PMID- 37675929
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240214
IS  - 2047-2927 (Electronic)
IS  - 2047-2919 (Linking)
VI  - 12
IP  - 3
DP  - 2024 Mar
TI  - Role of serotonin, estrogen, and TNF-alpha in the paroxetine-impaired steroidogenesis 
      and testicular macrophages polarization.
PG  - 655-673
LID - 10.1111/andr.13513 [doi]
AB  - BACKGROUND: Paroxetine, a selective serotonin reuptake inhibitor (SSRI) 
      antidepressant, has caused male sexual dysfunction; however, the paroxetine 
      mechanisms of action in testes are still unclear. OBJECTIVES: Paroxetine 
      serotonergic effects in testes were evaluated, focusing on steroidogenesis and 
      the correlation between macrophages population and possible TNF-alpha-derived 
      oxidative stress. We also verified whether the changes are reversible following 
      treatment interruption. MATERIALS AND METHODS: Adult rats received paroxetine 
      (PG35 and PG65) or tap water (CG) for 35 days. PG65 was maintained without 
      treatment for 30 more days. Intratesticular testosterone (IT), nitrite, and 
      malondialdehyde concentrations were measured. To confirm serotonergic and 
      estrogenic effects, Htr1b and Esr1 expressions were analyzed. The daily sperm 
      production (DSP), frequency of abnormal seminiferous tubules (ST), SC number, ST 
      area, and Leydig cells nuclear area (LCnu) were evaluated. TUNEL(+) germ cells, 
      M1 (CD68(+) ), and M2 (Perls(+) ) macrophages were quantified. 17beta-HSD7, CYP19A1, 
      NDRG2, oxytocin, TNF-alpha, and iNOS were evaluated by immunoreactions. Oxytocin and 
      NDRG2 protein levels as well as Tnfa mRNA expression were also analyzed. RESULTS: 
      The Htr1b downregulation in testes confirmed the paroxetine serotonergic effect. 
      The testicular sections showed abnormal ST frequency, ST atrophy and reduction of 
      DSP, LCnu, SC number and Perls(+) macrophages. TUNEL(+) germ cells and LC were 
      associated with strong NDRG2 immunoexpression. Paroxetine reduced IT levels and 
      17beta-HSD7 immunoexpression in parallel to increased CYP19A1, oxytocin, TNF-alpha and 
      iNOS. Esr1 and Tnfa overexpression and increased number of CD68(+) macrophages 
      were also observed together with high nitrite and malondialdehyde levels. Most 
      parameters were not recovered in PG65. CONCLUSIONS: Paroxetine serotonergic 
      effect impairs LC steroidogenesis, via aromatization, increasing 
      estrogen/testosterone ratio, which in turn upregulate NDRG2, promoting apoptosis, 
      and impairing sperm production. Serotonin-estrogen pathways may be responsible 
      for M2/M1 polarization, Tnfa upregulation, and induction of oxidative stress. The 
      unrecovered testicular changes after treatment discontinuation are due to 
      persistent paroxetine serotonin/estrogen effects.
CI  - (c) 2023 American Society of Andrology and European Academy of Andrology.
FAU - Beltrame, Flavia Luciana
AU  - Beltrame FL
AUID- ORCID: 0000-0003-1833-1150
AD  - Department of Morphology and Genetics, Federal University of Sao Paulo, Sao 
      Paulo, Brazil.
AD  - Institute of Health Sciences, Paulista University (UNIP), Sao Paulo, Brazil.
FAU - Moyses, Thiago Henrique Pereira
AU  - Moyses THP
AD  - Institute of Health Sciences, Paulista University (UNIP), Sao Paulo, Brazil.
FAU - Coelho, Monica Pereira
AU  - Coelho MP
AD  - Institute of Health Sciences, Paulista University (UNIP), Sao Paulo, Brazil.
FAU - Steinvascher, Maria Clara Rossetto
AU  - Steinvascher MCR
AD  - School of Dentistry, Department of Morphology, Genetics, Orthodontics and 
      Pediatric Dentistry, Sao Paulo State University (Unesp), Araraquara, Brazil.
FAU - de Oliveira, Salmo Azambuja
AU  - de Oliveira SA
AD  - Department of Morphology and Genetics, Federal University of Sao Paulo, Sao 
      Paulo, Brazil.
FAU - da Silva, Andre Acacio Souza
AU  - da Silva AAS
AD  - Department of Morphology and Genetics, Federal University of Sao Paulo, Sao 
      Paulo, Brazil.
FAU - Cerri, Paulo Sergio
AU  - Cerri PS
AD  - School of Dentistry, Department of Morphology, Genetics, Orthodontics and 
      Pediatric Dentistry, Sao Paulo State University (Unesp), Araraquara, Brazil.
FAU - Sasso-Cerri, Estela
AU  - Sasso-Cerri E
AD  - School of Dentistry, Department of Morphology, Genetics, Orthodontics and 
      Pediatric Dentistry, Sao Paulo State University (Unesp), Araraquara, Brazil.
LA  - eng
GR  - 2017/19829-6/FAPESP/
GR  - 2021/07207-6/FAPESP/
GR  - 2021/09328-5/FAPESP/
GR  - 2022/10560-2/FAPESP/
GR  - code 001/CNPq; CAPES/
GR  - Vice-Reitoria de Pos-Graduacao e Pesquisa (UNIP)/
PT  - Journal Article
DEP - 20230907
PL  - England
TA  - Andrology
JT  - Andrology
JID - 101585129
RN  - 41VRH5220H (Paroxetine)
RN  - 333DO1RDJY (Serotonin)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 50-56-6 (Oxytocin)
RN  - 0 (Nitrites)
RN  - 3XMK78S47O (Testosterone)
RN  - 0 (Estrogens)
RN  - 4Y8F71G49Q (Malondialdehyde)
SB  - IM
MH  - Male
MH  - Rats
MH  - Animals
MH  - *Testis/metabolism
MH  - *Paroxetine/pharmacology/metabolism
MH  - Serotonin
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Oxytocin
MH  - Nitrites/metabolism/pharmacology
MH  - Semen
MH  - Testosterone/pharmacology
MH  - Estrogens/metabolism
MH  - Macrophages
MH  - Malondialdehyde/metabolism/pharmacology
OTO - NOTNLM
OT  - Leydig cells
OT  - SSRI
OT  - apoptosis
OT  - nitric oxide
OT  - testosterone
EDAT- 2023/09/07 12:41
MHDA- 2024/02/14 12:42
CRDT- 2023/09/07 07:53
PHST- 2023/07/19 00:00 [revised]
PHST- 2023/01/26 00:00 [received]
PHST- 2023/08/08 00:00 [accepted]
PHST- 2024/02/14 12:42 [medline]
PHST- 2023/09/07 12:41 [pubmed]
PHST- 2023/09/07 07:53 [entrez]
AID - 10.1111/andr.13513 [doi]
PST - ppublish
SO  - Andrology. 2024 Mar;12(3):655-673. doi: 10.1111/andr.13513. Epub 2023 Sep 7.