Abstract
‘Very little is known about the effect of sex on the pathophysiology, long-term outcome, associated symptoms or medication response in inflammatory bowel disease.’
Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory conditions of the digestive tract known as inflammatory bowel disease (IBD). These conditions are characterized by abdominal pain, diarrhea and at times, rectal bleeding, as well as numerous extraintestinal manifestations. A recent estimate of the prevalence of UC in Olmstead County (MN, USA), was 229/100,000, while the prevalence of CD was 133/100,000 [1,2]. The two conditions combined affect approximately 1 million people in the USA. The peak onset of both UC and CD occurs between 20 and 40 years, with a second peak between 50 and 80 years in CD. Although CD and UC generally have a similar incidence in men and women, some studies suggest a slight male predominance in UC and a slight female predominance in CD [1,2]. Very little is known about the effect of sex on the pathophysiology, long-term outcome, associated symptoms or medication response in IBD. The studies that have shown sex differences in IBD suggest that unmasking further differences will contribute to better therapy and understanding of the disease.
Since IBD affects women in their reproductive years, special consideration of issues involving body image, sexual function, contraception and pregnancy are of particular importance. In this issue of Women's Health, Dr Sunanda Kane summarizes these important sex-specific issues in women with IBD [3]. Studies show increased concerns of women compared with men who have IBD, including a poor body image, a feeling of isolation and problems with pregnancy.
Absent or infrequent intercourse is common in women with CD, occurring in 24% of 50 women compared with 4% of age-matched controls, in a study by Moody and colleagues [4]. Dyspareunia, reported by 60% of CD patients, was commonly cited as a reason for the lower frequency of sexual intercourse. Other contributing factors for infrequent intercourse include abdominal pain, diarrhea and fear of incontinence [4]. Dyspareunia may result from scarring from previous surgery, the presence of recto-vaginal and entero–vesicular fistulas, inflammation involving the vagina or perineal abscesses. In UC, dyspareunia occurs in approximately 38% of women [5].
The menstrual cycle affects the gastrointestinal symptoms of patients with IBD. In an important study published in 1998 by Kane and colleagues, patients who experienced IBD or irritable bowel syndrome frequently had cyclical increased diarrhea and abdominal pain during the premenstrual and menstrual periods compared with control patients [6]. It is important to recognize that endometriosis, a condition where the uterine lining is found outside the uterus, can cause similar symptoms. When symptoms are severe and cyclical this entity should be considered. However, it is important to note that up to two out of three women with bowel involvement in endometriosis may have symptoms that are not cyclical [7].
The safety of oral contraceptive pills (OCPs) in women with IBD is controversial. Most studies show that OCPs adversely impact the activity of CD, although this is not universally true [8–10] (see Kane's article in this journal [3]). The impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on the analyses of the data in these studies is unclear. Not all studies report NSAID use in the cohort. Even if excluded during the study period, little is known about use prior to study onset. This is of particular importance since NSAIDs can cause an exacerbation of IBD or ulcerations and symptomatology identical to IBD. Many women take OCPs to improve premenstrual or menstrual symptoms or symptoms of endometriosis, not purely for contraception. NSAIDS are also frequently used to treat these problems, potentially confounding the interpretation of the study results.
When voluntary childlessness is considered, fertility rates in patients with IBD are comparable to the general population [11,12]. The exception is in patients post ileal pouch–anal anastomosis (IPAA) in whom the ability to conceive is markedly reduced [13,14].
The risk of inflammatory disease in offspring may vary depending on whether one or both parents have IBD, as noted by Kane [3]. One study suggested that among non-Jewish families, IBD was more likely to be transmitted to offspring from the mother than from the father [15]. Further studies are necessary to confirm this sex difference in disease transmission and to identify the genes that may be involved.
As summarized by Kane, the greatest risk to pregnancy is active IBD [3]. In order to achieve a successful outcome in pregnancy, the goal should be to maintain remission in the mother by using effective drugs with a low risk to the fetus. All women with IBD should be encouraged to wait until they are in remission before conception. With the exception of an increased risk for premature delivery, which has been confirmed by numerous studies, and lower birth-weight infants (of little clinical significance) [16–19] pregnancy outcome should be the same as in women without IBD. Rates of relapse in pregnant women with UC and CD are similar to those of nonpregnant women [20]. Kane and colleagues showed fewer symptoms in women who were disparate from their fetuses in two human leukocyte antigen (HLA) loci, suggesting immunologic downregulation or tolerance [21]. Drug therapy during pregnancy is similar to that in nonpregnant women, with some notable exceptions [3]. Methotrexate should be avoided. Metronidazole (Flagyl®) should be avoided in the first trimester and ciprofloxacin (Cipro®) should be avoided if at all possible. Infliximab (Remicade®) is thought to be safe in pregnancy, but does cross the placenta [22]. Little is known about the safety of drugs during breastfeeding [23].
Sex-specific issues are not limited to sexual function and pregnancy. A wide range of associated extraintestinal manifestations in IBD can occur; including erythema nodosum, pyoderma gangrenosum, iritis, arthritis and ankylosing spondylitis, biliary tract disease, kidney stones, gallstones and a hypercoagulable state. The incidence of some of these conditions differs in females and males. Erythema nodosum and iritis/uveitis are more likely to occur in women [24,25]. Primary sclerosing cholangitis and ankylosing spondylitis, on the other hand, are more common in men [25]. Other chronic inflammatory diseases increased in IBD include arthritis, asthma, bronchitis, thyroiditis, psoriasis, multiple sclerosis, chronic renal disease and pericarditis [26]. Of these conditions, women with UC are at increased risk compared with men for bronchitis, arthritis and chronic renal disease; whereas men with UC are at increased risk compared with women for multiple sclerosis. In CD, only bronchitis appears to have a sexual disparity, being increased in women. The reasons for these sex-based differences in extraintestinal manifestations are unclear.
Osteopenia and osteoporosis are problems for all women, especially those with IBD. These conditions are common in postmenopausal women, in male and female patients with IBD and as potential complications of medical therapy of IBD. Osteopenia is a reduction in bone mass between 1 and 2.5 standard deviations below peak bone mass (T-score), while osteoporosis is a reduction in bone mass greater than a T-score of −2.5. These conditions increase the risk of fracture, particularly in trabecular bone present in vertebrae, ribs, pelvis and the ends of long bones. In the general population, it is estimated that the lifetime risk of developing a hip fracture is 14% for Caucasian women and 5–6% for Caucasian men [27]. Osteopenia is present in 29–78% of patients with IBD, while osteoporosis is present in 23–60% of these patients [28–30]. The reduction in bone mass in these patients translates into a 40% increased risk of fracture in both men and women, as demonstrated in a large cohort study [31,32]. While many studies suggest that patients with CD are at greater risk of osteopenia and osteoporosis than patients with UC, several studies also indicate that patients with UC have a significant reduction in bone mineral density (BMD) [33–35].
In the general population, the major risk factors for osteoporosis include Caucasian or Asian race, female sex, advanced age and postmenopausal status, vitamin D and calcium deficiency, low body mass index, sedentary lifestyle and smoking. Additional risk factors for osteoporosis in patients with IBD include malabsorption, hypogonadism, decreased calcium intake due to avoidance of dairy products, corticosteroid therapy and systemic inflammation. Malabsorption may result from extensive small bowel disease or prior small bowel resection, resulting in impaired vitamin D and calcium absorption. Chronic inflammation results in elevated levels of cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor, which stimulate osteoclast activity.
Medical therapy for IBD can potentially lead to osteopenia and osteoporosis. Corticosteroids and cyclosporin can exacerbate bone loss through their effects on calcium metabolism and bone resorption. Most studies demonstrate that osteoporosis risk correlates with the dose and duration of steroid therapy [31,33–37]. With high-dose steroid usage, bone loss may be rapid, occurring at a rate of 5–15%/year, with the greatest decrease in bone density observed in the first 6–12 months of therapy.
While steroid therapy is an important contributor to osteopenia in patients with IBD, it remains difficult to predict which patients will develop clinically significant bone loss. In a prospective study of bone loss in patients with IBD, 26% of patients receiving steroid therapy did not lose bone mass, while bone loss was observed in 34% of patients who were not receiving steroid therapy [38]. The interplay of disease pathophysiology, individual risk factors and medical therapy determines the risk of accelerated bone loss in patients with IBD.
Prevention of osteoporosis in male and female patients with IBD may be achieved by encouraging weight-bearing exercise, increased intake of dietary calcium (1000–1300 mg/day depending on age), intake of vitamin D (400–800 IU/day) and smoking cessation. In patients requiring steroids, an attempt should be made to use the lowest effective dose for the minimum amount of time. Steroid-sparing medications such as 6-mercaptopurine (Purinethol®), azathioprine (Imuran®) or remicade should also be used to reduce the dose and duration of corticosteroid therapy.
Studies of budesonide (Entocort®) in IBD are limited, with conflicting results on the effect of this topically acting corticosteroid with a high first-pass metabolism in the liver on the risk of osteopenia/osteoporosis in patients with IBD. Cino and colleagues followed 32 patients with CD treated for 2 years with budesonide and found that, at doses of 6 and 9mg, there was no significant difference in BMD of the spine or femoral neck as measured by dual energy x-ray absorptiometry (DEXA) at 1 and 2 years [39]. Another study by the same author; however, concluded that patients treated with budesonide for 2 years actually had a greater degree of bone loss as measured at the femoral neck and lumbar spine compared with patients treated with prednisone [40]. A recent study by Schoon and colleagues showed that in corticosteroid-naïve patients only, there is a reduction in bone marrow density at 24 months of 1.04 and 3.35% in CD patients taking daily budesonide 9 mg or prednisone 40 mg, respectively [41]. Statistical significance was limited by the small number of patients. Therefore, additional long-term studies are necessary to determine whether budesonide is a safer alternative to other corticosteroids with respect to osteoporosis risk.
In patients with established osteoporosis, therapeutic interventions including calcium supplementation, vitamin D, estrogen replacement and bisphosphonates may be used depending on the patients' risk factors for osteoporosis and use of therapies that may exacerbate bone loss. The jury is still out on whether bisphosphonate therapy will prevent more fractures than just vitamin D and calcium supplementation [42,43]. There is still some question as to whether bisphosphonates taken by a woman prior to pregnancy will impact the fetus adversely.
‘As more studies are performed analyzing data by sex, further differences may emerge in many aspects of inflammatory bowel disease. Analyzing the cause for these differences and utilizing information gleaned from the studies may make an impact on the disease in both sexes.’
Two aspects of the natural history of IBD appear to be impacted by gender. As discussed by Kane, Nwokolo and colleagues found, in a retrospective study, that women who had been pregnant prior to the onset of distal ileal or colonic CD had fewer surgical resections compared with a published resection group [44]. Wagtmans and colleagues also found that the lag time between bowel resection and recurrence of disease was significantly shorter in women [24]. Substantiation of the possible protective effect of pregnancy will require prospective studies with case controls, rather than retrospective results.
Another intriguing effect of sex differences is on colorectal cancer occurrence in IBD. It has long been known that UC is associated with an increased risk of colorectal carcinoma, beginning at 8–10 years of disease, which may be as much as 30% after 35 years of disease. In CD, the risk of colorectal cancer is also substantially increased. Using a population database from Manitoba (Canada), Bernstein and colleagues showed a similar incidence of colon cancer in UC and CD [45]. However, there was a higher risk in males than females. The disparity in risk was age-based, persisting from birth through to age 59 years and disappearing after the age of 60 years. This pattern is almost identical to the sex disparity found by Schoenfield and colleagues in the prevalence of advanced neoplasia in a control population [46]. An approximately twofold increased risk in men compared with women exists from 50–69 years, but disappears after the age of 70 years. Further investigation is warranted to try to tease out the cause(s) of the sex disparities.
As more studies are performed analyzing data by sex, further differences may emerge in many aspects of IBD. Analyzing the cause for these differences and utilizing information gleaned from the studies may make an impact on the disease in both sexes. More studies are needed on the impact of differing hormones in women. Understanding the protective effects of the milieu during late pregnancy may impact treatments outside of pregnancy. More studies need to be carried out to ascertain the effects on the fetus and breastfeeding newborn of medications given to the mother during pregnancy and lactation.