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Sex Hormones
The two main female sex hormones are estrogen and progesterone . Although testosterone is considered a male hormone, females also produce and need a small amount of this, too.
Until peri menopause / menopause, the woman's ovaries make most estrogen and progesterone hormones, although the adrenal glands and fat cells also make small amounts of these hormones. Small amounts of testosterone come from the adrenal glands and ovaries. During peri menopause, the production of estrogen and progesterone in the ovaries decreases. It is the big drop in estrogen and progesterone levels that causes most of the symptoms of peri menopause. Between two to four years after the beginning of peri menopause, women reaches menopause where ovulation stops , leading to even a bigger drop in estrogen and progesterone levels. Then , the adrenal glands take over the production of estrogen and progesterone and testosterone from the declining ovaries. This is a natural process and a healthy body can adjust in post-menopause , meaning that healthy adrenal glands produce enough estrogen and progesterone needed in the body at this period of life.
To understand various symptoms in perimenopause / menopause , it is important to assess three things: your estrogen levels : are they within the normal ranges ,are they high or low?
Your progesterone levels: are they within the normal ranges, are they high or low?
Your estrogen levels in comparison with your progesterone levels: One of the most common hormonal imbalances in peri menopause / menopause is what we call estrogen dominance. This means that estrogen levels are too high relative to progesterone. The most common cause for this is poor estrogen detoxification , meaning estrogen is reabsorbed and reactivated instead of being removed from the body. Each situation can be healed but requires a different treatment.
2A-Estrogen
Estrogen is the major female hormone. The lion’s share comes from the ovaries, but small amounts are produced in the adrenal glands and fat cells. Estrogen plays a big role in reproductive and sexual development. Estrogen also affects the brain, cardiovascular system, hair, musculoskeletal system, skin and urinary tract.
Estrogen Metabolism
Estrogen metabolism is the complex process in which your body converts estradiol , estrone and estriol into a water-soluble inactive form that the body excretes through urine and feces. The estrogens are taken up by the liver where they will be bio-transformed into different metabolites in 3 phases
Phase I
Estrogen Metabolism
During phase I, estrone (E1) and estradiol (E2) are hydroxylated into 2-OH (2-OH-E1 and 2-OH-E2) , 4-OH (4-OH-E1 and 4-OH-E2) , and 16-OH ( 16-OH-E1 and 16-OH-O2 ) metabolites. All of these phase I metabolites have oxidative or damaging potential; however, some are more damaging than others.
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2-OH-E1 and 2-OH-E2 are the less toxic phase I estrogen metabolites
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This is the preferred pathway because the 2-OH are the most stable phase 1 estrogen metabolites that cause the least amount of harm to the body ; their bond with the estrogen receptor is the weakest so they are removed from estrogen receptors most efficiently.
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CYP1a1 is the enzyme responsible for the metabolism of E1 to 2-OH-E1 and E2 to 2-OH-E2.
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4-OH-E1 and 4-OH-E2 are the most toxic phase I estrogen metabolites , the 4-OH-E1 being the most dangerous
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the 4-OH estrogen metabolites are considered the most genotoxic as it can become reactive quinones that have the potential to cause DNA damage and increase risk of breast and prostate cancer.The 4-OH metabolites have the strongest bond to the estrogen receptor. It takes a lot more energy from the body to break off the 4-OH metabolites for detoxification than the other metabolites . If the body is not able to neutralize the 4-OH metabolites well or efficiently, they can wreak havoc on DNA The most dangerous estrogen metabolite is the 4-OH-E1 as the 4-OH-E2 metabolite may not have the same carcinogenic effects.
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CYP1b1 is the enzyme responsible for the metabolism of E1 to 4-OH-E1 and E2 to 4-OH-E2.
- 16-OH-E1 can contribute to estrogen sensitive tissue proliferation (breast, endometrial, prostate, tumors , etc.).
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Elevations in 16-OH-E1 can cause estrogen sensitive tissue ( breast , endometrial, ovarian tissues , tumor , prostate ) proliferation and may exacerbate estrogen excess symptoms such as fibrocystic breasts , heavy bleeding and ovarian cysts .
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16-OH-E2 (also known as E3, or estriol) is a safer estrogen metabolite, as it is a very weak estrogen and may have protective properties.
The 16-OH-01 metabolite binds more tightly to estrogen receptors than the 2-OH metabolites ( making its methylation more energy consuming ) but less than
the 4-OH metabolites .
CYP3a4 is the enzyme responsible for the metabolism of E1 to 16-OH-E1, and E2 to 16-OH-E2
Phase II Metabolism:
2-OH and 4-OH methylation and 16-OH glucuronisation and sulfation
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Methylation of 2-OH and 4-OH
.The process of methylation takes dangerous, oxidative Phase I metabolites and neutralizes them into stable, water-soluble metabolites that are ready for excretion . 2-OH-E1 is transformed in 2-methoxy- E1 , 4-OH-E1 is transformed in 4-methoxy-E1 , 2-OH-E2 is transformed in 2-methoxy-E2 and 4-OH-E2 is transformed in 4-methoxy-E2.
Methylation is a very important step in estrogen metabolization
Low methylation activity may cause the 2-OH and 4-OH estrogen metabolites to stay and build up in Phase I, thus increasing risk for reactive quinone formation and DNA damage . Even if a person is metabolizing most of their estrogen into the preferred 2-OH metabolites in phase I , if these 2-OH metabolites are not adequately methylated, they can still be oxidizing. Oxidation can lead to cellular stress, poor cellular health, and increased risk for abnormal cell function.
Methylation is dependent on catechol-o-methyl transferase (COMT) enzyme function. COMT relies on sufficient cofactors such as S Adenosyl L-Methionine (SAM), vitamin B6, and magnesium to function optimally. If COMT activity is slow, then the body may not be able to appropriately methylate estrogens through this final step of detoxification in the liver .
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Glucuronidation and sulfation of 16-OH
These processes are extremely important , especially for the proliferative 16-OH-E1 , as it neutralize the 16-OH into stable , water-soluble metabolites that are ready for excretion . Low activity of glucuronidation and sulfation may cause the 16-OH-E1 metabolite to stay and build up in Phase I , which can enhance estrogen estrogen sensitive tissue proliferation , including breast tumors .
Phase III Metabolism:
Healthy Stool Evacuation
Phase II metabolites in the liver migrate to Phase III detoxification in the intestines. Phase III ends in the stool. Without quality stools and digestive regularity , estrogens stay trapped in the body. These estrogens recirculate, increasing the amount of estrogen to be detoxified.When the body is overloaded with toxins, or unable to efficiently metabolize toxins, the burden of estrogen may start to create issues. For instance , repeated exposure to the 4-OH metabolites (by poor Phase III clearance) increases the opportunity for DNA damage .
In the wheel of essence program , we will
- support best pathways in phase 1 detoxification
Support CYP1a1 activity to enhance the preferred 2-OH pathway
Inhibit CYP1b1 and CYP3a4 enzymatic activity
- Support phase II methylation of the 2-OH and 4-OH metabolites and
glucuronidation and sulfation of the 16-OH-E1 metabolites
- support phase III estrogen detoxification via the bile / stool by supporting bile and liver health
2B-Progesterone
2C-Androgens
Thyroid Hormones System
Thyroid hormones are produced through the hypothalamus-pituitary-thyroid (HPT) axis, also known as the thyroid system
The process begins when the pituitary gland releases thyroid-stimulating hormone (TSH) into the bloodstream. In response to TSH, the thyroid gland produces thyroxine (T4), the primary thyroid hormone.
T4 is then converted into two other thyroid hormones: triiodothyronine (T3) and reverse T3 (rT3), through the action of the enzyme 5-deiodinase.
Among these, T3 is the only biologically active form of thyroid hormones . Both T4 and rT3 are inactive. Since T3 is produced in much smaller amounts than T4, the body's ability to efficiently convert T4 into T3 is crucial for maintaining proper thyroid function.
The Cortisol System
The production of the hormone cortisol is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. When necessary, the hypothalamus and pituitary gland signal the adrenal glands to produce cortisol.Cortisol serves several important functions in the body
Interactions Between Sex Hormones and Thyroid Hormones
Some perimenopause symptoms are similar to, and can overlap with, those of an underactive or overactive thyroid, making it difficult to identify the exact cause without precise testing.
Some studies show that perimenopausal and menopausal women are at an increased risk of developing thyroid conditions. In fact, thyroid issues often do not emerge until after menopause, as they are more common in women over the age of 60. According to the British Thyroid Foundation, it is particularly common for perimenopausal and menopausal women to develop an underactive thyroid (hypothyroidism).
Furthermore, symptoms and risks associated with menopause can be more severe if a thyroid condition is also present.
Here are a few examples:
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Both estrogen and thyroid hormones play a crucial role in maintaining bone health. A decline in estrogen during menopause, along with an underactive thyroid, can significantly increase the risk of fractures.
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The risk of cardiovascular disease rises during menopause; thyroid disorders also elevate this risk.
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Women going through menopause who also have an underactive thyroid may experience weight gain. This is because hypothyroidism slows down the body’s metabolism.
Conclusion
During perimenopause and menopause, an untreated thyroid condition can make symptoms worse. Hormone Replacement Therapy (HRT) or bio-identical hormones may offer only limited relief if the thyroid is not also addressed. To achieve true recovery, both thyroid function and sex hormone levels need to be assessed and treated appropriately.
Interactions Between Thyroid Hormones and Cortisol
Some studies highlight the complex interaction between cortisol and thyroid function. Cortisol initially increases thyroid-stimulating hormone (TSH), but when cortisol levels remain high, it signals the pituitary gland to reduce TSH production. This leads to decreased stimulation of the thyroid gland and a subsequent reduction in the production of thyroxine (T4).
In addition, elevated cortisol inhibits the activity of the enzyme 5’-deiodinase, which is responsible for converting T4 into triiodothyronine (T3), the active form of thyroid hormone. As a result, high cortisol levels can impair the availability of active thyroid hormones and contribute to symptoms of hypothyroidism.
It is also important to note that the bacteria Helicobacter pylori (H. pylori) can create chronic stress in the body, leading to persistently high cortisol levels and further disrupting thyroid hormone function.
Conclusion
High cortisol levels suppress both T4 and T3 production. Therefore, treating a thyroid condition without also addressing elevated cortisol may lead to suboptimal results.
Interaction Between Cortisol
and Sex Hormones
During perimenopause and menopause, cortisol plays a significant role in hormone regulation. As ovarian function declines, the adrenal glands take over the production of estrogen and progesterone. However, if the adrenal glands are continuously producing high levels of cortisol due to chronic stress, they may not be able to produce adequate amounts of estrogen and progesterone. In this case, the body prioritizes survival over reproduction, which can worsen symptoms of perimenopause and menopause.
This hormonal interplay is also a "chicken-and-egg" situation: low estrogen itself acts as a physiological stressor, potentially increasing cortisol levels. As estrogen decreases, it disrupts the balance with progesterone. Because hormones operate in an interconnected system, a decline in one can trigger a domino effect—leading to a decline in others.
Progesterone, often referred to as the "feel-good" hormone, helps buffer the effects of stress by balancing cortisol. When estrogen levels drop, progesterone levels typically fall as well. This reduces the body’s ability to regulate stress, further increasing cortisol production.
In summary, during perimenopause and menopause, elevated cortisol levels can reduce the adrenal glands’ ability to produce estrogen and progesterone. Furthermore , declining estrogen is closely linked with declining progesterone, which reduces the body's natural stress-buffering capacity. As a result, women in these stages of life may experience heightened stress and elevated cortisol levels. Breaking this cycle requires proactive stress management to support hormonal balance.
