Faculty Bibliography

BACKGROUND: In most recent large efficacy trials of barrier contraceptive methods, a high proportion of participants withdrew before the intended end of follow-up. The objective of this analysis was to explore characteristics of participants who failed to complete seven months of planned participation in a trial of spermicide efficacy. METHODS: Trial participants were expected to use the assigned spermicide for contraception for 7 months or until pregnancy occurred. In bivariable and multivariable analyses, we assessed the associations between failure to complete the trial and 17 pre-specified baseline characteristics. In addition, among women who participated for at least 6 weeks, we evaluated the relationships between failure to complete, various features of their first 6 weeks of experience with the spermicide, and characteristics of the study centers and population. RESULTS: Of the 1514 participants in this analysis, 635 (42%) failed to complete the study for reasons other than pregnancy. Women were significantly less likely to complete if they were younger or unmarried, had intercourse at least 8 times per month, or were enrolled at a university center or at a center that enrolled fewer than 4 participants per month. Noncompliance with study procedures in the first 6 weeks was also associated with subsequent early withdrawal, but dissatisfaction with the spermicide was not. However, many participants without these risk factors withdrew early. CONCLUSIONS: Failure to complete is a major problem in barrier method trials that seriously compromises the interpretation of results. Targeting retention efforts at women at high risk for early withdrawal is not likely to address the problem sufficiently

OBJECTIVE: To estimate the effectiveness, side effects, and retention rate of the levonorgestrel two-rod implant used as a long-acting contraceptive. METHODS: Voluntary participants, ages 18-40 years and desiring long-acting contraception, were enrolled in the study. The original design was to observe the participants for 5 years. Later, the follow-up period was extended to 6 years. RESULTS: A total of 249 women underwent two-rod implant insertion and were observed for a total of 823 woman-years. There were two pregnancies observed during the study, yielding a pregnancy rate of 0.24 per 100 woman-years. One pregnancy occurred in the first month, and the other occurred after 6 years of use. The major side effect was menstrual irregularity. No serious side effects were observed during the study. Insertion of the device was easy and took less than 2 minutes; removal time averaged 4.5 minutes. CONCLUSION: The levonorgestrel two-rod implant system is an effective, convenient, long-acting, and well-tolerated method of contraception

OBJECTIVE: To analyze the factors that influence the detection of uterine cancers by Pipelle and Tao Brush endometrial sampling devices. STUDY DESIGN: Seventy-nine Pipelle currettages were followed by Tao Brush sampling. The curettage specimens were fixed in formalin for histology and reported by surgical pathology, whereas the Tao Brush specimens were fixed in CytoRich Red for histology and cytology and reported by cytopathology. Uterine size and features of residual tumors were obtained from hysterectomy reports. Follow-up for clinically benign cases ranged from 16 to 52 months (mean, 33.7; median, 34). RESULTS: There were 10 uterine cancers and 9 hysterectomies. Five cases of centrally located adenocarcinoma, ranging from 0.4 to 3 cm, were detected by both samplers. Additionally, a Tao Brush sampled an adenocarcinoma located near the cornu. An endometrial stromal sarcoma found with a Tao Brush was reported as necrotic tissue by Pipelle. Both samplers missed a microscopic focus of adenocarcinoma, an in situ adenocarcinoma in a polyp and a large leiomyosarcoma. CONCLUSION: The size and type of tumor and its location within the uterine cavity, the mechanism of sampling and preparation method influence the detection of uterine cancer by the Pipelle and Tao Brush

Abnormal uterine bleeding is the leading indication for discontinuation of long-term progestin-only contraceptives (LTPOCs). Histological sections of endometria from LTPOC-treated patients display abnormally enlarged blood vessels at bleeding sites. Paradoxically, a trend toward reduced endometrial perfusion in LTPOC users has been reported in these patients. We hypothesized that hypoxia/reperfusion-induced free radical production inhibits the expression of angiopoietin-1 (Ang-1), a vessel stabilizing factor, leaving unopposed the effects of endothelial Ang-2, a vessel-branching and permeability factor. Immunohistochemical studies confirmed selective decreases in stromal cell Ang-1 in LTPOC-exposed endometrium. To indirectly assess whether LTPOC enhances endometrial free radical production, immunostaining was conducted for the phosphorylated form of the stress-activated kinases SAPK/JNK and p38. These kinases were greatly increased in endometria from LTPOC-treated patients. Interestingly, the endothelial cells but not the stromal cells displayed enhanced immunostaining for the phosphorylated mitogen-activated kinase (pMAPK) after LTPOC treatment. To further examine the effects of progestin, hypoxia, and reactive oxygen species (ROS) on the regulation of Ang-1 and Ang-2 as well as the activation of MAPK, SAPK/JNK, and p38 by the relevant cell types, we conducted in vitro studies with cultured human endometrial stromal cells (HESCs) and human endometrial endothelial cells (HEECs). Cultures of HESCs were treated with vehicle control, estradiol (E(2)), or with medroxyprogesterone acetate +/- E(2) under hypoxic and normoxic conditions. Although medroxyprogesterone acetate but not E(2) increased Ang-1 expression, hypoxia greatly decreased Ang-1 protein and mRNA expression. In contrast, HESCs did not appear to express Ang-2 protein or mRNA. Conversely, cultured HEECs did not appear to express Ang-1, but expressed Ang-2, the levels of which were significantly increased by hypoxia. Hypoxia also induced the phosphorylation of SAPK/JNK and p38 in both cultured HESCs and HEECs. Moreover, ROS such as that observed after hypoxia/reperfusion resulted in the activation of SAPK/JNK and p38 in HESCs and HEECs and inhibited Ang-1 in cultured HESCs. These effects could be blocked by oxygen radical scavengers. Consistent with the in vivo studies, MAPK was activated after ROS treatment in HEECs but not in HESCs. Our findings suggest that LTPOC-induced endometrial bleeding occurs as a result of hypoxia/reperfusion-induced free radicals that directly damage vessels and alter the balance of Ang-1 and Ang-2 to produce the characteristic enlarged and permeable vessels that are prone to bleeding

Serum levonorgestrel concentrations were assayed in a multicenter, 7-year study of 199 users of Jadelle rod implants. We examined drug levels, patterns of changes, factors affecting drug levels, and concentrations at which pregnancies occurred. Mean levonorgestrel concentrations declined from 435 pg/mL at 1 month of use to 64% of that value (280 pg/mL) at the end of 3 years. Between the end of the third and fifth years neither mean nor median serum levels varied markedly. At 5 years the mean concentration was again 64% of the first month's mean. Declining levels were observed thereafter through the end of 7 years when the mean, 224 pg/mL, was 52% of the 1-month value. Last measured drug concentrations of women who became pregnant during Jadelle use had mean and median values of 152 and 144 pg/mL, respectively, and a maximum value of 180 pg/mL. Analyses indicated ponderal index, body weight, duration of use, and a single clinical center were the most important variables affecting measured levonorgestrel levels. Approximately one-third of assays in the sixth and seventh years were found to be below 180 pg/mL, suggesting that Jadelle levonorgestrel implants would not maintain sufficiently high levels of effectiveness against pregnancy after 5 years and that heavier women would then be at greater risk of pregnancy.

OBJECTIVE: To evaluate a new technique for processing endometrial cytology for the diagnosis and exclusion of endometrial cancer. STUDY DESIGN: All women at risk for endometrial cancer with clinical indications for endometrial biopsy were evaluated by endometrial brush biopsy (Tao Brush, Cook OB-GYN, Bloomington, Indiana) and Pipelle (Cooper Surgical, Shelton, Connecticut) endometrial biopsies during one office visit. Patients were followed longitudinally for the development of endometrial cancer or until undergoing dilatation and curettage or hysterectomy. All comparisons were analyzed using the chi 2 or t test. RESULTS: One hundred one women (mean age, 58; range, 35-86) had endometrial biopsies performed. Median follow-up was > 21 months (range, 3-29). Twenty-two had cancer or atypia, while the remaining had benign diagnoses. When correlated with the final diagnosis, the Tao Brush had 95.5% sensitivity and the Pipelle, 86% sensitivity. Both devices had 100% specificity, positive predictive value of 100% and negative predictive value of 98%. When the results of the two biopsy devices are considered together, the positive and negative predictive value for detecting or excluding endometrial cancer was 100%. Based on 1998 Medicare reimbursements, a simultaneous second office biopsy using the Tao brush could save approximately $67 per case as compared to a sonohistogram and much more when compared to dilatation and curettage. CONCLUSION: Endometrial cancer can be reliably detected and excluded using these two distinct office biopsy devices simultaneously during one office visit. In patients with an indication for endometrial biopsy, no further diagnostic test may be necessary to exclude or diagnose endometrial cancer or atypia

Abnormal uterine bleeding after Norplant administration is primarily responsible for the high discontinuation rate of this safe and effective long-acting implantable progestin-only contraceptive agent. Although tissue factor (TF) is the primary initiator of hemostasis, previous studies indicated that Norplant-associated bleeding persists despite relatively high TF levels in the stromal compartment. Recently, we determined that progestin-enhanced TF expression during decidualization of human endometrial stromal cells involves both the epidermal growth factor receptor and progesterone receptor (PR]. The current study evaluated TF levels in endometrial bleeding (BL) and nonbleeding (NBL) sites obtained by camera-guided hysteroscopy during Norplant contraception. After 1 yr of therapy, immunohistochemical TF levels were unexpectedly higher at BL than at NBL sites. Use of immunohistochemistry and Western blotting indicated that both sites displayed elevated epidermal growth factor receptor levels and that the BL sites exhibited high levels of the PR, as well as the PR(A) and the PR(B) isoforms. Microscopic examination of 1-yr biopsies revealed that significantly larger numbers of enlarged, distended vessels were present in BL, compared with NBL sites. Elevated TF levels and abnormally enlarged blood vessels in the BL sites are consistent with the recently discovered angiogenic role of TF. By promoting aberrant angiogenesis, chronic endometrial overexpression of TF could produce fragile vessels, which are at increased risk to bleed. Analysis of endometrial BL and NBL sites, during Norplant contraception, offers the potential of elucidating local mechanisms that control enhanced TF expression, leading to abnormal angiogenesis at specific endometrial sites

Abnormal uterine bleeding accounts for the unacceptably high discontinuation rate of progestin-only contraceptives. Previously, we found that in-vivo and in-vitro decidualization of human endometrial stromal cells was associated with elevated concentrations of tissue factor (TF), the primary initiator of haemostasis. Moreover, enhanced TF expression required progesterone receptor (PR) and epidermal growth factor receptor (EGFR) mediation. In the current study, endometrial biopsies were sampled from bleeding (BL) and non-bleeding (NBL) sites under camera-directed hysteroscopic guidance after Depo-provera injections. When compared with control biopsies, immunohistochemical examination revealed that 3 months of Depo-provera contraception reduced TF concentrations at the BL sites. However, there were ample EGFR and PR concentrations at BL and NBL sites. Moreover, there was a trend towards the appearance of pathologically enlarged blood vessels at the BL sites. The use of Western blotting revealed that after 3 months of Depo-provera, concentrations of both PRB and PRA isoforms were lower at BL versus NBL sites with decreased PRA concentrations attaining statistical significance. Separate sampling of endometrial BL and NBL sites as shown here for Depo-provera contraception could prove particularly useful in identifying local factors that determine the onset of bleeding during the more protracted time-course of Norplant contraception

OBJECTIVE: To compare the effects of three commonly prescribed estrogen replacement therapies-oral conjugated equine estrogens (CEE; n = 37), oral micronized estradiol (ME; n = 25), and transdermal estradiol (TE; n = 24)-on the binding characteristics of plasma estradiol as related to the concentrations of blood sex hormone-binding globulin (SHBG), estradiol, and estrone. DESIGN: Menopausal volunteers, opting for estrogen replacement therapy, gave blood at 0, 2, and 4 months. SHBG was assayed by automated immunoabsorbent technology. Estradiol and estrone were determined by quantitative gas chromatography/mass spectrometry. After tritiated estradiol was added to serum, the percentage of estradiol not bound to protein was determined by ultrafiltration and the percentage of estradiol bound to SHBG was measured by a method exploiting that this protein, even when bound to estradiol, binds avidly to Concanavalin A-Agarose. RESULTS: In each study, 2- and 4-month data were similar. Increases in SHBG concentrations were 100% (p < 0.001), 45% (p < 0.001), and 12% (nonsignificant) for subjects who were receiving CEE, ME, and TE regimens, respectively. Decreases in the percentage of estradiol not bound to protein and increases in the percentage of estradiol bound to SHBG correlated with changes in the concentrations of this protein mediated by the therapies. The order for increases in estradiol was ME-TE >> CEE, whereas for estrone, the order was ME > CEE >> TE, divergent from the SHBG responses. CONCLUSIONS: The diverse responses observed can be explained by differences in the estrogen load delivered to target tissues as controlled by the intermediary circulation and metabolism of the hormones introduced in these regimens