2598

Neuroactive Steroid Levels are Modified in Cerebrospinal Fluid

and Plasma of Post-Finasteride Patients Showing Persistent
Sexual Side Effects and Anxious/Depressive Symptomatology

Roberto Cosimo Melcangi, PhD,* Donatella Caruso, PhD,* Federico Abbiati, PhD Student,*
Silvia Giatti, PhD,* Donato Calabrese, PhD Student,* Fabrizio Piazza, PhD, and Guido Cavaletti, MD
*Department of Pharmacological and Biomolecular SciencesCenter of Excellence on Neurodegenerative Diseases,
University of Milan, Milano, Italy; Department of Surgery and Translational Medicine, University of Milan-Bicocca,
Monza, Italy; Department of Neurology, S. Gerardo Hospital, Monza, Italy

DOI: 10.1111/jsm.12269

ABSTRACT

Introduction. Observations performed in a subset of subjects treated with nasteride (an inhibitor of the enzyme
5a-reductase) for male pattern hair loss seem to indicate that sexual dysfunction as well as anxious/depressive
symptomatology may occur at the end of the treatment and continue after discontinuation.
Aim. A possible hypothesis to explain depression symptoms after nasteride treatment might be impairment in
the levels of neuroactive steroids. Therefore, neuroactive steroid levels were evaluated in paired plasma and
cerebrospinal uid samples obtained from male patients who received nasteride for the treatment of androgenic
alopecia and who, after drug discontinuation, still show long-term sexual side effects as well as anxious/depressive
symptomatology.
Methods. The levels of neuroactive steroids were evaluated by liquid chromatographytandem mass spectrometry in
three postnasteride patients and compared to those of ve healthy controls.
Main Outcome Measures. Neuroactive steroid levels in plasma and cerebrospinal uid of postnasteride patients
and healthy controls.
Results. At the examination, the three postnasteride patients reported muscular stiffness, cramps, tremors, and
chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Severity and
frequency of the anxious/depressive symptoms were quite variable; overall, all the subjects had a fairly complex
and constant neuropsychiatric pattern. Assessment of neuroactive steroid levels in patients showed some interindi-
vidual differences. However, the most important nding was the comparison of their neuroactive steroid levels with
those of healthy controls. Indeed, decreased levels of tetrahydroprogesterone, isopregnanolone and dihydrotest-
osterone and increased levels of testosterone and 17b-estradiol were reported in cerebrospinal uid of postnasteride
patients. Moreover, decreased levels of dihydroprogesterone and increased levels of 5a-androstane-3a,17b-diol and
17b-estradiol were observed in plasma.
Conclusion. The present observations conrm that an impairment of neuroactive steroid levels, associated with
depression symptoms, is still present in androgenic alopecia patients treated with nasteride despite the discontinu-
ation of the treatment. Melcangi RC, Caruso D, Abbiati F, Giatti S, Calabrese D, Piazza F, and Cavaletti G.
Neuroactive steroid levels are modified in cerebrospinal fluid and plasma of postfinasteride patients showing
persistent sexual side effects and anxious/depressive symptomatology. J Sex Med 2013;10:25982603.
Key Words. Progesterone; Testosterone; 5a-Reductase; Depression; Liquid ChromatographyTandem Mass
Spectrometry

J Sex Med 2013;10:25982603 2013 International Society for Sexual Medicine

Neuroactive Steroids in Post-Finasteride Patients
Report
F inasteride (Propecia or Proscar) is a
5a-reductase (5a-R) inhibitor used for the
treatment of human benign prostatic hyperplasia
and androgenic alopecia (male pattern hair loss)
[1]. The enzyme 5a-R converts testosterone (T)
into dihydrotestosterone (DHT), which is then
converted by the action of the 3a-hydroxysteroid
dehydrogenase into 5a-androstane-3a,17b-diol
(3a-diol) or by the 3b-hydroxysteroid dehydroge-
nase into 5a-androstane-3b,17b-diol (3b-diol)
[24]. Benign prostatic hyperplasia and male
pattern hair loss are androgen-dependent disor-
ders and are associated with an increase of 5a-R
activity and, consequently, an increase in DHT.
Therefore, nasteride treatment is considered
an efcient therapeutic tool for these disorders.
However, observations obtained in multiple
double-blind randomized controlled trials for
male pattern hair loss have indicated that nas-
teride treatment is associated with sexual dysfunc-
tion [57]. Moreover, observations performed in a
subset of subjects treated with the drug seem to
indicate that persistent sexual side effects, such as
low libido, erectile dysfunction, decreased arousal,
and difculty in reaching orgasm, may persist even
after discontinuation of the treatment [8,9].
Recent observations have also indicated that
patients may develop depression during nasteride
treatment [10,11] and that this symptomatology
can persist despite treatment withdrawal [12]. A
possible hypothesis to explain depression symp-
toms after nasteride treatment might be reduc-
tion in the levels of neuroactive steroids. This
steroid family includes both steroid hormones
produced in peripheral glands and steroids directly
synthesized in the nervous system (i.e., neuroster-
oids) [3]. Neuroactive steroids act as important
physiological regulators of nervous function,
affecting mood, behavior, reproduction, and cog-
nition, as well as acting as protective agents in
models of injury and neurodegenerative diseases
[3,13,14].
Indeed, 5a-R activity also converts progester-
one (PROG) into dihydroprogesterone (DHP),
which is subsequently converted by the action
of the 3a-hydroxysteroid dehydrogenase into
tetrahydroprogesterone (THP), also known as
allopregnanolone, or by the 3b-hydroxysteroid
dehydrogenase into isopregnanolone (i.e., the
3b-isomer of THP) [3]. In this context, it is impor-
tant to highlight that both THP and the 3a-diol (a
metabolite of DHT) are known as ligands of the
2599
g-aminobutyric acid A (GABA-A) receptor [3].
Moreover, isopregnanolone does not bind directly
to the GABA-A receptor [15], but it antagonizes
the effect of THP on the GABA-A receptor [16].
Changes in levels of GABA and neuroactive
steroids in plasma and cerebrospinal uid (CSF)
are associated with depression in several human
studies [17]. However, whether these changes
might occur after nasteride treatment in young
men with male pattern hair loss has never been
evaluated.
To explore this possibility, neuroactive steroid
levels were evaluated in paired plasma and CSF
samples obtained from three male patients who
received nasteride for the treatment of andro-
genic alopecia, resulting after drug discontinua-
tion in long-term sexual side effects as well as
anxious/depressive symptomatology (Table 1).
Patients were recruited through the Italian
Network on Finasteride Side Effects, through
which the opportunity to undergo CSF and plasma
examination in the context of an approved pilot
study was made available. Given the exploratory
nature of the study, no exclusion criteria were
established, except the use of drugs known to
potentially interfere with neuroactive steroid
levels. Symptoms reported by the patients were
collected using a standardized questionnaire pre-
pared after consensus among the members of the
Italian Network on Finasteride Side Effects, based
on an extensive collection of the reported symp-
toms, and the presence of these symptoms was
necessary to be eligible for neuroactive steroid
assessment.
The questionnaire was used as a method to
systematically collect information on patients
conditions and not as a validated tool to assess the
features of postnasteride syndrome. In order to
limit selection and recall bias, it was lled in by
patients only once, before they were made aware
of the possibility of undergoing neuroactive
steroid assessment.
The study procedure was approved by the
Ethics Committee of the S. Gerardo Hospital,
Monza, Italy, and the participating subjects pro-
vided their written informed consent before
enrollment. Although the severity and frequency
of the anxious/depressive symptoms were quite
variable, overall all the subjects had a fairly
complex and constant neuropsychiatric pattern.
Moreover, all these patients, at the moment
of clinical and laboratory assessment, reported
muscular stiffness, cramps, tremors, and chronic
fatigue in the absence of clinical evidence of any
J Sex Med 2013;10:25982603
 2600

Table 1 General data and self-reported frequency of the most severe symptoms reported by the patients at the moment of cerebrospinal fluid sampling
Patient 1 Patient 2 Patient 3

J Sex Med 2013;10:25982603

Age (years) 43 32 44
Drug Proscar Propecia Propecia
Treatment dose (mg/day) 1.25 1.00 1.00
Treatment duration (days) 3,100 183 665
Interval before CSF and plasma sampling 1,734 1,388 3,344
(days)
Major symptoms related to treatment Before During After (worst) After (current) Before During After (worst) After (current) Before During After (worst) After (current)
Reduction in self-confidence 2 2 4 3 1 3 4 2 1 2 2 4
Decreased initiative 2 2 4 2 1 4 3 2 1 3 3 3
Difficulty in concentration 1 2 4 2 1 3 4 3 1 3 3 4
Forgetfulness or loss of short-term memory 1 2 3 2 1 2 2 2 1 3 3 3
Irritability or easily flying into a rage 2 3 1 3 2 3 3 3 2 4 4 4
Depression, feelings of worthlessness 1 2 4 3 1 4 4 3 1 2 2 3
Suicidal thoughts 1 1 3 2 1 2 2 1 1 1 2 2
Anxiety and panic attacks 1 3 4 3 2 4 3 2 2 3 3 4
Sleep problems 2 2 4 4 1 3 3 2 1 4 4 4
Loss of libido and sexual desire 1 1 4 4 1 2 3 2 1 2 3 4
Difficulty in achieving an erection 1 2 4 4 1 1 2 1 1 2 3 4
Genital numbness or paresthesia 1 1 4 4 1 3 3 2 1 4 4 4
Tics, muscle spasms and fasciculations 1 1 4 4 1 3 3 2 1 4 4 4
Tremors 1 1 4 4 1 2 2 1 1 2 4 4
Muscle tension and contraction 1 1 4 4 1 3 4 4 1 2 4 4
Tension headache 1 1 3 2 1 3 4 4 1 1 1 1
Chronic fatigue, weakness, ataxia 1 2 4 3 2 3 4 4 1 4 4 4
Joint pain and muscular ache 1 1 4 4 1 3 4 4 1 3 4 4

1 = never, 2 = sometimes, 3 = often, 4 = always

Melcangi et al.
Neuroactive Steroids in Post-Finasteride Patients 2601

Table 2 Levels of neuroactive steroids in cerebrospinal fluid of post-finasteride patients and controls
PREG PROG DHP THP Isopregnanolone DHEA T DHT 3a-diol 3b-diol 17a-E 17b-E
Patients
1 1.16 0.30 u.d.l. u.d.l. u.d.l. 0.24 0.07 0.29 0.26 u.d.l. 0.03 0.06
2 1.10 0.36 u.d.l. u.d.l. u.d.l. 0.38 0.25 0.35 0.29 u.d.l. u.d.l. 0.06
3 0.23 0.11 u.d.l. u.d.l. u.d.l. 0.13 0.14 0.18 0.13 u.d.l. u.d.l. u.d.l.
Mean 0.83 0.26 u.d.l. u.d.l. u.d.l. 0.25 0.15 0.27 0.23 u.d.l. 0.023 0.047
SEM 0.3 0.07 0.07 0.052 0.05 0.05 0.003 0.013
Students t-test ** * * * *
Controls
1 0.74 0.15 u.d.l. 0.32 1.11 0.12 0.07 0.49 0.23 u.d.l. u.d.l. u.d.l.
2 0.95 0.16 u.d.l. 0.34 0.38 0.18 0.08 0.27 0.44 u.d.l. u.d.l. u.d.l.
3 0.91 0.10 u.d.l. 0.77 0.44 0.14 0.05 0.80 0.44 u.d.l. u.d.l. u.d.l.
4 0.71 0.19 u.d.l. 0.51 0.15 0.16 0.09 1.26 0.38 u.d.l. u.d.l. u.d.l.
5 0.70 0.18 u.d.l. 0.45 0.49 0.16 0.09 1.00 0.23 u.d.l. u.d.l. u.d.l.
Mean 0.80 0.16 u.d.l. 0.48 0.51 0.15 0.08 0.76 0.34 u.d.l. u.d.l. u.d.l.
SEM 0.05 0.002 0.08 0.16 0.01 0.007 0.18 0.05

*P 0.05; **P < 0.01

Data are expressed as pg/mL SEM
Mean and SEM values are in bold
Detection limit was 0.25 pg/mL for DHP, 0.1 pg/mL for THP and isopregnanolone, 0.05 pg/mL for 3b-diol, 0.02 pg/mL for 17a-E and 17b-E
PREG = pregnenolone, PROG = progesterone, DHP = dihydroprogesterone, THP = tetrahydroprogesterone, DHEA = dehydroepiandrosterone, T = testosterone,
DHT = dihydrotestosterone, 3a-diol = 5a-androstane-3a,17b-diol, 3b-diol = 5a-androstane-3b,17b-diol, 17a-E = 17a-estradiol, 17b-E = 17b-estradiol, SEM =
standard error of the mean, u.d.l. = under detection limit

muscular disorder or strength reduction. To
perform a complete neurological assessment,
before CSF drawing (4 mL) under sterile condi-
tions after local anesthesia, the postnasteride
patients underwent brain magnetic resonance
imaging, with normal results in all subjects. The
standard examination of CSF (i.e., protein,
glucose, and cellular content) was normal in all
cases.
The levels of pregnenolone (PREG), PROG
and its derivatives, DHP, THP and isopreg-
nanolone, dehydroepiandrosterone (DHEA), test-
osterone (T) and its derivatives, DHT, 3a-diol,
3b-diol, 17a-estradiol (17a-E), and 17b-
estradiol (17b-E) were evaluated by liquid
chromatographytandem mass spectrometry (LC-
MS/MS) in plasma and CSF as previously
described [18,19]. The levels of neuroactive ste-
roids in CSF and plasma of the three postnas-
teride patients were compared with those of ve
male, age-matched controls, represented by sub-
jects who underwent a diagnostic lumbar puncture
for a suspected neurological disease but eventually
proved to be healthy; the CSF and plasma were
obtained at the S. Gerardo Hospital CSF and
plasma bank (Tables 2 and 3).
As reported, neuroactive steroid levels were
very similar in patients 1 and 2, and they were
slightly different from those observed in patient 3.
In particular, patient 3 showed lower PREG and
PROG levels in both CSF (Table 2) and plasma
(Table 3), higher isopregnanolone levels in plasma
(Table 3), and levels of DHT, 3a-diol, 3b-diol, and
17b-E that were under detection limit in plasma
(Table 3). In this patient the CSF levels of 17b-E
were also under detection limit, in contrast to
those of patients 1 and 2 (Table 2).
Levels of DHEA in all patients were quite
similar in CSF (Table 2), but not in plasma, where
they were much higher in patient 2 in comparison
with the others (Table 3). A quite similar pattern
was present for T (Tables 2 and 3). Thus, CSF
levels were comparable, but patient 3 showed
higher plasma levels in comparison to patient 1
and 2 (Table 2).
In comparison with the healthy controls, the
three patients presented a quite different neuroac-
tive steroid pattern. In particular, as reported in
Table 2, CSF levels of THP and isopregnanolone
were under detection limit in all three patients. By
applying Students t-test, it was found that the
CSF levels of THP and isopregnanolone in post-
nasteride patients were signicantly different
from those of the healthy controls (THP, P < 0.01;
isopregnanolone, P = 0.05). THP levels were also
under detection limit in the plasma (Table 3).
Moreover, as reported in Table 3, plasma levels
of DHP (the precursor of THP and isopreg-
nanolone) were under detection limit in all three
patients and signicantly different compared with
those of healthy controls (P < 0.001). As reported
in Table 2, T and DHT levels were, respectively,
higher and lower in the CSF of patients as com-
pared with controls (P < 0.05). CSF levels of
17b-E were also signicantly higher in postnas-
teride patients than in healthy controls (P < 0.05).
As reported in Table 3, plasma levels of DHT and
of its metabolites (3a-diol and 3b-diol) were under

J Sex Med 2013;10:25982603

2602 Melcangi et al.

Table 3 Levels of neuroactive steroids in plasma of post-finasteride patients and controls

PREG PROG DHP THP Isopregnanolone DHEA T DHT 3a-diol 3b-diol 17a-E 17b-E
Patients
1 1.56 0.40 u.d.l. u.d.l. 0.28 3.17 3.17 0.34 1.49 0.19 u.d.l. 0.05
2 2.48 0.64 u.d.l. u.d.l. 0.58 20.1 7.94 0.44 2.51 0.12 u.d.l. 0.07
3 0.72 0.16 u.d.l. u.d.l. 3.39 1.69 10.5 u.d.l. u.d.l. u.d.l. u.d.l. u.d.l.
Mean 1.59 0.40 u.d.l. u.d.l. 1.42 8.32 7.2 0.28 1.35 0.12 u.d.l. 0.047
SEM 0.51 0.14 0.99 5.9 2.15 0.12 0.71 0.04 0.001
Students t-test *** * *
Controls
1 1.10 0.47 0.27 0.10 0.11 3.15 6.69 0.53 0.05 0.05 u.d.l. u.d.l.
2 0.87 0.35 0.32 0.10 0.10 1.28 5.80 0.53 0.05 0.05 u.d.l. u.d.l.
3 1.29 0.40 0.31 0.10 0.11 4.21 12.04 0.63 0.05 0.05 u.d.l. u.d.l.
4 0.83 0.24 0.25 0.22 1.28 7.16 13.90 0.31 0.05 0.18 u.d.l. u.d.l.
5 1.36 0.15 0.22 0.14 0.51 4.36 5.86 0.22 0.07 0.53 u.d.l. u.d.l.
Mean 1.09 0.32 0.27 0.13 0.42 4.03 8.86 0.44 0.05 0.17 u.d.l. u.d.l.
SEM 0.11 0.05 0.02 0.02 0.22 0.95 1.71 0.08 0.004 0.09

*P < 0.05; ***P < 0.001

Data are expressed as pg/mL SEM
Mean and SEM values are in bold
Detection limit was 0.25 pg/mL for DHP; 0.1 pg/mL for THP; 0.05 pg/mL for DHT, 3a-diol and 3b-diol; 0.02 pg/mL for 17a-E and 17b-E.
PREG = pregnenolone, PROG = progesterone, DHP = dihydroprogesterone, THP = tetrahydroprogesterone, DHEA = dehydroepiandrosterone, T = testosterone,
DHT = dihydrotestosterone, 3a-diol = 5a-androstane-3a,17b-diol, 3b-diol = 5a-androstane-3b,17b-diol, 17a-E = 17a-estradiol, 17b-E = 17b-estradiol, SEM =
standard error of the mean, u.d.l. = under detection limit

detection limit only in patient 3. Plasma levels of
3a-diol and 17b-E (Table 3) in the three postn-
asteride patients were signicantly higher than in
the healthy controls (P < 0.05).
The present results show for the rst time, in
three male patients with pattern hair loss, that
persistent sexual side effects and anxious/
depressive symptomatology despite discontinua-
tion of nasteride are associated with changes in
CSF and plasma levels of neuroactive steroids. In
particular, in CSF we observed a decrease in
metabolites of PROG and T, such as THP, iso-
pregnanolone, and DHT, associated with an
increase in T and 17b-E. In contrast, in plasma, a
decrease in DHP levels associated with an increase
of 3a-diol and 17b-E was observed. The few
observations so far present in the literature have
mainly focused on the role of 3a-reduced metabo-
lites of PROG and particularly of THP in anxious/
depressive symptomatology. Indeed, there is
general agreement that THP is decreased in CSF
and plasma in patients with anxious/depressive
symptomatology and that this disequilibrium can
be corrected with different antidepressants [17,20
22]. Interestingly, we here observed a decrease not
only in THP but also in isopregnanolone in CSF,
as well as a decrease in levels of THPs precursor
DHP in plasma. Moreover, we also report a
decrease in DHT in CSF. Indeed, association
between androgen deciency and depression has
also been proposed [23]. Altogether, these results
provide a molecular basis for the anxious/
depressive symptomatology occurring despite dis-
continuation of nasteride treatment in male
patients with pattern hair loss and indicate the
need for a conrmatory study in a larger cohort of
patients.
Acknowledgments
The authors thank the study subjects for their time and
participation. We also thank the Post-Finasteride Foun-
dation and the nancial support of Fondazione San
Paolo (Progetto Neuroscienze PF-2009.1180) to R.C.
Melcangi.
Corresponding Author: Roberto Cosimo Mel-
cangi, PhD, Department of Pharmacological and Bio-
molecular SciencesSection of Biomedicine and
EndocrinologyCenter of Excellence in Neurodegen-
erative Diseases, University of Milan, Italy, Via Balza-
retti 9, 20133 Milano, Italy. Tel: +39-02-50318238; Fax:
+39-02-50318204; E-mail: roberto.melcangi@unimi.it
Conict of Interest: The authors report no conicts of
interest.
Statement of Authorship
Category 1
(a) Conception and Design
Roberto Cosimo Melcangi; Guido Cavaletti
(b) Acquisition of Data
Guido Cavaletti; Federico Abbiati; Donato Cala-
brese; Silvia Giatti; Fabrizio Piazza

J Sex Med 2013;10:25982603

Neuroactive Steroids in Post-Finasteride Patients
(c) Analysis and Interpretation of Data
Roberto Cosimo Melcangi; Donatella Caruso;
Guido Cavaletti
Category 2
(a) Drafting the Article
Roberto Cosimo Melcangi; Donatella Caruso;
Guido Cavaletti
(b) Revising It for Intellectual Content
Roberto Cosimo Melcangi; Donatella Caruso;
Guido Cavaletti
Category 3
(a) Final Approval of the Completed Article
Roberto Cosimo Melcangi; Donatella Caruso;
Guido Cavaletti
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