Hormone Replacement Therapy (HRT)
Understanding Bioidentical Hormone Replacement Therapy Options
What Is Hormone Replacement Therapy (HRT)?
Hormone Replacement Therapy (HRT) refers to the use of estrogen, progesterone, and sometimes testosterone to ease symptoms that arise as hormone levels decline during perimenopause, menopause, or surgical menopause. When used appropriately, HRT can dramatically improve quality of life - addressing vasomotor symptoms (hot flashes, night sweats), mood changes, sleep disruption, mental performance, sexual health, metabolic changes, and long-term risks such as bone loss and cardiovascular decline.
Over the past two decades, attitudes towards hormone replacement therapy have evolved. Today we have clearer distinctions between hormone types, routes, and timing, all of which significantly influence benefits and safety profiles.
At Kass Precision Medicine, we emphasize evidence-guided, individualized hormone therapy using bioidentical (physiologic) formulations that match the hormones naturally produced by the human body.
Bioidentical vs. Non-Physiologic Hormones
Hormones used in HRT fall into two broad categories:
1
Bioidentical (Physiologic) Hormones
These are molecularly identical to human hormones.
Examples include:
17B-estradiol (the primary estrogen produced by the ovaries)
Micronized progesterone (produced by the ovaries )
Bioidentical testosterone (produced by the ovaries and adrenal glands and used off-label for women)
These hormones interact with receptors exactly as endogenous hormones do, leading to more predictable physiologic effects.
2
Non-Physiologic (Synthetic or Animal-Derived) Hormones
These differ structurally from human hormones.
Examples include:
Premarin / CEE (conjugated equine estrogens)
Provera / Medroxyprogesterone acetate
Drospirenone (newer synthetic progestin)
These agents do not behave the same way as bioidentical hormones in the body, and their risk profiles are markedly different.
A Quick History: The WHI “Drama” and 30 Years of Confusion
For nearly 30 years, women were told to fear HRT. The 2002 Women’s Health Initiative (WHI) used Premarin + Provera - non-physiologic hormones - and reported elevated risks of breast cancer, stroke, and clotting. The result was panic, mass discontinuation of HRT, and decades of misinformation among both providers and patients.
Key Problems With the WHI Trial
(Often Not Explained to Patients)
They did not use bioidentical hormones.
The estrogen in WHI was Premarin (CEE) - derived from pregnant mare urine - not human estradiol.
The progestin used was Provera (medroxyprogesterone) - a synthetic compound with known adverse vascular and breast effects.
We cannot apply WHI risks to modern bioidentical therapy.
Risks associated with CEE + Provera cannot be extrapolated to estradiol + micronized progesterone, because they act differently on estrogen and progesterone receptors and have different metabolic and vascular effects.
The breast cancer signal came from the synthetic progestin - not estrogen.
WHI follow-up showed no increase in breast cancer with estrogen alone, and in fact estradiol-only users had lower breast cancer incidence.
The elevated risk was tied specifically to Provera, not to bioidentical progesterone and not to estrogen.
The population was older, high-risk, and decades past menopause.
The average age was 63, with many participants in their late 60s and 70s!
Many had pre-existing heart disease, hypertension, obesity, and metabolic disease.
They studied women initiating hormones for the first time at an older age.
Starting estrogen many decades after menopause, in women with established vascular disease, confers different risks, and does not reflect how HRT is generally used.
This “late start” is part of what drove cardiovascular risks in the study
The trial was stopped early, but the context of why was never communicated clearly.
The abrupt halt amplified fear without explaining that risks were small, specific to certain subgroups, and tied to outdated hormone formulations.
Follow-up analyses have since reversed many original conclusions.
Later publications consistently show that:
Estradiol is cardioprotective when started earlier in menopause.
Micronized progesterone does not increase breast cancer risk like Provera did.
The risks widely publicized in 2002 do not apply to physiologic bioidentical HRT.
Recent Updates:
FDA Removal of the Black-Box Warning
In 2025, the FDA removed the long-standing black-box warning that had suggested HRT broadly increased cardiovascular risk and breast cancer risk. This landmark decision was likely driven by a reevaluation and a clearer understanding of the WHI trial along with accumulating evidence that suggests physiologic hormones behave very differently than premarin and provera.
You can read a full breakdown in our blog:
Hormone Replacement Therapy: FDA Removes Black Box Warning
What Are the Signs That I Might Need HRT?
Symptoms commonly treated with HRT include:
Hot flashes and night sweats
Fatigue or low energy
Mood changes
Sleep disruption
Weight gain or metabolic slowdown
Vaginal dryness or discomfort
Joint pain or stiffness
Brain fog or cognitive slowing
Loss of libido
Dry skin or hair changes
The 10-Year Timing Window
Initiating HRT within 10 years of menopause (or ideally during perimenopause) is associated with the greatest cardiovascular and neurologic benefit. Starting too late (after decades of deficiency) may carry different risks - particularly with non-bioidentical formulations.
Bioidentical vs. Non-Bioidentical HRT: What You Need to Know
17B-Estradiol vs. Premarin (CEE)
This is one of the most important distinctions in all of hormone therapy. Bioidentical estradiol provides meaningful cardiovascular benefits particularly when started early. Conjugated equine estrogens (CEE / Premarin) did not and in some cases increased cardiovascular risk.
Blood Clot / Thrombotic Risk
17B Estradiol: Does NOT increase clot risk.
Conjugated equine estrogens (CEE) doubled the risk of venous thromboembolism (VTE).
Vascular Health
17B Estradiol reduces arterial stiffness (improves vascular compliance).
Conjugated equine estrogens (CEE) does not produce the same benefit.
Atherosclerosis Prevention
In the ELITE Trial, oral estradiol significantly slowed the progression of carotid artery plaque (CIMT).
CEE did not show comparable benefit.
Lipid Effects
Oral estradiol increases LDL catabolism, effectively lowering LDL
CEE lacks these favorable lipid effects
Provera vs. Micronized Progesterone (Bioidentical)
This is the second critical distinction.
Breast Cancer Risk
The increased breast cancer signal in the WHI was tied to Provera (medroxyprogesterone).
Micronized progesterone has not been associated with an increased breast cancer risk in observational studies.
Estradiol alone (in women without a uterus) was associated with lower breast cancer incidence in WHI follow-up.
Kass Precision Medicine does not prescribe Provera or synthetic progestins for routine HRT.
At Kass Precision Medicine, we believe patients deserve clearer differentiation based on physiology and outcomes, not outdated generalizations.
If you really want to nerd out, we Have A PDF with detailed charts outlining risk data between the two types of hormones.
What Are the Benefits of HRT?
Evidence-supported benefits include:
Relief of hot flashes and night sweats
Better sleep
Improved mood stability
Increased libido
Better cognitive function
Prevention of bone loss/osteoporosis
Improved metabolic health and body composition
Reduced risk of cardiovascular disease when initiated early
Better skin quality, hair, and connective tissue support
Reduced risk of long-term genitourinary syndrome of menopause
What Are the Risks of HRT?
While bioidentical hormones have a different safety profile than CEE/Provera, all medications carry potential risks.
Commonly referenced risks include:
Breast tenderness
Breakthrough bleeding (early in therapy)
Rare risk of blood clots (primarily with oral CEEs, not transdermal estradiol)
Possible increased breast cancer risk with Provera (non-bioidentical)
Increased blood clot and stroke risk in older women started on non-bioidenticals more than 10 years post-menopause.
Patients with hormone-receptor-positive cancer should not be on hormone replacement and would increase cancer growth rate and risk.
Risk varies depending on timing, formulation, route, and individual health profile
Bioidentical HRT Delivery Options
Oral Preparations
Estradiol and progesterone can also be delivered orally, while testosterone cannot. . Micronized progesterone is most commonly taken this way and is well-tolerated, standard, and often improves sleep. Oral estradiol can be used strategically.
Benefits:
Familiar and easy-to-use format
Micronized progesterone supports sleep and mood
Oral estradiol may offer additional lipid and cardiovascular benefits in select patients
Convenient alternative for women who do not absorb or tolerate transdermal options
Downsides:
Progesterone may cause next-day grogginess in some women
Not suitable for individuals with certain liver or metabolic conditions
Transdermal Patches (estradiol only)
Transdermal estradiol patches are bioidentical and are commonly a first recommendation. No bio-identical progesterone patch or testosterone patch for women exists.
Benefits:
Widely considered safest thrombotic profile of all estrogens
Provides steady, physiologic hormone levels
Easy, infrequent dosing (1–2 times per week)
Downsides:
Occasional skin irritation or adhesive sensitivity
Patch may loosen with sweat, heat, or friction
Visibility on the skin may bother some women
Creams and Gels
Testosterone, estradiol, and progesterone can all be delivered through transdermal creams or gels applied to the skin.
Benefits:
Flexible dosing with easy titration
Non-invasive and well tolerated
Downsides:
Must be applied daily, which some find inconvenient
Progesterone transdermally does not provide same sleep benefits as oral
Risk of hormone transfer to partners, children, or pets if not fully absorbed
Variable absorption based on skin thickness, hydration, or application technique
Can feel messy or interfere with clothing for some patients
Pellets
Estradiol and testosterone can both be delivered through subcutaneous pellets - tiny cylinders about the size of a grain of rice inserted under the skin and absorbed slowly over 3 - 4 months.
Benefits:
Extremely convenient (no daily dosing)
Provides steady, stable, effective hormone levels
Avoids first-pass liver metabolism
Useful for patients who prefer long-acting therapy or have difficulty with adherence
Particularly useful for women who’ve had a hysterectomy (no concerns about breakthrough bleeding)
Downsides:
Dose cannot be adjusted once inserted
Sometimes temporary hormone “peaks” early in the cycle.
Requires an in-office procedure
Occasional issues like extrusion, localized soreness, or rarely infection
Estrogen pellets can cause spotting in women with a uterus
Testosterone dosing via pellets may be harder to fine-tune, especially in sensitive patients
Non-Bioidentical HRT Options
Used historically and in the WHI trial:
Premarin (CEE)
Provera (medroxyprogesterone acetate)
Rarely used today at KPM, with the exception of certain newer synthetic progestins like drospirenone, which may be useful in select cases for its mild diuretic effect.
