Overview of Sex Hormones
The primary glands involved in the regulation and production of sex hormones are the hypothalamus, pituitary, ovaries, adrenals, and fat or adipose cells.
It is important to note that with postmenopausal women estrogens are primarily produced in adipose tissue, from androgen precursors produced in the adrenal glands. The adrenal glands therefore become the dominant upstream supplier of hormone precursors after menopause.
The ovaries are no longer the primary factory.
This brings us to a very relevant topic. Since the adrenal glands “take over” sex hormone production in menopause, optimizing adrenal function is essential. If the adrenal glands must preferentially make high amounts of cortisol due to chronic stress and inflammation, they may not be able to keep up with the demand for sex hormone precursors. Stress will very likely reduce the already-diminished estrogen available to protect the BBB and support brain cholesterol metabolism.
There is an additional factor. Body mass is directly correlated with the rate of peripheral production of estrone and estradiol in postmenopausal women. Therefore, an obese woman may produce much more estrone and estradiol than a thin woman which may help explain the higher risk of osteoporosis observed in thin women. The fat tissue that society pressures women to minimize becomes a meaningful source of what little estrogen their body still makes.
Benefits of Various Sex Hormones
Progesterone
Bioidentical progesterone behaves fundamentally differently from synthetic progestins in every system that matters for postmenopausal health. It is a genuinely different molecule producing genuinely different outcomes, and the negative conclusions of the Women’s Health Initiative, which used MPA, the synthetic progesterone, should not be applied to bioidentical progesterone.
The primary role of micronized bioidentical progesterone is to protect the uterus from continued exposure to estrogen. Estrogen thickens the uterine lining which is important during the regular menstrual cycles but with menopause, estrogen therapy by itself raises endometrial cancer risk. Bioidentical progesterone counteracts this and thus, estrogens, even bioidentical estrogens should never be prescribed without progesterone.
When progesterone is low, cortisol production by the adrenals rises, which can trigger racing thoughts or a sense of impending doom. Over time, this chronic stress fueled by elevated cortisol takes a toll on the brain, which has been linked to increased risk for neurodegenerative diseases like Alzheimer’s.
A 2018 Stanford study found that progesterone levels were positively and significantly linked to verbal memory and global cognition in women who had gone through menopause within the past six years. The Kronos Early Estrogen Prevention Study indicated that progesterone has a positive effect on cognitive function.
Bioidentical progesterone has a calming and mood-stabilizing effect, whereas synthetic progestins such as medroxyprogesterone acetate and norethindrone acetate tend to be associated with a variety of unpleasant side effects.
Canadian researchers found that oral micronized progesterone helped perimenopausal and menopausal women sleep more soundly. In a randomized trial, nearly 200 perimenopausal women with night sweats and hot flashes took 300 mg oral micronized progesterone for three months and experienced significantly improved sleep.
Progesterone is involved in bone metabolism and can support bone-building activity when used as part of a hormone therapy plan, such as one that also includes estrogen, which is the primary protector against bone loss.
The E3N study showed that administering transdermal estrogen in combination with micronized progesterone significantly reduced the risk of diabetes. This contrasts with synthetic progestins, which can impair insulin sensitivity.
Bioidentical progesterone helps to reverse some postmenopausal changes by promoting new collagen production, helping to plump skin, increase elasticity, and reduce wrinkles
Estrogens
Estrone or E1
Estrone is the dominant circulating estrogen after menopause, produced primarily in adipose tissue from adrenal androgen precursors.
High levels of estrone may increase the risk of breast cancer because estrone is the weaker estrogen that binds estrogen receptors but with less efficiency. Estrone is not used therapeutically on its own for this reason.
Estradiol or E2
Estradiol is the dominant estrogen during reproductive years and the one with the broadest and most powerful systemic effects.
Estradiol acts as an antioxidant, increases HDL (“good” cholesterol), reduces triglycerides, LDL, and total cholesterol. It aids in memory preservation by increasing serotonin levels in the brain, aids in maintaining bone structure, and aids in the absorption of calcium, magnesium, and zinc.
Estradiol is the primary estrogen responsible for protecting the blood-brain barrier’s tight junction proteins, for supporting brain cholesterol synthesis, and reducing neuroinflammation. It is also the estrogen most associated with reducing Parkinson’s and Alzheimer’s risk in women.
A study of 23,000 women treated with natural estradiol and estriol showed no increase in breast cancer. A 10-year randomized hormone replacement study early after menopause revealed a significantly reduced risk of mortality, heart failure, and myocardial infarction without any apparent increase in risk of cancer, venous thromboembolism, or stroke in the natural estradiol population.
Estriol or E3
Estriol binds to estrogen receptors on breast cells but with much weaker activity. Therefore, it actually blocks the stronger estradiol from binding to those cells and subjecting them to higher estrogenic activity, which has been shown to be protective against breast cancer.
When estriol is given topically together with estradiol, the estradiol-specific stimulation to cells is decreased. This discovery explains how estriol reduces the cancerous effects of estradiol.
Estriol protects against breast cancer, decreases LDL, and increases HDL. Topical estriol is used for relief of postmenopausal atrophy, vaginal dryness, and urinary incontinence.
Research points to the benefits of estriol for heart health, post-menopausal urinary tract health, and protection against osteoporosis.
Bi-Est Combination of E2 & E3
The rationale for combining estrogens is to replicate the body’s natural hormonal environment more closely than any single estrogen can.
The compounded drug bi-estrogen (bi-est) is typically composed of 80% estriol and 20% estradiol. Although the estradiol concentration is less, it accounts for most of the estrogenic activity due to being eighty times more potent than estriol.
The high proportion of estriol provides a protective buffer on tissues like breast, while the smaller proportion of estradiol delivers the systemic benefits of cardiovascular protection, bone density, brain function, and BBB integrity.
Summary
Some conditions which benefit from bioidentical estrogens for post-menopausal women are the following.
- Host flashes and night sweats
- Vaginal dryness and atrophy (primarily estriol form)
- Sleep disturbances
- Mood and cognitive function
- Slows or prevents osteoporosis
- Reduces risk of fractures
- Improves lipid profiles by raising HDL and lowering LDL cholesterols
- May reduce arterial stiffness
Testosterone
With pre-menopausal women testosterone levels are 15–20 times higher than their estradiol levels. The medical establishment’s focus on testosterone as a “male hormone” created a gender bias. Testosterone is not a male intruder in women’s bodies. It is their most abundant sex hormone throughout life.
Relief of sexual symptoms was reported more frequently in bioidentical menopausal compounded hormone therapy including testosterone than in those using conventional menopausal hormone therapy.
There is growing evidence to support the use of physiological doses of testosterone for sexual function, osteoporosis prevention, brain protection, and breast protection.
Testosterone plays a direct role in maintaining lean muscle mass and metabolic rate. After menopause, declining testosterone contributes to the shift toward increased body fat, reduced muscle strength, and fatigue.
Women receiving bioidentical testosterone therapy demonstrated reduced breast cancer incidence compared to those not receiving treatment, suggesting testosterone provides protective benefits through its ability to oppose estrogen’s proliferative effects on breast tissue.
There is growing evidence for brain protection with physiological doses of testosterone. Testosterone receptors are widespread throughout the brain and testosterone can be locally converted to estradiol in brain tissue via aromatase — potentially supporting the brain’s own estrogen supply that we know protects the BBB and supports cholesterol homeostasis.
Administration of compounded transdermal bioidentical hormone therapy which includes testosterone significantly relieved menopausal symptoms in peri/postmenopausal women. Cardiovascular biomarkers, inflammatory factors, and immune signaling factors were favorably impacted.
Bioidentical testosterone is not FDA-approved for use in women in the United States, though oral methyltestosterone (a synthetic version) in combination with esterified estrogen does have FDA approval. In contrast, testosterone is licensed for women in the UK and routinely used in Australia and much of Europe.
Delivery Methods
Oral (Capsules/Tablets)
Oral micronized bioidentical progesterone functions as a sleep aid for women because it is converted to allopregnanolone during first-pass liver metabolism, which acts on GABA receptors to promote sleep. Oral is the preferred route.
However, for estrogen the oral is the least preferred route because of their impact upon the liver and the risk of blood clots. Oral estrogen also tends to convert heavily to estrone, the weaker, less protective estrogen, during liver metabolism.
Bioidentical testosterone is not effective orally because it is broken down in the liver before reaching the bloodstream.
Transdermal Patches
There is definitely evidence that supports transdermal estrogen as being metabolically friendlier since this method of delivery avoids the first-pass liver effect, so they do not impact clotting function. Patches deliver bioidentical estradiol directly into the bloodstream, bypassing the gut and liver entirely. The infrequent downsides are skin irritation, adhesion issues, and the need to change them weekly or twice weekly. At this time, only E2 patches are available.
Gels and Creams
Application of a transdermal hormone preparation bypasses liver metabolism. All body sites are not equally permeable, and application sites must be rotated.
For progesterone specifically, topical creams are problematic with inconsistent absorption, thus the oral capsules are sometimes preferred.
Sublingual Troches and Lozenges
These dissolve under the tongue or in the cheek, allowing direct absorption into the bloodstream through the mucous membranes, bypassing liver metabolism. They offer good bioavailability and can be convenient, though hormone levels can fluctuate with this method as well and dosing must be done one to three times daily.
Methods of Testing Hormone
To understand these methods, it is important to know how sex hormones travel through the blood. They are either stuck on a protein called Sex Hormone Binding Globulin or they are detached and referred to as free and available, meaning they can leave the bloodstream and interact with cells.
Blood Testing
This is the conventional standard used by most doctors but can only measure the total amount of each hormone, meaning the lab result is both the bound and the free hormone. Thus, a good result may be misleading if most of the hormone is bound, leaving very little that is available.
It is also just a snapshot, a result at the moment of the blood draw.
Saliva Testing
This is the preferred type of testing for integrative and functional medicine practitioners.
When the free sex hormone leaves the bloodstream, it travels through lymph on the way to interact with cells. This lymph fluid is the same as saliva, so with saliva testing we are measuring the free and available sex hormones.
Since saliva samples are collected four times throughout a day, it is more accurate than the single blood draw. This is especially true and important if a person is also collecting for the adrenal hormone cortisol.