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Menstrual cycles and patient care: a new view

While research is preliminary, some are treating patients with menstruation in mind

From the May ACP-ASIM Observer, copyright 2002 by the American College of Physicians-American Society of Internal Medicine.

By Deborah Gesensway

Research on menstrual cycles and common medical conditions

For Sunanda V. Kane, ACP-ASIM Member, a gastroenterologist and assistant professor of medicine at the University of Chicago, understanding how menstrual cycles can affect bowel function has changed the way she treats female patients with inflammatory bowel disease.

Based on research she published four years ago, Dr. Kane knows that some flare-ups do not need to be treated because they accompany the patient's menstrual cycle and will resolve on their own. "I can help these patients minimize and even avoid steroid exposure if I find out what part of the cycle they are in," she explained. "Sometimes, they have been put on steroids unnecessarily."

Cornelia Baines, MD, professor of medicine at the University of Toronto, counsels premenopausal women to schedule their screening mammograms for the first two weeks of their menstrual cycle (the follicular phase). According to her research, women experience significantly more false negatives when they undergo mammography in the last half of their cycle than in the first.

The reason? The density of breast tissue during that time, she explained, makes for a "less favorable signal-to-noise ratio."

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Some physicians use birth control pills to supress hormonal swings linked to menstruation.




While evidence on how women's menstrual cycles affect other aspects of their health is still preliminary, researchers say there may be good reasons to pay attention to patients' cycles. From premenstrual depression and migraine headaches to breast cancer screening and treatment, a growing body of evidence shows that the phase of a woman's monthly cycle (follicular, ovulatory, luteal or menstrual) may be related to an increase in symptoms or to better response to treatment.

"There are snippets of evidence here and there, but there is enough evidence that doctors will be hearing more" about the interaction between menstrual cycles and many medical interventions, explained Mary J. Berg, PharmD, professor of pharmacy at the University of Iowa. She said that sex hormones, after all, affect more than women's reproductive systems.

That's why in the not-so-distant future, physicians may ask female patients for the date of their last period to do more than rule out pregnancy. They might want that information to better treat conditions like asthma, diabetes or migraines; select a drug; or even order a procedure.

Clinical evidence

While the relationship between women's menstrual cycles and their health has begun to attract attention, definitive research is scarce. An Institute of Medicine (IOM) committee on the biology of sex and gender differences last year concluded that as the study of sex differences evolves into a mature science, medical researchers need to "identify the endocrine status of research subjects." The committee also said that researchers should consider information on menstrual cycles "an important variable" when possible.

"How much does the menstrual cycle contribute to various diseases? Some, clearly," explained Judith H. La Rosa, PhD, a professor of preventive medicine at the State University of New York, Downstate Medical Center in Brooklyn and a member of the IOM committee. "But we don't know a lot," she added, and more cycle-specific research is needed.

One of the few articles to review the existing evidence on the topic was published in a 1998 issue of Archives of Internal Medicine. (The article is available online.) It outlines current knowledge about several medical conditions for which physicians have recognized worsening symptoms during certain menstrual phases. The article also suggests how suppressing ovulation can help physicians diagnose and treat these exacerbations.

One of the article's co-authors, Robert L. Reid, MD, an ob-gyn in Kingston, Ontario, explained that he frequently notices a link between symptoms and menstrual cycle phase in patients referred to his clinic. Some women say they experience more asthma attacks just before their period, he said, while others complain that their diabetes spirals out of control cyclically.

Dr. Reid, who specializes in premenstrual syndrome, recalled one of the worst cases he ever saw: a woman who was experiencing such bad episodes of recurrent pneumothorax that she had already undergone surgery on one lung. After talking to her and gathering some information, however, he concluded that her pneumothorax problem was actually triggered by endometriosis. (He noted that he and other researchers do not know exactly how endometriosis causes pneumothorax, but he is convinced the two are connected.)

To arrive at his diagnosis, Dr. Reid used a gonadotropin-releasing hormone agonist to create what he called a "temporary menopause." Because the substance shuts off cyclical hormonal swings, he said, it gives him a chance to see if the symptoms resolve. "A woman's menstrual cycle has a profound effect on a lot of things, and I don't think we truly appreciate it," he explained.

To treat women whose conditions may be somehow caused or worsened by their menstrual cycle, Dr. Reid sometimes prescribes birth control pills or Depo-Provera injections. The goal, he said, is to shut down the ovarian cycles that cause the symptoms. By stabilizing hormone exposure day after day, he explained, he can help patients avoid hormonal swings that seem to precipitate certain illnesses.

With migraine headaches, researchers have similarly shown that focusing on menstruation can relieve some women's symptoms. Physicians have successfully treated these headaches with estrogen supplements. (See "Research on menstrual cycles and common medical conditions.")

Conflicting evidence

While such results are intriguing, the link between menstrual cycle and symptoms is not always clear cut. Researchers examining breast cancer treatment, for example, have found that surgeons can cure more breast cancers if they time surgery around ovulation and in the early luteal phase.

William Hrushesky, MD, professor of developmental biology and anatomy at the University of South Carolina in Columbia, S.C., said he has also found that treating breast cancer with chemotherapy at different times in the menstrual cycle can affect a woman's fertility and fecundity. (Chemotherapy during the luteal phase, for example, helps maintain fertility.)

The problem is that while some researchers have confirmed these conclusions, others have tracked patients' hormone levels at the time of surgery and found no link between cycle phase and outcomes.

Breast cancer is one area where clinical studies in the pipeline may help. The federal government is funding several studies that will examine whether timing breast cancer surgery based on the menstrual cycle makes a difference in terms of recurrence, disease progression or death.

One trial sponsored by the National Cancer Institute will examine how the menstrual timing of procedures like lumpectomy or mastectomy affects outcomes in women at various stages of breast cancer. And the National Institute of Mental Health is funding a study that looks at whether hormone replacement therapy can help reduce severe menstrually related mood disorders.

Chronobiology

Many researchers tackling menstrual cycle issues are coming from the budding fields of chronobiology and chronopharmacology, which explore how biological rhythms—both circadian and menstrual—affect health and disease. "We are starting to learn that all biological markers—such as cholesterol, blood pressure, thyroid-stimulating hormone and sex hormones—cycle," said University of Iowa's Dr. Berg.

Some research focuses on the absorption, distribution, metabolism and elimination of medicines according to the time of day and the menstrual cycle phase, she explained. "In the future," she said, "the phrase 'twice a day' may mean 8 a.m. and noon, not 8 a.m. and 8 p.m., because of absorption patterns."

She noted that a handful of studies have already shown that the body eliminates drugs like caffeine and theophylline less quickly during the luteal phase. Data also show that the body absorbs less ethanol and salicylates during ovulation but clears acetaminophen, antipyrine and methaqualone faster.

While evidence is still sketchy, physicians like Dr. Kane in Chicago say it's not too early to put some of this knowledge into practice. She regularly asks new patients suffering from irritable and inflammatory bowel, for example, about their menstrual cycles. If they don't see a relationship between their symptoms and their cycles, she asks them to keep a diary of symptoms through three cycles. This approach sometimes helps her decide which treatments to order-and which to forgo.

"Particularly with inflammatory bowel disease, women will call and say they are bleeding, having more pain or vomiting," Dr. Kane explained. "Because no one thinks to ask them what part of the cycle they are in, they get a prescription for steroids. Five days later when they feel better, everybody thinks it was because of the steroids, when it wasn't. It was because their period is over, and the steroids were unnecessary."

Sometimes, she added, menstrual diaries have helped her pick up on a patient's unrecognized problem with irregular periods. In these more serious cases, she can refer the patient to an ob-gyn. "It may be a warning signal of something else," she added.

Deborah Gesensway is a freelance writer in Glenside, Pa.

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP-ASIM.

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Research on menstrual cycles and common medical conditions

Research on the role of menstrual cycles in women's health runs the gamut, from small studies on the influence of menstrual cycle phases on skin-prick allergy testing to research examining the best cycle phase for women to successfully stop smoking. Here is an overview of common medical conditions where the most evidence exists:

  • Seizures. Some women with a seizure disorder experience more frequent seizures during the premenstrual period, a condition known as catamenial epilepsy. This may be caused both by hormonal changes and how the body metabolizes the anticonvulsant drug phenytoin.

    A study in a 1984 issue of Neurology found that mean serum levels of phenytoin during menses were lower in women taking the drug who experienced catamenial epilepsy than in women whose seizures were unrelated to menstruation. The authors concluded that the body's ability to metabolize phenytoin "may be slowed by competition from steroid hormones."

  • Breast cancer. Several studies published in the 1998 American Journal of Surgery and the 2000 Journal of Surgical Oncology suggested that carefully timing procedures like mammography-directed core biopsies and primary breast cancer resection can affect breast cancer recurrence and patient survival. They also concluded that breast cancer surgery is best done in the follicular phase of the menstrual cycle. (Other studies, however, have not found statistical significances to support these results.)

    Regarding mammography, researchers in a 1997 issue of Cancer concluded that premenopausal women who undergo screening mammography in the luteal phase of their menstrual cycles encounter more false negatives. A report in a 1998 issue of Journal of the National Cancer Institute came to a similar conclusion, finding that "breast tissue is less radiographically dense in the follicular phase than in the luteal phase."

  • Asthma. Women with asthma may be more likely to experience an exacerbation of their disease in the days just before they menstruate. A study in a 1996 issue of Archives of Internal Medicine described how nearly half of the women who came to an emergency room experiencing aggravated asthma were in the late luteal phase of their cycles.

    Moreover, according to a study in a 1990 issue of the European Journal of Clinical Pharmacology, the pharmacokinetics of the bronchodilator theophylline change throughout a women's menstrual cycle. The theory—confirmed in only very small studies—is that concentrations of theophylline may become low enough during a woman's luteal phase to exacerbate asthma.

  • Diabetes. Women with insulin-dependent diabetes appear to have differing levels of glucose metabolism depending on the phase of their menstrual cycle. A study in a 1992 issue of Diabetes Care found that some women exhibit "worsening premenstrual hyperglycemia and a decline in insulin sensitivity during the luteal phase."

  • Heart disease. Japanese researchers in a 2001 issue of Annals of Internal Medicine described how premenopausal women with variant angina experienced the fewest coronary spasms during the follicular phase of their cycles. The study also found that at the end of the luteal phase and start of the menstrual phase (menses), women experienced the most ischemic episodes. As a result of this and other limited studies, researchers suggest that exercise stress test reports for menstruating women should document the cycle phase when the test was completed. Further research may shed light on how menstrual timing affects test interpretation.

    Other studies have demonstrated a relationship between menstrual cycle phase and the degree of drug-induced QT prolongation related to torsades de pointes. A report in a 2001 issue of the Journal of the American Medical Association showed that the greatest increase in ibutilide-induced QT prolongation occurred during the follicular phase.

  • Migraines. Migraine headaches are two to three times more common in women than in men, and 60% of women with migraines link their attacks to menstruation. Some women, however (8% to 14% of women with migraines according to a report in a 1998 Archives of Internal Medicine), suffer migraines only during menstruation.

    Because migraines are vascular, researchers have examined the effect of estrogen on the vasculature. Women with menstrual migraines have been treated successfully when given estrogen both prophylactically and at the onset of symptoms.

  • Premenstrual syndrome (PMS). As many of 75% of menstruating women have some premenstrual symptoms. For 30%, however, the physical pain and emotional changes are so severe that they have to change their daily routines. While some PMS treatments relieve some symptoms (selective serotonin reuptake inhibitors for depression, for instance), others focus on minimizing monthly fluctuations in hormones. Both oral contraceptives and Depo-Provera injections, which stop ovulation, have been shown to help many women.

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