THE ESTRADIOL TO PROGESTERONE RATIO OTHERWISE CALLED ESTROGEN DOMINANCE

Estrogen Dominance (Excerpt from Dr Nkwenti's Ph.D Write-up)

Estrogen dominance is a term that explains the relative proportion of free unbound progesterone to estradiol with a ratio that helps in the evaluation of hormone needs for dosing purposes. This term was coined by Doctor Dr. Lee in his first natural progesterone book. It describes a situation in which a woman may have weak, normal or excessive estrogen but does not have or have little to no progesterone in her body. A woman who lacks progesterone but has estradiol available even in small quantities will most likely suffer from estrogen dominance with signs and symptoms such as anxiety, depression, autoimmune conditions, lupus erythematosus, thyroid gland abnormalities such as Hashimoto thyroids (Arduc et al., 2015), Sjögren's syndrome (Taiym, Haghighat, & Al-Hashimi, 2004), brain cancer (glioblastoma with high-dose progesterone administration producing a significant reduction in tumor size (~47%) and a significant increase in survival rate (~43%) without any significant toxicity to the liver and kidney amongst other organs (Atif, Yousuf, Espinosa-Garcia, Sergeeva, & Stein, 2019), and clinical signs and symptoms of hypothyroidism (Sathi, Kalyan, Hitchcock, Pudek, & Prior, 2013)

 No hormone works in isolation from other hormones; they all function within a dynamic, subtle network of interconnectedness. If thyroid levels are low, the development of cortisol and sex hormone lags. Estrogen reduces the activity of thyroid hormones and thus exacerbates thyroid deficiency. Progesterone, cortisol, and testosterone, on the other hand, are thyroid partners (Sathi et al., 2013), (Walter et al., 2012), (Krysiak, Kowalcze, & Okopien, 2019).

Hypothyroidism occurs mainly in women, particularly during the perimenopausal period when estrogens predominate, and progesterone is produced in smaller quantities. Persistent estrogen dominance throughout the perimenopausal phase results in a process of decreased thyroid activity, decreased SHBG, and a rise in bioavailable estrogen levels. The incidence of breast cancer is starting to rise sharply during this time thus necessitating the use of natural progesterone (Lieberman & Curtis, 2017, p. 79). Progesterone therapy also restores normal thyroid function, likely through its anti-estrogen action. Again, estrogen dominance unopposed by progesterone, underlies the correlation between thyroid dysfunction and breast cancer (Lee, Zava, & Hopkins, 2005), Dr. Zava (J. R. Lee, Hopkins, & Barry, 2019) hypothesized that low progesterone, if pregnant, would lead to children suffering from deficiency disorders due to lack of brain growth, since progesterone is important in the development of brain regions needed to shut down information and memory during the first trimester of pregnancy. The alarming rise in the number of children with attention deficit hyperactive disorder (ADHD) can be associated to the deleterious actions of endocrine disruptors from petrochemical sources (De Cock, Maas, & van de Bor, 2012)

Excess estradiol and estrone increase breast and endometrial cancers (Samavat & Kurzer,

 2015) and increase the risk for unpleasant side effects including PMS-like symptoms, weight gain, water retention, gallbladder issues, high blood pressure, breast swelling, fibrocystic breasts, and thromboembolism. There is an abundance of evidence to portray the fact that estrogenic signaling plays a crucial role in obesity development in menopausal women. Such women are up to three times most likely to have obesity or metabolic syndrome disorder than premenopausal women (Eshtiaghi, Esteghamati, & Nakhjavani, 2010). More so, the estrogen to progesterone replacement using bio identical hormone replacement therapy in menopausal women has proven to decrease visceral adipose tissue, fasting blood glucose levels and blood insulin levels (Gormsen et al., 2012).

Cases of thyroid resistance does exist whereby thyroid parameters measured in the blood are high (high TSH, T4, and T3), but there are symptoms indicative of low thyroid levels. Such patients almost always suffer from extreme imbalances in their steroid hormones according to Dr Zava, the founder of ZRT laboratories. After evaluating hundreds of thousands of salivary and blood samples, he found that estrogen dominance (usually associated with average or high estrogen, but often low progesterone) and adrenal dysfunction (low or high cortisol) are closely linked to symptoms similar to low thyroid disease. He then advices all patients with normal thyroid hormone levels with classic thyroid symptoms to check their steroid hormones using saliva, blood or urine tests.

Halogen exposure has a crucial role to play when it comes to estrogen dominance. The thyroid molecule is made up of a thyronine molecule with some iodine attached to it. The thyroid gland functions only in the presence of iodine. Iodine is a halogen, and it is a non-metallic element that also includes fluorine, chlorine and bromine. A closer look or analysis of the periodic table shows that the halogens of which Iodine is one of them are all short of one electron. They are all in a position to gain an extra electron. A Halogen that is more reactive has the capability of replacing a less reactive halogen and such is the case with Fluorine, which is very reactive when it comes to comparing reactivity potential. Iodine is the largest of the four halogens but exhibits the least reactivity while Fluorine smallest but powerfully reactive. Fluorinated water and Fluoride toothpastes usage worldwide has skyrocketed over the past years which has drastically increased our fluorine consumption and hence the capacity for fluorine to replace Iodine in the thyroid. Prior to fluorination, the normal daily intake of fluoride was close to 0.1 mg per day. Nowadays, Fluoride consumption has increased 30 to 40 times than in un-fluorinated populations. When fluorine replaces iodine in the structure of thyroxine, it renders it unsuitable for its key role of producing thyroid hormone (Lee, Zava, & Hopkins, 2005, p. 80). Also, consider the fact that long ago, fluoride was used to treat hyperthyroidism simply based on the explanation above. Now, this toxicity is or has been overlooked. There is also evidence that Fluoride replacement of iodine induces antibodies that could potentially lead to thyroid or Hashimoto disorder (Kheradpisheh et al., 2018).

Studies have shown that elevated serum heavy metals (cadmium and lead) and a reduction of essential trace metals such as zinc, copper and vitamin E may play a contributory role to recurrent spontaneous abortions (Ajayi, Charles-Davies, & Arinola, 2012). How do we manage this heavy metal detox problem or estrogen dominance quagmire using dietary supplements? First Indole-3-Carbinol (I3C) is a natural supplement extracted from cruciferous vegetables such as broccoli, arugula, and cauliflower. It helps facilitate phase 1 liver detoxification during the elimination of estrogen and estrogen metabolites. This compound has been known to encourage the use of 2-OH pathways, which produce metabolites that are uplifting to the patient including but not limited to the promotion of mood, libido, improved testosterone levels, healthy breast tissue and protection of our reproductive organs from the damaging effects of heavy metals including cancer (Katz, Nisani, & Chamovitz, 2018), (Auborn et al., 2003). In dole-3-Carbinol has also been found to play a crucial role in the prevention and treatment of cancer in women. It is now widely accepted that I3C and DIM affect multiple signaling pathways and target molecules that facilitate the control of cell division, apoptosis, or angiogenesis in deregulated cancer cells. It seems though that the application of Indole-3-Carbinol in prevention of the other cancers and in the prevention of cardiovascular disease, obesity, and diabetes and diabetic complications is also possible (Licznerska & Baer-Dubowska, 2016). On the other hand, Diindolylmethane (DIM) is an I3C-converted enzyme that helps facilitates the elimination of estrogens (especially the toxic type) from the bloodstream, allowing for greater metabolism in the liver. Like I3C, it helps improves estrogen metabolism by regulating 2-OH and 16-OH estrogen metabolic and removal pathways. DIM maximizes the absorption of estrogen in TPD (Thyroid Proliferative Disease) patients and can theoretically act as an anti-estrogen dietary supplement to help reduce the risk of developing TPD. The fact that DIM is found in thyroid tissue means that it can manifest its antiestrogen activity in situ in order to modulate Target organ damage (TOD) (Rajoria et al., 2011). Across all stages of breast cancer carcinogenesis, Bioactive DIM has demonstrated chemo preventative activities. DIM is one of the most well classified and abundant bioactive compounds found in widely used calciferous vegetables (Thomson, Ho, & Strom, 2016). DIM exhibited potent antiproliferative and antiandrogenic properties in human prostate cancer cells that are dependent on androgen. It was able to suppresses LNCaP cell proliferation and inhibited the stimulation of DNA synthesis by dihydrotestosterone (DHT). DIM was able to block the endogenous transcription of Prostate specific antigen (PAS) and decrease intracellular and secreted levels of DHT-PSA protein in LNCaP cells. Research shows that maintaining a proper ratio of 2-OH-Estrone and 16-OH-Estrone is a major wellness factor. DIM plays an important role in controlling this balance, which protects the different functions of the body. DIM also restricts the conversion of testosterone to estrogens. It can help restore hormonal equilibrium and reduce the effects of estrogen dominance, such as bloating, breast tenderness, heavy flow, and pain.

Calcium-D-Glucarate facilitates detoxification of the liver. It helps facilitate the elimination of excess estrogen and its toxic metabolites, which lead to the dominance of estrogen. Oral calcium-D-glucarate supplementation has been shown to inhibit beta-glucuronidase, an enzyme that is generated by the colonic microflora and involved in liver detoxification in Phase II. Elevated activity of beta-glucuronidase is associated with an increased risk for various cancers, especially hormone-dependent cancers such as cancers of the breast, prostate, and colon. Many possible oral calcium-D-glucarate clinical uses include control of estrogen metabolism and as a lipid-lowering agent ("Calcium-D-glucarate," 2002). As the levels of estrogen are elevated, Calcium-D-Glucarate binds to excess estrogen, safely flushing the excess out of the body safely and appropriately thus restoring the hormonal balance in the body and reducing or eliminating the symptoms of estrogen dominance. Calcium-D-Glucarate further facilitates estrogen detoxification by blocking enzymes that interrupt the bonding and removal in the liver.

In postmenopausal women, estrogen deficiency is considered the primary cause of increased appetite and weight gain. Reduced melatonin secretion (MEL) was also observed during this time period (Walecka-Kapica et al., 2015). The pea-based organ in the middle of the brain is the pineal gland. Melanin controls sleep cycles and also functions as an antioxidant that controls the hormones of the ovaries and the immune system. Melatonin rates in teenagers are extremely high, and the  level decline dramatically after puberty and then decline gradually as we age.

 Melatonin suppressed breast cancer cell's growth by 75% (Li et al., 2017). Several studies have shown that melatonin co-administration increases cancer responsiveness to traditional drug inhibition. The results that melatonin previously renders cancers resistant to treatment susceptible to these same therapies are even more important. Melatonin also prevents metastasis-associated molecular processes by restricting the entry of cancer cells into the vascular system and preventing secondary growth at remote sites (Reiter et al., 2017). Studies show that melatonin levels in urine at night are substantially lower in women with breast cancer than those of healthy women. Neurosurgeons have made a remarkable finding that the pineal gland of a woman with breast cancer is more likely to be calcified with lower circulating levels of melatonin with early breast cancer. To maintain optimum human health, intact and functional pineal gland is essential. Pineal calcification jeopardizes synthetic potential of melatonin and is associated with several neuronal diseases (Tan, Xu, Zhou, & Reiter, 2018). High levels of melatonin reduce ovarian development of estrogens and progesterone, and this feedback is thought to protect against breast cancer. Such studies, though not specifically designed to investigate the role of melatonin in breast cancer prevention, may eventually shed light on this important topic.

Obesity is another cause of the dominance of estrogen in menopausal women. Once we reach menopause, our ovaries almost stop producing estrogens and progesterone, but continue to produce androgens such as testosterone. Androstenedione is converted at this stage to estrogens. Androstenedione is a primary product of theca cells, used by FSH-stimulated granulosa cells as a substrate for aromatase enzyme and estradiol production. The testis, ovary and adrenal secrete Androstenedione. This is a weak androgen converted into more potent testosterone in the peripheral tissue. Thus, increased androstenedione secretion contributes to hirsutism through this conversion (Lee et al., 2005, p. 106). Data reveals that only 3 percent of women with PCOS have an elevated concentration of androstenedione alone (TotalBoox & Tbx, 2013).

The overwhelming presence of estrogen can also result from chronic exposure to xenoestrogen, generally from pesticides, solvents, like nail polish, plastics. Supermarket products, sprays of lawn and garden sprays, and indoor insect sprays may result in pesticide exposure. Chemicals like xenoestrogens that can imitate endogenous hormones can interact with endocrine processes and are collectively known as endocrine disruptors (Singleton & Khan, 2003). Adverse effects of endocrine-disrupting chemicals (particularly xenoestrogens) include a lot of wildlife and human developmental anomalies. Everyday single exposure may not be large, but continual low exposures over time may cause hormone disequilibrium.