Contraceptive activity of combinations of steroids and antiadrenergic preparations]

Experiments were conducted on mature female rats. Simultaneous administration through a tube for 14 days, daily, of mestranol (0.04 mg/kg) and megestrol acetate (0.8 mg/kg) gave no significant contraceptive effect, whereas the use of steroid preparations in the same doses in combination with antiadrenergic substances--dopegit (100 mg/kg) or pyrroxan (10 mg/kg) prevented pregnancy effectively.     

Contraceptive steroids alter the steady-state kinetics of bile acids

Contraceptive steroids increase the ratio of cholic acid to chenodeoxycholic acid in bile. This alteration may contribute to the development of cholesterol gallstones. The objective of this study was to measure the effects of contraceptive steroids on bile acid kinetics and to relate them to changes in cholesterol metabolism. Steady-state kinetics of bile acids were measured in 15 healthy women, on and off contraceptive steroids. Cholic acid synthesis increased 30.3% (P less than 0.025) and its pool increased by 37.4% (P less than 0.025). Chenodeoxycholic acid synthesis decreased 6.4% (P = 0.08) and its pool decreased by 11.8% (P less than 0.05) during use of contraceptive steroids. The fractional turnover rates of both primary bile acids did not change. The changes in kinetics of the primary bile acids were related to alterations in biliary lipid and cholesterol metabolism, separately reported. (J. Lipid Res. 1987. 28: 828-839). During use of contraceptive steroids, total bile acid pool and total bile acid synthesis correlated directly with cholesterol synthesis, assayed in mononuclear leukocytes (r = 0.50 and r = 0.54, respectively) but not with the plasma clearance of chylomicron remnants, measured with retinyl palmitate. The data indicate that contraceptive steroids directly alter the hepatic synthesis of bile acids and suggest that newly synthesized cholesterol may be a preferred substrate for bile acid synthesis during use of contraceptive steroids.     

Contraceptive steroids increase cholesterol in bile: mechanisms of action

Contraceptive steroids increase the risk of acquiring cholesterol gallstones. The factors responsible include an increase in cholesterol saturation of bile and an increase in rate of secretion of cholesterol into bile. The goal of this study was to investigate the mechanism(s) of these increases in biliary cholesterol. During the use of contraceptive steroids, cholesterol saturation of gallbladder bile and the amount of cholesterol secreted per mole of bile acid increased (P less than 0.05 and P less than 0.02, respectively). Cholesterol absorption, cholesterol synthesis, chylomicron remnant clearance, and the concentration of plasma and lipoprotein lipids were not altered by contraceptive steroids. Despite this apparent lack of effect, important correlations were present during steroid use. LDL (low density lipoprotein) cholesterol increased as dietary cholesterol increased (r = 0.58, P less than 0.025). Cholesterol synthesis correlated directly with VLDL cholesterol concentration (r = 0.64, P less than 0.01), biliary cholesterol secretion (r = 0.68, P less than 0.01) and with molar percent cholesterol in bile (r = 0.49, P = 0.06). Chylomicron remnant clearance also correlated with cholesterol secretion (r = 0.85, P less than 0.001). As either remnant uptake or synthesis increased, the effect of the other source of hepatic cholesterol on biliary cholesterol secretion diminished. These relationships were not observed in the same subjects when they were not taking the hormones. The findings suggest that both newly synthesized and dietary cholesterol contribute to the cholesterol secreted in bile. This is consistent with the hypothesis that cholesterol for secretion into bile and VLDL is derived from a common metabolic pool of free cholesterol. It is proposed that contraceptive steroids exert their effect on biliary cholesterol by increasing cholesterol entering the pool and/or by inhibiting hepatic ACAT (acylcoenzyme A:cholesterol acyltransferase) activity, a known effect of progesterone, so that an increase in free cholesterol entering the pool leads to an increase in output.     

Endogenous cardiotonic steroids and salt-sensitive hypertension

Endogenous cardiotonic steroids (CTS), also called digitalis like factors, have been postulated to play important roles in pathogenesis of hypertension for nearly half of a century. For the past 50 years biomedical scientists have been in quest of an unidentified factor or hormone that both increases blood pressure and renal sodium excretion; this “natriuretic hormone” was, in fact, postulated to interact with the Na/K-ATPase. Recent discoveries have led to the identification of steroid molecules which are present in humans, rodents and amphibians, and which, in a complex manner, interact with each other and with the other systems that regulate renal salt handling and contribute to the salt-sensitivity of blood pressure.Recent findings include the specific identification of endogenous cardenolide (endogenous ouabain) and bufadienolide (marinobufagenin) CTS in humans along with the delineation of mechanisms by which CTS can signal through the Na/K-ATPase. Although CTS were first considered important in the regulation of renal sodium transport and arterial pressure, more recent work implicates these hormones in the central regulation of blood pressure and regulation of cell growth, and development of cardiovascular and renal fibrosis in particular.     

Contraceptive steroids from pharmaceutical waste perturbate junctional communication in Sertoli cells

The potential health impact of pharmaceutical waste is now a growing concern. Contraceptive steroids are prominent environmental contaminants and thus may act as endocrine disruptors. Numerous xenobiotics hamper Sertoli cells junctional communication which is known to participate in spermatogenesis control. This has been associated with male subfertility and testicular cancer. We investigated three contraceptive molecules found in the environment for their potential impact on Sertoli cells gap junction functionality: 17a-ethynylestradiol, medroxyprogesterone acetate and levonorgestrel. Four other non-steroid drugs also found in the environment were included in the study. Communication disruption was analyzed in vitro in murine seminiferous tubules and the 42GPA9 Sertoli cell line. Steroids modulated connexin43 trafficking and impaired junctional communication through rapid effects apparently acting on the cell membrane but not on Cx43 expression. The 4 non-steroid compounds showed no effect. Longer exposure to steroids increased gap junction impairment, which was associated in part with Na/K ATPase internalization. Estrogen receptors (ER) did not appear to be involved in gap junction disruption: Sertoli cells are devoid of ERα and only express the cytoplasmic β isoform. ERβ localization was not modified by either steroid. The threshold level was surprisingly low, around 10^?16 M. We conclude that steroidal pollutants disrupt Sertoli cells junctional communication in vitro at concentrations that can be found in the environment.     

Contraceptive steroids increase hepatic uptake of chylomicron remnants in healthy young women

In an investigation of alterations in cholesterol metabolism during contraceptive steroid use, we studied plasma clearance of chylomicron remnants. Six healthy women were studied on and off contraceptive steroid therapy. Remnant clearance was measured from the disappearance of retinyl palmitate administered intravenously in plasma endogenously labeled with retinyl palmitate. We also measured cholesterol in HDL and its subfractions and postheparin lipoprotein lipase and hepatic triglyceride lipase activities. Plasma decay of retinyl palmitate was biexponential. The rapid component, reflecting chylomicron remnant removal, accounted for about 90% of the total clearance in all studies. During contraceptive steroid intake, both rapid and slow decay constants and the calculated plasma clearance rates were significantly increased (mean values: rapid decay constant, control 0.048 versus treated 0.101 min-1, P less than 0.05; slow decay constant, 0.004 versus 0.014 min-1, P less than 0.01; plasma clearance 74 versus 115 ml/min, P less than 0.025) indicating enhanced hepatic uptake of chylomicron remnants and probably an increased hepatic uptake of higher density lipoproteins (d greater than 1.006 g/ml). Total postheparin lipolytic activity and lipoprotein lipase activity were depressed in all six women (P less than 0.05) and hepatic triglyceride lipase activity was increased in four of five subjects. Contraceptive steroids also caused a decrease in the HDL2/HDL3 cholesterol ratio (P less than 0.05), implying impaired peripheral lipoprotein triglyceride hydrolysis and/or increased HDL2 clearance by hepatic triglyceride lipase. In conclusion, during intake of contraceptive steroids, the plasma clearance of chylomicron remnants and higher density lipoproteins was increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sex steroids and vascular responses in hypertension and aging

Background: Sex hormones play a significant role in human physiology. Estrogen may have protective effects in the cardiovascular system, as evidenced by the decreased incidence of cardiovascular disease (CVD) in premenopausal compared with postmenopausal women.Objective: This review highlights the acute and long-term effects of sex hormones on the vascular endothelium and vascular smooth muscle (VSM) in adults. Changes in the sex hormone mix, their receptors, and their effects on vascular function in hypertension and aging are also discussed.Methods: Literature collected from the National Centers for Biotechnology Information as identified by a PubMed database search, as well as our experimental work, was used to highlight current knowledge regarding vascular responses to sex hormones in hypertension and in aging.Results: Experiments in adult female animals have shown that estrogen induces endothelium-dependent vascular relaxation via the nitric oxide (NO), prostacyclin, and hyperpolarization pathways. Also, surface membrane estrogen receptors (ERs) decrease intracellular free Ca²⁺ concentration and perhaps protein kinase C-dependent VSM contraction. However, clinical trials such as the Heart and Estrogen/progestin Replacement Study (HERS), HERS-II, and the Women's Health Initiative did not support the experimental findings and demonstrated adverse cardiovascular events of hormone therapy (HT) in aging women. The lack of vascular benefits of HT may be related to the hormone used, the ER, or the patient's cardiovascular condition or age. Experiments on vascular strips from aging (16-month-old) female spontaneously hypertensive rats have shown reduced ER-mediated NO production from endothelial cells and decreased inhibitory effects of estrogen on Ca²⁺ entry mechanisms of VSM contraction. The age-related decrease in ER-mediated vascular relaxation may explain the decreased effectiveness of HT on CVD in aging women.Conclusions: New HT strategies should further examine the benefits of natural estrogens and phytoestrogens. Transdermal estrogen may be more effective than the oral form, and specific ER modulators may maximize the vascular benefits and reduce the risk of invasive breast cancer. Variants of vascular ERs should be screened for genetic polymorphisms and postmenopausal decrease in the amount of downstream signaling mechanisms. HT may be more effective during the menopausal transition than in late menopause. Progesterone, testosterone, or their specific modulators may be combined with estrogen to provide alternative HT strategies. Thus, HT type, dose, route of administration, and timing should be customized, depending on the patient's cardiovascular condition and age, thereby enhancing the vascular benefits of HT in aging women.     

Effects of ACTH on plasma levels of adrenal steroids in essential hypertension.

Plasma concentrations of progesterone (P), deoxycorticosterone (DOC), 17-hydroxyprogesterone (17-OH P), corticosterone (B), deoxycortisol (S), cortisol (F) and aldosterone (A) in 8 control subjects (mean age: 40.5 years) and 10 patients with essential hypertension (EH) (mean age: 48.5 years) were determined before, 4 and 8 hours after an infusion of ACTH at a rate of 25 units per 8 hours. Secretion rates (SR) of 18-hydroxy-11-deoxycorticosterone (18-OH DOC) were measured 24 hours before and again on the day of ACTH infusion. All subjects were studied on the fourth day of a diet containing 135 mEq of sodium and 90 mEq of potassium. There was no statistically significant difference between 8 control subjects and 10 patients with EH in the 7 plasma steroid levels and the SR of 18-OH DOC before ACTH infusion. The mean plasma P response to ACTH was slightly lower in controls than in patients with EH, while that of 17-OH P (in male subjects) was slightly higher. The mean plasma B response was significantly lower after 4 hours of ACTH infusion (p less than 0.01), while that of DOC was significantly higher after 8 hours of ACTH infusion (p less than 0.05) in patients with EH. The mean plasma S rose significantly more in patients with EH (p less than 0.025) at 4 and 8 hours after ACTH infusion. The mean plasma F response to ACTH infusion was slightly lower in patients with EH than in controls. The mean response of 18-OH DOC SR to ACTH infusion was slightly higher in patients with EH than in controls. The mean plasma A response was significantly higher in patients with EH than in controls 4 (p less than 0.05) and 8 hour (p less than 0.001) after an ACTH infusion. These results could be explained in part by abnormalities in the 17- and 11-hydroxylase systems, and that the abnormality in 11-hydroxylation was more pronounced than that in the 17-position. Furthermore, we suspect that the sensitivity of adrenal aldosterone to ACTH might be increased or another accelerated pathway to aldosterone biosynthesis might exist in patients with EH.     

Abnormalities of sodium pump function in hypertension and the role of endogenous cardiotonic steroids.

Elevated arterial blood pressure is a common heritable susceptibility in the human population. The high penetrance of this trait in industrialized societies may be influenced by the interactions of environmental factors and common genetic variants. This review examines the role of the renal sodium pump (sodium, potassium-ATPase, NKA) in hypertension and its integration into mechanisms of body sodium balance. In particular, renal NKA provides an appealing target by which inherited factors caninfluence renal sodium reabsorption. Recent work has indicated how some such genetic mechanisms may function. In this paper, the capacity of renal NKA to integrate environmental and heritable factors to increase blood pressure are examined.     

Response of adrenal steroids to angiotensin II in essential hypertension

The effect of angiotensin II (A II) on the plasma corticosteroid concentration and blood pressure was investigated in five normotensive subjects and 24 patients with essential hypertension (EH). Infusion of A II in normal subjects caused a significant increase in plasma aldosterone and significant decreases in plasma renin activity (PRA), plasma cortisol and dehydroepiandrosterone-sulfate (DHEA-S), while plasma levels of deoxycorticosterone (DOC) and ACTH remained unchanged. In patients with EH, A II infusion caused a significant decrease in PRA and a significant increase in plasma aldosterone. The percent increase in plasma aldosterone was greatest in patients with high PRA when compared to the low and normal PRA groups. The mean plasma levels of cortisol, DOC and DHEA-S after A II infusion were significantly increased in patients with high PRA but no significant changes were observed in patients with low or normal PRA. The mean blood pressure in patients with low PRA was sharply increased during the infusion when compared to the other two groups and did not return to the baseline level after cessation of the infusion. Hepatic blood flow as estimated by the disappearance rate constant of indocyanine green was significantly lower in patients with low PRA than in patients with high PRA. The above results suggest that different responses to A II infusion in steroid biosynthesis may exist between normal subjects and patients with EH. These observed phenomena may be due to biochemical (serum sodium) or functional (plasma A II level) differences in the A II receptor site or to the difference in the metabolic clearance of A II in patients with EH.