CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction.

Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P-value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

Weight gain prevention buffers the impact of CETP rs3764261 on high density lipoprotein cholesterol in young adulthood: The Study of Novel Approaches to Weight Gain Prevention (SNAP).

BACKGROUND AND AIMS: Two weight gain prevention strategies, one targeting small changes to diet and physical activity and a second targeting large changes, significantly reduced weight gain in young adulthood. We examined whether weight gain prevention blunts genetic risk for body weight increase and/or high density lipoprotein cholesterol (HDL-C) lowering over two years. METHODS AND RESULTS: Participants were 524 male and female young adults (mean age = 28.2, SD = 4.3; mean BMI = 25.5, SD = 2.6). Obesity-related SNPs accounting for ≥ 0.04% of the variance were genotyped and combined into a genetic risk score. For HDL-C, SNPs within CETP, LIPC and FADS2 were genotyped. The obesity-related genetic risk score did not predict change in BMI independently or in interaction with treatment arm. However, consistent with the prior literature, each copy of the HDL-C risk, C, allele at CETP rs3764261 was associated with lower HDL-C at baseline. Moreover, significant interaction between SNP and treatment arm for change in HDL-C was observed (p = 0.02). In the control group, HDL-C change was dependent upon rs3764261 (p = 0.004) with C allele carriers showing a continued reduction in HDL-C. In contrast, within the two intervention groups, HDL-C increased on average with no differential effect of rs3764261 (p > 0.24). Notably, even among carriers of the CC genotype, small and large change arms were associated with increased HDL-C and the control arm a reduction (p = 0.013). CONCLUSIONS: The C allele at CETP rs3764261 is a strong risk factor for low HDL-C in young adulthood but weight gain prevention may mitigate this risk. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: clinicaltrials.gov Identifier: NCT01183689, https://clinicaltrials.gov/.

Common variants associated with changes in levels of circulating free fatty acids after administration of glucose-insulin-potassium (GIK) therapy in the IMMEDIATE trial.

Glucose-insulin-potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ⩽5.51 × 10-7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 × 10-7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 × 10-7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes.

A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials.

We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.

Genetic modifiers of response to glucose-insulin-potassium (GIK) infusion in acute coronary syndromes and associations with clinical outcomes in the IMMEDIATE trial.

Modifiers of response to glucose, insulin and potassium (GIK) infusion may affect clinical outcomes in acute coronary syndromes (ACS). In an Immediate Myocardial Metabolic Enhancement During Initial Assessment And Treatment In Emergency Care (IMMEDIATE) trial's sub-study (n = 318), we explored effects of 132,634 genetic variants on plasma glucose and potassium response to 12-h GIK infusion. Associations between metabolite-associated variants and infarct size (n = 84) were assessed. The 'G' allele of rs12641551, near ACSL1, as well as the 'A' allele of XPO4 rs2585897 were associated with a differential glucose response (P for 2 degrees of freedom test, P2df ⩽ 4.75 × 10(-7)) and infarct size with GIK (P2df < 0.05). Variants within or near TAS1R3, LCA5, DNAH5, PTPRG, MAGI1, PTCSC3, STRADA, AKAP12, ARFGEF2, ADCYAP1, SETX, NDRG4 and ABCB11 modified glucose response, and near CSF1/AHCYL1 potassium response (P2df ⩽ 4.26 × 10(-7)), but not outcomes. Gene variants may modify glucose and potassium response to GIK infusion, contributing to cardiovascular outcomes in ACS.

Genetic variation at glucose and insulin trait loci and response to glucose-insulin-potassium (GIK) therapy: the IMMEDIATE trial.

The mechanistic effects of intravenous glucose, insulin and potassium (GIK) in cardiac ischemia are not well understood. We conducted a genetic sub-study of the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial to explore effects of common and rare glucose and insulin-related genetic loci on initial to 6-h and 6- to 12-h change in plasma glucose and potassium. We identified 27 NOTCH2/ADAM30 and 8 C2CD4B variants conferring a 40-57% increase in glucose during the first 6 h of infusion (P<5.96 × 10(-6)). Significant associations were also found for ABCB11 and SLC30A8 single-nucleotide polymorphisms (SNPs) and glucose responses, and an SEC61A2 SNP with a potassium response to GIK. These studies identify genetic factors that may impact the metabolic response to GIK, which could influence treatment benefits in the setting of acute coronary syndromes (ACS).

FTO predicts weight regain in the Look AHEAD clinical trial.

BACKGROUND: Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss. METHODS: Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and diabetes support and education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1. RESULTS: No single-nucleotide polymorphisms (SNPs) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, fat mass and obesity associated gene (FTO) rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, P=0.005), but not ILI (P=0.761), resulting in SNP × treatment arm interaction (P=0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (P=0.051). CONCLUSIONS: Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.

A syndrome of tricuspid atresia in mice with a targeted mutation of the gene encoding Fog-2.

Tricuspid atresia (TA) is a common form of congenital heart disease, accounting for 1-3% of congenital cardiac disorders. TA is characterized by the congenital agenesis of the tricuspid valve connecting the right atrium to the right ventricle and both an atrial septal defect (ASD) and a ventricular septal defect (VSD). Some patients also have pulmonic stenosis, persistence of a left-sided superior vena cava or transposition of the great arteries. Most cases of TA are sporadic, but familial occurrences with disease in multiple siblings have been reported. Gata4 is a zinc-finger transcription factor with a role in early cardiac development. Gata4-deficient mice fail to form a ventral heart tube and die of circulatory failure at embryonic day (E) 8.5 (refs 6,7). Zfpm2 (also known as Fog-2) is a multi-zinc-finger protein that is co-expressed with Gata4 in the developing heart beginning at E8.5 (refs 8-10). Zfpm2 interacts specifically with the N-terminal zinc finger of Gata4 and represses Gata4-dependent transcription. Here we use targeted mutagenesis to explore the role of Zfpm2 in normal cardiac development. Zfpm2-deficient mice died of congestive heart failure at E13 with a syndrome of tricuspid atresia that includes an absent tricuspid valve, a large ASD, a VSD, an elongated left ventricular outflow tract, rightward displacement of the aortic valve and pulmonic stenosis. These mice also display hypoplasia of the compact zone of the left ventricle. Our findings indicate the importance of Zfpm2 in the normal looping and septation of the heart and suggest a genetic basis for the syndrome of tricuspid atresia.

Changes in the intensity and pleasantness of human vaginal odors during the menstrual cycle.

Men and women estimated (by the method of magnitude estimation) the pleasantness and intensity of the odors of vaginal secretions sampled from consecutive phases of 15 ovulatory menstrual cycles of four women. On the average, secretions from preovulatory and ovulatory phases were slightly weaker and less unpleasant in odor than those from menstrual, early luteal, and late luteal phases. However, considerable variation in odor patterns was present across cycles from the same donor, as well as across cycles from different donors. These results indicate that human vaginal odors change slightly in both pleasantness and intensity during the menstrual cycle, but do not support the notion that such odors are particularly attractive to humans in an in vitro test situation.

Sexual and reproductive risk factors for invasive squamous cell cervical cancer.

A case-control study of 418 women with invasive squamous cell cervical cancer and 704 population controls enabled evaluation of risk factors for this relatively rare cancer. Consistent with an infectious etiology was a pronounced effect of multiple sexual partners, with those reporting 10 or more partners being at a significant threefold excess risk. Early first intercourse also was associated with some residual effect on risk, although the relationship was not linear, nor the explanation readily apparent. Those with multiple births were at significantly elevated risks, even after adjustment for sexual parameters. Menstrual and hygiene factors, including use of tampons, vaginal deodorants, and douching products, were not consistently related to risk. Histories of specific infections involving the genital tract were poor predictors of risk, since few women provided positive responses, but those with nonspecific diseases were at a significant twofold excess risk.

IUD use and unexplained vaginal bleeding.

The Women's Health Study, a concurrent case-control study at 16 hospitals in 9 cities across the United States, examined the relationship between intrauterine contraceptive device (IUD) use and unexplained vaginal bleeding severe enough to require hospitalization. There were 545 eligible cases and 3453 controls. Analysis of all patients showed no association between IUD use and hospitalization for unexplained vaginal bleeding. When cases were analyzed separately with regard to prior episodes of vaginal bleeding, those patients with a history of vaginal bleeding had a decreased risk of hospitalization. Among cases, no significant differences between IUD users and nonusers were found in rates of anesthesia, blood transfusion, dilatation and curettage, or hysterectomy. The significant decreased risk between current IUD use (within 3 months before the study) and hospitalization for unexplained vaginal bleeding among women with a history of vaginal bleeding may reflect selective nonprescription for IUDs related to past episodes of vaginal bleeding.

Cholelithiasis of the ovary.

BACKGROUND: Laparoscopic cholecystectomy is becoming a popular surgical option in the management of gallstone disease. Reports on complications of this procedure have usually focused on prolonged operative time, bleeding, and infections. We describe a case of cholelithiasis of the ovary following laparoscopic cholecystectomy. CASE: A 70-year-old woman, para 5-0-0-5, presented with a 2-month history of a pelvic mass following a laparoscopic cholecystectomy. Exploratory laparotomy demonstrated a 4 x 4-cm para-ovarian cyst as well as multiple rectal and pelvic implants. Pathologic findings confirmed gallstones of the ovary and pelvic peritoneum. These gallstones elicited mesothelial proliferation, local hemorrhage, and adhesion formation. CONCLUSION: The pathologic consequences of pelvic cholelithiasis can be marked. This was demonstrated in a postmenopausal woman, but has direct implications for the premenopausal patient as well. Our experience suggests that gallstones lost during laparoscopic cholecystectomy should be removed if possible.

Illicit use of clonidine in opiate-abusing pregnant women.

OBJECTIVE: To examine prevalence rates and psychosocial correlates of clonidine use in a sample of opiate-dependent pregnant women. METHODS: Clonidine use was assessed in 90 treatment-seeking, pregnant, opiate-abusing women using both self-report and urinalysis toxicology. Clonidine-positive and -negative subjects were compared for selected demographic, substance use, and psychosocial measures. RESULTS: One-third of the sample was clonidine-positive. Urinalysis identified 26 clonidine-positive subjects, whereas self-report detected only six cases. Logistic regression identified four predictors of clonidine use at treatment admission: recent clinical anxiety, greater severity of family or social problems, recent cocaine use, and recent drug treatment. CONCLUSION: Clonidine use is prevalent in treatment-seeking opiate abusers, particularly those with concurrent cocaine use. The abuse potential of the drug warrants further study in this high-risk population.

Effect of academic affiliation and obstetric volume on clinical outcome and cost of childbirth.

OBJECTIVE: To determine whether the academic affiliation and obstetric volume of the delivering hospital has an impact on clinical and economic outcomes. METHODS: We performed a cross-sectional analysis of data for all births in the State of Maryland during 1996. Acute hospital discharge data were obtained from the publicly available Maryland Health Services Cost Review Commission database. Institutions were classified as community hospitals, community teaching hospitals, and academic medical centers. Principal outcome variables included cesarean birth and complication rates, total hospital charges, and length of stay. RESULTS: A total of 63,143 cases were identified for analysis. The cesarean delivery rate was lower among academic medical centers, compared with community teaching hospitals and community hospitals (18.4% compared with 24.3% and 21.2%, respectively). After adjustment for patient case-mix, the adjusted odds ratio (OR) for cesarean birth was 0.66 at academic medical centers and 1.23 at community teaching hospitals compared with community hospitals (P <.01). Rates of episiotomy and serious complications were lower at academic medical centers compared with community hospitals. Adjusted total hospital charges were lower and length of stay was shorter for community hospitals compared with academic medical centers ($2937 compared with $3564 and 2.2 days compared with 2.5 days, respectively). CONCLUSION: Hospital academic affiliation was an important predictor of clinical outcomes. Better clinical outcomes were found primarily among patients at academic medical centers, although these institutions demonstrated moderately higher resource utilization, compared with community hospitals.

Comparison of adolescent and adult experiences with Norplant levonorgestrel contraceptive implants.

OBJECTIVE: To compare acceptability, tolerance of side effects, and continuation rates among adolescent and adult Norplant accepters. METHODS: An 18-month observational study was conducted of 136 adolescents and 542 adults who received Norplant at the Francis Scott Key Medical Center in Baltimore, Maryland. Data were collected from the following: a self-administered history form completed at the preinsertion visit, a self-administered follow-up form completed at routine follow-up visits, problem-visit chart review, and telephone contact for patients noncompliant with follow-up appointments. RESULTS: The adolescents ranged in age from 13-18 years (mean 16.4), and adults ranged in age from 19-46 (mean 24.7). The mean parity among teenagers was 1.4; among adults, 3.2. Thirty-nine percent of teenagers and 64% of adults had had one or more therapeutic abortions. Forty percent of adolescents and 47% of adults reported at least one contraceptive failure in the past. Both adolescent and adult Norplant accepters made few telephone calls or problem visits because of complaints or side effects. Compliance with routine annual follow-up was poor for adolescents (24 of 136, 18%) and adults (72 of 542, 13%). Follow-up of noncompliant patients revealed low rates of implant removal. Fifteen adolescents (11%) and 60 adults (11%) had Norplant removed. The most common reasons for removal included irregular bleeding, weight gain, headaches, and desire for pregnancy. CONCLUSIONS: Implant acceptability, continuation, and tolerance of side effects were high and comparable among adolescent and adult accepters. Initial implant users were primarily adolescents or adults who had experienced problems with other forms of reversible contraception. Adherence to scheduled follow-up appointments was poor, regardless of age.

Emotional distress patterns among women having first or repeat abortions.

Thirty-five percent of a sample of 413 women undergoing first-trimester abortions were repeating abortions. All patients rated their emotional symptoms on an SCL-90 scale and completed a brief demographic questionnaire. Preabortion and postabortion emotional distress factors and associated demographic characteristics were compared for women having first and those undergoing repeat abortions. Elevated distress levels were similar in both groups prior to abortion procedures, particularly depression, anxiety, and somatization. After abortion, repeat aborters continued to have significantly higher emotional distress scores in dimensions relating to interpersonal relationships. The variables that discriminated most between first and repeat abortion groups were number of living children, race, and phobic anxiety.

Psychosocial stressors and low birthweight in an urban population.

INTRODUCTION: Low birthweight is a major determinant of infant mortality, as well as a contributor to infant and childhood morbidity. A key issue is how to reduce the incidence of low birthweight in the United States. One emerging factor is exposure to psychosocial stressors. In this research, we evaluated the association between exposure to psychosocial stressors and low birthweight in a population of urban, low-income pregnant women. METHODS: Over 2,000 pregnant women 18 years of age and older were enrolled in this prospective study and recruited at their first prenatal care visit. We obtained information on maternal exposure to stressors. After the pregnancy, we abstracted clinical records of each woman enrolled in the study. Logistic regression was used to estimate the adjusted odds ratio for the association between stressor group membership and low birthweight, controlling for the effects of confounding factors. RESULTS: In logistic regression analyses stratified by race, for African-American women, the following variables were significantly associated with low birthweight: smoking, hypertension, low prepregnancy weight, hospitalization during pregnancy, previous preterm birth, and exposure to stressors. For Caucasian women, significant predictors were: smoking, drug use, hospitalization during pregnancy, hypertension, and previous preterm birth. Exposure to stressors was also significantly associated with many clinical and behavioral risks for low birthweight. CONCLUSION: Our results suggest two potential mechanisms for an association between stressors and low birthweight. Exposure to stressors may be indirectly associated with low birthweight through a relationship with clinical and behavioral risks for low birthweight. Exposure to psychosocial stressors may also be directly associated with risk of low birthweight among African-American women.

Fertility after contraception or abortion.

There is a very small correlation, if any, between the prior use of OCs and congenital malformations, including Down's syndrome. There are few, if any, recent reports on masculinization of a female fetus born to a mother who took an OC containing 1 mg of a progestogen during early pregnancy. However, patients suspected of being pregnant and who are desirous of continuing that pregnancy should not continue to take OCs, nor should progestogen withdrawal pregnancy tests be used. Concern still exists regarding the occurrence of congenital abnormalities in babies born to such women. The incidence of postoperative infection after first trimester therapeutic abortion in this country is low. However, increasing numbers of women are undergoing repeated pregnancy terminations, and their risk for subsequent pelvic infections may be multiplied with each succeeding abortion. The incidence of prematurity due to cervical incompetence or surgical infertility after first trimester pregnancy terminations is not increased significantly. Asherman's syndrome may occur after septic therapeutic abortion. The pregnancy rate after treatment of this syndrome is low. The return of menses and the achievement of a pregnancy may be slightly delayed after OCs are discontinued, but the fertility rate is within the normal range by 1 year. The incidence of postpill amenorrhea of greater than 6 months' duration is probably less than 1%. The occurrence of the syndrome does not seem to be related to length of use or type of pill. Patients with prior normal menses as well as those with menstrual abnormalities before use of OCs may develop this syndrome. Patients with normal estrogen and gonadotropin levels usually respond with return of menses and ovulation when treated with clomiphene. The rate for achievement of pregnancy is much lower than that for patients with spontaneous return of menses. The criteria for defining PID or for categorizing its severity are diverse. The incidence of PID is higher among IUD users than among patients taking OCs or using a barrier method. The excess risk of PID among IUD users, with the exception of the first few months after insertion, is related to sexually transmitted diseases and not the IUD. Women with no risk factors for sexually transmitted diseases have little increased risk of PID or infertility associated with IUD use. There appears to be no increased risk of congenital anomalies, altered sex ratio, or early pregnancy loss among spermicide users. All present methods of contraception entail some risk to the patient. The risk of imparied future fertility with the use of any method appears to be low.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: This is a comprehensive review of the risk of infertility or adverse effects on pregnancy outcome, such as chromosomal or congenital birth defects, amenorrhea, pelvic inflammatory disease (PID), or spontaneous abortion, after use of oral contraceptives, IUDs, induced abortion or spermicides. The sequelae reported for orals are chromosomal abnormalities, the VACTERL anomalies, masculinization of female fetus, Down's syndrome and post-pill amenorrhea. Several large studies found no increased risks for birth defects, although the risk of malformations when pregnant women inadvertently take the pill in early pregnancy was high in 1 of 2 such studies. Masculinization was reported with high dose combined hormone treatment and in 2 infants of a woman who took Enovid. the bulk of recent studies on secondary amenorrhea indicate that it is rare, but just as likely to occur in women with prior normal or abnormal menstrual patterns. One study found that amenorrhea is 7.7 times more likely to develop in women who took the pill to regulate menses. It is recommended that women with amenorrhea be screened for pituitary tumors and counseled before prescribing pills, and that those who fail to ovulate after stopping the pill be treated at least 6 months with clomiphene. A massing of all studies on the impact of 1st trimester induced abortion on subsequent fertility, premature delivery and spontaneous abortion, shows all relative risks around 1.0. After multiple abortions, the results are conflicting. In contrast, prior series analyzing illegal abortion have an unquestioned adverse effect on fertility and pregnancy outcome. Asherman's syndrome, a rare disorder of intrauterine adhesions, menstrual abnormalities, infertility and habitual abortion, has been associated with D & C abortion concurrent with pelvic sepsis, or traumatic pregnancy with D & C. This condition can be treated with moderate success. The bulk of IUD studies conclude that there is no overall decrement in fertility, while some disaggregated studies point the Dalkon shield as a higher risk and copper IUDs as a lower risk. PID and its consequences are now considered related to the immediate post-insertion time frame, or specifically to women who are at risk of contracting sexually transmitted disease, i.e., those with multiple partners, those with prior PID and nulliparas. Comprehensive review of current large series on spermicides shows no relationship between their use and spontaneous abortion or congenital malformation.

Oral contraceptives and neoplasia: 1987 update.

PIP: This article reviews the research evidence on the relationship between oral contraceptives (OCs) and neoplasia. More recent epidemiologic studies in this area are considered to have greater validity than earlier studies, largely because of improved assessment of confounding factors. Encouraging has been the finding of a protective effect of OCs on endometrial and ovarian neoplasia: about 2000 cases of endometrial cancer and 1700 cases of ovarian cancer are averted in the US each year as a result of OC use. No consistent association, either adverse or beneficial, has emerged between OCs and breast cancer; however, high-dose combined OCs exert a protective effect on the development of benign breast disease after 2 years of use. Longterm combined OC use appears to be related to the development of benign liver lesions, but the research evidence on the association between OCs and hepatocellular carcinoma remains inconclusive. Of concern is the finding that longterm OC use is associated with an increased risk of cervical neoplasia. The mechanisms by which OCs might exert adverse effects on cervical epithelium are unclear.^ieng