News relating to weight loss for obese infertility patients
By Norbert Gleicher, MD, Medical Director and Chief Scientist, at The Center for Human Reproduction in New York City. He can be contacted though The Reproductive Times or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu.
As repeatedly noted throughout the Reproductive Times website, obesity is closely associated with both female and male infertility – an association that also carries over to practically all infertility treatments. With the new family of weight loss medications, called GLP-1 agonists, revolutionizing healthcare in many subspecialty fields, we have previously pointed out that, because of the speed at which these drugs allow for clinically significant weight loss, this family of drugs for the first time offers the opportunity to include planned weight loss into selected fertility treatment algorithms. We, therefore, follow the weight loss literature closely and, from time to time, offer updates here with relevance to fertility practice. Today’s review is offered by Norbert Gleicher, MD.
THE LATEST NEWS ABOUT GLP-1s
Looking into the future
A quite lengthy feature article in Nature magazine recently drew our attention because of its title and subtitle: “How miracle weight-loss drugs will change the world” and “Models suggest societal upheaval from anti-obesity medicines – but their impacts are hard to predict” (1). For severely obese women and men, our center has been among the first to integrate the family of GLP-1 agonist drugs into routine fertility treatments because severe obesity – in either or both partners – not only can be associated with infertility but also with resistance to treatments for infertility.
The author started the article with a glance into the future, to the year 2030, when quoting anonymous analysts predicting that – simply due to these drugs – heart attacks and strokes will be down at least 20%. The drop in food consumption from the use of these drugs will leave more money in people’s wallets. Lighter passengers will, moreover, save airlines 100 million liters of fuel each year. And billions of people will be enjoying a better quality of life, with improvements to their mental and physical health. A Columbia University gastroenterologist is quoted as saying, “Short of some crazy unfortunate side effect, these drugs are going to change the world.” And the world needs such change because – otherwise – more than half of the world’s population by 2035 would be expected to be seriously overweight and/or have diabetes.
And these drugs are, indeed, already hard at work – in the process of changing the world: 12% of U.S. adults – per that article – have already used GLP-1 agonists (see figure below).
Forecasts of potential economic effects are almost mind-blowing. A global market already worth $47 billion is expected to grow tenfold by 2032. U.S. calorie consumption may, by 2035, drop by 1.3%, severely worrying the food industry. Other industries are also worried. For example, medical devices, such as knee implants or treatments for sleep apnea. Concerns also affect other industries: Car manufacturers, for example, expect more demand for smaller cars; the clothing industry will encounter significant changes in the demand for different sizes; etc.
The sister journal, Nature Medicine, in an unsigned editorial, asked the question: Are GLP-1 drugs really for everybody (2)? The answer was that these drugs have emerged as treatment options for medical problems far beyond diabetes and obesity. It becomes essential to differentiate how genetic, clinical, and sociodemographic differences impact their effects on weight loss (and other medical conditions).
Is there an impact on endometrial receptivity and implantation? Still no answer!
A very disappointing review article in Acta Obstetricia et Gynecologica Scandinavica pretends to address this question but really doesn’t! All the article offers is the cliché that GLP-1s hold promise for improving female fertility, especially in obese or PCOS patients (3). Clearly, a paper that can be skipped.
References
1. Reardon S. Nature 2024;635:22 -24
2. Editorial. Nat Med 2024;30:3029
3. Sola-Leyva et al., Acta Obstet Gynecol Scand 2024;00:1-9. DOI: 10.1111/AOGS.15010
OTHER WEIGHT AND DIET – RELATED ISSUES
BMI and PCOS – a self-fulfilling prophecy!
A recent study by Chinese investigators in JCEM ended up being nothing more than a self-fulfilling prophecy, with the conclusion that a Mendelian randomization analysis produced evidence of a causal relationship between elevated BMI and the risk of PCOS, suggesting in addition that the severity of PCOS may contribute to elevated BMIs (1).
None of that is really news. Moreover, how about differentiating between PCOS phenotypes? Isn’t the D-phenotype also called the “lean” phenotype? How many of those were in the study population? Unfortunately, this is just another example of one of the many worthless “desk studies” from China flooding our medical journals.
Reference
1. Fabg et al., J Clin Endocrinol Metab 2024;110(1):41-47
Fat cells unfortunately have memory
Maintaining weight loss is quite a challenge—even with GLP-1s. Why that is has remained mostly unknown. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms leading to the rebound in weight have remained largely unknown.
Now, however, in a recent paper by European and U.S. investigators in Nature, an interesting explanation is being reported (1). Using single-nucleus RNA sequencing, they discovered retained cellular transcriptional changes in human and mouse adipose tissues after appreciable weight loss, as well as persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli.
Mice carrying this obesogenic memory show accelerated rebound weight gain. Moreover, epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. These findings—at least to a degree—can explain the so-called “yo-yo effect” often accompanying dieting and, obviously, offer interesting potential directions to overcome rebounding weight gains.
Reference
1. Hinte et al., Nature 2024; 636:457-465