Adverse effects of 5α-reductase inhibitors: What do we know, don't know, and need to know?

Rev Endocr Metab Disord (2015) 16:177198
DOI 10.1007/s11154-015-9319-y
Adverse effects of 5-reductase inhibitors: What do we know,

dont know, and need to know?
Abdulmaged M. Traish 1 & Roberto Cosimo Melcangi 2 & Marco Bortolato 3 &
Luis M. Garcia-Segura 4 & Michael Zitzmann 5
Published online: 23 August 2015

# Springer Science+Business Media New York 2015
Abstract Steroids are important physiological orchestrators

of endocrine as well as peripheral and central nervous system
functions. One of the key processes for regulation of these
molecules lies in their enzymatic processing by a family of
5-reductase (5-Rs) isozymes. By catalyzing a key ratelimiting step in steroidogenesis, this family of enzymes exerts
a crucial role not only in the physiological control but also in
pathological events. Indeed, both 5-R inhibition and supplementation of 5-reduced metabolites are currently used or
have been proposed as therapeutic strategies for a wide array
of pathological conditions. In particular, the potent 5-R inhibitors finasteride and dutasteride are used in the treatments
of benign prostatic hyperplasia (BPH), as well as in male
pattern hair loss (MPHL) known as androgenetic alopecia
(AGA). Recent preclinical and clinical findings indicate that
5-R inhibitors evoke not only beneficial, but also adverse
effects. Future studies should investigate the biochemical
and physiological mechanisms that underlie the persistence
of the adverse sexual side effects to determine why a subset
of patients is afflicted with such persistence or irreversible

adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to
be adversely affected by such agents. Furthermore, research
on the non-sexual adverse effects such as diabetes, psychosis,
depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit
during their use in treatment of AGA or BPH. In this review,
we will summarize the state of art on this topic, overview the
key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and
highlight the need for further studies to ascertain the severity
and duration of the adverse effects of 5-R inhibitors, as well
as their biological underpinnings.
Keywords 5-Reductases . Finasteride . Dutasteride .
Sexual dysfunction . Adverse effects . Neurosteroids . Benign
prostate hyperplasia
1 Introduction
* Abdulmaged M. Traish
atraish@bu.edu
1
Department of Biochemistry and Department of Urology, Boston

University School of Medicine, 715 Albany Street, A502,
Boston, MA 02118, USA
Department of Pharmacological and Biomolecular Sciences- Center

of Excellence on Neurodegenerative Diseases, Iniversit degli Studi
di Milano, Milan, Italy
Department of Pharmacology and Toxicology, University of Kansas,

Lawrence, KS, USA
Instituto Cajal, C.S.I.C, E-28002 Madrid, Spain
Centre for Reproductive Medicine and Andrology, University Clinics

Muenster, Domagkstrasse 11, D-48149 Muenster, Germany
New emerging evidence in the literature suggests that finasteride and dutasteride may have important and serious
adverse side effects, such as sexual dysfunction, depression,
diabetes, high grade prostate cancer and vascular disease. In
this review we examined the potential role of 5-reductase
inhibitors (5- RIs) therapy on the presence and persistence
of adverse sexual side effects and on various pathologies. We
critically evaluated the contemporary data in the clinical literature with regard to the frequency and persistent adverse sexual side effects. Of critical importance was the issue of persistence of these sexual side effects and whether the evidence
presented is sufficient to warrant action or additional evidence
is needed before reaching such conclusions. There is a critical
178
need to evaluate the current clinical approaches of patient

management, especially those who report severe sexual adverse effects attributed to 5-RIs therapy. This review presents the summary of the data currently available in the contemporary medical literature and the impact of 5-RIs therapy
on sexual function and the important role of this family of
enzymes in the biosynthesis and metabolism of neuro-active
steroids in the peripheral and central nervous system and the
pathologies that may result from interference with the activities of these enzymes in response to 5-RIs therapy.
Finasteride and Dutasteride are selective inhibitors of 5Rs and were introduced as therapeutic agents for the treatment
of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH) in 1992 and 2002, respectively. In the prostate, these agents inhibit the conversion of
testosterone (T) to 5-dihydrotestosterone (5-DHT), a potent androgen receptor ligand. Finasteride and dutasteride result in reduction in the concentrations of 5-DHT in the prostate tissue causing decreased prostate volume due to inhibition
of epithelial cell growth and therefore attenuating the obstruction of urine flow, providing symptomatic relieve. This therapeutic approach reduces incidence of prostate surgery due to
large prostate volume in cases of urinary retention. Finasteride
was also approved for treatment of androgenetic alopecia
(AGA) in early 2000. These agents are currently taken by
approximately more than 30 million men for the treatment of
BPH and AGA. Although these medications are proven useful
in the management of BPH symptoms and reducing surgery,
there is now growing concern for the observed serious and
adverse sexual side effects, which have been adequately appreciated by the medical community.
As will be discussed further, while these drugs have proven
useful in treatment of lower urinary tract symptoms (LUTS) of
BPH and in hair restoration, the concern remains that in a
subset of patients these agents may not be effective and may
be associated with increased sexual adverse side effects, potential insulin resistance and diabetes, depression and cognitive dysfunction. Here we wish to highlight the potential adverse effects of these agents and raise awareness among the
medical community to appreciate the impact of such adverse
effects on their patients, especially since some of these adverse
effects are potentially persistent or irreversible.
transformation of multiple gonadal, adrenal and CNS produced steroid precursors into active functional hormones and
neuro-active steroids [1, 2].
Based on the analysis of primary DNA sequences, the family of 5-Rs is currently thought to encompass five enzymes,
including the three main 5-R isotypes (1, 2, and 3) and the
two trans-2,3 enoyl-CoA reductases (TECR and TECR-like)
[2, 3]. To date, no genetic deficiency has been reported for 5R type 1 enzyme. In contrast, the clinical consequences of
congenital 5-R type 2 deficiencies are well characterized
and consist in alterations of sexual differentiation [410]. Mutations in 5-R type 3 have also been described, and are associated with mental retardation and visual disturbances
[1114]. Although TECR mutations were recently associated
with mental retardation [15] the functions of this protein (as
well as TECRL) are still poorly understood, and no information is currently available on its relevance in steroidogenesis.
5-Rs catalyze the reduction of the double bond in the A ring
at the 4,5 position in C19 and C21 steroids. 5-Rs transfer a
hydride from NADPH to the 5 position of the steroid precursor
to generate its 5-reduced metabolite [16]. The substrates for 5Rs include T, progesterone (PROG), deoxycorticosterone
(DOC), corticosterone, cortisol and aldosterone. The products
of these reactions result in formation of 5-dihydro-derivatives
such as 5-DHT, 5-dihydroprogesterone (5-DHP) and 5dihydrodeoxycorticosterone (5-DHDOC), 5dihydrocorticosterone, 5-dihydrocortisol and 5dihydroxyaldosterone. The latter two metabolites are thought to
act as potential active mineralocorticoids [17].
Interestingly, as shown in Fig. 1, 5-Rs reaction is the ratelimiting step in the synthesis of 3, 5 steroid derivatives [2,
18]. Thus, the products of 5-Rs reactions often serve as substrates for 3-hydroxysteroid oxidoreductase (3-HSOR) and
3-hydroxysteroid oxidoreductase (3-HSOR) enzymes [10].
3-HSOR transforms 5-DHT to 3, 5-androstane, 17-diol
(3-diol), 5-DHP to 3, 5-tetrahydroprogesterone (THP; also
known as allopregnanolone), and 5-DHDOC to 3, 5tetrahydrodeoxycorticosterone (THDOC). 3-HSOR transforms
5-DHT to 3,5-androstane, 17-diol (3-diol) and 5-DHP
to isopregnanolone.
3 Peripheral physiological effects of 5-Rs activities

2 Role of 5-Rs in steroidogenesis
5-Rs are a family of isozymes expressed in a wide host of
organs and tissues, including the central nervous system
(CNS). 5-Rs serve a primary role in the regulation of development and physiology of male sexual differentiation and
metabolism [1]; in addition, these enzymes are implicated in
a host of biochemical pathways across various tissues and
organs. One of the major reactions of 5-Rs is the
The 5-Rs are involved in a host of physiological processes

via participation in the metabolism of sex steroid and glucocorticoid hormones [1]. By transformation of T to 5-DHT,
5-R type 2 plays an essential role in the development and
maintenance of male sexual organs [19]. In addition, 5-Rs
participate in the action of T in other tissues, including the
skin, muscle and adipose tissue among others [2022].
Glucocorticoids (GCs) mediate their physiological responses through various metabolic and immunologic
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Fig. 1 5-reductases catalyze a

critical rate limiting step in
steroidogenesis. Enzymes: 3hydroxysteroid dehydrogenase
(3-HSD); 3-hydroxysteroid
dehydrogenase (3-HSD): 17hydroxysteroid dehydrogenase
(17-HSD); Aldosterone
synthase (CYP11B2); Steroid
11-hydroxylase (CYP11B1);
Steroid 21-hydroxylase
(CYP21A2):17-hydroxylase/
17,20 lyase (CYP17A1).
Steroids: 5-Dihydroaldosterone
(5-DHAldo); 3,5Tetrahydroaldosterone
(3,5-THAldo); 5Dihydrocorticosterone
(5-DHB); 3,5Tetrahydrocorticosterone
(3,5-THB);
Deoxycorticosterone (DOC);
5-Dihydro deoxycorticosterone
(5 -DHDOC); 3,5Tetrahydrodeoxycorticosterone
(3,5-THDOC); 5Dihydroprogesterone (5-DHP);
3,5-Tetrahydroprogesterone
(allopregnanolone; AP);
Dehydroepiandrosterone
(DHEA); 5-Dihydrotestosterone
(DHT); 5-Androstane-3,17
-diol (3-diol)
signaling mechanisms. GCs regulate carbohydrate metabolism, gluconeogenesis and lipolysis. GCs are metabolized by
reduction of the A ring via 5-Rs and then cleared via specific
pathways involving conjugation and excretion. The principal
urinary metabolites of cortisol and cortisone are
tetrahydrocortisol and tetrahydrocortisone, cortols and
cortolones [23].
Aldosterone is also metabolized and cleared via conversion
to tetrahydroaldosterone. 5- and 5-Rs, 6 -hydroxylases,
20-reductases, and 11 -hydroxy-steroid dehydrogenases
(11-HSD) are key enzymes involved in GCs metabolism
and clearance mechanisms [23]. The majority of cortisol is
inactivated, principally via the A-ring reduced metabolites,
on a single pass through the liver [24]. However, this inactivation is offset by reactivation of cortisone into cortisol by
hepatic 11-HSD type 1; thus, the overall changes in the
gradient of cortisol in liver may be relatively small. An increase in the level of circulating cortisol may be related to
stimulation of 11-HSD type 1 or by inhibition of 5- or
5-R due to administration of 5-R inhibitors (5-R
inhibitors) in patients with BPH. The balance between the
activities of these enzymes maintains the physiological concentration of active GCs [2527].
4 Functions of 5-Rs in the central nervous system

The finding that both central and peripheral nervous systems
are able to synthesize several classes of steroids (generically
termed neurosteroids) from cholesterol is now a wellascertained concept [2833]. A schematic representation of
the major metabolic pathways of neurosteroids is represented
180
in Fig. 2. On the other hand, the nervous system is not only a

target for brain-borne steroids (i.e., neurosteroids) but also for
steroid hormones synthesized in the peripheral glands; therefore
the term Bneuroactive steroids^ which includes both steroid hormones and neurosteroids, for steroids affecting nervous functions
is commonly used [2833]. The main precursor of all steroids is
cholesterol, which is converted into pregnenolone (PREG) by
cytochrome P450 side-chain cleavage (CYP450scc). PREG is
then further transformed into PROG by the action of the enzyme
3-hydroxysteroid dehydrogenase (3-HSD) [28]. PROG undergoes multiple metabolic processes, mediated by different enzymes expressed in neurons, astrocytes, oligodendrocytes and
Schwann cells [34]. As mentioned above, one of the most predominant and best-characterized enzymatic reactions of PROG
metabolism is its transformation into 5-DHP by 5-R, and then
into 3,5-THP or isopregnanolone by 3-HSOR and 3HSOR, respectively [28]. Alternative to this metabolic pathway,
both PREG and PROG can serve as substrates for cytochrome
P450 17A1, which converts them into their respective 17hydroxylated metabolites and then into dehydroepiandrosterone
(DHEA) and androstenedione [28]. These steroids are further
converted into T and other androgens by 17-hydroxy steroid
dehydrogenase (17-HSD).
Similar to PROG, in neurons and glial cells T is then converted by the 5-Rs into 5-DHT [35] and subsequently by the
action of 3-HSOR or 3-HSOR into 3-diol or 3-diol, respectively [36]. It is worth noting that, in neurons and glia, androstenedione and T can also be respectively converted into estrone and 17-estradiol (17-E2) by cytochrome 19A1 (aromatase, ARO) [37]. While estrone mediates its effects through activation of the -estrogen receptor (ER), 17-E2 also activates
estrogen receptor (ER) and the membrane receptor GPER1.
The metabolism of PROG and T into their numerous derivatives has a critical physiological impact on the mechanism
of action of neuroactive steroids, through the involvement of
multiple receptors and signalling pathways. For example,
while PROG and 5-DHP interact with the classical PROG
receptor (PR), THP is a potent ligand of a non-classical steroid
receptor, such as GABA-A receptor [38, 39] . Conversely,
isopregnanolone, albeit unable to bind directly to GABA-A,
can antagonize the effect of THP on this receptor [28]. In
addition to these well-known mechanisms, emerging lines of
evidence are revealing a number of novel receptors that may
contribute to the effects of PROG and THP. For example,
PROG has been shown to bind to a number of membrane
receptors, including the family of membrane PROG receptors
(mPRs) and the progesterone membrane receptor component
1 (PGRMC1), which are abundantly distributed in several
brain regions [4042]. Furthermore, several effects of
THP appear to be mediated by mPRs and by the
pregnane X receptor (PXR) [42], as well as the modulation of the glutamate N-methyl-D-aspartate (NMDA)
receptor.
A similar variety of receptor-mediated mechanisms has been

shown for T and its 5-reduced metabolites; whereas 5-DHT
and T activate androgen receptors (AR), 3-diol and 3-diol
act as a positive allosteric modulator of GABA-A receptor and
an ER agonist, respectively [28, 43]. Although several authors
posited the involvement of membrane-bound receptors to account for several rapid actions of T, the molecular identity of
these targets remains currently elusive [44].
From this perspective, it is apparent that 5-Rs play a key
role in modulating the functions and signalling mechanisms of
neurosteroids in the brain, by enabling the conversion of
PROG and T into numerous neuroactive metabolites that can
modulate brain functions and behaviour through the action of
a broad array of receptors. Indeed, during development, 5-Rs
participates in the generation of T-induced sex differences in
the brain by the generation of 5-DHT [45]. In the adult brain,
5-Rs may mediate some of the rewarding effects of androgens [46] and is required for the inhibition exerted by T on the
response of the hypothalamo-pituitary-axis to stress [47].
5 Other physiological functions of 5-Rs

In addition to their abilities to transform steroids to 5-reduced
metabolites, 5-R type 3 (SRD5A3) catalyzes the reduction of
the terminal double bond of polyprenols to generate dolichols,
the precursor of dolichol phosphate [11]. The latter substrate is a
prerequisite for N-glycosylation of proteins. Dolichol phosphate
is required for the synthesis of dolichol-linked monosaccharides,
and oligosaccharide precursors employed in N-glycosylation.
Mutations in this enzyme appear to be involved in a number of
significant human pathologies [1114, 48, 49]. As mentioned
above, mutations in this enzyme has produced mental retardation
and opthalmologic and cerebral defects [11]. Indeed, several case
reports have suggested that inhibition of 5-Rs may contribute to
Intraoperative Floppy Iris Syndrome (IFIS) indicating possible
inhibition of N-glycosylation, thus contributing to this pathology
[50]. The loss of activity of this enzyme in the central nervous
system and the relationship to mental retardation is a subject of
intensive investigation.
6 Therapeutic indications of 5-Rs inhibitors

The development of 5-RIs was stimulated by the finding that
5-DHT promotes prostate trophism, and 5-R type 2 deficiency resulted in a lower prevalence of male-pattern alopecia. The
prototypical 5-RIs, finasteride, 17-(N-tert-butylcarbamoyl)-4aza-5-androst-1-en-3-one; Proscar, was originally characterized as a compound with relatively high selectivity for 5-R type
2 over 5-R type1 [51]. This drug proved to be highly effective
in reducing levels of 5-DHT and the progression of BPH, and
was approved for this use in 1992. In 1997, finasteride (under the
Fig. 2 Schematic representation of biosynthesis of steroids and neurosteroids from cholesterol and potential interaction of steroids and neurosteroids with their cognate receptors. Cholesterol is metabolized by the
CYP450scc enzyme resulting in cleavage of the cholesterol side chain and
producing pregnenolone. Pregnenolone serves as a substrate for the enzyme
CYP 450-17A1 which hydroxylates pregnenolone at the 17-positon
resulting in 17 hydroxypregnenolone. Pregnenolone is also metabolized
via 3 hydroxy steroid dehydrogenase (3-HSD) resulting in isomerization
of 5 to 4 double bond, producing progesterone. Hydroxylation of pregnenolone at the 17-position by the enzyme CYP450-17A1 and subsequent
cleavage of the two-carbon atom chain by the same enzyme complex produces dehydroepiandrosterone (DHEA). Progesterone is also metabolized by
the enzyme CYP450-17A1, which results in hydroxylation at the 17position followed by cleavage of the two-carbon atom chain and producing
Androstenedione. DHEA can be converted to Androstenedione by 3-HSD.
Androstenedione is metabolized via the CYP450 19A1 (aromatase) to produce estrone, which can be converted to estradiol via 17-hydroxysteroid
dehydrogenases. Similarly, Androstenedione is converted to testosterone via
17 -hydroxysteroid dehydrogenase. Testosterone serves as a substrate for
CYP450 19A1 (aromatase) to produce estradiol. Estradiol is the most potent
native estrogen, which binds to the classical estrogen receptor alpha (ER)
and estrogen receptor beta (ER). Estradiol also binds to as yet fully
uncharacterized membrane receptors. Testosterone is transformed by the family of 5-reductases to the potent androgen 5-dihydrotestosterone (5DHT). Both testosterone and 5-DHT bind specifically and with high affinity
to the androgen receptors (AR) in various target tissues. 5-DHT also servers
as a substrate for 3 and 3 hydroxy steroid oxidoreductases (3 and 3HSOR) and result in 3, 5-androstenediol or 3,5-androstenediol. These
181
neurosteroids interact with GABA-A receptors and also with Estrogen

receptors. Progesterone is a potent ligand for the classical progesterone receptors and also binds membrante progesterone receptors (mPRs). Progesterone
also undergoes metabolism via 5-reductases to produce 5dihydroprogesterone (5-DHP). The latter undergoes further metabolism
by 3-HSOR or 3HSOR to produce the neuroactive steroids,
allopregnanolone or Isopregnanolone, respectively. These neuroactive steroids interact with progesterone X receptors (PXR) and GABA-A receptors
and elicit a host of physiological responses. Abbreviations: 5 -reductases, 5
-Rs. Androgenetic alopecia, AGA. Benign prostatic hyperplasia, BPH.
Lower urinary tract symptoms, LUTS. Central Nervous System, CNS.
Tran s-2 ,3 eno yl-C oA redu ctas es, TEC R a nd TECR -lik e.
Deoxycorticosterone, DOC. 5-dihydroprogesterone, 5-DHP. 5 -dihydrotestosterone, 5-DHT. 5-dihydrodeoxycorticosterone, 5-DHDOC. 3hydroxysteroid oxidoreductase, 3-HSOR. Glucocorticoids, GCs. 11 hydroxy-steroid dehydrogenases, 11-HSD. 3-hydroxysteroid dehydrogenase, 3-HSD. 17-hydroxy steroid dehydrogenase, 17-HSD.
Tetrahydroprogesterone (allopregnanolone), THP. Testosterone, T. 17-estradiol, 17-E. Pregnenolone, Preg. Progesterone, Prog. Estrogen receptor-,
ER. Estrogen receptor , ER. Gama amino butyric acid receptor A,
GABA-A. Membrane PROG receptors, mPRs. Pregnane X receptor, PXR.
Androgen Receptor, AR. N-methyl-D-aspartate receptor, NMDA. Food and
Drug Administration, FDA. Randomized Clinical Trials, RTC. Nitric Oxide
Synthase, NOS. Endothelial nitric oxide synthase, eNOS. Inducible Nitric
Oxide Synthase, iNOS. American Urological Association, AUA. Erectile
dysfunction, ED. International Index of Erectile Function, IIEF. Alanine aminotransferase, ALT. Aspartate aminotransferase, AST
182
name of Propecia) was also approved for the treatment of

AGA [52].
The mechanism whereby finasteride inhibits 5-Rs is based
on the formation of a covalent NADP-dihydrofinasteride adduct,
which binds to the enzyme competing with endogenous substrates [53] and has a very slow turnover (T1/2 30 days), rendering the inhibition virtually irreversible [10]. Among several finasteride 4-azasteroid analogs, dutasteride (5,17)-N-{2,5bis(trifluoromethyl)-phenyl}-3-oxo-4-azaandrost-1-ene-17carboxamide; Avodart inhibits both 5-R type 1 and 5-R
type 2 with greater potency than finasteride [54], and has similar
efficacy to this latter drug on BPH symptoms. Other drugs, like
the selective 5-R type 1 inhibitor MK-386 [55, 56] have been
developed and tested clinically, but have not been approved by
FDA for any specific clinical indication. For a general overview
on the 5-RIs, the interested reader is referred to a review by
Aggarwal et al., [57].
7 Therapeutic efficacy of 5-R inhibitors in BPH

A compelling body of evidence from several clinical trials has
demonstrated the efficacy of 5-RIs in the treatment of BPH.
In a majority of patients, finasteride (5 mg/day) leads to significant reductions in symptom severity, improvement of urinary flow rate, reduction of prostate volume and risk of acute
urinary retention, as well as a reduction of the need for surgical
intervention [58, 59]. Likewise, dutasteride has been shown to
result in similar therapeutic effects as finasteride [6062]. Recent data, however, have shown that over 25 % of all BPH
patients do not experience any improvement in their urinary
symptoms following finasteride treatment, likely signifying
the lack of involvement of 5-R type 2 in specific subtypes
of BPH [63]. In particular, resistance to finasteride therapy has
been posited to be related to pathological variants in subjects
featuring no expression of prostatic 5-R type 2 [63].
8 Therapeutic efficacy of 5-RIs in AGA and other

dermatological conditions
Lower doses of finasteride are also indicated for the treatment
of AGA, both orally (1 mg/day) or locally (by gel). The mechanism is still based on the reduction of the effects of 5-DHT
on hair follicles. Finasteride has been shown to lead to a significant reduction in the progression of the baldness and to a
stimulation of new hair growth. Finasteride discontinuation
leads to a loss of positive effects on hair growth within
12 months [64]. In addition to AGA, finasteride therapy has
been also tested as a therapy for female hirsutism, with encouraging results [65], similar to antiandrogen agents [66, 67].
The employment of finasteride in young women, however, is
contraindicated in pregnant women, in view of the high risk of

birth defects.
9 Other potential therapeutic indications for 5-R

inhibitors
Over the past few years, preliminary data have highlighted the
possibility that 5-RIs, and, in particular, finasteride, may
have therapeutic effects for a number of neuropsychiatric conditions [2]. In particular, initial clinical data from open trials
and case reports point to the possibility that these therapies
may be effective in reducing the severity of tics in Tourette
syndrome [68, 69] and may even be useful in decreasing the
severity of iatrogenic problem gambling in Parkinsons disease patients [70]. These preliminary data, however, need be
confirmed in double-blind, placebo-controlled trials.
The mechanisms of these effects remain partially elusive,
but preclinical studies suggest that they may be related to the
ability of finasteride to exert antidopaminergic properties [71]
in the ventral striatum / nucleus accumbens [72], a key region
for the regulation of motivation and reward [73, 74]. Notably,
the use of 5-RIs may be advantageous in comparison with
existing therapies such as antipsychotics, given the lack of
extrapyramidal symptoms associated with this class of agents.
Further studies are needed to understand which 5-Rs isoenzymes and what neuroactive steroids may underpin these behavioral and neurochemical effects.
10 Adverse effects of 5-Rs inhibitors

Since its development and first clinical studies, finasteride was
reported to elicit very limited side effects in volunteers and
patients [75, 76]. Several randomized clinical trials have confirmed the tolerability and safety of long-term finasteride treatment [59, 77, 78]. In particular, the PLESS (Proscar LongTerm Efficacy and Safety) study, which involved 3040 male
BPH patients over 4 years reported that the drop-out rate was
higher in the placebo group (42 %) in comparison with the
finasteride-treated group (34 %) [79]. A meta-analysis on the
clinical effects of finasteride documented that the main side
effects associated to this drug were loss of libido and erectile
dysfunction (ED), observed in 1-8 % patients [80].
For all these reasons, 5-RIs have generally been described
as well-tolerated and relatively safe drugs. Indeed, the medical
literature is still replete with studies suggesting that the use of
finasteride for AGA is safe and effective, and that no persistent sexual adverse events are documented in RTCs [81, 82].
Nevertheless, emerging lines of evidence on the available
data have led to a more critical re-evaluation of these statements. In particular, recent increases in reported adverse
events have prompted the FDA to mandate a revision to the
labeling for all 5-RIs, with a warning of increased sexual

dysfunction, depression, and increased risk of high-grade
prostate cancer [83].
In the next sections, we will provide a comprehensive analysis of the state of the art on the clinical and preclinical evidence on the side effects of 5-Rs inhibitors, with a critical
analysis on key issues that need to be addressed to provide a
more accurate clinical and pathophysiological characterization of these phenomena.
11 Adverse effects on sexual function

Until recently, the adverse effects of 5-RIs therapy on sexual
function were thought to be minor and well-tolerated [8486].
For instance, meta-analyses of randomized controlled trials
(RCTs) of finasteride for AGA provided strong evidence for
low incidences of sexual adverse side effects, which ultimately resolve with continuous treatment [87]. Furthermore, other
investigators advanced arguments that only minimal decrease
in erectile function were recorded with finasteride therapy
when compared with the placebo arm and only a small proportion (27 %) of patients experience erectile dysfunction
[88].
However, a body of emerging findings suggests that the
current assessment of the sexual side effects of finasteride
and dutasteride may be underestimated. Recently Belknap
and colleagues [89] have reported that considerable bias and
inaccuracy exist in reporting of adverse effects from 34 clinical trials with 5-R inhibitors therapy in management of hair
loss or restoration. Thus, it is not surprising that similar potential bias and inaccuracies may have occurred in
reporting of adverse effects from previous trials on use
of 5-RIs in treatment of BPH. An editorial following
the report by Belknap [89] has highlighted the need to
re-think the safety of these drugs [90]. The following
section summarizes preclinical and clinical evidence
documenting how finasteride and dutasteride may impair
sexual function, including sexual desire, erectile, ejaculation and orgasmic function [23, 9195].
Evidence from Pre-clinical studies 5-DHT plays a key role
in erectile physiology [96100] (Table 1). Castrated animals
exhibit poor erectile response and T or 5-DHT treatment
reverses this effect on erectile physiology [101]. Administration of the 5-Rs inhibitor 17-testosterone carboxylic acid
(17TC) to castrated animals blocked the stimulatory effects
of T propionate (TP) on erection [97, 102]. Administration of
5-DHT with or without 17TC, restored sexual behavior in long-term castrated male rats and mice suggesting
a critical role for 5-DHT in erectile physiology [103].
Treatment with T together with finasteride did not restore erectile response in castrated animals while
183
administration of 5-DHT together with finasteride restored nitric oxide synthase expression and activity and
also restored the erectile response to electric field stimulation [104].
Castration in male animals eliminates non-contact erections and this response was restored by 5-DHT implantation
[105, 106]. Reduced erectile response and reflex erections
were observed in castrated animals and treatment of castrated
animals with T or 5-DHT restored the number of erectile
responses and reflex erections [107]. However, only 5DHT restored erectile responses and reflex erections,
when animals were treated with daily injections of the
5-Rs inhibitor MK-434 (1 mg/kg) together with T or
5-DHT [107].
ztekin et al., [95] and Pinsky et al., [94] demonstrated that
treatment of mature animals with dutasteride resulted in reduced serum 5-DHT levels by ~86.5 % after 30 days. A
significant decrease in the intracavernosal pressure (ICP)
was recorded in animals treated with dutasteride. Furthermore,
significant reduction in electrical field stimulation
(EFS)-induced and acetylcholine-induced penile smooth
muscle relaxations was noted. A marked increase in
connective tissue deposition was reported in the corpus
cavernosum of the dutasteride-treated animals. Expression of neuronal nitric oxide synthase (nNOS) was
markedly reduced concomitant with increased expression
of the inducible NOS (iNO S), suggesti ng that
dutasteride altered gene expression. A 2-week washout
period did not restore the persisted adverse effects on
ICP/MAP in the dutasteride treated animal, suggesting a
persistent effect of the drug on erectile physiology.
Endothelium-dependent smooth muscle relaxations were
diminished in the dutasteride treated animals, suggesting
discontinuation of dutasteride did not restore erectile
function, indicating a time-dependent detriment of
dutasteride on erectile physiology.
Treatment of mature male animals for 16 weeks with a daily
oral dose of 4.5 mg/kg finasteride significantly reduced 5-DHT
levels and attenuated penile erectile response to electrical field
stimulation of the cavernous nerve [108]. Trabecular smooth
muscle content was markedly reduced and connective tissue
deposition increased suggesting a change in tissue histoarchitecture [109]. Endothelial nitric oxide synthase (eNOS)
expression was attenuated by finasteride concomitant with
decreased autophagy and deterioration in the ultrastructure
of the corpus cavernosum, including mitochondria injury,
and trabecular smooth muscle cell death [108]. These data
suggest serious adverse effects of finasteride on the anatomy,
physiology and cell biology of erectile function.
In summary, preclinical studies demonstrated that finasteride and dutasteride have a significant pathogenic
impact on penile histo-architecture, and attenuate the
nitric oxide synthase (NOS) signaling pathway. Thus,
184
Table 1 Effects of 5 Reductase inhibitors on nitric oxide synthase expression and activity, trabecular smooth muscle content and erections in vivo as
assessed by intracavernosal pressure (ICP) or by behavioral observations
Study [Ref.]
5a reductase inhibitor
Penile nitric oxide synthase

expression or activity
Penile smooth muscle

content
In vivo assessment of
erections
Bradshaw et al. 1981 [97]
17 -testosterone
carboxylic acid
Finasteride
Dutasteride
Dutasteride
MK-434
Finasteride
Not Measured
Not Measured
Significant Decreasea
Significant Decrease
Not Measured
Significant Decreaseb
Lugg et al. 1995 [104]

Pinsky et al. 2011 [94]
Oztekin et al. 2012 [95]
Seo et al. 1999 [107]
Zhang et al. 2013 [108]
a
Erections were monitored visually during behavior studies
Penile erection was assessed by electric field stimulation (EFS) of the cavernosal nerve and measurement of the intracavernosal pressure
This table was adopted from Traish et al. 2014 (Reference # 206)
these drugs are likely to contribute to erectile dysfunction (ED) via well-established and characterized mechanisms [94, 95].
Table 2
Evidence from clinical studies A number of clinical studies

reported sexual adverse effects of finasteride and dutasteride
(Table 2) [58, 110113]. The American Urological
Effect of 5- reductase inhibitors on sexual function in clinical studies
Study
Nickel et al., 1996 [58]
Drug used
Drug N = Drug related sexual

adverse events (%)
Placebo N = Placebo related sexual

adverse events (%)
Libido
ED
EJD
Libido
10
15.8
7.7
303
6.3
6.3
1.7
5.4
7.7
6.0
65.4
5.2
3.1
5.2
3.3
5.0
8.1
6.7
8.0
67.4
9.0
3.6
7.1
5.4
5.6
4.0
4.7
3.0
60.4
1.4
3.6
4.7
3.3
3.9
579
NA
1516
9457
4126
NA
NA
181
3.3
3.3
3.0
59.6
2.9
NA
NA
1.1
3.8
4.0
3.0
61.5
5.7
NA
NA
3.9
0.9
1.7
0.5
47.3
0.2
NA
NA
3.3
Finasteride
310
Finasteride
Dutasteride
Finasteride
Finasteride
Dutasteride
Finasteride
Dutasteride
Gubelin-Harcha et al., 2014 [207] Dutasteride
Finasteride
1736
259
1524
9423
4105
197
211
184
179
Tenover et al., 1997 [110]

Hudson et al., 1999 [111]
Wessells et al., 2003 [86]
Thompson et al., 2003 [84]
Andriole et al., 2010 [85]
Kaplan et al., 2012 [120]
ED
Footnotes & comments
EJD
c
d
e
f
g
The incidence of adverse events related to sexual dysfunction were significantly higher in the finasteride group than in the placebo group (ejaculation
disorder 7.7 % v. 1.7 % and impotence 15.8 % v. 6.3 %; p<0.01 for both parameters)
Finasteride treatment led to a small but significant increase in plasma HDL cholesterol and apolipoprotein A1 levels with a concomitant increase in total
cholesterol levels, but had no significant effect on plasma LDL and VLDL cholesterol, apolipoprotein B, or triglyceride levels
The overall dropout rate was 37.4 %, and only 8.1 % of patients discontinued therapy because of treatment failure. These rates are consistent with the
dropout rates for nonresponders in previous 2-year finasteride studies, which ranged from 3.7 to 5.2 %
In men who discontinued with a sexual AE, 50 and 41 % experienced resolution of their sexual AE after discontinuing finasteride or placebo therapy,
respectively. [86] The authors did not discuss what happened to those whose sexual AE were not resolved nor did they indicate how many patients were
lost to follow up?
High-grade disease was noted in 6.4 % of the men in the finasteride group, as compared with 5.1 % of those in the placebo group. A difference in the rate
of high-grade disease was seen within the first year of the study
There was an unexpected imbalance in a composite event termed Bcardiac failure,^ which included conditions such as congestive heart failure, cardiac
failure, acute cardiac failure, ventricular failure, cardiopulmonary failure, and congestive cardiomyopathy
g
Compared with finasteride, treatment with dutasteride resulted in significantly greater erectile dysfunction, more sexual side effects leading to
discontinuation and a greater incidence of breast complicationsIn addition, at Year 5, BPH patients on dutasteride had significantly worsened IIEF
scores relative to baseline than did those on finasteride
h
Reported results occurred in less than 24 weeks
This table was adopted from Traish et al. 2014 (Reference # 206)
Association (AUA) clinical practice guideline reported erectile problems in 8 and 4 % of patients taking finasteride and
placebo, respectively [114]. In addition, data from several
studies reported incidence of loss of libido, ED and ejaculatory disorders higher than that observed in the placebo arm,
[8486, 115]. ED was consistently noted in observational
studies as well as in double-blind, randomized, placebo controlled trials. Roehrborn et al., [116] and Siami et al., [117]
reported that approximately six percent of the patients experienced ED in a 2 year follow up to the CombAT trial [116,
117]. Hudson et al. [111] reported that ED occurred more
frequent in patients treated with dutasteride than those treated
with placebo. Desgrandchamps et al., [118] reported that sexual disorders were the most common adverse event during
drug treatment.
In the PROSPECT study, ED was established but determined subjectively in an open-ended interview [58, 119].
McConnell et al. reported that BThe most common adverse
events that occurred more frequently in the finasteride group
than in the placebo group were erectile dysfunction, decreased
libido, or abnormal ejaculation [77].
Kaplan et al., [120] showed that both finasteride and
dutasteride resulted in sexual adverse effects. The authors suggested that dutasteride elicits more sexual side effects and
breast complications than finasteride [120]. Chi & Kim
[121] reported adverse effect of dutasteride treatment during
a 1-year follow-up period in Korean men. In a recent study
Fwu et al., [122] investigated effects of finasteride with or
without combined therapy with alpha blockers on sexual function and found that men assigned to finasteride (alone or in
combination with doxazosin) experienced a worsening of several domains of sexual function compared to placebo [122].
Data from clinical studies clearly showed that in some patients, treatment with 5-Rs inhibitors diminished libido,
erectile, and ejaculatory function. 5-R inhibitors therapy,
while improves urinary symptoms in patients with BPH and
may prevent hair loss in patients with MPHL, this therapy
produces significant sexual adverse side effects in some individuals including loss of libido, ED, ejaculatory dysfunction,
and potential depression. The effects of these agents on vascular health should also be noted in light of recent findings
that patients treated with 5-Rs inhibitors therapy had significant adverse cardiovascular events [85].
Recent retrospective studies have documented that, in a
subset of vulnerable patients, the sexual side effects of 5Rs inhibitors are long-lasting and may be persistent or irreversible [93, 123125]. Although these preliminary studies
have raised a number of methodological concerns due to recall
and selection bias, as well as lack of placebo-treated controls
[126], these observations parallel scientific observations on
the long-term pathophysiological changes induced by finasteride on multiple tissues, even after treatment discontinuation [127, 128].
185
Traish et al., [129] investigated the impact of finasteride

and tamsulosin on the severity of ED in BPH patients for a
period of 45 months. In 470 patients, finasteride increased the
severity of ED, as assessed by the International Index of Erectile Function (IIEF) and resulted in reduced total testosterone
levels [129]. In contrast, in 280 patients treated with
tamsulosin, no significant changes in the IIEF scale were noted nor there was a decrease in total testosterone. More importantly, the aging male symptom score (AMS) increased concomitant with increased activity of alanine amino transferase
(ALT) and aspartate aminotransferase (AST) suggesting
changes in liver function with finasteride but not with
tamsulosin. More importantly, this report [129] demonstrates that the sexual side effects do not resolve with
continuous treatment with finasteride as claimed previously [60, 61, 86].
The incidence of enduring sexual side effects of finasteride
is currently elusive, and the data from the Proscar Long-term
Efficacy and Safety Study (PLESS) trial failed to identify a
significant difference between finasteride and placebo with
respect to the resolution of the sexual side effect of this drug
after discontinuation [86]. The ascertainment of the actual
incidence of long-lasting sexual side effects may be a complicated task, also due to the existence of placebo and nocebo
effects [130]. Nevertheless, these data highlight the need for
further studies and pharmacovigilance programs that may help
characterize the frequency and duration of these long-lasting
side effects.
12 Prostate cancer chemo-prevention

Initial results from the Prostate Cancer Prevention Trial
(PCPT) showed that finasteride treatment was associated with
a reduction in prostate cancer risk, irrespective of age, ethnicity, family history and baseline PSA levels [84]. These results
were originally interpreted to reflect a long-hypothesized involvement of androgen hormones and AR in the pathogenesis
of prostate cancer. However, recent evidence indicates that
there is no conclusive evidence that T or 5-DHT cause initiation, promotion or development of this disease [131134].
Accordingly, Muller and colleagues showed that, in patients
enrolled in the placebo arm of the REDUCE trial, baseline
total T and 5-DHT levels were not correlated with prostate
cancer detection or grade [85, 134].
Following a general evaluation of clinical data, the FDA
panel discussion in 2010 established that the potential reduction in the incidence of prostate cancer secondary to finasteride treatment was not statistically significant and was mostly
confined to low grade tumors [Food and Drug Administration. Oncologic Drugs Advisory Committee - 2010 Meeting
Materials, Oncologic Drugs Advisory Committee. 2010]. Furthermore, recent evidence has documented an increase in
186
Gleason high-grade prostate cancers) in finasteride-treated patients. Theoret et al., [135] reported that even after reevaluation of the data from the PCPT [84] and the REDUCE
trial [85] with the revised Gleason scoring system, these drugs
were shown to increase the incidence of Gleason high-grade
PCa tumors. The authors concluded that Bthe trade-off inherent in using a 5R inhibitor for prostate cancer prevention is
the acceptance of one additional high-grade cancer in order
to avert three to four potentially clinically relevant low-grade
cancers^ [135]. Based on these results, finasteride therapy
was deemed to yield no significant clinical benefits for prostate cancer patients [136, 137], and the FDA denied approval
for use of finasteride and dutasteride as chemo-preventive
agents for prostate cancer.
Recent follow-up data on the PCPT have confirmed that
finasteride did reduce prostate cancer risk, mostly in low
Gleason score tumors but acknowledged that this therapy
was conducive to an increase in high-grade cancer (3.5 % vs
3.0 % with placebo); however, no significant difference in the
rates of overall survival or survival after prostate cancer diagnosis were detected between finasteride- and placebo-treated
patients [138].
As pointed out by Ehdaie et al. [139], while the medical
community is eager to provide early intervention for patients
with high prostate specific antigen (PSA) levels after therapy,
it remains critical to weigh the harm of treatments against the
uncertain benefits to the patients. It is incumbent that physicians critically evaluate the current evidence and weigh the
risks and benefits of such interventions. Since the PCPT [84]
and REDUCE trials [85] used prostate cancer incidence as an
end point instead of mortality, there is little data that one can
used to conclude the chemo-preventive nature of these agents
and their ability to prolong survival and improve quality of life
[140].
13 Cardiovascular side effects of 5-RI therapy

Data from a large, long-term Randomized Control Trial (RCT
ARI40005) raised a serious concern regarding the safety of the
5-R inhibitor dutasteride, because of significant increase in
the risk of Bcardiac failure^ [85, 141, 142]. As pointed out by
Justman [143] some of the unidentified risks of 5-Rs inhibitors may be attributed to the limitations of the clinical trials.
For example, these trials had no primary or secondary endpoints to detect cardiovascular events; therefore, some of
the events may have been overlooked or underestimated.
Moreover, since cardiovascular events were not investigated as part of the primary or secondary endpoint, clinical
trial investigators may have had different interpretations
and may have not given them serious consideration [83,
142, 143].
14 Effects of 5-RI therapy on insulin resistance

and diabetes
Tomlinson et al., [144] noted that fat mass correlated with GCs
secretion rate, and GCs secretion rate was inversely related to
insulin sensitivity. Insulin sensitivity increased when GCs secretion and 5-Rs activity decreased subsequent to weight
loss. These observations suggested that obesity is associated
with insulin resistance and increased cortisol secretion rates
within adipose tissue. Both insulin resistance and cortisol
levels are reversed with weight loss. It was suggested that
reduced 5-R activity, after weight loss, may attenuate the
activation of hypothalamo-pituitary-adrenal axis and reduce
GC metabolite production. However, 11-HSD type 1, which
generates active cortisol from cortisone, and 5-Rs, which
inactivates cortisol have been implicated in the pathophysiology of insulin resistance. Tomlinson et al., [144] hypothesized
that augmented GC inactivation may serve as a compensatory,
protective mechanism to preserve insulin sensitivity.
Altering of insulin sensitivity by GCs may result in tissuespecific resistance - mainly in the liver and skeletal muscle
[145]. Studies in animal models have demonstrated that altering cortisol concentration by inhibiting 11-HSD type1 results in a deleterious outcome in insulin function [146]. These
studies suggest that GC dysregulation plays a role in insulin
resistance by actions on lipid homeostasis [147]. It is inferred
that the 5-R inhibitor changes cortisol concentrations, result
in undesirable side effects, such as hyperglycemia and insulin
resistance (IR). Tomlinson et al. [144] examined 5R and
11-HSD type 1 activities in obese subjects and concluded
that enhanced activity of 5-Rs is associated with insulin resistance in both sexes. The authors suggested that the increase
in the activities of 5-Rs may be a compensatory mechanism
to ameliorate the reduction in insulin sensitivity. Solas et al.
[148] reported that not only does an association exist between
GC excess and IR, but also with cognitive delays and
depression.
Upreti et al., [149] presented data suggesting that
dutasteride increased IR. The authors have confirmed that
dutasteride decreased glucose disposal and impaired insulin
sensitivity in peripheral organs, including skeletal muscle
and/or adipose tissue [149]. They also reported increased body
fat and reduced insulin-mediated suppression of non-esterified
fatty acids in response to dutasteride treatment and suggested
that this is consistent with impaired insulin sensitivity in adipose tissue. The effects on insulin sensitivity are not mediated
by differences in the levels of circulating 5-DHT [149]. This
study raises the question whether decreased 5-DHT levels or
increased glucocorticoid action mediate the effect of
dutasteride on altered insulin action. Since impaired insulin
sensitivity predicts future risk of type 2 diabetes mellitus
[150], the authors pointed out that in older men with already
impaired insulin sensitivity might be more susceptible to the
metabolic consequences of 5-Rs inhibition. A recent preclinical study in 5-R type 1deficient mice, demonstrated that
this enzyme plays a key role in predisposition to metabolic
disease, modulating hepatic steatosis and body fat distribution
and insulin sensitivity [151, 152]. The marked increase in
susceptibility to steatosis increased the susceptibility to fibrotic liver injury. These observations suggest that 5-R type 1
deficiency or inhibition may contributed to enhanced progression of non-alcoholic fatty liver disease [151, 152]. Thus, it
can be hypothesized that the inhibition of the aforementioned
regulatory enzymes may result in an imbalance in steroid metabolism and clearance rates, ultimately purtrubing physiological processes. Substances inhibiting 5-Rs activities and reducing the clearance of glucocorticoids and mineralocorticoids may thus potentiate insulin resistance, type 2 diabetes
mellitus and, as a consequence, vascular disease.
15 Effects of 5-RI therapy on bone metabolism

A recent study on the effects of 5-Rs inhibitor on bone in
men treated for BPH in the Taiwanese National Health Insurance Research Database (NHIRD) which comprised of 1352
men with diagnosis of osteoporosis and 5387 men as control
cases without osteoporosis diagnosis [153]. In this population,
nested control study the authors noted that a 1.52-fold increase
in osteoporosis diagnosis among patients with BPH treated
with finasteride (95 % CI, 1.012.30) compared with controls.
They also noted that higher doses of finasteride were associated with higher osteoporosis diagnosis risk (OR=1.68; 95 %
CI, 1.012.81), compared to controls [153]. It was suggested
that finasteride increases the risk of osteoporosis diagnosis
among patients with BPH. A recent pre-clinical study [154]
in which 5-R type 1 was inactivated in male mice demonstrated reduced bone mass and forelimb muscle grip strength.
The authors suggested that these metabolic changes are attributed to lack of 5-R type 1 expression in bone and muscle.
Although several studies have suggested that the effects of
androgens on bone is mediated by T and not 5-DHT, those
studies are of short duration and may not have represented the
cumulative effects of 5-Rs inhibitor on the metabolism of
various other steroids including the GCs which may have a
role in bone metabolism.
16 Effects of 5-RI therapy on neurobehavioral

functions and neuropsychiatric disturbances
The evaluation of neuropsychiatric consequences of finasteride has been very limited to date. In a first case series report,
Altomare and Capella [155] listed 19 AGA patients who had
developed affective problems during Propecia treatment.
These depressive symptoms had resolved after drug
187
discontinuation. In a subsequent prospective study RahimiArdabili et al. [156] compared the depression and anxiety
scores of 128 patients before and after finasteride treatment,
and found very modest, yet significant increases in Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale - Depression (HADS-D) scores. The depressive
symptoms ceased after finasteride discontinuation, and were
not apparently associated with alterations in sex drive [156].
Recently, Irwig reported that, in a subset of patients, finasteride induced severe depression and suicidal behavior, which
persisted after drug discontinuation [125]. Taken together,
these data seem to indicate that, in vulnerable subjects, finasteride can facilitate the emergence of depressive symptoms,
the severity and duration of which is likely to depend on
specific genetic and/or neurobiological characteristic of the
individuals. If confirmed, these effects may be underpinned
by psycholeptic properties of finasteride, which may also account for anecdotal evidence indicating its effectiveness in
reducing impulse-control problems [69].
The primary evidence on the behavioral effects of 5-R
inhibitors comes from preclinical results. In rodents, finasteride has been repeatedly shown to reduce the synthesis of THP
and THDOC, as well as other 3,5-reduced neuroactive
steroids. These steroids play an important role in the regulation of brain functions, through their regulation of GABAA
and other receptors. Indeed, several lines of research in animal
models point to key roles for THP and other 5-Rs products in
emotional and cognitive regulation, as well as other key nervous functions and the pathophysiology of the major neuropsychiatric conditions.
THP participates in the control of affection and mood, being
an endogenous antidepressive and anxiolytic agent. Alterations
in brain THP levels participate in stress and stress-related disorders and in psychiatric disorders [157159]. Since THP
levels depend on 5-Rs activity, the enzymes have important
role in the control of affection and mood. Notably, an inverse
relationship between THP and depressive symptoms has been
noted [160], and several antidepressants have been reported to
increase the deficits in THP in patients affected by major depression [161164]. However, the antidepressant role of
neurosteroids has been challenged by recent reports, in which
the mood-enhancing effects of electroconvulsive therapy or
transcranial magnetic stimulation were not paralleled by changes in neurosteroid concentrations [165, 166].
Recently, it has been shown that 5-R is also involved in pain
regulation, since THP is antinociceptive [167169]. Moreover,
5-R metabolites of T have been also recently demonstrated as
potential agents for the treatment of diabetic neuropathic pain
[170]. Indeed, 5-DHT counteracts the effect of diabetes on
mechanical nociceptive threshold, pre- and post-synaptic components, glutamate release, astrocyte immunoreactivity and expression of interleukin-1, while its metabolite, 3-diol, was effective on tactile allodynia threshold, glutamate release, astrocyte
188
immunoreactivity and the expression of substance P, toll-like

receptor 4, tumor necrosis factor-, transforming growth factor
-1, interleukin-1 and translocator protien 18-kDa (TSPO)
[170].
THP attenuates edema, trauma, stress, inflammation, apoptosis, and reduces oxidative stress during trauma or brain
injury [31, 171173]. THP is a protective agent in ischemia
and maintains blood brain barrier integrity, memory and learning [173176]. Finasteride increases apoptotic cell death in
the cerebellum and hippocampus [177]. The inhibition of
5-Rs activity with finasteride results in the abolishment of
the neuroprotective actions of PROG in the hippocamous
against excitotoxicity induced by kainic acid and against cell
death induced by tributyltin [178, 179]. In contrast, PROG
treatment without finasteride provided a protective effect. This
is attributed to the conversion of PROG to 5-DHP by 5-Rs
and to THP by 3-HSOR. When THP was administered with
or without finasteride produced a markedly protective effect as
assessed by the reduced cell death [178, 179]. These findings
suggest that 5-Rs play a pivotal role in neuroprotection.
Mice treated with finasteride showed decreased cell proliferation in the hippocampus, suggesting that inhibitors of 5Rs block neurogenesis [180]. As reported by Mellon et al.,
[181] in an adult animal model of Niemann-Pick disease type
C (NP-C) the biosynthesis of THP is significantly reduced,
and this was supported by significant reduction in the activity
of 5-Rs and 3-HSOR in the brain of these animals [181].
The activity of 5-Rs was markedly reduced with the progression of the disease. This reduced 5-Rs activity may contribute to the observed accumulation of cholesterol in neurons and
gangliosides, Purkinje cell degeneration, demyelination and
neurodegeneration [181]. Thus, loss of 5-Rs and 3HSOR activity is attributed to loss of neurons expressing these
enzymes. Treatment with THP early at postnatal day 7 was
found most effective in preventing neurodegeneration and
correlates with reduced tremor, ataxia, and increased lifespan.
In the animal model, these findings indicate that the loss of
neurosteroid biosynthesis may be responsible for the disease
state and its progression. Therefore inhibition of 5-Rs by
finasteride and dutasteride in the course of treatment of nonlife threatening conditions, such as AGA or BPH may have
detrimental effects on the CNS in vulnerable subjects.
Furthermore, 5-Rs play a role in neuroprotection since
5-THP has neuroprotective and neuroreparative actions in
the central and peripheral nervous system, restores learning
and memory function in a mouse model of Alzheimers disease (AD) [31, 182]. This is in agreement with the general
decrease of neuroactive steroid levels observed in different
animal models of neurodegeneration, such as Parkinsons disease, multiple sclerosis, peripheral neuropathies and diabetic
encephalopathy [31, 171, 183193].
THP levels are significantly reduced in post-mortem human
brains of AD patients [194]. A negative correlation was noted
between THP levels and the degree of neurological degeneration

in the brain of AD patients [194]. PREG levels were greater in
the temporal cortex of AD patients, suggesting that this may be a
compensating mechanism for reduced 5-Rs activity.
Alteration in PROG metabolism has been also further confirmed in male brains from a mouse model of AD (i.e., 3xTgAD mice) [186]. An age-related decrease in the levels of
PROG, together with an increase in the levels of its metabolite
5-DHP, was detected in the limbic region of wild type (WT)
and 3xTg-AD mice. Concerning PROG metabolites in the
limbic region, a significant increase in the levels of 5-DHP
and isopregnanolone in 3xTg-AD compared to WT mice was
reported. In addition, 5-DHP positively correlated with THP
in young 3xTg-AD mice, and negatively correlated with
isopregnanolone in aged 3xTg-AD mice. These correlations
were not detected in WT mice. In contrast, 3xTg-AD mice did
not show the positive correlations in the levels of PREG and
DHP and in the levels of THP and isopregnanolone that were
detected in young and older WT mice, respectively [186]. In
addition, THP, and therefore 5-Rs, participates in brain maturation and protection during late gestation and in newborns
[195].
17 Discussion
Emerging clinical evidence strongly suggests that 5-Rs inhibitors therapy is associated with sexual adverse side effects,
which, in vulnerable patients, remain even after 4 years of
therapy [122, 129], contrary to prior claims [60, 61, 86]. Thus,
increased education and awareness of clinicians and patients
alike is necessary to spare many patients from the adverse sexual side effects. Also, since approximately 25 % of all
BPH patients do not benefit from 5-R inhibitor therapy, a need
exists to evaluate those who may benefit from those who may
not benefit from this therapy, thus reducing the risk of inflecting
unnecessary sexual side effects on such patients. A number of
observations raise much doubt concerning the severity and duration of the side effects of 5-RI therapy which may have been
initially underestimated, due to a number of methodological
shortcomings in several studies, including their lack of blind
design and/or validated scales for the detection and assessment
of sexual dysfunction severity. Furthermore, many reports focused on the effects of these drugs only over a short duration of
time, and thus dismissed data related to the persistence of these
effects after discontinuation of finasteride therapy.
The inadequacy of accurate data reporting in clinical trials
with 5-RIs therapy may have contributed to the confusion on
the impact of these drugs on human health. In particular, the
lack of valid measures or scales by which the sexual adverse
events were detected and assessed, increased the uncertainty
about 5-Rs inhibitors therapy. Furthermore, the bias in
reporting either due to potential conflicts of interest and the
dismissal by many investigators of significant adverse events

and the inaccurate statements with regard to total resolution of
the sexual adverse events suggested that prior clinical trial
analyses need be re-evaluated. Many reports on this subject
were dismissed. The suggestion that no significant reduction
or loss of libido, erectile dysfunction occurs in such trials and
that the adverse effects resolve with treatment appears inaccurate and unsupported by the evidence in the contemporary
literature. Some of the discrepancies and the arguments made
in the aforementioned sections will be now discussed.
The lack of adequate blinding in many of the reported
studies represents a serious and a major flaw in reporting on
the impact of finasteride therapy on sexual dysfunction in the
clinical trials. Indeed, drug safety and quality of reporting of
adverse effects are compromised when insensitive methods
were used for detection of adverse side effects coupled with
non-validated measures for assessing the magnitude of the
adverse events, and evaluating their degree of severity, and
determining their causality.
It is important to point out that the data provided by the
manufacturer in the package insert for finasteride, clearly
showed that loss and/or reduction in libido was noted in approximately 10 % of patients treated with finasteride and 12 %
for combination therapy with alpha blockers [HIGHLIGHTS
OF PRESCRIBING INFORMATION. These highlights do
not include all the information needed to use PROSCAR safely and effectively. See full prescribing information for
PROSCAR. PROSCAR (finasteride) Tablets Initial U.S. Approval: 1992. Revised: 09/2013]. Similarly, the erectile dysfunction was increased to approximately 18 % in the finasteride and a 22 % in the combination therapy. Abnormal ejaculation was reported as 7 % in the finasteride and 14 % in the
combination therapy. These findings represent significant adverse sexual side effects and raise the concern that such therapy does in fact bring about worsening of sexual function.
From the outset, it must be noted that the side effects of 5RIs therapy have been examined in many studies, but the
manner in which they were examined and the scales by which
they were evaluated suffer from significant deficiencies, as
reported in the body of medical literature. The databases utilized in these studies are weak because in the BPH studies,
often only a single blood draw was made in the beginning and
no adequate or appropriate validated questionnaires were utilized to detect and assess carefully the scope or the magnitude
of the adverse sexual side effects. Furthermore, many of the
BPH patients enrolled in the studies were hypogonadal and
this contributes to the confounding factors and to the assessment of the adverse sexual side effects of 5-R inhibitors
therapy. Since no treatment of hypogonadism were implemented in the BPH patients in such studies, it remains difficult
to ascertain the nature of the adverse sexual side effects. Although review of the literature reported serious concerns about
the potential side effect of 5-RIs therapy [23], such concerns
189
were not heeded. In fact, many continue to argue that since

clinical trial reports did not show significant adverse effects,
the drug is deemed safe and effective. Few clinicians are concerned with the value of the data from RTCs which suffer from
major methodological and interpretational flaws and suffer
equally from inadequate reporting. It should be noted that a
large number of RTCs and two metaanalyses have been published on 5-R inhibitors therapy in AGA. Based on this
volume of clinical research, one would expect that we have
adequate evidence-based medicine to assess and determine the
incidence of 5-R inhibitors therapy adverse effects in men
with AGA. However, the inadequate data reporting and poor
tools used to assess the adverse effects outcome remains a
challenge to all practicing physicians. Not all data reported
in clinical trials are unequivocal and accurate and therefore
we need to take a deeper look at the data reporting and have
better assessment of the data presented in order to arrive to a
real evidence based approach to determining the extent, scale
and scope of the adverse sexual side effects.
However, the persistence of such side effects, if confirmed,
remains poorly understood and controversial. There is an urgent need to investigate the hypothesis that 5-R inhibitors
therapy produces persistent sexual side effects. The suggestion that the adverse events, such as loss of libido, diminished
erections or ejaculation, appear early in the first 6 months and
then return back to normal is, at best, inaccurate and is not
supported by evidence based medicine. Recent data showed
that the symptoms were present even after 4 years of therapy
[122, 129]. Simply, the problems with inconsistent follow-up
and use of non-validated scales or questionnaires and in the
absence of spontaneous reporting of events did not permit
accurate assessment of the sexual adverse events and whether
they resolve or do eventually persist.
Another argument made to down play the severity and
presence of the adverse sexual side effects was that these adverse effects are expected due to the course of natural aging.
However, this argument cannot be used to defend poor methodological approaches utilized in the various clinical studies,
especially when physicians involved in such clinical trials
instructed patients to stop taking the drug if patients
complained about their poor erections. This type of data
reporting does not fall in the realm of scientific measurements
but represents a guessing game. The clinical trials lacked
spontaneous reporting, as well as quantitative and validated
scales to adequately assess reduction in sexual function. For
example, until recently, many of the previous trials did not
utilize the IIEF questionnaire, which is shown to be the standard for assessment of sexual dysfunction. Thus, we believe
that such studies suffer from significant methodological and
interpretational flaws and inaccurate data reporting. Future
studies need to take into account how the drugs are delivered
and the appropriate measures of the adverse sexual side effects
that patients experienced. Other questions include: Are the
190
investigators truly blinded, are the patients truly blinded

whether on placebo or active drug? Thus, there are quantifiable rate of side effects from use of 5-R inhibitor therapy.
However, the questions are i) what happens when the drug is
discontinued? ii) Do the sexual adverse effects persist or
resolve? iii) What is the severity of the side effects? iv); How
do we interpret withdrawal data and what are the reasons for
withdrawal from studies?
Another question remains to be addressed is whether 5DHT plays a role in human erectile function. Although in
animal models, the role of 5-DHT in erectile physiology is
well established, this remains controversial in humans due to
lack of any basic science studies in humans designed to delineate the role of 5-DHT in erectile physiology, for obvious
reasons. The only parallel is that patients who undergo radical
prostatectomy and lose most of the 5-DHT synthesis in the
prostate do experience irreparable erectile dysfunction. It has
been suggested that 5-R inhibitors therapy increases total T
by approximately 20 %, and yet erectile dysfunction and loss
of libido seem to increase. This is paradoxical and cannot be
explained by T levels alone. It is possible that as in the animal
model, 5-DHT indeed plays a role in sexual function in
humans.
It is imperative that we address the question Why are the
sexual side effects not reversible in some patients? Several
arguments have been made to suggest that discontinuation of
the drug resulted in resolution of the sexual adverse side effects. This is based on the observations that in many patients
the circulating levels of 5-DHT return to normal and the size
of the prostate and the levels of PSA also return to normal after
drug discontinuation. Unfortunately, the physiology of the
prostate and that of erections are not regulated by the same
signalling pathways, albeit under the same hormonal control.
The nature of innervations, blood supply and other endocrine
factors may be different in such tissues. Further, the histoarchitecture of the penis and the prostate differ significantly
and the nature of the cellular structure is certainly very different. For such reasons, one should not extrapolate that since the
prostate volume or PSA returns to normal, one would not
expect that the changes in the penile histo-architecture to return to normal post drug discontinuation.
In addition, 5-RIs therapy may influence the CNS and the
peripheral nerve network in a manner that may contribute to
the persistence of the sexual side effects. Finally, it has been
demonstrated that this therapy attenuates the expression of the
enzymes involved in 5-DHT formation and this may represent a silencing of some of the pathways involved in androgen
signalling. Thus, it is possible that in some individuals an
epigenetic switch is turned on and such changes are now irreversible and contributes to the persistence.
Indeed, the distribution of 5-Rs in the various tissues,
including the CNS suggests that 5-R inhibitors therapy
may affect not only the peripheral nervous system but also
affect the CNS and such effects may contribute to the observed effects on sexual dysfunction among other neurological or psychiatric disorders. Recent studies have shown that
men after 5-R inhibitors therapy have altered levels of
neurosteroids in the cerebrospinal spinal fluid and in plasma.
In particular, it was demonstrated that the block of 5-Rs by
finasteride induces not only as previously described [197,
198] a decrease of PROG and T metabolite levels during the
treatment, but also a persistent alteration of neuro-active steroid levels despite discontinuation of the drug. Indeed, after
discontinuation of the finasteride treatment a subset of patients
that was treated for AGA show sexual dysfunction as well as
anxious/depressive symptomatology associated to altered
levels of PREG, PROG and its metabolites, 5-DHP and
THP as well as T and its metabolites 5-DHT and 3diol in CSF. Moreover, changes in PREG, 5-DHP,
THP, T, 3-diol, 3-diol and 17-E2 levels also occurred in plasma of these patients [32, 199].
These findings coupled with a host of clinical studies demonstrating wide arrays of adverse effects suggest the need for
more rigorous studies of these inhibitors and their impact on
the peripheral as well as the CNS. One of the difficulties in
assessing the scope and the scale of these sexual side effects is
the overlap between the psychiatric and sexual function. It
would be critical to investigate the effects of these agents on
the sexual function and separate this from their effects on
psychiatric concerns. More importantly, the data from the
existing clinical trials do not provide sufficient information
on the sexual function and psychiatric issues at base line and
therefore it is not easy to infer the severity of these side effects
form previously reported trials, which also suffer from limitations in the methods of data extractions and evaluations. For
these reasons, we need to have a better definition of the baseline information in clinical trials as well as more rigorous
studies, including pre-clinical animal models. More importantly, there is a need to determine the risk factors and comorbidities that confound the outcomes of such studies. This is
critical in that 5-R inhibitors therapy in BPH represents a
different population from that treated for AGA.
There are limited studies evaluating the effects of other
drugs and medications that may have synergistic effects with
5-R inhibitors therapy. For example, recently, it was reported that alcohol appears to increase the risk of high
grade tumors in men treated with dutasteride. The exact
mechanism for why alcohol may increase the risk in
unknown [200].
Another confounding factor is management of patients
treated with 5-RIs therapy with other steroids, such as androgens for hypogonadism or glucocorticoids for other comorbidities. Such treatments confound the nature and scale
of findings with regard to sexual dysfunction. For example,
several studies have attempted to determine the impact of T
therapy together with 5-R inhibitor on urological parameters
and insulin sensitivity with differing outcomes [201, 202].

These studies had serious design flaws and limitations and
lack power and therefore did not provide meaningful results.
In addition, there are several studies in which the drugs are
given in a combination with alpha blockers [122] or with phosphodiesterase type 5 (PDE5) inhibitors [203]. These studies
also did not provide unequivocal information on exact benefits
of 5-RIs therapy in these patients. Finally, it is rather complex
to appreciate the confounding of antidepressants when given
together with 5-R inhibitor therapy. Since 5-R inhibitors
have an impact on the function of the CNS and this has been
demonstrated in a number of studies, it remains unclear what is
the risk or benefit of the combination of such therapies.
In order to provide better care and patient management, it is
imperative to define the clinical approaches or strategies for
5-R inhibitors therapy to treat and manage patients with
BPH and reducing the risk of adverse side effects including
sexual side effects. To do so, a more comprehensive approach
is needed and the algorithm or the steps taken to treat patients
may have to be standardized and evaluated. Concerns of combined medications and issues pertaining to mental health disorders have to be taken in considerations with appropriate and
thorough evaluations.
One of the key issues facing all clinicians who manage
patients with adverse side effects of 5-R inhibitors is the
ambiguous definition post 5-R inhibitors therapy syndrome.
Although the term post finasteride syndrome (PFS) has been
coined, it is not clear exactly what constitutes this syndrome. It
incumbent on all clinician/scientists dealing with this syndrome to understand what are the components of this
syndrome? Simply, other confounding factors need be determined and evaluated. For instance, it is critical that a full
work-up of depression is made and that the work up is carried
out using formal validated questionnaires.
191
to the incidence and prevalence of this condition, as well as its

clinical characteristics. Anecdotal reports from affected patients suggest that the long-term sequelae of finasteride treatment are highly variable in clinical course, duration and prognosis, suggesting that PFS may be a group of heterogeneous
nosographic entities with partially overlapping symptomatic
features, but distinct pathogenetic mechanisms. Indeed, given
the primary role of 5-Rs in the synthesis and metabolism of
multiple steroids, it is likely that the symptomatic differences
within the BPFS spectrum^ may reflect the diverse role of
multiple androgens and neurosteroids in the regulation of behavior, brain functions, sexual functions and metabolism,
through the involvement of different receptors and signaling
processes across several peripheral organs and brain regions.
Recently, the U.S. National Institutes of Health added postfinasteride syndrome (PFS) to its Genetic and Rare Diseases
Information Center. This action suggests that this disorder is
worthy of investigation. Thus, physicians should take
very seriously the adverse side effects of 5-RIs therapy.
In view of the recent observations, it is clear that a more
detailed description of the long-term sequelae of 5-RIs needs
to encompass a multidisciplinary approach (with the support
of sexual medicine experts, neurologists, neuropsychiatrists,
psychologists and endocrinologists) and the employment of
quantitative indices (including steroid levels in plasma and
CSF, as well as measurable neuropsychological phenotypes)
to enable a standardized and detailed definition of multiple diagnostic subgroups within PFS. This approach
may prove fundamental to frame specific hypotheses
on the pathophysiology of these conditions and potentially facilitate the identification of specific therapeutic
strategies. In addition to this critical goal, future studies
on PFS should provide detailed information on the relation between different dose regimens and the severity
of the long-term side effects, and ascertain the relevance
of other potential risk factors, such as:
18 Future research directions
The evidence presented in the previous sections has unequivocally documented that, in a subset of susceptible individuals,
the employment of finasteride and other 5-R inhibitors is
associated with a number of enduring sexual, mental and metabolic side effects, which can persist beyond the discontinuation of these therapies and profoundly compromise life quality. In 4910 cases of young men using low-dose finasteride,
577 patients had persistent sexual dysfunction and 39 exhibited suicidal thoughts [208]. The majority of these events were
considered serious (e.g., contributed to the patients death,
hospitalization, or disability) [208]. Indeed, the adverse effects
of these agents negatively impact patients psychological
well-being and quality of life.
While these findings strongly support the existence of a
PFS, numerous questions remain open, particularly in relation
premorbid and comorbid clinical conditions (including

personality traits, mood disorders, anxiety and Attention
Deficit Hyperactivity Disorder (ADHD), as well as preexisting alterations in sexual function and metabolism);
potential association with concomitant treatments and/or
substances of abuse (including alcohol and anabolic
steroids);
age-dependent differences in susceptibility: indeed, preliminary data suggest that PFS may occur more frequently in young males under treatment for male-pattern alopecia, rather than older patients receiving 5-R inhibitors
for BPH.
Given the reported difficulties in establishing successful

therapeutic approaches for the neuropsychiatric outcomes of
5-RIs, it will be particularly important to capture the severity
192
of multiple affective dimensions encompassed by anxiety and

depression, including melancholia, dysphoria, apathy, irritability, anhedonia, changes in appetite, motivated behaviors,
attention and sleep quality. Furthermore, in consideration of
the relevance of neurosteroids/neuroactive steroids in the regulation of stress response, these studies should include measurements of stress response through hormonal and behavioral
changes, as elicited by standardized paradigms, such as the
Trier social stress test [204].
The definition of different diagnostic criteria for multiple
manifestations within the PFS spectrum may also be particularly important to identify potential genetic and phenotypic
vulnerability factors, which may be used to predict the actual
risk for this condition before initiation of the treatment. This
development may be particularly important vis--vis recent
preclinical and clinical findings pointing to a therapeutic potential of 5-RIs for neuropsychiatric conditions, including tic
disorders and risk-taking behaviors [2, 68, 69]. In addition,
defining potential links between specific alterations of the
neurosteroid profile and behavioral changes may provide crucial knowledge on the specific role of these compounds in
mental regulation, also in relation to the development of
neurosteroid-related therapies for PFS and other related
conditions.
Another fundamental line of investigation should focus on
PFS pathophysiology through the coordination of clinical and
preclinical studies. In particular, one of the next goals will be
the development of a standardized animal model of PFS, which
should simulate the persistent biochemical, behavioral, sexual and
metabolic deficits observed in patients. Clearly, the validation of
such a model with respect to face, etiological and construct criteria
will be contingent on progress in the clinical definition of PFS. In
particular, studies on the behavioral characteristics of these animal
models should focus on potential alterations in intermediate phenotypes (i.e., quantifiable factors that reflect a more basic architecture than the whole array of pathological manifestations featured by PFS) [205] outlined by clinical studies, such as perturbations in cognitive or stress-response tasks. The identification of
intermediate phenotypes and biomarkers in these models will
complement the characterization of the disturbances induced by
5-R inhibitors in patients; in addition, this experimental approach will be be more amenable to effective translational strategies and may facilitate the identification of reliable targets for
prevention and therapy of PFS, by providing a reliable tool to test
specific hypotheses on the pathophysiology of this condition. In
particular, critical questions should focus on the involvement of
specific neurosteroids and different 5-R isoforms in the pathophysiology of PFS. Indeed, while most of the actions of 5-R
inhibitors on sexual functions are posited to reflect the action of
5-R type 2, the role of the three main isoforms of this enzyme in
the neuropsychiatric and metabolic effects of 5-RIs remains
elusive. As pointed out by Traish et al. [206] 5-RIs have a long
lasting impact on sexual dysfunction. Caution should be exercised
to utilization of data from studies that did not address the inaccuracy of reporting of adverse events, especially those from studies
on hair restoration [207], as pointed out very clearly by Belknap
and his colleagues [89].
19 Recommendations
1. The scope and scale and the degree of persistance of sexual side effects remains controversial and requires urgent
well thought out and well-designed studies to ascertain if
these drugs do indeed cause enduring sexual side effects
in vulnerable patients. More importantly, the underlying
pathology and epigenetics of these potential changes need
be investigated and delineated, in order to develop better
manaagment strategies.
2. The recent studies pointing out to adverse effects on glucose metabolism, insulin resistance and potentially type 2
diabetes raises additional concerns and need be
invesigated. In addition the epidemilogical studies
suggesing that these agents may impact bone metabolism
is of concern and also need be studied clinically.
3. The effects of 5-RIs therapy on the peripheral and CNS
is not fully understood and merits critical evaluation
through fundamental basic and clincial research. The data
reported by Melcangi and his colleagues (Melcangi
2013 [32]; Caruso, 2015 [199]) challenges the current
dogma and necessitates expanding such studies to understand the impact of these agents on the CNS in order to
appreciate the potential impact on depression, demential,
AD and other CNS related disorders.
4. Finally, although there is only rudementary data on the
potential effects of these drugs on the dolichol phosphate
pathway, the impact these agents may have on biochemical signaling and protein glycosylation is of critical importance and need be investigated.
Funding This study was not funded by any agency or industry. It is a
collaborative effort among several scientists and clinicians.
Conflict of interest Drs. Traish, Zitzmann and Garcia-Segura declare
they have no conflict of interest. Drs. Melcangi and Bortolato have received research grants from the Post-Finasteride Syndrome Foundation.
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Adverse effects of 5α-reductase inhibitors: What do we know, don't know, and need to know?

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Rev Endocr Metab Disord (2015) 16:177198

Adverse effects of 5-reductase inhibitors: What do we know,

Published online: 23 August 2015

Abstract Steroids are important physiological orchestrators

of patients is afflicted with such persistence or irreversible

Department of Biochemistry and Department of Urology, Boston

Department of Pharmacological and Biomolecular Sciences- Center

Department of Pharmacology and Toxicology, University of Kansas,

Instituto Cajal, C.S.I.C, E-28002 Madrid, Spain

Centre for Reproductive Medicine and Andrology, University Clinics

need to evaluate the current clinical approaches of patient

Rev Endocr Metab Disord (2015) 16:177198

3 Peripheral physiological effects of 5-Rs activities

The 5-Rs are involved in a host of physiological processes

Rev Endocr Metab Disord (2015) 16:177198

Fig. 1 5-reductases catalyze a

4 Functions of 5-Rs in the central nervous system

in Fig. 2. On the other hand, the nervous system is not only a

Rev Endocr Metab Disord (2015) 16:177198

A similar variety of receptor-mediated mechanisms has been

5 Other physiological functions of 5-Rs

6 Therapeutic indications of 5-Rs inhibitors

Rev Endocr Metab Disord (2015) 16:177198

neurosteroids interact with GABA-A receptors and also with Estrogen

name of Propecia) was also approved for the treatment of

7 Therapeutic efficacy of 5-R inhibitors in BPH

8 Therapeutic efficacy of 5-RIs in AGA and other

Rev Endocr Metab Disord (2015) 16:177198

contraindicated in pregnant women, in view of the high risk of

9 Other potential therapeutic indications for 5-R

10 Adverse effects of 5-Rs inhibitors

Rev Endocr Metab Disord (2015) 16:177198

labeling for all 5-RIs, with a warning of increased sexual

11 Adverse effects on sexual function

Rev Endocr Metab Disord (2015) 16:177198

Penile nitric oxide synthase

Penile smooth muscle

Bradshaw et al. 1981 [97]

Lugg et al. 1995 [104]

Erections were monitored visually during behavior studies

Evidence from clinical studies A number of clinical studies

Effect of 5- reductase inhibitors on sexual function in clinical studies

Nickel et al., 1996 [58]

Drug N = Drug related sexual

Placebo N = Placebo related sexual

Tenover et al., 1997 [110]

Footnotes & comments

Reported results occurred in less than 24 weeks

Rev Endocr Metab Disord (2015) 16:177198

Traish et al., [129] investigated the impact of finasteride

12 Prostate cancer chemo-prevention

13 Cardiovascular side effects of 5-RI therapy

Rev Endocr Metab Disord (2015) 16:177198

14 Effects of 5-RI therapy on insulin resistance

Rev Endocr Metab Disord (2015) 16:177198

15 Effects of 5-RI therapy on bone metabolism

16 Effects of 5-RI therapy on neurobehavioral

immunoreactivity and the expression of substance P, toll-like

Rev Endocr Metab Disord (2015) 16:177198

between THP levels and the degree of neurological degeneration

Rev Endocr Metab Disord (2015) 16:177198

dismissal by many investigators of significant adverse events

were not heeded. In fact, many continue to argue that since