Understanding Progesterone Resistance and Its Impact on Fertility.

What is Progesterone Resistance?

Progesterone resistance is a condition where the body’s tissues are less responsive to the hormone progesterone. This occurs due to the downregulation or dysfunction of progesterone receptors (PGRs), making it difficult for the body to utilize the hormone effectively. Despite normal or elevated progesterone levels, the tissues fail to respond, leading to various reproductive health issues. A 2018 observational study found women with unexplained infertility to have progesterone resistance as a result of impaired endometrial expression of progesterone receptors in the uterine lining.

Circumstances Where Progesterone Resistance is Likely to Occur

Progesterone resistance is commonly associated with conditions like endometriosis. This occurs because chronic inflammation and environmental toxins, such as dioxins, in the pelvic environment impair PGR expression and function. Additionally, genetic factors and epigenetic changes also contribute to the development of progesterone resistance.

• Endometriosis: Progesterone resistance is commonly observed in individuals with endometriosis. Endometriosis is a condition where endometrial tissue grows outside the uterus, perpetuating chronic inflammation. This inflammatory environment impairs the expression and function of progesterone receptors, leading to reduced responsiveness to progesterone.

• Chronic Endometritis: Chronic Endometritis is a persistent inflammatory condition of the endometrium characterized by the infiltration of plasma cells into the endometrial stroma. It’s frequently associated with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). Chronic inflammation exacerbated by CE can disrupt the normal hormonal balance and signaling pathways, leading to progesterone resistance. In the context of fertility, CE is particularly concerning because it can lead to fertility complications by impairing the endometrial lining’s ability to adequately respond to progesterone. This resistance worsens the difficulty in treating infertility and maintaining a pregnancy, thereby compounding the challenges faced by those struggling with these issues. Common symptoms of CE include abnormal uterine bleeding, pelvic pain, and infertility.

• Environmental Toxins: Exposure to certain environmental toxins, such as dioxins and endocrine disruptors, has been linked to the development of progesterone resistance. These toxins can interact with hormonal receptors and interfere with normal hormone signaling, leading to reduced progesterone activity.

• Genetic Factors and Epigenetic Changes: Genetic variations affecting the progesterone receptor gene or related signaling pathways may render individuals more susceptible to this condition. Epigenetic modifications, which involve changes in gene expression without altering the DNA sequence, can also contribute to progesterone resistance. But this can also include factors such as DNA methylation which impact PGR expression and function resulting in diminished progesterone responsiveness.

• Uterine Abnormalities: Structural abnormalities of the uterus, such as uterine fibroids or adenomyosis, can affect the local hormonal environment. These conditions may impair the proper functioning of progesterone receptors in the endometrial tissue, contributing to resistance.

• Polycystic Ovary Syndrome (PCOS): While PCOS is typically associated with elevated androgen levels, it can also contribute to progesterone resistance. The hormonal imbalances and chronic low-grade inflammation seen in PCOS can interfere with progesterone signaling.

How Progesterone Resistance Disrupts Fertility and Treatments

Progesterone plays a crucial role in preparing the endometrium (uterine lining) for implantation and maintaining pregnancy. When resistance occurs, the endometrial tissue fails to respond adequately, impairing decidualization and embryo implantation. This can lead to recurrent implantation failure and infertility. Progesterone resistance also reduces the effectiveness of conventional fertility treatments like progestin therapy following embryo transfer. Common progesterone therapies include progesterone injectables, vaginal progesterone gels or suppositories, oral micronized progesterone, progesterone patches. Rather than having a “cooling” or anti-inflammatory effect, individuals with progesterone resistance may experience increased inflammation noticeable in the form of bloating, swelling and severe fatigue (as in my experience).

Why is Progesterone Resistance Commonly Overlooked

Progesterone resistance is frequently overlooked due to its subtle presentation and the complexity of accurately diagnosing it. That is, diagnosing progesterone resistance requires specific tests such as endometrial biopsies, which are invasive and not always routinely performed. Standard fertility work-ups do not include specialized tests needed to detect progesterone resistance because complexity and cost.

More importantly, progesterone resistance is just one factor behind failed endometrium receptivity of an embryo. The symptoms of progesterone resistance often overlap with other conditions, making it difficult to identify without targeted testing. This can include conditions like endometriosis and chronic inflammation which share similar symptoms and can mask underlying progesterone resistance. Often enough, this can lead to a misdiagnosis or lack of consideration for this condition.

How to Resolve Progesterone Resistance

A clear understanding of the relationship between chronic inflammation (immune dysfunction) and progesterone resistance is crucial for developing effective treatment plans for such conditions that compromise fertility. This is because progesterone resistance occurs alongside chronic inflammation and the interplay between hormones and inflammation in the uterus is complex.

Decreasing the effects of progesterone resistance start by diminishing chronic inflammation, both in the uterine environment and throughout the body. Common inflammatory triggers include chronic infections, chronic stress, toxins, excess adipose tissue, food sensitivities or intolerances or allergens, processed foods high in refined sugar and unhealthy fats, sedentary lifestyles, nutritional deficiencies and sleep deprivation.

Chronic inflammation can be the result of various possible combinations of inflammatory factors that affect people differently and therefore cause them to express different symptoms. Unraveling the causes of chronic inflammation is the biggest challenge in treating inflammatory conditions and unexplained infertility. Healing begins with the patient, to recognize pattens of symptoms, relate family history and how diet, infections, exposures and lifestyle habits could be driving chronic inflammation and your unexplained infertility.

A Path Forward

In my personal experience with progesterone resistance, progesterone therapies that were needed for the transfer of my frozen embryos after IVF were actually increasing inflammation and perpetuating a pro-inflammatory environment that was inhospitable for the embryo to implant. Pausing from fertility treatments to reflect and uncover underlying factors behind my thyroid autoimmunity (otherwise immune dysfunction and chronic inflammation) were key steps in reestablishing the proper use and balance of progesterone in the uterine lining. Once I addressed my underlying factors for chronic inflammation, the need for assisted reproductive technologies like IVF and embryo transfer was no longer warranted as soon thereafter, I became pregnant naturally.

By better understanding the relationship between progesterone resistance and immune dysfunction, individuals and healthcare providers can better manage and address fertility issues, utilizing a more tailored approach to restoring health and fertility and improving pregnancy outcomes. It by far justifies the need for more holistic personalized healthcare, integrative treatment strategies and a greater collaborative effort between the patient and provider.

Study Reference

Petousis S, Prapas Y, Margioula-Siarkou C, Ravanos K, Milias S, Mavromatidis G, Kalogiannidis I, Haitoglou C, Athanasiadis A, Prapas N, Rousso D. Unexplained infertility patients present the mostly impaired levels of progesterone receptors: Prospective observational study. Am J Reprod Immunol. 2018 Jun;79(6):e12828. doi: 10.1111/aji.12828. Epub 2018 Feb 16. PMID: 29450939.