Beauty standards and reproductive health: increasing use of GLP-1 receptor agonists despite limited evidence

In ancient societies, when humans were still organized into nomadic societies and relied on hunting and gathering for food, the aesthetic standard for the female body was quite different from today. The Venus of Willendorf is a representation of what was beautiful and desired for women 28,000 years ago: a large, curvy body. This body is directly related to the importance of abundance and its relationship to fertility in prehistoric societies (1). Nowadays, a different reality is observed, with humans spending more time sedentary and eating more unhealthy foods (2,3). This is directly associated with increased Body Mass Index (BMI) and the increased prevalence of Type 2 Diabetes Mellitus (T2DM) (4). More than 42% of the population is overweight or obese (BMI ≥25 kg/m²), and around 6.28% is affected by T2DM (5,6). From a women's health perspective, obesity and T2DM are associated with adverse reproductive outcomes (7)(8)(9)(10)(11). In this context, science has sought to develop strategies to help patients with these conditions achieve healthier and longer lives. Recently, these strategies include the development of Glucagon-like peptide-1 receptor agonist (GLP-1RA) drugs. These drugs act by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and promoting satiety through acting directly in the hypothalamus (12). This drug-class, initially developed for the treatment of T2DM, was subsequently recognized as an effective weight loss treatment (13). Most GLP-1RA prescriptions remain within evidence-based clinical indications; however, off-label and cosmetic use is increasing, exposing more people to these drugs without medical counseling or monitoring. This is especially concerning for women of reproductive age, given the lack of safety evidence on GLP-1RA use during the perigestational period. This growing off-label use is driven in large part by the pursuit of extreme beauty standards. The aesthetic pressure is even higher in younger women, with extreme thinness being increasingly associated with health and beauty, which is further promoted throughout social media, with negative outcomes including eating disorders (14). There is a particular concern regarding the cosmetic use of GLP-1RAs by women of reproductive age as well as by those using these medications for medical reasons.Considering that several of them are of childbearing age, it is expected that some of them may become pregnant during treatment, and there is a lack of scientific evidence regarding its safety during the perigestational period. Studies investigating the mechanisms and safety of GLP-1RAs are being published at an increasing pace; however, there are still limited data on animal studies, as well as human case reports, making it difficult to estimate its safety profile for human reproduction. Therefore, we aim to discuss current evidence on the potential impacts of GLP-1RA use during the perigestational period and to review the current clinical recommendations regarding their use in this period.Glucagon-like peptide-1 (GLP-1) is naturally synthesized in the L-cells of the intestine, pancreatic α-cells and the central neurons from the nucleus of the solitary tract (15). GLP-1 secretion increases after meals and is responsible for glucose homeostasis by binding to its receptor (GLP-1R); GLP-1RAs mimic the endogenous GLP-1 and activates GLP-1R (12). The main difference between endogenous GLP-1 and GLP-1RAs is related to their pharmacokinetic properties. GLP-1RAs have a prolonged half-life, allowing sustained receptor activation, and reduction in blood glucose concentrations in both fasting and postprandial periods (16). Currently available GLP-1RAs include exenatide, dulaglutide, liraglutide, and semaglutide, all administered subcutaneously, except for semaglutide, which also has an oral formulation. More recently, tirzepatide, a dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, has also been approved. Only liraglutide, semaglutide and tirzepatide have been approved for weight loss.Research recently focused on two main factors: structural similarity of the compounds to the endogenous GLP-1, and a longer half-life. Together, these characteristics would contribute to improving the therapeutic outcomes, as well as greater adherence to treatment due to the reduction in injection frequency (17). This is the main advantage of newer GLP-1RA compounds. For instance, semaglutide has an amino acid substitution that prevents dipeptidyl peptidase-4 degradation and the addition of a C18 fatty di-acid chain, even having 94% similarity to the endogenous GLP-1, it has a much longer halflife (from 144 to 168 hours) (18,19).Although GLP-1RAs were initially developed for the treatment of T2DM, the observation of significant weight loss in patients undergoing treatment sparked interest in the off-label use of these drugs for the treatment of obesity and other health conditions affected by glycemic imbalance, such as polyendocrine metabolic ovarian syndrome (PMOS) (20).Subsequently, some of these compounds were reformulated at different dosages, which are now marketed specifically for weight loss. This rapid increase gained visibility on social media platforms, reaching the lay public, popularizing discussions such as the phenomenon dubbed "Ozempic babies", which is related to a possible baby boom association with GLP-1RAs use. However, scientific evidence does not support an increase in fertility or pregnancy rates associated with these medications (21). Some unexpected pregnancies can be explained by the restoration of ovulation in individuals with obesity-related anovulation, as weight loss may lead to the resumption and regulation of ovulatory cycles (22). To minimize the risk of unplanned pregnancies and gestational exposure to these drugs, the use of long-acting reversible contraceptive methods, such as hormonal implants and intra-uterine devices is recommended for patients