Biomedical subjects

A J Duleba

Publications and source records attributed to A J Duleba.

At least 19 recordsLinked to original sources

PubMed1999

Divergent mechanisms regulate proliferation/survival and steroidogenesis of theca-interstitial cells.

Luteinizing hormone (LH) and insulin-like growth factor I (IGF-I) are recognized as major regulators of ovarian theca-interstitial (T-I) function. This study was designed to compare the effects of LH and IGF-I on T-I proliferation and steroidogenesis. Purified rat T-I cells were cultured in chemically-defined media. DNA synthesis was evaluated by a radiolabelled thymidine incorporation assay. The cells were also directly counted. Progesterone production was assessed using a specific radioimmunoassay. DNA synthesis of T-I cells was stimulated by IGF-I (10 nM) but modestly inhibited by LH (100 ng/ml). The inhibitory effect of LH was mimicked by 8Br-cAMP (10(-4) to 10(-3) M); forskolin (10(-5) M), cholera toxin (10 ng/ml) and 3-isobutyl-methylxanthine (10(-5) M). Stimulation of protein kinase C with phorbol 12-myristate 13-acetate (10(-7) M) had no significant effect on DNA synthesis. Furthermore, DNA synthesis was not affected by testosterone (10(-10) to 10(-9) M) or progesterone (10(-9) to 10(-8) M). Accumulation of progesterone was co-operatively stimulated by LH and IGF-I. These results suggest that LH-induced inhibition of T-I proliferation and/or survival is mediated via the cAMP system. IGF-I may be viewed as a co-gonadotrophin with respect to steroidogenesis but not with respect to proliferation/survival. The divergence of the effects on proliferation/survival versus steroidogenesis underscores the complexity of the interactions between LH and IGF-I signalling pathways.

1-Methyl-3-isobutylxanthine↗

PubMed1999

Proliferation and differentiation of rat theca-interstitial cells: comparison of effects induced by platelet-derived growth factor and insulin-like growth factor-I.

This study was designed to evaluate mechanisms regulating proliferation of steroidogenically active and steroidogenically inactive theca-interstitial (T-I) cells, and, specifically, to evaluate the effects of platelet-derived growth factor (PDGF) and insulin-like growth factor-I (IGF-I). T-I cells obtained from immature Sprague-Dawley rats were cultured in chemically defined media. Proliferation was assayed by thymidine incorporation and cell counting. Steroidogenically active cells were identified by the presence of 3beta-hydroxysteroid dehydrogenase activity. Flow cytometry facilitated separation of dividing cells (in S and G2/M phases of the cell cycle) from nondividing cells (in G0 and G1 phases of the cell cycle). PDGF alone (0.1-1 nM) produced a dose-dependent increase in DNA synthesis by up to 136%. IGF-I alone (10 nM) increased DNA synthesis by 56%. In the presence of both IGF-I (10 nM) and PDGF (0.1-1 nM), DNA synthesis increased by 108-214%. PDGF (1 nM) increased the total number of T-I cells by 43%; this effect was due to an increase in the number of steroidogenically inactive cells (47%). In contrast, the stimulatory effect of IGF-I (10 nM) was predominantly due to an increase in the number of steroidogenically active cells (163%). Separation of dividing cells from nondividing cells was accomplished with the aid of flow cytometry. In the absence of growth factors, the proportion of steroidogenically active cells was 35% lower among proliferating than resting cells. PDGF (1 nM) decreased the proportion of steroidogenically active cells among both proliferating and resting cells (by 43% and 16%, respectively). In contrast, IGF-I (10 nM) increased the proportion of steroidogenically active cells among proliferating cells by 56%. These findings indicate that differentiated/steroidogenically active cells divide; furthermore, PDGF and IGF-I may selectively stimulate proliferation of individual subpopulations of T-I cells, thereby providing a mechanism for development of structural and steroidogenically active components of the T-I compartment.

Animals↗

PubMed1999

Tumor necrosis factor-alpha stimulates proliferation of rat ovarian theca-interstitial cells.

Tumor necrosis factor-alpha (TNF-alpha) is a potent modulator of ovarian function, affecting steroidogenesis of both granulosa and theca-interstitial (T-I) cells. Women with polycystic ovary syndrome (PCOS) have increased levels of serum TNF-alpha. The present study evaluated the effects of TNF-alpha on T-I cell proliferation. Purified rat T-I cells were cultured for 48 h with or without TNF-alpha (0.001-1 nM), insulin-like growth factor I (IGF-I; 10 nM), and/or insulin (10 nM). Proliferation was measured by [(3)H]thymidine incorporation assay and by counting the steroidogenically active (stained positive for 3beta-hydroxysteroid dehydrogenase; 3beta-HSD) and inactive (3beta-HSD negative) cells. TNF-alpha stimulated thymidine incorporation in a dose-dependent fashion (up to 3.2-fold; P < 0.01). Insulin and IGF-I stimulated T-I proliferation (respectively, by up to 2.4- and 3.1-fold; P < 0.001). TNF-alpha potentiated effects of insulin and IGF-I in a dose-dependent and additive fashion (up to 6.7-fold; P < 0.001). TNF-alpha (1 nM) increased total cell count (by 80%, P < 0.05) and the proportion of 3beta-HSD-positive cells (by 19%, P < 0.05). Flow cytometry DNA analysis revealed that TNF-alpha (1 nM) increased the proliferative index by up to 16% (P = 0.05). The present findings demonstrate that TNF-alpha stimulates mitotic activity of T-I cells by increasing the proportion of actively dividing cells and preferentially increasing the number of steroidogenically active cells. The effects of TNF-alpha appear to be independent of those induced by insulin and IGF-I. We postulate that TNF-alpha may play a pathophysiologic role in disorders of the T-I compartment, such as PCOS.

3-Hydroxysteroid Dehydrogenases↗

PubMed1998

Insulin and insulin-like growth factor I stimulate the proliferation of human ovarian theca-interstitial cells.

OBJECTIVE: To determine whether insulin and insulin-like growth factor I (IGF-I) affect the proliferation of human theca-interstitial cells. DESIGN: In vitro assays. SETTING: University laboratory. PATIENT(S): Premenopausal women undergoing oophorectomy for benign conditions. INTERVENTION(S): Purified theca-interstitial cells were cultured in chemically defined media with or without insulin and IGF-I. MAIN OUTCOME MEASURE(S): The proliferation of cells was evaluated by determination of [3H] thymidine incorporation and cell counting. RESULT(S): Insulin and IGF-I stimulated DNA synthesis by theca-interstitial cells in a dose-dependent fashion. Insulin-like growth factor I had a greater potency than did insulin. The effects of both approached, but did not reach, the level of DNA synthesis observed in cultures exposed to 10% fetal bovine serum. Direct counting of theca-interstitial cells revealed that IGF-I significantly increased the total number of cells (36% above control), whereas insulin induced a modest and statistically nonsignificant increase in the cell number (14% above control). CONCLUSION(S): The present results support the hypothesis that insulin and IGF-I promote the mitotic activity of theca-interstitial cells. These effects may represent mechanisms that lead to hyperplasia of the thecal/stromal compartment in polycystic ovary syndrome.

Adult↗

PubMed1998

Comparison of intrauterine insemination with timed intercourse in superovulated cycles with gonadotropins: a meta-analysis.

OBJECTIVE: To compare timed intercourse and IUI with the husband's sperm in patients with unexplained infertility who are undergoing superovulation with gonadotropins. DESIGN: Meta-analysis. All published reports of randomized, prospective studies with an English-language abstract extracted from MEDLINE were analyzed. A crossover search was done from the papers obtained. SETTING: Academic center. PATIENT(S): Couples with unexplained infertility. INTERVENTION(S): Meta-analysis of studies evaluating patients superovulated with gonadotropins and randomized for timed intercourse or IUI. MAIN OUTCOME MEASURE(S): Pregnancy rates (PRs) were obtained. The common odds ratio (OR) and 95% confidence intervals (95% CI) were calculated. RESULT(S): There were 49 pregnancies in 431 cycles of timed intercourse (11.37%), whereas there were 110 pregnancies in 549 cycles of IUI (20.04%). The PRs for IUI were significantly increased compared with those for timed intercourse in superovulation cycles (common OR = 1.84; 95% CI = 1.30-2.62). CONCLUSION(S): On the basis of the meta-analysis of 980 cycles in randomized and prospective studies, a patient's chances of becoming pregnant are greater with IUI with her husband's sperm than with timed intercourse in cycles superovulated with gonadotropins.

Adult↗

PubMed1998

Changes in personality profile associated with laparoscopic surgery for chronic pelvic pain.

STUDY OBJECTIVE: To determine whether surgical treatment of chronic pelvic pain is associated with changes in personality profile. DESIGN: Prospective clinical trial (Canadian Task Force classification II-2). SETTING: University-affiliated tertiary referral center. PATIENTS: Sixteen women undergoing laparoscopic surgery for evaluation and treatment of chronic pelvic pain. INTERVENTION: Before and 3 months after surgery all subjects completed the Minnesota multiphasic personality inventory-2 and the West Haven-Yale multidimensional pain inventory. MEASUREMENTS AND MAIN RESULTS: Laparoscopic surgery for chronic pelvic pain was associated with a postoperative decrease in pain severity score by 53% (p <0.001), increase in activity level score by 24% (p <0.001), decrease in hypochondriasis score by 6% (p = 0.049), decrease in depression score by 12% (p = 0.007), and decrease in conversion hysteria score by 7% (p = 0.02). Improvements in pain severity and activity level were comparable in women with abnormal and normal preoperative scores of hypochondriasis, depression, and conversion hysteria. CONCLUSION: Improvement in chronic pelvic pain is associated with an improvement in personality profile. Abnormal versus normal preoperative scores for hypochondriasis, depression, or conversion hysteria scales are not predictive of change in pain or activity level after surgery.

Adult↗

PubMed1998

The window for embryo transfer in oocyte donation cycles depends on the duration of progesterone therapy.

In 192 oocyte donation cycles performed between January 1993 and July 1996, we examined the width of 'the window for embryo transfer' using standard hormonal replacement methods. All transfers were performed within 48 h of insemination. We varied the day of embryo transfer with regard to the initiation of progesterone therapy and, thus, the duration of endometrial exposure to progesterone and analysed the resulting pregnancy rates. Patients were divided into five groups (I-V) and embryo transfers were performed 2, 3, 4, 5 or 6 days following initiation of progesterone therapy. The number of pregnancies per transfer cycle achieved in groups I-V were 0 (0%), 3 (12%), 16 (40%), 29 (48.3%), and 10 (20.4%) respectively. The increased pregnancy rate in group III in comparison to group II is statistically significant (P < 0.03). Furthermore, the pregnancy rate in group IV (5 days of progesterone administration before embryo transfer) was significantly higher than in group V (6 days of progesterone administration before embryo transfer; P < 0.005). We also noted that, when embryos were transferred 4 or 5 days after initiation of progesterone therapy, the pregnancy rates were not significantly different between menopausal and cycling recipients (50% vs 43.7%). Our results indicate that the window for embryo transfer is dependent on duration of treatment with progesterone; it begins approximately 48 h after starting progesterone administration and lasts for approximately 4 days. The optimum period for transferring embryos at the 4- to 8-cell stage corresponds to cycle days 18 and 19. Transfers performed on the 17th and 20th days of the cycle can result in successful implantation, although the rates of implantation are highest when transfers are done on days 18 and 19.

Abortion, Spontaneous↗

PubMed1998

The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.

Adult↗

PubMed1997

Preretrieval predictors of pregnancy in IVF.

PURPOSE: This study was designed to evaluate the predictive value of preretrieval parameters of ovarian stimulation in patients undergoing IVF-ET. METHODS: Women diagnosed with infertility due to tubal factor were compared to women with other and/or multiple diagnoses. Stepwise logistic regression evaluated 389 cycles to identify the best predictors of pregnancy among the following variables: age, primary or secondary infertility, cycle number, type and dose of gonadotropin, duration of gonadotropin administration, serum estradiol level, and number and size of follicles. RESULTS: In the tubal disease group, probability of pregnancy was greater in cycles with serum estradiol levels below 1100 pg/ml on the day of hCG (odds ratio, 4.7) and with administration of gonadotropins for less than 10 days (odds ratio, 3.7). In contrast, in the other/mixed diagnoses group, a serum estradiol below 1100 pg/ml was associated with a decreased probability of pregnancy (odds ratio, 0.6). CONCLUSIONS: Optimal parameters of ovarian stimulation may vary according to the etiology of infertility. In patients with tubal disease, the beneficial effects of greater stimulation, and thus the greater number of available oocytes, may be offset by adverse effects on the endometrium and on the quality of oocytes and embryos. In contrast, in other diagnostic groups, the advantage of an increased number of oocytes may outweigh the potential adverse effects of prolonged stimulation and higher estradiol levels.

Chorionic Gonadotropin↗

PubMed1997

Diagnosis of endometriosis.

Diagnosis of endometriosis requires careful interpretation of objective surgical and pathologic findings in the context of the patient's clinical presentation. Clinical assessment helps to identify patients at high risk of endometriosis and selects those who warrant further testing. Determination of the serum level of CA-125, and to a lesser extent, other proteins, may be helpful in evaluating selected population at risk and following the course of the disease. Selective use of imaging studies, especially ultrasound and magnetic resonance imaging, may also be helpful. Ultimately, the diagnosis of endometriosis is usually confirmed or refuted by laparoscopy, preferably performed in conjunction with histologic evaluation of excised lesions.

CA-125 Antigen↗

PubMed1997

Effects of insulin and insulin-like growth factors on proliferation of rat ovarian theca-interstitial cells.

Hyperplasia of the theca-interstitial (T-I) compartment, such as observed in polycystic ovary syndrome, is associated with ovarian dysfunction. Yet the mechanisms regulating proliferation of T-I cells are virtually unknown. This study was an investigation of the effects of insulin and insulin-like growth factors (IGF-I and IGF-II) on proliferation of rat T-I cells. Purified T-I cells were incubated in chemically defined media. Insulin (1-100 nM) and both IGFs (0.3-30 nM) dose-dependently stimulated DNA synthesis as determined by radiolabeled thymidine incorporation assay. IGF-I was most potent with EC50 = 1.4 +/- 0.4 nM, while IGF-II had EC50 = 4.3 +/- 0.18 nM and insulin had EC50 = 8.4 +/- 3.9 nM. The maximal effects of all three treatments were comparable. A combination of IGF-I at 10 nM (a concentration producing a near-maximal effect) with insulin or IGF-II resulted in DNA synthesis comparable to that achieved by IGF-I alone. IGF-I mutants with decreased affinity to IGF-binding proteins (IGFBPs)-long R3-IGF-I and des(1-3)IGF-I-produced greater effects on DNA synthesis than did IGF-I. The effects of insulin and IGFs on cell proliferation were confirmed by counting the steroidogenically active cells (stained positive for 3 beta-hydroxysteroid dehydrogenase [3 beta-HSD]) and steroidogenically inactive cells (3 beta-HSD negative). The number of steroidogenically active T-I cells was increased by insulin (by 3.7-fold, p < 0.001), IGF-I (by 3.2-fold, p < 0.001), and IGF-II (by 2.1-fold, p < 0.001). The number of steroidogenically inactive cells was not significantly altered. These findings indicate that 1) insulin- and IGF-dependent synthesis of DNA by T-I cells is stimulated via a common pathway, probably via type I IGF receptors; 2) endogenous IGFBPs may modify the effects of IGF-I; and 3) the increased DNA synthesis is reflected by an increase in the number of steroidogenically active cells. Insulin and the IGFs may play a role in the regulation of proliferation and differentiation of T-I cells under physiological and pathological conditions. In particular, the present observations may explain thecal and stromal hyperplasia accompanying hyperinsulinemic conditions such as polycystic ovary syndrome or hyperthecosis.

3-Hydroxysteroid Dehydrogenases↗

PubMed1996

Evaluation and management of chronic pelvic pain.

Evaluating patients with chronic pelvic pain is complex. A detailed medical history should be ideally supplemented by psychologic evaluation and assessment of the woman's social background. At the time of physical examination, the location and intensity of the pain should be mapped. Assessment of pain relief with the administration of a local anesthetic to trigger points or selected nerves may be useful in predicting the potential efficacy of surgical interventions such as uterosacral nerve ablation. Appropriate tests include pelvic ultrasound and magnetic resonance imaging. Ultimately, laparoscopy may provide the final diagnosis. Management should address the underlying cause(s) of pain; when this cannot be done, it should focus on treating the pain itself. When appropriate, empiric administration of antidepressants may be considered. In selected women, therapeutic goals may be achieved by electrical stimulation of nerves.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1996

Regression analysis and multivariate analysis.

Proper evaluation of data does not necessarily require the use of advanced statistical methods; however, such advanced tools offer the researcher the freedom to evaluate more complex hypotheses. This overview of regression analysis and multivariate statistics describes general concepts. Basic definitions and conventions are reviewed. The types of regression analysis are then discussed, including simple regression, multiple regression, multivariate multiple regression, and logistic regression. The various steps required to perform these analyses are described, and the advantages and disadvantages of each is detailed.

Analysis of Variance↗

PubMed1995

Baseline cyst formation after luteal phase gonadotropin-releasing hormone agonist administration is linked to poor in vitro fertilization outcome.

OBJECTIVE: To investigate the prognostic significance of baseline ovarian cysts after luteal phase GnRH agonist (GnRH-a) administration for IVF-ET. DESIGN: All nondonor IVF-ET cycles in one program in which luteal phase GnRH-a was administered between July 1993 and January 1994 were assessed for the formation of baseline ovarian cysts defined as a mean diameter > or = 15 mm. Outcome data from the IVF cycles were compared between patients with and without baseline ovarian cysts. RESULTS: Of 78 IVF cycles, baseline cysts > or = 15 mm were noted in 26 cycles. Cycles in which cysts were formed were associated with significantly older patients with significantly higher baseline FSH values. Cycles in which cysts were present demonstrated fewer follicles, retrieved oocytes, and embryos. Cyst cycles also demonstrated a lower peak E2 level, implantation rate, and clinical pregnancy rate (PR) per initiated cycle (7.7% versus 32.7%). Cyst cycles also demonstrated a higher cancellation rate. Logistic regression modeling, accounting for age, confirmed significantly lower clinical PRs in cycles with a baseline cyst. CONCLUSIONS: Baseline cyst formation after luteal phase GnRH-a administration is both a marker for poor responders and a reliable predictor of poor stimulation and low PRs in a given IVF-ET cycle.

Chorionic Gonadotropin↗

PubMed1995

Changes in magnetic resonance transverse relaxation times of two muscles following standardized exercise.

Magnetic resonance (MR) imaging studies of exercising leg muscles were performed to compare the changes in MR transverse relaxation times (T2) that result from exercise of the anterior tibialis (AT) and extensor digitorum/hallicus longus (E) in the anterior compartment of the lower leg with those T2 changes in the medial and lateral gastrocnemius (G) in the posterior compartment. Spin-echo MR images were obtained at 1.5 Tesla before and during the first 14 min of recovery from dynamic exercise. In order to normalize the exercise, workloads for each subject were set at 25% of the measured maximum voluntary contraction (MVC) of the anterior and posterior compartments. In separate exercise sessions, a nonmagnetic, pneumatic exercise apparatus was employed for either dorsiflexion or plantarflexion against a fixed constant resistance for two different exercise durations (1 min 45 s or 5 min). Transaxial MR images (TR = 1000 ms, TE = 30, 60, 90, 120 ms, 128 x 256 matrix, 1.5 cm slice) were used to calculate T2 values. Although subjects performed approximately 7-fold more work (P < or = 0.001, dorsiflexion vs plantarflexion) during plantarflexion than during dorsiflexion at both exercise duration's, the exercise induced T2, while being greater than those at rest (P < or = 0.001), were not significantly different in the different compartments. We conclude that, when exercised at the same workload (25% of MVC), these two muscles produce T2 changes that are not significantly different from each other.

Adult↗

PubMed1993

Sandostatin has no direct effect on ovarian steroidogenesis in vitro.

Rat granulosa and theca-interstitial cells from immature, oestradiol-treated rats were isolated and incubated for 144 h with follicle stimulating hormone (FSH), luteinizing hormone (LH), insulin alone or in combinations, and with two doses of sandostatin (10(-7) M and 10(-6) M per culture). Oestradiol and testosterone production by granulosa and theca-interstitial cells, respectively, was measured in culture media. The stimulatory effects of FSH alone and FSH with insulin but not insulin alone on oestradiol production by granulosa cells were observed. Similarly, increased testosterone concentrations after treatment with LH alone and LH with insulin but not insulin alone were found in media from theca-interstitial cells. The addition of high or low doses of sandostatin to the cultures did not affect the production of oestradiol or testosterone. It was concluded that sandostatin does not exert any direct effect on ovarian steroidogenesis in vitro.

Animals↗

PubMed1993

Insulin actions on ovarian steroidogenesis are not modulated by metformin.

Metformin, an agent used in treatment of non-insulin-dependent diabetes mellitus, is believed to act by potentiating the effects of insulin on glucose metabolism. This study was designed to determine whether metformin affects the actions of insulin on ovarian steroidogenic capability. Rat thecal-interstitial (T-I) and granulosa (G) cells were cultured in chemically defined media for 144 h with or without gonadotrophins [luteinizing hormone (LH) at 100 ng/ml or follicle stimulating hormone (FSH) at 100 ng/ml], insulin (1 microgram/ml) and/or metformin (1 and 5 micrograms/ml). Production of testosterone and progesterone by T-I cells, and 17 beta-oestradiol and progesterone by G cells were assessed. Insulin potentiated LH-dependent stimulation of testosterone production by T-I cells and FSH-dependent stimulation of 17 beta-oestradiol production by G cells, but did not significantly affect progesterone production by T-I cells or G cells in the presence or absence of gonadotrophins. Metformin did not affect any of the actions of insulin on steroidogenesis. These results suggest that insulin may modulate ovarian steroidogenesis via a pathway separate from that modulating glucose metabolism. Actions of insulin on steroidogenesis are selective with regard to stimulation of specific aspects of steroidogenesis and do not simply amplify gonadotrophin effects.

Animals↗

PubMed1992

Expectant management of choriocarcinoma limited to placenta.

Choriocarcinoma limited to placenta was discovered "incidentally" following a seemingly uneventful term pregnancy. The newborn had unsuspected severe anemia and thrombocytopenia, due to fetomaternal hemorrhage. His recovery was good following transfusions. The mother was asymptomatic and her extensive workup for metastatic choriocarcinoma was negative. She was subsequently managed expectantly and monitored with serial serum beta-hCG, demonstrating near-logarithmic decline to non-pregnant levels within 5 weeks of delivery.

Adult↗