​HRT: The ‘infamous’ 2002 Women’s Health Initiative study and the black box

By Ellie Liverani

In November 2025, the FDA initiated the removal of the “black box” warning from Hormone Replacement Therapy (HRT). The “black box” warning is a FAD safety warning for healthcare providers and patients about a drug with serious, life-threatening risks, such as cancer, suicide, and/or cardiovascular diseaseAs.

HRT will be “just like another drug.” Is it good news or bad news? So far, it is just news.

Is HRT dangerous? Or is it the miracle drug that has been underutilized?

Estrogen levels in women vary with age (and in men, too, by the way). They peak in your 20s, and then they start declining after 40 until menopause, where they settle at a low level. When estrogen drops, a series of health issues start to surface. Joint and muscle pain, decreased bone density and increased risk of cardiovascular disease are just a few examples. Some are just annoying, like hot flashes. Others are life-threatening, like strokes. And most are in between, like bone loss. It is a challenging time, not only physically but also emotionally, because post-menopausal women are perceived differently in our society.

Since the low levels of estrogen seem to be the “problem,” what if we reintroduce estrogen? In the 1920s, chemists started to isolate estrogen to answer this question, and it was in the 1930s that they were able to isolate estrogen from pregnant women. It was then produced and sold as Emmarin. It was expensive, and in time it was replaced by other better drugs/formulations. In the 1940s and 1950s, estrogen therapy became more and more popular. This popularity came from books and articles, more than from science. In the 60s, a book called “Feminine Forever” — funnily enough, a book written by a man — boosted drug sales. It was positive that women not only found relief from their symptoms, but they also felt “feminine again”.

Once women started to assume estrogen therapy on a large scale, complications and side effects were reported, such as an increase in cervical cancer and cardiovascular diseases. In the 80s, progestin (progesterone) was added in combination with estrogen in women who had not had a hysterectomy. However, the sales still decreased, and estrogen therapy started to lose popularity.

A large clinical trial was funded only in 1992, one of the largest to this day. It was a study led by cardiologists, so the data collected has particular attention to cardiovascular diseases. There was an increase in cancer and CVD in women using estrogen therapy, but overall, the data were inconclusive. It is very hard to understand everything from just one study.

Still, this ” infamous” study caused a significant decrease in the prescription of estrogen therapy. And the skepticism for HRT has continued to this day.

It is really not surprising that estrogen therapy is not that easy.

First, despite how similar the “re-introduced“ estrogen is to the “naturally” produced one, externally-administered estrogen becomes a drug, so we need the right dose, the right time and method of administration. This needs to be personalized. In addition, like every drug, it comes with side effects, and it does not solve everyone’s problems. In fact, sometimes it can even make it worse.

Moreover, there are a few extra challenges with hormones. They are not isolated molecules; they work together in the body, so changing one (even in small amounts) may unbalance the whole body. That is why they added progesterone later on. They vary with age, weight, lifestyle or when other diseases are present. If we change our diet or our weight fluctuates, and we will have different hormonal productions. Even where we live changes our hormones.

The 2002 “infamous” study is one of the largest to this day. Despite women being more than 50% of the population, we still know very little about menopause and estrogen.

What about studies done in the following 24 years?

There were several studies and we now have two HRT options available. One is estrogen therapy and the other is combination therapy (estrogen and progesterone). There are different ways of administration, such as locally or systemically, taking a pill, administering a gel and so on. The right therapy strategy needs to be discussed with your doctor based on your age, overall health and health history. They are safer (as safe as a drug can be). However, there is still the possibility of increased risk of cancer and cardiovascular diseases. We are closer to a personalized strategy, but we need more science.

Even if HRT nowadays is not as “deadly” and the black box will be removed, it is still a drug. It has to be tailored to your age, your health history and your current overall health. Only a doctor can help you. Periodical check-ins are also mandatory, as you can still have unexpected complications.

It is very important to listen to the media and to read books and articles, but ultimately, they cannot be a substitute for your doctors and science. Let’s remember that menopause and aging in women have a sociological component that needs some extra attention that a pill alone cannot provide. We need a new way for aging women to still feel feminine or to identify a “femininity” unrelated to estrogen levels.