Menopause hormone therapy (MHT) — often called "hormone replacement therapy" (HRT) or simply "hormone therapy" (HT) — isn't one treatment. It's a broad category covering many different hormones and many ways of delivering them. 

Synthetic hormones (and others, e.g. conjugated equine estrogens - CEEs) are available, however, the hormones most often used in bioidentical hormone therapy include estradiol (E2), estrone (E1), estriol (E3), pregnenolone, progesterone (P4), DHEA, and testosterone. Routes of administration (ROAs) include transdermal (to the skin), oral, sublingual, injections, vaginal delivery, rectal delivery, and hormone pellet therapy.  

Choosing among these methods requires balancing symptom relief against individual risk factors, and clinical literature has increasingly emphasized that how a hormone is delivered can matter as much as which hormone is used. 

This DUTCH article focuses on the most commonly prescribed options: estradiol (oral, transdermal, vaginal), progesterone (oral, vaginal), and DHEA (oral, vaginal). 

Estradiol Therapy

Estradiol therapy is FDA-approved for hot flashes, night sweats, vaginal atrophy, preventing osteoporosis, and low estrogen from surgical menopause or early ovarian failure, but it may have other benefits for sleep, mood, brain health, etc. It may not be a good fit for anyone with a history of estrogen-sensitive cancer, blood clots, stroke, heart attack, coronary heart disease, blood clotting disorders, liver disease, or unexplained uterine bleeding. 

Oral E2 

Oral estrogen is the most common way to take menopausal hormone therapy — a simple daily pill. It is convenient to take and has all the benefits of transdermal estrogens; However, oral hormones are initially processed through the liver, and estrogen has several significant impacts on the liver. One benefit of oral estrogen is it increases the liver’s uptake of circulating cholesterol, lowering serum cholesterol levels, which women often see rise in the menopausal transition. Unfortunately, some do not tolerate this cholesterol absorption and can develop gallstones. In addition, estrogen promotes liver clotting factor synthesis andtherefore increases the risk of blood clots and stroke more than skin-absorbed estrogen. Therefore estrogen through the oral route should be avoided if 10-year ASCVD cardiovascular risk is 5% or higher. 

Transdermal E2  

Transdermal E2 is a safer option than oral E2 since it skips the liver's first-pass effect — meaning less impact on clotting, gallbladder risk, and cardiovascular/stroke risk. FDA-approved gels and patches, along with compounded creams, are available, but doses aren't interchangeable: patch labels reflect what's absorbed, while creams and gels reflect what's applied, and compounded creams often absorb less than FDA-approved gels at the same dose. 

Low-Dose (Localized) Vaginal E2  

Low-dose vaginal estradiol treats vulvovaginal atrophy and genitourinary symptoms — dryness, thinning tissue, and painful sex, chronic UTI’s — that affect up to 84% of postmenopausal women. Available as a cream, ring, or insert, it's dosed low enough to avoid raising circulating estrogen beyond normal postmenopausal levels.  

It's generally considered safe with a breast cancer history, including on tamoxifen, once nonhormonal options have failed, though it's best to consult one’s oncologist first. Some find application invasive, and exceeding low-dose ranges can raise systemic exposure unpredictably. Side effects include discharge, yeast infections, breast pain, and bleeding (which needs follow-up). It's best for women with normal endometrial risk and vaginal/urinary symptoms, alone or alongside systemic E2 therapy.  

Progesterone Hormone Therapy

Women with a uterus on systemic estrogen need a progestogen added specifically for endometrial protection as estrogen alone can lead to endometrial hyperplasia and cancer. However, many argue that even women without a uterus may benefit from balancing estrogen therapy with progesterone’s numerous benefits. 

Oral Micronized Progesterone (OMP) 

When taken orally, most progesterone is broken down by the liver into metabolites that have a calming effect on the brain, which is why OMP tends to support mood and sleep better than vaginal progesterone. The tradeoff is more drowsiness and dizziness for some patients, and the FDA-approved product, Prometrium, is not an option for those with peanut allergies as it contains peanut oil (compounded versions are an alternative). It's best suited for women on estrogen with a uterus, particularly those dealing with anxiety and poor sleep. For endometrial protection, it's typically dosed at 100 mg nightly, 200 mg nightly, or 200 mgfor 12–14 sequential nights a month. 

Vaginal Micronized Progesterone (VMP) 

Vaginal progesterone via Prometrium capsules, Crinone gel, or compounded preparations, is placed high in the vaginal vault, where it reaches the uterus more directly. Because it doesn’t undergo first-passmetabolism in the gut and liver, patients don’t tend to experience drowsiness and dizziness as with oral progesterone, but this also means VMP tends to be less of a mood/sleep support. It's invasive for some, requires avoiding intercourse shortly after application, and correct placement matters; applying too low in the vagina won't protect the uterus. Evidence for endometrial protection is not as strong as for oral dosing, but it is an alternative for women who can't tolerate oral progesterone. 

DHEA Therapy

Oral DHEA 

When taken by mouth, DHEA is absorbed and converted by the liver into DHEA-S, a longer-lasting form that provides more stable circulating levels. From there, it converts back to DHEA in tissues throughout the body and serves as a precursor to both testosterone and estradiol. 

Oral DHEA isn't FDA-approved, so there's no official indication list, but it's often used for low muscle mass, low mood, low libido, fatigue, or cognitive concerns. Because it can raise estrogen levels depending on dose and duration, it carries the same contraindications as estrogen therapy — things like a history of breast cancer, blood clots, liver disease, or unexplained bleeding, etc. 

Benefits may include more muscle mass, better mood, improved libido, and less joint pain, but drawbacks include unwanted hair growth, acne, and estrogen effects like breast tenderness. Research shows E2 increases become more significant with oral DHEA in postmenopausal women, those 60 and older, or with higher doses (e.g. 50 mg), or longer use (26+ weeks). In short, oral DHEA can act much like adding estrogen. It may be appropriate to test both DHEA-S and E2 in a postmenopausal woman on DHEA therapy. If E2 increases above the menopausal range, progesterone should be considered to protect the endometrium.   

Vaginal DHEA  

Vaginal DHEA converts locally into estradiol within vaginal tissue, improving moisture and elasticity, while also providing local androgens that may support sexual function — offering a potential edge over vaginal E2with less estrogen reaching the endometrium. Prasterone (6.5 mg) is FDA-approved for moderate-to-severe painful intercourse, and compounded DHEA creams are typically dosed at 5–10 mg. 

Contraindications mirror those for estrogen and androgens, including breast cancer history, blood clots, liver disease, and unexplained bleeding. Still, a 52-week trial found no meaningful rise in estradiol and no endometrial changes with the 6.5 mg vaginal dose. Both The American College of Obstetricians and Gynecologists (ACOG) and The Menopause Society (TMS) consider it safe for women with a history of estrogen-sensitive breast cancer whose vaginal symptoms haven't responded to other options. 

The most common side effect is abnormal discharge; abnormal Pap smears occurred in a small percentage of trial participants, underscoring the importance of routine screening. 

Where DUTCH Testing Comes In 

With so many hormones and routes to choose from, how do you know if a therapy is actually landing where it should? That's where DUTCH Testing can be helpful. As an at-home hormone test, DUTCH lets patientscollect samples in the comfort of their own home rather than booking multiple blood draws, and it captures a fuller picture of hormone exposure over 24 hours instead of a single snapshot in time from a serum or saliva sample.  

It can be used to monitor circulating levels of E2 when transdermal or vaginal E2 is used, and it can monitor estrogen metabolism regardless of what E2 therapy ROA is used. This matters because converting too much estrogen down the 4-OH or 16-OH pathways may increase risk for breast cancer or estrogen-excess associated side effects, respectively.  

DUTCH testing can also show how one is metabolizing oral progesterone (which matters for those calming, sleep-friendly effects of the alpha progesterone metabolites) and can track androgen and estrogen metabolism relevant to DHEA therapy. It's not a stand-in for an endometrial biopsy when it comes to confirming uterine protection, but as one piece of the puzzle, hormone testing via DUTCH may provide more context for fine-tuning the treatment plan. 

The Bottom Line 

There's no single "best" hormone therapy type. Oral estradiol may be used successfully in younger healthy women with low clotting and cardiovascular risk, while transdermal estradiol may be the better call as women get older and that risk climbs. Low-dose vaginal estradiol and vaginal DHEA both handle local symptoms with slightly different perks, including options for women navigating certain cancer histories alongside their oncology team. For progesterone, OMP tends to win on mood and sleep, while VMP is the go-to (used off-label) for those who can't tolerate OMP's side effects or want less brain-sedating effects. And DHEA, whether oral or vaginal, comes with its own set of considerations tied to how much it behaves like adding estrogen. Whatever combination is chosen, tools like DUTCH testing can help make sure thehormone therapy is actually working as intended — and being metabolized optimally.  

To learn more about menopausal hormone therapy (MHT), check out our DUTCH course: Introduction to HRT - free for all registered DUTCH Providers. If you’re not yet a DUTCH Provider, become one here. 

References 

1. ACOG. ACOG Committee Opinion: Treatment of Urogenital Symptoms in Individuals With a History of Estrogen-dependent Breast Cancer Obstet Gynecol. 2021;138(6):950-960. 
2. Cicinelli E, et. al. Plasma concentrations of progesterone are higher in the uterine artery than in the radial artery after vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women. Fertil Steril. 1998 Mar;69(3):471-3. 
3. de Ziegler D, et al. Vaginal progesterone in menopause: Crinone 4% in cyclical and constant combined regimens. Hum Reprod. 2000;15 Suppl 1:149-158. 
4. Di Carlo C, et al. Transdermal estradiol and oral or vaginal natural progesterone: bleeding patterns. Climacteric. 2010;13(5):442-446. 
5. Goldštajn MŠ, et al. Effects of transdermal versus oral hormone replacement therapy in postmenopause: a systematic review. Arch Gynecol Obstet. 2022;307(6):1727-1745. 
6. Hamoda H; BMS medical advisory council. British Menopause Society tools for clinicians: Progestogens and endometrial protection. Post Reprod Health. 2022 Mar;28(1):40-46.  
7. Ke Y, et al. Serum levels of sex steroids and metabolites following 12 weeks of intravaginal 0.50% DHEA administration. J Steroid Biochem Mol Biol. 2015;154:186-196. 
8. NAMS. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause. 2020;27(9):976-992. 
9. NAMS. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794. 
10. Newman M, et al. Comparative estrogen exposure from compounded transdermal estradiol creams and Food and Drug Administration-approved transdermal estradiol gels and patches. Menopause 2023;30(11). 
11. Portman DJ, et al. Treatment of moderate to severe dyspareunia with intravaginal prasterone therapy: a review. Climacteric. 2019;22(1):65-72. 
12. Ross D, et al. Randomized, double-blind, dose-ranging study of the endometrial effects of a vaginal progesterone gel in estrogen-treated postmenopausal women. Am J Obstet Gynecol. 1997;177(4):937-941. 
13. Rutkowski K, et al. Dehydroepiandrosterone (DHEA): Hypes and Hopes. Drugs. 2014;74(11):1195-1207. 
14. Sriprasert I, Mert M, Mack WJ, Hodis HN, Shoupe D. Use of oral estradiol plus vaginal progesterone in healthy postmenopausal women. Maturitas. 2021 Dec;154:13-19. 
15. The Nonhormone Therapy Position Statement of The North American Menopause Society" Advisory P. The 2023 nonhormone therapy position statement of The North American Menopause Society. Menopause.2023;30(6):573-590. 
16. Van Erpecum KJ, et al. Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women. Gastroenterology. 1991;100(2):482-488. 
17. Walsh BW, et al. Effects of Postmenopausal Estrogen Replacement on the Concentrations and Metabolism of Plasma Lipoproteins. N Engl J Med. 1991;325(17):1196-1204. 
18. Zhu Y, et al. The effect of dehydroepiandrosterone (DHEA) supplementation on estradiol levels in women: A dose-response and meta-analysis of randomized clinical trials. Steroids. 2021;173:108889.