Two studies have reported that reproductive hormone levels in females with obesity may be partially restored by lowering blood glucose levels and for men living with obesity - their semen quality can be improved if they lose weight and maintain the weight loss.
In the first study, ‘Dapagliflozin partially restores reproductive function in MC4R KO obese female mice’, published in the Journal of Endocrinology, researchers from the University of Queensland, Australia, reported that altered levels of reproductive hormones in a well-established mouse model of obesity may be partially restored by a common type 2 diabetes medication that reduces blood glucose levels.
Many women with obesity that experience fertility issues also have altered levels of reproductive hormones. Currently there is no effective therapy to address this. Development of a therapy that not only improves women's' metabolic health but also treats obesity-related infertility would be a significant advancement, with the potential to improve many people's quality of life.
Although fertility problems are well established in women with obesity, there remains a lack of effective and targeted treatments to address them. Obesity is a growing health epidemic, which means more women are being affected by reproductive difficulties. Obesity-related fertility issues are complex but evidence suggests that, in part, they may be linked to changes in energy metabolism, which lead to altered levels of reproductive hormones that can then disrupt the menstrual cycle and ovulation. People with obesity are at a greater risk of developing type 2 diabetes and often have high blood glucose levels, as well as other metabolic changes.
The MC4R gene knock-out (KO) mouse is a well-characterised model of obesity, which also exhibits irregular reproductive cycles with altered hormone levels that lead to declining fertility. The mouse reproductive cycle is similar to that of humans, in that the profile of hormone level changes is analogous, although it is much shorter in duration, so the MC4R KO mouse is a good, representative model for initial investigations of metabolic and reproductive function in obesity.
Dapagliflozin is a drug commonly used to treat type 2 diabetes, where it reduces blood glucose levels and improves other markers of metabolic health but its effects on reproductive health and fertility have yet to be investigated.
In this study, Professor Chen and colleagues at the University of Queensland, investigated the effects of dapagliflozin treatment on metabolic health and reproductive hormone levels in the MC4R mouse model of obesity. After just eight weeks of treatment blood glucose levels were normal, body weight was reduced, the reproductive cycle was normalized and levels of reproductive hormones and ovulation were partially restored, compared with non-treated mice.
"We often see low fertility in women with obesity in clinical practice", commented primary author, Dr Cui, a visiting fellow from Chengdu Women and Children Hospital in China, "So this research provides hope for a future, effective treatment."
"These data suggest that normalising blood glucose metabolism with dapagliflozin in obesity may be a promising route for at least partially restoring reproductive function. This could improve fertility in women where no other successful therapy is currently available,” added Chen. “Although encouraging, these studies were conducted in mice and much more work needs to be done to confirm that these findings could be replicated effectively in women. However, people with obesity are at much greater risk of developing type 2 diabetes, so the known health benefits of correcting blood glucose levels may be extended to also improving fertility in those affected."
The team now intend to further investigate the therapeutic benefits of using dapagliflozin to improve reproductive function by examining the molecular pathways involved, which could identify better targets for future fertility treatment in women.
Sperm count
In the second study, ‘Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial’, published in Human Reproduction, researchers from the University of Copenhagen and Hvidovre Hospital showed that men with obesity improve their semen quality if they lose weight and maintain the weight loss. The findings may be good news for the fertility field, as a link between higher sperm count and faster achievement of pregnancy has previously been shown.
"It was surprising to us that such a big improvement can be shown in the semen quality in connection with a weight loss. And as 18 percent of Danes have obesity, this new knowledge may actually make a difference," explained Professor Signe Torekov who headed the study together with Professor Romain Barres at the Novo Nordisk Foundation Center for Basic Metabolic Research.
Torekov explained that it has long been known that obesity is associated with reduced semen quality. Previous studies have also suggested a link between weight loss and increased semen quality, but these studies have had so few participants or such modest weight loss that it has been difficult to draw conclusions from them.
"But now we are ready to do just that. This is the first long-term randomized study, where we have shown that semen quality in men with obesity improve with a sustained weight loss," she added.
The study included 56 men with obesity, aged 18-65 years and with a BMI 32-43.
"The men lost an average of 16.5kg, which increased the sperm concentration by 50 percent and the sperm count by 40 percent eight weeks since the weight loss. During the 52 weeks, the trial lasted following the weight loss, the men maintained the improved semen quality. But only the men who maintained the weight loss: after a year, these men had twice as many sperm cells as before their weight loss. The men who regained weight, lost the improvements in semen quality," she explains.
The study is a sub study of a major publication on weight loss, which was published in the New England Journal of Medicine in May 2021. A total of 215 Danes with obesity participated in the larger study. It was among these participants that 56 of the men also provided semen samples to investigate whether semen quality and weight loss could be related.
In the trial, all participants first followed an eight-week regimen with a low-calorie diet, resulting in a weight loss. Then the participants were randomly divided into four groups.
Two of the groups received placebo medication, while the other two groups received obesity medication. Among the two placebo groups, one group had to follow an exercise program where each week, they had to do a minimum of 150 minutes of moderate physical training or 75 minutes of hard training or a combination.
The other group did not change their usual level of physical activity. The two groups that received obesity medication were divided in the same way, into a group with and a group without an exercise programme.
After a year, it was shown that the group that only exercised and did not receive medication, as well as the group that only received obesity medication and did not exercise, maintained the weight loss of 13 kg. The group that both received obesity medication and exercised lost additional weight and improved health. The placebo group had regained half of the weight loss with aggravation of many of the risk factors related to development of type 2 diabetes and cardiovascular disease.