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Hormone Replacement Therapy for Women: Some Basics

Updated: Oct 6, 2023

WHAT IS HRT & BHRT?

HRT stands for hormone replacement therapy and BHRT stands for bioidentical hormone replacement therapy. The former may include hormones with a chemical structure distinct from those naturally found in the body (ex. progestin) whereas the latter includes hormones (whether derived from nature or produced in a lab) that have chemical structures identical to those produced endogenously (i.e. naturally produced by the body).


BHRT is a relatively common therapy used to treat both men and women who experience sub-optimal levels of various hormones. For women, the term BHRT generally alludes to 3 sex hormones- testosterone, estrogen (namely, estradiol) and progesterone.


Other hormones such as pregnenolone (the precursor hormone to all steroid hormones in the body, available in supplement form), DHEA (an adrenal hormone available in supplement form) and bioidentical thyroid medications like Armour thyroid (available by prescription and containing T3 and T4 thyroid hormones) are also technically included under the BHRT umbrella, but for our purposes today we're talking about the 3 main sex hormones.


So without further ado, let's get some basic info on hormone replacement therapy for women.


TESTOSTERONE IN WOMEN

Women naturally produce testosterone in their ovaries and adrenal glands. Lower testosterone levels can result from issues with the ovaries (ex. ovary removal/oophorectomy, PCOS, etc.) and issues with the adrenals (ex. adrenal fatigue/insufficiency, etc.). Testosterone plays an important role in female bone density, muscle mass, body fat, libido/sex drive, red blood cell production and overall energy levels. For most women testosterone levels naturally begin to drop in their mid-20s and continues through middle age and late adulthood. [1]


ESTROGEN IN WOMEN

Women naturally produce estradiol in their ovaries, adrenal glands and adipose tissue (body fat). There are 3 main types of estrogen…


*estrone/E1 (a weaker estrogen that plays a more central role during menopause)

*estradiol/E2 (the dominant form of estrogen and the most common estrogen used in BHRT)

*estriol/E3 (a weaker estrogen that plays a more central role during pregnancy)


Estrogen imbalance (either high or low levels) can result from issues with the ovaries (ex. ovary removal/oophorectomy, PCOS, etc.), issues with the adrenals (ex. adrenal fatigue/insufficiency, etc.), excess body fat, liver diseases, exposure to xenoestrogens (found in some plastics, pesticides, preservatives, smoke, etc.) and certain birth control medications.


Estrogen plays an important role in female bone density, regulation of body fat levels (especially belly fat), reproductive health, libido, skin health, temperature regulation and energy levels. For most women estrogen naturally begins to drop after age 40 and drops even more significantly after menopause. [2]

Average testosterone and estradiol for women across lifespan

Image Data Source: https://pubmed.ncbi.nlm.nih.gov/23380529/ (2013 study on T therapy in women)


PROGESTERONE IN WOMEN

Most progesterone production in women happens in the ovaries. The adrenal glands and placenta also produce smaller amounts. Progesterone plays a primary role in menstruation and pregnancy. Progesterone levels generally rise significantly during pregnancy. This is one of the reasons synthetic progesterone is used in certain birth control meds- the elevated levels “trick” the body into thinking the woman is pregnant, which stops the ovaries from releasing an egg.


There’s relatively sparse clinical data on the dangers of high progesterone. Low progesterone, on the other hand, can cause a myriad of health problems, particularly when the ratio of progesterone and estrogen are out of balance. This is called estrogen dominance and is relatively common among women 35-65 years old. [3]


ESTROGEN DOMINANCE

One of the things that commonly happens to women from about age 35 through menopause and after is a drop in both estradiol and progesterone. However, for many women the drop in progesterone is more drastic than the drop in estradiol, and this results in an imbalance between the 2 hormones, often called "estrogen dominance.” It's the declining levels of these sex hormones and the imbalance that are largely responsible for many of the unpleasant symptoms that often accompany this season of life (which includes perimenopause, menopause and post menopause).

Drop in estrogen and progesterone due to aging

Low progesterone and/or estrogen dominance can contribute to menstrual and reproductive problems (ex. PMS, heavy or irregular periods, infertility, fibrocystic breasts, endometriosis, uterine fibroids, etc.), as well as mood issues (irritability, anxiety, depression, etc.), weight gain, hair loss, acne, low libido, insomnia, migraines and bloating. [4]


HORMONE FLUCTUATIONS DURING MENSTRUAL CYCLE & WHEN TO TEST

For premenopausal women I think it's important to understand some basic fluctuations that happen during the menstrual cycle. As the image below illustrates, during the follicular phase (generally days 1-14 of a 28 day cycle), progesterone (P) is often near undetectable levels while estradiol (E2) is slowly rising. At ovulation there's a spike in E2 and a small jump in testosterone (T), and from there for about the next week P is rising significantly until peaking around day 21, after which it drops again.

Sex hormone fluctuation during menstrual cycle

What I generally recommend for premenopausal women is that they test for E2 and P twice- once during the first week of the follicular phase (day 3 is ideal), and once about a week after ovulation, which is usually around day 21 for a normal 28 day cycle (this is usually when P peaks). Total testosterone (and free T if possible) should also be tested during one of those blood draws (it usually doesn’t matter when T is tested, as T levels should be relatively stable through a premenopausal woman’s cycle, except for the slight increase that often happens around ovulation). [5]


SEX HORMONE DEFICIENCIES/IMBALANCES, LIFESTYLE & THE VALUE OF BHRT

When it comes to these 3 sex hormones, an increasing number of women in the U.S. -- especially women over the age of 35 -- experience adverse health and quality-of-life issues related to declining hormones and/or hormone imbalances.


While positive lifestyle changes (ex. diet, supplements, exercise, activity levels, sleep, stress management, etc.) can have significant impacts on sex hormone levels, oftentimes these lifestyle interventions aren’t enough to move levels into optimal ranges where a woman feels her best (and adverse symptoms abate).


It’s in situations like these where BHRT (i.e. supplementing with exogenous bioidentical testosterone, estrogen and/or progesterone) holds tremendous therapeutic value. Unfortunately, the poorly designed but highly influential Women’s Health Initiative (WHI) study from 2002 turned many providers and patients off to the idea of HRT, and the number of women using HRT to combat lifestyle and age-related hormone deficiencies and imbalances plummeted in the years following the study’s release. [6-8]


OPTIMAL TEST RANGES, METHODS OF HRT ADMINISTRATION

AND THERAPEUTIC DOSAGES

One of the first steps in optimizing sex hormone levels is having your sex hormones tested. Unfortunately, testing sex hormones is not standard practice when it comes to conventional lab testing in the United States, and many women will run into age and/or lifestyle-related sex hormone imbalance symptoms before they’ve ever had a testosterone, estrogen or progesterone biomarker run.


While there are several sex hormone biomarkers that have practical relevance, for simplicity’s sake I usually recommend women start with just 3: total testosterone, estradiol/E2 and progesterone. Free testosterone, SHBG (sex hormone binding globulin) and DHT are 3 additional markers I’d suggest for those who want an even more complete view of sex hormone activity and are ok with paying for it (as oftentimes sex hormone testing like this isn’t covered by health insurance).


In addition to the relative infrequency of hormonal lab testing among mainstream providers, another element that makes BHRT confusing is the number of routes or methods of administration for testosterone, estradiol and progesterone. Depending on the specific hormone, these may include…


*Injections (either subcutaneous or intramuscular/IM)

*Injected pellets

*Suppository (either rectal or vaginal)

*Oral (usually only for progesterone)

*Transdermal (includes gels, creams and patches) [9]


TESTOSTERONE: OPTIMAL LABS, DELIVERY METHOD, DOSAGES


TOTAL TESTOSTERONE LAB TARGETS

The common reference range for total testosterone is usually 2-75 ng/dL (I say usually because different labs will often use slightly different levels for their reference range). [10]


One of the big problems with testing and BHRT is that optimal levels are often VERY different than the normal reference ranges, and this is true with total testosterone as well.


Optimal levels for many women taking exogenous testosterone may be 75-250 ng/dL (I know of some women who feel great with levels even into the 400s!). [11]


With BHRT, it’s also very important to consider the person and their quality of life and symptoms rather than just the biomarker. For example, one woman on BHRT might feel her best with total testosterone levels between 75-100, while another only feels amazing when she’s between 150-200.


FREE TESTOSTERONE LAB TARGETS

The common reference range for free testosterone is usually around 0.1-0.6 ng/dL.


Optimal levels for many women taking exogenous testosterone may be 0.3-0.6 ng/dL (the upper half of the normal reference range) but may be as high as 3-6 ng/dL (which is 10 times higher than the upper half of the normal reference range).


Note that free T is often given in pg/mL instead of ng/dL. To convert ng/dL to pg/mL simply multiply ng/dL by 10 (or conversely, divide pg/mL by 10 to get ng/dL).


TESTOSTERONE DELIVERY METHODS

When it comes to exogenous testosterone these are generally the options…


*Injections (either subcutaneous or intramuscular/IM)

*Injected pellets

*Transdermal (includes gels, creams, vaginal/labia creams and patches)


I believe injections (either SubQ or IM) are the most effective delivery method for improving suboptimal T levels. Whatever the weekly dose, it should be split up into two separate injections 3-4 days apart. As far as esters go, I prefer testosterone cypionate.


I personally don’t like injected pellets as they take 3-6 months to dissolve (and I prefer to be able to adjust dosages more often than that). That said, some prefer the convenience (and effectiveness) of the pellets and I can understand why.


When it comes to transdermal options (gels, creams, patches), the feedback I’ve received is that creams applied to the inner labia are the most effective transdermal way of raising T levels and improving symptoms related to suboptimal testosterone. Application to the inner thigh is also generally effective, although usually not as effective as labial application. In creams and gels, testosterone is suspended in a base cream or gel.


Look for bases made by Medisca (ex. their Versapro cream or gel) and PCCA (ex. their VersaBase cream or gel). These creams and gels tend to be more hypoallergenic. Some compounding pharmacies even use coconut oil as a base for their transdermal HRT products.


In short, I’d suggest T injections 2x a week as my first/preferred choice, and 2x a day labial application using a cream (or gel) as my second choice.


TESTOSTERONE DOSAGES

With injections, a common therapeutic dose is 2-10mg injected 2x a week (which equates to 4-20mg weekly). Most women will start on the lower side of this range (2-4mg 2x a week). Twice a week injections (or every 4 days) are recommended because of the half-life of testosterone esters. Injecting at this frequency also helps to avoid higher peaks and lower troughs that are typical with 1x a week (or less frequent) injection protocols, which often result in adverse symptoms. Note that injectable testosterone can come in vials of different strengths (ex. 50 mg/ml, 100 mg/ml, 200 mg/ml, etc.). Instructions for injecting are generally given in ml (ex. 0.1 ml 2x a week) but understanding your dosage should be based on mg per week and not ml.


With creams/gels, a common therapeutic dose is 1-7.5mg applied 2x a day (which equates to 2-15mg daily). [12]


ESTROGEN (ESTRADIOL): OPTIMAL LABS, DELIVERY METHOD, DOSAGES


ESTRADIOL LAB TARGETS

The common reference range for estradiol depends on where a woman is in her cycle (premenopausal woman). There is also a reference range for postmenopausal women. There ranges usually look something like the following…


*Follicular phase, days 1-14 of cycle, 20-150 pg/mL

*Ovulation, day 14/15 of cycle, 50-350 pg/mL (some will range as high as 400 pg/mL)

*Luteal phase, days 15-28 of cycle, 50-200 pg/mL

*Post menopause, <30 pg/mL [13]


Note that during pregnancy a woman’s level of circulating estradiol increases dramatically and may be as high as 20,000 pg/mL!


Again, one of the big problems with lab testing and BHRT is that optimal levels are often VERY different than the normal reference ranges, and this is true with estradiol as well.


Optimal levels for many women taking exogenous estradiol often hover between 100-350 pg/mL. I know of some women who feel great with levels even into the 400s.


Something that should be emphasized with BHRT is the importance of hormone balance. For instance, a woman might feel her physical best when her estradiol hovers around 200 pg/mL AND her testosterone is at 150 and her progesterone is at 15, but she might suffer from several health issues when her estrogen is 200 pg/mL BUT her testosterone is at 30 and her progesterone is at 4. This is one of the main reasons phrases like “balancing hormones” and “hormone imbalance” are used- the goal isn’t just to hit a certain range with one biomarker, but to find individual levels AND ratios that help a woman feel her best.


For women past menopause, the majority of mainstream providers likely won’t be comfortable seeing estradiol levels over 100 pg/mL, so keep that in mind if you’re consulting with a mainstream provider on HRT and estradiol.


ESTRADIOL DELIVERY METHODS

When it comes to exogenous estradiol these are generally the delivery method options…


*Injections (either subcutaneous or intramuscular/IM)

*Injected pellets

*Oral (although this delivery method is discouraged by many)

*Transdermal (includes gels, creams and patches)


I believe injections (either SubQ or IM) are the most effective delivery method for improving suboptimal estradiol levels. Whatever the weekly dose it should be split up into two separate injections 3-4 days apart. As far as esters go, I prefer estradiol cypionate (DEPO-estradiol).


And as with testosterone, I personally don’t like injected estradiol pellets as they take 3-6 months to dissolve (and I prefer to be able to adjust dosages more often than that). That said, some prefer the convenience (and effectiveness) of the pellets and I can understand why.


Oral estrogen is available, but it tends to be much less bioavailable (due to the effects of first pass metabolism) and it tends to increase E1 (estrone), which can be problematic for many women.


When it comes to transdermal options (gels, creams, patches), the feedback I’ve received is that creams applied to the inner labia are the most effective transdermal way of raising estradiol levels and improving symptoms related to suboptimal estradiol. Application to the inner thigh is also generally effective, although usually not as effective as labial application.


In short, I’d suggest E2 injections 2x a week as my first/preferred choice, and 2x a day labial application using a cream (or gel) as my second choice.


ESTRADIOL DOSAGES

With injections, a common therapeutic dose is 1-3mg injected 2x a week (which equates to 2-6mg weekly). Twice a week injections (or every 4 days) are recommended because of the half-life of estradiol. Injecting at this frequency helps to avoid higher peaks and lower troughs that are typical with 1x a week (or less frequent) injection protocols, which often result in adverse symptoms. Note that estradiol cypionate can come in vials of different strengths (usually either 5mg/mL or 10mg/mL). Instructions for injecting are generally given in ml (ex. 0.15 ml 2x a week) but understanding your dosage should be based on mg per week and not ml.


With creams/gels, a common therapeutic dose is 1-3mg applied 2x a day (which equates to 2-6mg daily). As with testosterone creams and gels, inner labia application of estradiol gels/creams is generally recommended, with inner thigh application the next most effective transdermal application area. [14]


PROGESTERONE: OPTIMAL LABS, DELIVERY METHOD, DOSAGES


PROGESTERONE LAB TARGETS

Like estrogen, the common reference range for progesterone depends on where a woman is in her cycle (premenopausal woman). There is also a reference range for postmenopausal women. There ranges usually look something like the following…


*Follicular phase, days 1-14 of cycle, ~0 ng/mL

*Ovulation, day 14/15 of cycle, 2-25 ng/mL

*Luteal phase, days 15-28 of cycle, 2-25 ng/mL

*Post menopause, <1 ng/mL [15]


Note that during pregnancy a woman’s level of circulating progesterone increases dramatically and may be as high as 200 ng/mL!


Optimal levels for many women taking exogenous progesterone often hover between 5-25 ng/mL.


Remember, striking an optimal “hormone balance” between testosterone, estradiol and progesterone is key to a woman feeling her best and avoiding unpleasant physical effects, not simply hitting optimal numbers on one hormone biomarker (ex. progesterone).


PROGESTERONE DELIVERY METHODS

When it comes to exogenous progesterone these are the options…


*Suppository (either rectal or vaginal)

*Oral

*Transdermal (includes gels, creams and patches)


While progesterone is commonly prescribed in oral form (brand name Prometrium), some research (and many anecdotal reports) indicate that serum progesterone levels are more effectively impacted when Prometrium (progesterone gel caps) is taken as a suppository (either vaginal or rectal routes). For instance, a 2004 study of 60 women found that those who took progesterone vaginally had blood progesterone levels 63% higher than those who took the same progesterone dose orally. [16]


As such, taking progesterone as a suppository (either vaginal or rectal routes) is generally recommended as the most effective delivery method for improving suboptimal P levels. Because exogenous progesterone can lead to feelings of sleepiness, taking P at night is recommended.


When it comes to transdermal options (gels, creams, patches), the feedback I’ve received is that transdermal progesterone isn’t nearly as effective as taking it as a suppository or consuming it orally. For those who do want to go the transdermal route, creams applied to the vagina are generally the most effective at raising progesterone levels.


In short, I’d suggest taking progesterone as a rectal suppository as my first/preferred choice, and oral consumption as my second choice. For both methods, once a day administration in the evening is suggested.


PROGESTERONE DOSAGES

With oral or rectal suppository use, a common therapeutic dosage of progesterone is 100-200mg taken in the evening. I have seen women on dosages as high as 800mg/day, but generally, therapeutic dosages will fall in the 100-400mg/day range. [17]


With creams/gels, a common therapeutic dose is 20-40mg a day. I’ve seen women take up to 100mg/day of topical/transdermal progesterone but again, the common dose is 20-40mg/day (and I strongly encourage women to consider suppository or oral use of progesterone over transdermal methods). [18]


SUMMARY OF OPTIMAL LEVELS, PREFERRED DELIVERY METHOD & DOSAGES

Optimal lab test ranges and dosages for sex hormones

SOURCES

1 https://pubmed.ncbi.nlm.nih.gov/26358173/ (2015; clinical significance of T in women)

2 www.ncbi.nlm.nih.gov/books/NBK538260/ (2023; statpearls on estrogen in women)

3 www.ncbi.nlm.nih.gov/books/NBK558960/ (2023; statpearls on progesterone in women)

4 www.ncbi.nlm.nih.gov/pmc/articles/PMC8870180/ (2022; estrogen dominance and the role of sex hormone imbalances in common gynecological disorders)

7 www.ncbi.nlm.nih.gov/pmc/articles/PMC1630688/ (2006; critique on WHI study)

8 www.ncbi.nlm.nih.gov/pmc/articles/PMC6780820/ (2019; critique on WHI study)

11 www.mdpi.com/1424-8247/16/4/619 (2023; study on T therapy in women, “Successful results have been observed with subQ testosterone therapy in reducing symptoms with minimal side effects by maintaining serum T levels between 150 and 250 ng/dL in women.”)

12 www.health.harvard.edu/womens-health/study-identifies-effective-testosterone-dose-for-women (2014 study on 5mg and 10mg/day transdermal testosterone)

16 https://pubmed.ncbi.nlm.nih.gov/15222511/ (2004 study on effectiveness of vaginal progesterone administration over oral)

17 www.rxlist.com/prometrium-drug.htm (dosages for oral progesterone)

18 www.drugs.com/npp/progesterone.html (dosages for topical progesterone)

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