Need documents for PAS, PFS, PSSD and diagnosis question

finasteride
ssri
research
isotretinoin
#1
  1. This is somewhat urgent as I need whatever documents you can find that shed light on our situations that we can show to doctors and other relevant people. I am going to meet a person tomorrow who works in drug control for my govt. Please link all the useful information you can find. I am a PAS sufferer but any info is welcome.

  2. We all have been to doctors and we all see our readings come back normal. Maybe its because we all do the same tests ( testo, prolactin, etc). But there has to be SOME reading, some indication in some test that will come abnormal for us. If we are able to find some abnormal reading, we can try to treat the cause of each abnormal reading and try to cure ourselves part by part indirectly. Has anybody done this? There has to be some test, please brainstorm here and we can all try to conduct these tests and find a pattern.

  3. There is a 60k $ prize pool on https://rxisk.org/ !!! I don’t understand why that money is just lying dormant waiting to be given IF someone does figure something out. Why hasn’t that money been used to conduct studies, conduct research. 60 K is not small, perhaps we might have already discovered something if this money just wasn’t sitting idle. Is anybody in contact with the team. Regardless, can we all try and get in touch with the team and start communicating.

#2

Well the Rxisk prize was designed to raise $100,000 dollars as an incentive to encourage researchers. They are going to award this to a researcher that can find a cure. Historically prizes like this have helped advance science, like the Longitude prize. The trouble is that the donations seem to have tailed off. It did say originally that if the target wasn’t met that they would give the amount donated to researchers. You should contact Dr David Healy who runs Rxisk and ask him about it, he normally is very responsive.

#3

I understand your statement. I think its better to use the collected funds to start some research instead of waiting for some miracle, especially when said miracle needs funds, interest, manpower.

#4

Oh yep I’m with you on that mate. I think it’s time they used the cash for research.

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#5

Here is a link to some relevant papers about PSSD:

http://postssrisexualdysfunction.blogspot.com/?m=1

Good luck guy ; )

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#6

This site is good! I will try to show him tomorrow.

#7

One of the formerly active post-Accutane advocates collated the following information to show doctors. You could try to copy/paste and edit for style before printing it out:

Accutane – Link with ED/Sexual Dysfunction

Isotretinoin (Accutane) direct link to ED/Sexual Dysfunction

Hogan, C., Le Noury, J., Healy, D., & Mangin, D. (2014). One hundred and twenty cases of enduring sexual dysfunction following treatment. The International Journal of Risk and Safety in Medicine , 26 (2), 109-116 .

  • There have been reports for over a decade linking serotonin reuptake inhibitors, finasteride and isotretinoin with enduring sexual dysfunction after treatment stops.

  • The availability of 120 reports from over 20 countries add to the case for the validity of the syndrome. This severe and enduring condition can result in death. An understanding of its physiology and an approach to treatment are needed.

Tirado, S. A., & León, D. G. (2005). Erectile dysfunction during isotretinoin therapy]. Actas urologicas españolas , 29 (10), 974.

  • 6 out of 20 (30%) of patients receiving isotretinoin developed erectile dysfunction during the study.

  • Only 2 out of 35 (5%) of the control group, receiving an antibiotic (minocycline), developed erectile dysfunction during the same study.

Other Retinoids Expressing Similar Side Effects

Rossi, M., & Pellegrino, M. (2009). Acitretin-associated erectile dysfunction: a case report. Cases journal , 2 (1), 210.

  • Retinoids have been associated with male reproductive system dysfunctions in human and animal studies. Clinicians should be aware of the possibility of acitretin-induced erectile dysfunction.

5-alpha-reductase activity & ED/Sexual Dysfucntion

Traish, A. M., Hassani, J., Guay, A. T., Zitzmann, M., & Hansen, M. L. (2011). Adverse Side Effects of Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients. The journal of sexual medicine , 8 (3), 872-884.

  • Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men.

Boudou, P., Soliman, H., Chivot, M., Villette, J. M., Vexiau, P., Belanger, A., & Fiet, J. (1995). Effect of oral isotretinoin treatment on skin androgen receptor levels in male acneic patients. Journal of Clinical Endocrinology & Metabolism , 80 (4), 1158-1161.

  • The present study clearly demonstrated a decrease in androgen receptor binding capacity … The isotretinoin-receptor complex may interact with cis-acting response elements in the promoter region of regulated genes, repressing the gene transcription encoding for the androgen receptor, the gene transcription encoding for the 5-alpha-reductase activity , or both transcriptions simultaneously .

  • No change in serum testosterone and significant decreases in 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 alpha,17 beta-diol glucosiduronate, and androsterone glucosiduronate levels were observed after treatment. Androgen receptor status was investigated in back skin biopsies obtained in acne areas before and after 3 months of isotretinoin treatment. The treatment did not modify the binding affinity constant of skin androgen receptor (0.44 vs. 0.32 nmol/L), but it did induce a 2.6-fold decrease in its binding capacity constant (62 vs. 24 fmol/mg cytosolic protein), as assessed by Scatchard plot and confirmed immunologically by Western blot analysis. These data clearly showed that skin androgen receptor was sensitive to oral isotretinoin administration in acneic patients. The decrease in skin androgen receptor levels (this study) and the recently reported suppression of skin 5 alpha-dihydrotestosterone production by isotretinoin treatment appeared consistent with the involvement of androgen receptor and 5 alpha-dihydrotestosterone in the pathogenesis of acne.

Boudou P, Chivot M, Vexiau P, Soliman H, Villette, J. M., Julien, R., … & Fiet, J. (1994). Evidence for decreased androgen 5 alpha-reduction in skin and liver of men with severe acne after 13-cis-retinoic acid treatment. The Journal of Clinical Endocrinology & Metabolism , 78 (5), 1064-1069.

  • Exploration of androgen metabolism in serum samples, 24-h urine collections, and skin biopsies obtained before and at the end of the treatment revealed no significant alterations in serum levels of either adrenal or gonadal androgens. However, the treatment did induce significant decreases in serum levels of the 5 alpha-reduced androgens: 5 alpha-dihydrotestosterone (P < 0.02), androsterone glucosiduronate (P < 0.04), and 5 alpha-androstan-3 alpha, 17 beta-diol glucosiduronate (P < 0.004).

  • It is concluded that 13-cis-RA therapy in men with severe nodulocystic acne did not alter gonadal or adrenal functions, but it did induce 1) a highly significant decrease in 5 alpha-dihydrotestosterone formation by skin biopsies; 2) significant decreases in serum 5 alpha-dihydrotestosterone, androsterone glucosiduronate, and 5 alpha-androstan-3 alpha, 17 beta-diol glucosiduronate; and, finally, 3) deviation of the liver androgen 5 alpha- to 5 beta-reduction pathway. The effect of 13-cis-RA treatment on severe acne is consistent with the dramatic decrease in androgen 5 alpha-reduction observed mainly in the skin.

Di Loreto C, La Marra F, Mazzon G, Belgrano E, Trombetta C, Cauci S. (2014). Immunohistochemical evaluation of androgen receptor and nerve structure density in human prepuce from patients with persistent sexual side effects after finasteride use for androgenetic alopecia. PLoS One. 2014 Jun 24;9(6):e100237. doi: 10.1371/journal.pone.0100237.

  • Finasteride is an inhibitor of 5-α-reductase used against male androgenetic alopecia (AGA). Reported side effects of finasteride comprise sexual dysfunction including erectile dysfunction, male infertility, and loss of libido. Recently these effects were described as persistent in some subjects.

  • This study was designed as a retrospective case-control study to assess if androgen receptor (AR) and nerve density in foreskin prepuce specimens were associated with persistent sexual side effects including loss of sensitivity in the genital area due to former finasteride use.* Density of nuclear AR in stromal and epithelial cells was higher in cases (mean 40.0%, and 80.6% of positive cells, respectively) than controls (mean 23.4%, and 65.0% of positive cells, respectively), P = 0.023 and P = 0.043, respectively. Conversely, percentage of vessel smooth muscle cells positive for AR and density of nerves were similar in the 2 groups. The ratio of AR positive stromal cells % to serum testosterone concentrations was 2-fold higher in cases than in controls (P = 0.001).

  • Our findings revealed that modulation of local AR levels might be implicated in long-term side effects of finasteride use.

  • It cannot be excluded, for example, that epigenetic changes [39][45] induced by finasteride use could have modified the transcriptional activity of AR present in the nuclei, which is potentially able to modulate around 500 AREs and 200 AR responsive genes [46].

  • Hypoandrogenism is believed to cause corpora cavernosa fibrosis through collagen fibres deposition and inhibition of nitric oxide synthases [50], [51]. Moreover, Zhang and colleagues [52] demonstrated that 5-α-R inhibitor therapy attenuates erectile function by promoting apoptosis in the cavernous smooth muscle cells of aged rats, suggesting a new role for androgen in maintaining the structural and functional integrity of the erectile organ.

Gur, S., Kadowitz, P. J., & Hellstrom, W. J. (2013). Effects of 5-alpha reductase inhibitors on erectile function, sexual desire and ejaculation. Expert opinion on drug safety , 12 (1), 81-90.

  • Clinical trials with 5ARI report prevalence rates of de novo erectile dysfunction of 5 - 9%. Decreased circulating dihydrotestosterone (DHT) resulting from 5ARI use is associated with diminished sexual desire and/or orgasm. The presence of adverse sexual effects is associated with decreased self-esteem, quality of life and ability to maintain an intimate relationship. Inhibition of 5ARI additionally influences progesterone and deoxycorticosterone levels and may alter psychological functions, including increased depression, melancholy and loss of general well being.

Öztekin, Ç. V., Gur, S., Abdulkadir, N. A., Lokman, U., Akdemir, A. Ö., Cetinkaya, M., & Hellstrom, W. J. (2012). Incomplete Recovery of Erectile Function in Rat after Discontinuation of Dual 5 Alpha Reductase Inhibitor Therapy. Journal of Sexual Medicine , 9 (7), 1773-1781.

  • In vivo erectile activity (intracavernosal pressure [ICP]/mean arterial pressure [MAP] and total ICP) in treatment groups were significantly decreased compared with controls

Traish, A. M., Hassani, J., Guay, A. T., Zitzmann, M., & Hansen, M. L. (2011). Adverse Side Effects of Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients. The journal of sexual medicine , 8 (3), 872-884.

“In 1999, a 24-year-old male was diagnosed with androgenetic alopecia (AGA). He had normal stature (height, 182cm; weight, 80kg), had no history of any medical illness, and was not taking any medications. He reported having a normal sex drive and normal erectile capacity. He started treatment with finasteride (Propecia™), 1mg daily, and within 2–5 days experienced soreness of the testicles, total lack of sex drive, and complete inability to achieve an erection. He had difficulty concentrating and felt depressed. Expecting these initial side effects to be temporary, he continued treatment. Except for some improvement of the soreness in the testicles, he felt numbness and there was no improvement in his sex drive or erectile function. After a little more than 1 month, he discontinued treatment and the side effects diminished to some degree, but sexual function never returned to normal. In the following months and years, the symptoms persisted with loss of libido and erectile dysfunction (ED). In 2003, the patient consulted a specialty clinic for sexual medicine in Boston, MA, USA, and went through extensive examinations. At this point, treatment with Viagra had been tried with only marginal success. Because of hopelessness and depression, two types of antidepressants (citalopram and bupropion) had been prescribed, which helped by “taking away the deepest lows,” but with no improvement in either libido or erectile capacity. In addition, there were undesirable side effects to these drugs and treatment was discontinued after several months. In Boston, the patient had a psychological evaluation and underwent duplex Doppler ultrasonography.

Suffering from persistent symptoms of ED, loss of libido, and depression, the patient consulted a clinic in Copenhagen, Denmark, which specializes in testosterone treatment. The total testosterone (T) varied between 22.6 and 14.2 nmol/L (651 and 409 ng/dL) in the baseline state. The fluctuations were felt to be quite wide. No 5 α-dihydrotestosterone (5 α-DHT) measurements were available. The following baseline tests were all found to be normal: sex hormone binding globulin, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, T3, T4, prolactin, estradiol, dehydroepiandrosterone sulfate (DHEA-S), and androstenedione. He is currently under no treatment, but 11 years later, he still suffers from ED and loss of libido.”

Erdemir, F., Harbin, A., & Hellstrom, W. J. (2008). 5 Alpha Reductase Inhibitors and Erectile Dysfunction: The Connection. The journal of sexual medicine , 5 (12), 2917-2924.

  • The connection between 5ARIs and sexual dysfunction is apparent upon review of the literature.

Other Hypogonadal Side Effects

Ustun, I., Rifaioglu, E. N., Sen, B. B., Inam, M. U., & Gokce, C. (2013). Gynecomastia: a rare complication of isoretinoin?. Cutaneous and ocular toxicology , 32 (1), 93-94.

  • Development of gynecomastia after isotretinoin treatment.

Persistence of Side Effects
Csoka, A. B., & Szyf, M. (2009). Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Medical hypotheses , 73 (5), 770-780.

  • Here we present the hypothesis that commonly-used pharmaceutical drugs can cause such persistent epigenetic changes. Drugs may alter epigenetic homeostasis by direct or indirect mechanisms. Direct effects may be caused by drugs which affect chromatin architecture or DNA methylation. For example the antihypertensive hydralazine inhibits DNA methylation. An example of an indirectly acting drug is isotretinoin , which has transcription factor activity. A two-tier mechanism is postulated for indirect effects in which acute exposure to a drug influences signaling pathways that may lead to an alteration of transcription factor activity at gene promoters. This stimulation results in the altered expression of receptors, signaling molecules, and other proteins necessary to alter genetic regulatory circuits. With more chronic exposure, cells adapt by an unknown hypothetical process that results in more permanent modifications to DNA methylation and chromatin structure, leading to enduring alteration of a given epigenetic network. Therefore, any epigenetic side-effect caused by a drug may persist after the drug is discontinued.

  • The following adverse effects have been reported to persist, even after discontinuing therapy, suggesting persistent (or perhaps slowly-reversing) gene expression changes and epigenetic effects: alopecia, arthralgias, ocular abnormalities, inflammatory bowel disease, keloids, osteopenia, hyperlipidemia, erectile dysfunction, and psychiatric disturbances. Isotretinoin is postulated to have complex effects on the brain and central nervous system."

Effects on Brain (brief)

Melcangi, R. C., Caruso, D., Abbiati, F., Giatti, S., Calabrese, D., Piazza, F., & Cavaletti, G. (2013). Neuroactive Steroid Levels are Modified in Cerebrospinal Fluid and Plasma of Post Finasteride Patients Showing Persistent Sexual Side Effects and Anxious/Depressive Symptomatology. The journal of sexual medicine , 10 (10), 2598-2603.

  • The present results show for the first time, that persistent sexual side effects and anxious/depressive symptomatology despite discontinuation of finasteride are associated with changes in cerebrospinal fluid (CSF) and plasma levels of neuroactive steroids. In particular, in CSF we observed a decrease in metabolites of PROG and T, such as THP, isopregnanolone, and DHT, associated with an increase in T and 17β-E. In contrast, in plasma, a decrease in DHP levels associated with an increase of 3α-diol and 17β-E was observed.

  • Altogether, these results provide a molecular basis for the anxious/depressive symptomatology occurring despite discontinuation of finasteride treatment.

Bremner, J. D., Fani, N., Ashraf, A., Votaw, J. R., Brummer, M. E., Cummins, T., … & Nemeroff, C. B. (2005). Functional brain imaging alterations in acne patients treated with isotretinoin. American Journal of Psychiatry , 162 (5), 983-991.

  • RESULTS: Isotretinoin but not antibiotic treatment was associated with decreased brain metabolism in the orbitofrontal cortex (–21% change versus 2% change for antibiotic), a brain area known to mediate symptoms of depression.

Kontaxakis, V. P., Skourides, D., Ferentinos, P., Havaki-Kontaxaki, B. J., & Papadimitriou, G. N. (2009). Isotretinoin and psychopathology: a review. Ann Gen Psychiatry , 8 (2).

  • Strongly suggests a link between isotretinoin and psychopathology.

Strahan, J. E., & Raimer, S. (2006). Isotretinoin and the controversy of psychiatric adverse effects. International journal of dermatology , 45 (7), 789-799.

  • Isotretinoin disrupts the birth of new hippocampal cells.

The only blood marker found to be generally low (but still often within the broad reference range) in PFS patients was androstanediol glucuronide, which fits in with this condition according to the original theory paper that the PFS research is based around.

It is doubtful that your doctor would accept this as a diagnostic marker; though, it wouldn’t hurt to have another PAS patient have this tested.

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#8

From the Kontaxakis paper:

13-cis Retinoic acid (isotretinoin) binds weakly to the RA receptors. However, there is evidence that 13-cis retinoic acid is isomerised to all-trans retinoic acid in tissues and thus acts like all-trans retinoic acid to regulate transcription via the RA receptors [51]. RA receptors are distributed widely in the adult brain [48,49]. However, RA itself is much less widely distributed [52]. The regions of the brain that exhibit RA signalling include the limbic system, in particular the hippocampus and the medial prefrontal cortex, the cingulate cortex and subregions of the thalamus and hypothalamus [48,49].

Pretty much seems to point to one of the reasons for the mental issues.

What do you make about what we can do regarding these RA receptors?

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