PhD Nootrition - estrogen dominance - ovarian aging

Estrogen Dominance (Part 1 — Ovarian aging)

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Over the last 70+ or so years, estrogen dominance has become a major, yet for the most part overlooked, health threat. What’s worse, is that it is virtually dismissed in conventional medical practice. Although estrogen dominance is a condition that affects both men and women, this post will focus on the factors that affect women.

Estrogen Dominance — Is it real?

It is still common practice today that most conventional doctors continue telling women that menopause — and for that matter, all symptoms associated with the menopausal transition (MT) period (also known as perimenopause) — results from a drop in estrogen production. While this holds some truth and estrogen levels will decrease during menopause, they do not fall appreciably until after a woman’s last period (1). From this vantage point, the solution lies with using Estrogen Replacement Therapy (ERT) to restore estrogen levels back to normal.
In contrast, many alternative and functional practitioners believe that far more women suffer from the effects of “estrogen dominance” during the transition — that is, they have too much estrogen relative to progesterone. In fact, this camp believes that estrogen dominance — a term coined by the late Dr. Lee — is the real culprit behind the symptoms that women experience throughout their MT, and without enough “opposing” progesterone, estrogen levels will remain high in the second half of the menstrual cycle (2). In this view, the obvious solution lies in re-establishing the balance through progesterone supplementation.
Unfortunately, both of these views are overly simplistic and misleading for women, and overlook the dynamic interplay between hormones and environment, genes, and aging. But, the truth is somewhere in between. While I tend to lean more towards the “estrogen dominance’ camp in this debate, in my mind, the concept of estrogen dominance as it stands is far too simplistic, as is the idea of progesterone supplementation. This is largely due to the realization that since the death of Dr. Lee in 2003, we have witnessed huge leaps in our understandings about the biochemical mechanisms underpinning the menopausal transition, especially with respect to hormonal, genetic and environmental factors.
While I believe that estrogen dominance is very real, its significance goes beyond looking at the overall ratio of estrogen to progesterone. Calling this “estrogen dominance” can be catchy, but it is also misleading. It implies there is ONE problem — high estrogen relative to progesterone — which isn’t true. It also implies that there is ONE solution — progesterone supplementation to “oppose” and balance excess estrogen — which also isn’t true. Healthy hormonal balance is complicated. It isn’t just a matter of not enough progesterone.

A common misconception is that estrogen dominance results only from extremely high levels of estrogen. To the contrary, a woman can have deficient, normal or excessive levels of estrogen, but lack sufficient progesterone to counteract the effects of estrogen.

Symptoms of estrogen dominance.

To appreciate what estrogen dominance is and why it appears during a certain period of time in a woman’s life, we must go beyond this simple ratio theory and look at factors that throw this hormonal dance out of balance as a woman approaches the menopausal transition.
Estrogen dominance is simply a condition of hormonal imbalance that occurs when a woman enters the menopausal transition (MT) period of her life. But before we talk about what it really is (or is not), let’s speak about the symptoms that are left in its wake:

  • Decreased sex drive.
  • Bloating (water retention).
  • Hot flashes and night sweats.
  • Irregular or heavy menstrual periods.
  • Breast swelling and tenderness.
  • Premenstrual headaches.
  • Mood swings
  • Abdominal weight gain.
  • Thyroid dysfunction.
  • Cold hands and feet.
  • Hair loss.
  • Slow metabolism.
  • Brain fog, memory loss.
  • Heart palpitations.
  • Trouble sleeping/insomnia.
  • Fatigue.
It is important to note that not all women will experience all of these symptoms. Many will sail through “the change” without any symptoms at all. Others will experience a wide range of symptoms — for 10 to 15 years, beginning as early as age 35 — all of which have physical, emotional, and psychological ties to well being.

Estrogen dominance — A tale of two realities.

Women often ask me if estrogen deficiency or progesterone to estrogen ratio does not define estrogen dominance, then what does? Is Dr. Lee or the countless functional practitioners and patients who use Progesterone to balance excess estrogen wrong? My answer is no, they’re not wrong, but the story is a little more nuanced.

Fig. 1. HPO Axis
Fig. 1. A diagrammatic presentation of the hypothalamic-pituitary-ovarian (HPO) axis. Developed follicles secrete steroid hormones (estradiol and progesterone) and peptide hormones (inhibin, activin, and follistatin); all collectively control secretion of gonadotropic Releasing Hormone (GnRH). Estradiol and progesterone, depending on concentration, have either positive or negative feedback and can alter the frequency and/or amplitudes of pulses at the level of both the hypothalamus and pituitary.
Although menopause is associated with changes in the hypothalamic-pituitary hormones — follicle-stimulating hormone (FSH) and luteinizing hormone (LH) — that regulate the menstrual cycle (Fig. 1) (3-5), I do not consider it to be a central event, but rather a consequence of two perfectly natural processes:
  • Ovarian aging.
  • Tissue hormone receptor status (will be explored in part 2).

While on the outset, ovarian aging may have nothing in common with receptor status, as we will uncover here and in the next few posts, the two are intricately connected…Two sides of the same coin, if you will. Now, in reading the following paragraphs, it is imperative to keep in mind that while you may not have any control over some elements in this tangled web (such as time, genes or aging), there are others where judicious use of preventive strategies can delay and lessen the impact of the inevitable reality associated with estrogen dominance. Let’s tackle each one separately. I’ll cover ovarian aging first and explore the concept of receptor status in a separate post in the near future.


You may be wondering what does ovarian aging have to do with estrogen dominance and menopause? Well, a lot actually. Ovarian tissue is more sensitive to the ravages of time than any other tissue in the human body. As time marches forward, both the quantity and quality of ovarian follicles take a nose dive through a process we’ve come to know as ovarian aging. (6). Given that estrogen and progesterone production occurs primarily in the ovaries (via the theca and granulosa cells), the overwhelming importance of this process in affecting hormone levels should come as no surprise (7, 8).
The ability to synthesize the essential trio of hormones — progesterone, testosterone and estrogen — is an essential characteristic of healthy ovaries during the reproductive years. And the preservation of such characteristics throughout the menopausal transition period and beyond is central if a woman wishes to age gracefully. To understand how this works, we have to appreciate some of the basic features of ovarian function. The ovarian follicle is composed of three key cells (Fig. 2):

  • Theca cells. In the ovarian follicle, LH stimulates theca cells to produce Progesterone and androgens (androstenedione and testosterone) from cholesterol. These cells lack the capacity to produce Aromatase (CYP19), the enzyme responsible for converting testosterone into 17β-estradiol (E2; the potent form of estrogen).
  • Granulosa cells. In contrast to theca cells, granulosa cells cannot make androgens, but can convert androstenedione into estrone (E1) and 17β-estradiol (E2). So, androgen is released from theca cells and transported into granulosa cells where it is metabolized into estrogen by the enzyme Aromatase (9). Follicle stimulating hormone (FSH) then promotes the conversion of E1 to E2.
  • Oocyte. When a critical concentration of E2 is reached in the follicle, it causes positive feedback in the hypothalamus, resulting in an increase in GnRH secretion and an LH surge. The LH surge starts the process of ovulation, after which the follicle is transformed into the corpus luteum, which begins to mass produce progesterone to prepare the endometrium for implantation.
Fig. 2. Estrogen synthesis & folliculogenesis
Fig. 2. (a) Folliculogenesis. A primordial follicle consists of an oocyte and a layer of granulosa cells at the beginning of follicule development. Thecal cells form a layer surrounding the granulosa cells when the follicle is activated. At end of folliculogenesis, thecal cells luteinize to form the corpus luteum after ovulation. (b) Cell-specific estrogen synthesis in the ovary. Production of estrogens starts with the synthesis of pregnenolone from cholesterol, catalyzed by the cytochrome P450 side chain cleavage enzyme (P450scc). Pregnenolone is then converted to progesterone by 3-beta-hydroxysteroid dehydrogenase (3β-HSD) in both thecal and granusola cells. Progesterone is converted to androgens via cytochrome P450 17α-hydroxylase (P45017α) and 17-beta-hydroxysteroid dehydrogenase (17β-HSD) in thecal cells during the follicular phase. The conversion of E2 is catalyzed by Aromatase (P450Arom) in granulosa cells.

Ovarian aging is a long and complex process associated with a decrease in both follicular quantity and quality. At this level, because of a depletion in ovarian follicles (known as the follicular pool), the ovary is no longer able to respond to FSH and LH. This results in the drastic reduction in ovarian estrogen and progesterone production, which leads to estrogen dominance.

In addition to the number of follicles, quality also plays a BIG role in determining how fast this follicular loss occurs. Emerging studies show that aside from age-dependent aside from typical DNA damages that the oocytes incur in the course of a woman’s life (10), mitochondria — the organelles responsible for several aspects of cellular physiology, including energy production, steroid hormone production, calcium homeostasis, and metabolism — affects both the size (quantity) as well as quality of the oocytes (11, 12). Mitochondrial dysfunction as a result of oxidative stress is a central factor in determining age-related changes that occur in the quality of the oocytes and the granulosa and thecal cells that surround it (11). Indeed, these are the richest cells of the body in mitochondria and depends largely on these organelles to acquire cholesterol from circulation and convert it into progesterone, androgens and eventually estrogen.
Oxidative stress plays an integral part of the deterioration of oocytes and results from the overproduction of free radicals such as reactive oxygen species (ROS), which overwhelm the body’s antioxidant defense mechanisms, especially the cellular mitochondrial pool. Normally, antioxidants neutralize ROS and thus help to prevent over exposure from oxidative stress. However, as the body ages, antioxidant levels decline, leaving the human body susceptible to various age‐related diseases. Given that the initial steps of sex steroid hormone biosynthesis (conversion of cholesterol to pregnenolone) takes place in the mitochondria (see Fig. 2b), it is not surprising to see how oxidative damage can lead to mitochondrial dysfunction in oocytes, explaining why levels of hormone production drop with accumulated levels of oxidative stress over time.

Mitochondrial aging impacts not only a woman’s fertility but also define the timing and severity of her estrogen dominance symptoms during (and after) her menopausal transition period.

In sum, here’s the take home message:

  • Less oxidative stress means less damage to mitochondria in theca and granulosa cells,
  • Less mitochondrial damage increases cell quality and quantity (follicular pool size will die off slower),
  • Higher number and quality of cells means that hormone production will remain normal for longer,
  • This will delay the onset of estrogen dominance symptoms associated with the menopausal transition period.
Reduction of oxidative stress should be of paramount importance in preserving mitochondrial function against the ravages of time. But, while this entails a realization that the sooner such strategies are implemented — i.e., in your 20s and 30s — the more effective the outcome, it does not mean that women in their 40s, 50s or beyond are left with no options. Preservation of mitochondrial function should be part of everyone’s daily strategy, regardless of age, or sex.
Estrogen and progesterone — A delicate balance on the brink.
The real question is how ovarian aging leads to an imbalance in estrogen and progesterone? The process of hormone production is generally well supported through the reproductive (premenopausal) years as there is ample amount of follicles to maintain normal hormonal balance. During the menopausal transition period (loosely known as peri-menopause), as the follicular pool dwindles down to a critical threshold (usually around 25,000 at approximately the age of 37–38 (13)), the body comes face-to-face with a “supply and demand” issue; there aren’t enough follicular cells to produce the levels of progesterone and estrogen necessary to support normal operation of all tissues and organs in the body.
In premenopausal women, the ovaries are the principal source of 17β-estradiol (and ~50% of the testosterone), which functions as a circulating hormone to act on distal target tissues (see tab below for an analogy). However, in postmenopausal women when the ovaries cease to produce this hormone (through reduction of the follicular pool), the peripheral conversion of androstenedione into estrone (or E1) becomes prominent. But only 5% of this E1 pool from peripheral tissues is converted to 17β-estradiol through the action of 17-hydroxysteroid dehydrogenase (17β-HSD1) (14). This can have profound implications for women suffering from unexplained or sudden weight gain associated with the menopausal transition period and beyond. But, we will explore this specific connection further in a separate post.

In postmenopausal women, circulating levels of estrogens reflect rather than direct estrogen action, because it is produced in extra-gonadal tissues and acts locally at these sites. In other words, they are reactive rather than proactive.

To understand the difference between estrogen produced by the ovaries and the ones made by the peripheral tissues, the following analogy may help illustrate the point.
Imagine a car manufacturer like Ford representing the ovaries, the states and cities in the United States representing the peripheral tissues (e.g., brain, heart, bone, etc) and the roads representing the arteries and circulation. Now, let's imagine that Ford is the only car manufacturer in the US supplying automobiles to everyone. During good economic time, their factory is busy making and delivering millions of cars to virtually all cities across the nation via planes, trains and automobiles. Cities (and the residents) rely on a constant supply of cars for their residents at all times. Everything is good and everyone is happy.
Now, during tough economic times, the company may start losing talent and jobs (ovarian follicular pool diminishes), forcing management to shut the factory down, creating a serious "supply and demand" problem for the nation. Not enough supply and too much demand. The factory is gone and no cars are being shipped across state lines using the arteries (i.e., road, air, rail) that connect us all. The circulation is dry and it will affect everyone.
The consequences of this are wide reaching. Cities (and states) may be forced to start building their their own local factories to produce enough cars to keep the local economy churning. But, the production levels will be just enough to satisfy the needs of the state or city. Any automobile produced locally will be used locally, and not be shipped anywhere else.
This is precisely what happens in a woman's body as she approaches the dreaded (but inevitable) menopausal transition period. Good times means the ovaries are churning enough estrogen and other hormones (cars) to release them (shipping) into circulation where they are used by local tissues/cells (states and cities) to ensure proper functioning or those tissues. As a consequence of aging, ovaries (the factory) slow down and eventually run out of oocytes (workers). Hormone production declines. But since local tissues require proper levels in circulation, they are forced to change tactics and begin producing the hormones locally, for their own use.

The level of estrogen synthesis is highest during the reproductive years, declining during the menopausal transition and beyond. During the normal menstrual cycle (Fig. 3), E2 levels are highest immediately before ovulation (110–410 pg/ml) and levels of circulating E2 during the follicular and luteal phase are approximately 19–150 pg/ml, whereas in postmenopausal women they are below 35 pg/ml (15). During the menopause transition, E2 levels drop by 85–90% and E1 levels decrease by 65–75% from premenopausal levels (16, 17).
Fig. 3. Menstrual cycle
Fig. 3. Estradiol and Progesterone levels during a typical woman's menstrual cycle - The diagram shows the temporal (time) relationships between ovarian follicular estradiol production and luteal progesterone and estradiol production. The upper and lower ranges are denoted by solid blue (estradiol) and yellow (progesterone). A and B represent the levels of progesterone and estradiol at menstrual day 21, respectively. The ratio between A to B is used to determine the extent of Estrogen Dominance, which in healthy women of reproductive-age is between 100 to 500 and drops to below ~50 during the menopausal transition (or peri-menopause) period.
What about androgens?
During premenopause, both the adrenal glands and the ovaries share equally in androgen production (18). Bilateral oophorectomy (surgical removal of both ovaries) in premenopausal women results in a 50% reduction in serum androstenedione levels while postmenopausal ovaries contribute only 20% of its total circulating levels. Now, we know that this 30% gap represents the effects of ovarian aging (19). Why is this important? Well, let’s go back to Fig.1; If there’s not enough theca cells (due to follicular pool depletion), there won’t be enough supply of androgens to produce estrogen in granulosa cells. And if there’s not enough estrogen, progesterone production and signaling will be compromised (I will explore this in part 2 when discussing “receptor status”).

A drop in sex steroid hormones during menopause is mainly attributed to loss of ovarian follicles. Continuous ovulation and follicular degeneration, plus the inability of follicles to naturally regenerate, eventually lead to reduced sex steroid hormone production.

What about the estrogen to progesterone ratio?
Estrogen gradually declines very late (STRAW stage -1) in menopausal transition (MT) period as the follicular pool becomes exhausted (20–23). However, there is a trend for increased plasma E2 during the follicular phase and lower Progesterone to 17β-estradiol ratio (see tab below) during the menopausal transition period relative to women of reproductive age (24–26). In fact, a 1998 meta-analysis including 12 studies showed that the average follicular phase levels of E2 in blood was 30% higher in peri-menopausal vs. pre-menopausal women (23). Other studies have confirmed these trends as well (24, 26, 27).

People often confuse the utility of Progesterone (Pg) to estradiol (E2) ratio. This measure is helpful ONLY when both E2 and Pg are within range, yet the patient continues to have symptoms. It should not be used clinically when either E2 and/or Pg are outside of their expected ranges or if the patient does not exhibit any clinical symptoms.
A low ratio is simply when E2 is high relative to Pg (key operating word being "relative to"). This describes your classic situation of estrogen dominance I talked about. In general, either decreasing estrogen and/or increasing progesterone (bio-identical version of the hormones) are appropriate strategies. Women who are postmenopausal generally fall into this group.
A high ratio occurs when Pg is high relative to E2. This is most common with with women who take supplemental Pg. In this scenario, after an initial successful period of Pg treatment, a woman may complain of symptoms that fall within the purview of estrogen deficiency (e.g., hot flashes, anxiety, depression, sleep, etc). This is not unusual because excessive Pg down-regulates production of estrogen receptors — we will explore this in part 2 later when we talk about "receptor status". In general, either increasing E2 and/or decreasing Pg are the correct strategies (personally, I prefer decreasing Pg).
Calculating the Pg/E2 ratio.
In the functional world, it is generally accepted that the “optimal” ratio of Pg/E2 is between 100 to 500. But this range is only valid if blood levels of E2 and Pg (in the luteal phase; around day 21) are within a normal range; i.e., E2 is ~40-200 pg/mL and Pg is ~8-20 ng/mL. The ratio is calculated from the Pg value in pg/mL divided by the E2 value, also in pg/mL.
Say your E2 = 100 pg/mL and Pg = 20 ng/mL. The Pg units are first converted from ng/mL to pg/mL before calculating the ratio: 1 ng/mL is equivalent to 1000 pg/mL. Therefore, the ratio is: 20 ng/mL x 1000 = 20,000 pg/mL Pg, divided by 100 pg/mL E2. This translates to a Pg/E2 ratio of 200.
Relevance of Pg/E2 ratio in women using hormone therapy.
With some types of hormone therapies such as use of topical Pg, it is prudent for practitioners and patients to realize that because symptoms of both estrogen dominance and estrogen deficiency (naturally or from Pg therapy) can be the same, regular testing along with monitoring of symptoms is of paramount importance to help guide and determine the next steps.


Xenoestrogens and Metalloestrogens: The curse of civilization?

Fluctuating levels of naturally produced estrogens and other sex steroid hormones is not the only culprit behind estrogen dominance. As it turns out, environment plays a BIG part in causing bouts of sometimes ‘violent” symptoms that women experience as they transition into menopause. Since the lifetime exposure to estrogen is a well-established risk factor for many estrogen-related diseases such as breast cancer and endometriosis, anything that mimics its activity will likely contribute to the etiology of the disease. Scientists have long suspected a link between estrogen-disrupting chemicals, commonly referred to as EDCs in the environment and gynecological conditions. Exposure to many EDCs starts in the womb, and timing is important in determining risk later in life. The disrupting nature of the EDCs lies in the fact that chronic, non-stop exposure over time (as it happens in modern society) can lead to elevations in body’s estrogenic load, disrupting the cyclic “ebb and flow” of natural estrogens. This can have drastic consequences for women that results in unregulated and often unpredictable outcomes. Some of the notorious culprits are xenoestrogens and metalloestrogens, which I briefly cover below. Phytoestrogens, which are naturally occurring plant-based estrogen-mimics, will be the subject of a separate post. The reason is that unlike the xenoestrogens or metalloestrogens, phytoestrogens can successfully be used strategically to balance estrogen dominance and deficiencies during the menopausal transition period.


“Xeno” literally means foreign. Xenoestrogens therefore mean foreign estrogens. They are a sub-class of the EDCs and have been defined by the EPA as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process” (pheww! That is a mouthful) (28). By virtue of their structure, xenoestrogens mimic or antagonize the actions of naturally occurring estrogens. As such, they compete with estrogens with in binding with one or more of the nuclear estrogen receptor sites in the body.
As a consequence of modern civilization, xenoestrogens made their debut into the environment by industrial, agricultural and chemical companies and their consumers in the last 70 years or so. Out of the 100,000+ registered chemicals for use in the US, many have hormonal in addition to toxic effects. Ninety-nine percent of these man-made EDCs are poorly regulated. Table 1 lists a few of the compounds commonly used in day-to-day normal life.
PhD Nootrition - Xenoestrogen compounds list
How to Avoid Daily Exposure to Xenoestrogens?
Given the ubiquitous distribution of EDCs in our day-to-day life, it seems impossible to avoid their exposure entirely. However, the following simple measures could go a long way in ensuring protection:

  • Avoid all synthetic pesticides, herbicides and fungicides. Use natural pest control.
  • Wash your food well to get rid of pesticides.
  • Avoid using bottled water. Instead install a reverse osmosis (RO) water purification system.
  • Eat organic foods as often as possible.
  • Do not heat food or water with plastic containers in the microwave. Use glass or ceramics.
  • Do not leave plastic containers especially with drinking water in the sun. Avoid Teflon and other nonstick cookware. Use stainless steel instead.
  • Minimize consumption of food from tin cans. Over 85% of tin cans are lined with BPA that leaches when exposed to heat (note: “BPA-free” does not fare better).
  • Don’t drink from Styrofoam cups and containers.
  • Don’t use fabric softeners and dryer as they contain estrogen-mimicking petrochemicals.
  • Use organic soaps and tooth paste. Avoid fluoride.
  • Avoid shampoos, creams, sun screen lotions and cosmetic that have parabens. switch to more natural products. We use a solid shampoo bar called J.R. Liggett.
  • Avoid nail polish and nail polish removers.
  • Use only naturally based perfumes. Most perfumes are petrochemical-based.
  • Use old-fashioned household cleaners like baking soda, borax and vinegar.
  • Avoid nail polish and nail polish removers.
  • Ventilate your house frequently; avoid use of air fresheners, insecticides, foggers that release chemicals into the air.
  • Use a simpler method of birth control such as condom. Use one that does not use a spermicide such as nonoxynol.

Detoxification from xenoestrogens.
Obviously, we cannot completely avoid xenoestrogens in one’s life, so it is important to do some detoxification to help the body get rid of the xenoestrogens and other chemicals it is exposed to. We all know that liver breaks down all excess hormones for elimination, so supporting this vital organ is very helpful. Cruciferous vegetables contain compounds that help the liver breakdown and metabolize excess estrogen. Eating broccoli, cauliflower, cabbage and other vegetables such as celery, carrot, beetroot and parsley is a great way to support liver’s detoxification ability. One of the compounds in these vegetables that I really like is Indole-3-carbinol (or I3C), which is helpful in getting rid of excess estrogen. The other possible way to detoxify xenoestrogens that I have used successfully with my clients are:

  • Vitamin C; 500 mg daily.
  • Lipoic acid; 100‒500 mg daily.
  • N-acetyl cysteine; 500-1,500 mg daily.
  • Bio-identical progesterone cream; 20-100+ mg daily (depending on individual history/symptoms).
  • Increase fiber intake to promote elimination of excess xenoestrogens through bowel movement. Our household rule: consume unrestricted amount of organic fresh fruits and vegetables. Healthy Gut Girl‘s Catalina Martone has a fantastic program called The Total Gut Makeover. Check it out.
  • Improve systemic and lymphatic circulation via hydrotherapy, sauna and exercise.
  • Increase fiber intake to promote elimination of excess xenoestrogens through bowel movement. Our household rule: consume unrestricted amount of organic fresh fruits and vegetables.
  • Hydration…Drink plenty of water to support elimination of toxins through the kidney

The risks of xenoestrogenic compounds like the ones mentioned in table 1 may be overshadowed by a potentially more harmful class of EDCs that are not talked about: metalloestrogens. These are inorganic heavy metal ions with potent estrogenic properties. Many common metals have been found to mimic estrogen or interfere with hormone function in the body. The Who’s who list — which include arsenic, lead (Pb), Cobalt, Copper (Cu), Zinc (Zn), mercury (Hg), cadmium (Cd), and nickel (Ni) — are present naturally in the environment in trace amounts; however with the increased usage in certain industrial processes such as smelting and electroplating, they have emerged as an environmental contaminant of growing concern. These heavy metals tend to accumulate in the body — a phenomenon called bioaccumulation (29). Increased exposure to heavy metals is associated with impaired mitochondrial function (remember these guys?), oxidative stress, DNA damage, deregulated cell growth and cell death (30, 31).
Recent studies have suggested that some of these certain heavy metals such as cadmium (Cd) and nickel (Ni) are potent endocrine disruptors (32-34) that function via the estrogen receptors, independently of estradiol. This means that Cd can (and does) activate estrogen receptors, even in the absence of estrogen, making it a very strong estrogen-mimic. Although the data regarding the estrogenic properties of Cd is strong, evidence from population-based human studies remain conflicting (32-38).
Chronic exposure to Cd and Ni presents a threat to human health (39). It has no known beneficial role in human metabolism. Following exposure, Cd binds to red blood cells and is transported throughout the body where it concentrates mostly in the liver and kidneys and bone (40). It’s elimination is very slow and may remain in the body for more than 20-30 years (39, 40). As it mimics Zn, Cd is thought to exert its toxic activity by disrupting Zn metabolism; there are about ~3000 different enzymes and structural proteins that require Zn for proper activity (40). One such protein is the estrogen receptor (which we will talk about in part 2). Cd and Ni work differently to alter estrogen receptor activity. While Cd operates by replacing the Zn ions that are necessary for binding of the receptor to certain DNA regions and promote expression of a wide variety of genes (41), Ni competes with estradiol and blocks its binding to estrogen receptor (31).
What now?
As we age, we accumulate ‘stuff’ from our environment, as since our environment is anything but clean, our risks of heavy metal poisoning go up, especially Cd and Ni that are thought to be directly involved in disrupting estrogen signaling pathways. And since these metals can lodge themselves in our tissues for 20 or more years, it helps to be proactive in our approach. Here’s what you should do if you suspect heavy metal issues are wrecking havoc in symptoms associated with estrogen dominance:

  • Identify the presence of this toxic mineral in your body with a hair mineral analysis test.
  • Know where your leafy greens are coming from. Leafy vegetables are known to pick up more Cd when levels in soil are increased owing to sewage-contaminated water or Cd in high-phosphate fertilizers.
  • The high price of looking good – Mind your personal care products.
  • Stop smoking — One population in particular consistently takes in large amounts of Cd: Smokers. Forty to sixty percent of Cd is readily absorbed through the inhalation of cigarette smoke and can be absorbed through the skin.
  • High price of looking good — Mind your personal care products.
  • Careful detox — A well implemented detox regimen can go a long way in ensuring you naturally get rid of these metals from your body.
  • Mineral balance — Cd and Ni are notorious for replacing minerals like Zn, and Cu…so, if you have a deficiency in these, work towards fixing the imbalance. The Total Gut Makeover has a module about mineral balance.

I hope this post was successful in clarifying some of the hormonal dysregulations that are associated with estrogen dominance, and how ovarian aging contributes to the process. We also touched upon environmental estrogens and how they disrupt the “natural” hormonal milieu of a woman’s body, especially as she gets ready to transition into the prime years. In part 2, we’ll explore aspects of hormone receptor status and how it affects the etiology of estrogen dominance. So, stay tuned!


  1. Santoro, N., et al. (1996). Characterization of reproductive hormonal dynamics in the perimenopause. J. Clin. Endocrinol. Metab. 81(4): 1495-501.
  2. Lee, J.R., et al. (1996). What Your Doctor May Not Tell You About Menopause: The Breakthrough Book on Natural Progesterone. New York: Warner Books.
  3. Weiss G., et al. (2004). Menopause and hypothalamic-pituitary sensitivity to estrogen. JAMA 292(24): 2991-6.
  4. Barbieri, R.L., (2014). The endocrinology of the menstrual cycle. Human Fertility: Methods and Protocols 145-169.
  5. Rance, N.E., et al. (1994). Topography of neurons expressing luteinizing hormone-releasing hormone gene transcripts in the human hypothalamus and basal forebrain. J. Comp. Neurol. 339(4): 573-86.
  6. te Velde, E.R., et al.(2002). The variability of female reproductive ageing. Hum. Reprod. Update. 8(2): 141-54.
  7. te Velde, E.R., et al.(1998). Developmental and endocrine aspects of normal ovarian aging. Mol. Cell. Endocrinol. 145(1-2): 67-73.
  8. Li, Q., et al.(2012). Current understanding of ovarian aging. Sci. China Life Sci. 55(8): 659-69.
  9. Gougeon, A., et al. (1994). Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol. Reprod. 50(3): 653-63.
  10. Qiao, J., et al. (2014). The root of reduced fertility in aged women and possible therapeutic options: current status and future prospects. Mol. Aspects Med. 38: 54-85.
  11. May-Panloup, P., et al. (2016). Ovarian ageing: the role of mitochondria in oocytes and follicles. Hum. Reprod. Update. 22(6): 725-743.
  12. Velarde, M.C., (2014). Mitochondrial and sex steroid hormone crosstalk during aging. Longev. Healthspan. 3: 2-10.
  13. Hillier, S.G., et al.(1994). Follicular oestrogen synthesis: the ‘two-cell, two-gonadotrophin’ model revisited. Mol. Cell Endocrinol. 100(1-2): 51-4.
  14. Luu-The, V., et al.(2001). Type 5 17beta-hydroxysteroid dehydrogenase: its role in the formation of androgens in women. Mol. Cell Endocrinol. 171(1-2): 77-82.
  15. Grodin, J.M., et al.(1973). Source of estrogen production in postmenopausal women. J. Clin. Endocrinol. Metab. 36(2): 207-14.
  16. Stricker, R., et al.(2006). Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer. Clin. Chem. Lab Med. 44(7): 883-7.
  17. Khosla, S., et al.(1997). Effects of age and estrogen status on serum parathyroid hormone levels and biochemical markers of bone turnover in women: a population-based study. J. Clin. Endocrinol. Metab. 82(5): 1522-7.
  18. Luu-The, V., et al.(1986). Steroid and gonadotropin levels in women during the peri-menopausal years. Maturitas. 8(3): 189-96.
  19. Longcope, C., et al.(1986). Steroid and gonadotropin levels in women during the peri-menopausal years. Maturitas. 8(3): 189-96.
  20. Burger, H.G., et al.(2008). Cycle and hormone changes during perimenopause: the key role of ovarian function. Menopause. 15(4 Pt 1): 603-12.
  21. Harlow, S.D., et al.(2012). Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. J. Clin. Endocrinol. Metab. 97(4): 1159-68.
  22. Butler, L., et al.(2011). The reproductive endocrinology of the menopausal transition. Steroids. 76(7): 627-35.
  23. Prior, J.C. (1998). Perimenopause: the complex endocrinology of the menopausal transition. Endocr. Rev. 19(4): 397-428.
  24. O’Connor, K.A., et al. (2009). Progesterone and ovulation across stages of the transition to menopause. Menopause. 16(6): 1178-87.
  25. Prior, J.C. (2005). Ovarian aging and the perimenopausal transition: the paradox of endogenous ovarian hyperstimulation. Endocrine. 26(3): 297-300.
  26. Miro, F., et al.(2004). Origins and consequences of the elongation of the human menstrual cycle during the menopausal transition: the FREEDOM Study. J. Clin. Endocrinol. Metab. 89(10): 4910-5.
  27. Hale, G.E., et al.(2007). Endocrine features of menstrual cycles in middle and late reproductive age and the menopausal transition classified according to the Staging of Reproductive Aging Workshop (STRAW) staging system. J. Clin. Endocrinol. Metab. 92(8): 3060-7.
  28. Diamanti-Kandarakis, E., et al.(2009). Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 30(4): 293-342.
  29. Islam, E., et al.(2007). Assessing potential dietary toxicity of heavy metals in selected vegetables and food crops. J. Zhejiang Univ. Sci. B. 8(1): 1-13.
  30. Misra, U.K., et al.(2002). Cadmium-induced DNA synthesis and cell proliferation in macrophages: the role of intracellular calcium and signal transduction mechanisms. Cell Signal. 14(4): 327-40.
  31. Martin, M.B., et al.(2003). Estrogen-like activity of metals in MCF-7 breast cancer cells. Endocrinology. 144(6): 2425-36.
  32. Siewit, C.L., et al.(2010). Cadmium promotes breast cancer cell proliferation by potentiating the interaction between ERalpha and c-Jun. Mol. Endocrinol. 24(5): 981-92.
  33. Brama, M., et al.(2007). Cadmium induces mitogenic signaling in breast cancer cell by an ERalpha-dependent mechanism. Mol. Cell Endocrinol. 264(1-2): 102-8.
  34. Silva, N., et al.(2013). Metalloestrogen cadmium stimulates proliferation of stromal cells derived from the eutopic endometrium of women with endometriosis. Taiwan J. Obstet. Gynecol. 52(4): 540-5.
  35. Silva, N., et al.(2012). Cadmium a metalloestrogen: are we convinced? J. Appl. Toxicol. 32(5): 318-32.
  36. Jackson, L., et al.(2008). The association between heavy metals, endometriosis and uterine myomas among premenopausal women: National Health and Nutrition Examination Survey 1999-2002. Hum. Reprod. 23(3): 679-87.
  37. Nasiadek, M., et al.(2011). The effect of cadmium on steroid hormones and their receptors in women with uterine myomas. Arch. Environ. Contam. Toxicol. 60(4): 734-41.
  38. Thévenod, F., et al.(2013). Toxicology of cadmium and its damage to mammalian organs. Met. Ions. Life Sci. 11: 415-90.
  39. Sigel, A., et al.(2013). Cadmium: From Toxicity to Essentiality. 11: Dordrecht: Springer.
  40. Predki, P.F., et al.(1992). Effect of replacement of “zinc finger” zinc on estrogen receptor DNA interactions. J. Biol. Chem. 267(9): 5842–5846.
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