Mortimer Levitz

Maple Syrup Urine Disease

Serum amino-acid chromatogram. Note the intense leucine/isoleucine and valine spots. bronchopneumonia at 3 weeks, was drowsy from birth and fed poorly. Examination showed our patient to be unresponsive, with increased tone and occasional opisthotonic spasms. A strong odour of maple syrup was present. Investigations.-Urinary chromatograms showed marked increase in valine (from which the odour was detected), leucine, and isoleucine, with moderate increases in other amino-acids. The a-keto acids of the branched amino-acids were also present in large amounts. Indolyl-lactic acid was present in excess but not indolyl-acetic acid. Asparagine and ethanolamine were also detected. The serum and cerebrospinal fluid showed greatly increased amounts of valine,leucine, and isoleucine; other amino-acids were normal or low in quantity (see Fig.). COMMENT.-While clinically this case is one of maple syrup urine disease the biochemical findings suggest the presence of a renal tubular defect and hepato-cellular damage. Previously reported cases have shown an increase in indolyl-acetic acid; this was not present in the above case. Detailed biochemical findings will be published later, with the results of a dietary trial which is proceeding.

Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women

Experimental and epidemiological data support a role for sex steroid hormones in the pathogenesis of endometrial cancer. The associations of pre‐diagnostic blood concentrations of estradiol, estrone, testosterone, androstenedione, DHEAS and SHBG with endometrial cancer risk were investigated. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). Cases were 124 postmenopausal women with invasive endometrial cancer. For each case, 2 controls were selected, matching the case on cohort, age and date of recruitment. Only postmenopausal women who did not use exogenous hormones at the time of blood donation were included. Odds ratios (OR) and their 95% confidence intervals (CI) were estimated by conditional logistic regression. ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels, relative to the lowest were as follows: 4.13 (1.76–9.72), ptrend = 0.0008 for estradiol, 3.67 (1.71–7.88), ptrend = 0.0007 for estrone, 2.15 (1.05–4.40), ptrend = 0.04 for androstenedione, 1.74 (0.88–3.46), ptrend = 0.06 for testosterone, 2.90 (1.42–5.90), ptrend = 0.002 for DHEAS and 0.46 (0.20–1.05), ptrend = 0.01 for SHBG after adjustment for body mass index, use of oral contraceptives and hormone replacement therapy. The results of our multicenter prospective study showed a strong direct association of circulating estrogens, androgens and an inverse association of SHBG levels with endometrial cancer in postmenopausal women. The effect of elevated androstenedione and testosterone levels on disease risk seems to be mediated mainly through their conversion to estrogens, although an independent effect of androgens on tumor growth cannot be ruled out, in particular in the years close to diagnosis.

Postmenopausal endogenous oestrogens and risk of endometrial cancer: results of a prospective study.

We assessed the association of postmenopausal serum levels of oestrogens and sex hormone-binding globulin (SHBG) with endometrial cancer risk in a case–control study nested within the NYU Women’s Health Study cohort. Among 7054 women postmenopausal at enrolment, 57 cases of endometrial cancer were diagnosed a median of 5.5 years after blood donation. Each case was compared to 4 controls matched on age, menopausal status at enrolment, and serum storage duration. Endometrial cancer risk increased with higher levels of oestradiol (odds ratio = 2.4 in highest vs lowest tertile, P for trend = 0.02), percent free oestradiol (OR = 3.5, P< 0.001), and oestrone (OR = 3.9, P< 0.001). Risk decreased with higher levels of percent SHBG-bound oestradiol (OR = 0.43, P = 0.03) and SHBG (OR = 0.39, P = 0.01). Trends remained in the same directions after adjusting for height and body mass index. A positive association of body mass index with risk was substantially reduced after adjusting for oestrone level. Our results indicate that risk of endometrial cancer increases with increasing postmenopausal oestrogen levels but do not provide strong support for a role of body mass index independent of its effect on oestrogen levels.

The transfer and metabolism of corticosteroids in the perfused human placenta.

The transfer and metabolism of cortisol, prednisolone, betamethasone, and dexamethasone were investigated in vitro in the perfused human placenta. Maternal and fetal circuits were established but the steroid was added to the former only. The clearance expressed as a fraction of the antipyrine transfer rate varied from 0.27 to 0.50, but there were no significant differences among the four steroids. All the steroids were metabolized extensively to their respective 11-ketosteroids and again there were no material differences among the steroids. The metabolic conversions of dexamethasone and betamethasone were far greater in the perfused placenta than in minced placenta. From the standpoint of placental transfer and metabolism, as observed in the perfusion studies, none of the four corticosteroids offers a decisive advantage in the antepartum maturation of the fetal pulmonary surfactant system.

Transport of amino acids by placenta.

Abstract Placental transport has been studied in vivo in the guinea pig and in vitro with guinea pig and human placenta. Following the infusion of the nonmetabolized amino acid, AIB- 14 C, into pregnant guinea pigs for 2 to 4 hours, the fetal plasma concentration of the amino acid exceeded that in the maternal plasma. The concentration of the amino acid in maternal placenta (decidua) exceeded that in the maternal plasma. The concentration in the fetal placenta was higher than in both the maternal and fetal plasma, suggesting that transport may involve at least two steps, concentrative uptake into the placenta and release into fetal plasma. Perfusion of guinea pig placenta in situ, following removal of the fetus, demonstrated the primary role of the placenta in establishing a concentration gradient toward the fetus. It was also demonstrated that the amino acid was transferred across the placenta in both directions, apparently more rapidly toward the fetus than in the reverse direction. In vitro experiments with guinea pig and human placenta revealed concentrative uptake of the amino acid. This was decreased by metabolic poisons. The isolated villus of human placenta concentrated the amino acid more effectively than did placental slices. Insulin increased uptake into human placenta but not into guinea pig placenta. Growth hormone, lactogenic hormone, estradiol, estrone sulfate, and oxytocin produced no measurable response.

Transfer across perfused human placenta. II. Free fatty acids.

Extract: The rate of transfer of palmitic acid across human placenta was measured in an in vitro perfusion system. The rates of transfer from maternal to fetal circulation and in reverse direction were about the same, and were considerably less than those for antipyrine and leucine. The transfer rate for linoleic acid was similar to that for palmitic acid. An estimate of the absolute rate of transfer for free fatty acids was made which yielded a figure of 6.8 mmol/24 hr. which is less than that required for the deposition of fat by the fetus in the last trimester. These calculations indicate that during the period of rapid accumulation of fat the fetus converts glucose and/or amino acids to that purpose.Uptake and metabolism of palmitate by placental slices differs significantly in the human and the guinea pig.Speculation: It has been suggested that the placental capacity for transfer of some nutrients greatly exceeds requirements, whereas with respect to other nutrients, the capacity for transfer is far more limited. A general reduction in placental function may produce selective nutritional deficiencies in the fetus, beginning with those factors transferred with the smallest margin of safety.

Plasma estriol levels in normal and abnormal pregnancies: An index of fetal welfare

Abstract Serial plasma estriol determinations were conducted in the third trimester of human pregnancy on 22 normal, 25 diabetic, and 16 toxemic patients. In addition, 10 cases of suspected fetal death were evaluated. In normal pregnancy the levels rise in a generally regular fashion as pregnancy proceeds, increasing about fivefold in the last trimester. However, the individual curves vary considerably. The average plasma estriol level at term is about 27 μg per 100 ml. with a range between 10 and 55. The plasma estriol levels of the diabetic patients (Classes A, B, and C) in good control, were not statistically different from those of the normal patients. The toxemic patients could be classified into three groups according to their estriol levels. Those with severe symptoms and small fetuses had correspondingly low levels. The patients under good control had normal values while three patients with renal involvement superimposed on toxemia had surprisingly high levels. The values for patients with dead fetuses were extremely low. Although a larger number of cases involving fetal jeopardy must be studied before the contribution of plasma estriol determinations toward the improvement of fetal salvage rates can be assessed, the potential advantages of plasma assays over urine assays in this regard are discussed.

Estrogens in Pregnancy

Publisher Summary This chapter discusses the estrogens in pregnancy. A notable characteristic of normal human pregnancy is the extensive production of a variety of biologically active substances. These include (1) the protein hormones human chorionic gonadotropin and human placental lactogen, (2) the enzymes heat-stable alkaline phosphatase and diamine oxidase, and (3) the progestational and estrogenic steroid hormones. Considerable interest has been generated in the biosynthesis, production rate, metabolic clearance, and relationship to the status of the pregnancy of each of these substances. However, the estrogens have evoked the greatest interest. Estrogen synthesis in pregnancy is highly complex, involving interaction with the placenta of precursors made by specific organs of the fetus and mother. A deeper appreciation of the qualitative and quantitative aspects of estrogen synthesis in pregnancy may be gained from comparison with the nonpregnant state. Because the placenta is particularly rich in the enzyme activities responsible for estrogen synthesis and a limitless supply of fresh tissue is available to interested investigators, it is not unexpected that there is a copious literature on the isolation and purification of these enzymes.

Postmenopausal Levels of Endogenous Sex Hormones and Risk of Colorectal Cancer

Observational epidemiologic studies and randomized trials have reported a protective effect of oral hormonal replacement therapy on risk of colorectal cancer. Only one previous prospective study, the Womens Health Initiative Observational Study, has reported on the relationship between endogenous hormones and incident colorectal cancer. Contrary to expectation, the investigators found that women with higher circulating estradiol levels were at increased risk of developing colorectal cancer. We conducted a case-control study nested within the New York University Womens Health Study prospective cohort to evaluate the association between endogenous levels of estrone, estradiol, and sex hormone–binding globulin (SHBG) with risk of colorectal cancer. We measured hormones and SHBG in serum samples collected at enrollment from a total of 148 women who subsequently developed colorectal cancer and 293 matched controls. Circulating estrone levels were positively associated with risk of colorectal cancer: The odds ratio for the highest versus lowest quartile of estrone was 1.8 (95% confidence interval, 1.0-3.3). We found a nonsignificant inverse association between SHBG and colorectal cancer, which disappeared after adjusting for body mass index. We did not find an association between estradiol and colorectal cancer risk, but we cannot rule out a potential association because of substantial laboratory error in the measurement. Our results suggest that endogenous estrone is associated with increased risk of colorectal cancer in postmenopausal women. (Cancer Epidemiol Biomarkers Prev 2009;18(1):275–81)

Serum estradiol-binding profiles in postmenopausal women undergoing three common estrogen replacement therapies: associations with sex hormone-binding globulin, estradiol, and estrone levels.

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. (Menopause 2000;7:243‐250.