Dr. BreAnna Guan, ND

 

Subheadline

A whole-person exploration of how inflammation, endocrine disruptors, metabolic dysfunction, gut dysbiosis, and stress may impair progesterone signaling and compromise fertility.

Short Description

This article examines progesterone resistance as an underrecognized contributor to implantation failure and infertility, emphasizing the critical role of endometrial receptivity in successful conception. It explores an integrative framework for restoring progesterone responsiveness through targeted support for inflammation, metabolic health, gut-endometrial signaling, endocrine detoxification, and nervous system regulation.

Introduction

While other mucosal tissues, such as the gastrointestinal mucosa and the vascular endothelium, are well recognized for their essential roles in physiology, the endometrium has yet to be fully appreciated for its complex role in fertility. The vital functions of the endometrium may be compromised by progesterone resistance, which is increasingly recognized as a contributor to impaired fertility.

Endometrium and Actions of Progesterone

The uterine environment is dynamic, transitioning like the tide through the phases of the menstrual cycle. The uterine cycle begins with menstruation, then the proliferative phase, and finally the secretory phase, overlapping with the co-occurring ovarian cycle. The endometrium, a thin inner lining of the uterus, responds to the fluctuating hormone levels. It has been called immortal, regenerating nearly 450 times in a woman’s lifetime.

The hormone-sensitive endometrial tissue undergoes complex remodeling, including proliferation and differentiation, in response to varying levels of estrogen and progesterone. Estrogen is responsible for proliferation and growth during the proliferative phase. Whereas progesterone regulates and stabilizes growth in the secretory phase by modulating estrogen signaling. Progesterone activity also causes the endometrium to secrete proteins and glycogen to nourish and support the developing embryo, transiently inducing a receptive phenotype in luminal endometrial epithelial cells, which is essential for implantation.

Even more, one of the most important activities of progesterone is decidualization, in which elongated, fibroblast‐like mesenchymal cells in the uterus differentiate into rounded, epithelioid‐like cells during the menstrual cycle and pregnancy. Decidualization also includes cellular matrix remodeling, immune regulation and monitoring (ensuring tolerance), oxidative stress protection, suppression of estrogen receptors, and angiogenesis. (1,2)

“The interface between the inside and outside world of a woman’s body…philosophically speaking, it is the interface to our own existence, as all of us required the endometrium to begin our journey as human beings.” Dr. Bruce Lessey (3)

Decidualization is one of the most critical events in the preparation for pregnancy. Without proper decidual reaction, many pregnancy disorders can result, including infertility, uteroplacental disorders, and miscarriages. IVF Rates are compromised, with high-quality embryos, due to the failure of implantation, highlighting the importance of quality decidualization. (4)

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“Progesterone signaling is vital for decidualization and is a prerequisite to successful implantation, making progesterone the master regulator of pregnancy.”(4)

IMAGE Reproduced from: MacLean, J. A., & Hayashi, K. (2022). Progesterone Actions and Resistance in Gynecological Disorders. Cells, 11(4), 647. https://doi.org/10.3390/cells11040647 CC BY 4.0

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Progesterone Resistance

Progesterone activity is mediated by the classical nuclear progesterone receptors, PR-A and PR-B. Recent studies have found that endometrial responsiveness to progesterone differs profoundly between women with endometriosis and those without. “Progesterone Resistance” was as such, coined to describe the deregulation of differentiation-specific gene networks in the endometrium in patients with endometriosis. (4) Thus, progesterone resistance can be defined as reduced responsiveness to progesterone and/or a failure to activate progesterone receptor signaling pathways and gene networks.

Without sufficient progesterone activity, the effects of estrogen cannot be balanced, and progesterone is unable to induce its normal secretory transformation, namely decidualization, even when progesterone levels are sufficient. In the literature, progesterone resistance usually applies to women with endometriosis, although it can initiate or worsen other gynecological disorders such as adenomyosis, leiomyomas, and PCOS (PMOS), creating further obstacles to endometrial receptivity, implantation, and a healthy pregnancy.

​Progesterone resistance and its implications on implantation are increasingly recognized, but the underlying causes, dynamic pathophysiology, and therapeutic approaches to improve endometrial receptivity in fertility remain elusive. It is important to understand that progesterone resistance is not a simple downregulation of receptors or receptor dysfunction, but rather a complex response to unfavorable conditions such as chronic inflammation, hormonal imbalance, and endocrine-disrupting exposures. These conditions can lead to downstream genetic and epigenetic changes in endometrial tissue and function. (4)

​The nature of progesterone resistance is a complex process that arises in response to complex physiological processes. This is why progesterone treatment alone is often insufficient to restore the health of the endometrium. It is well established that environmental endocrine-disrupting exposures, inflammation, dysregulated hormones, and disruptions in signaling mechanisms can all affect endometrial cellular function. Other areas that should also be considered for restoring estrogen sensitivity are metabolic dysfunction, gut dysbiosis, and endotoxin signaling.

 

​Treating the Whole Person

Given the complexities of the menstrual cycle, hormonal cascades, and the imbalances that contribute to progesterone resistance, a personalized approach is needed to support and restore fertility.

​Inflammation and Nutrition

Chronic inflammation is a cornerstone and well-defined contributing factor to the development of progesterone resistance. Identifying sources and causes of inflammation, including dietary, metabolic, and environmental factors, is vital to restoring progesterone activity. Anti-inflammatory therapeutic strategies can also be utilized in treatment.

Metabolic dysfunction is associated with chronic inflammatory activity and also impacts reproductive hormone production and is often tied to gynecological disorders, especially PCOS. Insulin resistance extends to the reproductive organs and can impact ovarian function and the uterine environment. (5) Dysfunctional endometrial insulin signaling may increase oxidative stress and further reduce endometrial receptivity.

​Gut-Endometrial Axis

The gut-reproductive cross-talks impact the health and vitality of the endometrium. Specifically, gut dysbiosis has been associated with disruption of endometrial signaling, chronic inflammation, and hormone dysregulation. (6) The female reproductive tract has a unique microbiome as well, which has a dynamic relationship with the gut microbial populations. The gut-endometrial axis is established through bidirectional communication via immune, neural, endocrine, and metabolic axes. Even more, changes in the gut microbiota can reshape systemic estrogen levels, thereby impacting endometrial receptivity and embryo implantation. In addition, short-chain fatty acids, bile acids, endotoxins, and other microbial-derived metabolites influence immune tolerance, epithelial integrity, and inflammatory tone in the endometrium, thereby affecting progesterone’s functionality in the endometrium.(7) Together, the gut-endometrial axis has the potential to impact systemic inflammation and the endocrine system, by which it may influence endometrial receptivity and the endometrium’s relationship to progesterone.

​Endocrine Disruptors

EDCs (Endocrine Disrupting Compounds) are either natural or man-made chemicals that can disrupt the endocrine system by mimicking, blocking, or interfering with the body’s hormones, potentially causing adverse health effects in the woman, in this case, or her offspring. Unfortunately, many everyday items, such as plastic bottles, food wrappers, metal food can liners, cleaning agents, flame retardants, gadgets, and cosmetics, contain endocrine-disrupting chemicals, including PCBs, bisphenol A (BPA), phthalates and their metabolites, and alkyl phenols. Daily chemical exposures such as these can disrupt the delicate endocrine system, including hormone signaling and hormone production, ultimately leading to impacts on reproductive health. In fact, studies have shown that decidualization is especially sensitive to EDCs. BPA, for example, can dysregulate estrogen and progesterone receptor levels and also increase oxidative stress and ROS, impairing decidualization and leading to implantation and/or placentation failure, loss of pregnancy, or infertility. (8)

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Image Reproduced from: Tricotteaux-Zarqaoui S, Lahimer M, Abou Diwan M, et al. Endocrine disruptor chemicals exposure and female fertility declining: from pathophysiology to epigenetic risks. Front Public Health. 2024;12:1466967. Published 2024 Dec 12. doi:10.3389/fpubh.2024.1466967 CC BY 4.0

Nervous System and Circadian Rhythm

 

When stress becomes chronic, it disrupts the balance of the neuroendocrine and immune systems. It also activates the sympathetic nervous system and the HPA axis. This, in turn, can cause abnormal cortisol secretion and immune dysregulation. (9)  Several trials have shown that the rate of miscarriage is reduced in women (with unexplained miscarriages) who receive psychological support in early pregnancy. One study had found that plasma levels of epinephrine and norepinephrine were higher in women who had experienced recurrent pregnancy loss. Another study found relationships between endometrial decidualization and levels of stress hormones.(10)

There is also an exquisite relationship between the sleep-wake cycle and endocrine hormone systems, including prolactin, thyroid, and reproductive hormones. It has been found that melatonin can improve progesterone production from granulosa cells, whereas estrogen appears to negatively influence melatonin.(11) These bidirectional connections between stress, sleep, lifestyle, and endocrine balance all must be evaluated against the backdrop of endometrial function and progesterone activity for reproductive success.

​Conclusion

Progesterone resistance impacts one of the most vital aspects of conception – the health and receptivity of the endometrial environment. In light of the increasing prevalence of gynecological disorders and growing rates of infertility, a whole-person approach is essential for restoring the critical influence of progesterone on reproductive health. Addressing progesterone resistance through a multifactorial approach, identifying underlying causes, and correcting imbalances may help improve endometrial receptivity and support fertility.

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References

1) Huang Z, Jiang T, Yao J, et al. Progesterone resistance in atypical endometrial hyperplasia: Expression and mechanisms of hormone-responsive molecules. Medicine (Baltimore). 2026;105(18):e48452. doi:10.1097/MD.0000000000048452

2) Okada, H., Tsuzuki, T., & Murata, H. (2018). Decidualization of the human endometrium. Reproductive Medicine and Biology, 17(3), 220. https://doi.org/10.1002/rmb2.12088

3) Lessey BA. Endometrial Assessment: A Clinical Guide. Women’s Health. 2013;9(5):415-417. doi:10.2217/whe.13.43

4) MacLean JA II, Hayashi K. Progesterone Actions and Resistance in Gynecological Disorders. Cells. 2022; 11(4):647. https://doi.org/10.3390/cells11040647

5) Shan H, Luo R, Guo X, et al. Abnormal Endometrial Receptivity and Oxidative Stress in Polycystic Ovary Syndrome. Front Pharmacol. 2022;13:904942. Published 2022 Jul 25. doi:10.3389/fphar.2022.904942

6) Elkafas H, Walls M, Al-Hendy A, Ismail N. Gut and genital tract microbiomes: Dysbiosis and link to gynecological disorders. Front Cell Infect Microbiol. 2022;12:1059825. Published 2022 Dec 16. doi:10.3389/fcimb.2022.1059825

7) Escorcia Mora P, Valbuena D, Diez-Juan A. The Role of the Gut Microbiota in Female Reproductive and Gynecological Health: Insights into Endometrial Signaling Pathways. Life (Basel). 2025;15(5):762. Published 2025 May 9. doi:10.3390/life15050762

8) Tricotteaux-Zarqaoui S, Lahimer M, Abou Diwan M, et al. Endocrine disruptor chemicals exposure and female fertility declining: from pathophysiology to epigenetic risks. Front Public Health. 2024;12:1466967. Published 2024 Dec 12. doi:10.3389/fpubh.2024.1466967

9) Chang L, Shan J, Li D, Wang X. Neuroendocrine-Immune Axis in Endometriosis: A Review on How the Nervous System Goes Beyond Pain Perception. Biomolecules. 2025;15(11):1536. Published 2025 Oct 31. doi:10.3390/biom15111536

10) Wu J, et al. Maternal anxiety affects embryo implantation via impairing adrenergic receptor signaling in decidual cells. Commun Biol. 2022;5(1):840. doi:10.1038/s42003-022-03694-1

11) Shechter A, Boivin DB. Sleep, Hormones, and Circadian Rhythms throughout the Menstrual Cycle in Healthy Women and Women with Premenstrual Dysphoric Disorder. Int J Endocrinol. 2010;2010:259345. doi:10.1155/2010/259345

Bio:

Dr. BreAnna Guan, ND is a licensed naturopathic physician who has specialized in women’s health and hormones for over a decade. Her path into this field was shaped by her own struggles with hormonal imbalances and the lack of answers she found in conventional medicine. Through her consulting practice, she has supported hundreds of women in restoring balance to their hormones, fertility, and overall well-being. In addition to her clinical work, Dr. Guan has contributed to NIH-funded research and served as a medical consultant for a hormone-testing company, a leading fertility tracking app, and a botanical supplement brand. She’s passionate about helping women connect with their bodies and create health in their own lives.