Long-term Oral Contraceptives Research Articles

Abstract 3442: Factors modifying the association between hormonal contraception and risk of early-onset breast cancer

Abstract Breast cancer rates among women younger than 50 years-old have been steadily increasing since the mid-1990s. There is consistent evidence that use of combination estrogen and progesterone oral contraceptives (OCs)—including contemporary formulations with lower estrogen—increases breast cancer risk. It is unclear, however, if this risk varies by factors such as progestin type in the OC formulation, timing of OC use, histopathologic characteristics of the breast cancer, or individual patient characteristics. This study included premenopausal women aged <50 years and cancer-free when they enrolled in the U.S.-based American Cancer Society Cancer Prevention Study-3 cohort between 2006 and 2013 (n=101,838 women). At enrollment participants responded to a detailed life history questionnaire including questions about type, brand, duration, and recency of OC use. Incident breast cancers diagnosed between 2006-2018 were identified through cancer registry linkages (n=759). Participants were followed until the first of 1) breast cancer diagnosis, 2) age >50 years, or 3) December 31, 2018. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate associations between OC use and breast cancer risk. On average, participants were 39.3 years at baseline and were followed for 5.7 years (up to 12.3 years). Current versus never use of OCs for 10+ years was associated with a higher risk of breast cancer (10-<20 years: HR=1.46, 95% CI: 1.03-2.07; 20-<30 years: HR=1.66, 95% CI: 1.14-2.41; 30+ years HR= 2.51, 95% CI: 0.77-8.16). Cessation of OC use progressively attenuated the association down to the null 15 years after discontinuation of use (HR=1.04, 95% CI: 0.73-1.49). Associations with current OC use varied by generation of progestin in the formulation (first generation: HR=1.37, 95% CI: 0.93-2.02; second: HR=1.79, 95% CI: 1.20-2.67; third: HR=1.65, 95% CI: 1.13-2.42; fourth: HR= 0.91, 95% CI: 0.49-1.67). The strongest associations were observed for use of formulations with norgestrel: HR=2.82, 95% CI: 1.54-5.19; norgestimate: HR=1.80, 95% CI: 1.19-2.72; and levonorgestrel: HR=1.56, 95% CI: 1.00-2.43. The OC-breast cancer associations were primarily limited to localized, grade 1 or 2, and ER+ disease. Race, income, body mass index, physical activity, alcohol use, cigarette smoking, parity, and breastfeeding did not appear to modify the associations. There were also no clear differences in the associations based on age at first or last OC use or timing relative to pregnancy. Current, long-term OC use was associated with increased risk of early-onset breast cancer. These data suggest that risks may vary with progestin content, and future studies are needed to define formulations that minimize breast cancer risk while still maximizing protection against other female cancers. Citation Format: Lauren R. Teras, Emily L. Deubler, Mark E. Sherman, Clara Bodelon, Lauren E. McCullough, James M. Hodge, Sicha Chantaprasopsuk, Alpa V. Patel. Factors modifying the association between hormonal contraception and risk of early-onset breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3442.

Hepatic Adenoma Secondary to Long-Term Oral Contraception Use in a Young Female

Hepatic Adenoma Secondary to Long-Term Oral Contraception Use in a Young Female

Response to a Water Bolus in Long Term Oral Contraceptive Users.

The purpose of our study was to determine the responses to an acute water bolus in long-term oral contraception (OCP) users. Seventeen female volunteers (27 ± 5 y, 64.1 ± 13.7 kg, 39.6 ± 5.9 kg/LBM) provided consent and enrolled in our study. All were long-term OCP users and participated in two trials, one during the active pill (High Hormone, HH) dose of their prescribed OCP and one during the sham pill (Low Hormone, LH) dose. Participants reported to the laboratory euhydrated, were fed breakfast, remained seated for 60 min and were provided a bolus of room temperature water in the amount of 12 mL/kg/LBM. Urine output over 180 min was measured. Nude body mass was measured pre- and post-trial. Urine specific gravity (USG) and urine osmolality were analyzed. Between trials, there were no differences in 3-h total urine volume (P = 0.296), 3-h USG (P = 0.225), 3-h urine osmolality (P = 0.088), or 3-h urine frequency (P = 0.367). Heart rate was not different between trials (P = 0.792) nor over time (P = 0.731). Mean arterial pressure was not different between trials (P = 0.099) nor over time (P = 0.262). Perceived thirst demonstrated a significant main effect for increasing over time regardless of trial (P < 0.001) but there was no difference between trials (P = 0.731). The urgency to void was not different between trials (P = 0.149) nor over time (P = 0.615). Plasma volume change was not different between trials (P = 0.847) (HH: −3.4 ± 5.0, LH post: −3.8 ± 4.5%) and plasma osmolality did not differ between trials (P = 0.290) nor over time (P = 0.967) (HH pre: 290 ± 4, HH post: 289 ± 4, LH pre: 291 ± 4, LH post: 291 ± 4 mosm/L). Blood glucose significantly decreased over time (P < 0.001) but there was no difference between trials (P = 0.780) (HH pre: 95.9 ± 113.9, HH post: 86.8 ± 6.5, LH pre: 95.9 ± 13.5, LH post: 84.6 ± 9.4 mmol/L). Copeptin concentration did not differ between phases of OCP use (P = 0.645) nor from pre- to post-trial (P = 0.787) Despite fluctuations in hormone concentrations, responses to a water bolus seem to be unaffected in OCP users in euhydrated, resting conditions.

Association between Oral Contraceptive Use and the High-Sensitivity C-Reactive Protein Level in Premenopausal Korean Women.

Although oral contraceptives (OCs) are widely used, few national epidemiological studies have evaluated the association between OC use and serum high-sensitivity C-reactive protein (hs-CRP) levels in Korean women. This population-based cross-sectional study was conducted with data from the 2015–2018 National Health and Nutrition Examination Survey. In the sample of 5332 premenopausal women aged ≥19 years, hs-CRP concentrations were 1.087 mg/L among OC users and 0.953 mg/L among OC non-users. After adjustment for confounders, OC users had an increased likelihood of having risky (>1.0 mg/L) hs-CRP levels (adjusted odds ratio (aOR) = 1.58; 95% confidence interval (CI), 1.25–1.98) compared with OC non-users. In addition, the aOR for high-risk (>3.0 mg/L) hs-CRP levels in OC users compared with non-users was 1.51 (95% CI, 1.06–2.16). These findings demonstrate that OC use alters the concentration of hs-CRP, a biomarker of chronic low-grade inflammation, and suggest that long-term OC use is a risk factor in the pathogenesis of inflammatory diseases, including cardiovascular diseases.

Long term use of oral contraceptives comprising synthetic estrogens induces an excessive breast cancer risk in BRCA mutation carrier women: a meta-analysis

Background: The relationship between oral contraceptive (OC) use and breast cancer risk is highly debated. Recent publications support a slight increase in overall breast cancer risk among OC user women, in particular among the current users. Women with inherited BRCA1 (Breast cancer type 1) or BRCA2 (Breast cancer type 2) gene mutations are at increased risk of breast and ovarian cancers, which is often mistakenly attributed to their elevated endogenous estrogen levels. The aim of presented meta-analysis was to assess the effects of OC use on breast cancer risk in BRCA mutation carrier women with minimal bias. Methods: A systematic search strategy was used to identify relevant studies, Stata (version 15) was used for meta-analysis. Results: Individual datasets from 13 studies totaling 20,202 patients were analyzed. The combined results showed no significant increase in risk of breast cancer in BRCA mutation carriers who had ever used oral contraceptive (HR = 1.09, 95% CI: 0.71–1.69 among BRCA1 mutation carriers and HR = 1.19, 95% CI: 0.73–1.95 among BRCA2 mutation carriers, respectively). However, in correlation with long-term (&gt;5 years) OC users, the breast cancer risk was significantly increased in both BRCA1 mutation carriers (HR = 1.39, 95% CI: 1.19–1.60) and BRCA1 mutation carriers (HR = 1.61, 95% CI: 1.25–1.96). Conclusion: The presented results indicate that in BRCA mutation carriers women who have defective liganded activation of estrogen receptors (ERs), the use of synthetic estrogens means an additive factor for ER deregulation further increasing the risk for breast cancer. Long term OC use in BRCA mutation carriers results in a significantly increased risk for breast cancer by exhausting the compensatory genome defending process.

S2733 A Curious Case of a Bleed Without a Cause

INTRODUCTION: Spontaneous subcapsular hematoma of the liver is usually associated with pregnancy, coagulopathy or liver lesion. We report a rare case of spontaneous subcapsular liver hematoma without any of the above risk factors. CASE DESCRIPTION/METHODS: A 59-year-old lady with a history of hypertension presented with sudden-onset in the right upper abdomen, right chest, shoulder and neck pain. She was otherwise hemodynamically stable other than being mildly hypertensive. Work-up for cardiac ischemia was negative. She was noted to have a low hemoglobin of 10.4 g/dl (prior baseline was 13.7 g/dL) and she had mild hepatocellular injury (ALT 32 IU/L, AST 31 IU/L). She underwent CT scan to rule out pulmonary embolism which incidentally revealed a large subcapsular liver hematoma. MRI abdomen confirmed a large lenticular shaped subscapular collection along the right lobe of the liver measuring approximately 12 × 4 × 16 cm. There was no focal hepatic lesion to explain the cause of bleeding. She did not recall any preceding trauma and there was no obvious trauma on exam. She was not taking any blood thinners. She admitted to inadvertently using oral contraceptives (OCP) for over 30 years for purely birth control purposes. The patient was admitted for observation and remained clinically stable over the next few days. At her 1-month follow-up, an office ultrasound showed that the size of the hematoma had decreased when compared to her prior ultrasound during her hospitalization (thickness from intercostal view decreased from 42 mm to 35 mm). At her 1-year follow-up, an MRI abdomen was repeated that showed a minimal residual hematoma and no discrete underlying lesion. DISCUSSION: Spontaneous subcapsular hematoma of the liver represents an accumulation of blood between the capsule of Glisson and the liver parenchyma, and is frequently located around the right lobe. If it ruptures into the peritoneum, it can be potentially fatal. Our case is unique in that none of the usual risk factors such as pregnancy, trauma, blood thinner use or underlying liver lesion were present. To our knowledge, there are very few similar case reports that describe spontaneous subcapsular hepatic hematoma. OCP use is generally associated with the development of hepatic adenoma, which can in turn cause spontaneous subcapsular hematoma. Theoretically, long-term OCP use in a post-menopausal hypertensive lady (such as in our case) may mimic the pathophysiology of pregnancy and independently lead to spontaneous subcapsular bleeding.Figure 1.: MRI showing large hepatic subcapsular hematoma and no focal lesion.Figure 2.: MRI showing nearly resolved hepatic subcapsular hematoma.

The preventable burden of endometrial and ovarian cancers in Australia: A pooled cohort study

ObjectiveEvidence on the endometrial and ovarian cancer burden preventable through modifications to current causal behavioural and hormonal exposures is limited. Whether the burden differs by population subgroup is unknown. MethodsWe linked pooled data from six Australian cohort studies to national cancer and death registries, and quantified exposure-cancer associations using adjusted proportional hazards models. We estimated exposure prevalence from representative health surveys. We then calculated Population Attributable Fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death, and compared PAFs for population subgroups. ResultsDuring a median 4.9 years follow-up, 510 incident endometrial and 303 ovarian cancers were diagnosed. Overweight and obesity explained 41.9% (95% CI 32.3–50.1) of the endometrial cancer burden and obesity alone 34.5% (95% CI 27.5–40.9). This translates to 12,800 and 10,500 endometrial cancers in Australia in the next 10 years, respectively. The body fatness-related endometrial cancer burden was highest (49–87%) among women with diabetes, living remotely, of older age, lower socio-economic status or educational attainment and born in Australia. Never use of oral contraceptives (OCs) explained 8.1% (95% CI 1.8–14.1) or 2500 endometrial cancers. A higher BMI and current long-term MHT use increased, and long-term OC use decreased, the risk of ovarian cancer, but the burden attributable to overweight, obesity or exogenous hormonal factors was not statistically significant. ConclusionsExcess body fatness, a trait that is of high and increasing prevalence globally, is responsible for a large proportion of the endometrial cancer burden, indicating the need for effective strategies to reduce adiposity.

To Evaluate the Difference of the Efficacy of Short or Long-Term Cyclic Low-Dose Monophasic Oral Contraceptive (OC) Hormonal Therapy in the Recurrence of Endometrioma after Surgery

To Evaluate the Difference of the Efficacy of Short or Long-Term Cyclic Low-Dose Monophasic Oral Contraceptive (OC) Hormonal Therapy in the Recurrence of Endometrioma after Surgery

Administration of Oral Contraceptives Could Alleviate Age-Related Fertility Decline Possibly by Preventing Ovarian Damage in a Mouse Model.

Age-related fertility decline is hypothesized to occur mainly by the spontaneous exhaustion and deterioration of the ovarian follicle, and the accumulation of ovarian tissue damage resulting from the ovulation cycle may play roles in the process. In this study, we hypothesized that suppressing ovulation would exert protective effects against age-related fertility decline. To test this hypothesis, we established a mouse model in which oral contraceptives (OCs) were administered daily. Female C57BL/6N mice were administered OCs daily from the age of 2 months to 12 months as an ovulation suppression mouse model. Mouse fecundity was investigated by counting oocyte number after ovarian stimulation and by examining live fetuses after mating. We found that compared with control mice administered vehicle alone, 12-month-old mice administered 2-fold dose OCs used for treating humans exhibited a significantly greater average oocyte number after ovarian stimulation (8.5 ± 0.6 vs 5.9 ± 0.6, P < .01). In addition, spontaneous conception with living fetuses after mating was strikingly increased in 12-month-old mice administered OCs relative to controls (6.0 ± 1.2 vs 0.4 ± 0.3, P < .01). In the histological examination of mouse ovarian tissues, we did not detect a significant difference in ovarian follicle number, but reduced amount of brownish foamy fibrous tissues, which might reflect ovarian tissue damage, was detected in aged mice administered OCs. These results suggest the possibility that long-term OC administration might alleviate age-related fertility decline, and the improvement mechanism could be attributed to the prevention of ovarian tissue damage by suppressing ovulation.

Longer oral contraception history as a possible preventive factor against fetal trisomy 21 in advanced maternal age pregnancies

Down syndrome is the most common autosomal chromosomal abnormality. According to the classical interpretation, it is the result of meiotic nondisjunction. Its occurrence is more common in advanced maternal age. Despite intensive research, pathophysiology of this genetic disorder is not fully understood. According to recent studies, a different kind of mechanism may be found in the background of trisomy 21 than was previously considered. Based on the ovarian mosaicism model, the cause of trisomy 21 (or any common trisomy) is a segregation error of a chromosome in premeiotic mitosis. The cell entering meiosis will be an oocyte with preexisting trisomy, where its (so-called "secondary") nondisjunction is essential. Maturation of the trisomic oocytes appears to fall behind the disomic oocytes, resulting in their relative accumulation in the ovaries as time progresses. The ratio of trisomic/disomic cells becomes less favorable in maternal maturity. If ovulation is inhibited - although the number of oocytes will continue to decline due to apoptosis - it can be assumed that the trisomic/disomic oocyte ratio remains more favorable with the progression of age. In our summary report, presenting and updating our previous data, we would like to propose that - according to ovarian mosaicism model - long-term oral contraception in the anamnesis may be beneficial in pregnancies with advanced maternal age. Orv Hetil. 2018; 159(28): 1146-1152.

Exogenous Hormone Use and Endometrial Cancer in U.S. Black Women.

Background: Although endometrial cancer risk differs among white and black women, few data on its associations with exogenous hormone use in the latter group are available. Studies have reported lower endometrial cancer risk among users of oral contraceptives (OCs), but higher risk among users of estrogen-only female menopausal hormones (FMHs). Evidence for the risk among estrogen plus progestin FMHs users is equivocal.Methods: We followed 47,555 Black Women's Health Study participants with an intact uterus from 1995 through 2013. Data on exogenous hormone use, covariates, and endometrial cancer were obtained biennially. Self-reported incident cases of endometrial cancer were confirmed by medical records or cancer registries whenever possible. We estimated incidence rate ratios (IRRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression.Results: We observed 300 endometrial cancer cases during 689,546 person-years of follow-up. Compared with never use, ≥10 years' duration of OC use was associated with lower risk (multivariable IRR = 0.45, 95% CI, 0.27-0.74), but risk was higher among current users of estrogen-only (IRR = 3.78, 95% CI, 1.69-8.43) and estrogen plus progestin FMH (IRR = 1.55, 95% CI, 0.78-3.11). Risk was not increased among former users of estrogen-only (IRR = 0.87, 95% CI, 0.44-1.72) or estrogen plus progestin FMH (IRR = 0.63, 95% CI, 0.36-1.09).Conclusions: Current use of estrogen-only and estrogen plus progestin FMH was associated with increased risk of endometrial cancer. Risk appeared lower among former users of estrogen plus progestin FMH. Long-term OC use was associated with reduced risk.Impact: Our results are generally consistent with those among white women. Cancer Epidemiol Biomarkers Prev; 27(5); 558-65. ©2018 AACR.

Endometriosis surgery and preservation of fertility, what surgeons should know

Colorectal surgeons often participate in the multidisciplinary management of young females with endometriosis. Complications of endometriosis as well as its management often result in infertility since they can involve all pelvic organs including the procreative organs: uterus, ovaries and fallopian tubes. Complete excision of all endometriotic lesions should not be performed at the expense of irreversible destruction of the procreative organs; definitive infertility should not be the price to pay in order to obtain an improvement of the painful symptoms caused by endometriosis. Surgery for ovarian endometriomas should be specifically adapted to the patient's desire for future conception and to her preoperative ovarian reserve. Two main techniques are used to treat ovarian endometriomas: ovarian cystectomy excises the wall of the cyst while ablation consists of destruction of the internal surface of the cyst. The use of mono polar or biolar coagulation for cyst ablation is strongly contra-indicated. Ablation using laser or plasma energy has resulted in comparable rates of post-operative pregnancy to those obtained by ovarian cystectomy. Patients who wish to delay their attempt to conceive for some period of time, should be placed on long-term oral contraception with prevention of menstruation to reduce the risk of recurrent endometriosis. When surgery for colorectal endometriosis is necessary, the laparoscopic approach increases the chances of spontaneous conception compared to laparotomy. Surgery for deep-seated endometriosis has been accompanied by a high rate of spontaneous conception and successful pregnancy and does not seem to decrease the chances for conception by in vitro fertilization.

Oral Contraceptive Use and Risks of Cancer in the NIH-AARP Diet and Health Study.

Although use of oral contraceptives (OCs) is common, their influence on carcinogenesis is not fully understood. We used Cox proportional hazards models to examine OC use (never/<1 year (referent), 1-4, 5-9, ≥10 years) and development of incident cancers across body sites within the same base population: women in the prospective National Institutes of Health-AARP Diet and Health Study (enrolled 1995-1996 and followed until 2011). Adjustment for confounding varied by outcome; all models accounted for age, race, body mass index, and smoking status, and included at least 100,000 women. Any OC use conferred a 3% reduction in the risk for any cancer (hazard ratio = 0.97, 95% confidence interval: 0.95, 0.99). Expected risk reductions that strengthened with duration of use were identified for ovarian and endometrial cancers and were suggested for kidney cancer (all P for trend < 0.05). Non-Hodgkin lymphoma risk (hazard ratio = 0.79, 95% confidence interval: 0.64, 0.97) was reduced with 10 or more years of OC use. There was a 37% reduced risk for bladder cancer and 46% increased risk for pancreatic cancer among long-term OC users who were 60 years of age or younger at baseline. OC use did not influence risks for most other cancers evaluated. Given the high prevalence of use and changing formulations, additional studies are warranted to fully understand the chemopreventive effects of these medications.

Modification of the Associations Between Duration of Oral Contraceptive Use and Ovarian, Endometrial, Breast, and Colorectal Cancers

Although oral contraceptive (OC) use is common, the influence of OC use on carcinogenesis is not fully understood. A recent Agency for Healthcare Research and Quality report identified a need to understand the consistency of OC use and cancer associations across subpopulations, including smokers and obese women. To determine whether associations between duration of OC use and risk of specific cancers were modified by lifestyle characteristics. The prospective NIH-AARP Diet and Health Study (enrolled 1995-1996, followed until 2011), with population-based recruitment of AARP members in 6 states and 2 metropolitan areas. All analyses included at least 100 000 women who reported OC use at enrollment. We identified 1241 ovarian, 2337 endometrial, 11 114 breast, and 3507 colorectal cancer cases during follow-up. Data analysis was performed between September 2016 and April 2017. Duration of OC use (never or <1 year [reference], 1-4, 5-9, or ≥10 years). Development of ovarian, endometrial, breast, and colorectal cancers. We examined effect modification by modifiable lifestyle characteristics: cigarette smoking, alcohol consumption, body mass index (BMI), and physical activity. We used Cox models adjusted for age, race, age at menarche, and the modifiers of interest. The analytic population was aged 50 to 71 years (median, 62 years) at enrollment and largely white (91%) and postmenopausal (96%). For ovarian cancer, OC use-associated risk reductions strengthened with duration of use (long-term OC use [≥10 years] HR, 0.60; 95% CI, 0.47-0.76; P < .001 for trend) and were similar across modifiable lifestyle factors. Risk reductions for endometrial cancer strengthened with duration of use (long-term OC use HR, 0.66; 95% CI, 0.56-0.78; P < .001 for trend); the most pronounced reductions were among long-term OC users who were smokers (HR, 0.47; 95% CI, 0.25-0.88), had obese BMIs (0.36; 95% CI, 0.25-0.52), and who exercised rarely (HR, 0.40; 95% CI, 0.29-0.56). Associations between OC use and breast and colorectal cancers were predominantly null. Long-term OC use is consistently associated with reduced ovarian cancer risk across lifestyle factors. We observed the greatest risk reductions for endometrial cancer among women at risk for chronic diseases (ie, smokers, obese BMI). Oral contraceptive use may be beneficial for chemoprevention for a range of women with differing baseline cancer risks.

Abstract 3013: Duration of oral contraceptive use and the prevention of gynecologic cancers: Modification by modifiable factors

Abstract Background: Although oral contraceptive (OC) use is ubiquitous in the United States, the influence of OCs on the development of cancers is not fully understood. In 2013, an Agency for Healthcare Research and Quality Evidence Report identified several data gaps with regard to OC use and its associations with cancer, including a need to understand if associations are consistent across subpopulations of users, including smokers and obese women. Methods: To address this data gap, we used Cox proportional hazards models to examine duration of OC use (never/less than 1 year [reference], 1 to 4, 5 to 9, 10+ years) and subsequent development of incident ovarian or endometrial cancer among participants in the NIH-AARP Diet and Health Study. We further examined effect modification by a variety of modifiable risk factors, including body mass index (BMI), cigarette smoking, alcohol consumption, and physical activity, via interaction terms and a likelihood ratio test. Models were adjusted for age, race, age at menarche and the modifiers of interest. Results: For ovarian cancer (n=1,241 cases, 149,502 non-cases), a reduction in risk was conferred by OC use that linearly decreased with duration of use (hazard ratios [HR] ranging from 0.83 to 0.60 across categories of duration). We also identified linear, inverse associations between increasing duration of OC use and ovarian cancer risk across most potential modifiers. Some of the most pronounced reductions were observed among long-term OC users (10+ years) who were current smokers (HR compared to non-users of 0.44, 95% confidence interval [CI] 0.20, 0.97) or who engaged in moderate physical activity (0.44, CI 0.23, 0.85). For endometrial cancer (n=2,337 cases, n=112,132 non-cases), we observed pronounced reductions in risk associated with long-term OC use among women with obese BMIs (0.36, CI 0.25, 0.52) and those who exercised rarely (0.40, CI 0.29, 0.56) or moderately (0.50, CI 0.33, 0.75). However, long-term use was not associated with risk reductions among women with BMIs of less than 25 or among women who exercised at least three times per week. Conclusions: OC use is consistently associated with reduced risks of ovarian cancer across most strata of modifiable risk factors. For endometrial cancer risk, OC use seems to offer the greatest risk reduction among women in previously identified high-risk categories (i.e., overweight/obese BMI, physically inactive), findings which merit further discussion as these women may be more likely to have comorbid conditions that would contraindicate OC use (e.g., hypertension, diabetes). Citation Format: Kara A. Michels, Louise A. Brinton, Ruth M. Pfeiffer, Britton Trabert. Duration of oral contraceptive use and the prevention of gynecologic cancers: Modification by modifiable factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3013. doi:10.1158/1538-7445.AM2017-3013

Association of Combined Tobacco Smoking and Oral Contraceptive Use With Cervical Intraepithelial Neoplasia 2 or 3 in Korean Women.

BackgroundCigarette smoking and oral contraceptive (OC) use have been associated with cervical neoplasia, and the combination of smoking and OC use could influence cervical carcinogenesis. We aimed to assess the joint effect of smoking and OC use on the risk of cervical intraepithelial neoplasia (CIN).MethodsFrom a cohort of human papillomavirus-positive subjects recruited from 6 hospitals in Korea from March 2006 to November 2012, a total of 678 subjects (411 control, 133 CIN 1, and 134 CIN 2 or 3 cases) were selected for this study (mean age, 43 years). The risk of CIN associated with smoking and OC use on additive and multiplicative scales was estimated via multinomial logistic regression after adjustment for potential confounding factors. The relative excess risk due to interaction (RERI) and the synergy index (S) were used to evaluate the additive interaction.ResultsOC users (odds ratio [OR] 1.98; 95% confidence interval [CI], 1.07–3.69) and long-term OC use (≥20 months; OR 2.71; 95% CI, 1.11–6.59) had a higher risk of CIN 2/3, but had no association with CIN 1, compared to non-OC users. Smokers and heavy smoking (≥8 cigarettes/day) were not associated with any CIN grade. Combined smoking and OC use (OR 4.91; 95% CI, 1.68–14.4; RERI/S, 3.77/27.4; P for multiplicative interaction = 0.003) and combined heavy smoking and long-term OC use (OR 11.5; 95% CI, 1.88–70.4; RERI/S, 9.93/18.8; P for multiplicative interaction = 0.009) had a higher risk of CIN 2/3 but had no association with CIN 1 compared to combined non-smoking and non-OC use.ConclusionsOC use and smoking acted synergistically to increase the risk of CIN 2 or 3 in Korean women.

The Experience and Impact of Contraceptive Stockouts Among Women, Providers and Policymakers in Two Districts of Uganda.

Little is known about the impact of contraceptive stockouts on women and health care providers, or how policymakers perceive and handle such stockouts. In May-July 2015, a qualitative study on experiences of contraceptive stockouts was conducted in two districts of Uganda. It comprised three data collection components: eight focus groups with 50 women, 24 individual in-depth interviews with family planning service providers and facility managers, and 11 in-depth interviews with district-level policymakers and decision makers. Data analysis followed the content analysis approach. Contraceptive stockouts were common, particularly for long-term methods and oral contraceptives. For women, the consequences included stress, increased costs, domestic conflict, and unwanted or unplanned pregnancies. Providers reported emotional distress, blame from clients, deterioration of skills and lower demand for their services as a result of stockouts; they also felt unable to address stockouts under current supply systems. Despite the widespread prevalence and adverse impact of stockouts, policymakers reported being unaware of the scope of the problem. The findings suggest there is a critical need to raise awareness of the issue, reduce stockouts and mitigate their negative consequences. Efforts to eliminate stockouts should include addressing supply chain issues. Raising community awareness and engaging with men on family planning may be ways to deal with the consequences of stockouts.

Risk factors for a suboptimal response to gonadotropin-releasing hormone agonist trigger during in vitro fertilization cycles

To identify risk factors for a suboptimal response to gonadotropin-releasing hormone (GnRH) agonist trigger in in vitro fertilization (IVF) cycles. Retrospective cohort study. Academic medical center. All 424 patients undergoing fresh IVF cycles (n = 500) between August 2007 and June 2013 in whom a GnRH agonist was used as all or part of the ovulation trigger. GnRH-antagonist-based IVF cycles triggered with leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin. Suboptimal response to GnRH-agonist trigger, as defined by a serum luteinizing hormone (LH) level <15 mIU/mL on the morning after trigger. The rate of suboptimal response to the GnRH-agonist trigger was 5.2%. Patients with a suboptimal hormone response had lower follicle-stimulating hormone (<0.1 vs. 3.48) and LH (<0.1 vs. 2.51) levels on day 2 of the cycle start, lower LH (0.109 vs. 0.596) on the day of trigger, and required longer stimulation and more gonadotropins than those with an adequate response. Suboptimal responders were also more likely to have irregular menses and be on long-term oral contraception. Patients with an undetectable LH on the day of trigger had a 25% chance of a suboptimal LH surge. In our study cohort, limiting the use of the GnRH-agonist trigger alone to patients with a trigger day LH ≥0.5 would have reduced the rate of suboptimal response from 5.2% to 0.2%. Long-term hormonal contraception use is an independent risk factor for suboptimal response to GnRH-agonist trigger. Patients with very low endogenous serum LH levels on the day of LH trigger are at increased risk for a suboptimal GnRH-agonist trigger response. Understanding the at-risk phenotype and using trigger day LH as a marker for increased risk of suboptimal GnRH-agonist trigger response can be helpful for individualizing treatment and selecting a safe and efficacious trigger medication for patients undergoing IVF.

Clozapine toxicity due to a multiple drug interaction: a case report

IntroductionWe report the case of a multiple drug interaction involving clozapine, antifungals and oral contraceptives, which resulted in an increased clozapine plasma level, pericarditis with pericardial effusion and eosinophilia in a young Caucasian woman. These symptoms and signs disappeared a few days after discontinuation of clozapine. At present, we are not aware of reports of clozapine–antifungals interaction, whereas there is only one other case report on the interaction between oral contraceptives and clozapine. The purpose of this case report is to show the risk of potentially serious adverse effects stemming from drug interactions involving medications routinely used in clinical practice.Case presentationA 29-year-old Caucasian woman diagnosed with a schizoaffective disorder was admitted to a psychiatric unit for acute psychosis (hallucinations, delusions and catatonic behavior). She denied smoking tobacco products and was on long-term oral contraceptives. During the first month of hospitalization she was treated with antipsychotics and for 1 week she took simultaneously fluconazole and miconazole gel, after being diagnosed with oral candidiasis. On the last day of antifungals treatment, 29 days after admission, clozapine was started with resolution of psychotic symptoms. After 3 weeks, her clozapine plasma level had increased to 542ng/mL and eosinophilia was observed. She complained of nausea, vomiting and palpitations; echocardiography showed echocardiographic abnormalities and pericardial effusion. Oral contraceptives were discontinued and after 1 week clozapine was interrupted, with a complete resolution of side effects and pericardial effusion within 4 days.ConclusionsClozapine is metabolized by cytochrome P450. The use of inhibitors or other substrates of cytochrome P450, such as antifungals and oral contraceptives, can cause long-lasting interactions and clozapine toxicity. The Naranjo algorithm shows clozapine is a definite cause of pericarditis (score 9) and both clozapine–antifungals and clozapine–contraceptives interactions resulted probable (score 5) in Drug Interaction Probability Scale. A good knowledge on drugs that act as substrates, inhibitors or inducers of cytochrome P450 is mandatory. When those drugs are used in patients taking clozapine, blood level monitoring of clozapine should be recommended, since a lower dose of clozapine might be required to prevent clozapine toxicity.

Effects of long-term postoperative oral contraceptive use for the prevention of endometrioma recurrence on bone mineral density in young women

Concerns for negative effects of oral contraceptives (OCs) on bone mineral density (BMD) in long-term users have been raised, since OCs suppress the hypothalamic–pituitary–ovarian axis. However, there have been still limited data regarding the effects of long-term OC use on BMD in young women in the twenties. We investigated the effects of long-term OC use for the prevention of endometrioma recurrence on BMD in young women. Ninety-two women aged 20–30 years who underwent conservative surgery for endometrioma and used postoperative OC for at least 12 months to prevent the recurrence were included for this cross-sectional study, and BMDs after OC use were analyzed. The mean age at starting OC and duration of OC use was 25.6 ± 2.9 years and 40.7 ± 28.5 months, respectively. No correlation was found between BMDs and age at starting OC at all sites. In addition, BMDs were also not correlated with the duration of OC use, and were comparable according to the dose of OC (20 versus 30 μg). In conclusion, long-term use of OCs has no adverse effect on BMD in post-adolescent young women.