I believe it was Benjamin Franklin who said there are few things certain in this life besides death and taxes. But Ben was a man, so he failed to add menopause to the list. While some of us breeze through it, thrilled not to have to deal with the monthly mess, others are plagued with night sweats, daytime hot flashes, memory lapses, vaginal dryness, and an oh-so disappointing loss of libido. Not to mention a laundry list of mortifying physical changes—losing hair or fat in one place and finding it has shifted in surprising and unattractive ways.

By the late 20th century, estrogen was the top-selling prescription drug in the U.S.

It’s no wonder so many of us race to get relief and restoration in the form of hormone replacement therapy (HRT), which, true to its moniker, is designed to replace the hormones that nature has so cruelly put asunder. It’s estimated that by 2020, 50 million women in the U.S. will have joined the postmenopausal ranks. Once drafted, you have a clear binary choice—take HRT or not. Loads of women choose not to take HRT because of well-documented health risks, but if you decide to relieve your symptoms with HRT, the choices are many and the undisputed facts few.

Still, HRT falls into two very broad medical buckets: HRT formulations produced by pharmaceutical companies (synthetic or bioidentical as pills, patches, creams, suppositories or vaginal rings) and customized bioidentical compounded hormones prepared at pharmacies that specialize in compounding drugs of all kinds. Synthetic hormones have different chemical structures from hormones produced by the body but still provide relief for symptoms; bioidentical hormones, whether compounded at a pharmacy or manufactured by a pharmaceutical company, have the same chemical structure as what your body churned out before your ovaries took a permanent vacation.

The History of Hormones

Image: chrupka/iStock/Getty Images Plus

Before diving into more detail, a bit of HRT history is in order. While sex hormones were discovered in the late 19th century, HRT didn’t come into use until the 1940s. Since then, professionals’ opinions of HRT, and its popularity among women, have waxed and waned. But HRT hit a high point in 1966, when Robert Wilson, MD, a Brooklyn gynecologist, published his best-selling book, Feminine Forever (Pocket Books). He maintained that menopause was an estrogen-deficiency disease that should be treated with HRT to prevent inevitable “decay.”

In those pages, Dr. Wilson promised postmenopausal women that by taking HRT, which in the 1960s was available almost exclusively as synthetics, they could lead healthy, happy and sexually active lives to the end. By the late 20th century, estrogen was the top-selling prescription drug in the U.S., viewed not only as a way to relieve the symptoms of menopause, but as a veritable fountain of youth, staving off heart disease, osteoporosis, even wrinkles. It’s no wonder women lined up.

Then came the findings from the landmark Women’s Health Initiative (WHI) clinical trial in 2002. The large WHI study was designed to evaluate the health effects of HRT (Premarin® and Prempro®) on postmenopausal women. Premarin® was, and is, made with conjugated equine estrogen (that’s right, it comes from the urine of pregnant mares. In fact, that’s where the name comes from (PREgnant MARes’ uriINE). Even though it’s only partially modified and some of the estrogens it contains are stronger than human estrogen, it’s not considered to be fully synthetic. Also studied were the effects of Prempro®, a combination of Premarin® and progestin, a synthetic progesterone. Both Premarin® and Prempro® are currently made by Pfizer.

Bioidentical hormone therapy seemed to promise a safer, healthier alternative.

The upshot of those findings? While Premarin® helped alleviate hot flashes and vaginal dryness and decreased the risk of hip fractures, it didn’t help with all of the health problems it was thought to prevent. In fact, Premarin® and Prempro® were separately linked to a list of dire health problems, including breast cancer, stroke, pulmonary embolism, and dementia.

However, the average age of women enrolled in the WHI was 63.5 years old—more than 10 years after menopause for most women. In recent years, the advice from health professionals has been to stop HRT after two to five years or at the age of 60, whichever came first. But the North American Menopause Society (yes, there is such a thing) says that if you’re under the age of 60 or are within 10 years of menopause and have no specific health reasons to avoid HRT, the benefits of treating of hot flashes and reducing the risk for bone loss and fractures outweigh any risk. On the other hand, if you’re over 60 or 10 to 20 years postmenopausal, continuing HRT may increase your risk for coronary heart disease, stroke, blood clots, and dementia.

Still, the findings about the harmful effects of this specific HRT were so strong that the study was discontinued for the safety of participants, and in the aftermath of publicity about the frightening findings, lots of women tossed their HRT pills in the trash and turned to compounded bioidentical hormone therapy, which promised to be a safer and healthier alternative. With the help of enthusiastic endorsements and self-help books from celebrities like Oprah Winfrey, Kim Cattrall, and Angelina Jolie, bioidenticals have become the preferred choice for at least 2.5 million women.

The Boom in Bioidenticals

The popularity of compounded bioidenticals continues to grow. When asked if she had seen an increase in prescriptions for compounded bioidentical hormone replacement therapy in her 12 years of practice, Ashley Nolan, compounding lab manager at Lamar Plaza Drug Store in Austin, Texas, replied with a resounding, “Absolutely!” And she added that bioidentical progesterone, estrogen and testosterone are the most commonly prescribed compounded hormones in a variety of combinations and dosages.

No one knows if hormone levels or symptoms should be the target of HRT.

Proponents of compounded bioidenticals say a big advantage over hormones produced by pharmaceutical companies is that treatment can be individualized. They point out that HRT from pharmaceutical companies come in a limited number of dosages and combinations. The idea of individualized therapy and customized, compounded hormone therapy based on salivary hormone levels (a commonly used measuring stick) is incredibly appealing. But the levels of hormones in your saliva vary throughout the day and can even vary with what you had for breakfast—hardly a dependable reflection of hormone levels in the blood. And even if saliva hormone levels were accurate, it hardly matters, because no one knows the hormone levels to aim for, and it’s symptoms, not levels, that should be the target of therapy.

Isn’t “Natural” Always Better?

Just because a bioidentical is made from yams or soy, doesn’t mean it’s plucked straight from nature. Image: likephotoman/DepositPhotos

“Natural” is a tricky term. Most of us think of bioidenticals as being “natural” alternatives to synthetic products from “Big Pharma.” The truth? Several bioidentical hormone therapy products are produced by pharmaceutical companies, approved by the FDA and can be prescribed by your doctor. Despite what your hair stylist’s brother’s wife said, no plant exists that naturally produces a bioidentical hormone. While it’s true that bioidenticals used for compounding are derived from plants sources such as soy or wild yam, all bioidentical hormones are derived in a laboratory, not directly harvested from plants and then compounded by your pharmacist.

James Liu, MD, professor and chair of the Departments of Obstetrics and Gynecology and Reproductive Biology at the Case Western Reserve University School of Medicine says there’s a bit of magical thinking to this perspective that yams and soy are better because they’re natural. “Yams and soy do not contain biologically active ingredients, and so must be chemically converted to estradiol, estrone and estriol via a chemical reaction in a bioreactor.” Not so natural after all. The estradiol and estrone made from plant sources are typically purchased by a pharmacy from drug manufacturers or certified wholesalers such as the Professional Compounding Centers of America, a supplier of ingredients used by 3,200 compounding pharmacies in the U.S., for use in compounding. Although some over-the-counter products labeled “wild yam extract” claim that the body will convert it into bioidentical hormones as needed, it’s just not true. While the conversion is done routinely in the laboratory, the human body can’t do the same.

The way yams and soy are used, they’re not so ‘natural’ anymore.

A tad surprised? A lot confused? It’s no wonder. Depending on whom you ask about HRT options you can get astonishingly opposite answers. If you feel like you’ve been playing a game of Jeopardy where there are no right answers, you’re not alone.

When you think about it, one could argue that estrogens from pregnant mares’ urine are natural, but Premarin® is not bioidentical, at least not to human estrogen. The same tricky terminology goes for Cenestin® and Enjuvia®, two FDA-approved prescription hormone therapies, which are made from plant material but are not bioidentical. And it gets trickier still. There are some FDA-approved HRT medications that combine bioidentical estrogen with non-bioidentical progesterone (progestin). If the package insert lists “esterified or conjugated estrogens” or “progestins,” the product is not bioidentical. There are no pharmaceutical products that contain both bioidentical estrogen and bioidentical progesterone.

Another widely held belief is that the body doesn’t recognize synthetic hormones but it will recognize compounded bioidenticals. Appealing thought, but it just ain’t so. Synthetic hormones act differently, yes, but the body’s cells do recognize and use them, and they are effective in relieving symptoms. Thyroid, insulin, and growth hormones are examples of commonly prescribed synthetic hormones that are fully effective. “Synthetic thyroid hormones work similar to thyroid hormones from animal sources, but without the impurities found in the animal products,” says Dr. Liu.

Sussing Out the Safety Issue

It’s pretty clear that one of the main reasons women flock to compounded bioidentical hormones is that we’ve been led to believe they are not just safe, but far safer than hormone preparations produced by pharmaceutical companies. However, the truth is far more complicated than that.

FDA-approved hormone therapies produced by pharmaceutical companies, whether bioidentical or synthetic, have been tested and shown to relieve menopausal symptoms and to reduce the risk of thinning bones (osteoporosis). Compounded bioidentical hormones, on the other hand, have not been tested for safety or effectiveness and are not approved by the FDA. According to a 2017 joint position statement issued by the American Association of Clinical Endocrinologists and the American College of Endocrinology, there is no evidence that compounded hormone therapy products are safer and the potency of these products can vary wildly—either much more or much less of the biologically active hormones than your doctor prescribed. FDA tests revealed—frankly scary—variations in the potency of compounded hormones, making them a Whack-A-Mole target for testing. Additionally, the nearly infinite combinations of ingredients and dosages in compounded bioidenticals would make putting them all to the test a Herculean task, both logistically and financially.

Further complicating things, compounding pharmacies are regulated by state pharmacy boards, not the FDA, and, unlike pharmaceutical companies, they are not required to report side effects of compounded drugs, including hormones. As a result, there is no tracking system, no database of adverse effects to know what, if any, negative effects you should know about. In other words, there are no large controlled clinical trials similar to the WHI one that support claims for better effectiveness or improved safety.

While a compounded product’s potency can vary, depending on how it is compounded, the actual ingredients are the same as what you get in a pill from the pharmacy. “The estradiol that we use in compounding is the same chemical that is used in FDA-approved estrogen preparations,” says A.J. Day, PharmD, RPh, director of clinical services at the Professional Compounding Centers of America. He also says that when you weigh the pros and cons of compounded bioidenticals versus pills or creams from a pharmaceutical company, it’s important to remember that every medication has risks, even FDA approval is no guarantee of safety. That’s why package inserts exist.

What About the Cancer Connection?

The popularity of compounded bioidenticals continues to grow. Image: Enriscapes/Dreamstime Photos

But hold on—there’s something to further muddy the already murky HRT waters: Even though there are no studies on the subject, “survey findings and case reports provide limited, but plausible evidence of increased endometrial cancer risk in women using compounded bioidentical hormone therapy as compared with women using FDA-approved therapies.” This is according to research by JoAnn E Mason MD, DrPH from the Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, and Cynthia A. Stuenkel, MD, Department of Medicine, University of California, San Diego, School of Medicine, La Jolla.

No medications, even FDA-approved ones, are guaranteed to be safe.

If you decide on a bioidentical produced by a pharmaceutical company, you should know that there is only one pharmaceutical bioidentical estrogen in oral pill form (the other bioidenticals are patches, gels, rings, vaginal pills) and only one bioidentical progesterone in oral pill form. And a caution—the only oral bioidentical progesterone produced by a pharmaceutical company contains peanut oil, so it’s off limits for anyone with a peanut allergy. (See sidebar for alternatives.)

All of this is why The Endocrine Society, The North American Menopause Society, and many other medical societies recommend against compounded bioidentical hormone therapy for women who don’t have a medical condition, like an allergy, that prevents them from using an FDA-approved HRT.

Deciding Your Next Move

Bottom line? Assuming similar dosage and purity, compounded bioidenticals don’t appear to be any better than bioidentical HRT from a major drug manufacturer, like a Pfizer or a Wyeth, and could, in fact, be less safe. We just don’t know.

Work with an educated, experienced menopausal practitioner.

It would be great if the answer were black or white, this or that, synthetic or compounded bioidentical, but it’s just not. Talk to your health care provider, ask questions, and get a second opinion. Gather information and do your own research. In the end, there are no absolutes. The decisions to take or not to take HRT and the type to take are up to you and should be decided with your healthcare provider based on your symptoms, your medical history, and your risk factors.

Hormonal “balancing” is best done with an educated, experienced menopausal practitioner (here’s a link to help you find one near you). Your day-to-day and long-term health rely on your doing a deep dive to find what’s best for YOU.

Author’s note: In the interest of full disclosure, I should say that over a 12-year period (way longer than recommended) I used an FDA-approved bioidentical prescription HRT patch, a synthetic estrogen/testosterone combo pill and a compounded estrogen/testosterone cream but stopped it all when I was diagnosed with breast cancer. Now, I take medication to actually lower any circulating estrogen to reduce the risk of breast cancer recurrence. Was my 12 years of different forms of synthetic and bioidentical hormones the cancer trigger? There’s no way to know, and studies don’t exist to either suggest or disprove a connection.

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Densie Webb is a freelance editor and writer, mainly on health and nutrition topics. She has written for a wide range of publications, including The New York Times, Parade Magazine and Berkeley Wellness Letter, and has provided consulting for a number of public relations firms. She has recently added fiction to the mix and is working on completion of her third novel.