Therapeutic controversy: The safety of third-generation oral contraceptives.
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Adult↗
Biomedical subjects
R L Barbieri
Publications and source records attributed to R L Barbieri.
Reproducibility of plasma and urinary sex hormone levels in premenopausal women over a one-year period.
Although endogenous sex steroid hormones in premenopausal women may be associated with the risk of breast cancer and other illnesses, direct evidence to support this hypothesis is limited in large part by methodological issues in the conduct of relevant studies. One major unresolved issue is whether a single blood sample (such as is available in most epidemiological studies), collected in a specific phase of the menstrual cycle, reflects long-term levels in that phase. To address this issue, two sets of blood and urine samples were obtained from 87 premenopausal women over a 1-year period in both the follicular and luteal phases. Plasma estradiol, estrone, and estrone sulfate were measured in the blood samples obtained in both phases, whereas progesterone and urinary 2- and 16a-hydroxyestrone were measured in luteal-phase samples only. For all of the women combined, intraclass correlation coefficients (ICCs) ranged, with one exception, from 0.52 to 0.71 for the plasma estrogens and the urinary estrogen metabolites. The sole exception was for estradiol in the luteal phase (ICC = 0.19); inclusion of only women who were ovulatory in both cycles and who collected each sample 4-10 days before their next period resulted in a substantially higher ICC for estradiol in the luteal phase (ICC = 0.62; 95% confidence interval, 0.43-0.78). These data indicate that, for several plasma and urinary sex hormones, a single follicular- or luteal-phase measurement in premenopausal women is reasonably representative of hormone levels in that phase for at least a 1-year period.
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Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women.
BACKGROUND: A positive relationship has generally been observed between plasma estrogen levels and breast cancer risk in postmenopausal women, but most of these studies have been small and few have evaluated specific estrogen fractions (such as percent bioavailable estradiol). In addition, few studies have evaluated plasma androgen levels in relation to breast cancer risk, and their results have been inconsistent. We prospectively evaluated relationships between sex steroid hormone levels in plasma and risk of breast cancer in postmenopausal women by use of a case-control study nested within the Nurses' Health Study. METHODS: Blood samples were collected during the period from 1989 through 1990. Among postmenopausal women not using hormone replacement therapy at blood collection (n = 11,169 women), 156 women were diagnosed with breast cancer after blood collection but before June 1, 1994. Two control subjects were selected per case subject and matched with respect to age, menopausal status, month and time of day of blood collection, and fasting status at the time of blood collection. RESULTS: From comparisons of highest and lowest (reference) quartiles, we observed statistically significant positive associations with risk of breast cancer for circulating levels of estradiol (multivariate relative risk [RR] = 1.91; 95% confidence interval [CI] = 1.06-3.46), estrone (multivariate RR = 1.96; 95% CI = 1.05-3.65), estrone sulfate (multivariate RR = 2.25; 95% CI = 1.23-4.12), and dehydroepiandrosterone sulfate (multivariate RR = 2.15; 95% CI = 1.11-4.17). We found no substantial associations with percent free or percent bioavailable estradiol, androstenedione, testosterone, or dehydroepiandrosterone. The positive relationships were substantially stronger among women with no previous hormone replacement therapy. CONCLUSION: Our data, in conjunction with past epidemiologic and animal studies, provide strong evidence for a causal relationship between postmenopausal estrogen levels and the risk of breast cancer.
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Relation of luteinizing hormone levels to body mass index in premenopausal women.
OBJECTIVE: To assess the relationship between body mass index (BMI) and basal LH and the LH-FSH ratio in normally menstruating women. DESIGN: Cross-sectional analysis. SETTING: A teaching hospital clinic. PATIENT(S): Premenopausal women without cancer, not currently using oral contraceptives, selected from a familial ovarian cancer clinic or the general population. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Early follicular phase plasma LH and FSH. RESULT(S): Luteinizing hormone increased slightly and nonsignificantly (P = 0.44) from the first to the second quintile of BMI and decreased over all subsequent quintiles. Women in the highest quintile of BMI (> 27.1) had significantly lower LH levels than women in the lowest quintile of BMI (< or = 20.4; P = 0.003). Compared with women in the second quintile of BMI who had the highest LH levels, women in the highest quintile of BMI had LH levels that were 40% lower. The relationship between BMI and the LH-FSH ratio was similar, though not as strong. CONCLUSION(S): Over most of the range of BMIs observed in this study, BMI was inversely associated with LH. These results suggest that the upper limits of normal for LH may need to be shifted downward for heavier women.
Adult↗
Lateral cervical displacement is associated with endometriosis.
OBJECTIVE: To report on a series of cases of lateral cervical displacement and uterosacral ligament scarring associated with endometriosis. DESIGN: Case series. SETTING: Academic medical center. PATIENT(S): Three nulliparous women with chronic pelvic pain, lateral cervical displacement, and uterosacral nodularity. INTERVENTION(S): Physical examination to evaluate for lateral cervical displacement. Laparoscopic surgery to evaluate for endometriosis and uterosacral ligament involvement. MAIN OUTCOME MEASURE(S): Displacement of the entire cervix lateral to the midline of the vagina. Presence of endometriosis on the affected uterosacral ligament. RESULT(S): All three patients had lateral cervical displacement and implants of endometriosis and scarring on the uterosacral ligament ipsilateral to the displaced cervix. CONCLUSION(S): In women with pelvic pain, lateral cervical displacement due to uterosacral scarring may be a physical finding associated with endometriosis.
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Stenosis of the external cervical os: an association with endometriosis in women with chronic pelvic pain.
OBJECTIVE: To report a simple technique for diagnosing stenosis of the external cervical os and to evaluate an association between stenosis of the external cervical os and endometriosis in women with chronic pelvic pain. DESIGN: Case series. SETTING: Academic medical center. PATIENT(S): Twenty-five women with chronic pelvic pain and stenosis of the external cervical os. INTERVENTION(S): Measurement of the diameter of the external cervical os. MAIN OUTCOME MEASURE(S): Association between cervical stenosis and surgically documented endometriosis in women with chronic pelvic pain. RESULT(S): Endometriosis was visually documented at surgery for 24 of 25 women with chronic pelvic pain and stenosis of the external cervical os. CONCLUSION(S): Endometriosis is a common finding in women with both stenosis of the external cervical os and chronic pelvic pain.
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A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata.
OBJECTIVE: To investigate the risk of uterine leiomyomata in relation to reproductive factors and oral contraceptive use. DESIGN: A prospective study. SETTING: A cohort of female registered nurses from 14 states in the United States who completed mailed questionnaires in 1989, 1991, and 1993. PATIENT(S): Premenopausal nurses (n=95,061) aged 25-42 years with intact uteri and no history of diagnosed uterine leiomyomata or cancer in 1989. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Incidence of self-reported uterine leiomyomata confirmed by ultrasound or hysterectomy. In a sample of 243 cases, 93% of the self-reported diagnoses were confirmed in the medical record. RESULT(S): During 326,116 person-years of follow-up, 3,006 cases of uterine leiomyomata, confirmed by ultrasound or hysterectomy, were reported. After adjustment for other risk factors, the risk of uterine leiomyomata was significantly inversely associated with age at menarche, parity, and age at first birth, and positively associated with a history of infertility and years since last birth. The only notable association with any aspect of oral contraceptive use was a significantly elevated risk among women who first used oral contraceptives at ages 13-16 years compared with those who had never used oral contraceptives. CONCLUSION(S): Reproductive factors and oral contraceptive use at a young age influence the risk of uterine leiomyomata among premenopausal women.
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Effects of endometriomas on ooccyte quality, embryo quality, and pregnancy rates in in vitro fertilization cycles: a prospective, case-controlled study.
PURPOSE: The effect of endometriomas on oocyte quality, embryo quality, and pregnancy rates in in vitro fertilization (IVF) cycles was evaluated. METHODS: Forty-five women had "chocolate" cysts aspirated at the time of oocyte retrieval, and cyst fluid CA 125 levels were measured to ascertain presence of "true" endometriomas. Fifty-seven women without any complex cysts at the time of oocyte retrieval served as controls. IVF cycle outcome parameters were compared between the two groups. RESULTS: Women with endometriomas experienced a significantly higher rate of early pregnancy loss compared to controls (47 vs 14%). There was also a trend toward fewer oocytes retrieved and fewer embryos reaching at least the four-cell stage 48 hr after retrieval in patients with true endometriomas vs controls. CONCLUSIONS: The presence of endometriomas at the time of oocyte retrieval is associated with increased rates of early pregnancy losses. The number of oocytes retrieved and the embryo quality may also be affected adversely in the presence of endometriomas.
CA-125 Antigen↗
Cytogenetic abnormalities in uterine myomas are associated with myoma size.
Uterine leiomyomata (myomas) are associated with a variety of characteristic cytogenetic abnormalities. The significance of these chromosomal aberrations in the pathobiology of myomas remains to be determined. The present study investigated the relationship between myoma cytogenetic abnormalities and size. A total of 114 myoma specimens were obtained from 92 patients undergoing myomectomy or hysterectomy. The maximum diameter of each myoma was measured and a portion of each myoma obtained for cytogenetic analysis. Karyotypes were analysed and categorized as normal, abnormal (non-mosaic) or mosaic. Cytogenetic analyses revealed 73 (64%) normal, 20 (18%) abnormal (non-mosaic), and 21 (18%) mosaic karyotypes. Mean myoma diameter was 6.5+/-0.44 cm with a range of 0.4-27 cm. Differences between the mean myoma diameter of specimens with normal versus abnormal karyotypes was determined by the Kruskal-Wallis test. The mean myoma diameter among specimens with abnormal (non-mosaic) karyotypes was significantly greater than myomas with normal karyotypes (10.2+/-5.9 versus 5.9+/-4.2 cm; P < 0.001). The proportion of abnormal (non-mosaic) karyotypes in myomas >6.5 cm was compared to myomas <6.5 cm by chi2-analysis; myomas >6.5 cm demonstrated a significantly higher proportion of abnormal (non-mosaic) karyotypes when compared to myomas <6.5 cm (75 versus 34%; P < 0.02). In summary, a significant relationship exists between clonal cytogenetic abnormalities and myoma size, suggesting that chromosomal abnormalities associated with individual myomas enhance myoma growth.
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Half-life of estradiol in postmenopausal women.
Estrogen replacement is often advised for postmenopausal women to prevent menopausal symptoms, osteoporosis and heart disease. However, little information is available concerning the half-life of estradiol (E2) in postmenopausal women. This study was designed to determine the half-life and metabolism of transdermal E2. A prospective clinical study of 8 healthy postmenopausal women was performed in the Clinical Research Center of the Brigham and Women's Hospital. A transdermal E2 patch 0.10 mg was placed on the abdominal wall. Thirteen hours later, after an overnight fast, the E2 patch was removed and frequent blood sampling was performed over 6 h. Serum samples were assayed for E2, estrone (E1) and estrone sulfate (E1S). Serum samples were taken before E2 patch placement, for 30 min before patch removal, and for 6 h after patch removal. The basal E2 level of women prior to use of transdermal E2 was 19 +/- 2 pg/ml (mean +/- SE). Thirteen hours after transdermal E2 placement, steady state levels had been reached, with a mean E2 of 112 +/- 6 pg/ml. The mean half-life of E2 after removal of transdermal E2 was 161 min (range 107-221 min). There was a direct relationship between the subjects' weight and the half-life of E2 (r = 0.79, p = 0.02). Mean basal E1 levels were 23 +/- 5 pg/ml and mean E1 steady-state levels after E2 patch placement were 39 +/- 0.6 pg/ml. E1S levels rose from mean basal levels of 1.5 +/- 0.3 ng/ml to mean steady-state levels of 3.1 +/- 0.1 ng/ml after placement of the E2 patch. The apparent half-life of E2 after discontinuing a transdermal E2 patch is 2.7 h or 161 min.
Administration, Cutaneous↗
Endosalpingiosis: clinical presentation and follow-up.
OBJECTIVE: To define the clinical presentation and follow-up of women found to have endosalpingiosis. METHODS: Subjects included for retrospective study were identified as having had a pathologic diagnosis of endosalpingiosis. Those subjects without coinciding pathologic diagnosis of endometriosis were then identified; their clinical charts were reviewed for information regarding the clinical presentation, surgical findings, therapeutic management, and clinical follow-up. RESULTS: Review of 1,648 pathologic reports from Children's Hospital, Boston and 380 reports from Brigham and Women's Hospital identified 18 subjects with endosalpingiosis without pathologic evidence of endometriosis. Two clinical scenarios were identified, and designated Groups I and II. Group I consisted of 15 patients presenting with pelvic pain, and Group II consisted of 3 patients presenting with infertility, pancreatic cancer, and an abdominal abscess. Follow-up was obtained for 8 of the 15 patients in Group I for an average of 17 months, none of whom were pain-free off medications (oral contraceptives, danazol, or GnRH agonist), and 3 (38%) have required additional surgery (6, 10 or 12 months after the initial surgery) at which time all were found to have endometriosis. Follow-up was obtainable for the patient with infertility in Group II for 5 months, with no complaint of pelvic pain. CONCLUSIONS: We report 18 patients with endosalpingiosis without confounding endometriosis. The clinical presentation is one of either pelvic pain or that of an incidental finding; the clinical course and response of those with pain is similar to that of endometriosis.
Abdominal Abscess↗
Endometriosis and the estrogen threshold theory. Relation to surgical and medical treatment.
Estrogen-dependent diseases often regress when estrogen production is reduced. Endometriosis is an estrogen-responsive disease, and the pelvic pain associated with it improves when estrogen production is reduced with bilateral oophorectomy or chronic gonadotropin releasing hormone (GnRH) agonist treatment. Unfortunately, reduction of estrogen production is associated with adverse side effects, such as vasomotor symptoms and bone loss. In women with endometriosis and pelvic pain, the combination of bilateral oophorectomy plus postoperative low-dose estrogen treatment produces sustained improvement in pain symptoms and reduces the hypoestrogenic side effects associated with bilateral oophorectomy. In a parallel manner, chronic GnRH agonist treatment plus low-dose steroid therapy (estrogen plus progestin or progestin only) is effective in the treatment of pelvic pain caused by endometriosis and reduces the hypoestrogenic effects associated with hypoestrogenism caused by the GnRH agonist. Since chronic GnRH agonist treatment is reversible and avoids surgery, it may become an important alternative to bilateral oophorectomy for the treatment of endometriosis.
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Risk of uterine leiomyomata among premenopausal women in relation to body size and cigarette smoking.
To investigate whether factors influencing ovarian function affect risk of uterine leiomyomata, we examined prospectively the association of new diagnoses confirmed by ultrasound or hysterectomy with body mass index, weight change, height, and cigarette smoking among 94,095 premenopausal women with intact uteri, who were ages 25-42 years at the start of follow-up in 1989. We assessed body mass index and cigarette smoking from responses on the study questionnaire completed just before diagnosis. During 322,775 person-years, 2,967 new cases of uterine leiomyomata confirmed by ultrasound or hysterectomy were reported. Risk among all cases confirmed by ultrasound or hysterectomy increased with increasing adult body mass index. The multivariate relative risks (RR) and 95% confidence intervals (CI) according to body mass index categories of <20.0, 20.0-21.9, 22.0-23.9, 24.0-25.9, 26.0-27.9, 28.0-29.9, and > or =30.0 were 0.90 (95% CI = 0.79-1.03), 1.00 (referent), 1.08 (95% CI = 0.97-1.21), 1.16 (95% CI = 1.03-1.31), 1.21 (95% CI = 1.05-1.40), 1.36 (95% CI = 1.16-1.59), and 1.23 (95% CI = 1.09-1.39), respectively. The RRs for hysterectomy-confirmed cases generally were higher. Similarly, risk was positively associated with weight gain since age 18 years. Body mass index at age 18 years, height, and cigarette smoking were unrelated to risk of uterine leiomyomata. Elevated adult body mass index is associated with a modest increased risk of uterine leiomyomata among premenopausal women.
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Presence of 17 beta-hydroxysteroid dehydrogenase type 3 messenger ribonucleic acid transcript in an ovarian Sertoli-Leydig cell tumor.
OBJECTIVE: To evaluate the level of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) type 1, 2, and 3 transcripts in a Sertoli-Leydig cell tumor, adjacent theca lutein ovarian tissue, and normal control ovarian stromal tissue. SETTING: An academic medical center. DESIGN: Total RNA was extracted from formalin-fixed, paraffin-embedded tissue slides and used for reverse transcription-polymerase chain reaction (RT-PCR) with primers specific for 17 beta-HSD types 1, 2, or 3. The PCR products were subjected to Southern hybridization with 5' [32P] end-labeled internal primers for each type of the isozymes. PATIENT(S): A 35-year-old woman with a Sertoli-Leydig cell tumor on her right ovary. The tumor and the right ovary were surgically removed. Control ovarian stromal tissue was obtained from a woman undergoing hysterectomy for uterine leiomyomata. RESULT(S): In the control ovarian stromal tissue, the transcripts for the type 1 and type 2 isoforms were the predominant transcripts detected. In the Sertoli-Leydig cell tumor, the transcript for the type 3 isoform was the predominant transcript detected. Ovarian tissue from the same ovary as the Sertoli-Leydig cell tumor (diagnosed as theca lutein cysts on histologic examination) expressed the type 2 and 3 transcripts. CONCLUSION(S): The 17 beta-HSD type 3 isoform efficiently converts androstenedione to T and is the predominant HSD isoform in the testis. In hyperandrogenism caused by a Sertoli-Leydig cell tumor, both the tumor tissue and nontumor tissue from the same ovary expressed the "testicular" form of the 17 beta-HSD.
17-Hydroxysteroid Dehydrogenases↗
Exogenous gonadotropin stimulation is associated with increases in serum androgen levels in in-vitro fertilization-embryo transfer cycles.
OBJECTIVE: To examine serum androgen profiles in women undergoing ovarian stimulation with exogenous gonadotropins in the setting of IVF-ET. DESIGN: Prospective study. SETTING: University hospital IVF-ET program. PATIENT(S): Seventeen ovulatory women undergoing IVF-ET for endometriosis, male factor infertility, or tubal disease. INTERVENTION(S): A standard long protocol of GnRH agonist (GnRH-a) pretreatment (1 mg of leuprolide acetate SC for 10 days) was administered before ovulation induction with a urinary gonadotropin preparation. MAIN OUTCOME MEASURE(S): After 10 days of GnRH-a treatment and on the day of hCG administration, serum concentrations of LH, T, androstenedione (A), sex hormone-binding globulin (SHBG), and DHEAS; the free androgen index (T/SHBG); and the number of follicles, oocytes, and embryos were assessed. RESULT(S): Serum samples after 10 days of GnRH-a treatment showed incomplete LH suppression. While continuing the agonist during ovarian stimulation, LH values were suppressed further. However, serum T and A concentrations and the free androgen index showed a significant increase (samples drawn just before hCG administration). Serum T levels after 10 days of GnRH-a (before the administration of exogenous gonadotropins) were correlated negatively with the subsequent number of embryos. CONCLUSION(S): Serum LH suppression with a conventional regimen of GnRH-a is incomplete in this heterogeneous group of ovulatory women. Exogenous gonadotropin stimulation results in a marked increase in ovarian androgen secretion.
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Variation in the incidence of uterine leiomyoma among premenopausal women by age and race.
OBJECTIVE: To quantify the incidence of uterine leiomyoma confirmed by hysterectomy, ultrasound, or pelvic examination according to age and race among premenopausal women. METHODS: From September 1989 through May 1993, 95,061 premenopausal nurses age 25-44 with intact uteri and no history of uterine leiomyoma were followed to determine incidence rates of uterine leiomyoma. The self-reported diagnosis was confirmed in 93% of the medical records obtained for a sample of cases. Using pooled logistic regression, we estimated relative risks (RRs) of uterine leiomyoma according to race and examined whether adjustment for other potential risk factors could explain the variation in the race-specific rates. RESULTS: During 327,065 woman-years, 4181 new cases of uterine leiomyoma were reported. The incidence rates increased with age, and the age-standardized rates of ultrasound- or hysterectomy-confirmed diagnoses per 1000 woman-years were 8.9 among white women and 30.6 among black women. After further adjustment for marital status, body mass index, age at first birth, years since last birth, history of infertility, age at first oral contraceptive use, and current alcohol consumption, the rates among black women were significantly greater for diagnoses confirmed by ultrasound or hysterectomy (RR 3.25; 95% confidence interval [CI] 2.71, 3.88) and by hysterectomy (RR 1.82; 95% CI 1.17, 2.82) compared with rates among white women. We observed similar RRs when the cohort was restricted to participants who reported undergoing a screening physical examination within the 2 years before baseline. CONCLUSION: A higher prevalence of known risk factors did not explain the excess rate of uterine leiomyoma among premenopausal black women.
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Reoperation rates for recurrent ovarian endometriomas after surgical excision.
This was a retrospective study analyzing the need for reoperation for recurrent endometriomas after surgical therapy. There were 104 women who were followed after surgical excision of endometriomas, with a cross section of 46 gynecologic surgeons. When using a life-table for follow-up analysis, only 2.9% of all patients had reoperation for recurrence, with a maximum recurrence probability of 7% at 32 months of follow-up.
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Reduction in the size of a uterine leiomyoma following discontinuation of an estrogen-progestin contraceptive.
The effects of estrogen-progestin oral contraceptives on the volume of uterine leiomyomata is not well characterized. In this case report, a 45-year-old woman with a symptomatic uterine leiomyoma was observed to have a 47% reduction in myoma volume after discontinuation of an oral contraceptive. The volume of uterine leiomyomata may be influenced by oral contraceptives.
Contraceptives, Oral, Combined↗