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An acute injection of estradiol is known to cause a rapid redistribution of estrogen receptors in responsive cells, measurable as depletion of the cytosol receptor content with accompanying accumulation in the nucleus. We have examined the effects of progesterone on this process in the anterior pituitary and hypothalamus using an animal model in which sensitivity to steroidal feedback control of gonadotropin secretion has been defined. Ovariectomized immature rats were administered low dose estrogen replacement for 4 days. On the morning of the fifth day, groups of animals were injected according to one of the following protocols: 1) vehicle alone; 2) 5 or 10 micrograms estradiol; and 3) 0.8 or 3.2 mg progesterone, followed 1 h later by vehicle or 5 or 10 micrograms estradiol. All animals were killed 1 h after estradiol (or vehicle) injection, and levels of cytosol and nuclear estrogen receptors were measured. The only change occasioned by progesterone treatment was a decrease in anterior pituitary nuclear estrogen receptor levels. At the 5-microgram dose of estradiol, 0.8 and 3.2 mg progesterone were equally effective in diminishing nuclear estrogen receptor binding. When 10 micrograms estradiol were used to cause receptor redistribution, only the higher 3.2-mg dose of progesterone significantly depressed nuclear receptor binding. If ovariectomized animals were maintained in the absence of estrogen replacement, progesterone at either the 0.8- or 3.2-mg dosage was completely ineffective in altering the patterns of estradiol-induced cytosol or nuclear estrogen receptor levels. The results demonstrate a tissue-specific inhibitory action of progesterone on estrogen-induced enhancement of nuclear estrogen receptor binding. This inhibition can be partially overcome by increasing the level of estrogen used to effect receptor redistribution. The requirement for maintenance of a background level of estrogen suggests that the inhibitory action of progesterone is mediated through progesterone receptor interactions.

Two adults were seen with cirrhosis caused by different lipid storage diseases. A 42-yr-old woman with Niemann-Pick disease type B had marked hepatomegaly, ascites and recent variceal bleeding. Her evaluation showed chronic bilateral pulmonary infiltrates, multiple stigmata of chronic liver disease including the recent cessation of menses, diuretic-resistant sterile ascites, hepatic encephalopathy and variceal bleeding. Five percent of normal sphingomyelinase activity was measured in peripheral leukocytes. A 42-yr-old man with Gaucher's disease and a history of bilateral hip replacements presented with hepatomegaly, jaundice, refractory ascites and renal insufficiency. His evaluation showed 20% to 23% of normal glucocerebrosidase activity in peripheral leukocytes. Both patients underwent orthotopic liver transplantation with resolution of all aspects of decompensated liver function. Assessment of the underlying metabolic defect before and 6 to 14 mo after transplantation showed that after transplantation the patient with Niemann-Pick disease had above normal hepatic sphingomyelinase activity, a less-marked increase in peripheral leukocyte enzyme activity and lower than normal hepatic sphingomyelin and cholesterol content. In contrast, the patient with Gaucher's disease had only a 61% increase in hepatic glucocerebrosidase activity but had an elevated hepatic glucocerebroside content that was only 15% of the pretransplant level and decreased peripheral leukocyte enzyme levels. These findings suggest that variable relationships may exist between posttransplant hepatic and peripheral leukocyte enzyme activities in the different lipidoses, which may have implications for recurrence of glycolipid-induced liver damage.

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