Anthony G. H. Smals

Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years.

Premenopausal women develop occlusive artery disease less frequently than postmenopausal women. In coronary heart disease, higher blood levels of homocysteine-cysteine mixed disulphide have been reported. Therefore, in healthy subjects, we studied the role of menopausal status in the transsulphuration of methionine in 10 premenopausal and 10 postmenopausal women. To exclude the role of aging, we compared these results with those in 10 younger and 10 older men of comparable age groups. An oral methionine load (0.1 g/kg of body weight) was administered after overnight fasting. Before and during 8 h, thereafter, serum levels of methionine, homocystine, and homocysteine-cysteine mixed disulphide were measured. In the fasting state, serum methionine levels were similar in the premenopausal women and both groups of men. Postmenopausal women had significantly lower fasting levels. Peak levels and clearances of methionine after loading did not differ between the groups. In the fasting state, homocystine was never detectable; yet, after methionine loading, slight homocystinemia was present in 12 out of 20 men, and was more pronounced in all postmenopausal women. However, homocystinemia did not occur in any of the premenopausal women after loading. Fasting serum homocysteine-cysteine mixed disulphide levels did not differ between both groups of men and postmenopausal women. In premenopausal women, both fasting and postloading disulphide levels were significantly lower than in any other group. We conclude that premenopausal women have a unique efficiency of methionine handling, and thereby are preserved against the accumulation of homocysteine after methionine loading. We speculate that this phenomenon might account for the lower incidence of vascular disease in women in the reproductive life cycle.

Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts

SummaryPrevious data on tentative identification of the carrier state for homocystinuria due to cystathionine synthase deficiency using methionine loading or measurement of cystathionine synthase activity in tissue extracts are conflicting. We studied the results of standardized oral methionine loading in 20 obligate heterozygotes and compared them with those of determination of cystathionine synthase activity in cultured fibroblasts. Special attention was devoted to our recently reported observation on the small but striking differences in methionine metabolism between healthy pre- and postmenopausal women and men. Fasting and after load peak levels of methionine in serum did not discriminate the carriers from the control subjects. The mean fasting level of total homocysteine was only significantly higher in the group of premenopausal heterozygotes than in the corresponding control group. Nevertheless, the individual values overlapped with the normal range in 4 of 12 premenopausal heterozygotes. After loading peak levels of total homocysteine in 18 out of the 20 obligate heterozygotes exceeded the upper limit of the ranges in the three control groups. Thus, this parameter discriminated 90% of the obligate carriers. Measurement of cystathionine synthase activity in cultured fibroblasts from a skin biopsy identified the obligate heterozygotes to a similar degree (85%). No significant correlation between the measurements of cystathionine synthase activity and the after load peak levels of total homocysteine in the individual heterozygotes was established. Combination of both methionine loading and determination of cystathionine synthase activity in cultured fibroblasts identified all of these carriers.

Transition from Pituitary-Dependent to Adrenal-Dependent Cushing's Syndrome

PITUITARY-DEPENDENT bilateral adrenocortical hyperplasia (Cushings disease) is present in 70 to 80 percent of all patients with Cushings syndrome. In 20 to 40 percent of patients with Cushings d...

Concordance and discordance of estrogen and progesterone receptor content in sequential biopsies of patients with advanced breast cancer: Relation to survival

In 75 patients with advanced breast cancer, sequential biopsies were analyzed for estrogen receptor (ER). In 50 of these patients progesterone receptor (PgR) was also measured. All pairs of biopsies met the following criteria: (i) interval between the two biopsies: at least 6 weeks; (ii) biopsies performed at least 6 weeks after stopping endocrine therapy; and (iii) concordant histology. Discordance in ER was found in 14 of 75 patients (18.7%); PgR was discordant in 14 of 50 patients (28.0%). No significant differences were found between concordant and discordant groups of patients in age at first diagnosis, menopausal state, diameter of the primary tumor, time interval between the two biopsies and intervening therapy. The initial ER level in patients whose ER changed from positive to negative was significantly lower than in patients whose ER remained positive. PgR levels exhibited a rise only when ER rose at the same time. Sequential assays have increased the prognostic significance of ER and as a consequence the estimated survival time for patients whose tumors were ER-negative in both biopsies was significantly shorter than for patients whose tumors were ER-negative in only one of the two biopsies. We found no prognostic significance for PgR in either single measurements or repeated biopsies.

The HMG-CoA reductase inhibitor simvastatin suppresses human testicular testosterone synthesis in vitro by a selective inhibitory effect on 17-ketosteroid-oxidoreductase enzyme activity

In concentrations probably exceeding those achieved in vivo, the cholesterol lowering compound simvastatin was found to suppress the synthesis of the androgens androstenediol and testosterone in vitro by human testicular homogenates. It was demonstrated that simvastatin in addition to its known inhibitory effect on HMG-CoA reductase activity, also affects the later steps of testicular steroidogenesis by selectively inhibiting the 17-ketosteroid-oxidoreductase catalyzed conversion of dehydroepiandrosterone and androstenedione to androstenediol and testosterone respectively. There was no effect of simvastatin on the Cytochrome P-450-dependent microsomal enzymes. Although in doses conventionally used in the treatment of hypercholesterolemia, simvastatin does not affect testicular steroidogenesis, at higher doses--especially when inadvertently administered during early pregnancy--adverse effects on normal testosterone biosynthesis and thereby fetal development should be considered.

Pyridoxine treatment does not prevent homocystinemia after methionine loading in adult homocystinuria patients

Fasting homocystinemia in homocystinuria due to cystathionine synthase deficiency reportedly disappears on high-dose pyridoxine treatment. This does not necessarily reflect normal tolerance to methionine. The present study compares the effects of oral methionine loading on homocystine, cystine, and homocysteine-cysteine disulphide profiles in 8 adult homozygous homocystinuria patients on and off pyridoxine treatment and in 20 controls. Pyridoxine nearly normalized fasting serum amino acid levels. Nevertheless, with a similar methionine load the patients homocystine levels on and off treatment rose and the cystine levels decreased, reflecting the ongoing formation of the homocysteine-cysteine disulphide in the presence of impaired transsulphuration of homocysteine. In the controls homocystinemia remained virtually absent and cystine transiently rose which indicates normal transsulphuration. On treatment methionine loading evoked a brisk rise of the homocysteine-cysteine disulphide levels to values equal to those off treatment, when these levels virtually plateaued after the load. Thus, pyridoxine treatment attenuates the biochemical abnormalities in the fasting patients but leaves their impaired capacity to handle major methionine loads essentially unchanged.

Poikilothermia in man : Pathophysiology and clinical implications

Poikilothermia, the inability to maintain a constant core temperature independent of ambient temperature, markedly influences both the mental and physical function of affected patients; furthermore, prolonged hypothermia can induce numerous complications. To establish the pathophysiology of thermoregulation underlying poikilothermia in man, we compared 4 women with acquired poikilothermia, with 9 female control subjects. The activity of the main thermoregulatory effector mechanisms was assessed in a thermoneutral environment, and during subsequent cold stress and heat exposure. At thermoneutrality the patients had a significantly lower rectal temperature and resting metabolic rate compared with the controls; no patient showed peripheral vasoconstriction or shivering. Cooling revealed markedly reduced peripheral vasoconstriction in 3 patients and failure of the metabolic response in 2 patients; unlike controls, no patient exhibited shivering. Heat challenge revealed severely reduced capacity for heat dissipation in all patients. We conclude that in patients with poikilothermia, the mechanisms for both heat conservation and heat dissipation are seriously attenuated. Careful monitoring of the core temperature and adequate measures to maintain normothermia are of great importance in patients with poikilothermia in order to provide adequate treatment, improve the quality of life, and prevent serious complications.

Spironolactone and amiloride in hypertensive patients with and without aldosterone excess

The antihypertensive action of spironolactone has been ascribed to both a nonspecific diuretic and a specific antimineralocorticoid effect. To better evaluate the relative importance of these effects, we compared its effects with the mineralocorticoid‐independent drug amiloride. Spironolactone (400 mg/day) and amiloride (40 mg/day) were given to 10 patients with essential hypertension (EH) and to 10 patients with hypertension and supranormal aldosterone secretion (SNA). After 6 wk, blood pressure responded better to spironolactone (−20.5%) than to amiloride (− 10.4%) in patients with SNA, but the response was similar in patients with EH (−7.4% and −6.5%). The decrease in body weight—as a measure of volume depletion—was greater after spironolactone (−4.6%) than after amiloride both in patients with SNA (−4.6% and −0.8%) and in patients with EH (−3.7% and −0.6%). After both drugs, plasma sodium decreased (−3.4% and −2.6%) and plasma potassium increased (+37.2% and +32.6%) to the same extent in patients with SNA, reflecting a similar degree of antimineralocorticoid‐like activity. After spironolactone patients with SNA showed a greater rise in PRA than after amiloride (412% and 82%). Despite the greater rise in PRA, the rise in aldosterone excretion was in the same range after both drugs (113% and 195%), pointing to inappropriately low aldosterone excretion after treatment with spironolactone. We conclude that differences in volume depletion or antimineralocorticoid‐like activity cannot explain the better response in blood pressure of patients with SNA after spironolactone than after amiloride. Our data provide evidence for a specific antialdosterone effect of spironolactone in lowering the blood pressure, especially in patients with aldosterone excess.

Effect of Chronic Aromatase Inhibition by Δ1 ‐Testolactone on Pituitary‐Gonadal Function in Oligozoospermic Men

Summary:u2002 Aromatase inhibition by Δ1 ‐testolactone (Teslac®, 500 mg twice daily) for 6 months in 9 patients with idiopathic oligozoospermia lowered the levels of serum estradiol (E2) and thereby sex hormone binding globulin (SHBG) (rs= +0.40, p < 0.025) to values ‐35 and ‐25%, respectively, below the pretreatment values (P < 0.001 and < 0.005). The E2 decrease was accompanied by a temporary increase (+50%) in the levels of follicle stimulating hormone (FSH), not of luteinizing hormone (LH), and of 17 α‐hydroxyprogesterone (17α‐OHP), but less of testosterone (T) (+30%), which led to a transient rise in the 17α‐OHP/T ratio. The T/E2 ratio and “free T” index (T/SHBG) almost doubled until the end of the treatment period. During Δ1 ‐testolactone treatment the mean sperm density gradually rose from 8.1 ±1.3 (SEM) before to 21.3 ± 6.7 times 106/ml after 6 months (P < 0.01), whereas the total sperm count almost threefold increased (P < 0.05). Sperm concentrations exceeding 20 times 106/ml were achieved in 4 of the 9 patients. Two of these patients wives became pregnant. Although the data point to a pivotal role of estrogens in the pathogenesis of the spermatogenic lesion in some patients with idiopathic oligozoospermia, the lack of a benificial effect of estrogen lowering in others points to a multicausal nature of the disease entity.

Effect of lower versus higher doses of tamoxifen on pituitary-gonadal function and sperm indices in oligozoospermic men

Summary:u2002 Administration of the antiestrogen tamoxifen for one month to 12 patients with idiopathic oligozoospermia significantly increased the mean basal testosterone (T) level and the responses of luteinizing hormone (LH) and follicle stimulating hormone (FSH) to constant luteinizing hormone releasing hormone (LHRH) infusion but did not significantly influence the mean oestradiol (E2) levels or the E2 over testosterone ratio. Mean sperm concentration and total sperm output increased by about 70% after a mean treatment period of 5.5 ± 0.4 months. No statistically significant difference was found between the two subgroups of patients treated with either the lower (5 or 10 mg once daily) or higher dose of tamoxifen (10 mg twice daily) with respect to basal or LHRH stimulated gonadotropin and testosterone response or the E2/T ratio and the effect on sperm density and total sperm output. In both subgrounps the sperm motility and morphology remained unchanged.