Characteristics of menstrual cycles with or without intercourse in women with no known subfertility.

STUDY QUESTION: Does sexual intercourse enhance the cycle fecundability in women without known subfertility? SUMMARY ANSWER: Sexual intercourse (regardless of timing during the cycle) was associated with cycle characteristics suggesting higher fecundability, including longer luteal phase, less premenstrual spotting and more than 2 days of cervical fluid with estrogen-stimulated qualities. WHAT IS KNOWN ALREADY: Human females are spontaneous ovulators, experiencing an LH surge and ovulation cyclically, independent of copulation. Natural conception requires intercourse to occur during the fertile window of a woman's menstrual cycle, i.e. the 6-day interval ending on the day of ovulation. However, most women with normal fecundity do not ovulate on Day 14, thus the timing of the hypothetical fertile window varies within and between women. This variability is influenced by age and parity and other known or unknown elements. While the impact of sexual intercourse around the time of implantation on the probability of achieving a pregnancy has been discussed by some researchers, there are limited data regarding how sexual intercourse may influence ovulation occurrence and menstrual cycle characteristics in humans. STUDY DESIGN SIZE DURATION: This study is a pooled analysis of three cohorts of women, enrolled at Creighton Model FertilityCare centers in the USA and Canada: 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006) and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cycle phase lengths, bleeding and cervical mucus patterns and estimated the fertile window in 2564 cycles of 530 women, followed for up to 1 year. PARTICIPANTS/MATERIALS SETTING METHODS: Participants were US or Canadian women aged 18-40 and not pregnant, who were heterosexually active, without known subfertility and not taking exogenous hormones. Most of the women were intending to avoid pregnancy at the start of follow-up. Women recorded daily vaginal bleeding, mucus discharge and sexual intercourse using a standardized protocol and recording system for up to 1 year, yielding 2564 cycles available for analysis. The peak day of mucus discharge (generally the last day of cervical fluid with estrogen-stimulated qualities of being clear, stretchy or slippery) was used to identify the estimated day of ovulation, which we considered the last day of the follicular phase in ovulatory cycles. We used linear mixed models to assess continuous cycle parameters including cycle, menses and cycle phase lengths, and generalized linear models using Poisson regression with robust variance to assess dichotomous outcomes such as ovulatory function, short luteal phases and presence or absence of follicular or luteal bleeding. Cycles were stratified by the presence or absence of any sexual intercourse, while adjusting for women's parity, age, recent oral contraceptive use and breast feeding. MAIN RESULTS AND THE ROLE OF CHANCE: Most women were <30 years of age (75.5%; median 27, interquartile range 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators and nulliparous (70.9%). Cycles with no sexual intercourse compared to cycles with at least 1 day of sexual intercourse were shorter (29.1 days (95% CI 27.6, 30.7) versus 30.1 days (95% CI 28.7, 31.4)), had shorter luteal phases (10.8 days (95% CI 10.2, 11.5) versus 11.4 days (95% CI 10.9, 12.0)), had a higher probability of luteal phase deficiency (<10 days; adjusted probability ratio (PR) 1.31 (95% CI 1.00, 1.71)), had a higher probability of 2 days of premenstrual spotting (adjusted PR 2.15 (95% CI 1.09, 4.24)) and a higher probability of having two or fewer days of peak-type (estrogenic) cervical fluid (adjusted PR 1.49 (95% CI 1.03, 2.15)). LIMITATIONS REASONS FOR CAUTION: Our study participants were geographically dispersed but relatively homogeneous in regard to race, ethnicity, income and educational levels, and all had male partners, which may limit the generalizability of the findings. We cannot exclude the possibility of undetected subfertility or related gynecologic disorders among some of the women, such as undetected endometriosis or polycystic ovary syndrome, which would impact the generalizability of our findings. Acute illness or stressful events might have reduced the likelihood of any intercourse during a cycle, while also altering cycle characteristics. Some cycles in the no intercourse group may have actually had undocumented intercourse or other sexual activity, but this would bias our results toward the null. The Creighton Model FertilityCare System (CrM) discourages use of barrier methods, so we believe that most instances of intercourse involved exposure to semen; however, condoms may have been used in some cycles. Our dataset lacks any information about the occurrence of female orgasm, precluding our ability to evaluate the independent or combined impact of female orgasm on cycle characteristics. WIDER IMPLICATIONS OF THE FINDINGS: Sexual activity may change reproductive hormonal patterns, and/or levels of reproductive hormones may influence the likelihood of sexual activity. Future work may help with understanding the extent to which exposure to seminal fluid, and/or female orgasm and/or timing of intercourse could impact menstrual cycle function. In theory, large data sets from women using menstrual and fertility tracking apps could be informative if women can be appropriately incentivized to record intercourse completely. It is also of interest to understand how cycle characteristics may differ in women with gynecological problems or subfertility. STUDY FUNDING/COMPETING INTERESTS: Funding for the research on the three cohorts analyzed in this study was provided by the Robert Wood Johnson Foundation #029258 (Creighton Model MultiCenter Fecundability Study), the Eunice Kennedy Shriver National Institute of Child Health and Human Development 1K23 HD0147901-01A1 (Time to Pregnancy in Normal Fertility) and the Office of Family Planning, Office of Population Affairs, Health and Human Services 1FPRPA006035 (Creighton Model Effectiveness, Intentions, and Behaviors Assessment). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an inter-rater agreement study.

OBJECTIVE: To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially. DESIGN: Inter-rater agreement study. SETTING: Five urban surgical centres. POPULATION: Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study. METHODS: Laparoscopies were diagnosed, digitally recorded, and reassessed. MAIN OUTCOME MEASURES: Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias-adjusted kappa values (κ) were calculated for diagnosis, and weighted κ values were calculated for staging. RESULTS: Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean κ = 0.67, range 0.61-0.69; mean κ = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports (n = 148; mean κ = 0.88, range 0.85-0.89; mean κ = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases. CONCLUSION: Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments. TWEETABLE ABSTRACT: Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial.

Sexual and physical abuse and gynecologic disorders.

STUDY QUESTION: Is sexual and/or physical abuse history associated with incident endometriosis diagnosis or other gynecologic disorders among premenopausal women undergoing diagnostic and/or therapeutic laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: No association was observed between either a history of sexual or physical abuse and risk of endometriosis, ovarian cysts or fibroids; however, a history of physical abuse was associated with a higher likelihood of adhesions after taking into account important confounding and mediating factors. WHAT IS KNOWN ALREADY: Sexual and physical abuse may alter neuroendocrine-immune processes leading to a higher risk for endometriosis and other noninfectious gynecologic disorders, but few studies have assessed abuse history prior to diagnosis. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at 1 of the 14 surgical centers located in Salt Lake City, UT, USA or San Francisco, CA, USA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Prior to surgery, women completed standardized abuse questionnaires. Relative risk (RR) of incident endometriosis, uterine fibroids, adhesions or ovarian cysts by abuse history were estimated, adjusting for age, race/ethnicity, education, marital status, smoking, gravidity and recruitment site. We assessed whether a history of chronic pelvic pain, depression, or STIs explained any relationships via mediation analyses. MAIN RESULTS AND ROLE OF CHANCE: 43 and 39% of women reported experiencing sexual and physical abuse. No association was observed between either a history of sexual or physical abuse, versus no history, and risk of endometriosis (aRR: 1.00 [95% confidence interval (CI): 0.80-1.25]); aRR: 0.83 [95% CI: 0.65-1.06]), ovarian cysts (aRR: 0.67 [95% CI: 0.39-1.15]); aRR: 0.60 [95% CI: 0.34-1.09]) or fibroids (aRR: 1.25 [95% CI: 0.85-1.83]); aRR: 1.36 [95% CI: 0.92-2.01]). Conversely, a history of physical abuse, versus no history, was associated with higher risk of adhesions (aRR: 2.39 [95% CI: 1.18-4.85]). We found no indication that the effect of abuse on women's adhesion risk could be explained by a history of chronic pelvic pain, depression or STIs. LIMITATIONS, REASONS FOR CAUTION: Limitations to our study include inquiries on childhood physical but not sexual abuse. Additionally, we did not inquire about childhood or adulthood emotional support systems, found to buffer the negative impact of stress on gynecologic health. WIDER IMPLICATIONS OF THE FINDINGS: Abuse may be associated with some but not all gynecologic disorders with neuroendocrine-inflammatory origin. High prevalence of abuse reporting supports the need for care providers to screen for abuse and initiate appropriate follow-up. STUDY FUNDING/COMPETING INTERESTS: Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.

Pain typology and incident endometriosis.

STUDY QUESTION: What are the pain characteristics among women, with no prior endometriosis diagnosis, undergoing laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: Women with surgically visualized endometriosis reported the highest chronic/cyclic pain and significantly greater dyspareunia, dysmenorrhea, and dyschezia compared with women with other gynecologic pathology (including uterine fibroids, pelvic adhesions, benign ovarian cysts, neoplasms and congenital Müllerian anomalies) or a normal pelvis. WHAT IS KNOWN ALREADY: Prior research has shown that various treatments for pain associated with endometriosis can be effective, making identification of specific pain characteristics in relation to endometriosis necessary for informing disease diagnosis and management. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at one of 14 surgical centers located in Salt Lake City, UT or San Francisco, CA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Endometriosis was defined as surgically visualized disease; staging was based on revised American Society for Reproductive Medicine (rASRM) criteria. All women completed a computer-assisted personal interview at baseline specifying 17 types of pain (rating severity via 11-point visual analog scale) and identifying any of 35 perineal and 60 full-body front and 60 full-body back sites for which they experienced pain in the last 6 months. MAIN RESULTS AND THE ROLE OF CHANCE: There was a high prevalence (≥30%) of chronic and cyclic pelvic pain reported by the entire study cohort regardless of post-operative diagnosis. However, women with a post-operative endometriosis diagnosis, compared with women diagnosed with other gynecologic disorders or a normal pelvis, reported more cyclic pelvic pain (49.5% versus 31.0% and 33.1%, P < 0.001). Additionally, women with endometriosis compared with women with a normal pelvis experienced more chronic pain (44.2 versus 30.2%, P = 0.04). Deep pain with intercourse, cramping with periods, and pain with bowel elimination were much more likely reported in women with versus without endometriosis (all P < 0.002). A higher percentage of women diagnosed with endometriosis compared with women with a normal pelvis reported vaginal (22.6 versus 10.3%, P < 0.01), right labial (18.4 versus 8.1%, P < 0.05) and left labial pain (15.3 versus 3.7%, P < 0.01) along with pain in the right/left hypogastric and umbilical abdominopelvic regions (P < 0.05 for all). Among women with endometriosis, no clear and consistent patterns emerged regarding pain characteristics and endometriosis staging or anatomic location. LIMITATIONS, REASONS FOR CAUTION: Interpretation of our findings requires caution given that we were limited in our assessment of pain characteristics by endometriosis staging and anatomic location due to the majority of women having minimal (stage I) disease (56%) and lesions in peritoneum-only location (51%). Significance tests for pain topology related to gynecologic pathology were not corrected for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Results of our research suggest that while women with endometriosis appear to have higher pelvic pain, particularly dyspareunia, dysmenorrhea, dyschezia and pain in the vaginal and abdominopelvic area than women with other gynecologic disorders or a normal pelvis, pelvic pain is commonly reported among women undergoing laparoscopy, even among women with no identified gynecologic pathology. Future research should explore causes of pelvic pain among women who seek out gynecologic care but with no apparent gynecologic pathology. Given our and other's research showing little correlation between pelvic pain and rASRM staging among women with endometriosis, further development and use of a classification system that can better predict outcomes for endometriosis patients with pelvic pain for both surgical and nonsurgical treatment is needed. STUDY FUNDING/COMPETING INTERESTS: Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.

Effects of over-the-counter analgesic use on reproductive hormones and ovulation in healthy, premenopausal women.

STUDY QUESTION: Does use of commonly used over-the-counter (OTC) pain medication affect reproductive hormones and ovulatory function in premenopausal women? SUMMARY ANSWER: Few associations were found between analgesic medication use and reproductive hormones, but use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for potential confounders. WHAT IS KNOWN ALREADY: Analgesic medications are the most commonly used OTC drugs among women, but their potential effects on reproductive function are unclear. STUDY DESIGN, SIZE, DURATION: The BioCycle Study was a prospective, observational cohort study (2005-2007) which followed 259 women for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS, SETTING, METHODS: Two hundred and fifty-nine healthy, premenopausal women not using hormonal contraception and living in western New York state. Study visits took place at the University at Buffalo. MAIN RESULTS AND THE ROLE OF CHANCE: During study participation, 68% (n = 175) of women indicated OTC analgesic use. Among users, 45% used ibuprofen, 33% acetaminophen, 10% aspirin and 10% naproxen. Analgesic use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for age, race, body mass index, perceived stress level and alcohol consumption (OR 0.36 [0.17, 0.75]). Results remained unchanged after controlling for potential confounding by indication by adjusting for 'healthy' cycle indicators such as amount of blood loss and menstrual pain during the preceding menstruation. Moreover, luteal progesterone was higher (% difference = 14.0, -1.6-32.1, P = 0.08 adjusted) in cycles with follicular phase analgesic use, but no associations were observed with estradiol, LH or FSH. LIMITATIONS, REASONS FOR CAUTION: Self-report daily diaries are not validated measures of medication usage, which could lead to some classification error of medication use. We were also limited in our evaluation of aspirin and naproxen which were used by few women. WIDER IMPLICATIONS OF THE FINDINGS: The observed associations between follicular phase analgesic use and higher progesterone and a lower probability of sporadic anovulation indicate that OTC pain medication use is likely not harmful to reproduction function, and certain medications possibly improve ovulatory function. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275200403394C). The authors have no conflicts of interest to disclose.