Professional Documents
Culture Documents
DOI 10.1007/s11154-015-9319-y
1 Introduction
* Abdulmaged M. Traish
atraish@bu.edu
1
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
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.
179
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].
180
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
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182
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,
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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
In vivo assessment of
erections
17 -testosterone
carboxylic acid
Finasteride
Dutasteride
Dutasteride
MK-434
Finasteride
Not Measured
Not Measured
Significant Decreasea
Significant Decrease
Significant Decrease
Significant Decrease
Significant Decrease
Significant Decrease
Not Measured
Significant Decrease
Significant Decrease
Significant Decrease
Significant Decreaseb
Significant Decreaseb
Significant Decreaseb
Significant Decreaseb
Significant Decreaseb
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
Study
Drug used
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
ED
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
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
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].
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.
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
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
189
190
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
191
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
192
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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