New VA Treatments in the Pipeline

Sometimes we medical people get to hear about medications and treatments before they hit the doctor’s offices and pharmacies. Recently, MiddlesexMD advisor Dr. Michael Krychman interviewed Dr. James Simon, a well-connected expert in women’s sexual health, about new treatments that are under development to treat vulvovaginal atrophy (VA).

If you recall, VA is the thinning and inflammation of your delicate genital tissues, including the vagina, which is caused by loss of estrogen after menopause. As you can imagine (or already know), it causes genital irritation, an increase in minor infections, and uncomfortable—or downright painful—sex.

VA doesn’t go away, and it doesn’t get better by itself—it requires treatment, usually in the form of estrogen, whether taken internally or applied topically. Topical estrogen creams, tablets, and rings can be very effective in treating the effects of VA.

But a few new approaches are also under investigation. They are:

  • DHEA suppositories. DHEA (which, if you must know, stands for dehydroepiandrosterone), is a steroid that, according to Dr. Simon, is “taken up by the vaginal cells themselves, which convert them to testosterone and estradiol.” The estradiol eases symptoms of VA, and the testosterone improves muscular function and makes the vagina and clitoris more sensitive, so it also gives the libido a little boost. None of it is absorbed into the system, so the medication should be safe for women with breast or ovarian cancers. Don’t expect to see this little number on pharma shelves too soon. Dr. Simon advises patience, since the treatment in still in clinical trials and then must be approved by the FDA.
  • Treatment for VA in pill form. Because many women (and their partners) find topical treatments for VA—creams, rings, suppositories—messy, unpleasant, and a sex inhibitor, a new drug that is readily absorbed by the estrogen receptors in the vagina, but not in other places, such as the endometrium, is being tested.
  • Very low-dose estrogen tablet. In an ongoing effort to find the lowest effective dose of estrogen, Novo Nordisk, the manufacturer of Vagifem, recently found that 10 micrograms is effective in treating symptoms of VA. “It seems to work extremely well, even at these extraordinarily low doses,” said Dr. Simon. And even after taking it for a year, he points out, this dosage amounts to just over 1 gram of estrogen, an amount that is probably safe even for breast cancer patients. The disadvantage, warns Dr. Simon, is that, while the medication treats vaginal symptons well, it might not be as effective for the vulva (the external genitalia). In this case, women may still need an estrogen cream for the very important vulvar care.
Since over 40 percent of post-menopausal women experience symptoms of VA, an effective treatment that doesn’t increase our cancer risks would make us—and our partners—very happy. Take heart. “Many companies are dedicated to innovative treatments without rise in systemic hormones,” said Dr. Krychman.

The Stages of Menopause

Last week I wrote about the STRAW guidelines and STRAW + 10, an update based on the review of research done in the 10 years since the original guidelines were published. Because not all of us have reached menopause, defined as one year without menstruating, some of us are interested in what we can learn from the detailed phases!

For context, remember that STRAW draws three large phases: reproductive, menopausal transition, and post-menopausal. The recent review and enhancement of the model outlined four specific stages within that “menopausal transition” that has many of us looking for answers.

During Late Reproductive Years, your ability to have a child is declining. Your menstrual cycles may be shorter and either lighter or heavier. During the first week of your cycle, the follicle-stimulating hormone may rise more than before as your body works to continue reproduction. The length of this stage varies a lot, but it could be as much as nine years.

Perimenopause officially begins with the second stage, Early Menopausal Transition. During this stage, you’ll see more unpredictability in your menstrual cycle—you may even think it’s not predictable at all! And because your body is producing more estrogen but less progesterone, you may see an increase in PMS symptoms like irritability and bloating. This stage can last four years or longer.

Late Menopausal Transition is the second “half” of perimenopause (I put “half” in quote marks because it’s probably shorter than the first stage—a year up to a couple of years). This is when you’re likely to experience the “typical” symptoms associated with menopause: hot flashes, difficulty sleeping, and mood changes. You may not have a period for a couple of months. At this point, the big trend line for hormones is a decline, but both estrogen and progesterone production can vary wildly from day to day.

Finally, you reach Early Postmenopause. Again, this is marked by a full year without a period. If you haven’t already experienced hot flashes and other menopausal symptoms, you may now, or they may be worse for a while. Because estrogen and progesterone levels are very low, this is when other symptoms become apparent, like vaginal dryness or thinning of vaginal tissues.

As I’ve said before, there’s no clear roadmap that’s infallible for every one of us. I understand, though, the desire to understand what’s happening and to try to predict what lies ahead. I have a friend who’s 56 and still, by the STRAW + 10 stage definition, in “late reproductive years”; by the guidelines, she could be 69 before she reaches menopause. Can that be true? My medical equipment doesn’t include a crystal ball!

But not having a precise roadmap doesn’t change my recommendation to all of us: Learn about what lies ahead, whether it happens fast or slow, early or late. Do what you can to compensate for or manage the changes in your body as you’re aware of them, just as you pick up your reading glasses more often when the menus are hard to read. And, because it’s true that as hormones decline, we “use it or lose it,” stay as sexually active as you choose to be. It’s good for your health, it’s good for your relationship, and it’s good for your self-image.

Tracking Menopause: More Detailed Guidelines for Docs

About ten years ago, a group of medical professionals put their heads together to create a set of guidelines that would chart the course of normal menopause in a more systematic way. They came up with a series of three stages that were each divided into several phases that women normally experience during menopause. These were the reproductive stage, which contained three phases; the menopausal transition, which contained two phases; the postmenopausal stage, which contained two phases.

The stages were determined by the changes that normally occur in a woman’s menstrual cycle and by follicle-stimulating hormone (FSH) levels. (Read this MiddlesexMD blog post for more information about FSH.)

Each phase was given a number, from -5 for the early reproductive phase, in which a woman has regular menses but increasing FSH levels, to +2 for late postmenopausal phase, in which menstruation has completely stopped.

This diagnostic system is called the Stages of Reproductive Aging Workshop, or STRAW, and it’s been a widely used tool for further research. But clinicians have also found it useful as a roadmap for normal menopause—to determine where a woman is in the transition and to predict the course ahead.

Physicians felt that some sort of system was important because menopause marks such a significant change in a woman’s health and quality of life. Some of these changes are temporary (sleep disturbances, hot flashes), and others, such as changes in bone density and urogenital symptoms, are permanent. Given the importance of this transition, some guideline that outlines a normal course through menopause might help in making healthcare decisions about issues like contraception and hormone replacement.

“When women have an awareness of their progress during the shifting manifestations of natural aging, it can be very reassuring,” says Dr. Cynthia Steunkel at the University of California, San Diego, for an article in Menopause.

While helpful for “normal” menopause, however, the original STRAW guidelines specifically exclude women who smoke, are obese, engage in strenuous exercise, have had a hysterectomy, have a significant illness, such as AIDS or cancer, or who have chronic menstrual irregularities. It also fails to address possible differences due to ethnicity, age, and lifestyle.

In 2011, ten years after the first conference, the group reconvened to update the guidelines to take into account the significant body of new research that has emerged and to broaden the subgroups of women for whom the guidelines would apply. The updated guidelines that resulted from this latest review of the research is called STRAW + 10.

Specifically, the updated staging system includes new measures of specific hormones and other “biomarkers” that help to determine the stages of menopause. It added three new subphases that further define the late reproductive and postmenopausal stages. And it can be applied to “most women,” regardless of lifestyle and ethnic diversity, although some exceptions still apply for issues like ovarian failure and chronic illness.

Despite all the fancy testing and technology, however, the most dependable indicator of the stage of menopause is, still, a woman’s menstrual cycle. “...The menstrual cycle remains the single best way to estimate where a woman is along the reproductive path,” said Dr. Margery Gass, one of the coauthors of the new criteria and the executive director of the North American Menopause Society.

In fact, all those other tests for biomarkers are considered “supportive,” and because of the expense of testing and the need for additional research, they aren’t normally called for. I don’t recommend testing for FSH or other biomarkers, either. The tests just aren’t helpful enough.

The new STRAW + 10 guidelines fills in some gaps left by the original system and gives us all a clearer roadmap (which I'll detail in another blog post), but since it relies mainly on the menstrual cycle to determine the course of menopause, your best bet, as I said before, is to tune into your body and work to make peace with the changes you’re experiencing. You're not alone! We're here to help.

An Update on Testosterone Therapy

Recently, Dr. Sheryl Kingsberg, chief of behavioral medicine at University Hospitals Case Medical Center, professor in Reproductive Biology and Psychiatry at Case Western Reserve University, and a MiddlesexMD advisor, was interviewed by Dr. Michael Krychman, another MiddlesexMD advisor, for an online feature about the state of testosterone therapy for women.

Since we were able to be a fly on the wall, here’s the takeaway:

Despite a few advances in the research, the general state of affairs surrounding testosterone therapy for women remains fairly untested and inconsistent.

Unlike in Europe, which has approved Proctor & Gamble’s testosterone patch for women, the US Food and Drug Administration has no approved testosterone therapies. Women who receive testosterone therapy in the US get it “off-label,” meaning that either products designed for men are prescribed in small doses for women, or it’s compounded by a pharmacist without regulation or oversight. And that’s the way it’s been done in the US for decades.

In the meantime, research on testosterone products for women proceeds in fits and starts, and there simply hasn’t been a lot of it. Two large efficacy trials of BioSante Pharmaceuticals’ new LibiGel testosterone product found no significant difference between it and a placebo. The company is continuing with five-year safety trials, however, to determine if long-term use causes adverse health effects in women—specifically, cardiovascular disease or breast cancer.

“They’re moving forward with the [safety] trial, so that is hugely exciting,” says Sheryl.

The goal of testosterone treatment is to return a woman’s testosterone to pre-menopausal levels; treatment protocols for clinicians are fairly undefined, although the North American Menopause Society has recently updated its practice guidelines. Most blood tests aren’t sensitive enough to pick up such low levels of testosterone, and there’s no correlation between blood testosterone levels and libido. That means that while blood tests to establish baseline levels can be helpful, a clinician has to rely on observation and the patient’s reported experience.

And determining whether a woman is a good candidate for testosterone therapy also remains something of an art as well as a science.

“Testosterone is an important option for women—but it’s not for every woman,” says Sheryl. “We know that testosterone therapy won’t necessarily be effective in all women, so it’s important not only to measure efficacy and safety, but also to think about other treatment options.

“The first thing a clinician needs to assess is which women would really make use of testosterone replacement, and which women have something else going on,” she adds.

Good candidates are women who have lost their biological drive for sex, which is the classic definition of hypoactive sexual desire disorder: They have no desire, no fantasies, no dreams, no “hunger for sex,” as opposed to women who may have lost interest in sex, but who may have relationship issues or other stressors in their lives.

Because of the dearth of research and treatment protocols, clinicians should monitor their patients who are on testosterone therapy to make sure that it’s both effective and at safe levels, although, as Sheryl points out, the amount of testosterone in most treatments is very low.

And despite the frustrating lack of options and research surrounding testosterone therapy, women who are troubled by low libido shouldn’t be embarrassed about asking for help. “Hypoactive sexual desire disorder is the most common sexual problem across all ages,” says Sheryl. “About 10 percent of women have it, and they deserve to be assessed and treated because sex is important to overall health and quality of life.”

Q: Is my doctor right to keep me off estrogen?

You say your physician is reluctant to prescribe any hormones because you had a pulmonary embolism 10 years ago. After a hysterectomy, you're coping with physical issues reasonably well, but have vaginal dryness and pain with intercourse.

The clotting risks associated with estrogen use are documented to be with oral administration of the hormone. Oral estrogen is metabolized through the liver, which increases a clotting protein and puts women at greater risks for thrombosis or blood clots. Multiple studies suggest that other methods of administering estrogen—vaginal or transdermal applications—do not carry the same risks. I have many patients on non-oral estrogen who have had thrombosis.

As we get older, we have more risks for clotting: inactivity, weight gain, high blood pressure, and so on. We can't eliminate all the risks, but we don't increase that risk through non-oral extrogen—and your vagina is hungry for estrogen!

I'd call your OB/Gyn's attention to the ESTHER study. The conclusion of that study:

Oral but not transdermal estrogen is associated with an increased VTE [Venous Thrombus Embolism] risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and the use of progestogens. [2007;115:840-845]
If your physician is still unwilling to work with you to address this issue, you can look for a certified North American Menopause Society health care provider in your area at their website, menopause.org.

Bioidentical Hormones: Flap? Or No Flap?

Suzanne Somers touts them in her bestselling book, Ageless: The Naked Truth about Bioidentical Hormones. Oprah promotes their use. On the other hand, the Harvard Medical School, the North American Menopause Society, and the Endocrine Society take a more cautionary position toward compounded bioidentical hormones. And I find that many of my patients are just confused.

So what are bioidentical hormones and what’s all the controversy surrounding them?

We’ve written a lot on Middlesexmd.com about the importance of estrogen to vaginal health and sexual function. We’ve also discussed various options for replacing estrogen and enhancing vaginal comfort. And we explored the latest thinking about hormone replacement therapy (HRT).

In a nutshell, estrogen is critical to sexual comfort and function, and that’s the hormone we lose during menopause. Most therapies revolve around replacing estrogen to treat menopausal symptoms.

For many years, Premarin was the estrogen replacement of choice. This is a synthetic estrogen made from the urine of pregnant mares, which, according to the Harvard Women’s Health Watch,  “contains a mix of estrogens (some unique to horses), steroids, and various other substances.”

Bioidentical hormones, on the other hand, are defined by the Endocrine Society as “compounds that have exactly the same chemical and molecular structure as hormones that are produced in the human body.” Bioidentical hormones are usually extracted from plant sources.

Moderation in all things.Pharmaceutical companies manufacture many brands of bioidentical estrogens, such as Vivelle, Elestrin, Divigel, Evamist and one brand of bioidentical progesterone (Prometrium). These are FDA-approved bioidentical hormones. About 95 percent of my patients are on these FDA-approved bioidentical hormones. All hormones, whether they are synthetic or bioidentical, are labeled with the black-box warnings mandated since the massive Women’s Health Initiative study linked slightly higher rates of breast cancer, blood clots, and heart disease to hormone replacement therapy.

So far, so good.

Confusion enters in when bioidentical hormones are custom-compounded by pharmacies. Sometimes there are good reasons for a doctor to prescribe a custom-compounded hormone, if a patient is allergic to some agent in the FDA-approved hormones, for example, or if her dosage can be lower than those produced by pharmaceutical companies.

But hormones made by custom compounders aren’t subject to FDA oversight, nor must they adhere to FDA-approved processes. These custom hormones don’t come with black-box warnings because they don’t fall under the FDA umbrella.

In actual practice, there may not be that much difference between custom hormones and FDA-approved hormones. According to the Harvard Women’s Health Watch, in a 2001 random test of 37 hormone products from 12 compounding pharmacies, almost one-quarter (24 percent) were less potent than prescribed, while 2 percent of FDA-approved products were less potent.

The other problem with custom compounds is cost. Health insurance usually doesn’t cover them, so the regimen gets expensive very quickly.

While custom compounds may be a helpful option for some women, the controversy surrounds the claims about them made by celebrities like Suzanne Somers and even by some clinicians.

In the introduction to her book, Somers writes, “This new approach to health [bioidentical hormone replacement therapy] gives you back your lean body, shining hair, and thick skin, provided you are eating correctly and exercising in moderation. This new medicine allows your brain to work perfectly and offers the greatest defense against cancer, heart attack, and Alzheimer’s disease. Don’t you want that?”

Well, who wouldn’t? But like most claims that sounds too good to be true, so is this one.

The truth is that bioidentical compounds, no matter how “natural and safe” they may sound, are still drugs. There’s no scientific evidence that their effect is any different than synthetic hormones. Also, because hormonal levels vary from day to day, even from hour to hour, attempting to customize hormonal treatments is tricky business. “There’s no stable ‘normal’ value at all for salivary or blood levels of these hormones or levels that correlate with symptoms,” says the Harvard Women’s Health Watch.

The current medical advice is to take the lowest possible dosage of any hormone—synthetic or bioidentical—for the shortest period of time to alleviate menopausal symptoms. There is, unfortunately, no way to turn back the clock—"natural" or otherwise. In the meantime, the hormones that work for a woman can significantly improve her quality of life.

E Is for Estrogen

Estrogen is the queen of hormones. From our brains to our bones to our bottoms, estrogen keeps our systems regulated, lubricated, elastic, and running smoothly. Estrogen doesn’t just trigger sexual development in our breasts, uterus, vagina, and ovaries (although it does that, too), but it also regulates the production of cholesterol in our liver; it affects mood and body temperature from the brain; it protects again loss of bone density; and it keeps our sexual organs responsive and functional.

Estrogen is actually a category—a group composed of three chemically similar hormones. Estrone and estradiol are mostly produced in the ovaries, adrenal glands, and fatty tissue of all female mammals. Estriol is produced by the placenta during pregnancy. These estrogens circulate in the bloodstream and bind to receptors located throughout our bodies.

Not surprisingly, most of those estrogen receptors are located in the vulva, vagina, urethra, and the neck of the bladder, and that's  why we talk about estrogen so much in this blog and at MiddlesexMD. It’s the critical hormone that keeps our sexual apparatus healthy and functional.

Before menopause, a healthy vagina has

  • thick, moist “skin,” or epithelium
  • tissues with many folds (rugations) that allow the vagina to expand and become roomier
  • differentiated layers of cells—superficial and intermediate
  • secretions from the vaginal walls and cervix that help maintain a slightly acidic pH balance
  • an increase in blood flow and lubricating secretions during sexual arousal
  • toned pelvic floor muscles that help to hold our internal organs in place

So, ladies, it’s easy to see that when our estrogen levels drop dramatically during menopause, virtually all of us will experience significant change to our vulvovaginal tissue. The umbrella term for that change is “vulvovaginal atrophy.” Here’s what happens to our genital area when we lose estrogen:

  • the epithelium becomes pale, thin, and more likely to tear
  • the vagina shortens and narrows
  • vaginal walls lose rugations (those folds or pleats) and become smooth
  • cells become less differentiated—there are more intermediate and fewer superficial cells
  • the vagina becomes dry without secretions to maintain a good pH balance or to lubricate during sex
  • the vulva shrinks and pubic hair thins
  • the pelvic floor loses muscle tone, so organs relax and sometimes sag (prolapse)

It’s not a pretty list, but it’s our new, postmenopausal normal. Vaginal atrophy can bring more frequent vaginal and urinary tract infections as well as more painful sex. And since painful sex usually means less sex, both our relationship and our quality of life can suffer.

Fortunately, as we’ve discussed many times in this blog and at the MiddlesexMD website, there are simple and effective ways to ease the effect of estrogen loss. These include using moisturizers and lubricants or topical estrogen products, doing our kegels, and talking to our doctors about vulvovaginal changes.

Losing estrogen and its beneficial effects is inevitable as we grow older, but losing function, sexual or otherwise, isn’t. Sex—and life—can be just as enjoyable. They just take more maintenance now.

Q: Why do I feel premenstrual all the time--at 50?

Breast discomfort, bloating, acne, and cramps are all symptoms associated with perimenopause, I'm afraid. If your periods are irregular but still happening, what's going on is that your ovaries are not quite done producing hormones, but the fine-tuned system of regular ovulation is winding down. Some chaotic and unpredictable hormone shifts result, contributing to the symptoms you're experiencing.

What you describe sounds perfectly normal and will likely continue to some degree until menopause, when most of these symptoms will subside. Menopause is defined as 12 months without a period, and the average age for menopause is 51. It shouldn't be too long a wait!

Q: What does higher libido in perimenopause mean to my future?

Libido is, at best, complicated. Testosterone is the hormone that is linked to libido for women as well as men. After about age 25, our testosterone levels are slowly dropping. It’s estimated that a 50-year-old has about half the testosterone she once had.

I see this phenomenon with increased libido in perimenopause from time to time. Testosterone interacts with other circulating hormones, and it seems to be the relative balance and interaction of these hormones, not the absolute levels of each, that for some women works very favorably during perimenopause. Relatively speaking, testosterone may have some “dominance,” even though the levels are lower than they used to be. Enjoy!

There are some other possible factors: Obese women tend to have slightly higher testosterone levels, and some women have had weight gain in perimenopause. Or, because we’re complicated sexual creatures, it could be the empty nest or something else entirely (for some, the absence of "that bothersome uterus").

In general, women do experience a loss of libido with menopause, but the loss is not uniform across the board. We can hope you are that woman who doesn’t lose interest. In the meantime, seize the moment!

If you’re wondering when you might move from perimenopause to menopause, I’m afraid we can’t accurately predict that timing. We can only say that women, on average, become menopausal about age 50. Ninety percent of women have four to eight years of changed—and changing—menstrual patterns before becoming menopausal. Blood work is accurate in understanding estrogen, progesterone, and FSH levels for the day of the test, but it doesn’t accurately predict anything. Testosterone levels have fewer day-to-day fluctuations, so accurate measures can be made.

Perimenopause is a time to tune into your body, because as you move into menopause, your symptoms will be the best indicator of what’s actually happening.

Q: Is Vagifem safe for me after a thrombectomy?

Vagifem is a vaginal estrogen, applied locally. It is safe for someone with your medical history, posing no risk of thrombosis. Only oral estrogen, which enters the system rather than being applied directly to vaginal tissues, poses some risk of thrombosis or clotting.

You might find an earlier blog post about localized estrogen helpful; in it I described the benefits, forms, and cautions for using vaginal estrogen.