anybody have suspicious drugs like urination medicine on childhood ? Maybe we can find some common stories. eg. i took an urination medicine while i was 5
Itβs not this.
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Yeah no connection. I took nothing besides minor antibiotics for infections. Took Prozac for a short period of time and Zyrtec. Nothing other than that. Went from a lean, dense, confident stud to a soft chubby fuck with crippling brain fog and anxiety.
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i taked escitalopram before accutane. may be everybody was take ssri before fin ?
No SSRIs prior to fin. I had regular steroid injections for rheum arthritis which im convinced predisposed me.
I took accutane before SSRIs, but I doubt theres a connection
common point. know you anybody who had accutane and ssri but not had pssd ?
Fin was the only prescription drug I ever took besides a few antibiotics as a kid.
The accutane never gave you lasting side effects?
No it didnt, got lucky with that one⦠Not so lucky with the ssris.
my state same you. i used SSRI and not get PSSD. After use iso and get PAS.
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arrows again point to serotonin
Noβ¦ Have you not read the PFS paper? It explains what the commonality between these substances is. Theyβre all anti-androgens. The issue most likely stems from sex hormone receptor malfunction.
you said SSRI linked androgens ?
Yes, SSRIs are anti androgenic.
i didnt know
can you send me an article
The administrators of this forum have published an extensive paper on PFS and the commonality between finasteride, isotretinoin and SSRIs
Of particular relevance to your question
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 β(Melnik, 2017)β. 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 β(Boudou et al., 1995)β. Boudou et al. had previously illustrated that skin biopsies of eight men with severe acne treated with 3 months of isotretinoin βlost 80% of their ability to form 5 alpha-dihydrotestosterone (P <0.001)β β(Boudou et al., 1994)β.
AR signal transduction is crucial to acne pathogenesis, stimulating the size of sebocytes and sebum production as well as proliferation of keratinocytes β(Lai et al., 2012)β. IGF-1/PI3K/AKT-mediated inactivation of Forkhead box O1 (FoxO1) is vital to androgen receptor transactivation β(Fan et al., 2007)β. FoxO1 is repressive of AR owing to FoxO1βs inhibition of AR N/C terminal interaction (Q. Ma et al., 2009). IGF-1 has correlated to acne severity β(Cappel, 2005)β and isotretinoin decreases IGF-1 β(A.S. Karadag et al., 2009)β. As IGF-1 is inhibitory of AR β(Palazzolo et al., 2009; Yanase & Fan, 2009)β, 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 β(Ayse Serap Karadag et al., 2015)β. As with other anti-acne therapies, Isotretinion enhances p53 expression β(Melnik, 2017)β, which supresses AR expression β(Alimirah et al., 2007; Shenk et al., 2001)β. Additionally, p53 activates and increases FoxO1 expression β(Pappas et al., 2017)β. Human primary keratinocytes treated with isotretinoin show an increase in FoxO1 β(Shi et al., 2018)β, and significant increases in nuclear levels of FoxO1 protein are reported in skin biopsies from acne patients following isotretinoin treatment β(Agamia et al., 2018)β. In vitro evidence demonstrates all-trans retinoic acid profoundly downregulates the AR and abolishes the induction of androgen-induced functions β(Ubels et al., 2002, 2003)β, 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 β(Atli et al., 2017; Ilgin et al., 2017; Tanrikut et al., 2010)β. Fluoxetine is known to be endocrine disruptive, with evidence of nonmonotonic effects β(Cunha et al., 2018; Vandenberg et al., 2012)β. Rats administered Fluoxetine display delayed sexual development and decreased sexual behaviours β( Drugs@FDA, 2016)β. Griffin and Mellon found the enzymatic efficiency of 3Ξ±-HSD conversion of DHT to androstanediol increased 163-fold when the enzyme was incubated with fluoxetine and 63-fold with paroxetine β(Griffin & Mellon, 1999)β, 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 β(Hansen et al., 2017)β. A similar decrease in testosterone in this cell line following exposure to five SSRI drugs had previously been reported β(Jacobsen et al., 2015)β. 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 β(Munkboel et al., 2018)β.
Serotonin is recognised to be inhibitory of both male and female sexual behaviour and function β(Croft, 2017; Iovino et al., 2019; Olivier et al., 2010)β. SSRIs increase inhibition of serotonin reuptake β(Ferguson, 2001)β, and increase serotonin by a downregulation of autoreceptors which otherwise act to inhibit serotonin release β(Hagan et al., 2012; Neumaier, 1996)β. 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 β(FerrΓ©s-Coy et al., 2012)β. Increased extracellular serotonin levels in the ventral hippocampus of 5HT1b knockout mice were observed in response to SSRI administration β(Nautiyal et al., 2016)β. As well as reuptake inhibition, SSRIs have been observed to upregulate tryptophan hydroxylase β(Kim et al., 2002)β, mediatory of serotonin production in non-neuronal and neuronal tissue β(Walther, 2003; X. Zhang, 2004)β.
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 β(Ambar & Chiavegatto, 2009; Daly et al., 2001; Keleta et al., 2007; Martinez-Conde et al., 1985; Sundblad & Eriksson, 1997; L. Zhang et al., 1999)β. Testosterone promotes territorial behaviour, impulsivity, sexual behaviour and aggression β(Bing et al., 1998; Kimura & Hagiwara, 1985; Svensson, 2003; Wu & Shah, 2011)β, whereas serotonin appears to exert opposite effects β(Batty & Meyerson, 1980; Nelson & Chiavegatto, 2001; Olivier et al., 2010)β. 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 βirrelevantβ in the absence of testosterone. Additionally, inhibition of serotonin production failed to reinstate aggression in mice rendered hypoaggressive by early life brain AR knockout β(Studer et al., 2015)β.
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 β(Izumi et al., 2013; Nicholson et al., 2013; P. Zhang et al., 2015)β as well as a significant depletion of 5-HT β(Cockett et al., 1993)β. 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 Tph1β/β 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 β(Carvalho-Dias et al., 2017)β.
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 β(Joy et al., 2008)β. This is suggestive of increased production of serotonin following 5-HTP intake, which is the rationale underlying its supplemental use β(Hallin et al., 2012)β.
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 β(Cicero et al., 2019)β, is the most prevalent alternative therapy causative of the syndrome. This is usually taken as a βnaturalβ 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 β(Chen et al., 1995)β. 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 β(Munkboel et al., 2019)β. In vitro investigations have demonstrated minoxidil can directly bind to the AR, decrease transcriptional activity and interfere with AR function β(Hsu et al., 2014)β. Additionally, minoxidil has been shown to significantly downregulate 5 alpha reductase type 2 expression in human keratinocytes β(Pekmezci & TΓΌrkoΔlu, 2017)β. A 28 year old patient member of our site recently received a diagnosis of β5 alpha reductase inhibitor syndromeβ 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 β(Hiipakka et al., 2002)β and antiandrogenic at the receptor level β(Boam, 2015; Cicero et al., 2019; Kampa et al., 2017; Xing, 2001)β. Nordeen et al. noted the lack of data regarding purified concentrated flavonoid supplements, while providing evidence that two flavonoids, luteolin and quercetin, are βpromiscuous endocrine disruptorsβ that demonstrate anti-androgenic effects, suggesting caution regarding the potential βperilβ of supplementing these phenols far beyond the intake of a normal, healthy diet β(Nordeen et al., 2013)β.
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 β(Bourke et al., 2011)β. 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 β in addition to phthalates β 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).
thanks
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