Semaglutide and human reproduction: caution at the intersection of energy balance, ovarian function, and follicular development

Abstract

Obese or overweight patients considering IVF are generally counselled to reduce weight closer to target BMI (i.e., < 30 kg/m²) by interventions entailing dietary change with a structured exercise program. There is little disagreement that supervised weight loss can improve reproductive outcome when successful, although there are refractory cases where weight goals are unmet. Because low-grade chronic inflammation and altered immune function are characteristic of obesity and antagonize implantation, any pre-IVF weight loss facilitated by semaglutide (SG) would be helpful. However, no preclinical data have considered the ovarian implications of SG. Several formulations of SG are now available to assist in chronic weight management, treatment of type-2 diabetes, or both. SG is 31-amino acid lipopeptide with action at the glucagon-like peptide-1 (GLP-1) receptor, which augments insulin secretion while lowering hepatic glucagon output. SG thus enters a multiorgan network where insulin, AMP-activated protein kinase (AMPK), insulin-like growth factor-1 (IGF-1), mammalian target of rapamycin (mTOR), and sirtuin pathways manage ambient nutritional conditions. As GLP-1 directly influences insulin release and curtails satiety, SG adjusts many biochemical cascades where potential interference with oocyte development or embryo/endometrial crosstalk require clarification. Particularly if used outside manufacturer’s guidance (i.e., for aesthetic or personal reasons), SG could bring unwelcome challenges to fertility clinics where obesity and dyslipidemia are merely exchanged for the new problems of starvation and sarcopenia. Here we examine known GLP-1 actions where energy balance, ovarian aging, and oocyte competence converge; off label SG use should be avoided until its signaling effects throughout the reproductive axis are more carefully studied.

Introduction

Current national survey data show age-adjusted prevalence of severe (Class III) obesity among U.S. adults is just under 10%. Because overweight and obesity affect women more than men [1], the problem—and its treatments—cannot be ignored in clinical reproductive practice. While the overweight challenge has yet to be systematically investigated specifically in an assisted reproductive setting, single-center data are concerning. One study of in vitro fertilization (IVF) patients in Ecuador (n = 191) reported frequency of overweight and obese females at 45% and 19.9%, respectively [2]. Another sample from USA (n = 2069) found 49% of IVF patients had body mass index (BMI) 30-34.9, 26% had BMI 35-39.9, while 7% had a BMI > 50 [3]. It is possible that milder obesity cases may be beneficially managed with dietary counseling alone. For example, when nutritional features were tracked in infertile women (n = 300) and healthy fertile controls (n = 300), diets with high glycemic index, glycemic load, and dietary inflammatory index were more often associated with infertility [4]. Unsurprisingly, such patients typically have a more guarded prognosis than age-matched, normal weight peers, since obesity is accompanied by an increased pregnancy loss rate. This means that while obese patients may initially conceive by IVF, many such pregnancies will miscarry and not continue to term [5]. The higher observed miscarriage rate in obesity could be due to decreased oocyte quality, altered endometrial receptivity, or both [6]. The arrival of glucagon-like peptide-1 (GLP-1) modulators thus has met both caution and welcome in reproductive endocrinology, where effective adjuncts to weight control are urgently needed.

GLP-1, energy status, and reproduction

Weight loss occurs only when energy expenditure surpasses caloric input [7], and GLP-1 agents can approximate, if not surpass, results once possible only with invasive bariatric procedures [8, 9]. Nevertheless, using anti-obesity medications by overweight or obese patients requires awareness of sweeping endocrine effects [10] including how changes in cellular energy may cascade into reproductive biology. Ovarian capacity often declines earlier than other organs in normal aging [11]. Extremes in energy balance are considered harmful; either very low or very high adiposity impairs fertility. For obesity, its default state of low-grade, chronic inflammation and disordered immune function [12] severely lowers nicotinamide adenine dinucleotide (NAD+) at cellular, tissue, and systemic levels, leading to restricted cellular energy production [13].

Sustained energy shortage cues AMP-activated protein kinase (AMPK) to drive follicular atresia [14]. AMPK, a master regulator of energy homeostasis, induces autophagy in a dose-dependent manner. It also acutely inhibits the stimulatory effects of luteinizing hormone (LH)/protein kinase A (cAMP-dependent protein kinase) on progesterone production in luteal cells, an effect reversed by exogenous cholesterol [14]. AMPK is directly involved in human granulosa cell steroid production and other processes often disrupted in cell adhesion, lipid metabolism, and inflammation. Silencing AMPK promotes follicle growth accompanied by increased serum anti-Müllerian hormone (AMH) [15]. Importantly, the follicle-stimulating hormone receptor (FSHR)-mammalian target of rapamycin (mTOR)- hypoxia-inducible factor 1 (HIF1) pathway helps follicles avoid atresia for the duration of any local environmental stress [16].

The local nutritional climate is mediated by mTOR to regulate cell growth, differentiation, metabolism, and autophagy [17]. mTOR contributes to more than 700 different phosphorylation reactions including the tuberous sclerosis/TSC1 (hamartin)-TSC2 (tuberin) complex, which itself dampens the mTOR/S6K/4E-BP pathway (i.e., ribosomal protein S6 kinase 1/S6K and eukaryotic translation initiation factor 4E-binding protein/4E-BP) [18]. These imbricated systems remain incompletely mapped [19]. In mammalian reproduction, mTOR guides follicular recruitment, influences oocyte maturation in meiosis, coordinates signaling to granulosa/theca units, orchestrates puberty onset and influences ovarian aging [17, 20]. Reduced ‘silent mating type information regulation 2 homologue 3’ (SIRT3) in experimental oocytes increases mitochondrial reactive oxygen species (ROS) production, leading to impaired embryo competence and development [21].

NAD + and its reduced form (NADH) are coupled metabolites facilitating key redox reactions. They enable energy transfer through glycolysis and mitochondrial respiration to support cell growth and survival. Numerous regulatory enzymes broadly involved in cell functions require NAD + as a co-substrate for catalytic activity [22]. Improving intraovarian NAD + levels in aging mice can amplify the follicle pool, ovulation potential, and livebirth rate. Replenishing NAD + with nicotinamide riboside reduces ROS levels and decreases spindle anomalies in older oocytes, while raising mitochondrial transmembrane potential with decreased mitochondrial clustering [23]. Similar results were obtained in a murine model by nicotinamide mononucleotide (NMN), which enhanced oocyte meiotic competency by suppressing apoptosis, maintaining normal spindle/chromosome structure, and conservation of ovastacin—a cortical granule component [24].

Evidence and rationale for weight optimization

Clinical research has shown overweight and obese women experience high intracellular lipid toxicity, more inflammation, and greater oxidative stress which negatively impacts health generally and reproductive function specifically [2]. Adipose tissue serves an endocrine role by contributing to steroid output, carbohydrate control, and inflammatory signaling [25]. Its pleiotropic role is typified by synthesis and release of numerous adipokines with diverse and extensive signaling effects [26]. Although fat deposits can develop directly in mammalian ovarian tissue from pharmacologic blocking of steroidogenic synthesis and stromal lipid accumulation [27], this is neither common nor necessary to compromise ovarian function.

Health-promoting lifestyle programs are essential in the assisted reproductive technologies to optimize pregnancy and livebirth rates [28]. One recent study of infertile overweight or obese women scheduled for IVF (n = 2381) reported that a 60-day weight reduction intervention before treatment can increase neonatal birth weight, reduce maternal blood glucose concentration, and improve maternal insulin resistance [29]—all desirable goals prior to ovulation induction via gonadotropins.

A ‘first meal’ dose of β-glucan or arabinoxylan extract followed 6 h later by a 20% glucose solution (second meal) suppressed blood glucose elevation. Both arabinoxylan and β-glucan increased the levels of short-chain fatty acids in ileum and cecum, respectively. Of note, GLP-1 secretion in the blood increased with β-glucan and showed an increasing trend with arabinoxylan, suggesting barley β-glucan and arabinoxylan are fermented in the intestinal tract to favor endogenous GLP-1 release [30], thus mimicking SG effects. This was consistent with murine research which confirmed improved glucose tolerance after high β-glucan barley intake associated with a subsequent rise in GLP-1 secretion [31].

Several investigators have established a connection between dietary restriction and mitochondrial activity [32, 33]. The sirtuin-1 (SIRT1)-AMPK system processes metabolic information to increase number and function of mitochondria [34, 35] similar to resveratrol [36, 37] and metformin [38, 39]. A reaction to calorie restriction has been experimentally shown to affect lifespan in animals [40, 41] and humans [42, 43]. For example, rodents on severely restricted diets can suffer fertility impairment or total loss of reproductive capacity [44, 45]. In clinical practice, females underweight from profound dietary restriction likewise show lower fertility with endocrine features congruent with ovarian insufficiency [46]. However, in certain contexts limiting caloric intake is accompanied by desirable effects including an extension of ovarian operational capacity beyond expected limits. In nematodes, transient diet scarcity blunts reproduction by inducing latency in germline stem cells, a reversible process which is undone once ambient nutritional factors improve [47, 48]. Experimental studies have described how adversity can sharply attenuate reproductive success while defending germline reserves, with recovery of fertility when environmental conditions are more favorable [49, 50]. In many avian species, periodic molting to increase egg lay is attained commercially by programmed limitation of nutrients. Although induced molting is sometimes viewed as harmful or inhumane, it is known that wild birds do not eat despite plentiful food in nature. This biological process is especially evident in geese which may be anorexic for many weeks, and in king penguins where fasting can extend up to six months [51].

Intermittent fasting can likewise improve health and extend lifespan, but any superiority over caloric restriction has yet to be proven. In a murine model, improved oocyte quality was achieved with every-other-day fasting after one month [52]. Not only was antral follicle count and ovulation improved, both nuclear and cytoplasmic maturation were enhanced after this intervention. Of note, single-cell transcriptome analysis found the beneficial impact of intermittent fasting was mediated by restored NAD+/SIRT1-mediated antioxidant defenses [52]. These results were consistent with earlier murine data [53] where calorie restriction was noted to extend lifespan by increasing cellular NAD+/NADH ratio, promoting expression of peroxisome proliferator-activated receptors, and activating SIRT1 [53]. In human fibroblast Hs68 cells, calorie restriction has extended lifespan via boosted expression of nicotinamide phosphoribosyltransferase (NAMPT), intracellular NAD(+) levels, and SIRT1 action [54].

While some have noted the lack of evidence to support long-term calorie restriction [55], there is disagreement here. For example, when the growth hormone (GH)/Insulin like growth factor (IGF)-1 axis and insulin resistance were measured after intermittent fasting and caloric restriction over two years in non-diabetic obese subjects, metabolic parameters were positively impacted by caloric restriction, while intermittent fasting (with no caloric restriction) enhanced cellular resistance to disease but without weight loss [56].

It appears that moderate dietary restriction, can enhance ovarian function in mammals [57], although exactly how this works is not known. One hypothesis suggests metabolic resources are shunted to somatic maintenance which is prioritized over reproduction, where dietary scarcity temporarily favors pro-longevity processes [49]. The assessment may be incomplete since trade-offs between reproduction and lifespan during caloric restriction are not always easy to define [49].

GLP-1 as a metabolic “conductor”

Underscoring the broad dispersal of energy management tasks throughout cell populations, GLP-1 can contribute to any of the above biosystems where nutritional status directs a physiological process. Nutritional stress likewise influences longevity [58, 59] and recent work has given a sharper picture of these interconnected networks [57, 60]. GLP-1 is sufficiently critical to overall life function that no true GLP-1 deficiency state has ever been documented. And because AMPK, IGF-1, mTOR, and the sirtuin pathways all interlock with GLP-1, the relevance of SG to reproduction rightly draws notice.

GLP-1 is a highly conserved regulator of energy homeostasis with almost complete sequence homology across many mammalian species [61]. Classified first as an incretin, GLP-1 protects against carbohydrate overload by enhancing insulin secretion and inhibiting glucagon secretion [62]. Since GLP-1 actions are intimately connected to insulin balance, SG cuts across innumerable dynamic biochemical systems with relevance to overall ovarian function and follicle development [63, 64]. While insulin is the chief regulator of lipid and glucose metabolism, IGF-1 is an organizer of growth and development. They can co-bind to highly homologous receptors which share close structural similarity and have common distal signaling pathways [65], exemplified by their joint initiation of network signaling to promote activation of maturation-promoting factor (MPF), catalyzing oocyte entry into M-phase of meiosis I and II [66].

Processes known to be mediated by GLP-1 have enlarged and diversified over time; its receptor in endometrium may fluctuate during the menstrual cycle [67, 68]. GLP-1 appears to activate calmodulin-dependent protein kinase II via calcium influx at L-type voltage-gated calcium channels [69]. Additionally, GLP-1 alters interleukin (IL)-6 to modulate hyperglycemia-induced apoptosis and endoplasmic reticulum degradation from homocysteine excess [70], an effect apparently independent of insulin dynamics [71].

Transactivation has been suggested for other receptors, including GLP-1 dampening of K⁺ channels and binding to epidermal growth factor receptors, leading to activation of phosphatidylinositol 3-kinase (PI3K) [72] followed by inhibition of apoptosis-related transcription factors [62, 73]. Interestingly, although not yet observed in humans, the active transcriptional response to GLP-1/Notch signaling is evident in the germline stem cell pool in C. elegans [74].

Semaglutide: considerations before IVF

Semaglutide (SG) is a glucagon-like peptide-1 (GLP-1) receptor agonist which received U.S. FDA approval in 2021 (Wegovy^®, Novo Nordisk; Plainsboro, New Jersey) for chronic weight management in adults. It is administered as a weekly 2.4 mg subcutaneous injection [75]. Ozempic^® (Novo Nordisk) and Rybelsus^® (Novo Nordisk) are other SG formulations approved for type 2 diabetes, but not for weight loss. They improve glucose handling by boosting pancreatic insulin secretion while dampening hepatic glucagon release [76]. SG also modulates neuronal pathways to stimulate satiety and energy expenditure while reducing energy intake [77].

When combined with lifestyle changes of dietary modification and a structured exercise program, SG can provide beneficial results for adults with BMI ≥ 30, or BMI of at least 27 plus diabetes, hypertension, dyslipidemia, obstructive sleep apnea, vascular disease, or history of myocardial infarction [78]. Off-label use of SG for aesthetic or personal reasons among non-obese patients is growing [79, 80] and can be expected to elicit similar—but not yet adequately studied— responses as produced in overweight or obesity.

Specifically, SG is thought to facilitate autophagy via enhanced AMPK [81]. It also boosts IGF-1-mediated muscle protein synthesis, inhibits NF-κB-mediated ubiquitin-proteosome degradation, and directly augments heat-shock factor-1-mediated myogenesis in myocytes [82]. Insulin signaling and its associated AMPK pathway are enhanced by SG [83]. NK cell impairment is common in obesity, a disorder which is substantially rectified with SG by its apparent enhancement of the CD98-mTOR-glycolysis axis [84]. While SG may decrease expression of NF-κB, TNF-α and IL-1β in some cell populations [85], this has not been observed specifically in ovarian tissue.

Signal inputs necessary for ovarian folliculogenesis are numerous, and how SG interfaces with transforming growth factor-beta 1, growth differentiation factor-9 (GDF-9), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1) awaits full characterization (see Fig. 1).

Fig. 1.

Schematic of selected direct and secondary semaglutide (SG) responses related to insulin (INS) and insulin-like growth factor 1 (IGF-1), with emphasis on central and peripheral reproductive and proliferative effects (blue). IGF-1 can potentiate oocyte maturation via phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog (PI3K/AKT) signaling. VEGF = vascular endothelial growth factor; mTOR = mammalian target of rapamycin; GnRH = gonadotropin hormone-releasing hormone; KissP = kisspeptin; SHBG = sex hormone binding globulin; GLP-1 = glucagon-like peptide 1; LH = luteinizing hormone; FSH = follicle stimulating hormone; GC = granulosa cell; T = testosterone; cAMP = cyclic adenosine monophosphate; E₂ = estradiol; GnR = gonadotropin receptors

Platelet-derived growth factor and bone morphogenic proteins also appear central to cell migration, vascular support, and general ovarian function [86]. When cell exomes releasing these substances are inserted near undifferentiated oocyte stem precursors in an experimental ovarian insufficiency model, follicle development and restored reproductive capacity are observed [87]. How SG influences the function of these mediators remains to be studied in an ovarian setting.

Adverse but rare events associated with SG may include hypoglycemia, gastrointestinal upset, pancreatitis and pancreatic cancer, thyroid cancer, gallbladder events, or acute kidney injury [88]. Its packaging features a ‘black box’ warning for possible development of thyroid C-cell tumors, and the medication is contraindicated for those at risk for medullary thyroid cancer or type 2 multiple endocrine neoplasia. In addition, a history of acute pancreatitis is a relative contraindication [89].

More recently, an agent which targets both GLP-1 and GIP receptors (tirzepatide) received regulatory clearance for treatment of type 2 diabetes. It shares a similar mechanism of action with SG, and this dual receptor co-agonist affinity of tirzepatide may limit gastrointestinal symptoms [90].

SG is relatively long-acting with a half-life of about seven days when injected subcutaneously [91]. No formal guidance has been issued for a dosing schedule before or during fertility treatment. Because some data suggest possible harm to offspring, SG should be avoided in pregnancy or breastfeeding [10]. Of note, accidental SG use in pregnancy was reported in a diabetic patient (age 43yrs) where no adverse events were documented in mother or baby following intrapartum exposure of six months [92]. When used in advance of a programmed IVF cycle, discontinuation of SG for least 8 weeks before planned oocyte retrieval seems prudent [92] to reduce risk of anesthesia complications associated with delayed gastric emptying [93, 94].

Conclusion

Obesity is a major public health challenge with adverse metabolic and reproductive phenotypes. Affected patients face the dual stigmas of obesity and reproductive inadequacy, where fertility loss often induces shame, distress, and low self-esteem. Those seeking infertility treatment with overweight or obesity are at heightened risk of cardiometabolic consequences as well as negatively impacting reproductive outcome with IVF. Weight loss, physical activity, and dietary modification are thus laudable pre-conception interventions for overweight/obese women. Since SG is a potent modifier of insulin status, it sets the metabolic climate for ovarian function and determines reproductive capacity. As a new addition to the therapeutic repertoire in weight management, SG when properly applied, can improve treatment responses for an important subgroup of infertility patients. Yet, its numerous signaling targets involving the human ovary will need to inform future study, and off-label use of SG should be discouraged in the meantime.

Author contributions

ESS developed the project as Principal Investigator; ESS and SHW wrote the manuscript while CH, HIC, J-WW, and FY reviewed the literature and revised the manuscript. All authors read and approved the final version.

Funding

This research received no external funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.