Tolle Totum

Serena Goldstein, ND

Young girls today are developing breasts and starting their periods earlier than in previous generations. High estrogen levels are a likely key contributor to this premature development in girls. Excess estrogen over time places women at risk for hormonal issues such as early menopause and breast cancer. Early sexual development also increases risk of precocious sexual activity as well as psychological challenges such as eating disorders, depression, and substance abuse. There is no one cause of high estrogen levels. Studies suggest that emotional stress associated with growing up in households with high levels of conflict, early sexual abuse, or the absence of a girl’s biological father, can raise estrogen and promote early puberty.¹ Other contributors most likely include increasing body mass index (BMI) in the general population, dietary and lifestyle factors, and environmental estrogens. Indeed, estrogen dominance is not only a significant risk factor among girls, but also women in general. Along with estrogen-related cancers, excess estrogen increases risks of uterine fibroids, ovarian cysts, endometriosis, premenstrual syndrome, fibrocystic breasts, painful or heavy periods, and a more difficult perimenopausal transition.

Women have 4 reproductive hormones that are in constant flux (estrogen, progesterone, luteinizing hormone, and follicle-stimulating hormone), along with a generally steady level of testosterone. As a result, when certain concerns arise, especially in a premenopausal woman, any or all of these hormones may be affected to varying degree; in turn, hormone disruptions can also potentially imbalance other processes, due to the complexity of hormone regulation in the body. Estrogen dominance is one of the more common conditions among women. It can result from both normal physiology and environment/lifestyle, and contributes to a myriad of signs and symptoms. Rather than just replacing a hormone here and there, a more effective approach is to identify and address the underlying causes of hormone imbalance.

A Brief Review of Estrogen Physiology

Estrogen, which is made in the ovaries, adrenal glands, and adipose, is the main sex hormone in women. Estrogen is important for early development of primary and secondary sex characteristics, as well as embryonic and fetal development of brain networks. Estrogen also plays a major role in puberty onset, fertility, and the menstrual cycle, and helps protect against bone fractures, cardiovascular disease, and Alzheimer’s disease.² At the beginning of the follicular phase of a woman’s menstrual cycle, hormones in the hypothalamus signal pituitary release of follicle-stimulating hormone (FSH), which promotes the development of follicles in the ovary. These follicles predominantly produce estradiol, which thickens the endometrium. Estradiol levels rise sharply during the last few days before ovulation, reaching their maximum 1 day before the luteinizing hormone (LH) surge, and then rapidly decline. Assuming no fertilization, the corpus luteum post-ovulation produces increasing amounts of progesterone (and a slight rise in estradiol), and both hormones then decrease steadily in the week prior to menses. A new cycle begins. Once fully menopausal, circulating levels of both estrogen and progesterone fall to low levels.³ Estrogen deficiency in menopause causes LH and FSH levels to increase, with the latter remaining high well into menopause.⁴

The 4 forms of estrogen include 17β-estradiol, estrone, estriol, and estetrol (E4, aka human fetal steroid estetrol, which is only synthesized during pregnancy by the fetal liver; E4 is being explored as a possible form of hormone replacement therapy, as it antagonizes estradiol).⁵ Estradiol (E2) is the most potent estrogen and is the predominant estrogen in non-pregnant females of reproductive age; E2 is synthesized primarily in the ovaries, can be aromatized from testosterone, and can be converted in the liver to estrone and estriol. Estrone (E1) is also produced in peripheral tissues (ie, adipocytes) via aromatization from androstenedione. E1 is weaker than E2 and is the main form of estrogen after menopause, although small amounts of E2 continue to be produced. Estriol (E3) is the least potent estrogen (1000 times less potent than E2) and plays a large role in pregnancy, as it is produced by the placenta. E3 can also be formed from E1 through 16α-hydroxylation.²

E1 and E2 break down into metabolites called 2-hydroxy (OH)-estrone, 4-OH-estrone, 16α-OH-estrone, 2-OH-estradiol, and 4-OH-estradiol. The “2” form is considered protective against cancer, since it doesn’t stimulate cell growth, whereas the “4” and “16” forms are potentially deleterious; the former can develop as a result of environmental toxin exposure and damage DNA, while the latter has stronger estrogen activity and can be at higher concentrations in obese women.⁶ The protective 2-OH-estrone and 2-OH-estradiol metabolites are converted to 2-methoxy (Me)-estrone- and 2-(Me)-estradiol, respectively, by the enzyme, catechol-O-methyltransferase (COMT), which serves to suppress tumor cell proliferation and angiogenesis. COMT is also required to convert 4-(OH)-estrone and 4-(OH)-estradiol to 4-(Me)-estrone and 4-(Me)-estradiol, respectively, which are actually protective metabolites that help prevent oxidative metabolism of E2 and DNA damage. If COMT is deficient or its function is compromised due to genetic mutations, then variations of the “2” and “4” metabolites can have the opposite effect of being pro-inflammatory free radicals.⁶ Further conjugation by glucuronidation or sulfation facilitates safe removal of estrogens.

Estrogen receptors (alpha and beta subtypes) are present in many organ systems throughout the body. In women, estrogen receptor-alpha (ERα) is predominant in the mammary gland, thecal cells of the ovary, uterus, bone, liver, and adipose tissue, and plays more of a role in regulating metabolism.⁷ The estrogen receptor-beta (ERβ) is located mainly on the granulosa cells of the ovary, colon, and adipose tissue. ERβ has a larger role in the immune and central nervous systems and opposes the ERα-driven hyperproliferation in tissues such as the breast and uterus. Both ERα and ERβ receptors are also present in men.⁷

Estrogen Modifiers & Effects

Just as there are many ways that estrogen can be made and metabolized, there are many ways for these processes to be thrown off that contribute to hormonal imbalances. Most estrogen is held in reserve by being bound to hepatic sex hormone-binding globulin (SHBG) or (more weakly) to albumin. Thus, concentrations of SHBG are important determinants of bioavailable estrogen in the body. High SHBG concentrations have been associated with factors such as a high carbohydrate diet (35-40%), while low concentrations of SHBG have been linked with elevated prolactin, hyperinsulinemia, and obesity. Low SHBG results in greater amounts of free, unbound estrogen.⁸

Elevated estrogen increases thyroid-binding globulin, which has the effect of binding more thyroid hormone.⁹ Reduced amounts of unbound thyroid hormone results in slower metabolism and reduced energy expenditure (increasing the risk of weight gain), reduced lipolysis (increasing the risk of hyperlipidemia), and reduced gluconeogenesis (raising the risk of hypoglycemia).¹⁰ Keep in mind that the thyroid is strongly affected by stressors on the body (external or internal), in areas such as autoimmunity and activation of T3 from T4.¹¹

As mentioned, the metabolism of E1 and E2 into favorable metabolites occurs via methylation. Certain genetic variants of COMT (such as the Val/Met polymorphism that reduces enzyme function) can affect how efficiently these estrogens are metabolized. This same polymorphism can impact the degradation of dopamine, an excitatory neurotransmitter. Women with the Val/Val genotype have been shown to have greater COMT enzyme activity, hence lower dopamine levels, compared to women with the Met/Met genotype, who have been shown to have higher dopamine levels and impaired executive functioning as a result.¹² Because COMT also metabolizes estrogen, women with the Met/Met genotype and high estrogen may be at particular risk of impaired cognitive function in menopause.¹² More studies are needed to confirm this.  

Gut health can also influence estrogen metabolism and levels, as some bacterial species possess the enzyme beta-glucuronidase, which can reactivate the hormone. Estrogen that isn’t bound to SHBG is conjugated through phase 2 detoxification pathways, such as glucuronidation, and is then eliminated through the kidneys and gastrointestinal tract. However, too much bacterial beta-glucuronidase activity in the intestine can cause deconjugation of estrogen. This results in increased reabsorption of free estrogens into the body, potentially contributing to the development of estrogen-related cancers of breast, ovary, or endometrium.¹³

Additional Sources Of Estrogen

Environmental estrogens also contribute to overall estrogenic activity in the body, including the estrogens added to meats and dairy products,¹⁴ phytoestrogens in soy, and especially xenoestrogens, which are non-physiological compounds that bind ERα receptors and can evoke estrogen responses in the body as well as interfere with endogenous estrogen actions.¹⁵ Xenoestrogens are common in a wide variety of cleaning and beauty products (eg, parabens), plastics (eg, BPA, phthalates), pollution, and pesticides (eg, DDT, DDE), and artificial preservatives.¹⁶ Feminine hygiene products, such as tampons, used to be composed of more synthetic fibers, which can alter the vaginal pH and environment; now they are comprised of a single synthetic fiber and are mostly cotton.¹⁷ However, they also now contain trace amounts of dioxins (chemical byproduct of bleaching) that can be absorbed directly by the vulva without being metabolized. This constitutes a significant exposure, considering that a woman might be exposed to over 10 000 tampons during her lifetime.¹⁷ Switching to an organic pad or tampon or to a non-chemical alternative can help reduce this exposure.

Hormone Testing

Hormone testing can be done using blood, urine, or saliva.¹⁸ A serum test is convenient if you want to also evaluate organ systems that might be related to an estrogen imbalance; examples of useful blood tests include thyroid, vitamin D (precursor to sex steroids), CBC, CMP, iron, hemoglobin A1c, and possibly DHEA-S and SHBG. However, estrogen and progesterone may be best measured by urine and saliva because these tests measure the “free” (unbound) form of the hormones, ie, that fraction of hormone that is acting on the body; levels of total (free + bound) hormone in the blood can sometimes be falsely high or normal. Hormones are also pulsatile; since serum represents a snapshot in time, it’s difficult to discern if a lab value is at its high or low point.

In contrast to most hormone blood tests, salivary testing measures the free hormone and specimens can be collected throughout the day, thus lending more versatility and clinical value to the result. Salivary testing is also helpful in evaluating cortisol levels throughout the day if indicated, to gain an understanding of the patient’s stress levels. Limitations can include a patient being unable to produce adequate saliva.¹⁸

Urine tests are also useful for measuring hormones, either at a single point in time or in a 24-hour collection, to evaluate a patient’s natural rhythm. A 24-hour collection also provides insight into the various estrogen metabolites and liver function, which may point to specific paths for treatment. Limitations can include dehydration or excessive fluid intake.¹⁸

Finally, consider genetic testing (cheek swab) for COMT, to gain insights into estrogen metabolism and mood and to help guide your treatment.

Therapeutic Approach

As discussed, there are many possible reasons for why a woman is estrogen dominant, as well as multiple factors that can exacerbate estrogen excess. We therefore need a multi-systems approach in our treatment. A patient’s personal and family history, along with a thorough analysis of her environment, will help you identify the most significant obstacles to cure. In addressing the root cause of disease in a multi-factorial condition can be proverbially like peeling the layers off an onion. From there, a treatment plan can more easily come into view, often focused around nutrition, proper sleep, a healthful lifestyle, and certain combinations of supplements to help expedite healing and balance hormones.

Nutrition

Fruits and vegetables are great sources of fiber, vitamins, and minerals that support both estrogen metabolism and gut health and help prevent cancer. The American Institute of Cancer Research estimates that at least 5 servings of fruits and vegetables per day can reduce cancer rates by as much as 20%.¹⁹ Cruciferous vegetables, in particular, have been shown to protect against cancer more effectively than total intake of fruits and vegetables.¹⁹ Crucifers contain glucosinolates, selenium (also helpful for thyroid), sulforaphane, and indole-3-carbinol, all of which promote healthy estrogen metabolism, protect against reactive oxygen species, and optimize phase 1 and phase 2 detoxification pathways in the liver.

Soy is a type of phytoestrogen, a naturally-occurring plant compound that is structurally and functionally similar to estrogens and their metabolites. For this reason, soy is a controversial food group in terms of estrogen-related conditions; its phytoestrogen compounds mimic estrogen but it has also been a long-time staple in the traditional Asian diet and has been credited for Asians’ historically lower rates of menopausal symptoms, hormone-dependent cancers, obesity, diabetes, and cardiovascular disease compared to Western populations.^20,21 Until we know more about the extent to which soy isoflavones can counteract excessive estrogen or harmful estrogen metabolites (ie, 4-OH-estrogen), it might be best to err on the side of low-to-moderate consumption of soy, especially for a patient with a strong history of estrogen-related concerns.

Supplements

One of the most powerful ways to counteract estrogen dominance is by boosting progesterone concentrations. Vitex agnus-castus (chasteberry), which acts directly on the pituitary, is an especially effective way to do this. Chasteberry inhibits the secretion of FSH, which helps prevent increases in estrogen. It also promotes LH secretion, which supports corpus luteum production of progesterone. The herb also indirectly supports progesterone production by enhancing dopamine production by the pituitary. Dopamine inhibits prolactin, a hormone that can reduce progesterone production by suppressing the corpus luteum.²²

Calcium-D-glucarate, which is produced naturally in small amounts from dietary glucaric acid but is also available as a supplement, inhibits the bacterial enzyme beta-glucuronidase that reactivates estrogen in the colon. Calcium-D-glucarate helps counteract estrogen dominance, reducing the risk of hormone-sensitive cancers such as prostate, breast, and colon; it also appears to lower cholesterol.²³ Glucaric acid is found naturally in many fruits and vegetables, eg, apples, oranges, and cruciferous vegetables.²³

Indole-3-carbinol (I3C) and diindolylmethane (DIM), I3C’s metabolite, which are found naturally in cruciferous vegetables and are also available in supplement form, induce cytochrome P450 enzymes to produce the beneficial 2-OH-estrogens. One study demonstrated that 500 mg/day of I3C for 1 week significantly increased 2-OH-estradiol levels, an outcome that can help counter estrogen-dependent disorders.²⁴

A healthy liver is critical, since it is the organ that handles the bulk of detoxification of xenobiotics, metabolism of estrogen and other hormones, and the conversion of inactive to active thyroid hormone. Silybum marianum (milk thistle) is one of our most useful liver botanicals, as it not only provides support for detoxification pathways and regeneration of hepatocytes, but also has anti-cancer properties.²⁵

Sleep

We are in a day and age of constantly being on the go, where the phrase “I’ll sleep when I’m dead” is well known; it also reflects the pervasive lack of quality sleep. Sleep duration has decreased about 1.5-2 hours over the past 50 years.²⁶ Prioritizing sleep has multiple beneficial effects on our hormones, including inhibiting corticotropin-releasing hormone, optimizing TSH release, and regulating appetite and satiety via leptin and ghrelin release.²⁶

Conclusion

We can clearly take many steps to remove toxic burden from our environment, both physically and emotionally. Adopting a toxin-free lifestyle, cultivating supportive relationships, supporting gut health, and emphasizing a healthful diet can all help counter estrogen dominance; these measures will also improve thyroid and adrenal health, balance blood sugar, and promote a healthy weight. Key supplements can help in achieving this balance, but are meant to supplement, not to replace, an unhealthful lifestyle. Your patients’ hormonal issues did not occur overnight. Working with them long-term helps healthy habits be put into place so that everything they do can also double as prevention.

References:

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Serena Goldstein, ND, is a naturopathic doctor in New York City who specializes in hormonal concerns such as weight, mood, stress, PMS, peri/menopause, and andropause. Dr Serena has been published in well-known health and wellness resources, such as MindBodyGreen, Consumer Health Digest, and the Hearty Soul. She has appeared on Sirius XM NYU Doctor Radio, and has lectured at Lehman College and the American Cancer Society. Dr Serena is also on the Advisory Board for Natural Practitioner Magazine and lends her expertise to fellow doctors at NYU-Hospital Poison Control Center. Contact Dr Serena at: www.drserenagoldstein.com.