When it comes to Hormone Replacement Therapy (HRT), aka Menopause Hormone Therapy (MHT), timing is everything.  With the onset of menopause, when you’ve lost most of the estradiol and progesterone production by your ovaries, system-wide changes occur that are progressive and detrimental to your long-term health.  Starting hormones early in menopause (or even during perimenopause) can slow many of these deleterious changes in your bones, brain, blood vessels, muscles, and pelvic floor.  

Unfortunately, because of misinformation and misinterpretation of data from the Women’s Health Initiative in 2002, many women missed that critical window to begin hormone therapy.  What are you to do if you are more than ten years from menopause onset, never started hormone therapy, but are now interested in slowing the hands of time with HRT?  Is it too late?  What are the risks?  What are the benefits?  

We owe you an apology… 

First, I’ll start by acknowledging that I HATE that so many women missed that critical ten-year window after menopause onset to start HRT and see the biggest gains.  It’s unfair.  It’s sad.  It makes me want to scream that so many women had the option of taking hormones stolen from them.  I am so sorry we (doctors) took that opportunity away from you. 

My mother was part of this group.  She was on HRT after a hysterectomy but then was taken off hormones in 2002 when the Women’s Health Initiative (WHI) scared the pants off of so many women and their doctors.  She went more than ten years without hormones until 2013 when I started learning about their benefits and put her back on estradiol and progesterone.  I did this knowing that she wouldn’t get the FULL benefits of HRT because she’d been without hormones for so long, but I felt that in her case, the benefits of getting back on HRT outweighed the risks/costs.  

You are not my mom.  Your mom is not my mom.  Everyone is different, so you must discuss this with your doctor.  I’m not giving you medical advice.  

But, I also understand that this is such a complex topic and few people understand it very well, so I’m going to share with you how I think about using HRT in “Late-Starters” – ie, women who are more than ten years from menopause onset who haven’t taken hormones.  

Are Hormones Safe in Late Starters?

If we take guidance from NAMS (North American Menopause Society), then we’d be very nervous about giving HRT to these Late Starters.  They don’t say you CAN’T do it, but they do say, “Initiation of hormone therapy in women aged older than 60 years or more than 10 years from menopause onset has complex risks and requires careful consideration”

Why do they say this?  

NAMS and many other menopause and endocrine organizations do not generally differentiate between bioidentical/body-identical and non-body-identical hormones (aka “synthetic”).  They lump all estrogens into one category, whether or not they are chemically identical to what your body makes.  Same with progestogens.  This is common among researchers as well.  But that’s a bit like saying that all fruits or vegetables are the same. 

Bio/body-identical vs … Not-so-much

Let’s take a real-world example.  Premarin is a type of estrogen made from pregnant mare’s urine. It is composed of 15% estradiol and 85% other estrogens.  It is not identical to what your body makes unless you are a pregnant mare.  The generic name for Premarin is Conjugated Equine Estrogen (CEE).  Most of the HRT studies that have been done in the last 70 years used CEE as the estrogen.  However, CEE does not act the same in your body as estradiol, which is the primary estrogen that you make, and it’s the primary estrogen that is lost during menopause.  

This happens with progestogens, too.  Synthetic progestins, such as medroxyprogesterone acetate (MPA) are very different from your body’s progesterone.  Yet, most HRT studies used MPA.  We now know that MPA is much more inflammatory than actual progesterone and that some of the side effects associated with HRT in the Women’s Health Initiative were because they used MPA instead of progesterone.  

Okay, so now you understand a piece of the puzzle. When you or your doctor are reading a review article or position statement about HRT, you’re likely reading information from a compilation of studies that did NOT differentiate between body-identical hormones and non-body-identical hormones.  If I consider apples to be the same as bananas, then I might say, “eating fruit spikes your blood sugar too much and is bad for you.” – but if that’s only true for bananas, not for apples, then I’ve done you a disservice by lumping them together.  

So, back to the question…. Is it safe to start HRT if it’s been more than ten years since menopause? 

In the Women’s Health Initiative they saw a slight increase in the risk of heart attacks and strokes during the first 1-2 years of treatment in women who were more than 10 years from menopause when they started Premarin and MPA, the non-body-identical versions of estrogen and progesterone.

Why?  Because these women’s arteries had spent ten years without estradiol, which means they’d spent ten years developing plaque.  

Estradiol is protective against plaque (atherosclerosis) formation in the blood vessels, so when estradiol levels drop at menopause, that plaque starts accumulating faster than before menopause. The longer this goes on, the more plaque develops.  This is why women tend to have heart attacks later than men- they’ve been protected by estradiol until menopause, but then they lose that protection, and their rate of heart attacks accelerates to be more like that of men. 

So, suppose you went through menopause at age 50, and now you are 62 years old. In that case, you’ve had twelve years to develop endothelial dysfunction (the cells that line the blood vessel walls are dysfunctional) and atherosclerotic plaque.  Of course, if you have maintained a healthy lifestyle and have good genetics, you may have less plaque than other women your age. Still, you probably at least have endothelial dysfunction since that happens pretty early in the process.  

In the WHI, they gave Premarin (CEE) and MPA to women, and they noticed that women who were more than ten years from menopause onset had a (slightly) higher risk of developing heart attacks and strokes in the first two years after starting HRT.  

Roto-rooter vs gentle massage: 

Premarin is made of 15% estradiol and 85% other estrogens.  Those other estrogens are potent activators of an enzyme called MMP-9, which can make plaque unstable (Lewandowdki, 2006).  MMP-9 goes into the blood vessels and shakes up the plaque. 

Think:  Roto-rooter plowing through your plaque-filled arteries, and some of that plaque is dislodged, causing clots (thrombosis), which can lead to heart attacks and strokes in a small percentage of women during the first two years.   

Medroxyprogesterone acetate (MPA), the synthetic progesterone they used in the WHI, is also known to be inflammatory, which certainly didn’t help matters.  

Interestingly, the risk of heart disease DECREASED in these women in subsequent years.  And, just so you understand what that risk was, the rate of stroke went from 21 women in the placebo group to 29 women in the HRT group per 10,000 person-years. The rate of coronary heart disease went from 30 women (placebo) to 37 women (HRT) per 10,000 person-years.  So, we’re talking about VERY small numbers of women and a minimal increased absolute risk.  

Estradiol and progesterone in the blood vessels: 

Estradiol, the body-identical form of estrogen, has ten times less MMP-9 activation than Premarin.  So it doesn’t cause plaque rupture, but it can reduce plaque formation.  Think: Giving your blood vessel walls a gentle massage that helps prevent plaque from developing but doesn’t chip off chunks of it if you already have plaque.  

Several studies gave oral estradiol to older women (more than ten years from menopause onset) and did NOT see increased heart attacks, strokes, or blood clots.  These studies include the DOPS (1999) and  ELITE (2016) studies. 

Other studies gave women with known coronary heart disease and prior heart attacks oral estradiol (ESPIRIT, 2002;  EPAT, 2001; WELL-HART, 2003), and they, too, saw no increased rates of heart attack, stroke, or blood clots.  And, keep in mind, these were women who they KNEW had significant plaque in their arteries.  

When we look at the dementia literature, we see a similar pattern.  In some studies, when they started HRT more than ten years after menopause onset, they saw slightly increased rates of dementia later.  But, as with cardiovascular disease, most of these studies used Premarin and MPA, so we can’t say whether that data applies to body-identical forms of these hormones.   

And progesterone has never been shown to affect plaque or increase the risk of blood clots, heart attacks,  strokes, or dementia.  Progesterone is safe and has very few known long-term side effects.  

TLDR:  If you are a late-starter, bio/body-identical estradiol and progesterone are likely safe options and are not associated with an increased risk of heart attack or stroke, the two things that people worry most about when starting HRT late.   

But does HRT work if started late? 

Okay, so it seems safe enough, but is it helpful to start these hormones if it’s been more than ten years since menopause? 

As in, does it work?

The short answer is that when it comes to the prevention of cardiovascular disease, dementia, and osteoporosis, you really do want to start these things early.  Unfortunately, estrogen loses much of its ability to do good if you’re more than ten years from menopause.  

Early vs late estrogen for heart disease prevention:

We know that starting estrogen therapy within 6-10 years from menopause onset reduces coronary heart disease risk by 30-50%. This is better than any drug on the market.  Early use of oral estrogen has a positive effect on lipids like LDL, HDL, Apo-B, and Lp(a), and it positively affects the way the blood vessels work, making them more able to vasodilate (or open up) to deliver more blood to vital organs.  Also, early use of HRT helps prevent plaque accumulation in your arteries (ELITE, EPAT, PEPI).  

Unfortunately, starting these hormones more than 6-10 years from menopause does not seem to reduce cardiovascular disease risk.  

You must have a healthy endothelium (lining of the blood vessels) for estrogen to work its magic on the blood vessel walls (Hodis, 2022).  In an interesting study by Novella in 2012 they took the uterine arteries from menopausal women and ran experiments on them.  When they added estradiol to the uterine arteries of women < 5 years from menopause onset, they found that the estradiol caused a reduction in inflammatory markers within the blood vessels.  In the group that was 6-10 years from menopause, adding estradiol didn’t do much of anything, good or bad.  But, in the group > 10 years from menopause onset, adding estradiol to the (older, more broken arteries) caused an increase in inflammatory markers.  Ugh.  

Dementia:

The research looking at HRT for dementia is very similar.  Starting estrogen early reduces the incidence of dementia by about 34% and Alzheimer’s dementia by almost 40% (Hogervorst, 2000), but starting it late may not.  

Having said that, there are a couple of dementia studies where they started estrogen therapy in 75-year-old women (Estradiol or Premarin), and they saw significant improvements in verbal IQ and memory within a year (McDonald and Watson, 1952; Kantor, 1973). 

Osteoporosis: 

Regarding bone health, it’s a similar story: Early is better.  When started early, estrogen therapy is the MOST effective intervention for preventing osteoporosis.  Multiple studies have shown us that estrogen therapy (with or without progestogens) reduces the risk of hip fracture by 30-50%.  Given that a hip fracture in an older woman is associated with a 25% risk of dying within a year, this is not something to scoff at!

Nothing else does this – not exercise, supplements, or other medications.  

If you are more than ten years from the onset of menopause, your bones have had ten years to deteriorate.  And, re-building bones that have lost their resilience is much more difficult than preventing that loss of resilience in the first place.  

Does starting estrogen late help the bones at all?  There are some indications that it might.  In one study (JAMA 2001), they took 67 women >75 years of age with mild to moderate frailty and gave them estrogen (CEE).  They found that in as little as nine months, their bone mineral density increased by 4.3% (vs 0.4% in the placebo).  While this is promising, it doesn’t tell us about the fracture rate, which is really important.  

Ultimately, it takes about ten years of being on estrogen (or estrogen + progesterone) to affect your risk of fracture. And, if estrogen is stopped, you’re rate of hip fracture rapidly increases such that within six years, it would be like you’d never taken hormones at all. As Bruce Ettinger, an osteoporosis featured in the book “Estrogen Matters” said, “To provide maximal protection, estrogen treatment may have to be started at the time of menopause and never stopped.”  

Pelvic floor: 

Finally, a discussion about the benefits of hormone therapy wouldn’t be complete without mentioning the pelvic floor.  Estrogen therapy, whether given systemically (as in a pill or patch) or locally (as in low-dose vaginal estrogen), helps keep the pelvic floor healthy.  It not only reduces vaginal dryness and painful sex, it helps prevent urinary tract infections, reduces urinary incontinence, and makes all of your pelvic organs generally happy.  

We have a lot of data that tells us that starting localized vaginal estradiol late still works.  Many urologists in the know will start vaginal estrogen on women in their 60s, 70s, or even 80s, whether they’ve been on hormones before or not.  The pelvic floor doesn’t seem to mind as much as some of the other organs whether you’ve missed a few years of hormones – the vagina and bladder are ecstatic that you’re finally sending some estrogen their way!  

It makes sense then that if you are more than ten years from the onset of menopause and you start systemic estrogen (e.g., transdermal or oral estradiol), you’d see positive changes in your pelvic floor. And, even though this isn’t talked about as much as some of the other organ systems, there’s no doubt that keeping you free of bladder infections and free of painful sex is important for your long-term health and happiness.  However, unlike the other organ systems affected by estrogen, it is possible to give estrogen locally to the pelvic floor, and I recommend ALL women over the age of 50 consider using vaginal estradiol 0.01% several times a week, especially if they’re not taking systemic estrogen.  

Other potential benefits: 

Because there are estrogen receptors all over your body, giving estrogen, even if it’s been more than ten years since menopause, may improve other health areas.  For example, we know that estrogen is important for keeping your skin and joints healthy, so it’s possible you could see improvements in those areas.  Progesterone is great for sleep and anxiety, and that doesn’t change whether it’s started late or early.  Estrogen is helpful for depression symptoms in many women, and it’s unclear if that has to be given early.  Estrogen and testosterone are important for libido and arousal, and many women notice improvements in sexual health even when starting hormones later. 

Finally, estrogen therapy provides several metabolic benefits, including reducing your risk of developing diabetes, keeping your visceral fat down, and keeping lipids at healthy levels.  These benefits may still be seen in Late-Starters.  

Summary: 

It is NOT necessarily too late to start HRT if you’re more than ten years from menopause onset. Still, you will see fewer benefits, especially cardiovascular,  brain, and bone benefits,  than those who started HRT shortly after menopause.  

You may, however, still see other benefits, such as a healthier pelvic floor, firmer skin, less painful joints, lower blood sugar, reduced belly fat, and improved libido.

The risk is minimal if you choose bio/body identical estradiol and progesterone. 

I do NOT recommend Premarin and Provera, especially in this patient population. 

Although I generally prefer oral estradiol for CV disease prevention, in older women, in  “late starters,” I would opt for transdermal estradiol and oral micronized progesterone.

And, I have to warn you, it will be more difficult for you than for younger women to find doctors willing to prescribe these hormones because, although the risks are minimal, the benefits are also fewer than if you’d started early.  

If you’ve made it this far in this article, you understand how complex this question is.  It isn’t as simple as saying, “Yes, you should take hormones” if you have been without them for more than ten years.  But I also don’t think it’s fair to tell you, “too bad, so sad, it’s too late for you,” when these hormones might still have some benefits.  

In the case of my mom, I started her back on estradiol and progesterone at age 62.  She’s now in her mid-70s and is still taking them.  I do not plan ever to take her off these hormones. Are they helping her?  I don’t know for sure.  I can say that when her other doctors took her off hormones for a few months after her hip fracture, she noticed a big difference in her mental acuity, sleep, and urinary symptoms.  For her, taking these hormones every day makes sense.  

It may not make sense for you.  I’d recommend discussing your situation with your physician (or finding someone familiar with the nuances of HRT) to decide the best path forward for you.  

Hopefully, you now better understand the HRT landscape so you’ll feel comfortable weighing your options alongside your physician.