Sperm Count Is Increased by Diet-induced Weight Loss and Maintained by Exercise or GLP-1 Analogue Treatment

A Randomized Controlled Trial

Emil Andersen; Christian R. Juhl; Emma T. Kjøller; Julie R. Lundgren; Charlotte Janus; Yasmin Dehestani; Marte Saupstad; Lars R. Ingerslev; Olivia M. Duun; Simon B.K. Jensen; Jens J. Holst; Bente M. Stallknecht; Sten Madsbad; Signe S. Torekov; Romain Barrès

Disclosures

Hum Reprod. 2022;37(7):1414-1422.

Abstract and Introduction

Abstract

Study Question: Does diet-induced weight loss improve semen parameters, and are these possible improvements maintained with sustained weight loss?

Summary Answer: An 8-week low-calorie diet-induced weight loss was associated with improved sperm concentration and sperm count, which were maintained after 1 year in men who maintained weight loss.

What is Known Already: Obesity is associated with impaired semen quality. Weight loss improves metabolic health in obesity, but there is a lack of knowledge on the acute and long-term effects of weight loss on semen parameters.

Study Design, Size, Duration: This is a substudy of men with obesity enrolled in a randomized, controlled, double-blinded trial (the S-LITE trial). The trial was conducted between August 2016 and November 2019. A total of 56 men were included in the study and assigned to an initial 8-week low-calorie diet (800 kcal/day) followed by randomization to 52 weeks of either: placebo and habitual activity (placebo), exercise training and placebo (exercise), the Glucagon Like Peptide 1 (GLP-1) analogue liraglutide and habitual activity (liraglutide) or liraglutide in combination with exercise training (combination).

Participants/Materials, Setting, Methods: Inclusion criteria were men who delivered semen samples, 18 to 65 years of age, and a body mass index between 32 and 43 kg/m², but otherwise healthy. The study was carried out at Hvidovre Hospital and at the University of Copenhagen, and the participants were from the Greater Copenhagen Area. We assessed semen parameters and anthropometrics and collected blood samples before (T0), after the 8-week low-calorie dietary intervention (T1), and after 52 weeks (T2).

Main Results and the Role of Chance: The men lost on average 16.5 kg (95% CI: 15.2–17.8) body weight during the low-calorie diet, which increased sperm concentration 1.49-fold (95% CI: 1.18–1.88, P < 0.01) and sperm count 1.41-fold (95% CI: 1.07–1.87, P < 0.01). These improvements were maintained for 52 weeks in men who maintained the weight loss, but not in men who regained weight. Semen volume, sperm motility and motile sperm count did not change.

Limitations, Reasons for Caution: The S-LITE trial was a randomized controlled trial of weight loss maintenance. Analysis of semen was preregistered to explore the effects of weight loss and weight loss maintenance on semen parameters, but definite inferences cannot be made.

Wider Implications of the Findings: This study shows that sperm concentration and sperm count were improved after a diet-induced weight loss in men with obesity. Our findings indicate that either or both liraglutide and exercise as weight maintenance strategies may be used to maintain the improvements in sperm concentration and count.

Study Funding/Competing Interest(S): This work is supported by an excellence grant from the Novo Nordisk Foundation (NNF16OC0019968), a Challenge Programme Grant from the Novo Nordisk Foundation (NNF18OC0033754) and a grant from Helsefonden. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900). Saxenda (liraglutide) and placebo pens were provided by Novo Nordisk. Cambridge Weight Plan diet products for the 8-week low-calorie diet were provided by Cambridge Weight Plan. E.A.: shareholder, employee of ExSeed Health Ltd. Grant Recipient from ExSeed Health Ltd and listed on Patents planned, issued or pending with ExSeed Health Ltd; J.J.H.: consultant for Eli Lilly A/S and Novo Nordisk A/S. Lecture fees for Novo Nordisk A/S. Listed on Patents planned, issued or pending with the University of Copenhagen, Advocacy group for Antag Therapeutics and Bainan Biotech; S.M.: lecture fees for Novo Nordisk A/S. Recipient of Support for attending meetings from Novo Nordisk A/S. Advisory boards of Novo Nordisk A/S; Sanofi Aventis and Merck Sharp & Dohme. S.S.T.: research grant recipient Novo Nordisk. The remaining authors have no conflicts of interest to declare.

Trial Registration Number: The trial was approved by the Ethical Committee of the Capital Region of Denmark (H-16027082) and the Danish Medicines Agency (EudraCT Number: 2015–005585-32). ClinicalTrials.gov identifier (NCT number): NCT04122716.

Trial Registration Date: 11 May 2016.

Date of First Patient'S Enrolment: August 2016.

Introduction

The prevalence of obesity is increasing globally (Bentham et al., 2017), while meta-analyses indicate declining sperm count over time (Carlsen et al., 1992; Levine et al., 2017). A decline in utero exposure to maternal smoking has not reflected an overall improvement of semen quality at the population level in Danish men, which suggests that other adverse factors may maintain the low semen quality (Priskorn et al., 2018). Increasing BMI levels, overweight and obesity are associated with decreased sperm concentration, total sperm count, progressive sperm motility and sperm morphology (Andersen et al., 2015; Salas-Huetos et al., 2021). Increased BMI of both the woman and the male partner is also associated with subfertility (time-to-pregnancy > 12 months or use of assisted reproductive technology) (Hernáez et al., 2021). In line with these observations, results from a meta-analysis showed an increased risk of low (oligozoospermia) and very-low (azoospermia) sperm count in men with obesity compared to men with normal weight. Thus, compared to men with a BMI between 18.5 and 24.9 kg/m², the odds ratio for low sperm count increased to 1.28 for men with a BMI between 30.0 and 39.9 kg/m² and to 2.04 with a BMI above 40.0 kg/m² (Sermondade et al., 2013). Obesity is therefore considered a risk factor for development of male infertility.

The S-LiTE study, a diet-induced weight loss intervention followed by exercise, GLP-1 receptor agonist therapy or the combination to maintain weight loss, has shown that the detrimental metabolic effects of obesity are reversed, to a large extent, by weight loss (Lundgren et al., 2021). While studies in women have shown that weight loss achieved by combining diet and exercise interventions was associated with increased pregnancy rates, only a limited number of studies have investigated the effect of weight loss on male fertility (Best et al., 2017). Initial case reports of men with obesity who underwent bariatric surgery suggested that the dramatic weight loss was associated with an impairment of semen parameters (Lazaros et al., 2012), while a more recent and larger study suggests a modest improvement (Samavat et al., 2018). Likewise, combined diet and exercise-induced weight loss interventions have shown promising effects on sperm count, semen volume, sperm morphology and decreased sperm DNA fragmentation (Håkonsen et al., 2011; Faure et al., 2014; Mir et al., 2018). Higher self-reported moderate-to-vigorous physical activity was associated with higher levels of progressive and total motility in 746 potential sperm donors from China (Sun et al., 2019). Furthermore, the frequency of 10 min bouts of moderate-to-vigorous-intensity physical activity performed and assessed by accelerometers was associated with higher sperm concentration, sperm count, motile concentration and total motile sperm in a cross-sectional study (Pärn et al., 2015). However, it is unclear whether weight loss per se improves semen parameters and, if so, whether these improvements can be upheld with sustained weight loss.

Here, we investigated the effect of an 8-week diet-induced weight loss followed by randomization to one of four different 52 weeks weight maintenance strategies: placebo and habitual activity, placebo and exercise, liraglutide and habitual activity or liraglutide and exercise on semen parameters. The use of a GLP-1 receptor agonist, which induces and maintains weight loss, is of particular interest since a case report suggested that liraglutide therapy was detrimental to sperm concentration and motility (Fontoura et al., 2014).

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Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table I. Clinical characteristics before (T0) and after an 8-week low-calorie diet-induced weight loss (T1) (n = 47).
Characteristic	Time of sampling
Characteristic	T0 (n = 47)	T1 (n = 47)
Age (years)	41 (range 20–63)
Weight (kg)	122.3 (±13.7)	105.8 (±12.5) ^a
BMI (kg/m²)	37.0 (±2.8)	32.0 (±2.9) ^a
Waist circumference (cm)	119.3 (±8.4)	106.1 (±9.0) ^a
Hip circumference (cm)	118.5 (±6.8)	110.3 (±6.6) ^a
Waist:hip ratio	1.01 (±0.07)	0.96 (±0.07) ^a
Fat percentage (%)^b	34.1 (±3.9)	31.0 (±4.2) ^a
Plasma CRP (mg/l)^b	2.4 (±2.3)	1.9 (±2.4) ^a
HbA1c (mmol/mol)^b	35.8 (±3.5)	33.0 (±3.2) ^a
HbA1c (%)^b	6.0 (±0.5)	5.6 (±0.5) ^a
Plasma cholesterol (mmol/l)	4.8 (±0.9)	3.9 (±1.0) ^a
Plasma cholesterol HDL (mmol/l)	1.1 (±0.2)	1.0 (±0.2) ^a
Plasma cholesterol LDL (mmol/l)	3.0 (±0.9)	2.4 (±0.9) ^a
Plasma cholesterol VLDL (mmol/l)	0.8 (±0.4)	0.5 (±0.2) ^a
Plasma triglyceride (mmol/l)	1.7 (±0.8)	1.1 (±0.4) ^a
Semen volume (ml)	2.5 (±1.3)	2.6 (±1.7)
<1.5 ml, n [% of all]	11 [23]	14 [30]
Sperm concentration (million/ml)	78.5 (±74.9)	91.7 (±70.8) ^a
<15 million/ml, n [% of all]	8 [17]	6 [13]
Sperm count (million/ejaculate)	191.2 (±189.4)	250.6 (±319.4) ^a
<39 million/ejaculate, N [% of all]	11 [23]	9 [19]
Sperm motility (%)	33.3 (±20.2)	31.5 (±20.4)
<40%, N [% of all]	30 [64]	32 [68]
Motile sperm count (million/ejaculate)	71.3 (±90.9)	83.7 (±115.7)
<1 million/ejaculate, N [% of all]	6 [15]	1 [2]

Data are represented as mean (±SD) unless otherwise noted. Statistical values are highlighted in bold.
^aDifference versus T0 analysed with Student's t-test (Wilcoxon signed rank test where appropriate).
^bContains missing numbers.
CRP, C-reactive protein; HbA1c, haemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein.

Table II. Clinical characteristics of the two weight loss maintaining groups: poor maintainers (n = 19) and good maintainers (n = 18) before (T0) and after 52 weeks (T2).
Characteristic	Poor maintainers (n = 19)		Good maintainers (n = 18)
Characteristic	T0	T2	T0	T2
Age (years)	45 (range 28–63)		37 (range 19–60)
Weight (kg)	121.3 (±12.9)	113.7 (±13.3) ^a	124.3 (±15.5)	102.9 (±19.0) ^a
BMI (kg/m²)	37.4 (±3)	35.1 (±3.0) ^a	36.2 (±2.1)	29.9 (±3.9) ^a
Waist circumference (cm)	119.6 (±9.6)	113.0 (±8.9) ^a	118.6 (±8.3)	98.8 (±11.9) ^a
Hip circumference (cm)	116.9 (±6.8)	109.3 (±7.1) ^a	113.8 (±6.3)	117.0 (±6.8) ^a
Waist:hip ratio	1.02 (±0.08)	0.99 (±0.08) ^a	0.99 (±0.08)	1.02 (±0.08) ^a
Body-fat percentage (%)	33.5 (±3.7)	31.1 (±4.3) ^a	34 (±3.8)^b	27.2 (±6.3) ^a
Plasma CRP (mg/l)	2.3 (±2.5)	3.6 (±8.9)	2.5 (±2.2)	1.0 (±0.9) ^a
HbA1c (mmol/mol)	36.7 (±3.3)	34.4 (±2.5) ^a	34.8 (±4.1)^b	32.3 (±3.3) ^a
HbA1c (%)	6.2 (±0.5)	5.8 (±0.4) ^a	5.9 (±0.6)^b	5.5 (±0.5) ^a
Plasma cholesterol (mmol/l)	4.6 (±0.8)	4.6 (±0.8)	4.8 (±0.9)	4.3 (±0.8) ^a
Plasma cholesterol HDL (mmol/l)	1.1 (±0.2)	1.2 (±0.2) ^a	1.1 (±0.3)	1.3 (±0.3) ^a
Plasma cholesterol LDL (mmol/l)	2.7 (±0.7)	2.7 (±0.7)	3.1 (±0.9)	2.5 (±0.8) ^a
Plasma cholesterol VLDL (mmol/l)	0.9 (±0.4)	0.7 (±0.3) ^a	0.6 (±0.2)	0.5 (±0.2) ^a
Plasma triglyceride (mmol/l)	1.9 (±0.9)	1.4 (±0.6) ^a	1.3 (±0.5)	1.0 (±0.5) ^a
Semen volume (ml)	2.8 (±1.6)	2.2 (±1.1)	2.7 (±1.2)	3.0 (±1.2)
Sperm concentration (million/ml)	96.9 (±59.0)	90.6 (±78.6)	52.0 (±56.1)	63.0 (±52.3) ^a
Sperm count (million/ejaculate)	235.2 (±160.4)	186.4 (±142.9)	154.3 (±191.1)	206.2 (±222.1) ^a
Sperm motility (%)	39.9 (±16)	29.7 (±17.2)^b	36.0 (±24.5)	22.3 (±14.9)^b
Motile sperm count (million/ejaculate)	73.6 (±52.4)	47.9 (±44.4)^b	65.2 (±100.3)	56.9 (±72.3)^b

Authors and Disclosures

Emil Andersen^1,†, Christian R. Juhl^2,†, Emma T. Kjøller¹, Julie R. Lundgren², Charlotte Janus², Yasmin Dehestani¹, Marte Saupstad¹, Lars R. Ingerslev¹, Olivia M. Duun², Simon B.K. Jensen², Jens J. Holst^1,2, Bente M. Stallknecht², Sten Madsbad³, Signe S. Torekov^2,* and Romain Barrès^1,4,*

¹Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark ²Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark ³Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark ⁴Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Côte d'Azur and Centre National de la Recherche Scientifique (CNRS), Valbonne, France

*Correspondence address
Mærsk Tower 7.7, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Tel: +45-35-33-72-88; E-mail: barres@sund.ku.dk (R.B.) https://orcid.org/0000-0002-0158-519X; Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Panum 12.4.08, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. Tel: +45-22-98-38-27; E-mail: torekov@sund.ku.dk (S.S.T.) https://orcid.org/0000-0001-6779-0252

^†The authors consider that the first two authors should be regarded as joint First Authors

Authors' roles
E.A. collected semen samples, analysed results and wrote the manuscript. C.R.J. analysed results and wrote the manuscript. E.T.K., Y.D. and M.S. collected semen samples. S.S.T., J.R.L., C.J., S.B.K.J., J.J.H., B.M.S. and S.M. designed the S-LiTE trial. C.R.J., J.R.L., C.J., O.M.D. and S.B.K.J. collected data in the S-LiTE trial. L.R.I. analysed the results. R.B. and S.S.T. designed the study, analysed results and wrote the manuscript. All authors provided critical revisions to the manuscript and approved the final version.

Conflict of interest
E.A.: shareholder, employee of ExSeed Health Ltd. Grant Recipient from ExSeed Health Ltd and listed on Patents planned, issued or pending with ExSeed Health Ltd; J.J.H.: consultant for Eli Lilly A/S and Novo Nordisk A/S. Lecture fees for Novo Nordisk A/S. Listed on Patents planned, issued or pending with the University of Copenhagen, Advocacy group for Antag Therapeutics and Bainan Biotech; S.M.: lecture fees for Novo Nordisk A/S. Recipient of Support for attending meetings from Novo Nordisk A/S. Advisory boards of Novo Nordisk A/S; Sanofi Aventis and Merck Sharp & Dohme. S.S.T.: research grant recipient Novo Nordisk. The remaining authors have no conflicts of interest to declare.

Funding
This work is supported by an excellence grant from the Novo Nordisk Foundation (NNF16OC0019968), a Novo Nordisk Foundation Center for Basic Metabolic Research Synergy grant, Helsefonden, the University of Copenhagen and Danish Diabetes Academy. Saxenda (liraglutide) and placebo pens were provided by Novo Nordisk. Cambridge weight plan diet products for the first 8-week weight loss program were provided by Cambridge Weight Plan. This work was partly supported by a Challenge Programme Grant from the Novo Nordisk Foundation (NNF18OC0033754) to the Gametic Epigenetics Consortium against Obesity (GECKO). The Novo Nordisk Foundation Centre for Basic Metabolic Research is an independent research centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900).