Does an association exist between menstrual cycle length within the normal range and ovarian reserve biomarkers during the reproductive years? A systematic review and meta-analysis

BACKGROUND: Regular menstrual cycling during the reproductive years is an indicator of spontaneous ovulation but sometimes falsely perceived as an indicator of preserved fertility. In contrast, menstrual cycle shortening, a physiologic occurrence preceding the menopausal transition, is not usually perceived as an indicator of decreased ovarian reserve in the general population. OBJECTIVE AND RATIONALE: The individual decrease in menstrual cycle length (MCL) might represent a sensitive biomarker of diminishing ovarian reserve. The aim of this systematic review and meta-analysis is to examine the possible association between MCL in regularly cycling women (21-35 days) and ovarian reserve tests (ORT), fecundability in natural cycles and IVF outcomes. SEARCH METHODS: An electronic database search employing PubMed, Web of Science, Trip, EBSCO, ClinicalTrials.gov and the Cochrane library was performed to identify research articles, only on human, published between January 1978 and August 2019. Search terms were pregnancy OR fertility OR fecundity OR fecundability, anti-Miillerian hormone OR AMH OR antral follicle count OR AFC OR ovarian reserve OR ovarian reserve test, in vitro fertilization OR ART OR assisted reproductive therapy OR assisted reproductive treatment OR assisted reproductive technology OR IVF OR ICSI, menstrual cycle length OR menstrual cycle characteristics. We combined these terms to complete the search. All prospective and retrospective studies exploring an association between MCL and proxies of ovarian reserve were included. The exclusions included studies of PCOS, ovarian failure, oral contraception treatment, prior chemotherapy and/or radiotherapy or ovarian surgery. The Newcastle-Ottawa scale was used to assess the quality of studies that were eligible for meta-analysis. OUTCOMES: Eleven studies were eligible for meta-analysis, including 12 031 women. The included studies had a low risk of bias. Short MCL (21-27 days) was associated with lower ORT values as compared to normal (28-31 days), long (32-35 days) and all other (28-35 days) MCL sets. The estimated weighted mean difference (WMD) of AMH level was -1.3 ng/mL (95% CI: -1.75 to -0.86, P < 0.001) between the short and normal MCL sets. The estimated WMD of AFC values was -5.17 (95% CI: -5.96 to -4.37, P < 0.001) between the short and normal MCL sets. The weighted overall odds ratio (OR) of fecundability in natural cycles between women with short versus normal MCL sets was statistically significant (overall OR 0.81; 95% CI 0.72-0.91, P < 0.001). In the IVF setting, fewer oocytes were retrieved in short MCL in comparison to normal, long and all other MCL sets, with an estimated WMD of -1.8 oocytes (95% CI: -2.5 to -1.1, P < 0.001) in the short versus normal MCL sets. The weighted overall OR of clinical pregnancy rate between women with short versus all other MCL sets was statistically significant (overall OR 0.76; 95% CI: 0.60 to 0.96, P = 0.02). Low levels of heterogeneity were found in most meta-analyses of MCL and qualitative ovarian reserve biomarkers, while heterogeneity was high in meta-analyses performed for quantitative measures. WIDER IMPLICATIONS: MCL in regularly cycling women is closely related to ovarian reserve biomarkers during the reproductive years. A short MCL, as compared to normal, is significantly associated with lower ORT values, reduced fecundability and inferior IVF outcomes, independent of age. The results imply that short MCL may be a sign of ovarian aging, combining the quantitative and qualitative facets of ovarian reserve. Educational efforts ought to be designed to guide women with short MCL at a young age, who desire children in the future, to seek professional counselling.