Uterine Fibroids: Mechanisms, Treatment Challenges and the Power of Embracing a Functional Approach

Dear Colleagues:

Uterine fibroids are a huge, underappreciated issue. They are the most common gynecological disorder, affecting nearly half of women younger than 40 years old, and far more (>70%) for those older. Frankly, I don’t think we are doing enough to help these patients. Fibroids are the leading indication for hysterectomy in the US, accounting for 39% of all hysterectomies each year, and while some are asymptomatic, symptoms include heavy and prolonged periods, difficulty with intercourse, bowel dysfunction, non-cyclic pelvic pain, low back pain, urinary frequency and urgency, and constipation. Because not all fibroids cause heavy bleeding, their impact can be missed, think: refractory constipation or incontinence.

Beyond hysterectomy, conventional treatments include pharmacotherapy, myomectomy, and uterine artery embolization, however, these treatments leave much to be desired. Oral contraceptives or aromatase inhibitors may be used to manage bleeding (with potentially severe side effects in the latter), and even after myomectomy, fibroids often recur and 10% of women will undergo hysterectomy within 5 – 10 years.

It’s our time. Functional medicine is ideal to analyze the underlying, contributing causes and target treatments accordingly for each unique patient.

In this month’s blog, learn underlying mechanisms and practical treatment takeaways – and, really interesting to me (and something I’ve seen in practice) the role that progesterone plays in increasing fibroid size in some women. I suspect that our fibroid treatment failure in some cases has to do with prescribing progesterone to the wrong patient. With comprehensive treatment of hormones, diet, lifestyle, nutrition, and stress, functional medicine management of uterine fibroids can improve our female patients’ quality of life, and minimize the need for drug therapy and surgical interventions. Read on to find out how, and be sure to leave a comment, share to let us know what you think!

~DrKF

Uterine Fibroids: Mechanisms, Treatment Challenges and the Power of Embracing a Functional Approach

Uterine fibroids (leiomyomata) are surprisingly common: by the age of 50, around 80% of African-American women and at least 70% of white women develop fibroids, according to the National Institutes of Health. This means that a large majority of women in America will develop them. They are even more common than being overweight. Fibroids are challenging to treat, and conventional approaches consist mainly of surgical procedures for management of symptoms. Additionally, a few medications are being used to reduce symptoms pre-surgically, such as gonadotropin-releasing hormone agonists, SERMs (selective estrogen receptor modulators) and aromatase inhibitors.

To begin to understand fibroids, it is important to recognize that they are growths; technically, they are benign (not cancerous) tumors of uterine muscle tissue. Yet their growth is abnormal, begging the question “What makes them grow, and how can we reduce those risk factors?” While the answer isn’t known for certain, the high (and rising) prevalence of fibroids clearly indicates that contributing factors are quite common. Fibroids aren’t always symptomatic, but can result in chronic pain, abnormal bleeding, scarring, reduced fertility, and lower quality of life for women. Consequently, regular screening is advisable and there is much we can do with our Functional Toolkit.

A Finely-Tuned Environment

When considering the potential reasons for the development of uterine fibroids, it’s helpful to think about the total environment in which they develop. Within the uterus, a dynamic equilibrium among chemical mediators of growth and transformation constantly remodel the uterine environment. Eating and living habits can feed these mediators, which can serve as a trigger for fibroids, as we discuss later.

The uterus must perform an enormous metabolic undertaking. In women of reproductive age, it takes an intricate yet ever-changing balance among numerous growth hormones and related messengers to maintain fertility, regulate the maturation and release of eggs, and prepare a viable uterine environment for a healthy fetus. And all this must be accomplished on a monthly basis. If and when an egg is fertilized, this biochemical symphony must rapidly transition to keeping the fetus healthy. A mother’s blood circulation must be redirected, billions of precision cell divisions in a fetus must be supported, and specialized tissues needed to nourish the fetus’ rapid growth must be created. Mammary and central nervous functions are prepared in order to protect and nurture the new life.

In order to accomplish its primary function, the uterus is constantly undergoing an extraordinary amount of executive coordination between various hormones and messengers that help hormones do their jobs effectively. Specifically, there must be executive coordination among levels of the following hormones and enzymes:

• Rise and fall in multiple forms of estrogen (endogenous estradiol, estrone, and estriol as well as environmental xenoestrogens and dietary phytoestrogens) and estrogen receptors
• Rise and fall in progesterone and progesterone receptors
• Rise and fall in follicle-stimulating and luteinizing hormones (FSH and LH)
• Cortisol and other stress hormones, which can affect overall hormone balance
• Aromatase, COMT (catechol-O-methyltransferase), and other key sex hormone-metabolizing enzymes. COMT degrades catechol estrogens so they can be cleared from the body and polymorphisms of the enzyme are associated with an increased risk of fibroids. Aromatase is an enzyme that converts androgens into estrogens.
• Insulin-like growth factor (IGF), prolactin, sex hormone-binding globulin (SHBG), DHEA (dehydroepiandrosterone), testosterone, and thyroid hormones must also be optimized. For example, fibroids may have elevated IGF expression and may accompany metabolic disorders. Therefore, it is crucial to evaluate and address inputs that impact glucose and insulin responses. Furthermore, fibroids are often associated with a high prolactin level, which is linked to infertility.

Balancing hormones can reduce the risk of developing fibroids. Since they are also fundamentally important in energy metabolism, immune balance, and gastrointestinal function, optimizing hormones in women with fibroids may additionally improve inflammation, gut dysbiosis, sleep, and overall quality of life.

Fibroids Hear Growth Signals Loud and Clear

It’s long been noted that fibroids grow more rapidly during pregnancy and tend to regress after menopause, though perimenopausal hormonal fluctuations can provide growth impetus. We now know that not only do fibroids possess receptors for both estrogen and progesterone, but that a highly-estrogenized milieu may upregulate the genetic expression of progesterone receptors. Both estrogen and progesterone should be viewed as “growth hormones” for fibroids; it’s just that they promote different aspects of ovarian and uterine tissue function at different times of women’s reproductive cycles.

Thus, while optimizing balance among pro-estrogenic influences is a central focus in approaching fibroids, it is also important to consider how progesterone and the function of its receptors may be contributing to their growth. The 2016 Study of Women’s Health Across the Nation (SWAN) study additionally pointed out an interesting association between high testosterone levels and incidence of fibroids, especially if estradiol levels were also high. The study noted that receptors for androgens are highly expressed in fibroids. It also detected a doubled risk for fibroids with the use of exogenous hormone therapies, and an inverse relationship between FSH level and fibroid development.

An interesting question is: why do fibroids seem so “hungry” for growth hormone messages? While we don’t purport to completely answer this huge issue, part of the explanation may be that vitamin D, one of the body’s chief controllers of hormonal and immune responses, regulates sex steroid receptor expression in uterine fibroids. Vitamin D deficiency is relatively common, and through the above mechanism, this could play a key role in the development of fibroids.

Progesterone, Not Just Estrogen, Can Increase Fibroid Size

Traditionally, in treating fibroids, a greater focus was placed on estrogen’s role. SERMS (selective estrogen receptor modulators) are often used to treat fibroids. However, it has only recently become appreciated that progesterone also plays a key role in fibroid growth. Progesterone receptors (PRs) have two isoforms: A and B. Fibroids have heightened expression of both of these progesterone receptor isoforms. Additionally, high estrogen levels can signal an uptick in PR expression. Recognizing the likely role that progesterone plays in fibroids and the ability of estrogen to boost progesterone receptor expression, research is now focusing on SPRMs (selective progesterone receptor modulators), sometimes referred to as “antiprogestins,” that alter PR function—and thus cellular responsivity to progesterone. One SPRM, Ulipristal, has been proven to effectively treat fibroids long-term, although rare liver complications have been reported.

SPRMs serve as synthetic steroidal signals for PRs. They may act as agonists, antagonists, or both at various binding sites within PRs. SPRMs essentially recode PRs’ genetic programs for transcription. They also change a cell’s life-and-death cycle and alter immune signaling. Through these actions, they can induce programmed cell death (apoptosis) and suppress collagen formation within fibroids to limit their growth.

Lingering questions we have about SPRMs, include:

1. Especially since SPRMs are given continuously rather than mimicking the natural up-and-down cycle of progesterone, what are their long-term effects?
2. Since SPRMs affect basic cell programming in hormone-sensitive tissues (not just the uterus) and are known to change endometrial architecture in novel ways, are they associated with an increased risk for cancer

SPRMs are now being administered in Europe, so we’ll be paying close attention to outcomes there.

Given the apparent treatment benefit of interfering with progesterone receptors, it begs the question if progesterone supplementation, which is commonly used to balance estrogen, is beneficial for all women with fibroids. Perhaps progesterone should be carefully administered in these women or clinicians could stratify risk for using progesterone in women with fibroids. Monitoring response to therapy by tracking fibroid size with pelvic and/or transvaginal ultrasound is useful- just be consistent with timing, as fibroids change with cycle hormone ratios. Further, those with larger, palpable fibroids will likely know if an intervention is effective or not themselves.

Lifestyle and Dietary Factors Affecting Fibroids

Detoxification of steroid hormones in the liver and intestines can reduce circulating levels of hormones, and thus influence fibroid growth. Therefore, it’s necessary to address dietary factors to enhance healthy clearance of hormones. Prime examples include limiting intakes of caffeine and alcohol (which interfere with liver detox of estrogen), increasing dietary fiber intakes (to limit intestinal deconjugation of excreted estrogen metabolites), and increasing consumption of phytoestrogens. A few examples of phytoestrogens include flaxseed lignans, resveratrol, hops flavonoids, black cohosh, and isoflavones from red clover, soy, or kudzu. However, it’s good to keep in mind that different women respond differently to phytoestrogens.

Fibroids generally have high COMT and aromatase expression, which is involved in the breakdown of androgens into estrogens. Therefore, optimizing estrogen levels is crucial. More importantly, improving the balance between the formation of weaker 2-OH-estrones and the more potent  4-OH-estrones and 16α-OH-estrones is a focal point of fibroid treatment. 2-OH-estrones are estrogen metabolites that, when converted to their methoxy counterparts, block cancer growth. On the other hand, 16α-OH-estrones and 4-OH-estrones are estrogen metabolites that may promote cancer development in women. Suggestions for optimizing the balance between these two metabolites can include supporting healthy methylation function, encouraging regular sweat-inducing activity, regularly eating Brassica vegetables, and/or supplementation with DIM (diindolylmethane, a stable metabolite of sulforaphane), plus glutathione. These encourage formation of the more beneficial 2-OH-estrones, improve healthy estrogen metabolism, and help increase SHBG levels while discouraging formation of the more genotoxic estrogens.

Addressing Other Critical Risk Factors

Another risk factor for fibroids is visceral adiposity. A recent Chinese study found a remarkably strong link between visceral adiposity and risk for fibroids. In this population:

• Higher waist-to-hip ratio increased risk up to 7.7-fold (especially peri-menopausally)
• Greater body fat percentage, waist-height ratio, or visceral fat area each increased risk around 4-fold
• Higher body mass index (BMI) or waist circumference, each, increased risk almost 3-fold

Because obesity is associated with significant changes in immunometabolic and hormonal parameters, it seems likely that the strength of these findings will be confirmed in other populations. Consequently, these central obesity-related measures may present a simple and low-cost method of screening for fibroid risk.

Exposure to factors that can influence sex hormone levels, such as xenoestrogens, endocrine disruptors, and persistent organic pollutants may also play a role in fibroid development. Therefore, eliminating environmental exposure to these toxins may be beneficial.

Other research has shown that:

• Women with fibroids given 800 mg/day of a decaffeinated, EGCG-rich green tea extract showed significant reductions in fibroid volume and symptom severity, along with less bleeding and better quality of life. (Comparable to Lupron)
• Smoking, longer menstrual cycle or menstrual bleeding, and nulliparity can increase risk.
• Intakes of vitamin A, fruit, and vegetables relate inversely to fibroid risk; having citrus fruits at least 3 times weekly showed an especially strong protective association.
• African-American adults tend to have lower intakes of fruits, vegetables, vitamins A and C, carotenoids, and fiber, and are also less likely to take vitamin/mineral supplements—all of which may help explain African-American women’s particular susceptibility to developing fibroids.
• Weight gain during adulthood may heighten risk, even if weight remains normal.
• Though not confirmed in women, melatonin may selectively trigger apoptosis and autophagy in fibroid cells while sparing normal uterine muscle, according to preclinical research. Melatonin is also antiestrogenic and antioxidant.
• In an animal model, a flavonoid from licorice herb called isoliquiritigenin interfered with estrogen-induced fibroid growth and triggered apoptosis and autophagy in affected cells.
• Resveratrol also showed the ability to stimulate apoptosis and autophagy in fibroid cells, in a preclinical study.
• The seaweed polysaccharide fucoidan inhibited fibroid cell proliferation and encouraged apoptosis.

Beyond the EGCG paper cited above, it’s worth noting that in general flavonoids stand out as a way to address fibroids. An interesting 2017 study looking at the flavonoid kaempferol (in kale, spinach, dill, tarragon)  showed a potent inhibitory effect on both mRNA levels and protein levels of estrogen receptor, IGF-1. Additionally, impaired glucose metabolism and excessive glycation are linked to fibroid development, and flavonoids improve these two metabolic processes. Flavonoids have other actions that block fibroids including prebiotic effects, optimizing life-and-death cell cycle regulation, and improving overall redox and immune balance. Pair these “side benefits” with a paucity of adverse effects and flavonoids are an ideal choice.

How Genetics Influence Fibroid Growth

A 2015 study looked into genomic features that distinguish metabolic subtypes of fibroids, and discovered that genetic expression of insulin-like growth factor, prolactin, and Wnt/β-catenin proteins (involved in normal as well as abnormal cell proliferation) may characterize fibroids with different response patterns. It also identified several polymorphisms that play into fibroid development, including several that affect oncogenesis, immune factors, cell metabolism and migration, collagen formation, and endogenous antioxidant systems like Nrf2. Metabolomic profiling of fibroids reveals that some may have altered metabolism in relation to amino acids, heme, vitamin A, and antioxidants. Another project examines how -omics can distinguish between benign fibroids and those disposed to malignant transformation. While this avenue of research is in the early days, it will undoubtedly help clarify which treatments are best suited to each woman’s genetically unique fibroids.

Suggested Takeaways

• Optimize hormone levels and hormone messengers, including estrogen, progesterone, cortisol, IGF, prolactin, SHBG, DHEA, testosterone, and thyroid hormones.
• Evaluate and address inputs that impact glucose and insulin responses.
• Reduce visceral fat by optimizing glucose metabolism, hormones, and stress.
• Caution should be used when treating with progesterone. In some women, it likely promotes, rather than diminishes, fibroids.
• Thoroughly evaluate and address factors that can influence sex hormone levels, such as exposures to xenoestrogens, endocrine disruptors, and persistent organic pollutants. Eliminate sources of these pollutants by avoiding products that contain BPA, parabens, and phthalates.
• To better target particular treatments, consider testing for genetic variants relating to estrogen and progesterone receptors, aromatase, and COMT.
• Recommend that patients reduce intake of caffeine and alcohol (and animal products, too) to facilitate liver detox of estrogen while increasing dietary fiber intakes to block intestinal deconjugation of excreted estrogen metabolites. Increased intake of vegetables and fruits (especially citrus fruit) may also be helpful.
• Consider supplementation with phytoestrogens such as flaxseed lignans, resveratrol, hops flavonoids, black cohosh, and isoflavones from red clover, soy, or kudzu.
• Optimize levels of the estrogen metabolites 2-OH-estrones and 16α-OH-estrones by supporting healthy methylation function, encouraging regular sweat-inducing activity, regularly eating Brassica vegetables, and/or supplementation with DIM (diindolylmethane).
• Begin a supplementation protocol that includes EGCG-rich green tea extract, resveratrol, melatonin, fucoidan, and kaempferol.
• Optimize vitamin D levels.
• Appreciate how stress can devastate overall hormone balance. Consider nutritional support of adrenal function and cortisol levels and mind-body practices, careful exercise prescription, and the use of herbs like licorice.