The Rhythms that Bind Women

Ask a woman if her period affects her body beyond the reproductive system and she'll probably answer with a resounding yes. This seemingly basic question is now being asked by numerous investigators in various areas of women's health research. From the timing of mammograms to the mind-altering effects of drugs, researchers are now learning that the hormonal swings during a woman's menstrual cycle affect more than just reproduction, like metabolism rates and pain. A woman's menstrual cycle starts when menses flow begins, is followed by the follicular phase when estrogen rises and peaks at ovulation mid-cycle, then ends with the luteal phase when progesterone dominates. Until recently, researchers didn't include women in significant numbers in clinical trials, let alone consider the effects of menstrual cycles on female health.1 Several pieces of history combine to explain this lack of attention, says John M. Johnson, a physiology professor at the University of Texas Health Science Center, San Antonio, who studies hormonal effects on body temperature regulation. "One is the overall assumption that reproductive hormones had to do with reproduction, period, until it became obvious that these hormones have global effects." Ironically, he says, past studies relied on men as subjects, and not women, to avoid the confounding aspect of the menstrual cycle. Johnson says that this was why he hadn't considered fluctuating-female hormones as a factor. "Then when we got into it, we found it was really interesting in its own right," he says. Five years ago, his graduate student Nisha Charkoudian, who is now at the Mayo Clinic, found that two different nerve types in the skin were affected by a woman's hormonal status during different parts of her cycle, changing how and where body temperature is regulated.2 Some say that the reason the menstrual cycle hasn't been considered until lately is that it's a culturally forbidden subject among men and women. "I think it was taboo and I think it still is fairly taboo, especially in American culture," says Susan Brown, a psychology professor at the University of Hawaii, Hilo. "We're bleeding and nobody wants to even think or talk about that." For women, it's good that researchers have begun talking about, and researching, how the menstrual cycle can affect them. In 1998, epidemiologist Emily White and colleagues from the Fred Hutchison Cancer Center, Seattle, found that mammograms detect cancer more effectively in premenopausal women during the cycle's first two weeks.3 In the latter half, breast tissue becomes more fibrous and thus opaque -most likely due to hormonal fluctuations- so it is harder to detect small, early-stage malignancies. And several retrospective studies conducted in the United States and Europe during the early 1990s found that high progesterone levels expressed during the luteal phase might contribute to better survival after breast cancer surgery, concluding that the best time for surgery was just after ovulation when estrogen is low and progesterone is rising. Other Systems Many potential, non-reproductive connections between women's health and menstrual cycle are being studied: metabolic rate, temperature regulation, pain, gastrointestinal function, reaction to insulin in diabetics, and immune function. Susan Manzi, an associate professor of medicine and epidemiology, University of Pittsburgh, notes that 60 percent of women with the autoimmune disease lupus report adverse symptoms suggestive of disease activity during certain times of their cycle.4 "But, the bottom line is that very little is truly known," she adds. So far, much of the information has been anecdotal, reported by female lupus sufferers that some change occurs in disease activity during certain times of their cycle, but the timing isn't consistent among all women. Many say their symptoms worsen at the start of the luteal phase, at ovulation, when progesterone is at its lowest and estrogen is at its highest. But, the data on lupus activity and sex hormones are conflicting. Manzi is now studying whether women with lupus have significantly different sex-hormone profiles during their menstrual cycle. One hypothesis she is working with is that estradiol levels during the follicular phase and at ovulation are higher in women with lupus than age- and race-matched controls, and that progesterone levels during the luteal phase are lower. "Since estradiol tends to have more of an immunostimulatory effect and progesterone may have more immunosuppressive characteristics, variations in the levels of these hormones during the menstrual cycle may be important," she says. In the early 1990s, Margie Profet, an evolutionary biologist, introduced the controversial idea that menstruation was a way of ridding the body of pathogens to facilitate a clean implantation for a fertilized embryo.5 Based on this idea, Brown reasoned that during menses, the immune system would be heightened to clear the uterus and fallopian tubes of any bacteria, as Profet suggested, but at the time of implantation in the luteal phase, immune function would decrease because sperm and the embryo might be picked up by the immune system as nonself pathogens. "Our hypothesis was that during the follicular phase, women would experience fewer health problems and then during the luteal phase we expected them to experience more," says Brown. And they did. Based on the daily diaries of 59 women, who, for three cycles, kept note of general symptoms like runny noses, pimples, herpes cold sore outbreaks, flu-like ailments, and sore throats, Brown found that the participants displayed significantly fewer onsets and contractions of illness during menses. In contrast, the onset of symptoms and contractions of illness peaked during the luteal phase. For example, subjects reported cold symptoms coming on the week before menstruation started.6 Manzi plans to next look at the levels of antibodies and time of cycle. It's Not All in Her Head Courtesy of Marc J. KaufmanIschemic pain responses across the menstrual cycle Another area primarily relying on anecdotal information concerns the relationship between pain and the menstrual cycle. For example, Linda A. LeResche, research professor in the department of oral medicine, University of Washington, Seattle, says that researchers "know nothing about clinical pain and cycle with the exception of migraine headache." It's been known for a while that for some migraine sufferers, the headaches come right before, or at the onset of, menstruation.7 LeResche studies temporomandibular disorders, or TMD, which is characterized by pain in the joint at the front of the ear, called the temporomandibular joint, and the jaw muscles. She and others have noticed that TMD affects women more frequently; its prevalence peaks during reproductive years, and symptoms seem to decline after age 50. As with Manzi and her lupus work, LeResche naturally deduced a connection with reproductive hormones. She is currently looking at that relationship. Roger B. Fillingim, a clinical psychologist and associate professor in the College of Dentistry, University of Florida, Gainesville, also studies how women's perception of pain varies across the cycle. He's currently recruiting women for a study that will look at how interstitial cystitis, a painful bladder condition characterized by increased urinary urgency and frequency, is possibly exacerbated just prior to menstruation. Fillingim's hypothesis: enhanced pain before menstruation occurs because sex hormones affect the neurons in the brain and spinal cord that transmit pain-related information.8 Another area involving pain is the relationship between bowel disorders and menstrual cycle. "No one has actually measured ovarian hormones and compared them against gastrointestinal symptoms," says Margaret M. Heitkemper, professor and chairperson, department of biobehavioral nursing and health systems, and director, Center for Women's Health Research, University of Washington. Nonetheless, she adds, the evidence is "fairly compelling" that for many women, there is a heightening of symptoms in irritable bowel syndrome (IBS) and other GI tract ailments that occur around the time of menses.9,10 Heitkemper's ongoing study is one of the first to look at the relationship between the entire cycle and IBS, although others looked at symptom amplification at the onset of menses. "My own theory is that it's related to the hormone drop that occurs right before menses, for both progesterone and estrogen," she says. "Those hormones drop off during the late luteal phase, and I think it makes the gut more responsive to normal stimuli. We've shown in rats that estrogen slows down motility in gastric emptying." As researchers change their attitudes regarding the purported difficulty in data analysis due to women's menstrual cycles, investigators from many fields are finally making strides in understanding just how important the inclusion of menstrual cycle fluctuations really is. And it's just not research that's benefiting. "I think for many years women were reluctant to talk about symptoms that varied with their cycle," says Heitkemper. "We are beginning to appreciate the full impact of these distressing symptoms that vary with the cycle." Karen Young Kreeger (kykreeger@aol.com) is a contributing editor for The Scientist. References 1. K.Y. Kreeger, "Women health activists note progress but still see problems," The Scientist, 10[23]:1 Nov. 25, 1996. 2. N. Charkoudian and J.M. Johnson, "Female reproductive hormones and thermoregulatory control of skin blood flow," Exercise and Sports Science Reviews, 28:108-12, 2000. 3. E. White et al., "Variation in mammographic breast density by time in menstrual cycle among women age 40-49 years," Journal of the National Cancer Institute, 90(12):906-10, 1998. 4. A.D. Steinberg and B.J. Steinberg, "Lupus disease activity associated with menstrual cycle," Journal of Rheumatology, 12:816-7, 1985. 5. M. Profet, "Menstruation as a defense against pathogens transported by sperm," Quarterly Review of Biology, 68:335, 1993. 6. S.G. Brown et al., "The relation between phase of menstrual cycle and health related symptoms: an evolutionary perspective," Advances in Ethology, 32:67, 1997. 7. D.A. Marcus, "Clinical review: Interrelationships of neurochemicals, estrogen and recurring headache," Pain, 62:129-39, 1995. 8. R.B. Fillingim and T.J. Ness, "Sex-related hormonal influences on pain and analgesic responses," Neuroscience and Biobehavioral Reviews, 24:485-501, 2000. 9. M.M. Heitkemper et al., "Daily gastrointestinal symptoms in women with and without a diagnoses of IBS," Digestive Diseases & Sciences, 40:1511-7, 1995. 10. M.D. Crowell et al., "Functional bowel disorders in women with dysmenorrhea," American Journal of Gastroenterology, 89[11]:1973-7, 1994. Estrogen, Women, and Cocaine Addiction Courtesy of Marc J. KaufmanDifferences in vasoconstriction between follicular and luteal phases as compared to men. Drug-abuse researchers have known anecdotally that chronic, female cocaine abusers experience fewer disruptions in cerebral blood flow and less neuron loss compared to male habitual users. The reason was unclear; the reproductive hormones estrogen and progesterone that fluctuate during a woman's menstrual cycle were likely suspects. "Women appear to have better treatment outcomes," notes Marc Kaufman, assistant professor of psychiatry, Harvard Medical School, and associate research professor of pharmacology, McLean Hospital, Belmont, Mass. In a recent study at McLean, researchers intravenously delivered a dose of cocaine to 13 women, in their 20s and 30s, who were occasional cocaine users.1 They each received a dose in the middle of the estrogen-rich follicular phase of their cycles and again in the middle of the estrogen-low luteal phase. Using magnetic resonance imaging to measure blood flow to the brain, Kaufman and colleagues found that this flow was normal during the follicular phase but dropped off by 10 percent during the luteal phase. Men, the researchers found, experienced a 20 percent blood-flow reduction. Only during the luteal phase did women experience a significant degree of vasoconstriction from cocaine. Cocaine does at least two things to the body, Kaufman says: It activates a neuronal system called the reward pathway, and it constricts the vascular endothelial cells, the smooth muscles cells that line blood vessels. When vessels constrict, blood flow is reduced to the brain. But, estrogen makes the cells more supple, more elastic. Data also suggests that progesterone might counteract that effect or might independently reduce elasticity. In addition, testosterone can reduce elasticity. This is why researchers surmise men have more problems with cocaine than women do. Investigators hope that this research will one day be applied to developing an estrogen-like compound--called selective estrogen receptor modulators, or SERMs--to treat cocaine addicts. "If we could come up with a SERM that's more selective and not feminizing for men...our hope is to reduce brain damage and preserve cognitive function [to enable] people to adhere to their treatments and do better at maintaining jobs and family relationships," says Kaufman. --Karen Young Kreeger 1. M.J. Kaufman et al., "Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle," Biological Psychiatry, 49:774-81, 2001.

The Rhythms that Bind Women

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