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MELCANGI 2014 Altered Levels of Neuroactive Steroids in Cerebrospinal Fluid and Plasm of PFS Patients Journal of Steroid Biochemistry and Molecular Biolo .pdf



Nome del file originale: MELCANGI_2014_Altered Levels of Neuroactive Steroids in Cerebrospinal Fluid and Plasm of PFS Patients_Journal of Steroid Biochemistry and Molecular Biolo.pdf
Titolo: Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma
Autore: Donatella Caruso

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ARTICLE IN PRESS

SBMB-4178; No. of Pages 6

Journal of Steroid Biochemistry & Molecular Biology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Journal of Steroid Biochemistry and Molecular Biology
journal homepage: www.elsevier.com/locate/jsbmb

Review

Patients treated for male pattern hair with finasteride show, after
discontinuation of the drug, altered levels of neuroactive steroids in
cerebrospinal fluid and plasma
Donatella Caruso a , Federico Abbiati a , Silvia Giatti a , Simone Romano a , Letizia Fusco b,c ,
Guido Cavaletti b,c , Roberto Cosimo Melcangi a,∗
a
Department of Pharmacological and Biomolecular Sciences – Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano,
Milano, Italy
b
Department of Surgery and Translational Medicine, University of Milan-Bicocca, Monza, Italy
c
Department of Neurology, S. Gerardo Hospital, Monza, Italy

a r t i c l e

i n f o

Article history:
Received 27 January 2014
Received in revised form 28 March 2014
Accepted 31 March 2014
Available online xxx
Keywords:
Progesterone
Testosterone
Metabolites
5␣-Reductase
Depression
Liquid chromatography–tandem mass
spectrometry

a b s t r a c t
Observations performed in a subset of patients treated for male pattern hair loss indicate that persistent sexual side effects as well as anxious/depressive symptomatology have been reported even after
discontinuation of finasteride treatment. Due to the capability of finasteride to block the metabolism
of progesterone (PROG) and/or testosterone (T) we have evaluated, by liquid chromatography–tandem
mass spectrometry, the levels of several neuroactive steroids in paired plasma and cerebrospinal fluid
(CSF) samples obtained from post-finasteride patients and in healthy controls. At the examination, postfinasteride patients reported muscular stiffness, cramps, tremors and chronic fatigue in the absence
of clinical evidence of any muscular disorder or strength reduction. Although severity of the anxious/depressive symptoms was quite variable in their frequency, overall all the subjects had a fairly
complex and constant neuropsychiatric pattern. Assessment of neuroactive steroid levels in CSF showed
a decrease of PROG and its metabolites, dihydroprogesterone (DHP) and tetrahydroprogesterone (THP),
associated with an increase of its precursor pregnenolone (PREG). Altered levels were also observed for T
and its metabolites. Thus, a significant decrease of dihydrotestosterone (DHT) associated with an increase
of T as well as of 3␣-diol was detected. Changes in neuroactive steroid levels also occurred in plasma. An
increase of PREG, T, 3␣-diol, 3␤-diol and 17␤-estradiol was associated with decreased levels of DHP and
THP. The present observations show that altered levels of neuroactive steroids, associated with depression symptoms, are present in androgenic alopecia patients even after discontinuation of the finasteride
treatment.
This article is part of a Special Issue entitled ‘Sex steroids and brain disorders’.
© 2014 Elsevier Ltd. All rights reserved.

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Study design and sample preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Quantitative analysis of neuroactive steroids by LC–MS/MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Calibration curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Instrumental conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.
Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: 3␣-diol, 5␣-androstane-3␣,17␤-diol; 3␤-diol, 5␣-androstane-3␤,17␤-diol; 17␤-E, 17␤-estradiol; AR, androgen receptor; CSF, cerebrospinal fluid; DHEA,
dehydroepiandrosterone; DHP, dihydroprogesterone; DHT, dihydrotestosterone; IS, internal standards; LC-MS/MS, liquid chromatography tandem mass spectrometry; PREG,
pregnenolone; PROG, progesterone; T, testosterone; THP, tetrahydroprogesterone.
∗ Corresponding author. Tel.: +39 02 50318238; fax: +39 02 50318204.
E-mail address: roberto.melcangi@unimi.it (R.C. Melcangi).
http://dx.doi.org/10.1016/j.jsbmb.2014.03.012
0960-0760/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: D. Caruso, et al., Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma, J. Steroid Biochem. Mol. Biol. (2014),
http://dx.doi.org/10.1016/j.jsbmb.2014.03.012

G Model
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ARTICLE IN PRESS
D. Caruso et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2014) xxx–xxx

2

3.

4.
5.

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
General data and self-reported frequency of the most symptoms reported by the patients at the moment of sampling . . . . . . . . . . . . . . . . . .
3.2.
Assessment of neuroactive steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
Observations obtained in multiple double-blind randomized
controlled trials for male pattern hair loss have indicated that
finasteride (i.e., a 5␣-reductase inhibitor used for the treatment
of human benign prostatic hyperplasia and androgenic alopecia)
treatment was associated with sexual dysfunction [1–3]. Similar
side effects were also reported in patients treated for benign prostatic hyperplasia [4–7]. Very important, observations performed
in a subset of patients for male pattern hair loss seem to indicate
that persistent sexual side effects (e.g., low libido, erectile dysfunction, decreased arousal and difficulty in reaching orgasm) have been
reported even after discontinuation of the treatment [8,9]. Patients
also developed depression during finasteride treatment [10,11]
that still persisted despite treatment withdrawal [12]. Depression
after finasteride treatment might be due to impairment in the
levels of neuroactive steroids. This steroid family, which includes
both steroid hormones produced in peripheral glands and steroids
directly synthesized in the nervous system (i.e., neurosteroids), has
an important role in the control of nervous function, affecting mood,
behavior, reproduction and cognition, as well as being protective
agents in models of injury and neurodegenerative diseases [13–16].
Indeed, finasteride is not only able to block 5␣-reductase (5␣-R)
enzyme, which converts testosterone (T) into dihydrotestosterone
(DHT), but also the conversion of progesterone (PROG) into dihydroprogesterone (DHP) [16]. In this context, it is also important to
highlight that these neuroactive steroids are then converted by the
action of the 3␣- or 3␤-hydroxysteroid dehydrogenase into 5␣androstane-3␣,17␤-diol (3␣-diol) or 5␣-androstane-3␤,17␤ diol
(3␤-diol) in case of DHT and into tetrahydroprogesterone (THP),
also known as allopregnanolone, or into isopregnanolone in case of
DHP [16]. It is interesting to note that THP, as well as the 3␣-diol
(i.e., a metabolite of DHT), are known as ligands of GABA-A receptor [17]. Moreover, isopregnanolone does not bind directly to the
GABA-A receptor [18], but it antagonizes the effect of THP on the
GABA-A receptor [19,20]. Changes in GABA as well as in neuroactive
steroid levels in plasma and cerebrospinal fluid (CSF) are associated
with depression in several human studies [21].
Interestingly, our recent preliminary observations obtained in
three male patients who received finasteride for the treatment of
androgenic alopecia and that after drug discontinuation still had
long-term sexual side effects as well as anxious/depressive symptomatology showed altered neuroactive steroid levels in plasma
and CSF vs. those assessed in 5 healthy patients [22]. A further link
with neuroactive steroids may be supported by recent observations. Indeed, as reported in a subset of post-finasteride patients
with persistent symptomatology, a decline in their alcohol consumption was also observed [23]. This is very interesting, because
a relationship between GABAergic neuroactive steroids and ethanol
consumption is well documented [24].
On the basis of this interesting finding, we here extend our
observations analyzing by liquid chromatography–tandem mass
spectrometry (LC–MS/MS) the levels of neuroactive steroids, such
as pregnenolone (PREG), PROG and its derivatives, DHP, THP and
isopregnanolone, dehydroepiandrosterone (DHEA), testosterone
(T) and its derivatives, DHT, 3␣-diol, 3␤-diol and 17␤-estradiol

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(17␤-E), in paired plasma and CSF samples obtained from seven
post-finasteride patients (i.e., patients who received the drug for
the treatment of androgenic alopecia and resulting in long-term
sexual side effects as well as anxious/depressive symptomatology
after finasteride discontinuation) and comparing these levels vs.
those assessed in twelve healthy controls.

2. Materials and methods
PREG, PROG, DHP, THP, isopregnanolone, T, DHT, 3␣-diol,
3␤-diol DHEA and 17␤-E were purchased from Sigma Aldrich.
17,21,21,21-D4 -PREG (D4 -PREG) was kindly synthesized by Dr.
P. Ferraboschi (Dept. of Med. Biotech. & Translational Medicine,
University of Milano, Italy); 2,2,4,6,6-17␣,21,21,21-D9 -PROG (D9 PROG) was obtained from Medical Isotopes (Pelham, NH, USA);
2,3,4-13 C3 -17␤-estradiol (13 C3 -17␤-E) was obtained from SigmaAldrich, Italy. SPE cartridges (Discovery DS-C18 500 mg) were from
Supelco, Italy. All solvents and reagents were HPLC grade (Sigma
Aldrich, Italy).

2.1. Study design and sample preparation
Patients were recruited through the “Italian network finasteride
side effects”, where the possibility 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 steroids levels. Symptoms
reported by the patients were collected using a standardized questionnaire prepared after consensus among the members of the
“Italian network on finasteride side effects” based on an extensive
collection of the reported symptoms. The presence of a representative pattern 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 post-finasteride syndrome. In order to limit
selection and recall bias it was filled in by patients only once before
they were made aware of the possibility to undergo neuroactive
steroid assessment.
The study procedure was approved by the Ethics Committee of
the S. Gerardo Hospital, Monza-Italy and the participating subjects
provided their written informed consent before enrollment.
In order to obtain reliable normal control values, CSF and plasma
were collected from 12 subjects who underwent spinal anesthesia
for orthopedic surgery at San Gerardo Hospital of Monza. These
subjects were otherwise healthy, were carefully screened for the
absence of any neurological or psychiatric disorder in their personal or family history and gave their written informed consent to
the use for scientific purpose of the aliquot (approx 100–200 ␮l)
of CFS drawn to verify the correct position of the spinal needle,
according to the procedure approved by the Ethics Committee of
the S. Gerardo Hospital in Monza.

Please cite this article in press as: D. Caruso, et al., Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma, J. Steroid Biochem. Mol. Biol. (2014),
http://dx.doi.org/10.1016/j.jsbmb.2014.03.012

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2.2. Quantitative analysis of neuroactive steroids by LC–MS/MS
Extraction and purification of the samples were performed
according to Caruso et al. [25].
Briefly, samples were spiked with 13 C3 -17␤-E (1 ng/sample),
D9 -PROG (0.2 ng/sample) and D4 -PREG (5 ng/sample), as internal
standards (IS) and homogenized in MeOH/acetic acid (99:1 v/v)
using a tissue lyser (Qiagen, Italy). After an overnight extraction at
4 ◦ C, samples were centrifuged at 12,000 rpm for 5 min and the pellet was extracted twice with 1 ml of MeOH/acetic acid (99:1, v/v).
The organic residues were resuspended with 3 ml of MeOH/H2 O
(10:90, v/v) and passed through SPE cartridges, the steroids were
eluted in MeOH, concentrated and transferred in autosampler vials
before the LC-MS/MS analysis.
2.3. Calibration curves
Quantitative analysis was performed on the basis of calibration
curves daily prepared and analyzed as previously described [25].
Linear least-square regression analysis was performed and in addition, a blank (non-spiked sample) and a zero sample (only spiked
with IS) were run to demonstrate the absence of interferences at the
retention times and m/z corresponding to all the analytes. Moreover, the precision of the assay, inter-assay accuracy, precision and
reproducibility are calculated as described in [25] and are within
tolerance range for all the neuroactive steroids.
2.4. Instrumental conditions
Positive atmospheric pressure chemical ionization (APCI+)
experiments were performed with a linear ion trap – mass spectrometer (LTQ, ThermoElectron Co, San Jose, CA, USA) using
nitrogen as sheath, auxiliary and sweep gas. The instrument was
equipped with a Surveyor liquid chromatography (LC) Pump Plus
and a Surveyor Autosampler Plus (ThermoElectron Co, San Jose, CA,
USA). The mass spectrometer (MS) was employed in tandem mode
(MS/MS) using helium as collision gas.
The LC mobile phases were described by Caruso et al. [25]. The
Hypersil Gold column (100 mm × 3 mm, 3 ␮m; ThermoElectron Co.,
San Jose, CA, USA) was maintained at 40 ◦ C. Peaks of the LC–MS/MS
were evaluated using a Dell workstation by means of the software
Excalibur® release 2.0 SR2 (ThermoElectron Co., San Jose, CA, USA).
Samples were analyzed using the transitions previously reported
[26].
2.5. Statistical analysis
The linearity of the standard curve (r2 ) and all the validation
parameters of the method were judged by GraphPad4 PRISM (version 5). Student t test was used to compare control subjects and MS
patients. A p-value of less than 0.05 was considered significant.

3

fairly complex and constant neuropsychiatric pattern. The most
frequently reported symptoms were: reduction in self-confidence,
decreased initiative and difficulty in concentration (71%), forgetfulness or loss of short-term memory (43%), irritability or easily flying
into a rage (57%), depression and feelings of worthlessness (86%),
suicidal thoughts (14%), anxiety (57%) panic attacks (14%) and sleep
problems (86%). Loss of libido and sexual desire (86%), difficulty
in achieving an erection (71%) and genital numbness or paresthesia (57%) were also reported. Furthermore, all these patients
reported at the moment of clinical and laboratory assessment muscular stiffness and cramps (43%), tremors (57%), chronic fatigue
(86%) as well as joint pain and muscular ache (86%) in the absence
of clinical evidence of any muscular disorder or strength reduction. It is important to highlight that, with the exception of sleep
problems already reported by two patients, all these symptoms
were not present before treatment with finasteride. To perform a
complete neurological assessment, before CSF drawing under sterile conditions after local anesthesia, the post-finasteride 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.
3.2. Assessment of neuroactive steroids
The levels of neuroactive steroids in CSF and plasma of the seven
post-finasteride patients were compared with those of twelve
male, age-matched healthy controls. In comparison to the healthy
controls, the post-finasteride patients presented a quite different
neuroactive steroid pattern both in CSF and in plasma. Fig. 1 shows
the levels of PREG, its metabolite PROG, and the levels of the further metabolites, DHP, THP and isopregnanolone. As reported, the
levels of PREG were significantly increased in CSF and plasma of
post-finasteride patients. On the contrary, PROG was significantly
decreased in CSF but was unchanged in plasma. Its metabolites
had a similar pattern. Indeed, DHP, THP and isopregnanolone were
significantly decreased in CSF of post-finasteride patients with levels under detection limit. DHP and THP were also significantly
decreased in plasma, with the levels of THP that were under detection limit. Fig. 2 shows the levels of DHEA, its metabolite T, and the
levels of the further metabolites, DHT, 3␣-diol, 3␤-diol and 17␤-E.
As reported, DHEA levels were unchanged both in CSF and plasma;
on the contrary, both in CSF and plasma of post-finasteride patients
the levels of T were significantly increased. While the levels of the
first metabolite of T, DHT, were significantly decreased in CSF but
unchanged in plasma, the levels of the further metabolites, 3␣-diol
and 3␤-diol were significantly increased in plasma. Similarly to
what happened in plasma, the levels of 3␣-diol in CSF were significantly increased. Levels of 17␤-E were significantly increased
in plasma and unchanged in CSF.
4. Discussion

3. Results
3.1. General data and self-reported frequency of the most
symptoms reported by the patients at the moment of sampling
The seven post-finasteride patients we have considered in
our study had taken Propecia (1 mg/day) in 5 cases and Proscar
(1.25 mg/day) or Finasteride (1.25 mg/day) in 2 cases. Mean age
of these patients was 38 years old; mean of treatment duration
was 727 days. The interval between finasteride withdrawal and
CSF sampling was very wide (range 171–5000 days, median 1635
days).
Although the severity of the anxious/depressive symptoms was
quite variable in their frequency, overall all the subjects had a

The present results show that persistent sexual side effects as
well as anxious/depressive symptoms are associated with changes
of neuroactive steroid levels in CSF and plasma of seven male
patients with male pattern hair loss despite discontinuation of
finasteride. These results extend our previous preliminary observations that were obtained comparing three post-finasteride patients
vs. five control subjects [22]. It is important to highlight that the
controls used in our preliminary observations underwent a diagnostic lumbar puncture for a suspected neurological disease but
proved to be negative. However, because in those control patients
we cannot exclude a transitory inflammatory event, we have now
compared a higher number of post-finasteride patients with twelve
subjects who underwent spinal anesthesia for orthopedic surgery

Please cite this article in press as: D. Caruso, et al., Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma, J. Steroid Biochem. Mol. Biol. (2014),
http://dx.doi.org/10.1016/j.jsbmb.2014.03.012

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Fig. 1. Pregnenolone (PREG), progesterone (PROG), dihydroprogesterone (DHP), tetrahydroprogesterone (THP) and isopregnanolone levels in cerebrospinal fluid (CSF) and in
plasma of controls (CTRL) and post-finasteride patients (PFS). Data (n = 12 for CTRL and 7 for PFS) are expressed as pg/␮l ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001; the detection
limit for DHP is <0.25 pg/␮l, that for THP and isopregnanolone is <0.1 pg/␮l.

and were carefully screened for the absence of any neurological or
psychiatric disorder in their personal or family history.
In our preliminary observations we observed a decrease of
metabolites of PROG and T, such as THP, isopregnanolone and DHT,
associated with an increase of T and 17␤-E in CSF. On the contrary, in plasma a decrease in DHP levels associated with an increase
of 3␣-diol and 17␤-E levels was observed [22]. Observations here
presented show in CSF a decrease of metabolites of PROG, such as
DHP and THP, as well as of PROG itself. This finding was associated
with an increase of its precursor PREG. Altered levels were also
observed for T and its metabolites. Indeed, a significant decrease
of DHT associated with an increase of T as well as of 3␣-diol was
detected. Changes in neuroactive steroid levels also occurred in
plasma of post-finasteride patients. An increase of PREG levels was

associated with decreased levels of DHP and THP. An increase of
T also occurred in plasma and this was associated with increased
levels of 3␣-diol and 3␤-diol as well as of 17␤-E.
The few observations so far present in the literature have mainly
focused the attention on the role of 3␣-reduced metabolites of
PROG and particularly of THP in anxious/depressive symptomatology. In particular, this neuroactive steroid was decreased in CSF as
well as in plasma and this disequilibrium could be corrected with
different antidepressants [21,27–30]. At least in plasma, as reported
by others in patients suffering from depression, the decrease in
the levels of THP [31] was associated with an increase of isopregnanolone [27]. Here we report, a tendency of an increase, which
however did not reach the statistical significance, in plasma of
post-finasteride patients.

Please cite this article in press as: D. Caruso, et al., Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma, J. Steroid Biochem. Mol. Biol. (2014),
http://dx.doi.org/10.1016/j.jsbmb.2014.03.012

G Model
SBMB-4178; No. of Pages 6

ARTICLE IN PRESS
D. Caruso et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2014) xxx–xxx

5

Fig. 2. Dehydroepiandrosterone (DHEA), testosterone (T), dihydrotestosterone (DHT), 5␣-androstane-3␣,17␤-diol (3␣-diol), 5␣-androstane-3␤,17␤ diol (3␤-diol) and 17␤estradiol (17␤-E) levels in cerebrospinal fluid (CSF) and in plasma of controls (CTRL) and post-finasteride patients (PFS). Data (n = 12 for CTRL and 7 for PFS) are expressed as
pg/␮l ± SEM. *p < 0.05; the detection limit for 3␣-diol and 3␤-diol is <0.05 pg/␮l, that for 17␤-E is <0.02 pg/␮l.

A relationship between T levels and depression has also been
demonstrated [32]. Indeed, young hypogonadal as well as aged
men, showing decreased levels of T, exhibit a high prevalence
of anxiety disorders and major depressive disorder [33–36]. In
our study, we observed an increase in the CSF and plasma levels
of T. However, the active metabolite of T, DHT was significantly
decreased in CSF of post-finasteride patients. Indeed, finasteride
blocks the conversion of T into DHT [37], which is able, in comparison to T, to interact with the androgen receptor with a higher
affinity [16]. An intriguing finding of our study is represented by
the prolonged duration of psychiatric symptoms and CSF changes
after finasteride withdrawal, resembling the long-term/irreversible
effects of phenothiazines in patients affected by schizophrenia [38].
Recently, it has been demonstrated that treatment with finasteride induces a decreased of DHT levels in brain of mice associated
with a decrease of hippocampal neurogenesis [39,40]. Interestingly,
adult neurogenesis has been related to depression [41]. Indeed,
depressed patients show a reduced hippocampal volume related

with a reduced dendritic complexity, decreased neuronal soma
size, as well as reduced hippocampal neurogenesis [42,43]. In this
context it is important to highlight that GABA has crucial roles
in regulating different steps of adult neurogenesis, including proliferation of neural progenitors, migration and differentiation of
neuroblasts, and synaptic integration of newborn neurons [44].
As here demonstrated the levels of PROG and T, and particularly
those of their metabolites which, like for instance THP and 3␣-diol
are also to modulate GABA transmission through GABA-A receptors [17], are affected in post-finasteride patients and reported to
modulate adult neurogenesis [41,45].
5. Conclusions
Data here reported clearly show that the blockade of 5␣reductase by finasteride induces not only as previously described
[46,47] a decrease of PROG and T metabolite levels during the treatment, but it may also induce a persistent alteration of neuroactive

Please cite this article in press as: D. Caruso, et al., Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma, J. Steroid Biochem. Mol. Biol. (2014),
http://dx.doi.org/10.1016/j.jsbmb.2014.03.012

G Model
SBMB-4178; No. of Pages 6

ARTICLE IN PRESS
D. Caruso et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2014) xxx–xxx

6

steroid levels despite discontinuation of the drug. Indeed, as here
demonstrated, after discontinuation of the finasteride treatment a
subset of patients that was treated for male pattern hair loss show
sexual dysfunction as well as anxious/depressive symptomatology
associated with altered levels of PREG, PROG, DHP, THP T, DHT and
3␣-diol in CSF and of PREG, DHP, THP, T, 3␣-diol, 3␤-diol and 17␤-E
in plasma.

[21]

[22]

[23]

Acknowledgements
[24]

The authors thank the study subjects for their time and participation. We also thank the Post-Finasteride Foundation for the
financial support to R.C. Melcangi.

[25]

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Please cite this article in press as: D. Caruso, et al., Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma, J. Steroid Biochem. Mol. Biol. (2014),
http://dx.doi.org/10.1016/j.jsbmb.2014.03.012


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