Cholesteryl ester hydrolase activity in mononuclear cells from patients with type II hypercholesterolemia.

Cholesteryl ester hydrolase (CEH) activity was measured in freshly isolated mononuclear cells from patients with primary Type II hypercholesterolemia, heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (CFH). CEH activity was significantly lower in mononuclear cells from Type II patients than in cells from matched normolipidemic individuals. Moreover, the reduced CEH activity in cells from the hypercholesterolemic patients was accompanied by significant accumulation of cholesteryl ester. This pattern of reduced CEH activity and cholesteryl ester accumulation was identical for cells from both the FH and CFH patients. Since low density lipoprotein (LDL) cholesterol concentrations were higher in the Type II patients, we incubated mononuclear cells from normolipidemic individuals with high concentrations of LDL-cholesterol (greater than 150 mg/dl). Under these conditions CEH activity was significantly decreased, cholesteryl ester content increased, and cholesterol linoleate, in particular, accumulated. These data suggest that the intracellular accumulation of cholesteryl esters is determined in part by the extracellular concentrations of LDL-cholesterol and by the activity of CEH within the cells.

The effect of oral contraceptives on mononuclear cell cholesteryl ester hydrolase activity.

The influence of sex steroids on mononuclear cell cholesteryl ester hydrolase (CEH) activity in premenopausal women and women on combined estrogen-progestin oral contraceptives has been studied. In addition, plasma and mononuclear cell cholesterol and esters were measured along with plasma estrogen and progesterone levels. Mononuclear cell CEH activity in control women is highest on Day 20 of their menstrual cycle. The control women had significantly higher CEH activities than women on oral contraceptives. Plasma esters were higher in the oral contraceptive group. However, in mononuclear cells, free cholesterol but not cholesteryl esters were higher in women on oral contraceptives.

PIP: Premenopausal women, 1 control group (n=9) taking no medication or using no oral contraceptives (OCs) and 1 treated group (n=10) receiving OCs for contraception, were studied to determine any effects OCs have on mononuclear cell cholesteryl ester hydrolase (CEH) activity. 9 of the 10 medicated women were taking Ortho Novum 1/50 and the other person was receiving Norlestrin 1/50. Normally menstruating women (controls) showed a significant rise in CEH levels on Day 20 of the menstrual cycle (P .05). The enzyme activity in women on OCs was significantly lower than control women in 3 of 4 testing periods. In addition, plasma and mononuclear cell cholesterol and esters were measured along with plasma estrogen and progesterone levels. Although free cholesterol levels in normal cycling (control) women and in the OC group did not vary significantly during the menstrual cycle between the 2 groups, the women on OCs had significantly higher ester levels than the control women in 3 of the 4 test periods P .05-.005). When paired ratios of plasma cholesterol to esterified cholesterol were compared between control and OC groups, the ratio of free/esterified was significantly higher in the control group in 3 of 4 tests. In the mononuclear cells, on the other hand, the cholesterol/cholesteryl ester ratio was significantly lower in the control group during the 4 test periods. No association between levels of endogenous sex hormones (estradiol, progesterone) and CEH activity were found. CEH levels may be related to incidence of atherosclerosis, and women taking OCs may have increased chances of developing this disease.

Effects of indomethacin on corpus luteum function and pregnancy in rhesus monkeys.

Indomethacin was administered during the luteal phase of the menstrual cycle and during late pregnancy in rhesus monkeys. The plasma indomethacin concentrations achieved were within the ranges effective in inhibiting the microsomal prostaglandin synthetase, even when allowances were made for 90% binding to plasma proteins. There were no significant differences in duration of the luteal phase of menses or in luteal phase progesterone concentrations with indomethacin treatment. Our findings do not support the hypothesis that endogenous prostaglandins are important luteolysins in primates. They provide indirect evidence that administration of prostaglandin synthetase inhibitors would have no therapeutic benefit in treatment of the "short luteal phase" syndrome in women. Indomethacin administration in late pregnancy had a significant effect in prolonging gestation. Uteri of treated animals remained flaccid and distended after fundal hysterotomy and removal of fetuses. Maternal plasma concentrations of unconjugated estradiol, estrone, and progesterone during indomethacin treatment were within the expected ranges for late pregnancy in rhesus monkey, although in two animals we found transient, unexplained, high concentrations of estrone in maternal plasma. Chronic indomethacin administration was associated with continuing fetal and placental growth, a 50% fetal mortality rate, oligohydramnios, and meconium staining, and maternal anemia but normal bleeding times. Severe oligohydramnios was noted in preterm as well as post-term fetuses, indicating that indomethacin per se alters regulation of amniotic fluid volume.