Biomedical subjects
Publications and source records attributed to R L Barbieri.
Nafarelin, a gonadotropin-releasing hormone agonist, has been shown to be effective in the treatment of endometriosis. The standard dosage is 200 micrograms bid intranasally. Side effects most commonly include those associated with estrogen deprivation. By assessing estrogen status, the standard dosage can be manipulated to minimize these side effects and increase patient compliance.
Clinical observations indicate that there is an association between hyperinsulinemia and hyperandrogenism in women of reproductive age. The effects of insulin on ovarian steroidogenesis were studied in 4-day incubations of minced porcine theca. Insulin alone significantly stimulated dihydrotestosterone (DHT), testosterone (T) and androstenedione (delta 4A) accumulation in the media as compared to vehicle-treated controls. Insulin alone did not stimulate progesterone (P) accumulation. Insulin plus luteinizing hormone (LH) resulted in significantly greater accumulation of DHT, T and delta 4A than LH alone. Insulin plus LH did not stimulate P accumulation as compared to LH alone. Insulin, at high concentrations, may be a regulator of thecal androgen synthesis.
The (basal) level of FSH measured during early menses is emerging as a predictor of ovarian competence. In this study, correlates of basal FSH were examined in 222 premenopausal women who were not using oral contraceptives and selected from either the general population or a clinic for women with family histories of ovarian cancer. Using analysis of variance, the effect on FSH by age, smoking history, and reproductive variables was examined. Dietary galactose (as a potential oocyte toxin) was estimated, and red cell activity of galactose-1-phosphate uridyl transferase (GALT) was measured. Qualitative features of GALT were described by its electrophoretic or molecular genetic patterns. Possession of GALT polymorphisms previously linked with low GALT activity, including the Q188R mutation of classic galactosemia or N314D mutation of the Duarte galactosemia variant, was associated with significantly higher FSH, even in the heterozygous state. Other factors significantly influencing FSH included age, smoking history, cycle length, and cycle regularity. No effect of current galactose consumption was found, and GALT activity was only weakly correlated (inversely) with FSH. Applying multiple linear regression, variables independently predictive of high FSH were age of 40 yr or more, current smoking, and possession of a GALT polymorphism.
Polycystic ovary disease is a heterogeneous endocrinopathy with many interacting causal factors. One potential such factor is chronic hyperinsulinemia. Multiple, independent lines of evidence support the contention that chronic hyperinsulinemia causes ovarian hyperandrogenism. This evidence includes: (1) mutations in the insulin receptor gene that cause severe hyperinsulinemia appear to be associated with ovarian hyperandrogenism, (2) insulin stimulates ovarian thecal and stromal androgen secretion in vitro, and (3) in some experimental models, manipulation of circulating insulin concentrations results in changes in circulating androgens. Although the association between hyperinsulinemia and hyperandrogenism remains to be fully explained at the molecular level, chronic hyperinsulinemia appears to be an important cause of hyperandrogenism.
OBJECTIVES: The expression of connexin-43 was examined in human leiomyomas and in autologous myometrium. STUDY DESIGN: Indirect immunofluorescence was used to detect connexin-43 gap junctions in myometrial and leiomyoma tissues and in primary cultures. Immunoblot and Northern analyses were used to examine the levels of connexin-43 protein and cx43 messenger ribonucleic acid in primary cultures. RESULTS: Connexin-43 gap junctions were detected in leiomyoma tissue from nonpregnant premenopausal women but not in autologous myometrial tissue. Connexin-43 gap junctions form spontaneously in primary cultures of myometrium and leiomyoma in the presence of 17 beta-estradiol. Fluorescent dye injection confirmed that the gap junctions were coupled in the primary cells. Connexin-43 protein and messenger ribonucleic acid levels generally were higher in leiomyoma cells compared with those of autologous myometrial cells. Steady-state levels of cx43 messenger ribonucleic acid decreased with addition of medroxyprogesterone acetate to the cultures. CONCLUSIONS: Differences in the levels of cx43 expression in leiomyoma and myometrial cells may reflect differences in responses to steroid hormones.
Cigarette smoking has been associated with elevated levels of A and DHEAS in postmenopausal women. One possible mechanism postulated for this effect is enzymatic blockage by components of cigarette smoke. In this study, acute ACTH stimulation of postmenopausal cigarette smokers did not result in abnormal elevations of precursor steroids. Other possible mechanisms may be operative in vivo to account for the previously reported findings.
Tamoxifen therapy in premenopausal women with breast cancer may be associated with the development of ovarian cysts. In this report, a case of ovarian torsion associated with TAM therapy is described.
Women with symptomatic uterine myomas were randomized to receive LA depot or placebo for 12 weeks before myomectomy. Silver staining nucleolar organizer regions (AgNORs) per nuclei were assessed in the tissue obtained at the time of myomectomy. Myoma tissue from women treated with LA depot before myomectomy had significantly fewer AgNORs per nuclei than myoma tissue obtained from women treated with placebo. Leuprolide acetate depot may reduce the number of proliferating cells in myomas.
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OBJECTIVE: To test the hypothesis that the effects of estrogen reduction on uterine leiomyoma regression are mediated through changes in cell density or the extracellular matrix. METHODS: Uterine myomas were obtained from 20 women who had received randomly either the GnRH agonist leuprolide acetate depot for 3 months or placebo. The biochemical and morphologic characteristics studied included: total protein, DNA, and amino acid concentrations; histologic appearance; collagen content; and nuclear density. RESULTS: The absolute and relative concentrations of hydroxylysine, hydroxyproline, glycine, and proline were significantly greater (P < .05) in uterine myomas from patients pretreated with a GnRH agonist compared with placebo-treated controls. The GnRH agonist was also associated with trends toward increased mean total protein, DNA, and nuclear density, but the differences did not reach statistical significance. CONCLUSIONS: The concentrations of the amino acids contained in collagen were significantly greater in uterine myomas from patients treated with the GnRH agonist compared to myomas from placebo-treated controls. In addition, our observations suggest that the reduction in uterine myoma volume associated with GnRH agonist therapy is associated with alterations in the extracellular matrix.
OBJECTIVE: To assess the degree of intraobserver and interobserver variability in endometriosis staging using the revised American Fertility Society (AFS) classification of endometriosis. DESIGN: Videotapes of laparoscopies of 20 patients with endometriosis were each scored twice by five observers. SETTING: The reproductive endocrine unit of a tertiary care, university-affiliated hospital. SUBJECTS: Five subspecialty-certified reproductive endocrinologists. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Variability in assigned score was measured for each of the five components of the AFS classification, as well as total scores and stage of endometriosis. RESULTS: There was considerable variability in the scores assigned to each videotape, both by the same observer and by different observers. The grand total score, which ranged from 0 to 90, varied with an SD of 13.44 when a single patient was rated twice by the same observer and varied with an SD of 17.12 when a single patient was rated by two different observers. Among individual components of the score, the greatest variability occurred in endometriosis of the ovary and cul-de-sac obliteration, with less variability observed for peritoneum endometriosis and for ovarian and tubal adhesions. Comparison of intraobserver and interobserver scores resulted in a change in endometriosis stage in 38% and 52% of patients, respectively. There were statistically significant differences in mean endometriosis scores among the observers in four of the five anatomic categories examined. CONCLUSIONS: Intraobserver and interobserver variability was high for ovarian endometriosis and cul-de-sac subscores using the revised AFS classification of endometriosis.
In women with recurrent pelvic pain caused by endometriosis, hormonal therapy with a gonadotropin-releasing hormone agonist is an effective alternative to surgical therapy. The basis for medical treatment of endometriosis is that endometriosis lesions are dependent on estradiol for continued growth. Further, end organ tissue varies in its sensitivity to estradiol. This forms the basis of the estrogen threshold hypothesis, that is, that a concentration of estradiol that will partially prevent bone loss may not stimulate endometrial growth. Thus there is a hierarchy of organ response to estradiol such that calcium metabolism is most sensitive followed by gonadotropin secretion, vaginal epithelial growth, lipid metabolism, and liver protein production. Similarly, breast cancer is most sensitive and endometriosis is least sensitive to estrogen. These differences may allow the design of regimens with a gonadotropin-releasing hormone agonist that maintain a therapeutic response and ameliorate potential adverse effects.
OBJECTIVES: We attempted to test the hypothesis that distinct forms of the 17-ketosteroid oxidoreductase exist in the human ovary and to compare its activity in stroma obtained from normally cycling women and from hyperandrogenic women. STUDY DESIGN: Human ovarian granulosa-luteal cell and stromal 17-ketosteroid oxidoreductase were examined in cell incubations and subcellular homogenates. RESULTS: In subcellular homogenates of granulosa-luteal cells 17-ketosteroid oxidoreductase activity was greater in the cytosol fraction than in the membrane fraction. In contrast, in homogenates of both ovarian stroma and Leydig cells its activity was greater in the membrane fraction than in the cytosol fraction. At the substrate concentrations used estrone was a better substrate than androstenedione for the granulosa-luteal cell 17-ketosteroid oxidoreductase. In contrast, androstenedione was a better substrate than estrone for that in ovarian stromal and Leydig cell membranes. In incubations of ovarian stroma from hyperandrogenic women, significantly more testosterone accumulated in the medium per milligram of tissue than in the medium of incubations of ovarian stroma from normally cycling women (142 +/- 48 vs 7.9 +/- 7.5 pg testosterone per milligram of tissue per 48 hours, mean +/- SD, p less than 0.05). The ratio of testosterone to androstenedione was significantly higher in the medium of incubations of ovarian stroma from hyperandrogenic women than in that from normally cycling women (0.61 vs 0.25, mean, p less than 0.05). The ratio of serum testosterone to androstenedione was significantly greater in hyperandrogenic women than in normally cycling control women (0.31 +/- 0.11 vs 0.20 +/- 0.03, mean +/- SD, p less than 0.05). CONCLUSION: The localization (cytosol fraction) and substrate specificity (estrone) of the granulosa-luteal cell 17-ketosteroid oxidoreductase enzyme resembles that seen in human placenta. The localization (membrane fraction) and substrate specificity (androstenedione) of the ovarian stromal 17-ketosteroid oxidoreductase enzyme resembles that seen in Leydig cells. It may be one enzyme that exists in multiple forms or it may be two (or more) enzymes. In some hyperandrogenic women the ovarian stromal 17-ketosteroid oxidoreductase may be more active than in normally cycling women, contributing to an abnormally increased testosterone production rate.
OBJECTIVE: To develop a mathematical model to examine the factors that control the directionality of menstrual flow. DESIGN: The model consisted of a rigid cavity, filled with a viscous liquid, with three outflow ports: a set of paired outflow ports (fallopian tube ostia) and an additional single outflow port (cervical os). The Darcy-Weisbach equation was used to calculate flow rates through the ports. RESULTS: At cervical os diameters of less than 0.5 mm, more than 50% of flow was through the fallopian tubes over a wide range of values for cervical length and fallopian tube ostia diameter and length. The diameter of the fallopian tube ostia was also an important determinant of the directionality of flow. The lengths of the cervical os and fallopian tube ostia were of secondary importance in determining directionality of menstrual flow. CONCLUSION: If retrograde menstruation is a risk factor for the development of endometriosis, menstruating women with cervical os diameters less than 2.0 mm may be at increased risk for developing endometriosis.
In recent years, relationships of dehydroepiandrosterone and its sulfate ester dehydroepiandrosterone sulfate (DHEAS) with decreased risks of cardiovascular disease as well as a possible role in the aging process have been postulated. To explore the effects of cigarette smoking, a risk factor for cardiovascular disease, as well as age, on the levels of these adrenal androgens, we measured plasma levels of DHEAS in 543 healthy male subjects from the Physicians' Health Study. Blood specimens were collected between August 1982 and December 1984 and stored at -80 C. The overall mean DHEAS level was 3.47 mumol/L (+/- 2.12 SD). DHEAS levels were positively correlated with smoking habits (r = +0.16, P = 0.0002); current smokers had the highest age-adjusted DHEAS concentrations (4.27 mumol/L, P = 0.0005 compared with never smokers), followed by past smokers (3.47 mumol/L, P = 0.02) and never smokers (3.10 mumol/L). A marked linear decline of levels with age was observed, with an average decrease of 3% per year. These data suggest a moderate direct association with cigarette smoking and a powerful influence of age on decreasing levels of DHEAS. After adjusting for age and smoking habits, DHEAS concentrations were also inversely correlated with reported use of multivitamins (r = -0.16, P = 0.0002) and positively correlated with plasma retinol levels (r = 0.14, P = 0.002).
Mutations in the genes for the insulin receptor, 21-hydroxylase, 11 beta-hydroxylase, and 3 beta-hydroxysteroid dehydrogenase isomerase enzymes are associated with hyperandrogenism. These genetic causes of hyperandrogenism account for less than 10% of all cases. A major goal of future research will be to identify other genetic causes of hyperandrogenism. Evidence continues to accumulate that luteinizing hormone, insulin-like growth factor I, and insulin are major factors regulating ovarian androgen production. Optimal therapy for hyperandrogenism probably includes simultaneous suppression of androgen production and blockade of androgen action.
OBJECTIVE: To examine the serum levels of CA-125 in the menstrual, follicular, and luteal phases of the menstrual cycle in women with endometriosis and to determine if serum CA-125 levels drawn during menses improve the clinical utility of the test in diagnosing endometriosis. DESIGN: Serum CA-125 was measured in the menstrual, follicular, and luteal phases of the cycle preceding surgery. CA-125 levels for each phase were categorized by postoperative diagnosis and endometriosis stage. SETTING: The reproductive endocrine unit of a tertiary care university-affiliated hospital. PATIENTS: A total of 65 patients were recruited from the Fertility and Endocrine Unit and the Gynecology Service of Brigham and Women's Hospital. MAIN OUTCOME MEASURE: Serum CA-125 levels were measured by an immunoradiometric assay and were stratified by menstrual cycle phase, diagnosis, and stage of endometriosis. The menstrual cycle phase was confirmed by serum estradiol and progesterone measurements. RESULTS: Serum CA-125 levels in patients with stages II to IV endometriosis were significantly elevated in the menstrual phase compared with levels drawn in the nonmenstrual follicular and luteal phases. The sensitivity and specificity of CA-125 for the diagnosis of endometriosis were not significantly better in the menstrual than in the follicular or luteal phases. CONCLUSIONS: Despite menstrual cyclicity of CA-125, measurement of serum CA-125 during menses does not improve the clinical utility of the test in the diagnosis of endometriosis.
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