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Balancing the scales: the interplay of diet, exercise, GLP-1
receptor agonists, and obesity in shaping male
reproductive health
Omar F. Ammar
1,2
, Kashish Sharma
3
, George Liperis
4
, Juan J. Fraire-Zamora
5
, Munevver Serdarogullari
6
,
Zoya E. Ali
7
, Ranjith Ramasamy
8
, Sandra Laurentino
9
, Adam Watkins
10
, and Mina Mincheva
11,
*
1
Biomaterials Cluster, Bernal Institute, University of Limerick, Limerick, Ireland
2
School of Engineering, Faculty of Science and Engineering, University of Limerick, Limerick, Ireland
3
HealthPlus Fertility Center, HealthPlus Network of Specialty Centers, Abu Dhabi, United Arab Emirates
4
Westmead Fertility Centre, Institute of Reproductive Medicine, University of Sydney, Westmead, NSW, Australia
5
EUGIN Group, R&D, Barcelona, Spain
6
Department of Histology and Embryology, Faculty of Medicine, Cyprus International University, Northern Cyprus, Nicosia, Turkey
7
Research & Development Department, Hertility Health Limited, London, UK
8
Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA
9
Centre of Reproduction and Andrology, Institute of Reproductive and Regenerative Biology, University of Mu¨ nster, Mu¨ nster, Germany
10
Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham, UK
11
Independent Researcher, Maidenhead, UK
*Correspondence address. Independent Researcher, Maidenhead, UK. E-mail: mina.mincheva1@gmail.com https://orcid.org/0000-0003-2917-2546
GRAPHICAL ABSTRACT
The January 2023 Journal Club was dedicated to a study by Andersen et al. (2022), inspiring discussion about the effects of diet-induced weight loss
on male infertility, the long-term strategies to maintain improved semen parameters following weight loss and GLP-1 receptor agonist medications
as a strategy for clinical management of obesity-related infertility. Figure created with BioRender. GLP-1: glucagon-like peptide-1, GLP-1 RA: glucagon-
like peptide-1 receptor agonist, HPG axis: Hypothalamic-pituitary-gonadal axis.
V
CThe Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved.
For permissions, please email: journals.permissions@oup.com
Human Reproduction, 2023, 1–5
https://doi.org/10.1093/humrep/dead126
Peer Perspectives
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Introduction
The term ‘obesity’ refers to an excessive amount of fat accumu-
lating within the body and a high BMI 30 and has been linked to
a range of chronic diseases, including cardiovascular diseases
and cancer (WHO, 2021). The surge in obesity rates has coincided
with a steady decline in sperm quality, particularly sperm counts
reported over the last 50 years (Levine et al., 2017,2023). The vari-
ous processes involved in reproduction, such as hormone produc-
tion, gametogenesis, fertilization, and embryo development, can
be adversely affected by obesity and its associated metabolic dis-
orders. Data from animal studies strongly indicate that high-fat
diet-induced obesity and its associated metabolic disease nega-
tively affect fertility and reproduction (Pini et al., 2021). There is a
lack of data about the link between obesity and human reproduc-
tion due to the complicated interactions between obesity, dyslipi-
daemia, hyperinsulinemia, and the reproductive axis, so its effect
on fertility has not been fully studied. The evidence regarding the
impact of obesity on human semen parameters and male repro-
ductive function remains controversial (Craig et al.,2017;
Bellastella et al., 2019). Nevertheless, meta-analyses investigating
the association between BMI and sperm parameters have
reported negative correlations between BMI and sperm concen-
tration, total sperm count, sperm motility, and sperm morphol-
ogy (Sermondade et al., 2013;Guo et al., 2017;Salas-Huetos et al.,
2021). An association between obesity and severe sperm count
deficit, such as azoospermia, has also been shown, with over a
100% increase (OR: 2.04) in the odds of being azoospermic for
men with a BMI above 40 kg/m
2
(Sermondade et al., 2013). It is
usually regarded that men with BMI >29 kg/m
2
are likely to have
reduced fertility and that patient-specific weight management
should be considered to improve overall health and fertility
(National Institute for Health and Care Excellence, 2018,2023).
However, the question whether weight loss per se improves male
fertility, and sperm parameters in particular is still open (Best
et al.,2017). Consequently, it is unclear if the assumed potential
benefits of diet and/or exercise-induced weight loss on sperm
parameters are sustained in the short and the long-term run.
To fill in gaps on the topic, a recent study by Andersen et al.
(2022) provides supporting evidence of the hypothesis that diet-
induced weight loss has a beneficial effect on sperm concentra-
tion and sperm count. This sub-study of the S-LiTE trial (acronym
for ‘Synergy effect of LiragluTide and Exercise on maintenance of
weight loss and health after a low-calorie diet’; Jensen et al., 2019;
Lundgren et al., 2021) examined the effects of diet-induced weight
loss on semen parameters. The study included 47 male partici-
pants who underwent an 8-week low-calorie diet (800 kcal/day)
and were subsequently randomized into four intervention groups
for 52 weeks: placebo, exercise, liraglutide (a glucagon-like pep-
tide-1 receptor agonist, GLP-1 RA), or a combination of exercise
and liraglutide. Semen analysis was performed before (T0) and
after (T1) the 8-week diet period, and after 52 weeks of random-
ized intervention (T2). The study found an improvement in sperm
concentration and total sperm count at T1 (1.49- and 1.41-fold,
respectively). Importantly, these improvements were maintained
after 52 weeks (T2) only in men who sustained weight loss above
the median cut-off of 11.7 kg, regardless of the intervention
group. This suggests that exercise and/or liraglutide may aid in
maintaining improved sperm parameters following diet-induced
weight loss.
The study has potential clinical implications for addressing
obesity-induced male infertility and raises questions about the
effects of weight loss management on spermatogenesis and the
safety of pharmacological interventions for infertility in men
with obesity. These issues were discussed during the January
2023 ESHRE Journal Club.
What are the effects of exercise- and diet-
driven weight loss on reproductive health
and sperm quality?
The causes for obesity-induced negative effects on male repro-
ductive health are complex and multifactorial. It is well docu-
mented that obesity leads to hormonal imbalances, as men with
obesity often present with secondary hypogonadism (Fernandez
et al., 2019). Perturbed hormonal profiles due to increased periph-
eral aromatization of testosterone to oestrogen adversely affect
sperm production and quality (Craig et al., 2017). Obesity is also
associated with a pro-inflammatory environment that is likely
detrimental for spermatogenesis and sperm function (Leisegang
et al., 2021). Obesity-associated co-morbidities, such as metabolic
syndrome and increased scrotal temperature in case of increased
abdominal adiposity, are amongst other causal mechanisms
impacting the male reproductive axis and semen parameters
(Craig et al.,2017;Bellastella et al., 2019;Cazzaniga et al., 2020;
McPherson and Tremellen, 2020). Obesity not only impacts sperm
parameters but also influences sperm DNA integrity and epige-
netics (Craig et al., 2017;Bellastella et al., 2019). It has been dem-
onstrated that men with obesity display distinct sperm
epigenetic signatures compared to healthy-weight counterparts
(Donkin et al., 2016;Soubry et al., 2016;Keyhan et al., 2021), poten-
tially due to adiposity-induced oxidative stress damaging sperm
DNA (Shukla et al., 2014). Whilst studies have shown higher levels
of sperm DNA fragmentation in men with obesity (Dupont et al.,
2013;Cazzaniga et al., 2020) the most recent meta-analysis con-
cluded that there is insufficient evidence to demonstrate a clear
association between BMI and DNA fragmentation (Sepidarkish
et al., 2020).
Considering the complexity of mechanisms by which obesity
and associated co-morbidities affect reproductive fitness, it is
equally important to understand the implications of weight loss
on male fertility. The challenge of showing concrete evidence to
link diet and/or exercise with improved semen parameters in
men with obesity is attributed to the difficulty to control for a
number of confounding factors associated with such studies.
Obesity can be associated with unfavourable socioeconomic sta-
tus (Han et al., 2015;Newton et al., 2017) as well as with a range of
unhealthy modifiable lifestyle factors, including low level of
physical activity, poor diet, and smoking that may affect fertility
(Han et al., 2015;Salas-Huetos et al., 2017;Chen et al., 2022). Also,
some supplements intake, such as vitamin D, are known to be
positively associated with male fertility (Jensen, 2014;Tania et al.,
2023) and could create masking effects if taken by study partici-
pants. The current paucity of evidence does not allow for definite
answers about the direct effect of diet and exercise-based weight
reduction strategies on male infertility (Best et al., 2017). While
Andersen and colleagues provide new data to support the posi-
tive impact of diet-induced weight loss on semen parameters, it
is difficult to judge what impact weight loss and its maintenance
had on reproductive hormones since they were not measured in
the study (Andersen et al., 2022). Though it is known that obesity
is associated with reduced levels of reproductive hormones
(Salas-Huetos et al., 2021), very few studies have evaluated the
effects of diet-driven weight loss on the hypothalamic–pituitary–
gonadal (HPG) axis (Bellastella et al., 2019). To the best of our
knowledge only one study assessed the effect of combined diet-
and exercise-induced weight loss on both semen parameters and
2|Ammar et al.
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some reproductive hormones, showing an increase in total tes-
tosterone and sex hormone-binding globulin following interven-
tion (Ha˚ konsen et al., 2011). Previous studies have also shown an
association between increased insulin sensitivity and testoster-
one levels (Bellastella et al., 2019). Andersen et al demonstrated a
reduction in the percentage of men with oligozoospermia after
the initial 8-week diet weight loss from 17% (8/47) to 13% (6/47)
(Andersen et al., 2022). They further reported reduced glycated
haemoglobin levels after the 8-week diet period, which were
maintained in the combined—exercise and liraglutide—interven-
tion group. However, the mechanisms by which weight loss and
weight maintenance interventions may have influenced sperm
production and semen parameters in those men with oligozoo-
spermia cannot be ascertained without a comprehensive analysis
of the HPG axis hormones at baseline and after interventions.
It is widely accepted that physical activity has significant ben-
efits for general health (Bull et al., 2020) and it has been demon-
strated that low-to-moderate exercise has favourable impact on
male reproductive function in healthy males (Hajizadeh Maleki
et al., 2017;Riachy et al., 2020;Minas et al., 2022). As such, the ef-
fect of exercise on male obesity is seen as a positive factor for the
restoration of multiple physiological systems (endocrine, meta-
bolic, testicular function, oxidative stress) back to a healthy state
(Shaw et al., 2006;Hajizadeh Maleki et al., 2017;Riachy et al., 2020;
Minas et al., 2022). Therefore, exercise-driven weight loss in men
with obesity is considered a positive step for both general health
and for reproductive fitness. However, various factors such as
age and co-morbidities may modulate the effects exercise has on
sperm production, sperm quality, and steroidogenesis (Riachy
et al., 2020;Minas et al., 2022). Most importantly, type, volume, in-
tensity, and duration of exercise play a major role in how it will
affect male reproductive function in the short and long term
(Hajizadeh Maleki et al., 2017;Sansone et al., 2018;Riachy et al.,
2020).
The question remains open as to whether the observed
improvements in semen parameters are due to reduced calorie-
induced weight loss itself or the specific diet regimen, similarly to
the effects seen with exercise. Two major aspects, calorie restric-
tion and diet composition, would need to be accounted for to un-
ravel the effect of diet-induced weight loss on the reproductive
fitness of men with obesity. Increasing evidence from both ani-
mal and human studies indicates that the type of diet as well as
certain diet nutrients and nutritional supplements may play a
crucial role in modulating male reproduction (Salas-Huetos et al.,
2017;Pini et al., 2021). In experimental settings for diet-induced
obesity, most of the evidence comes from rodent dietary models
which focus on elevated levels of a single macronutrient, fat or
sugar (Pini et al., 2021). While such studies underlie important
effects of obesity on male reproduction, they do not allow for in-
terpretation of the complex, interacting effects of dietary macro-
nutrients (Pini et al., 2021). Subsequently, the single nutrient
approach limits the ability to draw conclusions on the most opti-
mal diet for healthy reproductive function. As regards to dietary
patterns and fertility, adherence to Mediterranean diet and simi-
lar healthy diets, which are rich in favourable fatty acids (unsatu-
rated and omega-3 polyunsaturated), antioxidants, and
micronutrients are associated with improved fertility parameters
(Karayiannis et al., 2016;Salas-Huetos et al., 2018,2019). The
Mediterranean diet—characterized by a high consumption of ol-
ive oil, fruit, nuts, legumes, vegetables, and whole cereals; a mod-
erate intake of fish and poultry; and a low consumption of full fat
dairy products, red meat, processed meats, and sweets—has con-
sistently been linked to better semen parameters in several
systematic reviews and meta-analyses (Giahi et al., 2016;
Karayiannis et al., 2016;Salas-Huetos et al., 2017,2019).
Clinical management of infertility in men
with obesity: do weight loss prescription
medications hold promise for male
infertility?
Arbitrary BMI thresholds, above which fertility treatment or pub-
licly funded assisted conception is not supported, have been put
in force or considered by some programs and national health sys-
tems (Penzias et al., 2021). However, BMI calculation does not di-
rectly measure body fat since it is based on the height
2
/weight
ratio; other anthropometric indicators, such as waist circumfer-
ence, body fat percentage, and lean mass (Liu et al., 2021), need to
be taken into account when considering obesity. Nevertheless,
obesity is a significant factor considered ahead of medically assis-
ted reproduction (MAR) and its management has clinical rele-
vance in the context of infertility.
Regarding clinical management of obesity-related male infer-
tility, weight loss through a combination of diet and exercise is
accepted as an effective weight loss intervention (Shaw et al.,
2006) since weight loss can ameliorate obesity-related infertility
(Cabler et al., 2010;Leisegang et al., 2021). Lifestyle changes can
improve overall health, and thus, exert a positive impact on re-
productive hormones (Fernandez et al., 2019;Leisegang et al.,
2021). Medical management of infertility in men with obesity is
directed to either treatment of obesity by addressing weight loss,
or by mitigation of obesity-related effects on the male reproduc-
tive system. The latter is used towards optimizing androgenic
hormonal pathways such as administering aromatase inhibitors
and short-acting testosterone formulations (Cabler et al., 2010;
Craig et al.,2017). Most weight loss medications mainly work
through temporary suppression of appetite, and hence would re-
quire patients to reduce energy intake and/or increase energy ex-
penditure for weight loss maintenance in the long term (Penzias
et al., 2021). Weight loss medications may be beneficial when
used in conjunction with lifestyle interventions and are consid-
ered for patients with a history of unsuccessful weight loss
(Penzias et al.,2021).
Glucagon-like peptide 1 (GLP-1) is a hormone released by in-
testinal enteroendocrine L cells in response to food intake and is
involved in glucose homeostasis (Comninos et al., 2014;Madrid
et al., 2022). It is thought that GLP-1 slows gastric emptying and
stimulates GLP-1 receptors in the gut to reduce food intake, while
also having an immunomodulatory activity (Jensen et al., 2019;
Madrid et al., 2022). Although the highest expression of the GLP-1
receptor is reported in the lung and pancreas, followed by the
stomach, intestine, kidney, heart, and brain (Jensterle et al., 2019),
there is very limited evidence for GLP-1 receptor expression in the
human testis (Jensterle et al., 2019;Caltabiano et al., 2020). It has
been shown that GLP-1 receptor agonists (Ras) facilitate weight
reduction, improve metabolic health, and reduce systemic in-
flammation; however, the mechanism of GLP-1 Ras action on
weight loss is not fully understood (Drucker, 2018;Jensen et al.,
2019;Madrid et al., 2022). The role of GLP-1 and GLP-1 Ras in re-
production is even less clear and is largely unaddressed in clinical
studies (Jensterle et al., 2019). Liraglutide (a GLP-1 RA) is approved
as an adjunct to diet and exercise for weight management in case
of failure of lifestyle modifications, for individuals with a BMI of
30 kg/m
2
or with a BMI of 27 kg/m
2
and co-morbidities, and for
male patients with a waist circumference above 102 cm
(Fernandez et al., 2019;Madrid et al., 2022). Comprehensive
January 2023 #ESHREjc |3
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evidence synthesis on the efficacy of liraglutide and other GLP-1
Ras as a strategy to induce weight loss is imminent (Madrid et al.,
2022). In this light, evidence by the study of Andersen and col-
leagues about the use of liraglutide in combination with exercise
for the long-term maintenance of diet-induced weight loss is very
promising (Lundgren et al., 2021;Andersen et al., 2022). It is worth
noting that very few of the weight loss prescription medications
have been investigated in the context of reproductive function,
fertility, and their effects on offspring health in either women or
men with obesity (Jensterle et al., 2019;Penzias et al., 2021). GLP-1
Ras such as liraglutide deserves special attention given increas-
ing evidence around the modulatory activity of GLP-1 in repro-
duction (Comninos et al., 2014).
Conclusion
Current evidence suggests that preconception treatment with
GLP-1 Ras might provide new strategies in the management of
weight and infertility in men with obesity, but full understanding
of the complex mechanisms linking metabolism and reproduc-
tion is required. Future studies addressing the effects of weight
loss per se on male reproductive function should include larger
cohorts from more diverse geographical areas and longer follow-
up periods. Additionally, monitoring of the HPG axis hormonal
profile, in conjunction with repeated semen analysis including
extended examination of sperm quality, such as sperm DNA in-
tegrity and epigenetics, would be necessary. Several clinically rel-
evant questions are yet to be addressed: Where are GLP-1
receptors expressed in male reproductive tissues? Is the impact
of GLP-1 RA in reproduction mainly mediated through weight
loss or by direct interactions with the GLP-1 receptors in the tes-
tis? What are the potential effects of preconception treatment
with GLP-1 RA in men with obesity on embryonic metabolism,
gene expression, and offspring health? These questions provide
the grounds for future studies considering the implementation of
liraglutide in MAR and reproductive health management for men
with obesity.
Data availability
No datasets were generated or analysed in the current article.
Acknowledgements
The authors would like to thank all the participants of ESHRE
journal club on Twitter for their contribution to the discussion.
Authors’ roles
O.F.A. and M.M. conceptualized the discussion topics; K.S., G.L.,
J.J.F.-Z., and M.S. wrote the discussion questions; O.F.A. and M.M.
revised the discussion questions; O.F.A. organized the discussion;
K.S., G.L., J.J.F.-Z., M.S., Z.E.A., and M.M. moderated the discus-
sion; O.F.A. prepared and led the discussion material and moder-
ation; R.R., S.L., and A.W. contributed intellectually to the
discussion as an expert; O.F.A. drafted the manuscript introduc-
tion; O.F.A. and M.M. prepared the graphical abstract; K.S., G.L.,
J.J.F.-Z., M.S., R.R., S.L., and A.W. provided outlines for the manu-
script content; and M.M., compiled and wrote the manuscript
and led the publication process. All authors provided critical revi-
sion to the manuscript and approved the final version.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
All authors declare no conflict of interest.
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