A. Louis Southren

The effect of alcohol ingestion on hepatic aromatase activity and plasma steroid hormones in the rat

Chronic alcohol ingestion in the rat resulted in increased hepatic aromatase activity, elevation of plasma estradiol, and a decrease in plasma testosterone levels. Testicular incubation studies indicated that the source of the estrogen was not of gonadal origin but was, most likely, due to increased peripheral conversion. The failure of HCG in vitro to restore testicular secretion of testosterone to normal levels suggested a direct action of alcohol, or a metabolic product, on gonadal secretory processes, as distinct from trophic hormone effects. This study demonstrates that many of the hormonal alterations seen in cirrhosis of the liver in man may be produced directly by alcohol feeding without cirrhotic changes in the rat.

Androgen metabolism in cirrhosis of the liver

Abstract Androgen metabolism was studied in male patients with cirrhosis of the liver. The plasma level, metabolic clearance, and production rates of testosterone were decreased while the conversion ratio and rate transport constant of testosterone to androstenedione was increased. Administration of testosterone produced a marked increase in the metabolic clearance rate of testosterone indicating that parenchymal hepatic dysfunction per se was not the cause for the reduced clearance rate. Moreover, the patients were found to have normal testicular reserve for the biosynthesis of testosterone as indicated by an almost fourfold increase in the plasma concentration of testosterone following the administration of human chorionic gonadotropin. These data demonstrate that the reduced production rate of testosterone in male cirrhotics is not due primarily to testicular disease but possibly reflects hypothalamic-pituitary suppression secondary to increased circulating estrogens. The increase in the rate of conversion of testosterone to androstenedione, found in the present study, is consistent with this hypothesis. The present investigation thus provides quantitative data on the hypogonadal state in cirrhosis and suggests possible mechanisms for the alteration in androgen metabolism.

Estrogen metabolism in hyperthyroidism and in cirrhosis of the liver

Estrogen metabolism was studied in spontaneous hyperthyroidism (Graves disease) and in alcoholic cirrhosis of the liver. The plasma concentration of estradiol-17beta (PCE2) was increased in men with hyperthyroidism. Although the metabolic clearance rate of estradiol-17beta (MCRE2) was reduced, the production rate (PR) of the steroid was increased above normal. The MCRE2 was also decreased in women with hyperthyroidism but the PCE2 and PRE2 was unchanged from normal. The conversion ratio of estradiol-17beta (CRE2E1) was increased in both hyperthyroid men and women. The PCE2 was significantly increased in men with cirrhosis of the liver. The MCRE2 was normal and this resulted in an increase in the PRE2 in this disorder. The CRE2E1 was significantly higher than normal. The plasma concentration of estrone (E1) was elevated in men with both disorders.

Growth Hormone Treatment of Adults with Prader-Willi Syndrome and Growth Hormone Deficiency Improves Lean Body Mass, Fractional Body Fat, and Serum Triiodothyronine without Glucose Impairment: Results from the United States Multicenter Trial

CONTEXTnGH replacement in Prader-Willi syndrome (PWS) children has well-defined benefits and risks and is used extensively worldwide. Its use in PWS adults has been limited by documentation of benefits and risks, as determined by larger multisite studies.nnnOBJECTIVESnOur objective was to evaluate the effectiveness and safety of GH in GH-deficient genotype-positive PWS adults.nnnDESIGNnWe conducted a 12-month open-label multicenter trial with 6-month dose-optimization and 6-month stable treatment periods.nnnSETTINGnThe study was conducted at outpatient treatment facilities at four U.S. academic medical centers.nnnPATIENTSnLean and obese PWS adults with diverse cognitive skills, behavioral traits, and living arrangements were recruited from clinical populations.nnnINTERVENTIONnHuman recombinant GH (Genotropin) was initiated at 0.2 mg/d with monthly 0.2-mg increments to a maximum 1.0 mg/d, as tolerated.nnnMAIN OUTCOMES MEASURESnLean body mass and percent fat were measured by dual-energy x-ray absorptiometry.nnnRESULTSnLean body mass increased from 42.65 +/- 2.25 (se) to 45.47 +/- 2.31 kg (P < or = 0.0001), and percent fat decreased from 42.84 +/- 1.12 to 39.95 +/- 1.34% (P = 0.025) at a median final dose of 0.6 mg/d in 30 study subjects who completed 6-12 months of GH. Mean fasting glucose of 85.3 +/- 3.4 mg/dl, hemoglobin A1c of 5.5 +/- 0.2%, fasting insulin of 5.3 +/- 0.6 microU/ml, area under the curve for insulin of 60.4 +/- 7.5 microU/ml, and homeostasis model assessment of insulin resistance of 1.1 +/- 0.2 were normal at baseline in 38 study initiators, including five diabetics, and remained in normal range. Total T(3) increased 26.7% from 127.0 +/- 7.8 to 150.5 +/- 7.8 ng/dl (P = 0.021) with normalization in all subjects, including six (20%) with baseline T(3) values at least 2 sd below the mean. Mildly progressive ankle edema was the most serious treatment-emergent adverse event (five patients).nnnCONCLUSIONSnThis multicenter study demonstrates that GH improves body composition, normalizes T(3), and is well tolerated without glucose impairment in PWS genotype adults.

Androstenedione metabolism in patients with endometrial cancer.

The plasma concentration of androstenedione and the instantaneous conversion of androstenedione to estrone was increased in patients with endometrial cancer as compared to postmenopausal control subjects. Moreover, the per cent of estrone derived from androstenedione was increased in the cancer group.

Diamine oxidase in human pregnancy: Plasma diamine oxidase in nonpregnant and normal pregnant patients

Abstract Plasma diamine oxidase was measured in 72 nonpregnant patients and during normal pregnancy with the use of a recently developed radioassay procedure. The mean level of plasma diamine oxidase in the normal nonpregnant state was found to be 3.4 units with a standard deviation of plus or minus 1.5 units. In the group of nonpregnant patients with a variety of disease states, there were 5 instances, including 3 cases of Laennecs cirrhosis, in which the plasma titer of the enzyme was considerably greater than the mean for the group. A sharp rise in plasma diamine oxidase occurred in pregnant patients approximately 5 to 6 weeks following the last normal menstrual period and rapidly reached a plateau where it remained until parturition. The plasma enzyme activity following parturition did not reach normal nonpregnancy levels for approximately 10 to 14 days, and the rate of decline was not influenced by the removal of the uterus. The large maternal to fetal ratio of plasma diamine oxidase, as well as the normal nonpregnancy levels in a case of choriocarcinoma, suggested that the source of the enzyme is the maternal placenta.

Effect of Chronic Alcohol Use on Hepatic Testosterone 5α-A-Ring Reductase in the Baboon and in the Human Being

Hepatic testosterone 5-alpha-A-ring reductase (HTAR) activity was measured in open liver biopsies in eight alcohol-fed baboons and eight pair-fed controls. The animals were studied after at least 1 yr of alcohol feeding. In the alcholol-fed animals, a significant fall in enzyme activity was noted. This occurred whether the enzyme levels were related to soluble protein, to DNA, or to wet tissue weight, showing that the change was due to a decrease in the specific activity of the enzyme. In addition, aspiration liver biopsy specimens were obtained from 14 men and women with alcoholic liver disease. Again, there was a significant decrease in HTAH activity in these patients compared with a normal population. No relationship was found between hepatic histology and HTAR levels in either the baboon or human population with alcoholic liver disease, suggesting that the changes in enzyme activity were related to an alcohol effect rather than to liver disease per se. This study demonstrates that chronic alcohol use decreases the function of the enzyme which controls an important rate-limiting step in the metabolism of testosterone in the liver and that this effect may be due primarily to alcohol.

The effect of 2, 2-Bis (2-chlorophenyl-4-chlorophenyl)-1, 1-dighloroethane (o, p'-DDD) on the metabolism of infused cortisol-7-3H

Abstract o, p-DDD was administered to a subject with Cushing s syndrome and to an adrenalectomized castrated subject maintained on a constant cortisol intake. Measurements of the secretion, metabolism and metabolic clearance rate of cortisol were made before and during the administration of the drug. In the adrenalectomized subject the “cortisol secretion rate” was an estimate of the administered cortisol. The results of this study indicated that o, p-DDD affected both the adrenal secretion and the extraadrenal metabolism of cortisol. During the early phase of drug administration however, the extra-adrenal effect predominated. In addition, it was shown than an increased circulating level of cortisol, whether due to exogenous administration or Cushings syndrome, was associated with an increased plasma clearance of the steroid.

Metformin and carbohydrate-modified diet: a novel obesity treatment protocol: preliminary findings from a case series of nondiabetic women with midlife weight gain and hyperinsulinemia.

The authors conducted a retrospective analysis of a new obesity treatment protocol, metformin and hypocaloric, carbohydrate-modified diet, in high-risk, nondiabetic hyperinsulinemic women with progressive midlife weight gain (refractory to diet and exercise). Thirty consecutive nondiabetic women with glucose-mediated area-under-the-curve (AUC) insulin elevations (>or=100 microU/mL) in two body mass index (BMI) categories (group I: 25 to 32.9 kg/m(2) and group II: 33 to 41.7 kg/m(2)) participated in a 1-year treatment program of metformin (mean daily doses of 1,500 mg/day [group I] and 2,000 mg/day [group II]) and carbohydrate-modified dietary regimens. Follow-up body weight (at 3, 6, and 12 months), percentage of patients meeting goal weight attainment (10% reduction in body weight or BMI normalization), and fasting insulin levels (as available) are reported in 26 women (18/18 in group I and 8/12 in group II) who returned for one or more follow-up visits. Significant weight loss was observed at 3, 6, and 12 months in both group I (3.47 [SE 0.68], 6.41 [0.72], and 8.06 [0.96] kg, P < 0.0001) and group II (4.4 [0.8], 9.7 [2.3], 15.1 [3.3], P = 0.001, 0.004, 0.011). Twenty-five of 26 (96%) patients lost >or=5% of their body weight at 6 months and 21/26 (81%) patients lost >or=10% of their body weight at 12 months. Posttreatment fasting insulin decrement (-35.5 [8.2]%) was the most significant predictor of 1-year weight loss (R(2)=0.656, regression coefficient = 0.810, P = 0.005). Following completion of the 1-year intervention study, weight stabilization (within 1 kg) was observed at a 6-month surveillance in 8/9 patients who attained goal weight and continued metformin without additional nutritional counseling, in contrast to weight gain (>or=4 kg or 50% of lost weight) in 5/6 patients who discontinued metformin. The authors concluded that metformin and carbohydrate-modified hypocaloric diet could be an effective novel treatment for long-term weight management in nondiabetic, hyperinsulinemic women.

Ovarian follicular fluid β-endorphin levels in normal and polycystic ovaries

Abstract The possibility of local ovarian production of β-endorphin prompted us to measure β-endorphin levels in 19 follicular fluid samples obtained from normal ovaries and compare them with β-endorphin plasma levels in 19 women with normal ovulation. β-endorphin was extracted through Sepharose-treated chromatography columns and assayed with a specific anti-β-endorphin antibody. Follicular fluid β-endorphin levels (21.3 ± 10.8 pg/ml) were significantly higher (p 1 cm in size contained more β-endorphin than follicles