CD often sets on in a child-bearing age[1]. It remains a controversy that CD impairs fertility of women. Studies have shown a low fertility rate in CD women compared to the healthy. However, this low rate may be attributed to delayed fertilization or woman’s unwillingness to be fertilized. This unwillingness can be aroused by disease activity, medication history, surgery, etc[15]. Meanwhile, as the fertilization delays, the ovarian reserve declines. In addition, CD may also involve the ovarian ducts and the ovaries, the inflammation of which also damages female fertility[16, 17]. Therefore, it is a clinical urgency to define the association of CD with female fertility, as well as the risk factors of decreased ovarian reserve[18, 19]. This information can help CD women to design an optimal strategy for pregnancy.
AMH, a member of transforming growth factor family, is produced by antral or preantral follicles, and can be first detected as a follicle-released substance in the periphery blood. Its level fluctuates mildly during the menstrual period, thus making it more convenient and accurate than other indexes in evaluating ovarian reserve[20]. A low AMH level predicts a low ovarian reserve or weaker response to ovarian stimulation. A study has verified the accuracy of AMH in predicting the ovarian reserve in females with lupus erythematosus, indicating that AMH can be used to evaluate the toxicity in sexual glands. Therefore, AMH was introduced into the present study to judge the ovarian reserve and potential fertility of females with CD.
In this study, the AMH level in CD women was significantly lower than that in the healthy (2.17±2.23ug/L vs 3.95±2.01ug/L; 95%CI [1.34 to 2.21], P<0.001,), so was the incidence of decreased ovarian reserve (AMH≤1.1 ug/L) (42.15% vs 0%, P<0.001). These findings verify that the ovarian reserve declines in CD women, thus explaining why CD women show a lower fertility rate than the healthy[17, 21].
Ovarian reserve falls as age increases, which is also proven in the present study. In both groups, the AMH levels decreased with age, but their decreasing rate showed no significant between-group difference. Subgroup analysis further demonstrated that age>30 years (OR, 2.905; 95%CI [1.053-8.531], P=0.017) was an independent risk factor of decreased ovarian reserve in CD women, a finding that supports the profile of AMH in these patients. Therefore, for CD women aged over 30 years and refusing fertilization, health education should be carried out to alleviate their anxiety about disease heritability and adverse pregnancy outcomes.
During the development of CD, pro-inflammatory factors are released into the blood, then penetrate the bowel wall, and trigger peritoneal inflammation that may further involve the ovaries. This pathology, though having not led to reproductive organic damage, may still decline fertility. Winger has found that the use of a TNF-alpha inhibitor and intravenous immunoglobulin (IVIG) significantly improves in vitro fertilization (IVF) outcome in young infertile women withTh1/Th2 cytokine elevation[22]. In a study including 35 CD women, the AMH level is inversely associated with the score of Crohn’s Disease Activity Index (CDAI)[23]. In the present study, we found a consistent result that disease activity (OR, 4.314; 95%CI[1.561-12.910], P=0.002) is an independent risk factor of decreased ovarian reserve. It has also proven that the risk of adverse pregnancy is higher in the active phase than in the remitting phase[21, 24]. Therefore, accelerating the disease into the remitting phase can reduce the damage to ovarian reserve and increase the odds of successful fertilization.
Some drugs have been suspected to have negative effects on ovarian reserve. In the present study, we reviewed the history of medication in CD women. Multivariate analysis discovered use of thalidomide (OR,12.628; 95%CI[4.351-42.380]; P<0.001) as an independent risk factor for decreased ovarian reserve, which is consistent with our previous finding that thalidomide exerts negative effects on ovarian reserve[5]. Thalidomide, as a palliative and antiemetic, has been marketized to treat during-pregnancy vomiting, but later withdrawn for its teratogenic effect[25]. In 1960, its immunomodulatory effect was exploited to deal with Behcet’s disease and erythema nodosum[26]. Currently, this drug is selected for refractory CD that fails first-line and second-line treatments[27, 28].
We speculate that thalidomide can repress TGF to inhibit follicular growth and decrease ovarian reserve. TGF-α acts to promote the proliferation and differentiation of germ cells. In vitro studies have exhibited that TGF-α is expressed in ovarian follicles and theca-interstitial cells and regulates follicular growth, degeneration and atresia[29]. In the primordial phase, TGF-α is highly expressed in the oocytes, and as the primordial follicles develop, its expression decreases, indicating that it mainly modulates the development of primordial follicles and oocytes[30].
Thalidomide can suppress the expression of TNF-α, IL-6, IL-8, as well as TGF-α and TGF-β[31]. TGF downregulation further inhibits follicular growth, thus decreasing ovarian reserve. Therefore, CD women, if willing to be fertilized or pregnant, should avoid use of thalidomide. If unavoidable, their ovarian reserve should be closely monitored during medication.
We next assessed the effect of CD duration, extent, behavior and surgery on ovarian reserve. The results showed that they decreased ovarian reserve, but this decrease was not statistically significant. Previous studies have presented that surgery may decline the fertility of patients with inflammatory bowel disease, which can be explained by the fact that pelvic surgery, especially ileum pouch-anal anastomosis (IPPA), may injure reproductive organs, mainly the ovaries and oviducts[32]. But we did not find out the association between surgery and decreased ovarian reserve. As to reasons, we suppose that for CD patients, related abdominal surgery brings less injury to pelvic organs. In addition, the low fertility in CD women is not just associated with decreased ovarian reserve, but also post-surgical adhesions[33]. In the present study, we just evaluated the effect of ovarian reserve on fertility.
Despite above-mentioned inspiring results, the present study, as a retrospective study, should be challenged with better-designed studies in the future. The mechanism underlying the effect of CD (such as activity, behavior) and medication on ovarian reserve should be elucidated through prospective and clinical studies. We believe that our findings in the present study can be used to improve the management of CD women.