Impact of duloxetine on male fertility: A randomised controlled clinical trial

Design

Double-blind, placebo-controlled, randomized, clinical trial

N= 68

Objective

To assess the impact of duloxetine on semen parameters, sperm deoxyribonucleic acid (DNA) fragmentation and serum hormones

Study Groups

Placebo (n= 34)

Duloxetine (n= 34)

Inclusion Criteria

Healthy male volunteers, aged 18 to 65 years

Exclusion Criteria

Varicoceles, abnormal semen analysis; ongoing attempts to initiate pregnancy; current sexual dysfunction (moderate or severe on the International Index of Erectile Function [IIEF] survey); history of seizure disorder, previous chemotherapy or radiation, current psychiatric disorder, bipolar disorder or family history (including cousins and grandparents) of bipolar disorder, major depressive disorder or suicide; used any psychotropic agents, anticonvulsants or sleeping pills more than once per week, hormonal medications (daily or intermittent, including glucocorticoid pills, inhalers or creams in the previous three months), medications that impact sexual function or prescription or nonprescription medications that enhance sexual function

Methods

Patients were randomized (1:1) to receive either placebo or duloxetine 60 mg once daily for 5 weeks, followed by 1 week of 30 mg once daily for a total of 6 weeks on duloxetine. Placebo group received an identical appearing placebo for 6 weeks. All semen samples were analyzed for total volume, sperm concentration, motility and morphology and also assessed for sperm DNA integrity utilizing the TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labelling) assay.

Duration

Treatment: 6 weeks

Follow-up: 10 weeks

Outcome Measures

Baseline Characteristics

Placebo (n= 34)

Duloxetine (n= 34)

Age, years

Race/ethnicity

Asian

Black

Hispanic

Mixed

Native American

White

1 (2.9%)

13 (38.2%)

3 (8.8%)

3 (8.8%)

1 (2.9%)

13 (38.2%)

2 (5.9%)

18 (52.9%)

4 (11.8%)

1 (2.9%)

0

9 (26.5%)

Not significant

Children

Sexually active

Sexual dysfunction

Median IIEF scores (IQR)

ED function

Orgasmic function

Sexual desire

Intercourse satisfaction

Overall satisfaction

29 (24.2 to 30)

10 (7 to 10)

9 (8 to 9)

11.5 (9 to 13)

8 (6 to 10)

29 (23.5 to 30)

9.5 (6.3 to 10)

9 (8 to 9.8)

13 (8.5 to 14)

8.5 (5.3 to 10)

Median MSHQ (IQR)

Erection

ED Bother

Ejaculation

Bother

Satisfaction

Additional

15 (12 to 15)

5 (4 to 5)

32 (28 to 33)

5 (5 to 5)

25 (22 to 30)

28 (25.3 to 29)

14 (12.3 to 15)

5 (5 to 5)

32 (30 to 33)

5 (5 to 5)

26 (23 to 30)

27.5 (26 to 30)

ED, erectile dysfunction; IQR, interquartile range; MSHQ, Men's Sexual Health Questionnaire

Results

Endpoint

Placebo (n= 34)

Duloxetine (n= 34)

p-value

TUNEL > 25%

On treatment (week 2 and 6 combined)

Week 2

Week 6

Off treatment (week 8 and 10 combined)

Week 8

Week 10

5/68

2/34

3/34

2/68

0/34

2/34

1/68

1/34

0/34

1/68

1/34

0/34

0.009

-

-

0.56

-

-

Median TUNEL (IQR), %

Week 0

Week 2

Week 6

Week 8

Week 10

6.8 (3.7 to 9.3)

6.1 (3.4 to 11.7)

6.4 (2.7 to 10.6)

5 (3.8 to 11.3)

5.2 (3.7 to 12.7)

6.2 (4.5 to 9)

7.7 (3.8 to 9.5)

6.2 (4.2 to 14.7)

5.3 (3 to 8.4)

9.5 (3.2 to 9.7)

0.97

0.6

0.4

0.4

0.19

Change in testosterone at week 2, ng/dL

-2.2

-28.1

0.02

Change in estradiol at week 8, pg/mL

-9.47

4.6

0.05

Serum estradiol at week 8, pg/mL

43.9 ± 24.3

57.8 ± 30

0.04

There was no difference in testosterone or serum estradiol at any time point except for when specified above. There were no differences in follicle-stimulating hormone (FSH), luteinizing hormone (LH), or prolactin at any time points.

There were no differences in semen parameters (sperm concentration and sperm motility) between groups at any time point.

There were no differences in either IIEF or MSHQ scores compared with baseline levels at all times points of duloxetine treatment, except for greater ejaculatory bother on the IIEF for participants on treatment at Week 2 (p= 0.03), MSHQ bother scores at week 2 (p< 0.01) and MSHQ erection scores at week 10 (p= 0.04).

Adverse Events

See 'Results' section

Study Author Conclusions

This is the first known human study to evaluate the potential adverse effects of an SNRI (duloxetine) on male fertility. We found no clinically relevant negative impacts on semen parameters or sperm DNA integrity. For men taking SSRIs who are interested in fertility and have abnormal sperm DNA integrity, change of medication to an SNRI may be considered to maintain fertility potential. In addition, only subtle changes in serum testosterone were observed with duloxetine in this study, unlike the profound changes in serum T seen previously on paroxetine.

InpharmD Researcher Critique

Some subjects were lost to follow-up at different time points, which may have decreased the power of analysis at each subsequent time point studied. For this reason, a difference at some time points may have been present between placebo and duloxetine, despite there being no difference in the actual analysis. Adherence to duloxetine or placebo was not monitored and may pose as a potential confounder in this study. The short duration of analysis also limits any knowledge of the long-term effects of SNRI therapy with duloxetine on male fertility outcomes.

Design

Retrospective cohort study

N= 3,694

Objective

To compare associations between individual antidepressants and newborn outcomes

Study Groups

Bupropion (n= 406)

Citalopram (n= 385)

Desvenlafaxine (n= 16)

Duloxetine (n= 139)

Escitalopram (n= 581)

Fluoxetine (n= 579)

Paroxetine (n= 55)

Sertraline (n= 1,653)

Venlafaxine (n= 132)

Inclusion Criteria

Exclusion Criteria

Not specified 

Methods

Data were compiled utilizing electronic medical records. Exposure to antidepressants was defined as having a prescription written during the time period studied. Adaptation syndrome was defined as any diagnosis of “neonatal abstinence syndrome” (NAS) or "pediatric adaptation syndromes" (PAS); two different terms exist due to a change in the hospital's coding to become more specific during the study period. Only the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) of interest were included in the analysis. 

Duration

Delivery occurred between January 1, 2010 and December 31, 2019.

Outcome Measures

Primary: neonatal intensive care unit (NICU) admission and any adaptation syndrome

Other outcomes: neonatal/fetal death, transient tachypnea of the newborn (TTN), intubation, pulmonary hypertension, seizures, juandice, cardiac malformations, 5 min APGAR < 7, preterm birth

Baseline Characteristics

Bupropion
(n= 406) 

Citalopram (n= 385)

Duloxetine
(n= 139)

Velafaxine (n= 132)

Maternal age (SD), years

Exposure 

Early 

1st trimester

3rd trimester

39.9%

25.1%

42.4%

49.3%

28.0% 

46.2%

37.5%

31.2% 

50.0%

43.9%

26.6% 

42.4%

45.7%

27.5%

48.7%

44.9%

26.1%

47.5%

54.5%

30.9%

18.2%

44.9%

27.6%

53.4%

46.2% 

31.1%

43.2%

White

Comorbidities 

Diabetes

Hypertension

12.1%

21.7%

8.8%

14.6%

0

6.2%

18.0%

25.2%

7.9%

14.3%

9.7%

15.2%

9.1%

16.4%

9.5%

16.1%

12.1%

18.9%

Results

Endpoint

Bupropion
(n= 406)

Citalopram (n= 385)

Velafaxine (n= 132)

TTN

Any adaptation syndrome

NICU admission

Only results with statistically significant rate differences of outcome distribution between the drugs (p < 0.05) are presented here. 

Adjusted odds ratio (aORs; 95% confidence interval) for:

Any adaptation syndrome: citalopram 1.81 (1 to 3.27), duloxetine 3.04 (1.54 to 5.98), escitalopram 2.26 (1.30 to 3.95), and paroxetine 2.60 (1.01 to 6.71)

Any adaptation syndrome specific early in pregnancy: duloxetine 2.31 (1.11 to 4.80), escitalopram 1.72 (1.09 to 2.71)

NICU admission: duloxetine 2.47 (1.40 to 4.34), escitalopram 1.64 (1.21 to 2.22)

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique

Cardiac malformations, the only type of birth defect included in this study, were not found to occur at a significantly different rate between any of the SSRI/SNRIs studied, but this study was not powered to find differences between individual drugs for more rare adverse outcomes, including cardiac malformations. 

The Effect of Antidepressants on Fertility

Design

Secondary analysis of Time to Conceive (TTC), an ongoing prospective time-to-pregnancy cohort study

N= 957

Objective

To assess the effects of antidepressants on the natural fertility in women

Study Groups

No antidepressant (n= 865)

Antidepressant (n= 92)

Inclusion Criteria

Women 30 to 44 years old who had been attempting to conceive for < 3 months

Exclusion Criteria

History of infertility, polycystic ovary syndrome, pelvic inflammatory disease, endometriosis, pelvic radiation, or a partner with a history of infertility

Methods

Information was collected via web-based questionnaires and daily diaries. While attempting to conceive, women completed an online daily diary for four months or until pregnancy was detected. If the woman did not conceive in the first four months of enrollment, she completed an online questionnaire monthly thereafter, which also collected information on medication use. Women took selective serotonin reuptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), serotonin antagonist and reuptake inhibitors, norepinephrine reuptake inhibitors, norepinephrine/dopamine reuptake inhibitors, tri- and tetracyclic antidepressants, monoamine oxidase inhibitors, and other antidepressants.

Duration

Enrollment: April 2008 to July 2015

Outcome Measures

Fecundability

Baseline Characteristics

No antidepressant (n= 865)

Antidepressant (n= 92)

Age, years

30 to 34

35 to 37

≥ 38

611 (70%)

157 (18%)

97 (11%)

64 (69%)

14 (15%)

14 (15%)

Not significant

Race

Non-Hispanic

Caucasian

652 (75%)

213 (25%)

84 (91%)

8 (8%)

< 0.01

Nulligravid

Previous pregnancy

Never been pregnant

445 (51%)

420 (49%)

53 (58%)

30 (42%)

Body mass index, kg/m²

< 18.5

18.5 to 24.9

25 to 29.9

≥ 30

23 (3%)

538 (62%)

175 (20%)

128 (15%)

1 (1%)

54 (59%)

24 (26%)

13 (14%)

Partner age, years

< 50

≥ 50

853 (99%)

11 (1%)

92 (100%)

0

Past year hormonal contraceptive use

391 (45%)

48 (52%)

Results

Women who were taking antidepressants at enrollment had an adjusted fecundability ratio (FR) of 0.86 (95% confidence interval [CI] 0.63-1.20).

Antidepressant use in a given cycle was associated with a reduced probability of conceiving in that cycle (adjusted FR 0.75; 95% CI 0.53-1.06).

After adjusting for a history of anxiety/depression as reported on the baseline questionnaire, the association between antidepressant use and fecundability remained (adjusted FR 0.66; 95% CI 0.45-0.97). There was also an association when restricting the analysis to women with a history of anxiety/depression (adjusted FR 0.64; 95% CI 0.43-0.94).

Adverse Events

N/A

Study Author Conclusions

Our data suggest that antidepressants may reduce the probability of a woman with a history of depression to conceive naturally. Future studies are needed to differentiate the extent to which this association is due to the antidepressant itself versus the underlying depression.

InpharmD Researcher Critique

This study did not exclusively include patients who were taking SNRIs and may not be generalizable to these patients. Additionally, the number of patients taking SNRIs was not reported. SSRIs may have been responsible for the reduction in fecundability since it was reported that patients were primarily taking SSRIs at baseline.