Liraglutide and Male Reproductive Health
This prospective study compared fertility and sexual markers in obese men with low testosterone and erectile dysfunction who took liraglutide, uFSH + HCG, or testosterone. Liraglutide is a GLP-1 agonist approved for weight loss (brand name Saxenda) and for Type 2 diabetes (brand name Victoza).
Study Background
WHAT
Comparison of reproductive, sexual, and metabolic effects from liraglutide vs. uFSH + hCG vs. testosterone therapy on obese men of child-bearing age
WHY
To find alternate treatments to improve semen quality and erectile dysfunction in hypogonadal obese males
WHERE/WHEN
University of Catania, Italy; dates not stated (protocol approved twice in 2022)
WHO
Inclusion Criteria:
Men ages 18-35 years
Obese with BMI 30-39.99 kg/m2, waist circumference over 94 cm / 37 in
Severe ED (IIEF-5 score < 7 and PDE5i unresponsive x 3 months)
Hypogonadism (total testosterone < 12 nmol/L)
Low SHBG and normal-low gonadotropin levels (FSH, LH)
HOMA IR > 2.5
Exclusion Criteria:
Primary testicular disease
High prolactin or thyroid stimulating hormone
Hypothalamus or pituitary lesions
Impaired fasting blood glucose or diabetes, hypertension, dyslipidemia
HOW
Adherence to low-carb diet (1400-1800 kCal/day)
Divided into three non-randomized groups based on fatherhood intentions
Group A (n = 35): actively seeking fatherhood. Took urofollitropin (uFSH) 150 IU subQ three times weekly + hCG 2000 IU subQ twice weekly x 4 months.
Group B (n = 35): not actively seeking fatherhood. Took liraglutide 0.6 mg subQ daily for one week, then increased by 0.6 mg every week until max of 3 mg. Took 3 mg from week five until 4 months of treatment had concluded.
Group C (n = 40): fathers NOT seeking further fatherhood. Took 60 mg transdermal testosterone gel (2%) daily x 4 months.
Measured fasting hormone levels before and after treatment
Semen analyses after 2-7 days abstinence, evaluated per WHO 2021 guidelines
Statistics
Chi-square for differences in PDE5-i use
Within group differences: ANOVA then Tukey-Kramer post hoc test
Significant to p < 0.05
Results
Baseline demographics similar
Best outcomes in Group B (liraglutide group) for anthropometric, biochemical, and laboratory parameters
10.3% decrease body weight
16.7% decrease BMI
8.3% decrease waist circumference
192.9% increase in serum total T levels
157.1% increase in SHBG levels
All above results were significant compared to baseline and to Groups A & C: Group A did not have improved T levels
Significant Improvements in FSH, LH, and HOMA-IR seen in Group B vs. Groups A & C
Reproductive outcomes best in Group B
All sperm parameters increased significantly (p < 0.05)
Sperm motility increased by 142.9% in Group B vs. 58.3% increase in Group A (Group C data was not collected)
ED outcomes showed that group B had significantly higher IIEF-5 score but lower use of PDE5is vs. Groups A & C at end of treatment
Authors’ Thoughts
Liraglutide
Unable to assess full genomic impact on testosterone/testicular function due to relative brevity of study (4 months vs. 6-12 months needed)
Liraglutide’s may induce protect effect against NAFLD by increasing SHBG
Significant weight loss may have reduced inflammatory processes in plasma of semen, thereby reducing infertility
Lack of improved T levels in Group A potentially due to low-intermediate dosing of hCG
Study limitations: no placebo, physical activity not controlled or treated, small sample size, penile vasculature not assessed
Planning to conduct a placebo-controlled trial to validate current results
This Pharmacist’s Thoughts
(-) lack of safety discussion – assume there were no adverse events?
Rises in prostate-specific antigen (PSA) and hematocrit (HCT) can occur with use of testosterone therapy
Gastrointestinal distress is often a cause for GLP-1 drug discontinuation
Dropout rate not noted or discussed—> unable to assess if dosing frequency (daily testosterone vs. weekly liraglutide) or if adverse drug reactions impacted results
Ways to enhance the upcoming placebo-controlled trial
Pregnancy outcomes needed
if retaining hCG arm, allow for dose escalation before assessing restoration of T levels
if retaining testosterone as one arm, assess for paternity since testosterone therapy is “an imperfect contraceptive”
include arm with a newer GLP-1 that has been shown to produce more significant weight loss akin to upcoming Swiss comparative trial with semaglutide in male fertility (Klinefelter’s)
Conclusions
Preliminary results from this study suggest potential for liraglutide (and potentially the larger class of GLP-1s) to improve fertility, sexual, and metabolic function in obese men of child-bearing age with low testosterone (hypogonadism). The follow-up placebo-controlled trial is intended to verify these preliminary results, which will likely be of high interest to the fields of fertility, internal medicine, and sexual medicine.
Resources
Giagulli VA, Carbone MD, Ramunni MI, et al. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology. 2015;3(6):1094-1103. doi:10.1111/andr.12099
Jensterle M, Podbregar A, Goricar K, Gregoric N, Janez A. Effects of liraglutide on obesity-associated functional hypogonadism in men. Endocr Connect. 2019;8(3):195-202. doi:10.1530/EC-18-0514
Latif W, Lambrinos KJ, Rodriguez R. Compare and Contrast the Glucagon-Like Peptide-1 Receptor Agonists (GLP1RAs). In: StatPearls. Treasure Island (FL): StatPearls Publishing; March 27, 2023.
La Vignera S, Condorelli RA, Calogero AE, Cannarella R, Aversa A. Sexual and Reproductive Outcomes in Obese Fertile Men with Functional Hypogonadism after Treatment with Liraglutide: Preliminary Results. J Clin Med. 2023;12(2):672. Published 2023 Jan 14. doi:10.3390/jcm12020672
Papadakis G. Sex Steroids Balance for Metabolic and Reproductive Health in Klinefelter Syndrome (KLIN-HEALTH). ClinicalTrials.gov identifier: NCT05586802. Updated April 4, 2023. Accessed September 27, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05586802
