Hormone replacement therapy was created primarily for postmenopausal women in the 1970s. There was a rapid increase in the use of hormones until the 2001 Women's Health Initiative (WHI). Many news outlets discussed the finding of the study that linked hormone replacement therapy to an increase in breast cancer as well as held significant cardiovascular risk. Within three months of the publication, estrogen and progesterone prescriptions were down by over 60%. However, the type, dose, and duration of the hormone being used are significant, and risk may vary greatly depending upon those three factors or a combination of them.

Bioidentical hormone therapy monitoring can help assess these factors and determine which route of administration and dose is appropriate. This article will discuss bioidentical hormones specifically, what they are, why they would be used, how to monitor them, and additional alternative therapies that can be used in conjunction with them.

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What are Bioidentical Hormones?

Menopause marks the end of fertility for women and is diagnosed after a woman goes without a menstrual period for 12 months. Women's ovaries produce hormones, specifically estradiol and progesterone, from the first period to the last. Once menopause occurs, the levels of those hormones plummet and can lead to various symptoms, including hot flashes, night sweats, sleep disturbances, mood changes, and more.

The symptoms can be severe and significantly alter a woman's quality of life. Hormone replacement therapy is an option for women who suffer from menopause-related symptoms. There are two main types of hormone therapy: bioidentical and non-bioidentical. Bioidentical hormones are hormones produced in a lab that are identical to our body's hormones. Non-bioidentical hormones are also made in a laboratory, but their chemical structure differs from the hormones innately made by women.

Certain bioidentical hormones are approved for use by the Federal Drug Administration (FDA) and are available at traditional pharmacies. There are also compounded bioidentical hormones. These hormones are made by a compounding pharmacy and may have variability in the amount of hormone contained in the end product. It is because of this that the FDA advises against them.  

Bioidenticals vs. Synthetic Hormones

As stated earlier, the WHI changed the public perception of hormone replacement therapy in women. As the largest randomized, placebo-controlled trial ever done on menopausal women, the findings were concerning: it showed an increased risk of breast cancer, stroke, deep vein thrombosis, and Alzheimer's disease with estrogen and progesterone therapy. However, it's important to note that only one type of estrogen was used, synthetic oral conjugated equine estrogen (CEE), and one type of progesterone, synthetic progestin (medroxyprogesterone acetate).

Results of the WHI suggest estrogen therapy increases the risk of DVTs. However, a 2007 study in the journal Circulation showed that estrogen given topically does not carry this same risk. Most topical estrogen medications are bioidentical.

Another study assessing breast cancer risk in over 54,000 women showed that progesterone carried a lower risk profile as opposed to progestins, the synthetic form of progesterone. Additionally, the same study showed that transdermal estrogen and synthetic progestin had an increased risk of breast cancer, whereas the risk of transdermal estrogen and natural progesterone had no increased risk of cancer compared to controls. The study followed the patients for eight years.

Bioidentical Hormones Include:

Estradiol: Estradiol is the dominant type of estrogen in premenopausal women. It acts as a growth hormone on the uterine lining and breast tissue. It prevents bone breakdown, aids in cognitive functioning, including memory, and helps maintain healthy cholesterol levels. Hot flashes, night sweats, vaginal dryness, mood changes, weight gain, and difficulty sleeping are symptoms of low estradiol.

Estrone and Estriol: These estrogens have similar effects to estradiol, although they have less of an effect as they are weaker estrogens.

Progesterone: Progesterone aids in the function of the uterine lining, helping to prepare it in anticipation of a fertilized egg. It also exerts an anti-anxiety and antidepressant effect. Hot flashes, mood changes, and difficulty sleeping can result from low progesterone.

Testosterone: Testosterone is what women make estrogens from. Low libido, fatigue, brain fog, and weight gain can be seen in women with low testosterone.

DHEA: DHEA is what we refer to as a "prohormone"; all the hormones listed above can, and often are, synthesized from DHEA. Low levels of DHEA are associated with fatigue and mood changes.

When to Consider Bioidentical Hormone Replacement Therapy

There are pros and cons to bioidentical hormone replacement. Hormone replacement therapy is FDA approved for the following:

Vasomotor Symptoms (VMS): Hormone therapy is the first-line therapy recommended for moderate to severe VMS (hot flashes and night sweats) due to menopause. VMS, on average, lasts for 7.4 years and can cause difficulty sleeping, irritability, concentration difficulties, and overall lower quality of life and poorer health status. VMS was associated with cardiovascular, cognitive, and bone risks. Hormone therapy was found to reduce weekly VMS by 75% while also reducing the severity of symptoms.

Prevention of bone loss: Hormone therapy can be used to prevent bone loss, and thus osteoporosis, in postmenopausal women. Five to seven years of hormone therapy has been shown to significantly reduce the risk of spine, hip, and non-spine fractures.

Premature hypoestrogenism: Hormone therapy can be used for hypoestrogenism caused by bilateral oophorectomy (removal of both ovaries) or primary ovarian insufficiency. Hormone therapy in these women can reduce menopausal symptoms, bone loss, heart disease, and cognitive decline.

Genitourinary symptoms: Vulvovaginal atrophy (VVA), or thinning and inflammation of the vaginal walls as a result of menopause, can be benefited from hormone therapy. Often a result of VVA, but not always, dyspareunia, or painful intercourse, can also benefit from hormone therapy.

Functional Medicine Labs for Monitoring Bioidentical Hormones

Because hormones are not active when they are excreted, and because the amount taken directly impacts the amount in the body (linear pharmacokinetics), testing is not recommended by governing bodies such as the North American Menopause Society or the American College of Obstetrics and Gynecology. However, many practitioners find testing useful to aid in symptom relief while minimizing the risk associated with hormone therapy.

Bioidentical hormones can be measured through blood, urine, and saliva, each testing method giving different information. The timing of testing is determined by the hormone, the route of administration, and the type of testing. Ideal doses are individualized as they depend on multiple factors, including symptom relief, age, weight, genetics, and more.

Blood Testing

Blood testing of hormones can be useful for injections, pellets, and oral formulations. This is because these routes of administration allow the active hormone to go into the blood. However, hormones in the blood are bound to carrier proteins, as these hormones are hydrophobic (they don't like water). This creates problems in testing, as hormones bound to carrier proteins are not readily available for use. However, recent years have provided advances in testing methods. The liquid chromatography-tandem mass spectrometry test (lc/ms-ms) is a testing method that provides greater sensitivity and specificity for sex hormones, making it an optimal choice. Estradiol, estrone, progesterone, and testosterone can all be ordered with the lc/ms-ms testing method.

Serum testing should be done at the same time for every blood draw when on hormones, as innate hormone secretion may still occur and varies throughout the day. Also, the timing of the last dose of hormone therapy should be recorded and kept consistent with the blood draw to ensure the values are comparable.

Saliva Testing

Saliva testing can be incredibly helpful in measuring topical hormones found in patches, creams, and gels. This is because saliva measurements represent the tissue level of hormones.

When a topical hormone is applied, it gets absorbed through tiny blood vessels called capillaries. Once in the bloodstream, these hormones attach to red blood cells (RBCs). Red blood cells take them to their targeted tissues. In blood testing, the red blood cells are discarded from the sample with processing, making it a less accurate way of testing topical hormones. Salivary testing by ZRT laboratories applies the lc/ms-ms method discussed above, making it a great salivary testing choice. Optimal test levels will ultimately depend on symptom relief. This test cannot monitor troches or sublingual hormones. Results will be skewed since the route of administration and absorption is the same as the testing site.

Urine Testing

Urine testing, such as the DUTCH test, shows metabolites or breakdown products of hormones that have gone through liver metabolism. This is incredibly important when bioidentical hormones, or any hormones, are being used. You want to ensure the hormones you give or take are properly excreted. Problems with estrogen metabolism specifically can lead to the growth of tissues and certain cancers. Urine metabolites parallel with blood testings. The DUTCH test can monitor oral progesterone, transdermal and vaginal estrogen and testosterone, pellets, patches, and injections of all hormones. The DUTCH test, however, is not appropriate to measure transdermal and vaginal progesterone, oral estrogen, or sublingual (troche) hormones as these hormones' metabolism does not accurately match the amount of hormone in the body.

Bioidentical Hormones Treatment Options

Bioidentical hormones come in oral forms, topical forms such as patches, gels, creams and emulsions, transdermal sprays, dissolvable forms such as lozenges and troches, vaginal inserts and suppositories, and injectables including pellets, tiny implants just underneath the surface of the skin that hold hormones.

Estradiol

FDA approved:

Patches: Alora, Climara, Esclim, Fempatch, Menostar, Vivelle, Vivelle-Dot, and various generics

Gels: Estraderm, EstroGel, Elestrin, Divigel

Topical Emulsion: Estrasorb

Transdermal Spray: Evamist

Vaginal cream: Estrace vaginal cream

Vaginal ring: Estring, Femring

Vaginal Tablets: Vagifem, Vagifem LD

Injection: Depot-estradiol, Delestrogen

Oral: Femtrace, Estrace, and various generics

Compounded/Non-FDA approved:

Cream: Bi-est (20% estradiol 80% estriol), Tri-Est (10% estradiol, 10% estrone, 80% estriol)

Progesterone

FDA approved:

Oral: Prometrium

Non-FDA-approved formulations available

DHEA

FDA approved:

Vaginal insert: Intrarosa

Non-FDA-approved formulations available from compounding pharmacies

Testosterone

No FDA-approved formulations:

‍Compounded only.

**Testosterone therapy is recommended in women with Hypoactive Sexual Desire Disorder, commonly diagnosed in postmenopausal women. Yet, the FDA recommends other types of medications for this disorder.

*A Note About Dosing

As estrogen has a growth-inducing effect on the lining of the uterus, any woman on hormone replacement therapy with a uterus must be given progesterone with estradiol to prevent endometrial hyperplasia, a precancerous thickening of the uterine lining.  

As discussed above, oral estrogen carries a higher risk than topical administration. Estrogen and progesterone need to be balanced to achieve symptom relief. The type, dose, and administration route can significantly impact the risk associated with hormone therapy.

Additional Treatment Options for Women on Bioidentical Hormones

Nutrition

The Mediterranean Diet may be helpful for menopausal symptoms. In a study of 100 obese menopausal women, adherence to the MD lessened menopausal symptoms. They noticed statistically significant correlations between legume intake and olive oil intake, with legumes reducing menopausal symptom severity and olive oil specifically reducing psychological symptoms.

Estrogen Detoxification Support

Because of the risk associated with estrogen therapy, ensuring proper estrogen metabolism is essential. Estrogen detoxification support such as Indole-3-carbinol, magnesium, b vitamins, calcium-d-glucarate, and fiber can be beneficial in aiding in healthy estrogen metabolism. It's important to note that these compounds can affect the estrogen level in the body, meaning dosages may need to be adjusted.  

Summary

Hormone replacement therapy can be life-changing for women with menopausal symptoms. All women on hormone therapy should know the differences in the types of hormones, the associated risks, and the differences in administration and testing. Bioidentical hormone testing can be an invaluable tool to help assess the patient's risk and ensure the proper dose while concurrently alleviating symptoms.