Anthony Cecutti

Maternal weight loss associated with hyperemesis gravidarum: A predictor of fetal outcome

Over a 5-year period in our center 64 patients were hospitalized with a diagnosis of hyperemesis gravidarum. Patients were classified into two groups to determine whether weight loss was an objective predictor of pregnancy outcome. Patients whose weight loss was greater than 5% of their prepregnancy weight were classified as group A (n = 30). Patients with nausea and vomiting of pregnancy but with maintenance of at least 95% of prepregnancy body weight were in group B (n = 34). Infants in group A were significantly smaller with respect to average birth weight expressed as a percentile for gestational age: 38.11 percentile, versus 72.00 percentile for group B (p less than 0.025). Macrosomia (greater than or equal to 4000 gm) was significantly associated with group B (18% versus group A, 0%; p less than 0.025). Growth retardation (less than or equal to 10th percentile weight at birth) was significantly associated with group A (30% versus group B, 6%; p less than 0.01). Three integumentary system abnormalities (3 of 30 cases) occurred in group A compared with none in group B. Although hyperemesis gravidarum has been viewed as a positive predictor, those patients who also demonstrate weight loss and electrolyte disturbance may be a distinct entity and at greater risk for growth retardation and fetal anomalies.

Comparison of the antioxidant effects of equine estrogens, red wine components, vitamin E, and probucol on low-density lipoprotein oxidation in postmenopausal women.

Objective Oxidized low-density lipoprotein (LDL) seems to play an important role in the etiology of atherosclerosis. To further study this, we performed two studies: (1) we determined the ability of 10 estrogen components of the drug, conjugated equine estrogen (CEE), trans-resveratrol (t-resveratrol) and quercetin (red wine components), trolox (vitamin E analog), and probucol (a serum cholesterol-lowering drug) to delay or prevent the oxidation of plasma LDL isolated from untreated postmenopausal women, and (2) we assessed the effect of long-term (>1 year) estrogen replacement therapy and hormone replacement therapy on LDL oxidation by ex vivo methods. Design For the in vivo study, three groups of postmenopausal women were selected based on whether they were on long-term CEE therapy (group A: 0.625 mg CEE;n = 21), on combination CEE plus progestogen therapy (group B: 0.625 mg CEE + 5.0 mg medroxyprogesterone acetate, 10 days;n = 20), or not on any hormone therapy (group C;n = 37). For the in vitro study, only LDL samples obtained from group C were used. The kinetics of LDL oxidation were measured by continuously monitoring the formation of conjugated dienes followed by determination of the lag time. Results All compounds tested protected the LDL from oxidative damage. The relative antioxidant potency of estrogen components was generally greater than that of the other compounds. The minimum dose (nmoles) required to double the lag time from the control lag time of 57 ± 2 min was 0.47 for 17&bgr;-dihydroequilenin , 17&agr;-dihydroequilenin, &Dgr; 8 -estrone; 0.6 to 0.7 for &Dgr; 8 -17&bgr;-estradiol, equilenin, and quercetin; 0.9 for 17&bgr;-dihydroequilin and 17&agr;-dihydroequilin; 1.3 for equilin, estrone, 17&bgr;-estradiol, 17&agr;-estradiol; 1.4 for trolox; 1.9 for probucol; and 3.0 for t-resveratrol. The data from the in vivo study indicate that after long-term estrogen replacement therapy (group A) and hormone replacement therapy (group B), the LDL was significantly (p < 0.01) protected (higher lag time) against oxidation compared with the control (group C). There was no difference between groups A and B. Conclusions The oxidation of LDL isolated from postmenopausal women is inhibited differentially by various estrogens and other antioxidants. The unique ring B unsaturated estrogen components of CEE were the most potent, and t-resveratrol, the red wine component, was the least potent. Long-term CEE or CEE + medroxyprogesterone acetate administration to postmenopausal women protects the LDL against oxidation to the same extent. These combined data support the hypothesis that some of the cardioprotective benefits associated with CEE therapy and perhaps red wine consumption may be due to the ability of their components to protect LDL against oxidative modifications.

Discordant expression of insulin-like growth factors and their receptor messenger ribonucleic acids in endometrial carcinomas relative to normal endometrium.

The inappropriate expressions of insulin-like growth factors (IGF-I and II) and IGF-I receptor (IGF-IR) are implicated in the malignant growth of many cancers. To determine changes, if any, in the levels of expression of IGFs and IGF receptor genes in neoplastic endometrium, relative to normal endometrium, the mRNA levels of IGF-I and II and of IGF-IR and IIR were measured in samples of endometrial carcinomas (EC) and normal endometrium, through all phases of the menstrual cycle, by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) assays. In normal endometrium, the mRNA levels of IGF-I were elevated in the proliferative and early secretory phases. The IGF-II mRNAs were relatively high in the proliferative phase, but unaltered through early and late secretory phases. Significantly elevated levels of IGF-II transcripts were observed during the menstrual phase, suggesting a possible role of IGF-II in endometrial regeneration. A positive correlation between the levels of IGF-I and IGF-IR mRNAs, apparent in the samples of normal endometrium, was not observed in endometrial carcinomas. The IGF-IR and IIR mRNA levels were elevated in endometrial carcinoma samples. On the other hand, the IGF-I and II mRNA levels were conspicuously low in many carcinoma samples, which were not associated with hyperplasia (type II EC), but relatively elevated in two other carcinoma samples, associated with adenomatous hyperplasia (type I EC). These results albeit with few samples suggest the possibility that the overexpressed receptor, IGF-IR, could be activated differently in two types of endometrial carcinomas, namely ligand-dependently in type I ECs and ligand-independently in type II ECs.

Biologic effects of delta-8-estrone sulfate in postmenopausal women

Objective: To determine in postmenopausal women the biological effects of delta-8-estrone sulfate, a novel estrogen component of Premarin (Wyeth-Ayerst, Philadelphia, PA). Methods: An open-label, nonrandomized study of six healthy postmenopausal women was conducted. Each subject took 0.125 mg of delta-8-estrone sulfate daily for 8 weeks. Blood samples were collected at day 0 (baseline) and once a week for 8 weeks. Urine was collected on day 0 and at weeks 2, 3, 5, 6, 7, and 8. Serum gondotropins (follicle-stimulating hormone/luteinizing hormone), plasma binding proteins (corticosteroid-binding globulin/sex hormone-binding globulin), a marker for bone turnover (urinary n-telopeptide), and markers for cardiovascular effects (cholesterol, low-density lipoproteinc, high-density lipoproteinc, low-density lipoprotein oxidation, and rate of diene formation) were measured. Results: Follicle-stimulating hormone levels decreased from 84.0 ± 8.5 to 67.0 ± 8.5 mlU/mL (P = .02), whereas luteinizing hormone levels did not change. Corticosteroid-binding globulin levels increased from 3.30 ± 0.16 to 4.10 ± 0.16 mg/dL (P = .02), and no change in sex hormone-binding globulin was noted. The n-telopeptide levels decreased an average of 31% from 40.7 ± 4.9 to 28 ± 7.0 nmol/L bone collagen equivalents/mmol/L creatinine (P = .03). Plasma diene concentration and diene production rate decreased by 34% and 40%, respectively; these changes were not significantly different from baseline values. In contrast, a significant (P = .03) 68% increase in the lag time for low-density lipoproteinc oxidation (38.5 ± 5.5 minutes versus 64.8 ± 8.5 minutes) was observed. No significant change occurred in total cholesterol, high-density lipoproteinc, and low-density lipoproteinc. Conclusion: Small doses (0.125 mg) of delta-8—estrone sulfate have profound estrogenic effects in postmenopausal women. The changes observed in n-telopeptide levels and the lag-time delay in oxidation of low-density lipoproteinc indicate that this estrogen contributes toward the overall beneficial effects on bone and cardiovascular system associated with Premarin therapy.

Endometrial transcripts of human insulin-like growth factors arise by differential promoter usage

By the application of RT-PCR, we have demonstrated that in the human endometrium mRNAs for insulin-like growth factors, IGF-I and II, and their receptors are expressed not only in the intact endometrium, but also in the freshly isolated stromal and epithelial cells. The expression of multiple transcript forms of the IGF-I and II at various phases of the menstrual cycle, occurs by differential use of all four IGF-I transcriptional start sites, and two of the four known promoter sites of the IGF-II gene. The complete spectrum of transcripts is displayed by the proliferative phase and the menstrual phase endometrium. During the secretory phase, the exon 1 upstream start site of the IGF-I gene and the P2 promoter of the IGF-II gene are not used. Irrespective of the phase of the menstrual cycle, the stromal cells always display the same transcriptional patterns of both growth factor genes as those of the intact endometrium. In contrast, the epithelial cells do not express IGF-I transcript originating from the exon 2 upstream initiation site. These results indicate that the expressions of the IGF-I and II genes in the intact endometrium and stromal and epithelial cells are modulated at the transcriptional level during the menstrual cycle by differential usage of promoters and start sites.

Potential role of the interaction between equine estrogens, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in the prevention of coronary heart and neurodegenerative diseases in postmenopausal women

BackgroundAn inverse relationship between the level of high-density lipoprotein (HDL) and coronary heart disease (CHD) has been reported. In contrast, oxidized HDL (oHDL) has been shown to induce neuronal death and may play an important role in the pathogenesis of CHD. In the present study we have investigated a: the effect of various equine estrogens on HDL oxidation, b: the inhibition of LDL oxidation by HDL and c: the effect of these estrogens on LDL oxidation in the presence of HDL.ResultsAll 11 equine estrogens tested protected the HDL from oxidation in a concentration dependant manner. Equilenin, 17β-dihydroequilenin, and 17α-dihydroequilenin (Δ6–8-estrogens) were found to be the most potent inhibitors of HDL oxidation. Some of the novel ring B unsaturated estrogens were 2.5 to 4 times more potent inhibitors of HDL oxidation than 17β-estradiol. HDL was found to delay LDL oxidation. The protection of LDL oxidation by HDL is enhanced by the addition of estrogen, with equilenin being again more potent than 17β-estradiol.ConclusionsEquine estrogens can differentially inhibit the oxidation of HDL with the Δ6–8-estrogens being the most potent antioxidants. The ability of estrogens to enhance HDLs antioxidant activity is to our knowledge the first report of an interaction of estrogen with HDL that results in the delay or inhibition of LDL oxidation. This may be another mechanism by which estrogens may reduce the risk of CHD and neurodegenerative diseases in healthy and younger postmenopausal women.

Abdominal Pregnancy Complicated by Genital and Renal Tuberculosis and Hemolytic Anemia

After a 10-year period of primary infertility, a patient presented with abdominal pregnancy. Known to have had previously treated genital tuberculosis, on admission she was found to have renal tuberculosis and autoimmune hemolytic anemia. After fetal death, laparotomy was performed and the fetus was removed. The patients anemia responded well to steroid therapy and she was discharged on antituberculous triple therapy. The literature on hemolytic anemia in pregnancy and in association with tuberculosis, as well as on ectopic gestations, was reviewed.

Metabolism of [3H] 17β-dihydroequilin and [3H] 17β-dihydroequilin sulfate in normal postmenopausal women

Abstract The metabolism of 17β-dihydroequilin and 17β-dihydroequilin sulfate was investigated after intravenous administration of [ 3 H] 17β-dihydroequilin and [ 3 H] 17β-dihydroequilin sulfate to postmenopausal women Urine was collected for 3 days and 46.2±10.5% and 54.5±8.7% of the injected dose of [ 3 H] 17β-dihydroequilin and [17β- 3 H]dihydroequilin sulfate was excreted in the urine respectively. The estrogens present in urine were extracted and fractionated into unconjugated, sulfate, and glucuronide conjugated forms. With both precursors, the major amount (63–64%) of metabolites were excreted in the urine conjugated with glucuronic acid. From the unconjugated, sulfate, and glucuronide fraction, 17β-dihydroequilenin, 17β-dihydroequilin, equilenin, and equilin were isolated. The conversions with both precursors were similar and 17β-dihydroequilenin was the major metabolite isolated from all three fractions; however, the highest levels of all four metabolites were present in the glucuronide fraction. Along with these identifiable metabolites, a large amount (51–81%) of radioactivity was present in the form of metabolites which are more polar than any of the known ring-B unsaturated estrogens. These appear to by polyhydroxy 17β-reduced ring-B unsaturated estrogens which remain to be identified. The in-vivo formation of equilenin and 17β-dihydroequilenin indicates the presence of the enzyme 6,8(9) steroid dehydrogenase in humans. (Steroids 59 :389–394, 1994)

Pharmacokinetics of 17β-Dihydroequilin Sulfate in Normal Postmenopausal Women Under Steady State Conditions

Objective: In the present study, the constant infusion of [3H]17β-dihydroequilin sulfate ([3H]17β-EqS) was used to estimate the metabolic clearance rate (MCR) of 17β-dihydroequilin sulfate (17β-EqS) and to measure the conversion of this estrogen to equilin sulfate (EqS), equilenin sulfate (EqnS), 17β-dihydroequilenin sulfate (17β-Eqn) in normal postmenopausal women. Methods: In seven healthy postmenopausal women, infusion of [3H]17β-EqS was started 30 minutes after a priming dose and continued at a constant rate of 10-20 μCi/hour, for 3-6 hours. Three blood samples were taken during and at the end of infusion. From the plasma, unconjugated and sulfate-conjugated estrogens, 17β-EqS, EqS, EqnS, 17β-EqnS, Eq, Eqn, 17β-Eq, and 17β-Eqn were isolated and purified by high performance liquid chromatography. The MCR of 17β-EqS and the conversion ratios and transfer constants (p) for precursor (17β-EqS) to products were calcualted. Results: The mean MCR of 17β-EqS was calculated to be 797 ± 90 L/day or 506 ± 60 L/m2 per day. The mean conversion ratio (CRPRE-PRO BB) was 2.4 ± 0.4 for EqS, 0.3 ± 0.04 for EqnS, 0.25 ± 0.03 for 17β-EqnS, 0.09 ± 0.02 for Eq, 0.03 ± 0.01 for Eqn, 0.08 ± 0.02 for 17β-Eq, and 0.03 ± 0.01 for 17β-Eqn. In both the sulfate-conjugated and unconjugated forms, the most abundant metabolite formed was Eq. Based on the previously reported MCR of EqS (170 L/M2 per day) and 17β-Eq (1252 L/M2 per day), the transfer constants [ρ]BB were calculated to be 0.8 ± 0.10 and 0.20 ± 0.03, respectively. The results indicate that a large portion of 17β-EqS is converted to EqS and the more potent estrogen 17β-Eq. The ratio of ρEqS-17β-EqS to ρ17β-EqS-EqS was calculated to be 0.8 ± 0.1 and represents the extent of C-17-oxidation and reduction and indicates that substantial amounts of 17β-reduced metabolites will still be presnet in the blood although the oxidation reaction was somewhat greater. Conclusion: The data indicate that, compared with the classic estrogens, the in vivo metabolism of ring B unsaturated estrogens is complex. Thus, although the amount of 17β-EqS originally present in the conjugated equine estrogens is small, the pharmacokinetics and pharmacodynamics of EqS, 17β-EqS, and the extensive interconversions between these estrogens support the hypothesis that the major in vivo activity of the EqS present in conjugated equine estrogens is expresed through its metabolism to 17β-EqS and 17β-Eq. Furthermore, the increased estrogenic activity associated with this drug may in part be due to the formation of these 17β-reduced metabolites.