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Biomedical subjects

D F Archer

Publications and source records attributed to D F Archer.

At least 19 recordsLinked to original sources
PubMed2006

Endometrial expression of epithelial neutrophil-activating peptide-78 during the menstrual cycle or in progestin-only contraceptive users with breakthrough bleeding and the influence of doxycycline therapy.

BACKGROUND: Endometrial breakthrough bleeding is characterized by an inflammatory reaction and increased production of proinflammatory mediators, one of which may be epithelial neutrophil-activating peptide-78 (ENA-78), a chemokine with neutrophil-activating properties. METHODS AND RESULTS: We therefore investigated the endometrial expression of ENA-78 in Norplant users as progestin-only contraceptive with various bleeding patterns (n=35) as compared with non-users with a normal menstrual cycle (n=55). The endometrial stromal cells (ESCs) were the major site of ENA-78 expression with the highest levels found during the secretory phase. The expression of ENA-78 was increased in Norplant users with irregular bleeding as compared with those with regular cycles and amenorrhoea. The levels of ENA-78 detected in uterine washes and sera after the use of Norplant for 3-6 months (n=25) increased compared with baseline (P < 0.05). These levels did not significantly change in Norplant users who received doxycycline (Dox) therapy (25 mg/twice daily for 6 months) when measured midway through or at the conclusion of study when compared with the baseline (n=25). Treatments with medroxyprogesterone acetate (MPA) and tumour necrosis factor-alpha (TNF-alpha) (25 ng/ml), but not 17beta-estradiol (E2) or E2 + MPA (10(-8) M), representing endometrium exposed to contraceptive and inflammatory conditions, respectively, increased the levels of ENA-78 production by ESCs, and this was reduced by co-treatments with Dox (25 microg/ml) (P < 0.05). CONCLUSIONS: The endometrial production of ENA-78 is altered in progestin-only contraceptive users experiencing breakthrough bleeding and is regulated by MPA and TNF-alpha in ESCs. Although Dox therapy did not alter uterine ENA-78 secretion, its suppression in ESCs suggests that Dox, acting site-specifically and through an anti-inflammatory mechanism, may influence the outcome of breakthrough bleeding in contraceptive users.

Adolescent↗
PubMed2006

Effects of 17beta-estradiol, progesterone, synthetic progestins, tibolone, and raloxifene on vascular endothelial growth factor and Thrombospondin-1 messenger RNA in breast cancer cells.

To determine the effect of 17beta-estradiol, raloxifene, progesterone, medroxyprogesterone acetate (MPA), levonorgestrel (LNG), norethindrone (NET), tibolone and tibolone metabolites on vascular endothelial growth factor (VEGF) isoforms 121 and 165 and Thrombospondin-1 (TSp-1) messenger RNA (mRNA) in two breast cancer cell lines, MCF-7 and T47-D. MCF-7 and T47-D cells were cultured to 80% confluence, in vitro. After 24 h incubation in serum-free media, 1.0, 0.1, and 0.01 muM of 17beta-estradiol, raloxifene, raloxifene plus ICI 182780, tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone were added to MCF-7 cells. Progesterone, MPA, LNG, NET, and Delta(4) tibolone at 1.0, 0.1, and 0.01 muM were added to T47-D cells. The cells plus steroids were incubated for a further 24 h. Total RNA was isolated using TRIZOL and reverse transcriptase-polymerase chain reaction was carried out using primers for VEGF, TSP-1, and cyclophilin, the latter as an internal control. Semiquantitative analysis was performed using 33P-CTP for radioactive labeling during the polymerase chain reaction. 17beta-estradiol, raloxifene, tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone had no effect on VEGF mRNA in MCF-7 cells. Progesterone, MPA, LNG, and NET increased VEGF mRNA in T47-D cells. Delta(4) tibolone also increased VEGF mRNA but to a lesser extent than the progestogens. Raloxifene increased TSP-1 mRNA, this effect was not reversed by the addition of ICI 182780 to the media. 17beta-estradiol, raloxifene, tibolone and tibolone hydroxy-metabolites had no effect on VEGF mRNA in MCF-7 cells. Progesterone and progestins increased VEGF mRNA in T47-D breast cancer cells. Delta(4) tibolone was less effective than progestogens on this angiogenic gene in the T47-D cells. Raloxifene increased TSP-1. These differential effects may be related to breast cancer growth.

Breast Neoplasms↗
PubMed2002

Safety of single daily use for one week of C31G HEC gel in women.

Genital irritation and user acceptability was compared after seven nightly bedtime exposures to 1.2% C31G hydroxyethyl cellulose (HEC), 2% nonoxynol-9 (N-9) (Gynol II) or HEC vehicle alone. Sixty healthy women over 18 years old at low risk for sexually transmitted disease with normal menses were randomly assigned to one of three groups. Entrance and exit pelvic exams documented vaginal pH and Gram stain. Genital irritation was assessed by patient diaries, a telephone call 24 to 48 h after first use, colposcopy done the day after last product use, and an acceptability questionnaire at exit. Eighty percent of the women using C31G HEC experienced symptoms of vaginal burning or heat compared to 25% of the N-9 users and 5% of the vehicle users. Colposcopic findings were similar for the active treatments of C31G HEC and N-9: 50% vs. 60% developed new lesions, 25% vs. 20% had lesions that disrupted epithelial integrity, and 50% vs. 45% had minor lesions, respectively. Findings with the HEC vehicle were half as frequent. Twelve percent of women had epithelial disruption that was assessed by the colposcopist as applicator-related. Gram stains were half as likely to show bacterial vaginosis after N-9 use (6 --> 3) and one fourth as likely after vehicle or C31G HEC use (4 --> 1). When asked if they would use the product if it were an effective contraceptive, 55% of the vehicle users, 35% of the N-9 users, and 25% of the C31G HEC users agreed. Product acceptability of C31G HEC was limited by the sensation of heat or burning. The C31G HEC product had a similar safety profile to N-9 in this comparative trial.

Administration, Intravaginal↗
PubMed2002

The assessment of bleeding patterns in postmenopausal women during continuous combined hormone replacement therapy: a review of methodology and recommendations for reporting of the data.

OBJECTIVES: To systematically review methods used to report data on bleeding patterns among postmenopausal women enrolled in clinical trials of continuous combined hormone replacement therapy (HRT); and to propose the use of standardized terms, definitions, and methods for collecting and reporting bleeding data in such trials. METHODS: A MEDLINE search identified 18 published reports of bleeding patterns among postmenopausal women enrolled in prospective clinical trials that included a continuous combined HRT treatment arm. Only two of these trials were not randomized. Methods for collecting and analyzing bleeding pattern data were collated from these published reports and examined for consistency. RESULTS: Comparisons across studies revealed little consistency in definitions and indices utilized to report bleeding patterns among postmenopausal women administered continuous combined HRT regimens in clinical trials. While a majority of the trials incorporated definitions established by the World Health Organization for the evaluation of bleeding with hormonal contraception, a number of the studies expanded on these definitions to reflect additional dimensions of bleeding such as volume. Indices calculated from daily bleeding data to describe bleeding patterns in treatment groups were highly variable among studies. CONCLUSION: Inconsistencies among clinical trials in bleeding pattern definitions and indices limit understanding and comparison of typical bleeding patterns with continuous combined HRT regimens. Standardized definitions, data collection procedures, and indices are proposed to enhance understanding of bleeding patterns with hormone therapy and enrich the quality of patient counselling on HRT.

Clinical Trials as Topic↗
PubMed2001

Single and multiple exposure tolerance study of cellulose sulfate gel: a Phase I safety and colposcopy study.

Vaginally applied gels offer a promising approach for preventing unwanted pregnancies and sexually transmitted infections. Cellulose sulfate (CS) is a non-cytotoxic antifertility agent that also exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV. This was a randomized, double-blinded, Phase I study of 2.5 mL and 5.0 mL doses of 6% CS gel. A single vaginal application of the gel followed by five consecutive daily doses was assessed for genital irritation, safety, vaginal leakage, and product acceptability compared to two controls, Conceptrol, which is a marketed contraceptive gel containing nonoxynol-9, and K-Y jelly. The results suggest that the safety of 6% CS was comparable to that of Conceptrol and K-Y jelly, and it may be associated with less genital irritation. The 2.5 mL dose of CS may be preferable according to the participants' reports of leakage. All the products had similar acceptability profiles.

Administration, Intravaginal↗
PubMed2001

Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding.

OBJECTIVE: To evaluate vaginal bleeding profiles with lower doses of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) as continuous combined therapy. DESIGN: The Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) study, a randomized, double-blind, placebo-controlled trial. SETTING: Study centers across the United States. PATIENT(S): Two thousand six hundred seventy-three healthy, postmenopausal women. INTERVENTION(S): Women received CEE, 0.625 mg/d; CEE, 0.625 mg/d, plus MPA 2.5 mg/d; CEE, 0.45 mg/d; CEE, 0.45 mg/d, plus MPA, 2.5 mg/d; CEE 0.45 mg/d, plus MPA, 1.5 mg/d; CEE, 0.3 mg/d; CEE, 0.3 mg/d, plus MPA, 1.5 mg/d; or placebo for 1 year. MAIN OUTCOME MEASURE(S): Bleeding data were analyzed in efficacy-evaluable and intention-to-treat populations. RESULT(S): Cumulative amenorrhea and no bleeding rates were higher with lower doses of CEE/MPA than with CEE 0.625/MPA 2.5. A linear trend between time since menopause and cumulative amenorrhea was observed (P<.05) in all CEE/MPA groups except the CEE 0.45/MPA 1.5 group. The proportion of patients who experienced no bleeding in cycle 1 was 89%, 82%, and 80% in the CEE 0.3/MPA 1.5, CEE 0.45/MPA 1.5, and CEE 0.45/MPA 2.5 groups, respectively. These values were significantly greater than the incidence of no bleeding in the CEE 0.625/MPA 2.5 group (P<.05). CONCLUSION(S): Lower-dose regimens of CEE and MPA produce higher rates of amenorrhea and no bleeding compared with CEE 0.625/MPA 2.5 and may be appropriate for newly menopausal patients.

Amenorrhea↗
PubMed2001

A randomized, controlled trial of a low-dose contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonorgestrel for acne treatment.

OBJECTIVE: To evaluate the efficacy of a low-dose oral contraceptive (OC) containing 100 microg of levonorgestrel (LNG) and 20 microg of ethinyl estradiol (EE) compared with placebo for the treatment of moderate acne. DESIGN: Multicenter, randomized, double-blind, placebo-controlled clinical trial. SETTING: Outpatient dermatology clinics. PATIENT(S): Women (> or =14 years old; n = 350) with normal menstrual cycles and moderate acne were randomized to receive LNG/EE or placebo for six cycles. INTERVENTION(S): Twenty microg of EE and 100 microg of LNG. MAIN OUTCOME MEASURE(S): Acne lesion counts and clinician global assessment were performed at baseline and at each cycle. Patient self-assessment was carried out at baseline and at cycles 4 and 6; blood pressure and weight were measured at baseline and at cycles 1, 3, and 6. RESULT(S): Inflammatory, noninflammatory, and total lesion counts at cycle 6 with LNG/EE were significantly lower compared to placebo. Patients in the LNG/EE group also had significantly better clinician global and patient self-assessment scores than those in the placebo group at cycle. Changes in weight from baseline were similar between patients in the LNG/EE and placebo groups at all measured time points. CONCLUSION(S): This double-blind, placebo-controlled study demonstrates that a low-dose OC containing 20 microg of EE and 100 microg of LNG is an effective and safe treatment for moderate acne.

Acne Vulgaris↗
PubMed2001

New contraceptive options.

New contraceptive modalities that are being introduced into the US marketplace reflect many changes in the delivery of existing steroidal products. These products are available now not only as oral medications but also as transdermal, intravaginal, intrauterine, and implantable or injectable devices. Each of these has its own unique profile and enhances the ability of consumers to pick and choose the product that is most acceptable to them. However, development of new barrier contraceptives, particularly those that have the potential to reduce the heterosexual transmission of HIV or to reduce a bacterial infection such as Chlamydia or Neisseria gonorrhea, continues to be moving forward in clinical trials. These products can have a lower efficacy compared with the steroidal products but, because of their other benefits, may be of significant medical use.

Choice Behavior↗
PubMed2000

Evaluation of human spermatozoa in cervical mucus: comparison of different microscopic and extraction techniques.

This study was designed to describe an accurate and consistent microscopic technique for the assessment of sperm number and motility in sperm-cervical mucus samples, such as those of postcoital tests (PCTs), and to identify a suitable method to extract functional spermatozoa from cervical mucus (CM). Sperm-CM preparations containing various sperm concentrations were counted using three different microscopic illuminations. The dark field-Makler technique was compared with the more classical bright field-slide technique currently used by our clinicians. Several sperm extraction techniques were applied first to bovine (BCM) and then to human (HCM) cervical mucus. Dark field microscopic illumination provided accurate, fast, and easy sperm identification. Counting variability was significantly greater with bright field-slide than with dard field-Makler, while sperm motility was always higher with this latter methodology. A high degree of agreement (intraclass correlation coefficient = 0.965) among three raters, i.e., low interobserver variability, was obtained only with dark field-Makler. Extraction procedures based on "swim-out," Percoll, trypsin, an enzyme cocktail, and mercaptoethanol resulted in small sperm yields in BCM. Mercaptoethanol and trypsin also showed poor sperm recovery in HCM. Among the protocols with the largest yields, the mechanical technique had the largest amount of residual CM, and bromelain reduced sperm motility. The extraction with dithiothreitol (DTT) showed the best results with a mean sperm recovery of 76% and enhanced sperm motility. Sperm viability as well as spontaneous and induced acrosome reaction were conserved in all techniques. In conclusion, use of the dark field-Makler counting technique in combination with DTT extraction of spermatozoa from CM samples, such as those of PCTs, would allow accurate and functional assessment of spermatozoa for preliminary contraceptive efficacy or infertility evaluation.

Cervix Mucus↗
PubMed2000

Norethindrone acetate and estradiol-induced endometrial hyperplasia.

OBJECTIVE: To identify the lowest effective continuous dose of norethindrone acetate that significantly reduces 12-month incidence of endometrial hyperplasia associated with unopposed 17beta-estradiol (E2), 1 mg. METHODS: In a double-masked, randomized, multicenter study, 1176 healthy postmenopausal women 45 years of age or older without evidence of endometrial abnormalities were given 12 months of treatment with unopposed E2, 1 mg, or continuous-combined regimens of E2, 1 mg, and norethindrone acetate, 0.1 mg, 0.25 mg, or 0.5 mg. Endometrial histology was evaluated at the end of the treatment period. RESULTS: Continuous-combined E2-norethindrone acetate regimens significantly reduced 12-month incidence of endometrial hyperplasia compared with unopposed E2 1 mg (P <.001). Endometrial hyperplasia occurred in 14.6% of women treated with unopposed E2 1 mg, whereas in all continuous-combined groups, the rate decreased to less than 1%. Among patients who received E2-norethindrone acetate 0.1 mg, incidence was 0.8%; among those who received 0.25 mg and 0.5 mg, it was 0.4%. CONCLUSION: Continuous norethindrone acetate at doses as low as 0.1 mg combined with E2 1 mg effectively negated risk for endometrial hyperplasia associated with unopposed E2 1 mg, at least for the first year of therapy.

Climacteric↗
PubMed2000

Hormone replacement therapy: effect of progestin dose and time since menopause on endometrial bleeding.

OBJECTIVE: To analyze the effects of two continuous combined hormone replacement regimens on bleeding profiles in postmenopausal women, based on progestin dose and time since the patient's last spontaneous menstrual period. METHODS: A randomized, double-masked, multicenter trial was conducted in 1724 women recruited from 99 sites. Six hundred seventy-eight women received a continuous regimen of oral conjugated equine estrogens (CEE), 0.625 mg/day, combined with medroxyprogesterone acetate (MPA), 2.5 or 5.0 mg/day, for 1 year. RESULTS: After 1 year, no bleeding was reported by over 89% of women. More women in the 5.0 mg/day MPA group than in the 2.5 mg/day MPA group reported no bleeding (93.8% versus 89.5%; P<.089). Of those women who had had their last menstrual period 3 years ago or less, a significantly higher percentage in the 5.0 mg/day MPA group (72.4%) did not experience bleeding after three cycles compared with the 2.5 mg group (59.0%; P<.001). Although the percentage of patients without bleeding was also higher in the 5.0 mg/day MPA group after six cycles and 1 year, the differences between groups were not statistically significant. Of the women who had their last menstrual period more than 3 years ago, 94.7% of those in the 5.0 mg/day MPA group and 90.7% of those in the 2.5 mg/day MPA group reported no bleeding at 1 year. CONCLUSION: A continuous combined regimen of CEE plus 5.0 mg MPA may be more suitable for women closer to the onset of menopause or for women starting therapy who are unwilling to tolerate irregular bleeding. The improved bleeding profile with CEE and 5.0 mg/day MPA is likely to enhance compliance with hormone replacement therapy.

Aged↗
PubMed2000

The effect of progestins on vascular endothelial growth factor, oestrogen receptor and progesterone receptor immunoreactivity and endothelial cell density in human endometrium.

One common side-effect of contraceptive use is that it often leads to disrupted endometrial bleeding patterns. This may be due to changes in endothelial density and vessel integrity. To investigate whether the level of endometrial immunoreactive vascular endothelial growth factor (VEGF), oestrogen receptor or progesterone receptor (PR) have any role in this, women were treated with either Mircette, a monophasic oral contraceptive, or Implanon, a long-acting gestagen, and immunohistochemistry performed. In addition a small number of endometria were studied from women treated with levonorgestrel released from an intrauterine coil. During the untreated normal cycle, there was a significant increase in glandular VEGF immunoreactivity and a significant decrease in PR immunoreactivity in the midand late secretory phases compared to the proliferative phase. There was a significant positive correlation between stromal VEGF immunoreactivity and endothelial cell density. This correlation was also apparent during treatment with Implanon, but not with Mircette. Disrupted bleeding patterns were associated with Implanon and to a lesser extent with Mircette. Both contraceptives significantly reduced glandular VEGF immunoreactivity but the intrauterine treatment with levonorgestrel resulted in strong glandular epithelial staining and intense staining of decidualized stromal cells. Implanon significantly increased glandular PR staining, but Mircette significantly reduced stromal PR staining when compared to secretory phase before-treatment biopsies. There were no changes in endothelial cell density or glandular or stromal ER during the normal cycle, or with use of either contraceptive. There was no association of the parameters measured with bleeding patterns or histological category.

Cell Count↗
PubMed1999

Efficacy and safety of a low-dose monophasic combination oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol (Alesse). North american Levonorgestrel Study Group (NALSG).

The efficacy and safety of a low-dose 21-day combination oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol were evaluated in an open-label, multicenter trial. A total of 1708 subjects with regular menstrual cycles (27,011 cycles) were evaluated. The oral contraceptive was administered once a day for 21 days, followed by 7 days of placebo for a complete cycle. During 26,554 cycles evaluated for efficacy, 18 pregnancies occurred (Pearl index of 0.88); 6 of these events were attributable to subject noncompliance. After 30 cycles of exposure the cumulative rate of withdrawal as a result of accidental pregnancy was 1.9%. Breakthrough bleeding (with or without spotting) occurred in 12.9% of the cycles and spotting alone occurred in 10.1% of the cycles. The 2 most common adverse events cited as reasons for discontinuation were headache (2% of subjects) and metrorrhagia (2%). One serious event led to withdrawal of a subject. Overall, the results of this study demonstrate that the monophasic regimen of 100 microg levonorgestrel and 20 microg ethinyl estradiol offers effective contraception, acceptable cycle control, and a good tolerability profile.

Adolescent↗
PubMed1999

The effects of a low-dose monophasic preparation of levonorgestrel and ethinyl estradiol on coagulation and other hemostatic factors.

OBJECTIVE: This study was undertaken to evaluate the effects on hemostatic factors of a low-dose preparation of levonorgestrel and ethinyl estradiol in a 12-cycle study. STUDY DESIGN: Thirty healthy women began taking 100 microg levonorgestrel and 20 microg ethinyl estradiol on the first day of the menstrual cycle, continued to take the preparation for the next 21 days, and then took placebo for 7 days. Mean changes in prothrombin time, partial thromboplastin time, and levels of factors VII and X, antithrombin, plasminogen, fibrinogen, protein S, thrombin-antithrombin complexes, and D-dimer were analyzed at baseline and at cycles 3, 6, and 12 with paired Student t tests. RESULTS: Factor X, plasminogen antigen and activity, and D-dimer levels were significantly increased (P </=.01) during all 3 cycle periods. Antithrombin antigen and protein S total antigen levels were significantly (P </=.001 ) decreased at cycles 3, 6, and 12, whereas factor VII and protein S activity levels were significantly (P </=.05) decreased at cycle 3 and at cycles 3 and 6, respectively. CONCLUSION: The effects on hemostatic factors in healthy women of a monophasic preparation of 100 microg levonorgestrel and 20 microg ethinyl estradiol were similar to those of other low-dose oral contraceptives.

Adult↗
PubMed1999

Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. The Esclim Study Group.

OBJECTIVE: Our purpose was to evaluate the efficacy and safety of 3 dosages of Esclim, delivering 0.025 mg, 0.050 mg, or 0.100 mg 17beta-estradiol per 24 hours, in the treatment of moderate to severe vasomotor symptoms. STUDY DESIGN: In this double-blind, placebo-controlled, parallel-group, multicenter trial, 196 highly symptomatic menopausal women received 12 weeks of continuous unopposed treatment with 1 of the 3 dosages of Esclim or a matching placebo patch. RESULTS: The reduction in frequency of moderate to severe vasomotor symptoms was statistically significant compared with placebo (P <.05) from week 2 onward in the Esclim 50 and 100 groups and from week 3 onward in the Esclim 25 group. Symptom severity was also reduced. Estrogen-related adverse events, particularly metrorrhagia and endometrial hyperplasia, were less frequent in the Esclim 25 group than in the higher-dosage groups. CONCLUSION: All 3 dosages of Esclim were effective in the treatment of vasomotor symptoms. The efficacy and safety of Esclim 25 indicate a good risk-benefit ratio.

Administration, Cutaneous↗
PubMed1999

Interleukin-6 and tumor necrosis factor-alpha concentrations in the intrauterine cavity of postmenopausal women using an intrauterine delivery system releasing progesterone. A possible mechanism of action of the intrauterine device.

Intrauterine devices (IUD) provide effective contraception. The current study evaluates the concentration of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the intrauterine fluid of postmenopausal women using an intrauterine delivery system releasing progesterone (IDS-P). Intrauterine fluid was obtained by lavage, and IL-6 and TNF-alpha were analyzed using an enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed with a one-way analysis of variance (ANOVA). Intrauterine fluid IL-6 levels were 33.6 vs 6.09 pg/sample IDS-P vs no IDS-P (p = 0.0301). Intrauterine TNF-alpha levels for women using the IDS-P were higher than in nonusers, but the differences did not reach statistical significance. IL-6 and TNF-alpha levels were increased in the intrauterine cavity of postmenopausal women with an IDS-P. These data suggest that secreted cytokines could be a potential mechanism of IUD contraceptive efficacy.

Enzyme-Linked Immunosorbent Assay↗