Sertraline Suppresses Testis and Adrenal Steroid Production and Steroidogenic Gene Expression While Increasing LH in Plasma of Male Rats Resulting in Compensatory Hypogonadism

The following study relates sexual dysfunction during SSRI treatment to very significantly decreased levels of T and DHT production, as well as decreased expression of steroidogenic acute regulatory protein (StAR), in the testes.

In addition, the full text describes lowered levels of Androstanediol (ADIOL) in the testes and significantly decreased levels of T, DHT, and ADIOL in the brain.

C. H. Munkboel, L. W. Larsen, J. J. Weisser, D. Møbjerg Kristensen, and B. Styrishave, “Sertraline Suppresses Testis and Adrenal Steroid Production and Steroidogenic Gene Expression While Increasing LH in Plasma of Male Rats Resulting in Compensatory Hypogonadism,” Toxicol Sci, vol. 163, no. 2, pp. 609–619, Jun. 2018.

Selective serotonin reuptake inhibitors are used as first line treatment in major depressive disorder. However, selective serotonin reuptake inhibitors have also been associated with sexual disorders, abnormalities, and sexual dysfunction, although mechanisms are unclear. The aim of this project was to investigate the possible endocrine disrupting effect of sertraline (SER) on sex steroid production in male rats exposed to 3 therapeutically realistic doses of SER 1.25, 5, and 20 mg/kg/day. To achieve this, we analyzed all the major steroids in testis, adrenals, brain, and plasma using Liquid chromatography tandem mass spectrometry. Furthermore, we investigated the potential effects on gene expression on the major genes involved in testicular, adrenal and brain steroidogenesis using quantitative PCR. Moreover, plasma luteinizing hormone (LH) levels were analyzed. We observed significant reduction in steroid production, in particular on the testicular Δ-4 axis and on the adrenal CYP17-hydroxylase axis. Effects in brain and plasma were less pronounced. Testicular gene transcription was also significantly down-regulated except for the CYP19 (aromatase) gene. In contrast, no effects on the adrenal gene expression were observed, except for an up-regulation of the CYP17. Plasma LH and LH/TS were increased, in particular in the lowest exposure group, indicating some degree of compensatory hypogonadism. In conclusion, this study demonstrates extensive endocrine disruption during SER exposure in male rats, both directly on steroid production in major endocrine tissues, but also indirectly by affecting gene expression. Furthermore, increased LH levels may augment decreased sex steroid production, in particular testosterone production, inducing a state of compensatory hypogonadism.


Sertraline is a horrible drug, it’s what initially gave me PSSD 3 years ago with delayed ejaculation and reduced glans sensitivity, looking back that was a blessing compared to full blow PFS/PAS that I have now. But I wonder if our genetic makeup is predisposed to get these conditions, for example if I was to try finasteroid before any of this I wound have no doubt I’d of got the same thing, as I did with ssri’s before accutane.


It was awful for me during treatment. COMPLETE anorgasmia, worsened numbness and ED, and felt very unlike myself. This was on top of pre-existing post-Accutane issues. Why any doctor would prescribe this stuff to someone complaining of sexual symptoms is beyond me. It’s more or less a prescription for causing sexual dysfunction, even for those who don’t develop PSSD.

The only saving grace is that the effects of the SSRI wore off after I quit and went back to baseline post-Accutane syndrome.

Many PFS/PAS guys have mentioned trying fluoxetine/Prozac or sertraline/Zoloft to increase allopregnanolone, but this appears to decrease allopregnanolone (3a-5aTH PROG) after long-term use:

M. Serra et al., “Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain,” Psychopharmacology (Berl.), vol. 158, no. 1, pp. 48–54, Oct. 2001.

Recent preclinical and clinical studies have shown that selective serotonin re-uptake inhibitors modulate neurosteroid synthesis in an opposite manner.

The action of long-term administration of fluoxetine was investigated on the peripheral and central concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-TH PROG) and 3alpha,5alpha-tetrahydrodeoxycorticosterone (of 3alpha,5alpha-TH DOC), progesterone, and pregnenolone in rats. We also investigated the effect of chronic treatment with fluoxetine on the foot-shock stress-induced increase in the plasma and brain concentrations of these steroids.

Fluoxetine was administered acutely (20 mg/kg) or chronically (10 mg/kg, once daily for 15 days). Steroids were extracted from plasma and brain, separated and purified by means of high-performance liquid chromatography, and quantified by means of radioimmunoassay.

A single dose of fluoxetine (20 mg/kg, i.p.) induced in 20 min significant increases in the cerebral cortical and plasma concentrations of 3alpha,5alpha-TH PROG (+96% and +13%, respectively), 3alpha,5alpha-TH DOC (+129 and +31%, respectively), progesterone (+111 and +58%, respectively), and pregnenolone (+151 and +59%, respectively). In addition, the plasma concentration of corticosterone was also significantly increased (+24%) after acute administration of fluoxetine. In contrast, long-term administration of fluoxetine reduced the basal concentrations of these various steroids (ranging from -22 to -43%), measured 48 h after the last drug injection, in both brain and plasma. A challenge injection of fluoxetine (20 mg/kg, i.p.), however, was still able to increase the concentrations of steroids in both the brain and plasma of rats chronically treated with this drug. Acute foot-shock stress increased the cortical and plasma concentrations of steroids in rats chronically treated with fluoxetine to extents similar to those apparent in control rats.

A repetitive increase in the brain concentrations of neuroactive steroids may contribute to the therapeutic action of fluoxetine.

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Had the same sides after coming off Fluoxetine and then Escitalopram. Finasteride initially cleared up those issues after I quit the first time, and then I got PFS after using it the second time. There has to be a connection.

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