances. For all three drug groups there were reports of profound dysfunction appearing within days of stopping. while Finasteride and Isotretinoin are stopped abruptly, SSRIs are often tapered. Interestingly, three subjects on SSRIs reported an increasing loss of sexual function as the dose was tapered, suggesting that PSSD may be equally likely following abrupt or gradual discontinuation of an SSRI or SNRI. They conclude the need for comparative investigation in these cohorts and a systematic approach with structured symptom sets to establish the existence of a single syndrome ​(David Healy et al., 2018)​.

The antiandrogenic commonality of substances causing an ostensibly similar persistent syndrome

Accutane, Roaccutan, Generics (Isotretinoin)

Retinoids possess important antiandrogenic endocrine disrupting properties. Isotretinoin is a 3-cis-retinoic acid which is marketed under the brand name Accutane, Roaccutan, and as branded generic preparations. The main application is treatment of acne, which is strongly linked to androgenic activity in the skin ​(Melnik, 2017)​. Boudou et al. reported that after three months of isotretinoin treatment to six male patients with severe acne, complete resolution of acne was achieved in four patients and the remaining two patients improved significantly. No changes were recorded in serum testosterone but a significant decrease in DHT was observed. Androgen receptor status was investigated in back skin biopsies obtained in acne areas before and after three months of isotretinoin treatment. Treatment induced a 2.6-fold decrease in AR binding capacity constant (62 vs. 24 fmol/mg cytosolic protein), demonstrating a marked sensitivity of androgen receptor in the skin to oral isotretinoin. The authors concluded the data supported previous observations of DHT suppression and were consistent with the key role of the AR and DHT in acne, noting sebum is under androgen control and that androgen responsiveness of the pilosebaceous unit is implicated in acne pathogenesis ​(Boudou et al., 1995)​. Boudou et al. had previously illustrated that skin biopsies of eight men with severe acne treated with 3 months of isotretinoin “lost 80% of their ability to form 5 alpha-dihydrotestosterone (P <0.001)” ​(Boudou et al., 1994)​.

AR signal transduction is crucial to acne pathogenesis, stimulating the size of sebocytes and sebum production as well as proliferation of keratinocytes ​(Lai et al., 2012)​. IGF-1/PI3K/AKT-mediated inactivation of Forkhead box O1 (FoxO1) is vital to androgen receptor transactivation ​(Fan et al., 2007)​. FoxO1 is repressive of AR owing to FoxO1’s inhibition of AR N/C terminal interaction (Q. Ma et al., 2009). IGF-1 has correlated to acne severity ​(Cappel, 2005)​ and isotretinoin decreases IGF-1 ​(A.S. Karadag et al., 2009)​. As IGF-1 is inhibitory of AR ​(Palazzolo et al., 2009; Yanase & Fan, 2009)​, Karadag et al. hypothesised that a consequential nuclear increase in FoxO1 would significantly contribute to the downregulation of AR and thus a decrease of androgen-responsive gene transcription ​(Ayse Serap Karadag et al., 2015)​. As with other anti-acne therapies, Isotretinion enhances p53 expression ​(Melnik, 2017)​, which supresses AR expression ​(Alimirah et al., 2007; Shenk et al., 2001)​. Additionally, p53 activates and increases FoxO1 expression ​(Pappas et al., 2017)​. Human primary keratinocytes treated with isotretinoin show an increase in FoxO1 ​(Shi et al., 2018)​, and significant increases in nuclear levels of FoxO1 protein are reported in skin biopsies from acne patients following isotretinoin treatment ​(Agamia et al., 2018)​. In vitro evidence demonstrates all-trans retinoic acid profoundly downregulates the AR and abolishes the induction of androgen-induced functions ​(Ubels et al., 2002, 2003)​, suggesting a common androgen antagonism among retinoids. Taken together, there is significant evidence for the conclusion that oral Isotretinoin exerts a potent antiandrogenic effect.

Antidepressants

SSRI/SNRI class antidepressants exert significant antiandrogenic activity and have been associated with reproductive toxicity in male rats and humans ​(Atli et al., 2017; Ilgin et al., 2017; Tanrikut et al., 2010)​. Fluoxetine is known to be endocrine disruptive, with evidence of nonmonotonic effects ​(Cunha et al., 2018; Vandenberg et al., 2012)​. Rats administered Fluoxetine display delayed sexual development and decreased sexual behaviours ​( Drugs@FDA, 2016)​. Griffin and Mellon found the enzymatic efficiency of 3α-HSD conversion of DHT to androstanediol increased 163-fold when the enzyme was incubated with fluoxetine and 63-fold with paroxetine ​(Griffin & Mellon, 1999)​, which greatly reduces intracellular DHT.

Using the H295R cell line, Hansen et al. demonstrated that commonly used SSRIs fluoxetine, paroxetine, citalopram, escitalopram, sertraline and fluvoxamine exert significant endocrine disrupting properties in vitro. Despite different steroidogenic enzymes being affected across the six different drugs, the outcome was the same in terms of a marked decrease in testosterone. Observing that the steroidogenic interruptions may partly explain some of the sexual disorders associated with SSRIs, Hansen et al. suggest that the endocrine disrupting potential of these drugs at pharmacologically relevant doses should encourage their careful use in therapy ​(Hansen et al., 2017)​. A similar decrease in testosterone in this cell line following exposure to five SSRI drugs had previously been reported ​(Jacobsen et al., 2015)​. Munkboel et al. demonstrated that steroidogenesis was significantly disrupted in rats exposed to therapeutic doses of sertraline. The most significant effects observed on testicular sex steroid production, particularly the Delta 4 steroidogenic pathway (comprising progesterone, 17-hydroxyprogesterone, Androstenedione, Testosterone, DHT). Testosterone production was significantly decreased in all 3 exposure groups, and DHT was significantly decreased in the testis, plasma and brain. A 53% decrease of testosterone was reported in testis of rats exposed to 5 mg/kg/day alongside a general decrease on the D4 axis. Munkboel et al. note that this corresponds to the human starting dose of 50mg per day and this pronounced effect suggests the possibility of significant consequences on reproductive and health endpoints. They conclude that men treated with sertraline should be monitored carefully for sexual dysfunction ​(Munkboel et al., 2018)​.

Serotonin is recognised to be inhibitory of both male and female sexual behaviour and function ​(Croft, 2017; Iovino et al., 2019; Olivier et al., 2010)​. SSRIs increase inhibition of serotonin reuptake ​(Ferguson, 2001)​, and increase serotonin by a downregulation of autoreceptors which otherwise act to inhibit serotonin release ​(Hagan et al., 2012; Neumaier, 1996)​. Both 5HT1a receptor knockdown and interference using siRNA molecules of has demonstrated antidepressant effects accompanied with greater increases in extracellular serotonin in response to either stress or fluoxetine ​(Ferrés-Coy et al., 2012)​. Increased extracellular serotonin levels in the ventral hippocampus of 5HT1b knockout mice were observed in response to SSRI administration ​(Nautiyal et al., 2016)​. As well as reuptake inhibition, SSRIs have been observed to upregulate tryptophan hydroxylase ​(Kim et al., 2002)​, mediatory of serotonin production in non-neuronal and neuronal tissue ​(Walther, 2003; X. Zhang, 2004)​.

There is a well-studied and remarkable antagonism between testosterone and serotonin in terms of their behavioural effects that aligns with the significant impact of androgens on serotonergic activity in the brain ​(Ambar & Chiavegatto, 2009; Daly et al., 2001; Keleta et al., 2007; Martinez-Conde et al., 1985; Sundblad & Eriksson, 1997; L. Zhang et al., 1999)​. Testosterone promotes territorial behaviour, impulsivity, sexual behaviour and aggression ​(Bing et al., 1998; Kimura & Hagiwara, 1985; Svensson, 2003; Wu & Shah, 2011)​, whereas serotonin appears to exert opposite effects ​(Batty & Meyerson, 1980; Nelson & Chiavegatto, 2001; Olivier et al., 2010)​. Studer et al. demonstrated that while the pro-aggressive effect of testosterone is apparently independent of serotonin, the inhibitory effect of serotonin to dampen maladaptive aggression is “irrelevant” in the absence of testosterone. Additionally, inhibition of serotonin production failed to reinstate aggression in mice rendered hypoaggressive by early life brain AR knockout ​(Studer et al., 2015)​.

Recent evidence in tissue outside the brain shows that serotonin exerts a powerful downregulatory effect on the androgen receptor. BPH tissue has been observed to demonstrate AR upregulation ​(Izumi et al., 2013; Nicholson et al., 2013; P. Zhang et al., 2015)​ as well as a significant depletion of 5-HT ​(Cockett et al., 1993)​. Carvalho-Dias et al explored the relationship between 5-HT and androgen signaling, demonstrating a clear inhibitory influence of serotonin on the androgen pathway, providing robust data from a number of elegant in vitro and in vivo observations. In vitro, 5-HT significantly inhibited rat prostate cell growth through a 5-HT1a and 5-HT1b mediated down-regulation of AR either with or without testosterone supplementation. In cultured human cell lines, proliferation of BPH epithelium and normal prostate stroma cells supplemented with testosterone was significantly reduced by 5-HT or specific 5-HT1a and 5HT1b agonists. Proliferation of normal prostate epithelium cells was not affected. Testosterone was observed to upregulate the AR in BPH epithelium and markedly in normal stroma, while 5-HT or specific 5-HT1a and 5HT1b agonists inhibited this upregulation. Importantly, the absence of an inhibitory action of 5HT or an agonist of either autoreceptor on viability and proliferation of normal epithelium cells, with or without testosterone supplementation, was coincidental with a complete absence of AR expression in these cells. They additionally demonstrated that tryptophan hydroxylase type 1 knockout mice exhibit a remarkable 37% higher prostate-to-body weight ratio compared to wild-type at 20 weeks without difference in overall body weight, with prostate histology revealing areas of hyperplasia in epithelium and stroma. These mice displayed significantly larger seminal vesicles than controls, supportive of negative androgenic regulation by 5HT beyond the prostate cell lines. qRT-PCR revealed increased AR levels in the dorsolateral prostate of Tph1−/− mice. Remarkably, 5HT treatment significantly reduced prostate weight and seminal vesicles near to that of controls, and reduced AR mRNA to levels comparable to controls ​(Carvalho-Dias et al., 2017)​.

Collectively, these in vitro and in vivo studies demonstrate that the inhibition of 5alpha reductase type 2 with finasteride and steroidogenic dysregulation with SSRIs have a clear mechanistic commonality: A considerable disruption to androgen signaling. As with isotretinoin, SSRIs exert antiandrogenic endocrine disruptive activity through distinct actions. Further supporting this hypothesis, a significantly affected patient registered on propeciahelp.com suffers the syndrome following over the counter use of 5-hydroxytryptophan, a serotonin precursor observed to increase excretion of 5-HIAA with significant interindividual variation ​(Joy et al., 2008)​. This is suggestive of increased production of serotonin following 5-HTP intake, which is the rationale underlying its supplemental use ​(Hallin et al., 2012)​.

Saw Palmetto (Serenoa repens)

Amongst propeciahelp membership, Serenoa repens (saw palmetto), an extract with markedly antiandrogenic properties commonly used in treatment of BPH and LUTS ​(Cicero et al., 2019)​, is the most prevalent alternative therapy causative of the syndrome. This is usually taken as a “natural” hair loss remedy. Although proportionally rarer, topical antiandrogenic products are causing patients to present with the syndrome, and these include finasteride, ketoconazole, the antiandrogen RU-58841 and minoxidil. In animals, Finasteride has been demonstrated to have significant systemic effects following topical application ​(Chen et al., 1995)​. Ketoconazole is antiandrogenic and suppressive of steroid production, exhibiting nonmonotonic activity. As with other imidazole azole class drugs, the extremely potent endocrine disruptive properties of ketoconazole are attracting increasing scrutiny given their prevalence as antifungal treatments ​(Munkboel et al., 2019)​. In vitro investigations have demonstrated minoxidil can directly bind to the AR, decrease transcriptional activity and interfere with AR function ​(Hsu et al., 2014)​. Additionally, minoxidil has been shown to significantly downregulate 5 alpha reductase type 2 expression in human keratinocytes ​(Pekmezci & Türkoğlu, 2017)​. A 28 year old patient member of our site recently received a diagnosis of “5 alpha reductase inhibitor syndrome” after one week of oral quercetin-3-O-rutinoside under physician direction led to the rapid development of persistent symptoms including severe muscle loss, increased adiposity, osteoporosis of the hip and lumbar spine, severe penile atrophy, post orgasmic illness, impotence, anxiety, depression and insomnia. Polyphenols can be potent 5alpha reductase inhibitors ​(Hiipakka et al., 2002)​ and antiandrogenic at the receptor level ​(Boam, 2015; Cicero et al., 2019; Kampa et al., 2017; Xing, 2001)​. Nordeen et al. noted the lack of data regarding purified concentrated flavonoid supplements, while providing evidence that two flavonoids, luteolin and quercetin, are “promiscuous endocrine disruptors” that demonstrate anti-androgenic effects, suggesting caution regarding the potential “peril” of supplementing these phenols far beyond the intake of a normal, healthy diet ​(Nordeen et al., 2013)​.

Fig. Finasteride, Accutane and SSRIs are all potent antiandrogenic endocrine disruptors.

While this large range of pharmaceutical and natural substances may seem broad and mechanistically distinct, the notable commonality is dramatic antiandrogenic endocrine disruption. Any treatments targeting the AR or suppressing androgens are known to have adverse effects on other critical physiological functions ​(Bourke et al., 2011)​. Narrow mechanistic perspectives often inform substance grouping for analysis of the risk of permanent male reproductive malformations and irreversible sexual disorders in the developing foetus. Through analysis of adverse outcome pathway networks, Kortenkamp illustrated that independent mechanistic effects from a very broad range of substances meet at nodal points in the network to result in common down-stream antiandrogenic effects and adverse outcomes. Kortenkamp suggested that – in addition to phthalates – substances capable of AR antagonism, cholesterol transporter down-regulation, and interruption or inhibition of steroidogenic or cholesterol synthesising enzymes should be included in an expanded consideration of substances capable of inducing male reproductive malformation. A non-exhaustive list of chemicals identified as a starting basis included vinclozolin, bisphenol A, finasteride, paracetamol, ibuprofen, ketoconazole and simvastatin (Kortenkamp, 2020).

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