Use of statins and risks of ovarian, uterine, and cervical diseases: a cohort study in the UK Biobank.

PURPOSE: To examine the associations between use of statins and risks of various ovarian, uterine, and cervical diseases, including ovarian cancer, endometrial cancer, cervical cancer, ovarian cyst, polycystic ovarian syndrome, endometriosis, endometrial hyperplasia, endometrial polyp, and cervical polyp. METHODS: We conducted a cohort study among female participants in the UK Biobank. Information on the use of statins was collected through verbal interview. Outcome information was obtained by linking to national cancer registry data and hospital inpatient data. We used Cox proportional hazards regression to examine the associations. RESULTS: A total of 180,855 female participants (18,403 statin users and 162,452 non-users) were included. Use of statins was significantly associated with increased risks of cervical cancer (adjusted hazard ratio (HR), 1.55; 95% confidence interval (95% CI), 1.05-2.30) and polycystic ovarian syndrome (adjusted HR, 4.39; 95% CI, 1.68-11.49). However, we observed no significant association between use of statins and risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial hyperplasia, endometrial polyp, or cervical polyp. CONCLUSION: Our findings suggest that use of statins is associated with increased risks of cervical cancer and polycystic ovarian syndrome, but is not associated with increased or decreased risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial polyp, or cervical polyp.

Prostatic Metaplasia of the Vagina and Uterine Cervix: An Androgen-associated Glandular Lesion of Surface Squamous Epithelium.

Prostatic-type differentiation in the lower female genital tract is encountered rarely and its causes and clinical associations are not well established. Within the vagina, reports to date have invariably described ectopic prostatic-type differentiation as restricted to the lamina propria. We recently encountered a patient receiving testosterone for gender dysphoria whose vaginectomy specimen showed a prostatic glandular proliferation within the surface epithelium. To elucidate its potential association with androgen exposure, we sought similar lesions, resected over a 26-year period, from patients with exogenous or endogenous androgen excess. Thirteen cases were identified, involving the vagina (n=12) and exocervix (n=1). The most common clinical context was gender dysphoria with long-term testosterone therapy; the lesion was present in 7 of 8 gender-dysphoric patients examined. Four other patients had congenital disorders of sexual development associated with endogenous androgen excess (congenital adrenal hyperplasia, 46,XY disorder of sexual development, and ovotesticular disorder of sexual development). Two had no known exposure to androgen excess. Immunohistochemically, glands stained for NKX3.1 (100% of cases), androgen receptor (100%), CK7 (92%), and prostate-specific antigen (69%). Follow-up (median duration, 11 mo) showed no masses or neoplasia. We propose the designation "androgen-associated prostatic metaplasia" for this form of prostate tissue with distinctive clinical, histologic and immunohistochemical features. It is novel and previously unrecognized within the vagina. It is strikingly prevalent among patients undergoing gender-affirming surgery, an increasingly common procedure. Recognition is important to distinguish it from other potentially neoplastic glandular lesions and facilitate accrual of more follow-up data to better understand its natural history.

Association of Cervical Microglandular Hyperplasia With Exogenous Progestin Exposure.

OBJECTIVES: Although microglandular hyperplasia is a benign endocervical lesion, it may raise concern of malignancy in an inexperienced pathologist, because clinicians may not be familiar with it on a report. It has been reported to occur in association with progestational stimulation, but this has not been well studied. The aim of the study was to evaluate this potential association. MATERIALS AND METHODS: This was an observational case control study of patients seen from January 01, 1991 to November 01, 2014 at the University Hospital, Newark, New Jersey. Cases of microglandular hyperplasia and controls were identified from the files of the Department of Pathology. Controls were cases of endocervical curettages for whom no microglandular hyperplasia was detected. Medical records were reviewed for evidence of exogenous progestin exposure within the previous 6 months. RESULTS: Eighty-nine cases of microglandular hyperplasia and 97 controls were identified. Of the cases of microglandular hyperplasia, 26 (29.2%) of 89 cases had exposure to progestational medication, significantly greater than that of controls (10/97, 10.3%; p = .0014). CONCLUSIONS: Our data show that a significantly higher percentage of women with microglandular hyperplasia had progestin exposure than women who do not exhibit this benign lesion. Clinicians and pathologists should be aware of this association, as well as the benign nature of the lesion.

The impact of glucocorticoids and anti-cd20 therapy on cervical human papillomavirus infection risk in women with systemic lupus erythematosus

OBJECTIVE: To identify the prevalence and factors associated with cervical human papillomavirus infection in women with systemic lupus erythematosus METHODS: This cross-sectional study collected traditional and systemic lupus erythematosus-related disease risk factors, including conventional and biologic therapies. A gynecological evaluation and cervical cytology screen were performed. Human papillomavirus detection and genotyping were undertaken by PCR and linear array assay. RESULTS: A total of 148 patients were included, with a mean age and disease duration of 42.5±11.8 years and 9.7±5.3 years, respectively. The prevalence of squamous intraepithelial lesions was 6.8%. The prevalence of human papillomavirus infection was 29%, with human papillomavirus subtype 59 being the most frequent. Patients with human papillomavirus were younger than those without the infection (38.2±11.2 vs. 44.2±11.5 years, respectively; p = 0.05), and patients with the virus had higher daily prednisone doses (12.8±6.8 vs. 9.7±6.7 mg, respectively; p = 0.01) and cumulative glucocorticoid doses (14.2±9.8 vs. 9.7±7.3 g, respectively; p = 0.005) compared with patients without. Patients with human papillomavirus infection more frequently received rituximab than those without (20.9% vs. 8.5%, respectively; p = 0.03). In the multivariate analysis, only the cumulative glucocorticoid dose was associated with human papillomavirus infection. CONCLUSIONS: The cumulative glucocorticoid dose may increase the risk of human papillomavirus infection. Although rituximab administration was more frequent in patients with human papillomavirus infection, no association was found. Screening for human papillomavirus infection is recommended in women with systemic lupus erythematosus. .

Vascular endothelial growth factor induces growth of uterine cervix and immune cell recruitment in mice.

Knowledge of uterine cervical epithelial biology and factors that influence its events may be critical in understanding the process of cervical remodeling (CR). Here, we examine the impact of exogenous vascular endothelial growth factor (VEGF) on uterine cervical epithelial growth in mice (nonpregnant and pregnant) treated with VEGF agents (recombinant and inhibitor) using a variety of morphological and molecular techniques. Exogenous VEGF altered various uterine cervical epithelial cellular events, including marked induction of growth, edema, increase in inter-epithelial paracellular space, and recruitment of immune cells to the outer surface of epithelial cells (cervical lumen). We conclude that VEGF induces multiple alterations in the uterine cervical epithelial tissues that may play a role in local immune surveillance and uterine cervical growth during CR.

The impact of glucocorticoids and anti-cd20 therapy on cervical human papillomavirus infection risk in women with systemic lupus erythematosus.

OBJECTIVE: To identify the prevalence and factors associated with cervical human papillomavirus infection in women with systemic lupus erythematosus METHODS: This cross-sectional study collected traditional and systemic lupus erythematosus-related disease risk factors, including conventional and biologic therapies. A gynecological evaluation and cervical cytology screen were performed. Human papillomavirus detection and genotyping were undertaken by PCR and linear array assay. RESULTS: A total of 148 patients were included, with a mean age and disease duration of 42.5±11.8 years and 9.7±5.3 years, respectively. The prevalence of squamous intraepithelial lesions was 6.8%. The prevalence of human papillomavirus infection was 29%, with human papillomavirus subtype 59 being the most frequent. Patients with human papillomavirus were younger than those without the infection (38.2±11.2 vs. 44.2±11.5 years, respectively; p = 0.05), and patients with the virus had higher daily prednisone doses (12.8±6.8 vs. 9.7±6.7 mg, respectively; p = 0.01) and cumulative glucocorticoid doses (14.2±9.8 vs. 9.7±7.3 g, respectively; p = 0.005) compared with patients without. Patients with human papillomavirus infection more frequently received rituximab than those without (20.9% vs. 8.5%, respectively; p = 0.03). In the multivariate analysis, only the cumulative glucocorticoid dose was associated with human papillomavirus infection. CONCLUSIONS: The cumulative glucocorticoid dose may increase the risk of human papillomavirus infection. Although rituximab administration was more frequent in patients with human papillomavirus infection, no association was found. Screening for human papillomavirus infection is recommended in women with systemic lupus erythematosus.

Histologic and cytologic detection of endocrine and reproductive tract effects of exemestane in female rats treated for up to twenty-eight days.

The objective of this study was to determine the shortest period of time necessary to detect histologic evidence of estrous cycle disruption in Sprague-Dawley rats treated for up to 28 days with the aromatase inhibitor exemestane at 1,000 mg/kg. Rats were evaluated on day 5, 8, 15, or 29. Vaginal mucification, uterine and cervical epithelial atrophy, uterine luminal epithelial vacuolation, decreased uterine granulocytes, and hypertrophy/hyperplasia of mammary ducts and alveoli were noted by day 5 and persisted throughout the study. From day 8 to day 29, absence of recent basophilic corpora lutea, increased atresia of antral follicles, interstitial cell hyperplasia, and increased luteinized follicles were present in the ovaries of treated rats. Vaginal smears detected persistent diestrus, confirming estrous cycle disruption between days 5 and 8. Ovary and uterine weights were largely unaffected. Serum hormone levels were not useful due to the study design employed. Other effects of exemestane included decreased adrenal weights and decreased cell size in both the adrenal zona fasciculata and the pituitary pars distalis. While early histologic changes were evident on day 5, only after 8 days of treatment were findings considered sufficient to clearly identify exemestane-induced estrous cycle disruption using microscopy alone.

Mitochondrial decay is involved in BaP-induced cervical damage.

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon and a potent inducer of carcinogenesis. Many studies have reported that the carcinogenic effects of BaP might be due to its intermediate metabolites and to reactive oxygen species (ROS) that cause oxidative damage to the cells. However, the mechanisms of BaP-induced oxidative damage in cervical tissue are still not clear. We studied these mechanisms in female ICR mice treated with BaP either orally or intraperitoneally by measuring (1) several general biomarkers of oxidative stress in serum, (2) mitochondrial function in the cervix, and (3) the morphology of mitochondria in cervical tissue. BaP treatment (1) significantly lowered levels of vitamins A, C, and E and of glutathione; (2) reduced activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferases; and (3) significantly increased lipid peroxidation levels. In addition, significant increases in the levels of superoxide anion, hydrogen peroxide, and hydroxyl radical were observed. These results were confirmed by morphological changes in mitochondria and by decreases in membrane potential levels and in succinate dehydrogenase and malate dehydrogenase activities. The changes in these biomarkers and mitochondrial damage were BaP-dose-dependent and eventually induced both cell apoptosis and necrosis in cervical tissue. As mitochondria are the major sites of ROS generation, these findings show that mitochondrial decay greatly contributes to BaP-induced cervical damage.

Depot medroxyprogesterone acetate: a risk factor for cervical stenosis after loop electrosurgical excisional procedure management of cervical intraepithelial neoplasia?

OBJECTIVES: In our anecdotal experience and sporadically in the literature, gynecologists have observed a connection between patient's use of depot medroxyprogesterone acetate (DMPA) and increased occurrence of cervical stenosis during follow-up after loop electrosurgical excisional procedure (LEEP). We decided to formally examine this association in our clinic population. MATERIALS AND METHODS: We performed a chart review, enrolling 257 patients and tabulating data on demography, use of hormonal contraceptives, characteristics of the LEEP, and presence or absence of cervical stenosis at 1- and 6-month follow-up evaluations. Univariate tests of association between the independent variables and the dependent variable of cervical stenosis were examined via the chi and Student t tests for discrete and continuous variables, respectively. To characterize the relative importance of independent variables significantly associated with cervical stenosis, logistic regression was performed. RESULTS: Of the 257 charts reviewed, 127 patients (49.4%) completed 1 and 6 months after LEEP follow-up appointments, providing adequate data for analysis. In this population, we observed 25 cases of cervical stenosis, or an overall rate of 19.7%. Of patients using DMPA at the time of LEEP or during the follow-up period, 9 (41.0%) of 22 developed stenosis, whereas of those who did not use DMPA, 16 (15.2%) of 105 developed stenosis, indicating a significant difference (odds ratio = 3.85, 95% CI = 1.41-10.50). CONCLUSIONS: In our clinic population, use of DMPA was associated with higher rates of development of cervical stenosis, calling for larger studies of the association of DMPA in this LEEP complication.

Sensitive methods to detect epithelial disruption: tests for microhemorrhage in cervicovaginal lavages.

The toxic effects of topical microbicides might include epithelial disruption, and if sufficiently severe, may cause visible bleeding. We have developed two sensitive methods to detect hemorrhage far below the visual detection threshold: an enzyme-linked immunosorbent assay for human hemoglobin and a method for staining and enumerating red blood cells by fluorescent microscopy. We have applied these methods to cervicovaginal and introital lavages, and found them to be sensitive and quantitative over a broad range. Comparing the new techniques with a standard heme-detection assay (Hemastix) we found them to be more sensitive, more objective, more fully quantitative, and more likely to be indicative of recent events. In pilot studies we found that the red blood cell and hemoglobin concentrations in samples taken in the luteal phase of the menstrual cycle are low, but still within the detection range of the new assays, providing a quantifiable baseline from which increases in blood from epithelial disruption can be detected and quantified. We propose that these new methods may be used for the safety assessment of microbicides by detecting and quantifying microhemorrhage in cervicovaginal secretions before and after exposure to microbicide.

Rupture of the cervix in a sulprostone induced abortion in the second trimester.

The authors report one case of cervical rupture in a normal uterus of a 43 years old second gravida, during an abortion at 16 weeks induced by sulprostone, a prostaglandin analogue. Case history and analysis of permittent condictions are listed. They conclude that uterus rupture remains an actual side effect of this prostaglandin E2 use, also when predisposing risk factors as scarred uterus, primigravid patients, age <20 years have been excluded, and gemeprost vaginal suppositories to ripen the cervix have been used.

Prevalence of visible disruption of cervical epithelium and cervical ectopy in African women using Depo-Provera.

Associations between Depo-Provera (injectable, progesterone-only contraceptive) use and visible disruption of cervical epithelium and cervical ectopy were investigated using data collected as part of a cervical cancer screening study in periurban Cape Town, South Africa. Women were interviewed about their contraceptive use, and underwent a gynecologic examination that included two 35-mm photographs of the cervix after application of 5% acetic acid. Photographs of 723 subjects were reviewed (blind to clinical information and using systematic criteria developed before review) for evidence of atrophy and epithelial disruption, including inflammation and ulceration. The percentage of the cervix covered with columnar epithelium (ectopy) was also estimated from the photographs. A random sample of 85 photographs was reviewed again for reliability. A total of 121 current users of Depo-Provera were no more likely to have evidence of epithelial disruption (38%) than 574 nonusers (39%), odds ratio (OR) = 1.37, 95% CI: 0.89-2.11 adjusting for age and parity. The prevalence of significant ectopy (columnar epithelium covering > 10% of the cervix) was also no different among current Depo-Provera users (OR = 1.22, 95% CI: 0.80-1.86 adjusting for age and parity). Reliability of visual scoring of epithelial disruption and ectopy was excellent (kappa = 0.8). Although the underlying prevalence of visible disruption of cervical epithelium was very high, current use of Depo-Provera was not associated with increased prevalence of visible disruption of the cervical epithelium or with ectopy in this sample of African women.

PIP: The relationship between cervical epithelium disorders and cervical ectopy and Depo-Provera use was investigated among African women. The women, aged 35-65 years, had gynecologic examinations, which included various cervical cancer screening tests including two 35-mm colored photographs of the cervix. Cervical photographs from 723 participants were reexamined for the signs of disruption. Results showed that among 121 current Depo-Provera users, 38% showed no steady increase in epithelial disruption compared with 34% of past users and 49% of nonusers. There was no difference in the odds ratio (OR = 1.37; 95% CI: 0.89-2.11). The percentage of women with significant ectopy was higher in current and past users of Depo-Provera, but no trends remain after age adjustment and parity (OR = 1.22; 95% CI: 0.80-1.86). The credibility of the diagnosis of cervical disruption combined (either ulceration, inflammation, or athropy) was excellent (K = 0.8). However, the results were doubtful in light of the concept that simple epithelial thinning may account for putative effects of Depo-Provera. The validity of this method needs further investigations.

Necrotizing vasculitis of the skin and uterine cervix associated with minocycline therapy for acne vulgaris.

In recent years, minocycline has become a commonly used agent for the treatment of acne vulgaris and rosacea. With this increased use have come reports of severe and in some cases life-threatening toxicity, often occurring in otherwise healthy young women after prolonged courses of minocycline. These adverse reactions include hepatotoxicity, drug-induced lupus erythematosus, eosinophilic pneumonitis, and hypersensitivity syndrome. We describe a 35-year-old woman who had necrotizing vasculitis of the skin and uterine cervix after 2 years of minocycline therapy for acne vulgaris. Skin and cervical biopsies revealed acute inflammation involving through-and-through necrosis of vessel walls with thrombosis, focal fibrinoid change, and a perivascular lymphohistiocytic infiltrate. The disease fully resolved within 3 months of discontinuance of the minocycline therapy. Patients should be informed of these rare but potentially serious adverse effects before the initiation of minocycline therapy. Early recognition of these complications can result in complete resolution.

Genetic damage in exfoliated cells of the uterine cervix. Association and interaction between cigarette smoking and progression to malignant transformation?

OBJECTIVE: To determine, through the micronucleus (MN) test, the cytogenetic effects of cigarette smoking on exfoliated cells from the uterine cervix in women with normal smears and women with inflammatory atypia, squamous intraepithelial lesion (SIL) (cervical intraepithelial neoplasia [CIN] 1-3) and cervical cancer. STUDY DESIGN: The study group consisted of 200 women divided into three subgroups: group 1 (n = 116), women periodically undergoing cervical cytology and residents of Salvador-Bahia; group II (n = 57), women residing in São Paulo and previously selected because of a possible cytopathologic test positive for such conditions as human papillomavirus infections or malignant or premalignant cervical lesions (CIN 1-3); group III (n = 27), inmates of the Tatuapé Penal Institution, São Paulo. All the women underwent cytologic and colposcopic examination, and biopsies were performed on 68 of them. RESULTS: Considering the samples as a whole and using the chi(2) test for rare events, the number of MNs in smokers was significantly greater than in nonsmokers. It was also greater in women with larger exposure to smoking. The occurrence of MN was significantly lower in women with normal smears (smokers and nonsmokers) than in those showing any kind of pathologic alteration. In nonsmokers the occurrence of MN was similar between those with inflammatory atypia (IA) or low grade (L) SIL (CIN 1) and significantly higher in women with more severe lesions or high grade (H) SIL (CIN 2 and 3). Smokers with LSIL (CIN 1) showed a higher number of MNs than nonsmokers with a comparable diagnosis and smokers with IA. No differences were observed when compared with smokers with HSIL (CIN 2 and 3). MN occurrence was not associated with other risk factors for SIL or cancer development, such as age at first coitus, number of sexual partners, multiparity and use of hormonal contraceptives. CONCLUSION: These results suggest that the mutagenic effect of cigarette smoking occurs in cervical cells and that the progression of SIL is associated with increased frequency of chromosomal damage. Moreover, the data suggest that cigarette smoking introduces an additional risk to the progression of low grade LSIL (CIN 1). MN testing would be helpful in monitoring smokers with this kind of lesion.

PIP: Previous studies have shown that cigarette smoking increases the risk of developing squamous intraepithelial lesion (SIL) and cervical cancer. The present study used the micronucleus test to assess the cytogenic effects of smoking on exfoliated cells from 3 subgroups of Brazilian women: group 1 (n = 116), women periodically undergoing cervical cytology; group 2 (n = 57), women with a possibly positive cytologic test for human papillomavirus or malignant or premalignant cervical intraepithelial neoplasia (CIN 1-3); and group 3 (n = 27), inmates of the Tatuape Penal Institute. Overall, micronucleus frequency was significantly greater in smokers than in nonsmokers. The occurrence of micronuclei was significantly lower in women with normal smears (regardless of smoking status) than in women with any evidence of pathologic alterations. In nonsmokers, micronucleus frequency was similar in women with inflammatory atypia or low-grade CIN and significantly higher in women with more severe lesions and CIN 2-3. Smokers with CIN 1 had more micronuclei than nonsmokers with a comparable diagnosis and smokers with inflammatory atypia. No differences were observed in comparisons with smokers with CIN 2-3. Micronucleus occurrence was not associated with age at first coitus, number of sexual partners, multiparity, or use of hormonal contraception. These findings suggest that the mutagenic effect of smoking occurs in cervical cells and that SIL progression is associated with an increased frequency of chromosomal damage. The data further suggest that smoking adds to the risk of progression of low-grade SIL (CIN 1). Micronucleus testing, along with the cervical cytologic smear, is recommended to monitor smokers with this type of lesion.

The daughters of diethylstilbestrol. Lessons from an error.

Diethylstilbestrol (DES) has been used extensively to prevent pregnancy disorders in Europe but at different levels depending upon the countries. Lessons from the DES story can be learned for research, information for physicians, communication, administration and industry. However, this paper will focus on the incidence of this story in our practice. We will propose guidelines for different conditions: clear cell adenocarcinoma, adenosis, cervical dysplasia, infertility and pregnancy.

Lymphoproliferative disorder involving the cervix in a patient being treated with FK-506.

FK-506 is an immunosuppressive agent used mainly to prevent allograft rejection in organ transplant patients. Recently, it has been applied as a treatment for patients with autoimmune disorders. An entity called posttransplant lymphoproliferative disorder (PTLD) is a well-recognized result of immunosuppression in transplant patients receiving long-term immunosuppression. This disorder is a complication of treatment with FK-506 in 0.7 to 1.6% of transplant patients and is usually of B-cell origin. A majority of patients have serologic evidence of EBV infection. We report a case of a patient receiving long-term FK-506 therapy for multiple sclerosis who developed lymphoproliferative disorder involving the cervix. We will discuss the possible role of FK-506 initiation of this tumor.

Comparison of spermicides on vulvar, vaginal, and cervical mucosa.

The objective of this study was to compare the tolerability of Advantage 24 to two other spermicides containing non-oxynol-9 (N-9). These spermicides were Today Sponge (Sponge) and Conceptrol. In order to examine the incidence of complaints and the clinical observation of vaginal ulceration and irritation of the three spermicides, a randomized, open label, three period cross-over trial was conducted. Thirty-three women, ages 18-45, with a normal vaginal environment based on physical exam, Pap smear, vaginal wet prep, colposcopy, and serum N-9 were randomized into four treatment groups. Each treatment was for seven consecutive days with a 21-day washout. Data obtained were studied by one-way analysis of variance, chi-square, and Kruskal-Wallis test. No vulvar or vaginal abnormality was observed from either spermicide. Subjects had fewer and less severe cervical lesions by colposcopy during treatment with Advantage 24 than with Conceptrol or Sponge (p < 0.01). Comparison of the incidence of abnormal gynecological findings, serum N-9 levels, and the incidence of adverse events before and after treatment with the three study drugs indicate that most subjects had normal examinations pre- and post-treatment. Pap smear and colposcopy changes from normal to abnormal accounted for about 50% of all gynecological findings during the Conceptrol and Sponge treatments, but less than 20% during treatment with Advantage 24. All serum N-9 levels were below the level of detection (< 1.9 microgram/ml). Advantage 24 is better tolerated than Conceptrol or the Sponge. Furthermore, the cervical mucosa appears to be less resilient to spermicides than vulvo-vaginal mucosa.

Human papilloma virus--H.P.V. condyloma. Current studies in diagnosis, treatment and prognosis.

Since 1982, in the Republic of Panama, we evaluated 5,400 women who showed the oncological risk (R.O.) in 59% and in which the participation of pure or associated HPV was 87.6%. The incidence of the HPV in our female population is 52% with a prevailing age of 20-40 years.

Frequent use of menfegol spermicidal vaginal foaming tablets associated with a high incidence of genital lesions.

Menfegol is a spermicide with in vitro activity against human immunodeficiency virus (HIV). A randomized placebo-controlled safety study covered the use of menfegol foaming tablets for 14 days at increasing frequencies of insertion by 125 prostitutes in Dakar, Senegal. The frequencies of colposcopically diagnosed genital lesions were 5.0%, 11.8%, 27.8%, 49.7%, and 29.4% among menfegol recipients when tablets were used once every other day or 1, 2, 4, or 8 times a day, respectively (P < .05). Among placebo recipients, frequencies were 11.1% and 23.5% when tablets were used < 8 times daily and 8 times daily, respectively. There was no association between subjective genital symptoms and the incidence of colposcopically detected lesions. The high incidence of genital lesions when menfegol foaming tablets were used more than once daily suggests that their frequent use should not be recommended to prevent HIV transmission. In use at low frequency, the tablets' toxicity might be balanced by anti-HIV properties. Safety studies on vaginal microbicides should use objective methods, such as colposcopy, to assess the incidence of lesions.