International Women’s Day

Estradiol’s Vital Role on Body Weight Regulation: A Review

By: Jeesa Joseph

Director’s Note: On March 8th we celebrate International Women’s Day. Today, we highlight an article published in 2022 titled, “The importance of estradiol for body weight regulation in women.” [1] The lead author, Dr. Pilar Vigil, is an outstanding physician and friend of FACTS based in Chile. Summarized by FACTS elective student Jeesa Joseph, Vigil et al’s article addresses the significant regulatory role of estradiol and its impact on everything from the menstrual cycle to metabolic health, insulin sensitivity, and even neuroprotective functions. Dr. Vigil has served as a speaker at FACTS conferences, and we are delighted to make those presentations available via our online, self-paced CME course. To learn more from Dr. Vigil about ovulation, PCOS, and other women’s health topics, consider enrolling in the FACTS CME course.

Introduction

Estrogen, the master regulator of female physiology, orchestrates intricate processes — from shaping reproductive cycles to influencing neural circuits — which underscores its captivating role in the tapestry of life. Three primary forms of estrogen exist: (1) estrone, observed post-menopause, (2) estriol, present during pregnancy, and (3) estradiol, the most potent estrogen, found predominantly in the ovaries during the reproductive years. While factors like diet and exercise influence body weight, genetic and hormonal imbalances, particularly related to sex steroids like estradiol, also play a significant role. According to Vigil et al, estradiol’s impact on body weight regulation in women is substantial, influencing the menstrual cycle, various signaling pathways, and demonstrating synergistic effects with glucagon-like peptide-1 (GLP-1) receptor agonists to promote weight loss and possibly prevent neurodegeneration. [1]

“Three primary forms of estrogen exist: (1) estrone, observed post-menopause, (2) estriol, present during pregnancy, and (3) estradiol, the most potent estrogen, found predominantly in the ovaries during the reproductive years.”

Estradiol and the Ovarian Cycle

Estradiol influences food intake during different phases of the menstrual cycle, impacting psychological perceptions of food. While odor detection decreases in the periovulatory phase, it increases during the menstrual and early follicular phases. Concurrently, dopaminergic reward activity for high-energy foods intensifies in the periovulatory phase. [2] Women typically reduce food intake and increase energy expenditure during the periovulatory phase. These hormonal influences on food intake and somatic perceptions could suggest that ovulatory dysfunction from hormonal imbalance may contribute or lead to obesity. Furthermore, estradiol peaks before ovulation in normal menstrual cycles, suggesting a role in decreasing appetite and increasing satiety. On the other hand, low estradiol and high progesterone levels in the luteal phase may result in binge eating.

Low estradiol levels in adolescence, perimenopause, and menopause may cause or contribute to weight gain. Conversely, consistently high estradiol levels, as in pregnancy or metabolic issues, often increase appetite. Anovulatory states linked to low or consistently high estradiol are associated with increased appetite. Low estradiol may not generate a sufficient anorectic response, while high estradiol may blunt anorexic effects. [3] Thus, estradiol is crucial in homeostatic feeding during the normal menstrual cycle and prevention of obesity in women.

Estradiol’s Central and Peripheral Effects

Estradiol functions as a signaling molecule for weight regulation through its influence on various physiological processes, particularly in the central nervous system (CNS) and the hypothalamus. Within the hypothalamus, estradiol targets specific nuclei such as the ventromedial hypothalamus (VMH) and the arcuate nucleus (ARC). The VMH participates in thermogenesis and energy expenditure, with estradiol promoting calorie-burning in brown adipose tissue, thereby regulating body temperature. Simultaneously, in the ARC nucleus, estradiol modulates both appetite-suppressing neurons (pro-opiomelanocortin, POMC) and appetite-stimulating neurons (neuropeptide Y, NPY; agouti-related peptide, AgRP). Through these actions, estradiol directly influences the balance between satiety and hunger, which is essential for metabolic equilibrium and maintenance of body weight. Understanding these central effects illuminates the intricate role of estradiol in weight regulation and metabolic homeostasis.

“Estradiol directly influences the balance between satiety and hunger, which is essential for metabolic equilibrium and maintenance of body weight.”

While estradiol has central effects regulating food intake, it also has peripheral effects through interaction with hormones involved in appetite regulation, including cholecystokinin (CCK), leptin, insulin, and GLP-1. Released in response to food intake, CCK induces satiety, and studies propose that estradiol enhances CCK release, potentially reducing food intake. Leptin, produced by adipose tissue, signals satiety, and estradiol may influence its production and sensitivity, enhancing leptin’s anorexigenic effects. Additionally, estradiol enhances insulin sensitivity in muscle and adipose tissue. [1] Its anti-inflammatory properties inhibit pathways that contribute to insulin resistance. Estradiol influences pancreatic function, promoting insulin secretion; it also regulates adipose tissue distribution, impacting insulin sensitivity. Estradiol optimizes insulin sensitivity by modulating intracellular signaling pathways associated with insulin action.

The complex relationship between estradiol and insulin is influenced by factors such as the menstrual cycle, menopause, and hormone replacement therapy. Maintaining appropriate estradiol levels is crucial for overall metabolic health and insulin sensitivity in women, highlighting the hormone’s multifaceted role in regulating energy balance and glucose metabolism. In parallel, GLP-1 plays a crucial role in glucose metabolism by stimulating insulin secretion from pancreatic beta cells, enhancing insulin sensitivity and blood glucose regulation. GLP-1, released in response to food, stimulates insulin release and reduces appetite. Studies suggest estradiol enhances GLP-1 secretion, contributing to its anorexigenic effects and its role in regulating food intake. [4] Understanding estradiol’s influence on these peripheral hormones provides insights into its multifaceted role in appetite regulation and metabolic balance.

“Maintaining appropriate estradiol levels is crucial for overall metabolic health and insulin sensitivity in women, highlighting the hormone’s multifaceted role in regulating energy balance and glucose metabolism.”

Estradiol and the Future of Reproductive/Obesity Medicine

Research suggests a potential synergistic enhancement of GLP-1 agonists in females with elevated estradiol levels, outperforming metformin in treating insulin resistance and weight gain. Liraglutide, in particular, demonstrates superior clinical outcomes in this regard. [5] Despite the promising prospects of a GLP-1-estradiol conjugate to combat insulin resistance and weight gain, concerns about estrogen’s oncogenic and gynecologic consequences limit research. Encouraging findings in obese male rats and ovariectomized female rats receiving GLP-1-estradiol conjugates hint at weight loss benefits without evidence of uterine weight increase, addressing concerns about endometrial hyperplasia in women. [6][7] These insights fuel ongoing investigations into the potential development and application of GLP-1-estradiol conjugates for effective insulin resistance management and weight control.

“Research suggests a potential synergistic enhancement of GLP-1 agonists in females with elevated estradiol levels, outperforming metformin in treating insulin resistance and weight gain.”

If studied in humans, such combinations may help women maintain a healthy weight and protect cognitive function, crucial for those with abnormal estradiol levels due to ovarian issues (e.g., anovulation, PCOS) or menopause. GLP-1-estradiol conjugates may enhance central insulin sensitivity, potentially mitigating insulin resistance and lowering the risk of neurodegenerative disorders. Future research should focus on determining optimal dosage, timing, safety, and frequency for administering these conjugates to address body weight disorders.

Conclusion

Estradiol appears to play a modulatory role in the release and activity of appetite-regulating hormones such as CCK, leptin, and GLP-1. The intricate interplay between these hormones contributes to the complex regulation of energy balance and body weight in women. Fluctuations in estradiol levels can impact the responsiveness of these hormonal systems, influencing appetite and metabolism. Understanding these interactions is essential to comprehend the broader picture of how hormonal changes and regular menstrual cycles contribute to homeostatic regulation of body weight in women.

References

[1] Vigil P, Meléndez J, Petkovic G, Del Río JP. The importance of estradiol for body weight regulation in women. Front Endocrinol (Lausanne). 2022;13:951186. Published 2022 Nov 7. doi:10.3389/fendo.2022.951186.
[2] Dreher JC, Schmidt PJ, Kohn P, Furman D, Rubinow D, Berman KF. Menstrual cycle phase
modulates reward-related neural function in women. Proc Natl Acad Sci U S A. 2007;104(7):2465-2470. doi:10.1073/pnas.0605569104.
[3] Leeners B, Geary N, Tobler PN, Asarian L. Ovarian hormones and obesity. Hum Reprod
Update. 2017;23(3):300-321. doi:10.1093/humupd/dmw045.
[4] Alhadeff AL, Mergler BD, Zimmer DJ, et al. Endogenous Glucagon-like Peptide-1 Receptor
Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control. Neuropsychopharmacology. 2017;42(7):1471-1479. doi:10.1038/npp.2016.246.
[5] Wilding JP, Overgaard RV, Jacobsen LV, Jensen CB, le Roux CW. Exposure-response
analyses of liraglutide 3.0 mg for weight management. Diabetes Obes Metab. 2016;18(5):491-499. doi:10.1111/dom.12639.
[6] Vogel H, Wolf S, Rabasa C, et al. GLP-1 and estrogen conjugate acts in the supramammillary
nucleus to reduce food-reward and body weight. Neuropharmacology. 2016;110(Pt A):396-406. doi:10.1016/j.neuropharm.2016.07.039.
[7] Schwenk RW, Baumeier C, Finan B, et al. GLP-1-oestrogen attenuates hyperphagia and
protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice. Diabetologia. 2015;58(3):604-614. doi:10.1007/s00125-014-3478-3.

ABOUT THE AUTHOR

Jeesa Joseph

Jeesa Joseph is a fourth-year medical student at Philadelphia College of Osteopathic Medicine in Suwanee, GA. She completed her undergraduate education at Mercer University in Macon, GA. She plans to pursue residency in family medicine and is interested in preventive medicine and patient education. She enrolled in the FACTS elective to gain a better understanding of natural family planning methods and to share this knowledge with future patients. Through such personalized care, she hopes they will feel more empowered over their health and reproductive decisions.