File PDF .it

Condividi facilmente i tuoi documenti PDF con i tuoi contatti, il Web e i Social network.

Inviare un file File manager Cassetta degli attrezzi Ricerca PDF Assistenza Contattaci



MELCANGI 2013 Neuroactive Steroid Levels are Modified in Cerebrospinal Fluid of PFS Patients Journal of Sexual Medicine .pdf



Nome del file originale: MELCANGI_2013_Neuroactive Steroid Levels are Modified in Cerebrospinal Fluid of PFS Patients_Journal of Sexual Medicine.pdf
Titolo: Neuroactive Steroid Levels are Modified in Cerebrospinal Fluid and Plasma of PostFinasteride Patients Showing Persistent Sexual Side Effects and Anxious/Depressive Symptomatology

Questo documento in formato PDF 1.3 è stato generato da XPP / PDFlib PLOP 2.0.0p6 (SunOS)/Acrobat Distiller 7.0.5 (Windows), ed è stato inviato su file-pdf.it il 12/10/2015 alle 10:52, dall'indirizzo IP 134.19.x.x. La pagina di download del file è stata vista 1350 volte.
Dimensione del file: 81 KB (6 pagine).
Privacy: file pubblico




Scarica il file PDF









Anteprima del documento


1

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 Sciences—Center 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 finasteride (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 finasteride treatment might be impairment in
the levels of neuroactive steroids. Therefore, neuroactive steroid levels were evaluated in paired plasma and
cerebrospinal fluid samples obtained from male patients who received finasteride 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 chromatography–tandem mass spectrometry in
three postfinasteride patients and compared to those of five healthy controls.
Main Outcome Measures. Neuroactive steroid levels in plasma and cerebrospinal fluid of postfinasteride patients
and healthy controls.
Results. At the examination, the three postfinasteride 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 interindividual differences. However, the most important finding was the comparison of their neuroactive steroid levels with
those of healthy controls. Indeed, decreased levels of tetrahydroprogesterone, isopregnanolone and dihydrotestosterone and increased levels of testosterone and 17b-estradiol were reported in cerebrospinal fluid of postfinasteride
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 confirm that an impairment of neuroactive steroid levels, associated with
depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation 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 **;**:**–**.
Key Words. Progesterone; Testosterone; 5a-Reductase; Depression; Liquid Chromatography–Tandem Mass
Spectrometry

© 2013 International Society for Sexual Medicine

J Sex Med **;**:**–**

2
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 dehydrogenase into 5a-androstane-3b,17b-diol (3b-diol)
[2–4]. Benign prostatic hyperplasia and male
pattern hair loss are androgen-dependent disorders and are associated with an increase of 5a-R
activity and, consequently, an increase in DHT.
Therefore, finasteride treatment is considered
an efficient therapeutic tool for these disorders.
However, observations obtained in multiple
double-blind randomized controlled trials for
male pattern hair loss have indicated that finasteride treatment is associated with sexual dysfunction [5–7]. 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 difficulty in reaching orgasm, may persist even
after discontinuation of the treatment [8,9].
Recent observations have also indicated that
patients may develop depression during finasteride
treatment [10,11] and that this symptomatology
can persist despite treatment withdrawal [12]. A
possible hypothesis to explain depression symptoms after finasteride treatment might be reduction 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., neurosteroids) [3]. Neuroactive steroids act as important
physiological regulators of nervous function,
affecting mood, behavior, reproduction, and cognition, as well as acting as protective agents in
models of injury and neurodegenerative diseases
[3,13,14].
Indeed, 5a-R activity also converts progesterone (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 important to highlight that both THP and the 3a-diol (a
metabolite of DHT) are known as ligands of the

J Sex Med **;**:**–**

Melcangi et al.
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 fluid (CSF)
are associated with depression in several human
studies [17]. However, whether these changes
might occur after finasteride 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 finasteride for the treatment of androgenic alopecia, resulting after drug discontinuation 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 prepared after consensus among the members of the
Italian Network on Finasteride Side Effects, based
on an extensive collection of the reported symptoms, 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 postfinasteride 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 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 provided 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

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

After (current)
3
2
2
2
3
3
2
3
4
4
4
4
4
4
4
2
3
4

Before
1
1
1
1
2
1
1
2
1
1
1
1
1
1
1
1
2
1

After (worst)
4
4
4
3
1
4
3
4
4
4
4
4
4
4
4
3
4
4

Before
2
2
1
1
2
1
1
1
2
1
1
1
1
1
1
1
1
1

During
2
2
2
2
3
2
1
3
2
1
2
1
1
1
1
1
2
1

32
Propecia
1.00
183
1,388
During
3
4
3
2
3
4
2
4
3
2
1
3
3
2
3
3
3
3

Patient 2

43
Proscar
1.25
3,100
1,734

Patient 1

After (worst)
4
3
4
2
3
4
2
3
3
3
2
3
3
2
4
4
4
4

After (current)
2
2
3
2
3
3
1
2
2
2
1
2
2
1
4
4
4
4

Before
1
1
1
1
2
1
1
2
1
1
1
1
1
1
1
1
1
1

44
Propecia
1.00
665
3,344
During
2
3
3
3
4
2
1
3
4
2
2
4
4
2
2
1
4
3

Patient 3

After (worst)
2
3
3
3
4
2
2
3
4
3
3
4
4
4
4
1
4
4

General data and self-reported frequency of the most severe symptoms reported by the patients at the moment of cerebrospinal fluid sampling

Age (years)
Drug
Treatment dose (mg/day)
Treatment duration (days)
Interval before CSF and plasma sampling
(days)
Major symptoms related to treatment
Reduction in self-confidence
Decreased initiative
Difficulty in concentration
Forgetfulness or loss of short-term memory
Irritability or easily flying into a rage
Depression, feelings of worthlessness
Suicidal thoughts
Anxiety and panic attacks
Sleep problems
Loss of libido and sexual desire
Difficulty in achieving an erection
Genital numbness or paresthesia
Tics, muscle spasms and fasciculations
Tremors
Muscle tension and contraction
Tension headache
Chronic fatigue, weakness, ataxia
Joint pain and muscular ache

Table 1

After (current)
4
3
4
3
4
3
2
4
4
4
4
4
4
4
4
1
4
4

Neuroactive Steroids in Post-Finasteride Patients
3

J Sex Med **;**:**–**

4
Table 2

Melcangi et al.
Levels of neuroactive steroids in cerebrospinal fluid of post-finasteride patients and controls

Patients
1
2
3
Mean
SEM
Student’s t-test
Controls
1
2
3
4
5
Mean
SEM

PREG

PROG

DHP

THP

Isopregnanolone

DHEA

T

DHT

3a-diol

3b-diol

17a-E

17b-E

1.16
1.10
0.23
0.83
0.3

0.30
0.36
0.11
0.26
0.07

u.d.l.
u.d.l.
u.d.l.
u.d.l.

u.d.l.
u.d.l.
u.d.l.
u.d.l.

u.d.l.
u.d.l.
u.d.l.
u.d.l.

0.24
0.38
0.13
0.25
0.07

u.d.l.
u.d.l.
u.d.l.
u.d.l.

0.03
u.d.l.
u.d.l.
0.023
0.003

*

0.29
0.35
0.18
0.27
0.05
*

0.26
0.29
0.13
0.23
0.05

**

0.07
0.25
0.14
0.15
0.052
*

0.06
0.06
u.d.l.
0.047
0.013
*

0.32
0.34
0.77
0.51
0.45
0.48
0.08

1.11
0.38
0.44
0.15
0.49
0.51
0.16

0.12
0.18
0.14
0.16
0.16
0.15
0.01

0.07
0.08
0.05
0.09
0.09
0.08
0.007

0.49
0.27
0.80
1.26
1.00
0.76
0.18

0.23
0.44
0.44
0.38
0.23
0.34
0.05

u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.

u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.

u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.

0.74
0.95
0.91
0.71
0.70
0.80
0.05

0.15
0.16
0.10
0.19
0.18
0.16
0.002

u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.

*P ⱕ 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 conditions after local anesthesia, the postfinasteride
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 isopregnanolone, dehydroepiandrosterone (DHEA), testosterone (T) and its derivatives, DHT, 3a-diol,
3b-diol, 17a-estradiol (17a-E), and 17bestradiol (17b-E) were evaluated by liquid
chromatography–tandem mass spectrometry (LCMS/MS) in plasma and CSF as previously
described [18,19]. The levels of neuroactive steroids in CSF and plasma of the three postfinasteride patients were compared with those of five
male, age-matched controls, represented by subjects 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
J Sex Med **;**:**–**

(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 neuroactive 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 Student’s t-test, it was found that the
CSF levels of THP and isopregnanolone in postfinasteride patients were significantly 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 isopregnanolone) were under detection limit in all three
patients and significantly 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 compared with controls (P < 0.05). CSF levels of
17b-E were also significantly higher in postfinasteride 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

5

Neuroactive Steroids in Post-Finasteride Patients
Table 3

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

Patients
1
2
3
Mean
SEM
Student’s t-test
Controls
1
2
3
4
5
Mean
SEM

PREG

PROG

DHP

THP

Isopregnanolone

DHEA

T

DHT

3a-diol

3b-diol

17a-E

17b-E

1.56
2.48
0.72
1.59
0.51

0.40
0.64
0.16
0.40
0.14

u.d.l.
u.d.l.
u.d.l.
u.d.l.

u.d.l.
u.d.l.
u.d.l.
u.d.l.

0.28
0.58
3.39
1.42
0.99

3.17
20.1
1.69
8.32
5.9

3.17
7.94
10.5
7.2
2.15

0.34
0.44
u.d.l.
0.28
0.12

1.49
2.51
u.d.l.
1.35
0.71
*

0.19
0.12
u.d.l.
0.12
0.04

u.d.l.
u.d.l.
u.d.l.
u.d.l.

0.05
0.07
u.d.l.
0.047
0.001
*

0.10
0.10
0.10
0.22
0.14
0.13
0.02

0.11
0.10
0.11
1.28
0.51
0.42
0.22

3.15
1.28
4.21
7.16
4.36
4.03
0.95

6.69
5.80
12.04
13.90
5.86
8.86
1.71

0.53
0.53
0.63
0.31
0.22
0.44
0.08

0.05
0.05
0.05
0.05
0.07
0.05
0.004

0.05
0.05
0.05
0.18
0.53
0.17
0.09

u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.

u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.
u.d.l.

***
1.10
0.87
1.29
0.83
1.36
1.09
0.11

0.47
0.35
0.40
0.24
0.15
0.32
0.05

0.27
0.32
0.31
0.25
0.22
0.27
0.02

*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 postfinasteride patients were significantly higher than in
the healthy controls (P < 0.05).
The present results show for the first time, in
three male patients with pattern hair loss, that
persistent sexual side effects and anxious/
depressive symptomatology despite discontinuation of finasteride 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, isopregnanolone, 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 metabolites 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 THP’s precursor
DHP in plasma. Moreover, we also report a
decrease in DHT in CSF. Indeed, association
between androgen deficiency and depression has
also been proposed [23]. Altogether, these results
provide a molecular basis for the anxious/

depressive symptomatology occurring despite discontinuation of finasteride treatment in male
patients with pattern hair loss and indicate the
need for a confirmatory 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 Foundation and the financial support of Fondazione San
Paolo (Progetto Neuroscienze PF-2009.1180) to R.C.
Melcangi.
Corresponding Author: Roberto Cosimo Melcangi, PhD, Department of Pharmacological and Biomolecular Sciences—Section of Biomedicine and
Endocrinology—Center of Excellence in Neurodegenerative Diseases, University of Milan, Italy, Via Balzaretti 9, 20133 Milano, Italy. Tel: +39-02-50318238; Fax:
+39-02-50318204; E-mail: roberto.melcangi@unimi.it
Conflict of Interest: The authors report no conflicts 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 Calabrese; Silvia Giatti; Fabrizio Piazza

J Sex Med **;**:**–**

6
(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

References
1 Finn DA, Beadles-Bohling AS, Beckley EH, Ford MM, Gililland KR, Gorin-Meyer RE, Wiren KM. A new look at the
5a-reductase inhibitor finasteride. CNS Drug Rev 2006;12:
53–76.
2 Traish AM. 5a-reductases in human physiology: An unfolding
story. Endocr Pract 2012;18:965–75.
3 Melcangi RC, Garcia-Segura LM, Mensah-Nyagan AG.
Neuroactive steroids: State of the art and new perspectives.
Cell Mol Life Sci 2008;65:777–97.
4 Handa RJ, Pak TR, Kudwa AE, Lund TD, Hinds L. An
alternate pathway for androgen regulation of brain function:
Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5a-androstane-3b,17b-diol. Horm Behav
2008;53:741–52.
5 Olsen EA, Hordinsky M, Whiting D, Stough D, Hobbs S,
Ellis ML, Wilson T, Rittmaster RS. The importance of dual
5a-reductase inhibition in the treatment of male pattern hair
loss: Results of a randomized placebo-controlled study of
dutasteride versus finasteride. J Am Acad Dermatol 2006;55:
1014–23.
6 McClellan KJ, Markham A. Finasteride: A review of its use in
male pattern hair loss. Drugs 1999;57:111–26.
7 Kaufman KD, Olsen EA, Whiting D, Savin R, DeVillez R,
Bergfeld W, Price VH, Van Neste D, Roberts JL, Hordinsky
M, Shapiro J, Binkowitz B, Gormley GJ. Finasteride in the
treatment of men with androgenetic alopecia. Finasteride
Male Pattern Hair Loss Study Group. J Am Acad Dermatol
1998;39:578–89.
8 Irwig MS. Persistent sexual side effects of finasteride: Could
they be permanent? J Sex Med 2012;9:2927–32.
9 Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med 2011;8:1747–53.

J Sex Med **;**:**–**

Melcangi et al.
10 Altomare G, Capella GL. Depression circumstantially related
to the administration of finasteride for androgenetic alopecia.
J Dermatol 2002;29:665–9.
11 Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki
A. Finasteride induced depression: A prospective study. BMC
Clin Pharmacol 2006;6:7.
12 Irwig MS. Depressive symptoms and suicidal thoughts among
former users of finasteride with persistent sexual side effects.
J Clin Psychiatry 2012;73:1220–3.
13 Schumacher M, Hussain R, Gago N, Oudinet JP, Mattern C,
Ghoumari AM. Progesterone synthesis in the nervous system:
Implications for myelination and myelin repair. Front Neurosci 2012;6:10. doi: 10.3389/fnins.2012.00010
14 Panzica GC, Balthazart J, Frye CA, Garcia-Segura LM, Herbison AE, Mensah-Nyagan AG, McCarthy MM, Melcangi
RC. Milestones on Steroids and the Nervous System: 10 years
of basic and translational research. J Neuroendocrinol
2012;24:1–15.
15 Bitran D, Hilvers RJ, Kellogg CK. Anxiolytic effects of 3
a-hydroxy-5 a[b]-pregnan-20-one: Endogenous metabolites
of progesterone that are active at the GABAA receptor. Brain
Res 1991;561:157–61.
16 Wang M, He Y, Eisenman LN, Fields C, Zeng CM, Mathews
J, Benz A, Fu T, Zorumski E, Steinbach JH, Covey DF,
Zorumski CF, Mennerick S. 3b-hydroxypregnane steroids
are pregnenolone sulfate-like GABA(A) receptor antagonists.
J Neurosci 2002;22:3366–75.
17 Zorumski CF, Paul SM, Izumi Y, Covey DF, Mennerick S.
Neurosteroids, stress and depression: Potential therapeutic
opportunities. Neurosci Biobehav Rev 2013;37:109–22.
18 Caruso D, Pesaresi M, Maschi O, Giatti S, Garcia-Segura LM,
Melcangi RC. Effects of short- and long-term gonadectomy on
neuroactive steroid levels in the central and peripheral nervous
system of male and female rats. J Neuroendocrinol 2010;22:
1137–47.
19 Caruso D, Barron AM, Brown MA, Abbiati F, Carrero P, Pike
CJ, Garcia-Segura LM, Melcangi RC. Age-related changes in
neuroactive steroid levels in 3Â¥Tg-AD mice. Neurobiol Aging
2013;34:1080–9.
20 Romeo E, Strohle A, Spalletta G, di Michele F, Hermann B,
Holsboer F, Pasini A, Rupprecht R. Effects of antidepressant
treatment on neuroactive steroids in major depression. Am J
Psychiatry 1998;155:910–3.
21 Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP,
Costa E, Guidotti A. Increase in the cerebrospinal fluid
content of neurosteroids in patients with unipolar major
depression who are receiving fluoxetine or fluvoxamine. Proc
Natl Acad Sci U S A 1998;95:3239–44.
22 Uzunova V, Sampson L, Uzunov DP. Relevance of
endogenous 3a-reduced neurosteroids to depression and antidepressant action. Psychopharmacology (Berl) 2006;186:351–
61.
23 Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML.
Adverse side effects of 5a-reductase inhibitors therapy: Persistent diminished libido and erectile dysfunction and depression
in a subset of patients. J Sex Med 2011;8:872–84.


Documenti correlati


Documento PDF melcangi 2013 neuroactive steroid levels are modified in cerebrospinal fluid of pfs patients journal of sexual medicine
Documento PDF melcangi 2014 altered levels of neuroactive steroids in cerebrospinal fluid and plasm of pfs patients journal of steroid biochemistry and molecular biolo
Documento PDF cauci 2014 immunohistochemical evaluation of ar and nerve structure density in human prepuce from pfs patients public library of science one
Documento PDF ac2 100606
Documento PDF test hvlp
Documento PDF clinics in dermatology volume 19 issue 4 2001 doi 10 1016 2fs0738 081x 2801 2900189 4 marcia ramos e silva doris maria hexsel marcio santos rutowits hydroxy acids and retinoids in cosmetics


Parole chiave correlate