Case Study: Adverse Side Effects of 5α-Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients

iwontgiveup · May 25, 2018, 6:37am

onlinelibrary.wiley.com/doi/10.1111/j.1743-6109.2010.02157.x/abstract

Adverse Side Effects of 5α-Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients

Abdulmaged M. Traish PhD1,
John Hassani MA1,
Andre T. Guay MD2,
Michael Zitzmann D, PhD3,
Michael L. Hansen MD4

Article first published online: 22 DEC 2010

DOI: 10.1111/j.1743-6109.2010.02157.x

Issue
The Journal of Sexual Medicine
The Journal of Sexual Medicine

Volume 8, Issue 3, pages 872–884, March 2011

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Keywords:

Finasteride;
Dutasteride;
Alopecia;
Benign Prostatic Hyperplasia;
Sexual Dysfunction Depression;
Gynecomastia

ABSTRACT

Introduction. 5α-reductase inhibitors (5α-RIs), finasteride and dutasteride, have been approved for treatment of lower urinary tract symptoms, due to benign prostatic hyperplasia, with marked clinical efficacy. Finasteride is also approved for treatment of hair loss (androgenetic alopecia). Although the adverse side effects of these agents are thought to be minimal, the magnitude of adverse effects on sexual function, gynecomastia, depression, and quality of life remains ill-defined.

Aim. The goal of this review is to discuss 5α-RIs therapy, the potential persistent side effects, and the possible mechanisms responsible for these undesirable effects.

Methods. We examined data reported in various clinical studies from the available literature concerning the side effects of finasteride and dutasteride.

Main Outcome Measures. Data reported in the literature were reviewed and discussed.

Results. Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men, raising the possibility of a causal relationship.

Conclusions. We suggest discussion with patients on the potential sexual side effects of 5α-RIs before commencing therapy. Alternative therapies may be considered in the discussion, especially when treating androgenetic alopecia. Traish AM, Hassani J, Guay AT, Zitzmann M, and Hansen M. Adverse side effects of 5α-reductase inhibitors therapy: Persistent diminished libido and erectile dysfunction and depression in a subset of patients. J Sex Med 2011;8:872–844.

iwontgiveup · May 25, 2018, 6:37am

Heres the guys who did the study:

Author Information

1

Departments of Biochemistry and of Urology, Boston University School of Medicine, Boston, MA, USA
2

Center for Sexual Function/Endocrinology Lahey Clinic, Northshore, Peabody, MA, USA
3

Centre for Reproductive Medicine and Andrology/Clinical Andrology Domagkstrasse 11 University Clinics Muenster, Germany
4

Department of OB/GYN, Stavanger University Hospital, Stavanger, Norway

iwontgiveup · May 25, 2018, 6:37am

ncbi.nlm.nih.gov/pubmed/21122055

Finasteride-induced depression: new insights into possible pathomechanisms.

Römer B, Gass P.

Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany. benediktroemer@hotmail.com
Abstract

5-alpha-reductase is involved as a rate-imitating enzyme in the metabolism of steroids. Several 5-alpha-reduced steroids such as dihydrotestosterone, allopregnanolone or tetrahydrocorticosterone have neurotrophic, neuroprotective, and anxiolytic properties. Reduced 5-alpha-reductase activity has been observed during depressive illness in humans. Finasteride inhibits 5-alpha-reductase and can robustly induce anxious and depressive behaviors in rodents. In humans finasteride treatment has been linked to an increase of depressive symptoms. A recent study reported that finasteride treatment inhibits hippocampal neurogenesis in mice. As hippocampal neurogenesis has been linked to emotional behavior, this could be of possible relevance for the pathophysiology of affective disorders. Further studies are needed to evaluate potential neuropsychiatric side effects of finasteride treatment in humans.

iwontgiveup · May 25, 2018, 6:37am

YK11 Is a Partial Agonist of the Androgen Receptor

The androgen receptor (AR) is a member of the nuclear receptor (NR) superfamily of ligand-dependent transactivation factors. AR is structurally characterized by an amino-terminal trans-activation domain [NTD/activation function 1 (AF1)], a DNA binding domain (DBD), and a ligand binding domain (LBD) including a carboxy-terminal transactivation domain [activation function 2 (AF2)].

In the absence of a ligand, AR is localized in the cytoplasm, where it forms complexes with chaperones. Upon ligand binding, AR translocates into the nucleus. Following nuclear translocation, AR binds to androgen responsive elements (ARE) in the promoter regions of its target genes as a homodimer. Generally, the transcriptional activity of nuclear receptors is modulated by their interaction with cofactors such as coactivators and corepressors. The type of ligand that binds to the receptor determines which type of cofactor is chosen. In the case of agonists, AR interacts with coactivators dominantly over corepressors, and vice versa in the case of antagonists.

Unlike other nuclear receptors, AR AF2 demonstrates weak transcriptional activity. However, ligand-dependent interaction between NTD and LBD/AF2 (which is termed as the N/C interaction) endows AR with synergistic transactivation potential. Thus, the N/C interaction is important for the ligand-dependent transactivation potential of AR.

In a preliminary screening for novel AR ligands, a steroid compound, (17a ,20E)-17,20-[(1-methoxyethylidene) bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11), behaved apparently as a partial agonist of AR in an ARE-luciferase reporter assay (unpublished data). In this report, they show that YK11 blocks the N/C-interaction required for the full-agonistic function of wild-type AR, inducing selective AR-target genes owing to the constitutive transactivation potential of AF-1 subdomain in endogenous AR-expressing MDA-MB 453 cells.

Kanno Y, Hikosaka R, Zhang SY, et al. (17alpha,20E)-17,20-[(1-Methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene -21-carboxylic Acid Methyl Ester (YK11) Is a Partial Agonist of the Androgen Receptor. Biol Pharm Bull 2011;34(3):318-23. jstage.jst.go.jp/article/bpb/34/3/318/_pdf

A novel steroid compound, (17alpha,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene -21-carboxylic acid methyl ester (YK11), was found to be a partial agonist of the androgen receptor (AR) in an androgen responsive element (ARE)-luciferase reporter assay. YK11 accelerates nuclear translocation of AR. Furthermore, YK11 does not induce amino/carboxyl-terminal (N/C) interaction and prevents 5-alpha-dihydrotestosterone (DHT)-mediated N/C interaction. Thus, YK11 activates AR without causing N/C interaction, which may in turn be responsible for the partially agonistic nature of YK11 observed in the ARE-luciferase reporter system. YK11 acts as a gene-selective agonist of AR in MDA-MB 453 cells. The effect of YK11 on gene expression relative to that of androgen agonist varies depending on the gene context. YK11 activated the reporter gene by inducing the translocation of the AR into the nuclear compartment, where its amino-terminal domain (NTD) functions as a constitutive activator of AR target genes. Our results suggest that YK11 might act as selective androgen receptor modulator (SARM).

Read more from the MESO-Rx Steroid Forum at: forum.mesomorphosis.com/mens-health-forum/online-first-134301507-17.html#ixzz1HlW9wxNJ

iwontgiveup · May 25, 2018, 6:37am

Irwig MS, Kolukula S. Persistent Sexual Side Effects of Finasteride for Male Pattern Hair Loss. The Journal of Sexual Medicine. Persistent Sexual Side Effects of Finasteride for Male Pattern Hair Loss - Irwig - 2011 - The Journal of Sexual Medicine - Wiley Online Library

Introduction. Finasteride has been associated with reversible adverse sexual side effects in multiple randomized, controlled trials for the treatment of male pattern hair loss (MPHL). The Medicines and Healthcare Products Regulatory Agency of the United Kingdom and the Swedish Medical Products Agency have both updated their patient information leaflets to include a statement that “persistence of erectile dysfunction after discontinuation of treatment with Propecia has been reported in post-marketing use.”

Aim. We sought to characterize the types and duration of persistent sexual side effects in otherwise healthy men who took finasteride for MPHL.

Methods. We conducted standardized interviews with 71 otherwise healthy men aged 21–46 years who reported the new onset of sexual side effects associated with the temporal use of finasteride, in which the symptoms persisted for at least 3 months despite the discontinuation of finasteride.

Main Outcome Measures. The types and duration of sexual dysfunction and the changes in perceived sexual frequency and sexual dysfunction score between pre- and post-finasteride use.

Results. Subjects reported new-onset persistent sexual dysfunction associated with the use of finasteride: 94% developed low libido, 92% developed erectile dysfunction, 92% developed decreased arousal, and 69% developed problems with orgasm. The mean number of sexual episodes per month dropped and the total sexual dysfunction score increased for before and after finasteride use according to the Arizona Sexual Experience Scale (P < 0.0001 for both). The mean duration of finasteride use was 28 months and the mean duration of persistent sexual side effects was 40 months from the time of finasteride cessation to the interview date. Study limitations include a post hoc approach, selection bias, recall bias for before finasteride data, and no serum hormone levels.

Conclusion. Physicians treating MPHL should discuss the potential risk of persistent sexual side effects associated with finasteride.

Read more from the MESO-Rx Steroid Forum at: forum.mesomorphosis.com/steroid-forum/fucked-finasteride-calling-all-134299629-9.html#ixzz1HlWv1OcY