Tag Archives: estrogen

‘It’s a Gamble:’ St. John’s Wort, Depression and Drug Interactions

In my 20s, I wasn’t much for traditional medicine. For one thing, navigating our labyrinthine health care system seemed like a lot of unnecessary work. For another, I was broke. Plus, I used henna to dye my hair. I wanted something natural.

That meant that when I felt down in the winter and was quick to worry and anxiety, I didn’t go to the doctor. I went to the drug store and got myself a bottle of St. John’s wort (Hypericum perforatum).

By the time I started taking St. John’s wort around 2003, the plant had been used to rid the environment of evil spirits in ancient Greece and medicinally to menstrual cramps, heal wounds, and treat kidney conditions in later centuries. Today, it’s primarily used to treat depression.

What those early practitioners didn’t know and what I didn’t, either, was that St. John’s wort can interact with prescription medicines in ways that can be serious. With everything from hormonal contraception to organ-transplant drugs interacting with the supplement, the more you know about the interactions, the better off you are.

Powerful or Placebo

In 1998, St. John’s wort was the second most popular supplement in the US, according to the nonprofit supplement industry group the American Botanical Council.

That’s when I first heard about it. But what I didn’t know was that, 4 years earlier, passage of the Dietary Supplement Health and Education Act created the category of dietary supplements and prevented the FDA from requiring supplement companies to prove their products were safe, certify levels of active ingredient or produce evidence that they work.

So, I was working with spotty knowledge. I wasn’t the only one.

Research on St. John’s wort was positive early on, but over the years, the findings have been more muddy, said D. Craig Hopp, PhD, deputy director of the Division of Extramural Research, National Center for Complementary and Integrative Health (NCCIH), part of the National Institutes of Health (NIH) . St. John’s wort seems to be associated with a “strong” reduction in depressive symptoms, including lack of interest in once-pleasurable activities, sleep or eating changes, hostility, irritability, and feelings of guilt, worthlessness or helplessness.

“But you get the same response from the placebo,” he said. “It’s not real clear whether it has [any] benefit.”

A 2002 NCCIH-funded study found that neither St. John’s wort nor the antidepressant tested was any more powerful than placebo for major depression. Another study found the same for mild depression.

On the other hand, a 2008 Cochrane review of 29 studies on the herb found that St. John’s wort is as effective as antidepressants in ameliorating mild to moderate depressive symptoms. But there was a catch: In countries where supplements are regulated and prescribed, the results were more positive. Studies conducted in the US had less positive results.

In any case, Hopp added, “St. John’s wort by itself is safe. But when taken in combination with something else, it dramatically influences how well those medicines work.”

Multiple Interactions

That’s because when you’re taking a whole-herb supplement, you aren’t just getting whatever the active ingredient of the herb is — you’re getting everything else that comes with it, too.

It’s unclear what St. John’s wort’s active ingredient is, though researchers have studied 2 components, hyperforin and hypericin. What researchers do know is that St. John’s wort also delivers significant doses of enzymes that help the body break down medications.

Any drug that is broken down by these particular enzymes breaks down a lot faster than it would otherwise. Drugs include the heart medication digoxin, the opioid oxycodone, some HIV medications, cancer drugs like irinotecan, cyclosporine for organ transplants, and the anticoagulant warfarin. That means that the medication exits the body more rapidly.

In the case of HIV medications, that could mean that the virus mutates and develops resistance to the drug so it never works as well again. In the case of heart medicines, it can increase the risk of a cardiac event.

And in the case of organ transplants, it can be fatal.

“Studies have shown that St. John’s wort would clear immunosuppressive medicines 10 times faster,” Hopp said, “That could cause organ rejection and organ failure.”

Plus, because St. John’s wort is unregulated, you don’t know exactly how much active ingredient you’re getting. That limits doctors’ ability to adjust dosages to accommodate St. John’s wort use, said Austin De La Cruz, PharmD, BCPP, a clinical pharmacist who treats mental health disorders. In addition, he teaches psychiatric treatment and over-the-counter medications at the University of Houston College of Pharmacy.

“It is definitely a gamble,” he said. “If you’re taking St. John’s wort with digoxin and switch to a different St. John’s wort brand that has lower amounts of active ingredient, that can lead to significant toxicity with digoxin.”

Birth Control and St. John’s Wort

Notably, since the majority of people reporting depressive symptoms are women, St. John’s wort seems to break down the contraceptive hormone ethinyl estradiol, a component of most estrogen-containing birth control, about twice as fast as when it is taken alone.

“There were also a number of unintended pregnancies because women taking oral birth control were not getting effective doses,” Hopp said of studies on the topic. “This isn’t fatal [the way organ failure is] but it is still a serious adverse event.”

Treating Accurately

For De La Cruz, all of this makes it hard for him to recommend St. John’s wort. He also pointed to a ban on sale of St. John’s wort in France and Ireland, and careful regulation in other countries as evidence of concern.

If people are interested in non-pharmacological approaches to depression, he recommends therapy. Cognitive behavioral therapy has been found to be more effective than antidepressants alone, he said, and carries no risk of side effects.

Then he’ll make sure patients are trying everything that drugs can’t address — like exercise, food and sleep habits — and light therapy lamps if the depression is seasonal.

“It’s important to identify if the depression can be managed by self-care,” De La Cruz said. For instance, a patient may only come in when they feel depressed, but they may also have bouts of mania. Using only St. John’s wort or an antidepressant could exacerbate manic episodes in bipolar disorder.

Besides, he said, 800,000 people die by suicide related to depression every year.

“Depression is a serious illness,” he said. “I have a hard time recommending St. John’s wort.”

NCCIH’s Hopp was less absolute. If you don’t take any of the medications that interact with St. John’s wort, its risk is essentially zero. But because it interacts with so many medications, people should tell their doctors they are taking it.

“It’s not that you can’t take St. John’s wort,” he said. “But it warrants a high level of extra care.”

Need to Know: Birth Control Pills

Though birth control pills, also known as oral contraceptives or “the pill,” are commonly prescribed, understanding all the facts about this medication can help you make informed decisions about the type of birth control you use.

Common Names

Ortho-Cept (desogestrel/ethinyl estradiol), Natazia (estradiol/dienogest), Yasmin (drospirenone/ethinyl estradiol), Beyaz (drospirenone/ethinyl estradiol/levomefolate), Zovia (ethynodiol diacetate and ethinyl estradiol), Seasonale (ethinyl estradiol/levonorgestrel), Ortho Micronor (norethindrone), Loestrin (ethinyl estradiol/norethindrone), Ortho-Cyclen (ethinyl estradiol/norgestimate), Ogestrel (norgestrel/ethinyl estradiol)

How They Work (Method of Action)

Birth control pills release small amounts of a version of the hormones estrogen (estradiol) and progesterone (progestin) that prevent pregnancy in 3 different ways: suppressing ovulation, which is the body’s monthly release of an egg; creating thicker cervical mucus so it’s more difficult for sperm to get into the uterus; and thinning the lining of the uterine wall so that if an egg is fertilized, it’s unlikely it will be able to implant and grow.

Though birth control pills are most often used for contraceptive purposes, their methods of action allow them to be used for other purposes such as relief by women experiencing heavy periods, endometriosis (tissue found inside the uterus grows outside it), acne, painful cramps and polycystic ovarian syndrome (PCOS).

There are 2 types of birth control pills: combination pills, which contain both an estrogen and progestin, and progestin-only pills, also called “mini pills.”

Most combination pills come in 28-day pill packs. The first 3 weeks worth of pills contain active hormones while the final week are placebo pills. If the pills are taken as directed during the first 21 days, a woman should be protected against pregnancy during the placebo week, when she will typically have a lighter than normal period.

Side Effects and What to Do About Them

Birth control pills can have many and varied side effects, but these are less likely to occur with the mini pill. The most common are breast tenderness, migraines, moodiness, weight gain, menstrual changes and nausea. However, these side effects are typically mild and go away after a few months of treatment. If they persist, your physician may switch you to a different medication.

Serious side effects include blood clots, high blood pressure, stroke and heart attack. These effects are more likely in women who smoke; are over 35; have blood-clotting disorders, diabetes or high blood pressure; or who are overweight. Warning signs of more serious problems include chest pain, stomach pain, severe headaches, swelling in the legs, breathing difficulties or blurred vision. Seek medical help right away if you experience any of these.

User Experiences

Leah Ingram, 51, took Demulen in her 20s, but began to suffer from severe migraine headaches after years of taking it. She finally had an episode so bad that she lost vision in one eye and thought she was having a stroke. “My husband took me to the ER, where the doctor said what I had experienced was a pre-migraine aura. I was referred to a neurologist after that and told immediately to stop taking birth control pills,” Ingram says. “About a month after I stopped taking the pill, I had one last bad migraine and then never had one again.”

J. Scheel, 37, started on Ortho Tri-Cyclen at age 15 for dysmenorrhea (severe cramps). She experienced weight gain and her periods stopped completely. When she was 21, her cramps came back, so she switched to Depo-Provera, an injection. At 32, her doctor put her on Jolessa, another pill, but it didn’t help her dysmenorrhea at all, so after about a year, she switched back to Depo-Provera.

Michelle Decker, 41, has been on Zovia/Kelnor since she was 20, with a break to have her child. Though she has experienced side effects such as severe headaches and a one-day period, she says the headaches aren’t bad enough to warrant a switch. Her headaches, which have always started the day before her period and lasted a few days, vary in severity; sometimes she can ignore them and sometimes they require popping pain relievers all day. She says they seemed to be worse when she was on the name-brand version, Zovia.

Drug Interactions

Certain drugs, particularly antibiotics and anti-seizure medications, may decrease the pill’s effectiveness. Some HIV medications, herbal remedies and anti-fungal medications may also be problematic. Be sure to let your doctor know about any medications, whether prescribed or over-the-counter, supplements or herbs you’re taking.

Effectiveness and Considerations

Because of the variation in the amounts of hormones they contain, it can take trying a few different types of pills before finding one that causes the least troublesome side effects. Birth control pills work best if they are taken at the same time each day. In general, 5 to 9 women in 100 using birth control pills become pregnant each year. When the pill is taken at the same time every day, 2 to 3 women out of 100 will get pregnant. The mini pill is slightly less effective than the combination pill.

If you miss a pill, take it as soon as you remember and be sure to use a backup contraceptive method until you finish your pack. In the case of the mini pill, if you don’t take it within 3 hours of your normal time, you will need to use a backup method for 48 hours.

Vomiting and diarrhea can lessen the effectiveness of the pill, so if you get sick, be sure to have another contraceptive method such as condoms or spermicide available.

Birth control pills do not protect against sexually transmitted infections (STIs).

Alternatives to Birth Control Pills

There are many alternatives for contraception, including barrier methods such as condoms, spermicide, sponges or diaphragms; IUDs (intrauterine devices); a progestin shot called Depo-Provera that is given every 3 months; the birth control patch, known as Ortho Evra, that gets changed every week; the vaginal ring and fertility awareness methods.

The Tricky Chemistry of Gender Transitioning

Laura Arrowsmith knows what it’s like to go through gender transitioning. She struggled to find a provider willing to prescribe the hormone therapy that would allow her body to reflect the woman she knew herself to be.

Medical transition care — that is, the prescribing and managing of feminizing or masculinizing hormones for people whose perceived gender differs from the sex assigned to them at birth — has been prescribed for decades. But only now are physicians beginning to offer the treatment more readily, said Arrowsmith, herself a DO (doctor of osteopathic medicine) who runs a transgender care clinic in Oklahoma City.

“I have patients who travel from all over Oklahoma, Texas and Arkansas,” said Dr. Arrowsmith, who has been a physician for 38 years. “The medications we use have been prescribed for years and years and years. Even though the treatment is for off-label use, it’s still highly effective and relatively safe.”

Clear, comprehensive guidelines are available from the World Professional Association for Transgender Health (WPATH) and academic institutions, such as the University of California, San Francisco’s Center for Excellence in Transgender Care.

And while the topic of hormone therapy for transition care is understudied — there is little data on the long-term impact of hormone use — managing transition care for transgender patients is fulfilling, said Dr. Ray Martins, senior director of clinical education and training for Whitman-Walker Health, a Washington, DC-based center for lesbian, gay, bisexual and transgender patients.

“Out of everything we do in medicine, [caring for transgender patients] may be my favorite thing,” he said. “It’s not that often that you get to take care of someone and help them become who they really are.”

Sharing Treatment Decisions

By the time Arthur Douglas*, 17, decided to begin medical transition last year, he’d been in talk therapy for months, had discussed the topic with his pediatrician and his parents, and done his own research.

“It does take a while,” he said. “There’s a lot of counseling involved, a lot of talking through what you want. It’s not like plastic surgery: ‘What do you want?’ It’s, ‘What do you expect from your life? What would make it easier for you to live?’ Because it’s like, ‘What care do you need to survive?’”

So it’s important to share decision making, said Martins.

“With this more than any other medical decision, I give them the information as an expert, but I never say, ‘We’re going to do this,’” he said. “Go through the potential benefits and the issues.”

A Hormone How-To

Arrowsmith starts a consultation by asking what the patient’s goal is. Not all transgender people need hormone therapy. Some need hormone therapy but not gender-affirming surgery. Others require all of that to feel whole.

Arrowsmith follows WPATH’s standard of care, which calls for a letter from a therapist before beginning hormone therapy, confirming that it is medically necessary.

Then the discussion of hormones begins.

“Out of everything we do in medicine, [caring for transgender patients] may be my favorite thing. It’s not that often that you get to take care of someone and help them become who they really are.” — Dr. Ray Martins, senior director, Whitman-Walker Health.

For people transitioning to female, the most common medication prescribed is spironolactone, which blocks the production of testosterone, and the hormone estrogen in the form of estradiol. Often patients take one tablet of estradiol twice a day, but sometimes injections, skin patches or gels are indicated.

For patients transitioning to male, doses of testosterone are administered to induce secondary male sex characteristics.

And then there are gender-fluid or non-binary patients who don’t desire to transition gender, but instead want a more androgynous appearance. For them, Arrowsmith will prescribe very small doses of testosterone to those assigned female at birth, or an androgen blocker like spironolactone to those assigned male.

Similarly, physicians can medically delay puberty in pre-teen transgender children using Luprin, a reversible gonadotropin releasing hormone (GnRH) analog. Luprin’s generic name is leuprorelin or histrelin. Then, if indicated, physicians can induce gender-appropriate puberty using standards of care.

Watching for Side Effects

Then the monitoring begins.

“It’s basically well-patient care for the most part,” said Arrowsmith. “Most patients are young and healthy.”

For those using estrogen, that means, primarily, an increase in the risk of blood clots and a risk of hyperkalemia, which can lead to cardiac problems and arrhythmias, from spironolactone. Potassium levels can be monitored in regular blood tests, and, if necessary, spironolactone doses can be lowered to see if that normalizes potassium levels. Arrowsmith said she hasn’t seen that happen, however.

Feminizing hormones are associated with gallstones, and may be associated with increased risk of breast cancer and heart disease, though those last two are speculative for now.

She regularly checks patients for leg pain as a sign of deep vein thrombosis, or shortness of breath from a pulmonary embolism.

Because of the blood clot risk, cigarette smoking is “a big no-no,” Arrowsmith said. She asks people to quit smoking immediately, and if they haven’t quit by six months, she stops seeing them.

“Hormones are a big motivation,” she said. “Most are so desperate to get this medical care that they will do it.”

There is also a remote risk of prolactinoma, a benign tumor of the pituitary gland. At every visit, Arrowsmith checks patients for breast discharge and for vision problems, also a symptom of prolactinoma. If a patient begins to lactate, she sends her for an MRI of the pituitary.

Testosterone, usually administered as an injection every two weeks, is associated with increased blood production, which can be treated by the patient becoming a blood donor or by decreasing the dose of testosterone, Arrowsmith said.

Also associated with testosterone are increases in cholesterol. People on testosterone also should not take the blood thinner warfarin, as there’s some evidence that it increases warfarin’s blood thinning capability. Martins switches patients to other blood thinners.

For people who are diabetic, there’s some evidence that testosterone can lower blood sugar, so Martins monitors for effectiveness of diabetes medications, and potentially adjusts doses, especially directly after testosterone injection, when hormone levels are especially high.

For people taking testosterone with preexisting mental health conditions such as bipolar disorder, additional mental health care may be important. In some cases, mental health conditions can be exacerbated by hormone therapy, said Martins.

Fertility Effects

And while medical transition therapy is associated with decreased fertility, it doesn’t always completely eliminate it. So, transgender men with intact uteruses should consider a copper IUD (intrauterine device) to prevent pregnancy if they continue to have vaginal sex, said Martins. Hormonal contraceptives are ineffective in people taking testosterone.

Some patients want to maintain their fertility by banking sperm or harvesting eggs before they begin transition care. Arrowsmith said that transgender men are often still capable of becoming pregnant if they are willing to discontinue hormone therapy for the duration of their pregnancies.

Another Side Effect: Unhappiness

Given this litany of side effects, it might seem counterintuitive to provide transition care to healthy patients. But hormone therapy isn’t like other well-person care, Arrowsmith said. A report from the Williams Institute at UCLA School of Law found that about 60% of patients refused hormone therapy attempted suicide.

“It becomes somewhat life or death,” said Arrowsmith. “It becomes very, very desperate. I can speak on a personal level about that.”

If depression and anxiety are side effects of not receiving care, the opposite may also be true. For 17-year-old Arthur, the only side effect he’s had is acne. But he’ll take acne, hair loss, a big gut, heart disease — any of the side effects described in the several-page-long disclosure form he signed when he began therapy — to live in the world as himself.

“Transition care isn’t cosmetic,” he said. “It changes your life. You can look like a perfectly biologically healthy person, but that isn’t the case mentally. If you aren’t trans, it can be hard to understand the deep, misplaced feeling you get from being trans but not able to transition. It’s like a void that can’t be described. The loss is unfathomable… The fact that now others see me—and I see myself—and I never think, ‘Girl,’ that’s really the biggest thing.”

* Not his real name

Birth Control Pills Linked to Higher Risk of Developing Depression

Women who take hormonal oral contraceptive birth control pills are at an elevated risk of being diagnosed with depression and prescribed an antidepressant, according to one of the largest studies to date examining the link.

The most popular birth control pills in the U.S. combine two hormones, usually estrogen and a progestin. Researchers in Denmark found that women who took a combination birth control pill were 23% more likely to be given an antidepressant while on the pill compared to women not on birth control. And women who took progestin-only pills were 35% more likely to end up taking an antidepressant.

The findings, published in JAMA Psychiatry, are based on the medical records of over 1 million women between the ages of 15 and 34 years old who were tracked over 10 years. None of the women included in the study had a history of significant mental health illnesses.

A higher risk of depression with birth control pills was also associated with younger age. Adolescent girls on the combination pill were 80% more likely to be given antidepressants than those the same age not on any oral contraceptive.

The researchers also found that other types of hormonal contraceptives, such as implants, patches and IUDs (intrauterine devices), were also linked to higher rates of depression.

As to why the hormone-based birth control pills may cause depression, prior research has implicated changing levels of the female sex hormones estrogen and progesterone. Some studies have even argued raising progesterone levels can lower mood.

Quick Hits: Hormone Replacement Therapy Cancer Risk, Metformin and Weight Loss, & More

Hormone replacement therapy (HRT), which is used to treat the symptoms of menopause, may increase breast cancer risk dramatically. A new study that followed more than 100,000 women over 40 years found that women who took HRT (an estrogen and progestin pill) for about 5 years were nearly 3 times more likely to develop breast cancer compared to those who were just taking an estrogen pill, or nothing at all. And the longer a woman was on HRT, the higher the cancer risk became, according to data published in the British Journal of Cancer. For example, the breast cancer risk was 3.3 times higher for women on HRT for 15 years. While about 14 in 1,000 women in their 50s are expected to develop breast cancer, the rate is 34 in 1,000 for women on HRT, the study argues. Posted August 22, 2016. Via The Telegraph.

A common diabetes drug may help to reduce weight gain that results from atypical antipsychotic use in children with autism. The atypical antipsychotics Risperdal (risperidone) and Abilify (aripiprazole) are approved by the FDA to treat irritability in children with autism. A research team enrolled 60 children and adolescents between the ages of 6 and 17 with autism. Children were also taking an atypical antipsychotic for at least a month and experienced at least a 7% increase in body mass index (BMI) since starting the medication. The children were then randomized to receive either placebo or metformin. Those on the placebo saw no change in the BMI, while those on metformin experienced a statistically significant change, the researchers reported in JAMA Psychiatry. Posted August 24, 2016. Via JAMA Psychiatry.

The severity of side effects from breast cancer hormone treatments may be influenced by whether a patient expects side effects to occur. A new study examined 111 women who had undergone surgery for breast cancer and were about to start hormone therapy with tamoxifen or aromatase inhibitors. At that point, the women were asked about their expectations of side effects. They were then asked again after 3 months and 2 years of treatment. At the beginning, 8% expected no side effects, 63% expected mild side effects and 29% said moderate to severe effects. The results, published in Annals of Oncology, showed that women who expected side effects to be bad had nearly twice as many side effects after 2 years than women who expected no side effects or mild ones. In addition, the women who expected severe side effects tended to have lower quality of life during treatment. Posted August 24, 2016. Via Medical News Today.

Newer Breast Cancer Meds Have Serious Cardiovascular Risks

While the chemotherapy drug tamoxifen has long been associated with a risk of fatal cardiovascular events, a recent study shows that a newer class of breast cancer drugs has the same level of risk. However, aromatase inhibitors also have an increased risk of less severe cardiovascular complications compared to tamoxifen.

The three aromatase inhibitors on the market are anastrazole (Armidex), exemestane (Aromasin) and letrozole (Femara).

In older breast cancer survivors, cardiovascular disease is a leading cause of death. Prior research had already associated tamoxifen with an increased risk of fatal cardiovascular events, such as heart attack and stroke. But the new study is one of the first to demonstrate that aromatase inhibitors, though newer, have a similar risk profile in this area.

And it also found that women with breast cancer who had taken either aromatase inhibitors alone or after tamoxifen treatment had between a 26% and 29% higher risk of less serious cardiovascular events, such as irregular heart beat and swelling and irritation of a membrane surrounding the heart, compared to women who had only taken tamoxifen. The new research was published in JAMA Oncology.

“Our study is a comprehensive assessment of the impact aromatase inhibitors have on cardiovascular risk and provides reassurance that the hormone therapy to reduce breast cancer recurrence does not increase risk of the most fatal cardiovascular events,” Reina Haque, PhD, MPH, research scientist, Kaiser Permanente Southern California Department of Research & Evaluation, said in a statement.

“A particular strength of our study is that we accounted for women’s other potential cardiovascular risk factors as well as medication used to treat high blood pressure and high cholesterol,” she added.

Estrogen and progesterone are hormones produced by women that can promote the growth of some breast cancers. Aromatase inhibitors work by blocking the activity of an enzyme called aromatase, which the body uses to make estrogen in the ovaries and in other tissues. Tamoxifen binds to estrogen receptors and interferes with estrogen’s ability to stimulate the growth of breast cancer cells.

Clinical guidelines recommend tamoxifen for five years for women with breast cancer to cut the trisk of the cancer returning. Some postmenopausal women choose to only take aromatase inhibitors, while others choose to take tamoxifen for one to five years, followed by using aromatase inhibitors.

Tamoxifen for Breast Cancer: Success — For Some

You’ve finished treatment for breast cancer and your oncologist has said you are cancer-free “as far as we know.” But one tussle with the Big C is enough; you don’t want a recurrence.

Or maybe you have a high risk of getting breast cancer. Perhaps you have a strong family history, genetic predisposition and/or have had some concerning biopsies. You don’t want to have to face cancer; you’d rather try to prevent it in the first place.

Either way, you’re a good candidate — if you’re premenopausal — for tamoxifen.

A powerful chemotherapy treatment that’s been used for more than 30 years, tamoxifen decreases the chances of breast cancer occurrence or recurrence by about 50%, according to Worta McCaskill-Stevens, MD, MS, medical oncologist and Chief of the Community Oncology and Prevention Trials Research Group at the National Cancer Institute.

That benefit doesn’t disappear the minute you pop your last pill, either. Tamoxifen’s risk-reduction benefit lasts long after a woman takes the medication, up to 15 years later, notes Dr. McCaskill-Stevens. Some oncologists believe the benefits accrue for the rest of your life.

Recent research has suggested that taking tamoxifen for 10 years is even better than taking it for 5, but the 5-year regimen is still standard for most women, says Heidi Nelson, MD, MPH, research professor at Oregon Health & Science University and Medical Director at the Providence Cancer Center, Providence Health and Services. The exception is that doctors recommend 10 years for premenopausal women who have early-stage estrogen-receptor-positive breast cancer.

“Tamoxifen is a wonderful drug,” says Virginia Kaklamani, MD, Cancer Director at the University of Texas at San Antonio. “It saves millions of lives.”

Balancing Risk and Benefit

Tamoxifen is, without question, a powerful drug. But along with its benefits comes a range of side effects. The life-threatening side effects — increased risk of blood clots, strokes and endometrial and uterine cancers — are concerning to healthcare providers.

The risk of these serious side effects is small, experts say, and the actual level of risk varies from person to person. Younger women, especially those who have no other risk factors, are less apt to get blood clots or stroke. Women who’ve had a hysterectomy are unlikely to develop endometrial cancer.

Physicians usually determine a woman’s risk of breast cancer using the National Cancer Institute’s Gail Model, also known as the Breast Cancer Risk Assessment Tool (the Gail Model). The model isn’t perfect, says Dr. Kaklamani, but notes, “We don’t have anything better.”

“When you start looking at potential side effects of tamoxifen and the potential benefits, and cancer risk reduction you really want to focus on women who have a higher Gail Model risk score, probably over a 3. And the younger the woman, the less her risk of getting the side effects such as uterine cancer.”

Interestingly, women often base their tamoxifen decision as much on gut feelings as they do on objective medical data, according to Erika Waters, Ph.D., MPH, ‎assistant professor of surgery in the Division of Public Health Sciences at Washington University School of Medicine. “Some women know people who’ve taken tamoxifen and had side effects, and in those situations they don’t want anything to do with tamoxifen,” explains Waters. “In other situations, women have seen family members and close friends die of breast cancer and they don’t want to have anything to do with breast cancer and so they decide to take tamoxifen.”

The key is that the decision to take tamoxifen is as much about personal preferences and values as it is about objective medical data, notes Waters. “Two people with the exact same risk can come to two different conclusions, and as long as they really understand both the risks and benefits, they will both leave feeling good about the decision they made.”

Less Serious Side Effects

Tamoxifen is well-known for causing menopause-like side effects, prompting some women to refer to the drug as “chemo lite.” Julie, a premenopausal woman who took tamoxifen, found herself gaining weight on the drug. Denise, an independent business owner, experienced bloating, spotting, severe leg cramps and mental fogginess. Mitria, also premenopausal, had hot flashes and joint pain. All three stopped taking the medication as a result of these side effects.

‘It’s critical to find safe treatments that can rescue the brain from impairment’

Another important consideration is emotional health. Business owner Denise experienced “a sort of fogginess” in her brain while she was on tamoxifen and Susan, a New York City public school teacher, had blurry vision, intense depression and vivid suicidal thoughts. Again, these women stopped taking tamoxifen.

Until recently, it was thought that tamoxifen had no emotional side effects; any difficulties that patients experienced were linked to depression, which is certainly common enough in cancer patients and survivors. But “chemo brain,” as these adverse neurological results are called, is a very real effect of tamoxifen, according to Mark Noble, Ph.D., professor of genetics and neurobiology and anatomy at the University of Rochester Medical Center.

“It’s critical to find safe treatments that can rescue the brain from impairment,” Noble says, “because despite increasing awareness and research in this area, some people continue to endure short-term memory loss, mental cloudiness and trouble concentrating. For some patients the effects wear off over time, but others experience symptoms that can lead to job loss, depression and other debilitating events.”

Often, these side effects diminish after about 6 months, as the body adjusts to the medication, says Dr. Kaklamani. But, as with most things, there’s no guarantee.

How Tamoxifen Works

Tamoxifen belongs to a class of drugs called selective estrogen receptor modulators (SERMs), and it works by binding the estrogen receptor to body tissue, which in turn affects how much estrogen is produced. But the drug reacts differently with different types of tissue; sometimes it stimulates the estrogen receptor and sometimes it inhibits it and functions as an anti-estrogen.

As a result, estrogen has a different impact on various parts of the body. For example:

  • In the breast, tamoxifen works as an anti-estrogen which is why it prevents and treats breast cancer.
  • Throughout the bloodstream, tamoxifen works with estrogen, which is why it lowers the cholesterol slightly. It can also cause blood clots, which can lead to a stroke.
  • In the bones, tamoxifen works with estrogen to help prevent bone loss and help with osteoporosis.
  • In the uterus, tamoxifen works with estrogen and can cause uterine cancer.
  • In the brain, the drug works as an anti-estrogen, which is why it fools the body into thinking it’s in menopause; this is the part that causes hot flashes, mood swings, vaginal dryness, fatigue, thinning hair, irregular bleeding, headaches, loss of libido and weight gain.

It is difficult to know precisely how many women take tamoxifen specifically for risk reduction, says Dr. McCaskill-Stevens, because it has been approved by the FDA for various purposes. For example, tamoxifen is used in the treatment of breast cancer and of DCIS — ductal carcinoma in situ, a non-invasive form of breast cancer. tamoxifen is also used for risk reduction for primary cancer and recurrence, and studies don’t always reveal the reasons women choose to take the drug. Typically, there is some drop-off in the women taking the drug over the 5-year period — perhaps as much as 50% — though, again, the reasoning behind this decision is unknown, she says.

Decreased Effectiveness

Taking tamoxifen doesn’t ensure that you won’t have a recurrence. Some of the problem may relate to the body’s CYP2D6 enzyme; in some people, this enzyme isn’t fully effective. And if the enzyme doesn’t work as well as it should, neither will tamoxifen.

One other possible explanation for decreased effectiveness is its interaction with other medications, notably certain antidepressants. The problem lies with selective serotonin reuptake inhibitors, or SSRIs; these drugs can reduce the potency of tamoxifen.

The most common SSRIs are Wellbutrin, Prozac, Celexa, Luvox, Zoloft, Paxil, Lexapro and Brintellix. The good news is that there are plenty of other types of antidepressants; most oncologists will replace any of these drugs with another formulation of antidepressant that won’t decrease the effectiveness of tamoxifen. And this is a concern because according to the National Cancer Institute about a quarter of all breast cancer survivors experience some level of depression.

“So if a patient needs to be on an antidepressant, we try to put them on an antidepressant that doesn’t use CYP2D6 as much, such as Effexor,” says Dr. Kaklamani.

Other medications that can compromise the effectiveness of tamoxifen through the enzyme CYP2D6 are:

  • Most types of birth control pills
  • Quinidine, often used to treat abnormal heart rhythms
  • Diphenhydramine (Benadryl), an antihistamine
  • Thioridazine (Mellaril), an antipsychotic
  • Cimetidine (Tagamet), used to reduce stomach acid

The major concern, though, is really the SSRIs, says Dr. McCaskill-Stevens.

Other Medical Options

The only other medication that has FDA approval for breast cancer risk reduction, raloxifene, reduces risk a little less than tamoxifen — about 38% according to the NCI study — but has fewer side effects. “The fact that there are choices is good,” says Dr. Nelson. That said, raloxifene is approved for use only in postmenopausal women and is used primarily to avoid an initial experience with breast cancer, not for those hoping to prevent recurrence.

Another option is aromatase inhibitors, but again these are recommended only for postmenopausal women. Aromatase inhibitors function in a completely different way than tamoxifen and raloxifene. Anastrozole (Arimidex) is the best-known of the aromatase inhibitors, but there are two others: exemestane (Aromasin) and letrozole (Femara). These drugs lower estrogen levels by stopping the aromatase enzyme from converting other hormones into estrogen. Since the ovaries make most of the body’s estrogen, aromatase inhibitors only lower estrogen level in women who have already been through menopause.

Pill vs Gel

Tamoxifen is typically administered as a pill to be taken daily. Researchers at Northwestern University are currently exploring the possibility of supplying the hormonal treatment through a gel applied directly to the breast. The goal is to concentrate the medication where it is most needed and minimize the exposure to the rest of the body, thereby cutting the risk of blood clots, uterine cancer and other side effects.

“The gel is a way to minimize exposure to the rest of the body and concentrate the drug in the breast where it is needed,” says Seema Khan, MD, co-leader of the Breast Cancer Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and surgical oncologist at Northwestern Memorial Hospital. “Delivery of the drug through the skin of the breast means there will be very little drug circulating through the bloodstream and the body.”

This approach, though, is still in the experimental stage.

In the end, it is important that all tamoxifen patients be monitored regularly. Often, the side effects dissipate somewhat on their own, if not completely, after 6 months, says Dr. Kaklamani.

Perhaps more important, your doctor can often help. “Rather than saying ‘the drug’s not working for me because I’m having side effects,’ you might consider asking your doctor about it because there are things we can do to help with it,” says Dr. Kaklamani.

Beth Leibson lives and writes in New York City. She is author of The Cancer Survivor Handbook: Your Guide to Building a Life After Cancer (Skyhorse Publishing, 2014).

For more information

Additional Reading

Is testosterone the new estrogen?

Excellent article on adverse side effects of estrogen in HRT and tying it to proposed testosterone to improve sex lives. Missing history of DES (estrogen) that damaged women and fetus’ before HRT experiments. Via USC Annenberg.

HRT Increases Breast Cancer

The news about hormone replacement therapy (HRT) that combines estrogen AND progestin is not good. In a newly released analysis of the ongoing Women’s Health Initiative (WHI) study, the combined hormone therapy has an increased risk of breast cancer and not many benefits. This does NOT include HRT that has only estrogen in it, which can only be used by women who do not have a uterus. (Estrogen alone can increase endometrial cancer, located in the uterus.)

The WHI study is a massive, long-term study undertaken by the National Institutes of Health (NIH) to clarify the health benefits and risks of HRT. This large clinical trial attempts to examine the long-term effect of estrogen plus progestin on the prevention of heart disease and hip fractures and measuring possible increases in breast and colon cancers.

In July 2002 the women in the WHI study who were taking the estrogen/progestin combination were told to stop. The Monitoring Board detected an increase in breast cancer in that group after taking the combination for an average of 5.2 years (not before) and no decrease in heart attacks, strokes, and blood clots. The Board determined that the risks outweighed the benefits and it would create greater harm to continue that portion of the WHI study.

In the intervening years, several other studies were published that suggested the cancers that were linked to the estrogen/progestin therapy were less deadly. Some studies also suggested some benefits.

A new analysis of the WHI study that now has 11 years of data, finds that the breast cancers in HRT treated women are just as deadly as the breast cancers that non-treated women got. And since the estrogen/progestin combination results in more episodes of breast cancer, more women who take the hormone combination will die of breast cancer than those who do not — simply because more will get cancer.

Dr. Patricia Ganz, director of cancer prevention and control research at UCLA’s Johnsson Comprehensive Cancer Center, was quoted in an LATimes article, “If you’re going to take these therapies, you need to know there’s an increased risk,”…”Make sure there’s a good indication. And don’t take them for a long period of time.”