
==== Front
eBioMedicine
EBioMedicine
eBioMedicine
2352-3964
Elsevier

S2352-3964(24)00320-7
10.1016/j.ebiom.2024.105284
105284
Articles
Effects of the glucagon-like peptide-1 receptor agonist dulaglutide on sexuality in healthy men: a randomised, double-blind, placebo-controlled crossover study
Lengsfeld Sophia ab
Probst Leila ab
Emara Yara ab
Werlen Laura b
Vogt Deborah R. b
Bathelt Cemile ab
Baur Fabienne ab
Caviezel Brida ab
Vukajlovic Tanja ab
Fischer Manuel c
Winzeler Bettina bettina.winzeler@usb.ch
ab∗
a Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland
b Department of Clinical Research, University Hospital Basel, University of Basel, Spitalstrasse 8/12, 4031 Basel, Switzerland
c Reproductive Medicine and Gynecological Endocrinology (RME), Women's Health Clinic, University Hospital Basel, Vogesenstrasse 134, 4031 Basel, Switzerland
∗ Corresponding author. bettina.winzeler@usb.ch
04 9 2024
9 2024
04 9 2024
107 10528426 1 2024
31 7 2024
31 7 2024
© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Summary

Background

The reward-regulatory properties of GLP-1 are attracting increasing interest. Animal studies show that GLP-1 receptor agonists not only reduce consumption of addictive substances, but also influence sexual behaviour. We aimed to investigate the effect of dulaglutide versus placebo on sexual desire in humans.

Methods

In this randomised, double-blind, placebo-controlled crossover trial, healthy eugonadal men of normal weight, aged 18–50 years with active and satisfactory sex lifes were (1:1) randomly allocated to dulaglutide or placebo for four weeks. We assessed sexual desire (Massachusetts General Hospital-Sexual Functioning Questionnaire [MGH-SFQ]), hormones of the hypothalamic-pituitary-gonadal axis (total testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and sperm parameters. Changes in these parameters were compared under dulaglutide versus placebo using paired t-tests.

Findings

24 out of 26 randomised participants completed the study (13 participants randomised to dulaglutide first and 13 to placebo first). No change in the MGH-SFQ was observed after four weeks of dulaglutide versus placebo (estimated difference 0.58 [95% CI −0.83 to 2.00], p-value = 0.402). Hormones of the hypothalamic-pituitary-gonadal axis (estimated differences: total testosterone (nmol/l) 0.9 [95% CI −1.5 to 3.3], FSH (IU/l) −0.2 [95% CI −0.3 to 0.0] and LH (IU/l) −0.8 [95% CI −1.5 to 0.0]) as well as sperm parameters all remained in the normal range without significant differences between the treatments. No severe adverse events occurred.

Interpretation

In this study of healthy men, we found no evidence of negative impacts of a four-week treatment with the widely used GLP-1 receptor agonist dulaglutide on sexual desire, hypothalamic-pituitary-gonadal axis hormones or sperm parameters.

Funding

Swiss National Science Foundation (PZ00P3_193206 ), 10.13039/501100005688 Gottfried and Julia Bangerter-Rhyner Foundation , 10.13039/501100016071 Goldschmidt-Jacobson Foundation , Swiss Academy of Medical Sciences.

Keywords

Sexual desire
GLP-1
Reward
Hypothalamic-pituitary-gonadal axis
Sperm parameters
==== Body
pmc Research in context

Evidence before this study

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have attracted interest for their potential beyond insulin regulation and appetite suppression, showing promise in reward regulation. Animal studies suggest their ability to reduce the intake of addictive substances (e.g., alcohol, nicotine, cocaine), although human data are less consistent. Sexuality, another intrinsic reward, may also be affected by GLP-1 RA, as suggested by two studies of exenatide in mice. We searched PubMed using the terms “GLP-1” AND “sexual desire” OR “sexuality” OR “sexual behaviour” from September 2020 to April 2024 and reviewed clinical trials. To date, no clinical trials have been published on this topic, except in the specific context of obesity-related functional hypogonadism.

Added value of this study

In this double-blind, placebo-controlled crossover study of 24 lean healthy males, we found no impact of the GLP-1 RA dulaglutide on sexual desire compared to placebo.

Implications of all the available evidence

The results may suggest that the effects of GLP-1 RA on sexuality are different in rodents and humans. However, many other aspects could be at play: First, the effects of GLP-1 RAs on reward and addictive behaviour may be different in lean versus overweight/obese individuals, as suggested by a study in alcohol dependence. Second, different GLP-1 RAs may have different effects on different behaviours. Future studies should address these issues and, importantly, include women.

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for the treatment of type 2 diabetes mellitus and obesity due to their insulinotropic and satiation promoting effects. In recent years, Glucagon-like peptide-1 (GLP-1) has attracted attention as a potential modulator of other reward-seeking behaviours beyond food consumption. As an anatomical correlate in the brain, GLP-1 producing neurons of the nucleus of the solitary tract project directly to areas of the reward pathway (i.e. the nucleus accumbens, ventral tegmental area and laterodorsal tegmental area), where GLP-1-receptors (GLP-1-R) are widely expressed.1 Besides altering satiety and motivation for palatable food, different preclinical and clinical studies showed modulating effects of GLP-1 RA of the reward to addictive substances, such as alcohol, nicotine, amphetamine, opioids or cocaine2, 3, 4, 5, 6, 7, 8, 9 leading to reduced use of these substances (whereby the effect on alcohol consumption was only seen in obese, not normal weight people).

Sexual desire as another natural reward may equally be affected by GLP-1 RAs through a weakening of the resulting reward. Indeed, in sexually naïve male mice, sexual interaction behaviours decreased after administration of the GLP-1 RA exendin-4 by both acute systemic injection and infusion into the nucleus of the solitary tract.10,11 Sexuality is a very important aspect of human wellbeing, and the use of GLP-1 RAs is becoming more frequent in a broad spectrum of patients with diabetes and obesity in all age groups. To date, information about how GLP-1 RAs affect sexual desire and sexual health in humans is lacking. On one hand, one could speculate that GLP-1 RAs, similar as in the mouse study, reduce sexual desire. On the other hand, especially in obese individuals, it would also be conceivable that weight loss could lead to improved body image and functioning of the often altered hypothalamic-pituitary-gonadal (HPG) axis, which in turn could result in an increase in sexual desire and activity. The primary aim of this study was to investigate the influence of GLP-1 RAs on sexual reward and desire in a population, where altered body image or HPG axis are not typically an issue, namely healthy lean male individuals. GLP-1 RA's effects on other aspects of sexual health, including sex hormones and male fertility are also not fully understood. With regard to sperm quality, the literature is inconsistent. While two case reports described a worsening of sperm parameters with liraglutide and a dipeptidyl peptidase-4 inhibitor, more recent studies suggest a beneficial effect of GLP-1 RAs on sperm parameters.1,12, 13, 14, 15, 16

Further aims of the study were, therefore, to explore GLP-1 RAs effects on hormones of the HPG axis and on sperm parameters.

Methods

Trial design and participants

This is a single-centre, randomised, double-blind, placebo-controlled, crossover trial conducted at the University Hospital Basel in Switzerland. Healthy men were enrolled based on the following inclusion criteria: normal weight (BMI 18.5–25.0 kg/m2 or BMI 25.1–30.0 kg/m2 and waist circumference <102 cm), age between 18 and 50 years, an active sex life (sex with partner or masturbation ≥2 x/week), a satisfactory or very satisfactory sex life (grading was assessed by means of a questionnaire: dissatisfied, acceptable, satisfied, very satisfied) and eugonadism (morning total testosterone ≥12 nmol/l). Exclusion criteria included the presence of any pre-existing medical condition or regular use of addictive substances (full list of eligibility criteria is shown in the Supplementary Appendix. In view of the study outcomes “hormones of HPG axis” and “sperm parameters”, the study cohort was limited to men (less hormonal variability over time).

Ethics

The trial protocol was approved by the Northwestern and Central Switzerland Ethics Committee (EKNZ in Basel, Switzerland, BASEC2020-02572) and the National Agency for the Authorisation and Supervision of Therapeutic Products (Swissmedic, Berne, Switzerland, SNCTP000004202). Written informed consent was obtained from each participant. The trial was registered with ClinicalTrials.gov (NCT04687514).

Trial objectives and outcomes

The overall objective of the study was to evaluate whether four weeks of treatment with the GLP-1 RA dulaglutide alters sexual desire, hormones of the HPG axis (total testosterone, follicle-stimulating hormone [FSH] and luteinizing hormone [LH], sex hormone-binding globulin [SHBG] and free testosterone), sperm parameters and mood (through the Patient Health Questionnaire for depression [PHQ-9]) in healthy men as compared to placebo.

The primary endpoint was sexual desire, which was assessed by the difference of the absolute change in the Massachusetts General Hospital-Sexual Functioning Questionnaire (MGH-SFQ) sum score from baseline to end of treatment between dulaglutide and placebo.17

Randomisation and masking

Participants were randomised to dulaglutide and placebo in random order. The allocation to treatment sequence was randomised 1:1 on the basis of a previously generated randomisation list on www.sealedenvelope.com (randomly selected, varying block sizes; no stratification) by one unblinded person not involved in the study otherwise. The breakdown codes were kept in sealed envelopes. Participants, investigators, and nurses were blinded to the treatment arms except for unblinded study nurses administering the trial medication. Due to distinct injection devices for dulaglutide and placebo, unblinded staff not part of the trial conducted injections. Participants wore blindfolds during drug administration to prevent viewing the injection site or device.

Trial medication

The trial medication (dulaglutide or placebo) was injected weekly subcutaneously. Dulaglutide doses were 0.75 mg/0.5 ml for week 1 and 1.5 mg/0.5 ml for the following three weeks (see Supplementary Appendix for trial dose modification after trial start). Further dose reductions were allowed if necessary (see Supplementary Appendix). The control intervention received 0.5 ml sodium chloride (NaCl 0.9%).

Trial procedures

The trial procedures are displayed in Figure S1. At the baseline visit, the following actions were performed: assessment of demographics and medical history; a short physical examination (weight, BMI, blood pressure); sexual desire assessment via MGH-SFQ (a validated questionnaire consisting of five items addressing sexual interest, arousal, orgasm, erection, overall sexual satisfaction; each item is rated by a discrete score ranging from 1 to 6 [1 = greater than normal; 2 = normal; 3 = minimally diminished; 4 = moderately diminished; 5 = markedly diminished; 6 = totally absent]. The MGH-SFQ sum score ranges from 5 to 30, with 10 indicating normal functioning, values <10 indicating improved functioning, and values > 10 indicating diminished functioning. A positive score change indicates worsening of sexual functioning, see also MGH-SFQ in the Supplementary Appendix; further questions of sexual functioning inquiring frequencies and intensities (Supplementary Appendix); mood assessment (PHQ-9; a well-validated screening tool of nine questions to diagnose depression and asses severity; severity score 0–27: <5 = normal, 5 or higher values stand for higher severity of depression; see Supplementary Appendix).

Laboratory measurements were performed in the central laboratory of the hospital (HbA1c: Calibrator for automated systems, Roche/Hitachi, Cobas c 502M; total testosterone, FSH, LH and SHBG: automated electrochemiluminescence immunoassay, Roche Diagnostics, COBAS e801; free testosterone was calculated considering the methods of Vermeulen et al.).18

Semen samples were obtained on-site following at least two days of sexual abstinence and after collection in 110 ml sterile plastic containers (BD Falcon, Franklin Lakes, NJ, USA) allowed to liquefy at 37 °C for 30 min. Semen volume was determined by weight. Semen analysis was done by inspection using phase-contrast microscopy according to WHO guidelines (WHO, 2010) at room temperature (22 °C). Sperm concentration (million sperm/ejaculate), progressive motility (%) and morphology were assessed using a Computer Assisted Sperm Analyzer (CASA) (Sperm Class Analyzer—SCA, Microptic, Spain). Further information regarding semen analysis is given in the Supplementary Appendix.

At following visits, the MGH-SFQ, possible adverse events and change of medication were assessed. At the evaluation visit, a short physical examination, the PHQ-9 and laboratory tests were performed analogously to the baseline visit. Due to the physiology of sperm formation, follow-up visit of sperm analysis was planned >60 days after the last injection.

Sample size estimation

Since no data on MGH-SFQ under treatment with dulaglutide were available, we based our assumptions on the reported results of Abler et al. who assessed the MGH-SFQ before and after treatment with paroxetine and placebo in healthy men.19

Baseline values were assumed to have a mean score of 10.0 and a standard deviation (SD) of 2.0. We expected a small impairment due to the placebo treatment and expected a mean score (SD) of 11.0 (2.0) at the end of placebo treatment. We assumed that dulaglutide would clearly diminish sexual functioning leading to a mean score (SD) of 14.0 (4.0) at the end of dulaglutide treatment. A difference of ≥3.0 points in the MGH-SFQ-Score between baseline and evaluation visit compared to placebo was defined to be clinically relevant. We further assumed that within patients, baseline and end of treatment values are weakly to moderately correlated with ρ = 0.3.

To estimate the required samples size, we simulated synthetic data sets according to these assumptions (i.e. for each synthetic patient, we sampled the baseline and end of treatment values under placebo and verum from a multivariate normal distribution, rounded to integers) and performed the intended primary analysis—a two-sided paired t-test on the respective changes under verum and placebo—to each of the simulated data sets and rejected the null hypothesis if the p-value was smaller than the type I error rate, α = 0.05. To achieve the desired power of 80%, the analysis showed that a total of 24 patients should be recruited in order to end up with 21 evaluable patients (assuming a dropout rate of 10%).

Analysis sets

The analysis set includes all patients recruited into the study minus any who dropped out. As gastrointestinal symptoms are common adverse effects of GLP-1 RAs and may influence sexual desire, we defined an additional no-symptoms set excluding participants who experienced persistent moderate to severe gastrointestinal or other adverse effects at the evaluation visit.

Statistics

All analyses were performed in R version 4.2.2 Patched (2022-11-10 r83330).20 We calculated summary statistics for participant baseline characteristics as frequencies and percentages for categorical variables and as mean (SD) (or median and interquartile range [IQR], as deemed appropriate) for numerical variables.

The primary analysis tested the difference between dulaglutide and placebo in the primary outcome, i.e. the change of the MGH-SFQ sum score from baseline to end of treatment. For each estimate, we provided 95% confidence interval (CI) and corresponding p-values derived from the paired t-test. We repeated the primary analysis on the no-symptoms analysis set.

Statistics of secondary analyses are described in the Supplementary Appendix.

Role of funders

The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. SL and BW had access to all data and had final responsibility for the decision to submit for publication.

Results

Participant baseline characteristics

Between May 2021 and February 2022 (last participant out: July 2022), 26 participants were randomised (13 to dulaglutide followed by placebo and 13 to placebo followed by dulaglutide, respectively). Two participants discontinued the study in the first phase before the first evaluation visit took place: one due to logistical issues (placebo group) and one due to tolerability of treatment (dulaglutide group). These participants were replaced in order to reach the targeted sample size. The dulaglutide dose was reduced from 1.5 mg to 0.75 mg in 4/24 participants for a total of 4 visits (1 visit each) due to tolerability issues. The no-symptoms analysis set included 17 participants (10 to dulaglutide followed by placebo and 7 to placebo followed by dulaglutide, respectively), see Fig. 1.Fig. 1 CONSORT Flow Diagram (adapted from Dwan K, Li T, Altman DG, Elbourne D. CONSORT 2010 statement: Extension to randomised crossover trials. The BMJ. 2019; 366.). Consolidated Standards of Reporting Trials diagram of the progress through the phases of this single-centre, randomised, double-blind, placebo-controlled trial with crossover design including healthy male participants who received once-weekly placebo or dulaglutide subcutaneously in random order for 4 weeks each.

Baseline characteristics are shown in Table 1. Participants had a median age of 24.5 years [IQR 21.0–29.0], a median BMI of 23.9 kg/m2 [IQR 22.2–25.0]. Median HbA1c value was 5.1% [IQR 5.1–5.3], range was 4.2–5.5%. Sexual function as assessed by the mean (SD) cumulative score of the MGH-SFQ was 9.8 (1.0) (n = 24) before start of dulaglutide and 10.4 (0.7) (n = 24) before start of placebo (10 points correspond to an individual's usual range). Participants reported having a satisfactory (n = 16 [66.7%]) or very satisfactory (n = 8 [33.3%]) sex life. The majority (n = 19 [79.2%]) experienced sexual desire at least once per day. Sexual activity with a partner was reported to take place at least once per week in 14/24 (58.3%) and by masturbation at least once per week in 17/24 participants (70.8%). Desire for physical proximity was experienced at least once or several times per day by 14/24 (58.3%), several times per week by 6/24 (25%) and less than weekly by 4/24 (16.7%).Table 1 Baseline characteristics (n = 24).

	Overall	Treatment sequence	
Dulaglutide and placebo	Dulaglutide > Placebo	Placebo > Dulaglutide	
Age at inclusion, median [IQR]	24.5 [21.0–29.0]	23.5 [21.0–29.3]	25.0 [21.0–27.5]	
Ethnicity				
 Caucasian, n (%)	21 (87.5)	11 (91.7)	10 (83.3)	
 Mixed Caucasian/African	1 (4.2)	1 (8.3)	0 (0.0)	
 Mixed Caucasian/Hispanic	2 (8.3)	0 (0.0)	2 (16.7)	
BMI (kg/m2), median [IQR]	23.9 [22.2–25.0]	24.1 [22.7–25.4]	23.2 [22.2–24.5]	
Systolic blood pressure (mmHg), mean (SD)	118.5 (13.3)	118.3 (14.2)	118.8 (13.0)	
Diastolic blood pressure (mmHg), mean (SD)	64.8 (9.7)	64.4 (9.3)	65.3 (10.5)	
Satisfaction with sex life, n (%)				
 Satisfied	16 (66.7)	7 (58.3)	9 (75.0)	
 Very satisfied	8 (33.3)	5 (41.7)	3 (25.0)	
Relationship, n (%)				
 Permanent relationship	15 (62.5)	9 (75.0)	6 (50.0)	
 Casual sex partner/open relationship	2 (8.3)	0 (0.0)	2 (16.7)	
 Single	7 (29.2)	3 (25.0)	4 (33.3)	
Number of sex partners last month, median [IQR]	1.0 [1.0–1.0]	1.0 [1.0, 1.0]	1.0 [1.0, 1.3]	
Frequency of sexual desire, n (%)				
 More than once daily	8 (33.3)	4 (33.3)	4 (33.3)	
 Daily	11 (45.8)	7 (58.3)	4 (33.3)	
 More than once weekly (not daily)	5 (20.8)	1 (8.3)	4 (33.3)	
 Less than once per week	0 (0.0)	0 (0.0)	0 (0.0)	
Frequency of masturbation, n (%)				
 More than once daily	1 (4.2)	0 (0.0)	1 (8.3)	
 Daily	3 (12.5)	2 (16.7)	1 (8.3)	
 More than once weekly (not daily)	13 (54.2)	6 (50.0)	7 (58.3)	
 Less than once per week	7 (29.2)	4 (33.3)	3 (25.0)	
Frequency of sex with a partner, n (%)				
 More than once daily	2 (8.3)	1 (8.3)	1 (8.3)	
 Daily	1 (4.2)	0 (0.0)	1 (8.3)	
 More than once weekly (not daily)	11 (45.8)	6 (50.0)	5 (41.7)	
 Less than once per week	10 (41.7)	5 (41.7)	5 (41.7)	
HbA1c, %, median [IQR]	5.1 [5.1–5.3]	5.1 [4.9–5.4]	5.2 [5.1–5.2]	
Hormones of the HPG axis, median [IQR]				
 FSH	3.1 [2.4–4.9]	2.8 [2.5–3.8]	4.3 [2.3–5.1]	
 LH	5.6 [4.1–6.8]	5.5 [4.2–6.8]	5.7 [3.6–6.8]	
 Total testosterone	18.6 [15.4–22.6]	19.5 [15.4–22.0]	17.7 [16.1–24.0]	
MGH-SFQ, mean (SD)	10.1 (0.9)	9.8 (1.0)	10.4 (0.7)	
PHQ-9, median [IQR]	3.0 [2.0–4.0]	3.0 [2.8–4.0]	2.5 [1.8–5.0]	
Abbreviations: HPG axis, hypothalamic-pituitary-gonadal axis; FSH, follicle-stimulating hormone; LH, luteinizing hormone; MGH-SFQ, Massachusetts General Hospital-Sexual Functioning Questionnaire; PHQ-9, Patient Health Questionnaire-9 for depression.

Primary outcome: change in sexual desire

We first examined the data by plotting and inspecting the primary outcome according to trial arm and randomisation sequence. We did not observe evidence of a carry-over effect (see Figure S2 and Tables S1 and S2). We also checked that the assumptions for the paired t-test were not violated.

The MGH-SFQ only minimally increased (indicating worsening) by mean (SD) 1.0 (2.2) under dulaglutide and by 0.4 (2.7) under placebo after 4 weeks of treatment without any relevant difference between the groups: while a difference of 3 score points was assumed to be clinically relevant, the estimated difference was 0.6 [95% CI −0.8 to 2.0], p-value = 0.402, see Fig. 2 and Figure S3. We also did not observe relevant differences in the different sub-items, such as sexual interest, arousal, orgasm, erection, overall sexual satisfaction, during the study period and between treatment groups, see Table 2. Similar results were seen in the no-symptoms analysis set, see Supplementary Appendix.Fig. 2 Within-subject difference of the MGH-SFQ sum score after 4 weeks of treatment. In the y-axis, subjects are represented as bars. The x-axis shows the within-subject difference of the MGH-SFQ score from baseline to the evaluation visit between dulaglutide and placebo for each subject. The red bars represent the subjects for whom the MGH-SFQ sum score rose more under placebo than under dulaglutide (7 subjects), and the blue bars the subjects for whom the MGH-SFQ sum score rose more under dulaglutide than under placebo (10 subjects). For 7 subjects, there was no difference between how the MGH-SFQ sum score changed under the two treatments. Abbreviations: MGH-SFQ, Massachusetts General Hospital-Sexual Functioning Questionnaire.

Table 2 Outcome summary statistics (n = 24).

Variable	Evaluation visit, dulaglutide	Change from Baseline, dulaglutide	Evaluation visit, placebo	Change from baseline, placebo	Estimated difference in change dulaglutide-placebo [95% CI], p-valuea	
BMI (kg/m2), median [IQR]	22.6 [21.3–24.5]	−0.7 [−1.4 to −0.2]	23.4 [21.9–25.2]	0.1 [−0.2 to 0.4]		
Systolic blood pressure (mmHg), mean (SD)	116.9 (13.4)	−2.9 (12.4)	119.2 (10.8)	−1.0 (8.9)		
Diastolic blood pressure (mmHg), mean (SD)	65.3 (8.8)	−1.7 (6.8)	68.7 (8.7)	0.7 (7.9)		
MGH-SFQ, mean (SD)	11.0 (1.9)	1.0 (2.2)	10.8 (2.6)	0.4 (2.7)	0.6 [−0.8 to 2.0], 0.402	
 Sexual interest	2.3 (0.8)	0.3 (0.9)	2.2 (0.7)	0.2 (0.6)		
 Sexual arousal	2.1 (0.4)	0.1 (0.7)	2.2 (0.7)	0.2 (0.7)		
 Orgasm	2.2 (0.7)	0.2 (0.7)	2.1 (0.3)	0.0 (0.4)		
 Erection	2.0 (0.5)	0.1 (0.6)	2.1 (0.9)	0.1 (0.9)		
 Sexual satisfaction	2.4 (0.7)	0.3 (0.9)	2.2 (0.7)	−0.1 (1.0)		
PHQ-9, median [IQR]	4.0 [3.0–6.0]	1.0 [0.8–2.0]	3.0 [1.5–3.0]	0 [−1.0 to 1.0]		
HbA1c, %, median [IQR]	5.0 [4.9–5.1]	−0.2 [−0.3 to 0]	5.1 [5.0–5.2]	0.0 [−0.1 to 0.1]	−0.16 [−0.30, −0.03]b	
Hormones of the HPG axis, median [IQR]						
 Total testosterone (nmol/l)	19.7 [18.6–22.7]	0.7 [−0.4 to 2.0]	19.6 [17.9–21.0]	−1.2 [−2.6 to 3.1]	0.92 [−1.47, 3.32]b	
 FSH (IU/l)	3.1 [2.1–4.7]	0.0 [−0.2, 0.1]	3.2 [2.2–4.7]	0.0 [−0.3 to 0.4]	−0.16 [−0.33, 0.02]b	
 LH (IU/l)	5.2 [3.9–6.0]	−0.7 [−1.4 to 0.2]	4.7 [4.3–6.4]	0.0 [−1.1 to 0.8]	−0.75 [−1.54, 0.04]b	
 SHBG (nmol/l)	36.5 [30.1–43.8]	4.1 [0.2–7.4]	32.6 [27.8–38.7]	−0.2 [−4.9 to 2.4]	4.72 [−0.06, 9.50]a	
 Free testosterone (nmol/l)	0.4 [0.4–0.5]	0.0 [−0.1 to 0.0]	0.4 [0.4–0.5]	0.0 [−0.1 to 0.1]	−0.01 [−0.08, 0.06]a	
Semen analysis, median [IQR]						
 Sperm concentration (million sperm/ejaculate)	168.8 [52.5–248.9]	29.1 [−29.0 to 52.9]	97.9 [78.3–146.8]	−13.3 [−64.9 to 31.5]	36.01 [−8.64, 80.65]b	
 Sperm progressive motility (%)	54.0 [46.0–66.2]	−2.0 [−9.2 to 9.0]	56.0 [46.0–66.0]	−1.0 [−12.0 to 10.0]	−0.48 [−7.59, 6.64]b	
Abbreviations: CI, confidence interval; FSH, follicle-stimulating hormone; HPG axis, hypothalamic-pituitary-gonadal axis; LH, luteinizing hormone; MGH-SFQ, Massachusetts General Hospital-Sexual Functioning Questionnaire; PHQ-9, Patient Health Questionnaire-9 for depression; n, number; SHBG, sex hormone-binding globulin; y, years.

a Not adjusted for multiple testing.

b Unadjusted confidence interval.

Secondary outcomes

Further investigation of sexual functioning (frequency, intensity)

Frequency of sexual desire, sexual activity and desire for physical proximity slightly changed from baseline to end of treatment, but there was no consistent trend comparing dulaglutide versus placebo treated participants, see Figure S4.

Patient Health Questionnaire-9 for depression (PHQ-9)

PHQ-9 values fell within normal range (defined as <5 points) at baseline and evaluation visit under both treatments (dulaglutide: median [IQR] 4.0 [3.0–6.0]), median difference since baseline 1.0 [0.8–2.0]; placebo: median [IQR] 3.0 [1.5–3.0], median difference 0.0 [−1.0 to 1.0]), see also Table 2.

HPG axis: total testosterone, FSH, LH, SHBG and free testosterone

We observed no substantial change in total testosterone, FSH, LH, SHBG and free testosterone during the study, although total testosterone along with SHBG values tended to slightly increase under dulaglutide. Estimated differences in the change from baseline to end of treatment under dulaglutide and under placebo were as follows: total testosterone (nmol/l) 0.92 [95% CI −1.47 to 3.32], FSH (IU/l) −0.16 [95% CI −0.33 to 0.02] and LH (IU/l) −0.75 [95% CI −1.54 to 0.04], SHBG (nmol/l) 4.72 [95% CI −0.06 to 9.50], free testosterone (nmol/l) −0.01 [95% CI −0.08 to 0.06]). See also Table 2 and Fig. 3 and Figure S5.Fig. 3 Course of luteinizing hormone (a), follicle-stimulating hormone (b), total testosterone (c), sex hormone-binding globulin (d), free testosterone (e) before and after treatment with dulaglutide or placebo. The y-axis shows the absolute values of the hormones while the x-axis shows the baseline and evaluation visits. The line plots the mean values and course over the visits. Dulaglutide and placebo are represented by middle and light blue bars, respectively.

Semen analysis

No relevant differences have been observed concerning sperm progressive motility (%) −0.48 [CI −7.59 to 6.64] or sperm concentration (million sperm/ejaculate) 36.01 [−8.64 to 80.65]. See also Table 2 and Figure S6.

Tolerability of treatment

Gastrointestinal symptoms peaked at weeks 2–4 (week 2: 10 [41.7%] participants under dulaglutide and 4 [16.7%] under placebo), with abdominal pain and nausea as the most common complaints (see also Figure S7 and Table S3 in the Supplementary Appendix). Five incidents of gastrointestinal symptoms required treatment with medication (dulaglutide n = 3 [12.5%], placebo n = 2 [8.3%]).

Subjects under dulaglutide showed a weight reduction (−2.4 kg [−4.3 to −1]) in comparison with subjects under placebo (+0.2 kg [−0.5 to 1.2]). Likewise, HbA1c marginally decreased under dulaglutide (median [IQR] −0.2% [−0.3 to 0.0]) but not under placebo (median [IQR] 0.0% [−0.1 to 0.1]), estimated difference −0.16% [95% CI −0.30, −0.03].

28 adverse events were reported (11 under dulaglutide and 16 under placebo) with flu-like symptoms as the most common complaint (dulaglutide n = 4, placebo n = 7, before treatment n = 1). Most of the adverse events (19/28 [67.9%]) were not related to the study drug, while the remaining (9/28 [32.1%]) were judged to be possibly related (headache n = 7 [dulaglutide n = 5, placebo n = 2] and tiredness n = 2 [dulaglutide n = 1, placebo n = 1]). No serious adverse events were recorded. See also Table S4 of the Supplementary Appendix.

Discussion

Our study did not show any significant difference in sexual desire as assessed by the MGH-SFQ sum score after four weeks of dulaglutide treatment compared to placebo. We therefore have no evidence that the widely used GLP-1 RA dulaglutide impairs the sexual desire in healthy young men of normal weight.

Our findings contrast with those from preclinical data of Vestlund et al. showing altered behaviour in the sexual interaction chain in mice treated with the GLP-1 RA exendin-4 compared to placebo.10,11 While systemic administration of exendin-4 decreased the frequency and duration of mounting behaviours (sexual interaction phase), central administration into the nucleus tractus solitarius reduced additionally social (pre-sexual interaction phase) and self-grooming behaviours (post-sexual interaction phase).

Divergent results exist between animal and human studies on the impact of GLP-1 RAs on reward regulation particularly concerning nicotine and alcohol consumption: In animal studies, GLP-1 RA treatment (liraglutide and exendin-4) decreased the rewarding effects (assessed by conditioned place preference test) and the consumption of both alcohol and nicotine.4,5 However, these effects did not consistently translate to humans. In a randomised controlled trial of exenatide in alcohol use disorder, only effects (towards decreased consumption) were noted in obese people while effects on nicotine consumption were only evident in one preliminary study with exenatide, but not in a larger randomised controlled trial with dulaglutide.6,21,22 Obviously, several factors influence reward behaviour in different species, which may explain divergent effects. In conditions such as alcohol and nicotine dependence, intrinsic motivation of human individuals may relevantly influence abstinence rates in the placebo group. Further, impairment of sexual functioning, e.g., due to gastrointestinal side effects of GLP-1 RAs might have been an issue in animal studies, even if Vestlund et al. have suggested otherwise (kaolin intake in their exendin-4-treated rats unchanged).5,23,24 Also, clinical studies primarily focused on repeated treatment with GLP-1 RAs, while preclinical studies mostly highlighted the effects of acute rather than repeated treatment on reducing reward associated.22,24, 25, 26 Tolerance development may, therefore, play a role, as previously observed in cell culture and regarding gastric emptying.27,28

Interestingly, exenatide infusions were reported to “normalize” functional magnetic resonance imaging signals in areas associated with the reward system to a food paradigm only in a subgroup of patients with obesity (BMI >30 kg/m2) but not in lean individuals.29 Similarly, as mentioned above, exenatide once weekly for alcohol abuse disorder led to reduced alcohol drinking only in the subgroup of patients with obesity (BMI >30 kg/m2).22 The response to GLP-1 RAs may, therefore, be different in the setting of obesity, probably due to an altered GLP-1 signalling pathway.

In the slightly different context of men with obesity with or without diabetes and concomitant functional hypogonadism, GLP-1 RA treatment showed an improvement in sexual function.30,31 Since testosterone increased only moderately, the effect was mainly attributed to the weight loss and improved body image.30, 31, 32, 33 Furthermore, one could also speculate that by reducing the desire for food, further reward areas such as sexual desire might be reactivated.

Regarding GLP-1 RA effects on the HPG axis, an improvement of functional hypogonadism with increase of total testosterone, SHBG und gonadotropins was described in patients with obesity on liraglutide.30,31,34 Whether this is due to weight loss or additionally to direct GLP-1 RA effects is unknown. Of note, studies with acute intravenous GLP-1 infusions in healthy men suggested an impact on testosterone secretion pulsatility and duration, but not altered testosterone levels.35,36 In our study we observed the same tendencies as seen with chronic application in patients with obesity, but no significant or clinically relevant changes, which is well explained by the normal BMI and HPG axis of our healthy population.

As a last main outcome, our randomised placebo-controlled trial data did not provide evidence of impaired sperm concentration nor sperm progressive motility on dulaglutide compared to placebo. This is reassuring, as two case reports reported impairment of sperm parameters on liraglutide and on dipeptidyl peptidase-4 inhibitor.15,16 Our findings are also consistent with a prospective non-randomised non-placebo-controlled study including 110 men with obesity and functional hypogonadism reporting improvement of sperm parameters such as sperm motility, sperm activity or sperm count during a treatment with liraglutide.12 Preclinical data suggest that GLP-1 RA may directly impact sperm production since GLP-1 receptors have been found on sperm cells and an improvement of sperm parameters was observed on exendin-4 in vitro and in animal models.1,13

Concerning limitations, first, this single centre study of 24 healthy men between 18 and 50 years has limited generalisability and represents only an initial investigation to lay the groundwork for future research. The findings should be confirmed in female participants who were not included in this study due to practical limitations and increased variability in secondary outcomes such as sperm parameter and HPG hormones, respectively. Considering the potential variation in the effects of GLP-1 RAs among individuals with higher BMI or metabolic complications, who typically receive GLP-1 RAs in clinical settings, future investigations should also encompass these individuals. Second, we evaluated the primary outcome after a 4-week treatment period, a timeframe when GLP-1 RA effects on various cravings (e.g., food and drink) are observable, but gastrointestinal adverse effects have subsided. Our data does not allow to draw conclusions about the long-term impact of GLP-1 RA on sexual desire. Third, gastrointestinal side effects of GLP-1 RAs may be an important confounder. Yet, we addressed this concern through the auxiliary no-symptoms analysis set. Additionally, we considered other factors like testosterone and mood, both of which remained stable.27,29

Finally, there may be differences between GLP-1 RAs in potency, blood–brain barrier permeability and effects on different rewards. In rats, repeated administration of exendin-4, liraglutide, or dulaglutide had variable effects on food consumption or learning of skilled reach foraging.37 In humans, semaglutide has been shown to be more potent than dulaglutide with respect to weight loss and Hba1c improvement.38 The molecular weight of dulaglutide is higher (59.7 kDa) and therefore dulaglutide is less likely to be transported across the blood–brain barrier compared with the low molecular weight GLP-1 RAs exenatide, lixisenatide, liraglutide or semaglutide.39, 40, 41

The strengths of our study include the randomised controlled cross-over design.

Conclusion

Sexual desire is an important aspect of human wellbeing, and drug-related impairment must be carefully assessed. This study shows no evidence of negative impacts of the widely used GLP-1 RA dulaglutide on sexual desire, HPG hormones, mood or conventional sperm parameters in healthy and lean participants. As GLP-1 RAs may act differently in people with higher BMI, future studies investigating sexual desire should also include patients with obesity or diabetes who receive GLP-1 RAs in clinical routine and importantly also female individuals.

Contributors

SL and BW had accessed and verified the underlining data. SL wrote the protocol, collected, analysed and interpreted the data, did the literature search and wrote the manuscript. LP, YE, FB, CB, BC, TV contributed to the collection of data. DRV planned the statistical analyses and contributed to the manuscript. LW performed and interpreted the statistical analyses and contributed to the manuscript. MF contributed to the collection of data and interpreted the semen analyses. BW designed the study, wrote the protocol, collected, analysed and interpreted data, wrote the manuscript and, as the guarantor of this work, takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors edited and approved the final manuscript.

Data sharing statement

We share de-identified, individual participant-level data that underlie the results reported in this article and related documents, including the study protocol and the statistical analysis plan. Data will be available with the publication of our manuscript on receipt of a request detailing the study hypothesis and statistical analysis plan. All requests should be sent do the corresponding author. The steering committee of this study will discuss all requests and decide based on the scientific rigor of the proposal whether data sharing is appropriate. All applicants are asked to sign a data access agreement.

Declaration of interests

The authors have declared that no conflict of interest exists.

Appendix A Supplementary data

Clinical Study Protocol

me20ChristCrain3RAP_MainAnalyses Stand 6.9.22

Supplementary Appendix

Acknowledgements

We are grateful to our participants for taking part in the trial. We further thank the study personnel at the University Hospital Basel, and especially Nina Hutter, Joyce Santos de Jesus, Johannes Bitzer, Silke Scarascia, Fauzia Mughal, Jonathan Mudry, Klaus Ehrlich, and Nicole Salvisberg and all members of the clinical neuroendocrinology research team for their support.

Funding: This study was investigator-initiated. We thank the following organisations for their support: Swiss National Foundation (BW), the Gottfried & Julia Bangerter-Rhyner Stiftung (BW, SL), the Goldschmidt-Jacobson Foundation (BW), Department of Internal Medicine of the University Hospital of Basel (SL), Swiss Academy of Medical Sciences (SL).

Trial status: Completed.

Appendix A Supplementary data related to this article can be found at https://doi.org/10.1016/j.ebiom.2024.105284.
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