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Deleterious effects of selective serotonin reuptake inhibitor treatment on semen parameters in patients with lifelong premature ejaculation

Abstract

Premature ejaculation (PE), the most common sexual dysfunctions in men, is characterized by loss or absence of ejaculatory control. PE can be classified as either a lifelong or acquired condition. Although the prevalence of lifelong PE is rather low in the general male population, recent studies demonstrated that the patients who seek treatment for their rapid ejaculation mostly report lifelong PE. Although no drug for PE has been approved by regulatory bodies, chronic selective serotonin reuptake inhibitors (SSRIs) proved to be effective in treating lifelong PE. Despite the rising use and known effects of antidepressants on ejaculation, only a few reports have evaluated the impact of these drugs on the male fertility. Thus, the aim of this review is to evaluate the efficacy and adverse effects of SSRIs on semen parameters of patients with lifelong PE as well as to assess the safety of this treatment among sexually active couples who desire to have a child.

Introduction

Premature ejaculation (PE) is the most common sexual dysfunction in men. It is traditionally defined as the persistent or recurrent onset of orgasm and ejaculation with minimal stimulation before, on or shortly after penetration and before the person wishes it, which causes marked distress and interpersonal difficulty.1 The prevalence rate of PE has been reported to be between 21 and 31%,2, 3 and it is recognized that PE can impact on a man's life in many ways, such as reducing self-esteem, affecting interpersonal relationships, causing anxiety, embarrassment, depressed feeling and reducing overall quality of life.4, 5, 6

PE can be classified as either lifelong or acquired.7, 8 Lifelong PE is characterized as ejaculation that always or nearly always occurs before or within about 1 min of vaginal penetration; an inability to delay ejaculation on all or nearly all vaginal penetrations; and negative personal consequences, such as distress, bother, frustration and/or the avoidance of sexual intimacy.8

Managing PE can be somewhat challenging for physicians in part because the urologic regulatory bodies have not yet approved any pharmacological agents for treatment. Over the past decade, clinical evidence has emerged indicating a beneficial effect of selective serotonin reuptake inhibitors (SSRIs) for the treatment of men with lifelong PE, along with on-demand topical anesthetics.9, 10 In addition to their known efficacy, SSRIs have some adverse effects, which often decrease compliance when used chronically. Despite their wide off-label use for the indication of delaying emission and ejaculation, only a few reports have investigated their effects on male fertility.11, 12, 13

The aim of this review is to evaluate the overall efficacy and adverse effects of SSRIs on semen parameters in patients with lifelong PE and to assess the safety of this form of treatment on childbearing couples.

Efficacy and rationale of SSRI treatment in PE patients

Recent guidelines have proposed chronic use of SSRIs (for example, fluoxetine, sertraline, paroxetine and citalopram) for the treatment of PE.10 One randomized, comparative study demonstrated the efficacy and safety of fluoxetine, paroxetine and escitalopram in 100 normally potent men suffering from PE.14 There was a significant increase in mean intravaginal ejaculatory latency time and a decrease in the premature ejaculation diagnostic tool scores after 4 weeks of SSRI treatment.14 Another randomized, double-blind, placebo-controlled, fixed dose study, in 276 PE patients receiving escitalopram 10 mg per day, showed a 4.9-fold increase in the mean intravaginal ejaculatory latency time after 12 weeks, when compared with placebo.15 A systematic review and meta-analysis of all drug treatment studies confirmed the therapeutic benefits of SSRIs on PE.16 On the basis of this meta-analysis, SSRIs increase geometric mean intravaginal ejaculatory latency times 2.6- to 13.2-fold.16

On the basis of animal and human studies, Waldinger et al.17, 18, 19 postulated that lifelong PE is a neurobiological disorder related to decreased central serotonergic neurotransmission, 5-HT2C receptor hyposensitivity and/or 5-HT1A hypersensitivity. At least three serotonin receptor subtypes have been identified as having a role in ejaculation, where activation of the 5-HT1A receptor has a proejaculatory effect but activation of the 5-HT1B and 5-HT2C receptors delay ejaculation.20 To prevent overstimulation of post-synaptic 5-HT receptors, 5-HT transporters immediately return the 5-HT from the synapse back into the presynaptic neuron.9 The SSRIs block 5-HT transporter mechanisms and thereby increase 5-HT within the synapses. This in turn activates 5-HT1A and 5-HT1B receptors resulting in inhibition of serotonin release into the synapse. The result is sustained mild stimulation of all post-synaptic 5-HT receptors. With chronic administration of SSRIs, the receptors become desensitized and there is a reduction of inhibitory action on serotonin release.21 The overall effect is more serotonin release into the synapse causing activation of 5-HT2C receptors that adjusts the ejaculatory set point and delays the ejaculatory reflex.22

Adverse effects of SSRI on semen parameters

SSRI treatment is not without side effects. Common SSRI complaints include fatigue, drowsiness, nausea, vomiting, dry mouth and diarrhea; most of which are mild and gradually attenuate after 2–3 weeks.23 Sexual dysfunctions such as decreased libido, anorgasmia, anejaculation and ED have been well-documented side effects of SSRIs.23, 24 There are only a few studies that address the impact of SSRIs on spermatozoal function and fertility.

As paroxetine is known to bind to serotonin transporters by interacting with the sulfhydryl group, it has been hypothesized that SSRIs could cause deleterious effects on spermatozoa,25 because binding to sulfhydryl groups of sperm membrane is associated with spermicidal action.26, 27 In an experimental study, diluted SSRIs (paroxetine, sertraline and citalopram) and different human semen samples were mixed in vitro and evaluated under a microscope.28 The authors showed all three SSRIs caused a decrease in sperm motility and viability, suggesting a spermicidal action of SSRIs, probably related to their interaction with both spermatozoa and inner mitochondria membranes.28

From a clinical perspective, Tanrikut and Schlegel29 presented two cases with history of oligoasthenospermia who were prescribed SSRIs (citalopram and sertraline) for depression for longer than 6 months. They observed marked improvement in semen parameters within a few weeks of SSRI discontinuation. Considering this rapid deterioration and recovery of semen parameters (count, motility and morphology), the authors suggest that SSRIs may affect sperm transport, rather than sperm production.29

In addition to membrane damage and disruption of sperm transport, DNA changes may reduce sperm count, motility and normal morphology.30, 31, 32, 33 Some researchers observed significant impairment in all semen parameters (count, motility and morphology) and significant sperm DNA damage in depressed patients on SSRIs for more than 6 months.11 They observed further detrimental effects by SSRIs on semen parameters (count, motility and morphology) when the duration of treatment was extended and suggested that neuroendocrine factors have a central role in SSRI effects on spermatozoa.11

In a prospective study, Tanrikut et al.12 assessed semen analyses and sperm DNA integrity in 35 healthy men before receiving paroxetine for 5 weeks. After 5 weeks of paroxetine administration, higher DNA fragmentation rates were detected without any significant changes in other semen parameters. These finding reaffirm the authors’ hypothesis that impairment in sperm transport may alter sperm DNA integrity without effecting any changes in sperm count. The findings of this study showed that additional disruption occurred within 35 days, despite the fact that gonadotoxic effects on sperm function take at least 74 days.

Endocrine causes of infertility include hypopituitarism, where there is deficient follicle stimulating hormone and/or luteinizing hormone. We suggest that SSRI therapy induces changes in semen quality due to possible disruption of hormonal homeostasis. Serotonin increases prolactin by inhibiting dopamine and by stimulating the activity of prolactin releasing factors.34 Any increase in serum prolactin levels impairs fertility by one of several mechanisms, such as increasing dopamine (which suppresses gonadotropin releasing hormone) in the hypothalamus, suppressing follicle stimulating hormone and luteinizing hormone release in the pituitary and finally suppressing testosterone production. Furthermore, SSRIs may increase prolactin secretion by stimulating the 5-HT receptors.35

The single study, which demonstrates the impact of chronic SSRI treatment on semen parameters of lifelong PE patients, revealed semen parameters, which were initially normal.13 At the end of the 12-week escitalopram treatment, a significant decrease in sperm concentration, motility and normal sperm morphology was demonstrated. This prospective study revealed that prolonged SSRI treatment induced further deterioration in all the major semen parameters (concentration, motility, morphology).

Herein, the risk of male factor infertility becomes an important issue in men on long-term antidepressants. In 50% of childless couples there is a male factor present with semen changes, such as oligospermia and/or asthenospermia and/or teratospermia.36 In addition, drug use is a prognostic factor for male factor infertility in 3% of the infertile population.37 The potential effects of SSRIs on reducing fertility needs to be considered when using such drugs in the treatment of young men with lifelong PE. Physicians must be aware of this adverse effect of SSRIs and inform their PE patients who are in the reproductive age. Further studies are needed to elucidate how SSRIs affect spermatogenesis and determine if on-demand SSRI treatment has similar detrimental effects as occurs with daily SSRI treatment.

Conclusion

Published data clearly shows that chronic SSRI treatment has a detrimental effect on spermatogenesis, impairs sperm transportation, damages the sperm cell membrane, alters sperm DNA and/or effects hormonal homeostasis. Further randomized and placebo-controlled studies with larger series are needed to further delineate the underlying mechanisms causing sperm damage during daily SSRI treatment and determine if on-demand SSRI treatment may be more protective from sperm parameter changes.

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Correspondence to E C Serefoglu.

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Koyuncu, H., Serefoglu, E., Ozdemir, A. et al. Deleterious effects of selective serotonin reuptake inhibitor treatment on semen parameters in patients with lifelong premature ejaculation. Int J Impot Res 24, 171–173 (2012). https://doi.org/10.1038/ijir.2012.12

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Keywords

  • adverse effects
  • premature ejaculation
  • selective serotonin reuptake inhibitors

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