The Four Generations of HRT and Their Clinical Track Records

For decades, women have been sold short on hormone replacement therapy (HRT). What should be one of the most powerful tools for preserving mental health, menstrual function, vitality, cognitive health, physical health, and emotional stability has been reduced to a patchwork of low-dose protocols, quick fixes, and symptom management strategies that leave women frustrated, underserved, and miserable.

The problem isn’t just misinformation—it’s the outdated systems of HRT that dominate mainstream and even integrative and functional medicine. In my work, I use a framework I call the Four Generations of HRT. It’s not an academic classification; it’s a clinical map developed from decades of clinical tracking, research, patient care, self-experimentation, and observation of thousands of women taking all forms of HRT.

Each generation reflects a different dosing philosophy, mechanism, and clinical goals. This model clarifies the confusion, allowing women to see where they are on the spectrum—from legacy systems that fail almost immediately, to advanced protocols designed for full restoration and long-term results.

If you are a professional woman in your 40s, 50s, or beyond, this information is crucial. Your career, family, relationships, mental health, and quality of life depend on more than surviving perimenopause and menopause—and they depend on a brain and body powered by adequate estrogen and other hormones.

Let’s walk through these four generations, examine their track records, and my personal experience with each.

Generation 1: Old-School Synthetic – The Legacy Standard

The first generation of HRT is the legacy model set forth by the Menopause Society many women still encounter. This is the classic “old-school” approach: oral estrogens (e.g., conjugated equine estrogens, Premarin), synthetic compounds, or sometimes even contraceptive formulations repurposed as hormone therapy. Dosing is conservative: “lowest dose, shortest time.” The hope is symptom suppression — not restoration.

The philosophy here is simple but deeply flawed: lowest dose, shortest amount of time. Doctors trained in this system prescribe compounds designed not to fully restore hormones, but to suppress the body’s natural production. Women end up in a state of chemical menopause—with circulating estrogen levels so low that they remain starved, even though they are “on hormones.”

These protocols may ease hot flashes or night sweats for a few months, but within 6–9 months, most women are right back where they started, or worse. Frustrated, patients beg for higher estrogen doses, and doctors refuse, citing package insert guidelines and their underlying fear of estrogen, rather than specialized training and clinical outcomes. Too often, antidepressants, sleep aids, and other psychotropic drugs are added to cover symptoms that the hormones themselves should resolve.

For professional women, this is devastating. Imagine trying to lead a team, negotiate deals, manage your relationship, or parent teenagers while stuck in chronic fatigue, malcontent, mood swings, brain fog, and feeling like the “walking dead”. Gen-1 HRT sets women up to fail—and yet shockingly, it’s still taught as the “gold standard” in most medical institutions today, if HRT is taught at all.

This protocol was the first “HRT” I took in my late teens-20s. It is commonplace for physicians to prescribe oral contraception to manage menstrual cycles and the other side effects of estrogen deficiency in reproductive-aged women. In fact, the standard of care for managing horrible menstrual cycles is the cocktail of birth control pills and psychotropic drugs.

Hormonal contraception is not HRT. It is a hormone-like drug that tricks your brain into thinking that you have plenty of estrogen by keeping FSH low, but it also shuts down the ovarian production of estrogen and progesterone, so women cannot mentally or physically benefit from those hormones. This is why this approach is considered “chemical menopause”. From a young age, women are put into menopause, and they suffer the side effects of estrogen deficiency that need to be managed with drugs and treatments.

This is how it all starts for a lot of women. When young women are prescribed hormonal birth control, they don’t realize that they are being robbed of the very hormones their brains and bodies critically require. In fact, most women have never spent a day of their lives with plenty of estrogen because they started oral contraception at a young age and continued with it. This was the case with me. I spent the majority of my life taking oral contraception to “manage” my periods and my moods. If you read the package insert of the pill, you will notice that the side effects listed mimic those of “menopause.”

Very few women benefit from this approach because it keeps women estrogen-starved.

Generation 2: Bioidentical, But Still Underdosed

Second-generation brought a critical advancement and hope to hormone replacement therapy. With the introduction of bioidentical hormones—compounds structurally identical to those produced by the female body—many women and practitioners thought the answer had arrived. Patches, transdermal creams and compounds, sublinguals, sprays, and pellets offered “natural”, better delivery systems than oral synthetics, and for a time, women felt relief.

But the dosing philosophy remained the same: low and slow, with static daily doses that are never optimized. These hormone protocols are designed to keep a woman hormonally deficient. Women’s brains and bodies require more estrogen than what these low-dose protocols provide. As the brain and body adapt to the low dose, women can go back to feeling horrible, as if they weren’t on hormones at all. Many feel worse than when they started, and supplements are layered in to patch over symptoms rather than addressing the core deficiency. This approach can get very expensive and unsustainable.

To make matters worse, many practitioners turned this approach into a business model. Instead of fully restoring depleted hormones to meet the requirements of the female brain and body, they recommend hundreds of dollars in supplements—sometimes dozens of bottles a month—to manage symptoms that adequate estrogen and progesterone would have prevented in the first place.

To be clear: bioidentical is a step forward over synthetic—but not enough when dosing is underpowered. Relief is temporary, and within months, symptoms creep back. As a result, millions of women spend thousands of dollars on “bioidentical HRT” plus supplements, only to remain tired, depressed, and hormonally hungry. Functional medicine, for all its claims of root-cause healing, fails women right here. This HRT approach keeps women estrogen-hungry.

I took this HRT protocol for a few years. The challenges I had were the same as what most women experience from the side effects of hormone deficiency. I remember taking the highest dose this protocol offers, yet it felt like I needed more estrogen. In the beginning, appeared to work well, but my relief was short-lived. When I asked for a higher dose, I was told that I was on the maximum dose and the doctor wasn't "comfortable" increasing my dose, then I was offered another antidepressant.

This HRT protocol is good for those who do not want to restore and maintain a healthy menstrual cycle, but rather as a tool in an arsenal of items to manage the side effects of hormone deficiency they wish to maintain. The benefits of this protocol tend to peter out in about 3-6 months because the dose is too low for sustainable balance.

This protocol is good for women in their 70s-90s, and for young women who are still menstruating, needing a small luteal phase estrogen boost to combat PMS.

Generation 3: Rhythmic, Physiologic Dosing (Compounded)

The third generation was a hormone replacement therapy breakthrough: rhythmic, cycle-mimicking, physiologic dosing, such as the Wiley Protocol and its derivatives, which gained popularity among estrogen-forward practitioners. Instead of static daily dosing, women follow a dosing calendar which physiologically mimics a natural 28-day cycle, with rises and falls of estrogen and progesterone designed to recreate each hormone’s natural female cycle.

For the first time, many women regained a healthy menstrual cycle without PMS, PMDD, or crippling mood swings. Estrogen levels reached higher but only to moderate ranges—providing real relief for about 25% of women who take it. Personally, this protocol saved my life. At a time when my luteal-phase depression was unbearable, it gave me enough estrogen to clear the fog in my head and restore function, even though I had some negative side effects in the luteal phase. It completely got rid of my depression— deep, dark, lifelong depression that I thought was just part of “who I was.”

But this generation has inherent challenges:

• The luteal crash: the sharp decline in estrogen during the luteal phase in the cycle causes mood, energy, and cognitive dips. Women get tearful, depressed, and lethargic.
• Practitioners fail to get estrogen high enough in the follicular phase to allow for a smooth cycle experience.
• Clinical complexity: dosing against the protocol standards must be avoided, flattening the cycles; adherence, compounding quality, and physician training are far from universal.
• Patient variability in absorption, metabolism, and receptor sensitivity exposes flaws.

Some practitioners abandoned this protocol altogether out of frustration and lack of clinical support. Others modified it, creating independent compounding protocols that helped but still fell short of full restoration.

Generation 3 showed us something vital: physiologic rhythmic dosing and women thrive when estrogen is higher. But it wasn’t the final solution. Too many women were still left estrogen-hungry with this protocol.

This protocol allowed me, for the first time in my life, to experience a healthy menstrual cycle and what life was like without depression. But because of the luteal phase problems, I still had symptoms that needed to be managed during the last two weeks of my cycle. It was the best thing I ever experienced, until I discovered a protocol that addressed the clinical pitfalls this one has.

This protocol works well for about 25% of women. We have some patients who have been taking it for over three decades who wouldn’t think to change up their protocol. We no longer start patients on this protocol because of the advancements the 4th-generation HRT offers. 

Generation 4: Advanced Therapeutic Dosing for Full Restoration

Fourth-generation HRT represents the evolution of everything we’ve learned, plus some. It combines the best of rhythmic dosing with adequate, therapeutic hormone levels titrated by both clinical indicators and lab work. The goal is not symptom management—it’s full restoration. It’s what we call “Advanced HRT.”

In practice, this means restoring circulating estrogen to the range where women stop asking for more, and allowing progesterone to work as the supportive and complementary hormone to estrogen when it is taken in the luteal phase. Where negative clinical indicators—depression, anxiety, headaches, mood swings, brain fog, mental illness, weight gain—fall away. This protocol allows women to feel stable, happy, vibrant, and capable every single day.

This is what I call the Hormone Sweet Spot^™. It’s not “high dose” as some low dose prescribing critics claim—it’s adequate dose. Too little or too much produces negative symptoms; just right produces balance, stability, and optimal health.

And the results are undeniable. Women taking fourth-generation HRT protocols report:

• Depression and anxiety disappear
• Consistent energy, no inflammation, and organic motivation
• Emotional resilience and strength, self-reliance, and mood stability
• Increased self-esteem, self-worth, self-confidence, and inner peace
• Mental clarity, creativity, cognitive sharpness, and improved executive function
• Physical restoration: muscle tone, libido, skin, hair, nails, and joint health.
• Long-term benefits: preserved brain health, cardiovascular support, cancer-protection, neuro-protection, and telomere protection.

Unlike previous generations, Gen-4 protocols are clinically effective and sustainable for most generally healthy women. Women remain mentally and physically well for years, not months. Plateaus occur, but instead of decline, they represent a transition into maintenance—the point at which true balance has been achieved.

Generation 4 is not just about rhythm—it’s about adequate, therapeutic, adaptive dosing. The objective: full restoration, not just partial symptom relief.

Key features:

1. Therapeutic Dosing — enough estrogen to saturate key tissues like the brain, not spoon-fed minuscule low doses.
2. Rhythmic Modulation — physiological cycles rather than flat-flush.
3. Active Titration — using both clinical indicators (mood, cognition, energy, sleep, cycle symptoms) and lab biomarkers in near-real time.
4. Sustainable Maintenance — once a sweet spot is reached, the system is designed to plateau, not collapse. Optimal hormone homeostasis.

In my clinical experience, this is the first truly sustainable protocol: few women “outgrow” it; negative clinical indicators stay suppressed; mood, cognition, energy remain stable long term. Women stop “begging for more estrogen.”

I have been on this protocol for nearly 15 years and plan on never getting off of it. This protocol allows me to have control over how my brain works and how my body ages. I can’t imagine my life without hormones again.

Hormone replacement therapy is not for every woman, but it is for most. One of the most important things to understand about hormone therapy is what you want your hormone therapy to do for you. If you know what you want your hormone therapy to do for you, it makes it a lot easier to find a prescriber trained in that area of expertise.

If you are taking HRT now and it stopped working for you, or it’s not working like you think it should, you could be on the wrong HRT system or taking the wrong dose. There is no reason women should ever have to spend one day without enough estrogen. It is the elixir of life.