What the WHI Got Right—and Wrong—About Hormone Therapy:

A Balanced Look at Estrogen and Progesterone Supplementation

The Women’s Health Initiative (WHI) study, launched in the 1990s, remains one of the most influential—and controversial—studies in women’s health. Its findings caused a seismic shift in how hormone therapy (HRT) is viewed, leading many women and practitioners to abandon estrogen and progesterone supplementation altogether. But was this the right takeaway?

Let’s take a balanced look at what the WHI taught us, what it got wrong, and how newer research on bioidentical hormones—including progesterone—offers a more nuanced, individualized path forward.

The WHI Study: What It Got Right

- Massive sample size (over 160,000 women)

- Highlighted the importance of evaluating cardiovascular risks

- Brought attention to the clotting risks of oral, synthetic HRT

- Showed a need for better-informed consent and risk stratification

- Encouraged more research into personalized hormone care

The WHI Study: What It Got Wrong

- Average participant age was 63—well past menopause, skewing results

- Used synthetic hormones (conjugated equine estrogens and medroxyprogesterone acetate)

- All hormones were administered orally, which increases clotting risk

- Failed to stratify women by health status or time since menopause

- Results were generalized to all women, causing fear and confusion

The Real Takeaway:

Estrogen isn’t inherently safe or unsafe. It depends on:

- Type of hormone used (synthetic vs. bioidentical)

- Method of delivery (oral vs. transdermal)

- Timing of initiation (closer to menopause appears safer)

- Individual risk factors and overall health

This is where newer research—though still not perfect—helps fill in the gaps.

Enter KEEPS and ELITE: Reframing the Narrative

KEEPS (Kronos Early Estrogen Prevention Study)

Purpose:

To assess whether starting hormone therapy (HT) close to the onset of menopause slows the progression of cardiovascular disease in “healthy women”.

Who:

- 727 women

- Ages 42–58

- Within 3 years of their last menstrual period

- All healthy and free of cardiovascular disease

What They Used:

-Low-dose transdermal estradiol (50 mcg/day)

-Oral conjugated equine estrogen (0.45 mg/day)

- Both groups received oral micronized progesterone (Prometrium 200 mg/day for 12 days/month) if they had a uterus

- Placebo control group included

Key Findings:

- No difference in atherosclerosis progression (measured via carotid intima-media thickness)

- Hormone therapy improved hot flashes, mood, sleep, and bone density

- No increase in adverse events like stroke, blood clots, or breast cancer in this healthy population

ELITE (Early versus Late Intervention Trial with Estradiol)

Purpose:

To test the “Timing Hypothesis” — that estrogen therapy has different effects depending on how long it's been since menopause.

Who:

- 643 postmenopausal women

- Divided into two groups:

- Early post-menopause (within 6 years)

- Late post-menopause (10+ years since menopause)

What They Used:

- Oral estradiol (1 mg/day)

- Plus vaginal progesterone gel if they had a uterus

- Placebo group included

Key Findings:

- In the early group, estradiol slowed progression of atherosclerosis

- In the late group, no cardiovascular benefit was observed

- Supports the idea that starting HT early is safer and more effective

Why They Matter:

Both studies countered the fear generated by the WHI by showing that:

- Timing matters—earlier HT is better

- Type and route matter—bioidentical and transdermal hormones are safer

- Healthy women near menopause may benefit from HT with low risk

KEEPS Study – Limitations:

• Short duration (4 years): Not long enough to assess long-term risks like cancer or cardiovascular disease outcomes.

• Healthy participants only: Women were screened to be very healthy, which may not reflect the general population.

• Small sample size compared to WHI: Around 700 women, limiting statistical power to detect rare risks.

• Focused on early menopause only: Doesn’t provide insight for women starting HRT later in life.

ELITE Study – Limitations:

• Also had a smaller sample size (643 participants), which can miss less common risks or benefits.

• Like KEEPS, it included mostly healthy women, so findings may not apply to those with chronic conditions.

• It primarily measured carotid artery thickness as a proxy for heart disease—not actual cardiovascular events.

• Didn’t explore other potential risks like breast cancer, clotting, or cognitive effects in depth.

Overlooked Possibilities in Both:

• Didn’t compare bioidentical vs. synthetic hormones directly.

• Didn’t explore transdermal vs. oral effects on clotting and metabolism in a detailed way.

• No focus on genetic factors, detox pathways, or individual hormone metabolism.

The Gaps in hormone research:

- Very few long-term, large-scale studies using progesterone alone

- Little research on transdermal delivery despite its popularity

- Lack of data on how bioidentical progesterone impacts women with genetic variations or detoxification issues

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What about bioidentical progesterone?

Micronized bioidentical progesterone (like Prometrium) has been studied far less than estrogen, but the available data is promising.

What the Studies Show:

- Better safety profile compared to synthetic progestins

- Lower associated breast cancer risk (e.g., French E3N Cohort)

- Fewer negative effects on mood, lipids, and clotting factors

- Positive effects on sleep, anxiety, and hot flashes, even when used alone

Common Doses Used in Research:

Oral Micronized Progesterone:

- 100–200 mg per night (most commonly 200 mg for symptom support and endometrial protection)

Vaginal Progesterone:

- 45–200 mg per day (primarily used for fertility and endometrial health)

Transdermal Progesterone:

- 20–50 mg per day in clinical use, though not well studied in large trials. Absorption can vary based on formulation.

Why IS Progesterone Always the Afterthought?

Despite its critical role in hormone balance, sleep, mood, fertility, breast health, and even metabolism, progesterone continues to get sidelined in both research and clinical practice.

Much of the medical world still treats it as nothing more than an “estrogen buffer” or something you add in just to protect the uterus—completely ignoring its systemic benefits. And because synthetic progestins were used in major studies like the WHI (and incorrectly labeled as “progesterone”), the true effects of real, bioidentical progesterone were never properly studied or understood.

Add to that the common practice of underdosing it, delivering it in low-absorption formats, and rarely individualizing the approach—and it’s no wonder so many women are left struggling with symptoms that progesterone could help resolve.

It’s time we give progesterone the spotlight it deserves—as a foundational hormone, not a footnote.

Here are some promising studies involving bioidentical progesterone, but it's important to note that they all involve combination therapy with estrogen. While the findings are encouraging, they don’t isolate progesterone’s effects, highlighting the need for more research on progesterone as a stand-alone therapy.

French E3N Cohort Study: This extensive study investigated the association between different hormone replacement therapies (HRT) and breast cancer risk. It found that HRT combining estrogen with synthetic progestins was associated with an increased risk of breast cancer. In contrast, the combination of estrogen with micronized (bioidentical) progesterone did not show this increased risk, suggesting a potentially safer profile for bioidentical progesterone in HRT.

Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: A randomized, placebo-controlled trial that evaluated the effects of estrogen alone and in combination with progestins or micronized progesterone on heart disease risk factors in healthy postmenopausal women. The study found that while estrogen improved HDL cholesterol levels, the addition of micronized progesterone did not negate this benefit, unlike some synthetic progestins. This suggests that bioidentical progesterone may have a more favorable effect on cardiovascular risk factors compared to synthetic alternatives.

REPLENISH Trial: This phase 3 trial assessed the safety and efficacy of a combination capsule containing 17β-estradiol and natural progesterone (TX-001HR) in postmenopausal women with vasomotor symptoms. The study concluded that certain doses of this combination effectively reduced moderate to severe hot flashes and had a favorable endometrial safety profile, indicating potential benefits of bioidentical progesterone in managing menopausal symptoms.

Here are the few—but promising—studies on bioidentical progesterone used on its own. The fact that research in this area is so limited is a serious gap in women’s health. This absolutely needs to change. We know that progesterone influences multiple downstream hormones, including estrogen, and plays a central role in hormonal balance. More focused, high-quality research is not just warranted—it’s essential.

Progesterone for Sleep and Anxiety

Study: Cagnacci et al., 2010 [https://pubmed.ncbi.nlm.nih.gov/20570217/] -(https://pubmed.ncbi.nlm.nih.gov/20570217/)

Population: Healthy postmenopausal women

Intervention: Oral micronized progesterone 300 mg at bedtime

Findings: Women taking progesterone alone experienced significantly improved sleep quality, faster sleep onset, and fewer nighttime awakenings. These effects were attributed to progesterone’s influence on GABA-A receptors, indicating sedative and anxiolytic properties even in the absence of estrogen.

Progesterone for Vasomotor Symptoms

Study:Hitchcock et al., 2012 (The PROMISE Study) -

Population: 133 healthy postmenopausal women experiencing hot flashes

Intervention:Oral micronized progesterone 300 mg daily

Findings: Progesterone alone significantly reduced the frequency and severity of hot flashes and night sweats compared to placebo. The study concluded that oral micronized progesterone may be an effective monotherapy for vasomotor symptoms in postmenopausal women.

Progesterone in Premenstrual Syndrome (PMS)

Research Legacy: Dr. Katharina Dalton’s clinical research and case work in the mid-to-late 20th century

Population: Women with severe PMS symptoms

Intervention: Natural progesterone (often intravaginal or rectal suppositories)

Findings: Her work established the use of bioidentical progesterone for mood swings, irritability, breast tenderness, and fatigue during the luteal phase. Though not large-scale modern RCTs, her data laid the foundation for progesterone use in cycle-related mood disorders.

Summary of Work: [https://pubmed.ncbi.nlm.nih.gov/3897263/](https://pubmed.ncbi.nlm.nih.gov/3897263/)

Progesterone and Bone Health

Emerging Area: Some small studies and mechanistic data suggest progesterone plays a role in bone remodeling by stimulating osteoblast activity. This potential benefit has not been studied extensively in isolation, but researchers are beginning to explore it as part of hormone strategies for bone preservation in women who cannot or choose not to use estrogen.

Emerging Mechanistic Review: [https://pubmed.ncbi.nlm.nih.gov/12860327/](https://pubmed.ncbi.nlm.nih.gov/12860327/)

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In Summary

The WHI study was a turning point, but not the final word. While it rightly raised concerns about synthetic, oral hormone use in older women, it also led to fear-driven decisions and a retreat from hormone therapy altogether.

It’s true that more doctors are now prescribing bioidentical hormones, but the focus is overwhelmingly on estrogen and testosterone, while progesterone is often neglected —under-dosed, poorly delivered (usually orally), and treated as optional rather than foundational.

Even more frustrating is the way BHRT and HRT are being used interchangeably—when they are not the same thing. It’s somewhat forgivable when a layperson confuses the two, but when well-known “influencer” doctors and health figures start parroting this language, it becomes flat-out confusing and dangerous. The term HRT can include any of the following:

- Birth control pills

- Synthetic progestins like Provera

- Conjugated equine estrogens (Premarin)

- Testosterone pellets or patches

- DHEA

- Melatonin

- Thyroid hormone

This kind of conflation creates widespread confusion—much like the long-standing tendency to lump progesterone and progestins together in research and clinical practice. It misleads both patients and practitioners and obscures the need for truly individualized, root-cause-focused care.

On top of that, most hormone protocols are still based on basic blood labs, which barely scratch the surface of what’s happening hormonally. No one’s looking at tissue-level hormone activity, rarely is anyone running a 24-hour urine test (the gold standard), or checking prolactin levels, which can reveal a lot about hidden estrogen burden in tissues. And forget about a comprehensive thyroid panel—most women get a TSH and are told they’re “fine.”

What doctor is actually asking, “Hey, what is your body doing with your estrogen?” Are you pushing it down healthy detox pathways—or shuttling it into inflammatory, estrogen-dominant, even cancer-promoting pathways?

Is anyone checking your methylation status? Your gut health? Are you even pooping regularly, or are you recycling estrogen right back into circulation like it’s on a loop?

Because let’s be honest: if your motility is sluggish, your liver overwhelmed, and your microbiome imbalanced, you’re not detoxing estrogen—you’re marinating in it.

And while we’re at it, show me a doctor who’s testing for xenoestrogens. Seriously—where’s the lab slip for that? We’re swimming in endocrine disruptors from plastics, pesticides, skincare, and receipts, yet no one’s looking at how these compounds might be hijacking hormone receptors or bogging down detox pathways.

There are ways to get a read on this. Specialized labs can test for things like phthalates, BPA, parabens, dioxins, and even glyphosate—but they’re rarely offered, rarely covered, and rarely explained. You won’t find these panels next to your standard blood test or your “normal” TSH. But you better believe they’re influencing how your body uses and clears estrogen—and possibly why your hormones are “off” in the first place.

Have you signed up for my DETOX ESSENTIALS course yet?

The MINI-course is just $25, and the advanced course is open for early bird registration at $225 with code EARLYBIRD.

This is the kind of knowledge your doctor should have—but let’s be real… most don’t have a clue. So if you're tired of waiting for someone else to figure out your healing, it’s time to take the reins yourself. 💪

Your detox pathways aren’t going to fix themselves—let’s get to work.

And IF a woman is getting nutritional advice, many are told to fast, go keto, or restrict calories while recommending anti-metabolic dietary advice that can completely undermine hormone balance and thyroid function.

We’re overdue for a hormone revolution that actually addresses the elephant in the room: the environment, the metabolism, and the missing progesterone.

We can do better. True hormone therapy means more than just handing out estrogen and calling it a day. It means assessing the full picture, honoring the critical role of progesterone and thyroid, and supporting the body with metabolically sound nutrition and targeted, intelligent testing.

Hormone therapy isn’t one-size-fits-all. The safest and most effective results come from personalized care rooted in science, not fear.

"Beloved, I pray that all may go well with you and that you may be in good health, as it goes well with your soul." -3 John 1:2

Kitty Martone, Healthy Gut Girl