Levonorgestrel effects on serum androgens, sex hormone-binding globulin levels, hair shaft diameter, and sexual function.

OBJECTIVE: To determine the effects of levonorgestrel (LNG) on serum androgens, sex hormone-binding globulin (SHBG), hair shaft diameter, and sexual function in women. DESIGN: Substudy of a prospective randomized double-blind study in women using an LNG SC implant (LNG-SI), who were treated with doxycycline or placebo. SETTING: Medical school department of obstetrics and gynecology. PATIENT(S): Forty women were enrolled; 36 completed the study. INTERVENTION(S): Participants were randomized to doxycycline 20 mg or an identical placebo orally twice a day after LNG-SI insertion. MAIN OUTCOME MEASURE(S): Serum levels of total T (TT), free T (FT), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), androstanediol glucuronide (AG), SHBG, and LNG; hair shaft diameter; and sexual function using the Brief Index of Sexual Function for Women and the Arizona Sexual Experiences Scale were assessed. RESULT(S): Serum TT, A, DHT, DHEAS, and SHBG declined after LNG-SI insertion. No changes were found in FT, AG, hair shaft diameter, or sexual function. Serum LNG correlated with SHBG levels. There were no differences between the placebo and doxycycline groups. CONCLUSION(S): LNG reduced serum TT, A, DHT, DHEAS, and SHBG but had no effect on sexual function or markers of androgen bioactivity.

Ovarian activity and safety of a novel levonorgestrel/ethinyl estradiol continuous oral contraceptive regimen.

BACKGROUND: A continuous regimen of oral levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg was evaluated for inhibition of ovulation, time to return to ovulation after stopping treatment and safety. STUDY DESIGN: This open-label study was conducted in healthy women aged 18-35 years. Ovulation was documented before treatment, and then participants received oral tablets containing LNG 90 mcg/EE 20 mcg to be taken continuously for three 28-day intervals. Ovarian activity was assessed three times per week during the treatment period with transvaginal ultrasound scans and measurements of serum 17beta-estradiol, progesterone, follicle-stimulating hormone and luteinizing hormone concentrations. Safety assessments included physical examinations, laboratory evaluations and adverse event records. RESULTS: Thirty-seven of the 58 subjects who received treatment met predefined criteria for efficacy analysis. No on-treatment ovulations occurred in the efficacy or intent-to-treat population. There was evidence of ovulation within 37 days of stopping treatment for 46 (98%) of 47 subjects evaluated posttreatment. The final subject with a history of polycystic ovarian syndrome ovulated by Day 66. The safety profile observed during this 84-day continuous regimen was similar to that seen with other low-dose oral contraceptives administered in a cyclic regimen. CONCLUSIONS: The continuous LNG/EE regimen completely inhibited ovulation, with little evidence of follicular development and with rapid return of ovulatory capacity after stopping treatment.

Effects of doxycycline on serum and endometrial levels of MMP-2, MMP-9 and TIMP-1 in women using a levonorgestrel-releasing subcutaneous implant.

BACKGROUND: Endometrial spotting and/or bleeding (ESB) occurs in levonorgestrel subcutaneous implant (LNG SI) users. Matrix metalloproteinases (MMPs) may play a role in ESB. STUDY DESIGN: Women between 18 and 40 years with regular menstrual cycles had a baseline evaluation followed by LNG SI insertion and randomization to doxycycline (DOX; 20 mg) or placebo (PL) twice a day. MMP-2, MMP-9 and tissue inhibitor of MMP-1 (TIMP-1) in serum and the endometrium were estimated at baseline and at 1, 3 and 6 months after insertion. RESULTS: LNG increased serum MMP-9, while DOX decreased MMP-9 levels compared to PL after 1 month (p<.05). DOX decreased endometrial MMP-9 at 1 and 6 months compared to baseline and PL (p<.05). DOX increased endometrial TIMP-1 at 6 months compared with baseline and PL (p<.05). MMP-2 levels were unchanged. CONCLUSION: LNG SI increased serum MMP-9 and TIMP-1 levels, while DOX decreased both serum and endometrial MMP-9 levels.

Safety analysis of the diaphragm in combination with lubricant or acidifying microbicide gels: effects on markers of inflammation and innate immunity in cervicovaginal fluid.

OBJECTIVE: Diaphragms are being considered for use with vaginal microbicide gels to provide enhanced protection against sexually transmitted pathogens. The purpose of this study was to determine whether use of a diaphragm with microbicide or placebo gel causes cervicovaginal inflammation or perturbations in cervicovaginal immune defense. METHOD OF STUDY: Eighty-one non-pregnant women were randomized into three groups and instructed to use Milex (CooperSurgical, Inc., Trumbull, CT, USA)diaphragms overnight for 14 days in combination with one of the two acid-buffering microbicide gels [ACIDFORM (Instead Inc., La Jolla, CA, USA) or BufferGel(trade mark) (BG; ReProtect Inc., Baltimore, Maryland)] or placebo gel (K-Y Jelly); Personal Products Inc., Raritan, NJ, USA). Cervicovaginal lavages (CVLs) were performed prior to study entry and on days 8 and 16. Nine soluble mediators of vaginal inflammation or immune defense were measured in CVLs by Bio-Plex or ELISA. RESULTS: Use of diaphragms with placebo or microbicide gel was not associated with increased levels of inflammation markers. Concentrations of secretory leukocyte protease inhibitor (SLPI) were markedly reduced in the BG group. CONCLUSION: Daily use of a diaphragm with placebo or acidifying microbicide gel did not cause cervicovaginal inflammation. However, diaphragm/BG use was associated with markedly reduced levels of SLPI, an important mediator of innate immune defense. Further studies are warranted to establish the safety of diaphragm/microbicide gel combinations.

Communicating with women about menstrual cycle symptoms.

Eighty-five percent of reproductive-aged women experience physical or emotional changes with their menstrual cycle. Up to 40% of women are bothered by menstrual cycle-related symptoms and conditions, such as dysmenorrhea, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). These conditions influence women's lives, relationships and work. Dysmenorrhea is the most common reason for absenteeism for women younger than age 30, yet many do not discuss this with their clinicians despite potential treatment options that include selective serotonin reuptake inhibitors (SSRIs), nonsteroidal anti-inflammatory drugs (NSAIDs), certain oral contraceptives used continuously or intermittently, cycle ablation medicines and anxiolytics. Effective treatment of cyclic symptoms hinges on effective doctor-patient communication. Patients who report that their health care providers converse with them and engage them in decision making obtain more relief and are more satisfied with their health care. Given the frequency of symptoms and the availability of treatment options, health care providers should remember to routinely ask questions about cycle-related symptoms. This will encourage patients to provide information and to participate in the management of these symptoms, thus improving their productivity and quality of life.

Six-day randomized safety trial of intravaginal lime juice.

OBJECTIVES: Nigerian women reportedly apply lime juice intravaginally to protect themselves against HIV. In vitro data suggest that lime juice is virucidal, but only at cytotoxic concentrations. This is the first controlled, randomized safety trial of lime juice applied to the human vagina. METHODS: Forty-seven women were randomized to apply water or lime juice (25%, 50%, or undiluted) intravaginally twice daily for two 6-day intervals, separated by a 3-week washout period. Product application also was randomized: during 1 interval, product was applied using a saturated tampon and in the other by douche. Vaginal pH, symptoms, signs of irritation observed via naked eye examination and colposcopy, microflora, and markers of inflammation in cervicovaginal lavages were evaluated after 1 hour and on days 3 and 7. RESULTS: The largest reduction in pH was about one-half a pH unit, seen 1 hour after douching with 100% lime juice. We observed a dose-dependent pattern of symptoms and clinical and laboratory findings that were consistent with a compromised vaginal barrier function. CONCLUSIONS: The brief reduction in pH after vaginal lime juice application is unlikely to be virucidal in the presence of semen. Lime juice is unlikely to protect against HIV and may actually be harmful.

SILCS diaphragm: postcoital testing of a new single-size contraceptive device.

BACKGROUND: This study was conducted to compare the effectiveness of a new, single-size silicone contraceptive diaphragm used with either spermicide [2% nonoxynol-9 (N-9)] or lubricant in preventing sperm from penetrating midcycle cervical mucus. STUDY DESIGN: A crossover postcoital test (PCT) in healthy, sexually active women not at risk for pregnancy due to tubal occlusion was conducted. Couples had a baseline PCT without a device to verify normal fertility parameters. Qualified couples underwent up to two test cycles using the SILCS diaphragm with a metal spring. A subgroup of couples underwent a third test cycle with the SILCS polymer spring diaphragm used with N-9 gel. RESULTS: Fifteen couples completed a baseline cycle and were randomized to order of study gel. Of these, 14 couples completed a baseline cycle and at least one test cycle, 12 couples completed a baseline cycle and two test cycles and 8 couples completed a third test cycle with the polymer spring prototype. Sperm was detected in the vaginal pool in all completed test cycles. The SILCS metal spring diaphragms used with N-9 gel reduced the average number of progressively motile sperm per high power field in the cervical mucus from a baseline of 12.5 to 0, while use of this device with lubricant reduced the number to 0.5. The SILCS polymer spring diaphragm used with N-9 performed the same as the metal spring used with N-9. CONCLUSION: The SILCS diaphragm used with N-9 gel performed well. It is likely that the SILCS diaphragm will give acceptable results in a contraceptive effectiveness study but that adjunctive use of a chemical barrier such as N-9 gel will be necessary for it to be most effective.

A randomized six-day safety study of an antiretroviral microbicide candidate UC781, a non-nucleoside reverse transcriptase inhibitor.

GOAL: This study evaluated the effect of a single dose and 5 additional consecutive daily doses of UC781 gel at concentrations of 0.1%, 0.25%, 1.0%, and 0% on urogenital irritation. STUDY DESIGN: Forty-eight healthy sexually abstinent women were randomly assigned to 1 of 4 groups. METHODS: Urogenital irritation was assessed by pelvic examination, colposcopy, and reports of genital symptoms at baseline and after 1 and 6 doses. Vaginal health was assessed by wet mount and systemic safety by laboratory evaluation after 1 and 6 doses, and UC781 levels were assessed at baseline and after 6 doses. RESULTS: Some evidence of urogenital irritation was common in all treatment groups and was most often transient and mild. Colposcopic findings were infrequent in the placebo group (8%) and more common in the 3 treatment groups (24%-42%). Edema, which may indicate underlying inflammation, was observed in the vaginal fornix of 2 women exposed to UC781. There was no apparent increase in vaginal infection or clinically significant changes in laboratory values. Two of 12 participants randomized to 1% UC781 gel had detectable plasma levels that were less than the lower level of quantification. CONCLUSIONS: UC781 was well tolerated in this initial dose ranging safety study when used once daily for 6 days in sexually abstinent women. Five safety/pharmacokinetic studies of UC781 are currently underway in women and men, all utilizing UC781 concentrations less than 1%, with twice-daily dosing in some studies, and all involving careful monitoring of exposed epithelium.

Multicenter comparison of the contraceptive ring and patch: a randomized controlled trial.

OBJECTIVE: To understand if the contraceptive ring or patch was more acceptable, as measured primarily by continuation, to women using an oral contraceptive and interested in a nondaily, combined hormonal contraceptive. METHODS: Five hundred women were randomly assigned to use the contraceptive ring (n=249) or contraceptive patch (n=251) for four consecutive menstrual cycles, starting with their next menses. Participants returned for a single follow-up visit during the fourth cycle for an evaluation, which included a questionnaire to assess acceptability and adverse effects. RESULTS: Rates of completion of three cycles were 94.6% (95% confidence interval [CI] 91.0-97.1%) and 88.2% (95% CI 83.4-92.0%) for ring and patch users, respectively (P=.03). Of these women, 71.0% (95% CI 64.8-76.6%) and 26.5% (95% CI 21.0-32.6%), respectively, planned to continue their method after the study (P<.001). Women switching to the patch were significantly more likely than women switching to the ring to experience longer periods (38% compared with 9%), increased dysmenorrhea (29% compared with 16%), frequent nausea (8% compared with 1%), frequent mood swings (14% compared with 8%), and frequent skin rash (12% compared with 2%) and were less likely to experience frequent vaginal discharge (8% compared with 17%). Ring users preferred the ring to the oral contraceptive (P<.001), and patch users preferred the oral contraceptive to the patch (P<.001). Nugent scores increased only in patch users (P=.01), although most of these women were asymptomatic. CONCLUSION: Women satisfied with combined oral contraceptives and interested in a nondaily method are more likely to continue using the contraceptive ring than the contraceptive patch. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00269620. LEVEL OF EVIDENCE: I.

Cervicovaginal colposcopic lesions associated with 5 nonoxynol-9 vaginal spermicide formulations.

OBJECTIVE: This study was undertaken to compare the colposcopic appearance of the cervicovaginal epithelium with spermicide use vs condom use in a low-risk population. STUDY DESIGN: This was an ancillary study of a trial comparing the efficacy of 5 nonoxynol-9 spermicides. A cohort of women who used condoms without spermicide served as a control group. Colposcopic examinations were performed during product use to identify genital lesions. RESULTS: One hundred fifty-one participants had 1 or more follow-up examinations. At baseline, study groups differed only by the prevalence of baseline lesions. New lesions were identified at 49% of follow-up visits. Controlling for the presence of a baseline lesion, compared with condom use none of the spermicides were associated with an increase in new lesions (overall odds ratio, 0.8; 95% CI, 0.4-1.6; P = .5); and lesions characterized by epithelial disruption were less frequent with spermicide use (overall odds ratio, 0.3; 95% CI, 0.1-0.6; P < .001). CONCLUSION: In a low-risk population, women who used nonoxynol-9 spermicides were less likely to have lesions with epithelial disruption, and equally likely to have any new lesion compared with condom use.

A Phase I study of the functional performance, safety and acceptability of the BufferGel Duet.

BACKGROUND: The purpose of this study was to assess the functional performance of the BufferGel Duet, a buffering microbicide and spermicide gel applied to the cervix and vagina by a novel applicator that also serves as a mechanical barrier. STUDY DESIGN: This was a noncomparative Phase I safety trial in 30 healthy couples, aged 20-50 years, at low risk for sexually transmitted infections, who agreed to use the gel-device combination twice in 1 week and respond to detailed questionnaires about their experience. The female participants were examined with colposcopy before and 6-18 h after using the second device. RESULTS: Based on written instructions alone, 25 women successfully placed and 28 women successfully removed the device. Three women reported feeling the device dislodge around the time of intercourse. The product was equally acceptable to both men and women. Most users concluded that intercourse was the same or better with the device than with no product. About 73% would choose Duet over male condoms, and no one preferred the standard diaphragm. Colposcopic findings were noted in 79% of women with external genital findings (9) or cervicovaginal peeling (18) predominating. Only one finding breached the epithelium. Most product-related adverse events were mild (10/11) and confined to the genitourinary tract. CONCLUSIONS: The successful placements and acceptability suggest that further product development is warranted and could target over-the-counter use. During increased duration of use or more frequent dosing, cervicovaginal monitoring is advised based on the extent of peeling and external colposcopic findings in this short-term study.

Phase I safety trial of two vaginal microbicide gels (Acidform or BufferGel) used with a diaphragm compared to KY jelly used with a diaphragm.

OBJECTIVES: To assess the safety and acceptability of 2 vaginal microbicide gels (Acidform and BufferGel) used with a diaphragm compared to KY Jelly used with a diaphragm among low-risk, sexually abstinent women. STUDY DESIGN: Eighty-one women enrolled in a randomized, masked, phase I safety study using a diaphragm with Acidform, BufferGel, or KY Jelly for 6 to 10 hours nightly for 14 nights. Physical examination, colposcopy, and lab studies were performed after 1 and 2 weeks of use. Diaries and questionnaires were used to assess user acceptability. RESULTS: Sixty-nine participants (85%) completed the study. Safety and acceptability appeared similar among the 3 study groups and no serious adverse events related to the study products were reported. Adverse events were mild and anticipated. CONCLUSIONS: Acidform and BufferGel compared to KY Jelly, when used with diaphragm daily for 14 days, appeared to be safe and acceptable in a small study of low-risk abstinent women.

Fourteen-day safety and acceptability study of the universal placebo gel.

OBJECTIVE: This study evaluated the effect of the so-called universal placebo compared to the polystyrene sulfonate (PSS) placebo on genital irritation. DESIGN: A single-center, Phase I, randomized, closed-label study was performed to evaluate the genital irritation of microbicide placebo gels. Thirty healthy, sexually abstinent women were randomly assigned to apply 3.5 mL of either the universal placebo or the PSS placebo gel intravaginally twice daily for 14 days. METHODS: Genital irritation was assessed by signs as seen on pelvic examination and colposcopy and reports of symptoms. Vaginal health was assessed by wet mounts, Gram stains for Nugent score and polymorphonuclear leukocytes, and semiquantitative vaginal cultures. Acceptability was assessed as reported on the follow-up questionnaire. RESULTS: The universal placebo was less irritating than the PSS placebo with a lower proportion of women experiencing signs and/or symptoms of genital irritation throughout follow-up (36% compared to 80%, p=.0253). The universal placebo was associated with few and mild genital symptoms, few and minor colposcopic findings and good vaginal health with no clinically significant changes in genital flora. Most participants found the feel of the universal placebo gel neutral or pleasant, and all participants found it odorless. CONCLUSIONS: The universal placebo appeared safe and acceptable when used twice daily for 14 days. The strategy of creating a de novo inert universal placebo is a successful approach. The universal placebo is appropriate for use as a placebo gel in HIV prevention trials with microbicide candidates.

Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study.

BACKGROUND: Topical microbicides against the human immunodeficiency virus (HIV) 1 that are nonirritating to the female genital epithelium are urgently needed to slow the heterosexual spread of HIV infection. Products that are also effective contraceptives provide additional benefits. Cellulose sulfate (CS) is a noncytotoxic antifertility agent that exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV. METHODS: We performed a multicenter, Phase I, placebo-controlled, randomized study to evaluate the genital toxicity of CS. Two cohorts of healthy women used 3.5 ml of 6% CS gel or 3.5 ml of K-Y Jelly, vaginally, bid, for 14 days. The first cohort was sexually abstinent, and the second cohort was sexually active. RESULTS: CS was associated with only a slightly higher odds ratio (OR) of symptoms of minor urogenital irritation compared to the inactive lubricant K-Y Jelly (OR=2.02, 95% confidence interval=0.90-4.53). In addition, there were minor shifts in some genital flora, but there was no evidence of greater inflammation as evidenced by few colposcopic findings, decreased influx of polymorphonuclear cells and minimal changes in proinflammatory cytokines. Moreover, both products appeared acceptable to most women. Product leakage was identified as more of a problem in sexually abstinent women, but less so in women using the product for sexual intercourse, as would be the case in actual practice. CONCLUSION: CS was safe for twice-daily use for 14 days. CS is appropriate for future studies in effectiveness trials.

FemCap with removal strap: ease of removal, safety and acceptability.

OBJECTIVES: FemCap is a silicone-rubber barrier contraceptive approved for marketing in the United States. To address reported problems with removal and dislodgment, the device's developer added a strap to the device and increased the height of the brim. This trial assessed whether the new design reduced removal difficulties and had any effects on dislodgment, genital pain/discomfort, safety, and acceptability. METHODS: Women used the strapped device for 8 weeks with follow-up visits at 2 and 8 weeks. Outcome measures were obtained through diary cards, questionnaires, and naked eye examination. Data from these 120 women were compared with data from 419 women who used the unstrapped FemCap in a previous contraceptive effectiveness study. RESULTS: The strapped device was not significantly easier for users to remove than the unstrapped device. Similar odds of dislodgment and cervical/vaginal irritation were seen with the two devices. Both female and male participants were significantly more likely to report pain/discomfort with use of the strapped device. Female users of the strapped device were significantly more likely to say they disliked their device. In six weeks, two pregnancies were observed, but pregnancy was not an endpoint in the study and no conclusions should be drawn regarding pregnancy rates. CONCLUSIONS: The modifications to the FemCap did not significantly improve the ease of device removal and appears to have resulted in significantly more female and male partner pain/discomfort and decreased acceptability, compared with the unstrapped device.

Vaginal hormone therapy for urogenital and menopausal symptoms.

Reduction of ovarian steroids at menopause leads to significant changes in the urogenital tract. These changes often worsen with time, particularly in nonsmokers, affecting up to 38% of menopausal women. Urogenital symptoms that clearly respond to estrogen therapy include atrophic vaginitis, dryness, and accompanying dyspareunia. Estrogen reduces urinary tract infections in women plagued by frequent recurrence. The sensation of urgency improves with estrogen but urge incontinence improvement is similar to that with placebo. Stress incontinence does not improve with estrogen. Until recently, vaginal therapy was reserved for local symptoms. Rings make systemic vaginal therapy acceptable and even preferred by some users. Vaginal delivery, like other parenteral therapies, bypasses the gastrointestinal tract, with less anticipated impact on lipids, globulins, clotting, and fibrinolytic factors. Evidence of a lowered risk of venous thromboembolism is reviewed. Options for estrogen therapy include native, synthetic, or biologically derived estrogens delivered by cream, gel, insert (pessary), ring, or tablet. Even the lowest dose estradiol (7.5 mug daily or 25 mug twice per week) shows evidence of systemic absorption. In long-term placebo-controlled studies, bone density was better preserved and lipid profiles were more favorable. Therefore, even these low dose therapies should be opposed by occasional progestogen to prevent endometrial carcinoma. Intermittent therapy is best given for a minimum of 12 days based on laboratory data. Less frequent dosing, although preferred by patients, likely confers a slightly increased risk of hyperplasia. No combination estrogen/progestogen vaginal product is currently available. The best dose to reduce risk of endometrial pathology adequately in the lower dose therapies will be defined not only by the dose and potency of the exogenous estrogen but by the individual is body habitus and lifestyle choices.

Vaginal rings for menopausal symptom relief.

The vagina is an alternative delivery site of sex steroids for menopausal women. New ring technology provides continuous and consistent delivery of steroids for up to 3 months. Rings rest on the pelvic floor muscles in a nearly horizontal position and are usually imperceptible. Steroid is delivered directly into the systemic circulation which may result in less alteration of coagulation/fibrinolysis pathways as seen with transdermal hormone therapy. Fewer adverse effects are noted when progesterone is applied vaginally, possibly due to lower serum levels of metabolites such as alloprenanolone. Women often switch to a ring for the longer dosing interval but also appreciate the reduced messiness. Over 5700 healthy US women who evaluated an unmedicated ring as a drug delivery platform found it very acceptable independent of age or prior use of barrier contraceptives. Marketed rings in the US include: (i) a ring for systemic and vaginal menopausal therapy that provides average serum estradiol levels of 40.6 pg/mL for the 0.05 mg and 76 pg/mL for the 0.1 mg dose; (ii) a ring for urogenital menopausal symptoms only that minimally elevates serum estradiol, usually within the menopausal range, treating atrophic vaginitis and urethritis; and (iii) a ring labelled for contraception that provides ethinyl estradiol 15 microg and etonogestrel 120 microg appropriate for nonsmoking perimenopausal women. A ring for combination hormone therapy and another releasing progesterone for contraception in lactating women have been reported in the literature, but are not yet available commercially. These may offer future options for hormone therapy. Women with a uterus receiving estrogen, even in low doses, should be given progestogen to prevent endometrial hyperplasia or carcinoma. Even women who have had an endometrial ablation are likely to have some endometrial tissue remaining since long-term amenorrhoea is uncommon. Since no marketed combination ring product is available, other forms of progestogen are necessary. Vaginal rings offer a novel approach to menopausal hormone therapy producing consistent serum levels sustained for up to 3 months per unit dose with lower adverse effects than other vaginal products and high acceptability among users.

A phase I comparative postcoital testing study of three concentrations of C31G.

BACKGROUND: C31G is a broad-spectrum antibacterial agent that shows contraceptive properties in vitro. This postcoital testing study evaluated the ability of three C31G concentrations, 0.5%, 1.0% and 1.7%, administered as a 3.5-mL dose of a vaginal gel to prevent sperm from entering mid-cycle cervical mucus. Irritation of the genitalia and acceptability were also assessed. METHOD: At baseline, a mid-cycle cervical mucus test and a postcoital test were performed within 24 h of each other without use of any study products to establish normal mid-cycle cervical mucus and sperm penetration. Subjects then completed up to three test cycles using one of the three concentrations of study product during intercourse. RESULTS: Twenty-two of the 61 women enrolled completed a baseline cycle and at least one test cycle. An average of 14.6 progressively motile sperm per high power field was seen at baseline. This was reduced to 0.3 after use of 0.5% C31G, 0.5 after use of 1.0% C31G, and 0.4 after use of 1.7% C31G. There was no significant difference between test products (p >/= 1.000) but each test product was significantly different from baseline (p < 0.002). Very little genital irritation was observed. There were more reports of leakage and messiness with increasing C31G concentration. CONCLUSION: This study suggests that all three concentrations of C31G are likely to give reasonable results in a contraceptive effectiveness trial. Based on the results of this and other trials, the 1.0% concentration has been selected for further development, including Phase III trials of contraceptive effectiveness.

A comparison of techniques to assess cervicovaginal irritation and evaluation of the variability between two observers.

BACKGROUND: Colposcopy is used to evaluate effects of new vaginal products on cervicovaginal epithelium as part of the US Food and Drug Administration-mandated product approval process, yet few aspects of its use have been investigated. OBJECTIVES: To determine the effect of the colposcopic examination itself on the number and type of findings seen, to compare colposcopy with the AviScope hand-held device and the naked eye and to compare the findings reported by two examiners during a single visit. STUDY DESIGN: Fourteen healthy women volunteered for five paired examinations in random order: (1) naked eye inspection plus colposcopy done twice by a single examiner; (2) naked eye inspection plus AviScope examination, then naked eye inspection plus colposcopy by a single examiner; (3) Examination 2 repeated with the order of device reversed; (4) naked eye inspection plus colposcopy done by two examiners; (5) Examination 4 repeated with the order of examiner reversed. The colposcopic examinations were done per published standards but were limited to the areas visible without manipulation of the speculum. RESULTS: Length of colposcopic examination averaged 7 min. The number of colposcopic findings found when the examination was done twice by the same clinician was not statistically different (p = 0.12), suggesting that the examination itself did not induce findings. More findings were seen using magnification than naked eye. A similar number of findings were seen by AviScope compared to the colposcope (p = 0.99), but clinically significant findings were "undercalled" or "overcalled" by the AviScope. A weighted kappa score of the "worst" colposcopic finding was 0.32 (SE 0.10, p = 0.00), indicating moderate agreement between examiners. CONCLUSIONS: The colposcopic examination is not burdensome nor does it induce findings. If naked eye observation were used alone in practice, these data suggest that half the colposcopically detected findings would be missed. Using the naked eye observation for screening would minimally reduce the number of magnified observations carried out. For detecting epithelial changes, the colposcope seems to be the most sensitive technique, followed by the AviScope.

Single and multiple exposure tolerance study of polystyrene sulfonate gel: a phase I safety and colposcopy study.

OBJECTIVES: To evaluate symptoms and signs of genital irritation, vaginal leakage and acceptability of polystyrene sulfonate (PSS), which is being studied as a vaginal contraceptive and microbicide. METHODS: Forty-nine women applied 2.5 mL of either 5% PSS, 10% PSS, PSS vehicle, or Conceptrol (a marketed spermicidal product containing 4% nonoxynol-9) for 6 consecutive days. RESULTS: All women completed the study except one in the Conceptrol group who experienced vaginal symptoms after her first use and was discontinued. After both the first use and after all uses, irritation was seen among more women in the Conceptrol group than in the PSS groups, reaching statistical significance with regard to any evidence of irritation, signs of irritation and product-related irritation. There were no adverse events that were serious, unexpected and related to product use in any group. The 5% concentration of PSS may be preferable in terms of leakage and acceptability. CONCLUSION: The results suggest that PSS has a safety profile comparable to that of the marketed nonoxynol-9 product, Conceptrol, and appears to be associated with less genital irritation.