Menstrual cycle abnormalities in women with inflammatory bowel disease and effects of biological therapy on gynecological pathology

The most prevalent issue in adult women with IBD appears to be irregular menstrual cycles, including oligomenorrhea, secondary amenorrhea, and abnormal uterine bleeding, including menorrhagia and metrorrhagia. A study found that almost 60% of IBD patients reported experiencing these abnormalities[ 11 ]. Few studies focused on the menstrual cycle and symptoms in women with IBD. In total, Weber et al [ 11 ] interviewed 662 female patients who had undergone IBD surgery[ 11 ]. 58% of the respondents reported an irregular period, including 30% of women with CD. Furthermore, 22% of those with UC had oligomenorrhea or menstrual cycles that were more than 3 mo apart. In 23% of CD-suffering women and 15% of UC-suffering women, menstrual cycles were observed that were more frequent than every 3 wk. 25% of women with CD and 23% of women with UC reported menorrhagia, or periods that lasted more than 7 d. Furthermore, 28% of the CD patients and 22% of the UC patients had metrorrhagia or bleeding between periods. Dysmenorrhea and painful periods requiring medical attention were reported in 24% of CD cases and 20% of UC cases. Menstrual irregularities were observed in 29% of CD cases and 28% of UC cases[ 11 ]. However, a study by Saha et al [ 12 , 13 ] showed that the prevalence of dysmenorrhea was lower in the IBD group than in the control. These differences between the studies may be due to different populations analysed: Weber et al [ 11 ] focused on patients generally with IBD while Saha et al [ 12 , 13 ] focused on patients with CD. In another study by Saha et al [ 12 , 13 ], in the year before receiving an IBD diagnosis, 21% and 25% of the subjects exhibited changes in flow duration and cycle interval, respectively[ 12 , 13 ]. It is significant to note that while IBD and dysmenorrhea share many symptoms, it can be challenging to distinguish them. Individuals with both illnesses frequently experience diarrhea, mood fluctuations (irritability, depression), nausea, and vomiting[ 14 ]. It is even more challenging to identify the exacerbation of IBD, since acute symptoms possibly include dysmenorrheal symptoms. The pathophysiological mechanisms of prostaglandins may be a contributing factor to dysmenorrhea in women with IBD[ 15 ]. Although prostaglandins are known to be associated with inflammatory processes in IBD, it can be painful and uncomfortable when the endometrium secretes them in large amounts. Premenstrual prostaglandins cause the smooth uterine muscles to contract, causing the cramping that many women associate with menstruation. Patients experience diarrhea and stomach pain due to the effects of prostaglandins on intestinal smooth muscle contraction and electrolyte secretion[ 15 , 13 ]. Another mechanism is related to how estrogen affects the gastrointestinal system (GI). Estrogen receptors have been established to line the GI system and estradiol injections can alleviate stomach pain, according to a trial[ 15 , 16 ]. In one study, researchers discovered that 40% of the CD patients who participated in the study experienced severe pain and complained of dysmenorrhea[ 12 ]. Menstrual symptoms may make it more difficult for a patient to perceive the activity of IBD, according to the positive correlation between CD activity levels and the menstrual distress questionnaire distributed in the study[ 12 ]. In a study by Shirwaikar Thomas et al [ 17 ], patients with lower menstrual distress scores had better quality of life for IBD[ 17 ]. In one prospective trial, researchers looked at how women’s symptoms specific for and nonspecific for IBD changed during the menstrual cycle. Compared to the premenstrual and postmenstrual phases, the menstrual period was marked by greater abdominal discomfort for both the patient and the control groups. Compared to the control group, the patient group reported looser stools and more frequent feces, as well as more severe abdominal pain[ 18 ]. Another study assessed the severity of GI symptoms in patients with IBD who underwent biological therapy vs traditional treatments during menstruation. There were no discernible differences between the two groups of patients[ 17 ]. Clinicians should be aware of the potential impact of the cycle phases when assessing the cyclical aggravation of GI symptoms[ 17 ]. To improve women’s health during menstruation, treatment options should be used to reduce the cyclical aggravation of symptoms of IBD. A study by Lahat et al [ 15 ] identified risk factors in people with IBD, leading to worsening of symptoms during both the premenstrual phase and menstruation. Smoking was found to significantly worsen premenstrual symptoms including nervousness, lower back pain, nausea, and fatigue[ 15 ].

Endometriosis is a painful disorder in which endometrial tissue grows outside the uterus, covering the ovaries, fallopian tubes, and other pelvic tissues. Its prevalence varies from 5% to 10% in women[ 10 , 29 ]. In many cases, women with endometriosis have difficulty conceiving and experience abdominal and menstrual pain[ 10 , 30 ]. The beneficial impact of adalimumab in reducing endometriosis levels has been reported in animal studies[ 10 ]. In one study, rats affected by endometriosis were given adalimumab and the results were analyzed with respect to changes in histological and biochemical characteristics. Macroscopic and histological evaluations revealed a decrease in endometrium tissue. When evaluating biochemical markers, it was found that adalimumab treatment caused the concentration of fibrillin-1, a fibrosis indicator, to drop. Adalimumab is believed to have reduced endometriosis by suppressing TNF-α and other inflammatory factors because they are cytokines involved in the etiology of endometriosis[ 10 ]. This trial demonstrated the anti-inflammatory effects of adalimumab on histological alterations of endometriosis and a decrease in fibrosis in rats. Since most of the data come from animal studies, there is a major knowledge gap in this area and more studies are needed. The evaluation of the impact of infliximab on pain reduction in women with profound endometriosis produced some interesting results. TNF-α medication was expected to considerably decrease pain in endometriosis patients, since inflammation is related to the pathophysiology of the condition. According to the findings of a study, only 30% of individuals who received infliximab experienced pain relief[ 31 ]. This finding was comparable to the results in the placebo group. No discernible reduction in endometriosis was observed with infliximab administration when evaluating the degree of endometriosis at the time of surgery[ 31 ]. It is likely that treatment was ineffective because the etiologies of superficial and deep endometriosis pain are different[ 28 , 31 , 32 ]. Upon examination of other anti-TNF-α drugs, the authors found that the administration of an anti-TNF-α monoclonal antibody (C5N) had positive therapeutic effects in reducing endometriosis in baboons. The findings of one study demonstrated that, compared to the control group, anti-TNF-α C5N reduces both the extent of the damage and the area affected by endometriosis. The menstrual cycle had not been disrupted when the baboons received therapy. Therefore, these trials can serve as a crucial starting point in the search for an effective method of treating human endometriosis[ 33 ].

Adalimumab, a tumor necrosis factor alpha inhibitor, is a drug that is frequently used in the treatment of many inflammatory diseases. The Food and Drug Administration initially approved it for the treatment of rheumatoid arthritis[ 19 ]. Adalimumab is now authorized for the treatment of several different disorders, including rheumatoid arthritis, ankylosing spondylitis, CD, and UC[ 20 ]. The main side effects of Adalimumab include infections, lupus-like disease, and others[ 20 ]. Menstrual abnormalities are listed as potential, infrequent adverse effects of taking adalimumab, and there are relatively few case studies that discuss how to treat them[ 21 ]. In one published case report, a woman who used adalimumab and experienced menorrhagia and dysmenorrhea was described. When oral contraceptives were administered to the patient, menorrhagia and menstrual discomfort were reduced to manageable levels[ 5 ]. Another study presented a similar case, where adalimumab caused menorrhagia that was relieved by prescribing oral contraceptives[ 7 ]. Some studies have shown that TNF-α levels are crucial to maintaining a normal menstrual cycle, as they are significantly higher during the menstrual phase than during the luteal phase[ 22 ]. Moreover, TNF-α may also induce apoptosis and cell dissociation in the endometrium, resulting in menstrual shedding and excessive bleeding, according to another mechanism[ 23 ]. TNF-α and other inflammatory mediators have been administered in several trials, and as a result, endometrial bleeding and vascular injury have been observed. This evidence suggests that TNF-α administration may cause significant uterine bleeding[ 7 , 24 ]. In particular, adalimumab has been found to restore menstruation in premature ovarian failure, in addition to causing atypical menstrual bleeding. One case included a patient with adalimumab prescription. Her doctor administered a combination of progesterone and estrogen to prevent osteoporosis 20 mo before the start of adalimumab treatment because her menstrual cycle had completely stopped. The patient had menopausal-specific hormone levels, including significantly lower levels of estradiol and androgen and higher levels of follicular stimulating hormone. Her menstrual cycle returned 3 mo after the administration of adalimumab, and hormone therapy was discontinued[ 21 ].

It is difficult for clinicians to make the correct diagnosis and select the best course of treatment for women with IBD and gynecological diseases. It is crucial to perform a more detailed examination and to take a more holistic approach with patients who have both conditions, because their symptoms may overlap or do not signify the progression of these diseases. Furthermore, new research indicates that biological therapy may be used more widely than previously thought, and additional research is required to determine the safety and efficacy of its application for humans.

An electronic search of the global literature on menstrual disorders in patients with IBD and the effects of anti-TNF-α drugs on gynecological pathology was performed. The scientific literature was searched using the PubMed, Medline, and Web of Science information search systems. The period from which publications were collected was 1995-2023. The search used the following keywords and their compounds: Menstrual cycle changes in CD patients; menstrual cycle changes in ulcerative colitis (UC) patients; anti-TNF-α and menstruation; effect of adalimumab on gynecology; effect of adalimumab on menstruation; effect of infliximab on gynecology; effect of infliximab on menstruation. A total of 938 articles and abstracts met the initial search criteria. Of the 938 articles, 72 were chosen for full-text review. As many as 13 articles met the eligibility criteria and were included in the final review (Tables 1 - 3 ). Inflammatory bowel disease and menstrual abnormalities IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; MDQ: Mayo dysphagia questionnaire. Anti-tumor necrosis factor and gynecology in animal studies TNF: Tumor necrosis factor. Anti-tumor necrosis factor and gynecology: Case reports Studies were considered eligible if they met the following criteria: (1) The article meets the purpose of the review; and (2) the article is written in English. The exclusion criteria were as follows: (1) No full article available; (2) studies of children with primary amenorrhea; (3) studies analyzing the relationship between pregnancy and IBD; and (4) studies analyzing the effect of anti-TNF-α on pregnancy.

Inflammatory bowel disease (IBD) is a chronic condition that affects young individuals in their reproductive years[ 1 ]. IBD may have long-term implications on the reproductive, sexual, developmental, and mental health of those affected, so clinicians who treat IBD in women should emphasize this concern. Although population–based studies showed that the rate of infertility among patients with IBD is comparable to the incidence in the general population[ 2 ], psychological issues and mechanical complications caused by surgeries can affect fertility in women with IBD. Furthermore, Crohn’s disease (CD) has been associated with menstrual abnormalities[ 3 ]. In rare cases, the administration of biological therapy, which is now frequently used in the treatment of IBD, can also result in gynecological abnormalities in addition to the disease itself. Menstrual disorders are described as potentially unusual adverse effects associated with the use of infliximab or adalimumab. However, there are relatively few case studies or reports that discuss how to treat and diagnose these conditions. In addition, tumor necrosis factor-α (TNF-α) inhibitors, which are commonly used in the treatment of IBD, may be related to menorrhagia and may affect endothelial cell growth, function, and vessel remodeling in the uterus. Elevated production of pro-inflammatory mediators is believed to play a key role in the manifestation of the circumstances leading to polycystic ovarian syndrome or irregular uterine bleeding[ 4 ]. Furthermore, the TNF-α inhibitor adalimumab has been linked in several cases to reproductive diseases in women, such as irregular menstruation[ 5 - 7 ]. However, several animal studies have provided new information on the benefits of biological therapy for endometriosis and reproductive function[ 8 - 10 ]. The purpose of our review was to present potential menstrual cycle problems in patients with IBD and to discuss the impact of adalimumab and other anti-TNF drugs on gynecological pathology. Currently, there are no data available on different biologic treatments, including vedolizumab, ustekinumab, or the small molecule Janus kinase inhibitor tofictinib and menstrual cycle.