Feminization of the alcoholic: the estrogen/testosterone ratio (E/T)
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Biomedical subjects
Publications and source records attributed to R Lester.
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Prolactin responses to provocative thyrotropin releasing hormone (TRH) stimulation were evaluated in 20 cirrhotic men with gynecomastia. Fifteen of these cirrhotic men had normal responses with a minimum doubling of the prolactin concentration above basal in response to TRH. Five had abnormal (autonomous) responses in that they failed to double their basal level or had a paradoxical decrease from basal in response to TRH. Moreover, these same five men failed to have a sleep-related increase in plasma prolactin. Three of them also failed to respond to chlorpromazine stimulation. Such abnormal responses are generally associated with the presence of a prolactin secreting pituitary tumor. Basal plasma levels of prolactin were measured in all 20 men studied. The five men who failed to respond to TRH had significantly greater basal prolactin concentrations (80.5 +/- 18.7 ng/ml) than did the 15 men who responded normally (33.7 +/- 4.3 ng/ml) (p less than 0.01), although all 20 had increased prolactin levels relative to that of controls (10.8 +/- 0.9 ng/ml) (both p less than 0.01).
Reduced plasma levels of testosterone and a high frequency of azoospermia have frequently been reported in alcoholic men. Despite the high grade of gonadal failure present, plasma gonadotropins have ranged from normal to only moderately increased. This has been interpreted as suggesting that a central hypothalamic-pituitary defect also might exist in these men. Clomiphene stimulation studies have been consistent with the hypothesis of a central defect. The present work consists of studies utilizing luteinizing hormone-releasing factor and thyrotropin-releasing factor in an effort to examine the hypothesis of whether this central defect exists and, if so, whether at an anatomic, hypothalamic, or pituitary level.
The effect of ethanol feeding on ovarian function and structure in female rats was studied in alcohol-fed animals, isocalorically fed controls, and two ad libitum-fed control groups. Ovarian weight was reduced by 60% in alcohol-fed animals compared with the control groups. Gross disruption of ovarian architecture was noted, characterized by the absence of any corpus hemorrhagicum and corpus albicans. Moreover, plasma levels of estradiol were significantly reduced in the alcohol-fed animals (P < 0.01) compared with the levels found in isocaloric controls. Plasma levels of estrone and corticosterone were increased in alcoholfed and isocaloric control animals relative to those of ad libitum-fed animals suggesting a primarily adrenal, rather than ovarian, origin for these two steroids. Despite the increase in estrone, the secondary sex organs (uterus and fallopian tubes) reflected marked estrogen deprivation presumably as a result of estradiol insufficiency. Progesterone levels in the alcohol-fed animals were significantly less than levels in the isocaloric and intact ad libitum-fed controls but were not significantly different compared to oophorectomized animals. Plasma follicle-stimulating hormone levels were similar in alcohol-fed, isocaloric controls, and ad libitum-intact controls. They were, however, one-third the level of oophorectomized controls. Both alcohol-fed and isocaloric controls had increased levels of plasma luteinizing hormone, although levels were below those seen in oophorectomized controls (P < 0.01). The results establish that ingestion of a diet containing 5% ethanol for periods as short as 6 wk produces functional and histologic ovarian failure in the female rat.
To characterize the defect in the hypothalamic-pituitary-gonadal axis of alcoholic men, acute and chronic LRF responses were evaluated in 22 chronic alcoholic men with varying degrees of biochemically and histologically confirmed liver disease. In addition, acute LRF responses in 14 normal men, before and at the end of 72 h of administration of 2 ml/kg/day 95% ethanol, were evaluated. The alcoholics hd significantly reduced basal testosterone and elevated gonadotropin levels (both FSH and LH) compared to the normal volunteers (P less than 0.02). Serum concentrations of estradiol and PRL did not differ between alcoholics and normal volunteers. A 100-micrograms bolus of LRF resulted in a 3-fold increase of LH in alcoholic men as compared to a 6-fold increase of serum LH in normal volunteers. No significant difference in the LRF-induced FSH responses was observed. When the response of normal volunteers to LRF before and after ethanol administration was evaluated, basal levels of both gonadotropins were increased after alcohol administration and a reduced LRF-induced LH response was observed. Based upon these results, we conclude that: 1) the central hypothalamic-pituitary defect known to exist for LH secretion is in part due to inadequate pituitary secretion and 2) acute alcohol ingestion in normal men suppresses the LRF-induced LH but not the FSH response.
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Alcoholism affects nine million individuals in the United States according to United States Government estimates. As many as 80% of hard-core alcoholic men show evidences of feminization including impotence, testicular atrophy, sterility, gynecomastia and changes in bodily hair. The causes of feminization of male alcoholics have remained obscure until recently. Largely as a result of advances in the techniques of measurement of sex hormones, it has become possible to begin to examine the pathogenesis of feminization. The results of initial studies suggest that alcoholics become feminized through the secondary effects of alcohol-induced liver disease, and also through primary effects of alcohol on the endocrine system. It can be shown that liver disease permits the peripheral escape of steroid precursors and their conversion to estrogenic substances. These substances are then inadequately cleared by the liver. In addition, however, alcohol alters testicular steroidogenesis and testosteronogenesis. Hypothalamic-pituitary function also is diminished in chronic alcoholics, and this change contributes to the syndrome of feminization.
The effect of ethanol feeding on renal function, gross and microscopic morphology and constituent analysis was determined and compared to similar studies in isocalorically fed animals ingesting the same diet except that dextrimaltose was isocalorically substituted for ethanol. Alcohol-fed animals have significantly reduced renal function (p less than 0.01) and interstitial edema compared to their isocaloric controls. When renal mass and renal constituent analysis were normalized for body weight, alcohol-fed animals were found to have renal hypertrophy characterized by significantly increased absolute amounts of protein (p less than 0.01), fat (p less than 0.01) and water (p less than 0.01). All of these constituents increased in proportion to their percentage of total renal mass in control animals. In contrast, DNA content per kidney was similar for alcohol and isocalorically fed animals.
The effect of ethanol feeding on renal function, gross and microscopic morphology, and constituent content was determined in alcohol-fed rats and compared to similar studies in isocalorically fed animals ingesting the same diet except that dextrimaltose was isocalorically substituted for ethanol. Alcohol-fed animals have significantly reduced renal function and interstitial edema compared to their isocaloric controls. When renal mass and renal constituent analysis were normalized for body weight, alcohol-fed animals were found to have renal hypertrophy characterized by significantly increased absolute amounts of protein (p less than 0.01), fat (p less than 0.01), and water (p less than 0.01). All of these constituents increased in proportion to their percentage of total renal mass in control animals. In contrast, DNA content per kidney was similar for alcohol and isocalorically fed animals.
The intestinal absorption of sodium taurocholate was studied in the near-term fetal and neonatal dog. Absorption rates were measured in vivo in isolated loops of fetal jejunum and ileum. Absorption was also measured in vitro in everted sacs and rings of fetal and neonatal jejunum and ileum. The maximal rates of taurocholate absorption observed after instillation of 1 micronmol taurocholate into closed segments of fetal jejunum and ileum with intact blood supply were not significantly different (P less than 0.2), and equalled 0.282+/-0.026 (mean+/-SEM) and 0.347+/-0.051 micronmol/h per 10-cm segment length jejunum and ileum, respectively. Similarly, the rates of absorption from open segments of jejunum and ileum perfused with 0.4 and 1.0 mM taurocholate were nearly identical (0.232+/-0.040 and 0.255+/-0.039, respectively at 0.4 mM, and 0.470+/-0.065 and 0.431+/-0.013, respectively at 1.0 mm) (P greater than 0.2). At perfusate concentrations of 4.0 mM, moreoever, jejunal absorption exceeded ileal absorption (1.490+/-0.140 and 0.922+/-0.200, respectively (P less than 0.05). As expected, concentration of taurocholate by the mucosa was readily demonstrated in adult ileal, but not in adult jejunal everted rings. In contrast, there were no significant differences in mucosal uptake of taurocholate by fetal jejunal and ileal rings. Fetal ileal mucosal concentrations were not significantly above those in the incubation medium after 1-h exposure of the mucosa to 0.003, 0.03, and 0.3 mM taurocholate. Uptake was proportional to incubation medium concentration over the full range of values. This was also true of tissues from 1-wk-old neonates. However, by 2 wk of age, ileal mucosal concentration of taurocholate was evident and adult levels were attained by 5 wk of age. It is concluded that taurocholate is absorbed by the fetal gut and that ileal absorption is no more efficient than jejunal absorption. Although active glucose transport was demonstrable in both jejunum and ileum, it was not possible to demonstrate an ileal mechanism for active transport of taurocholate in the fetus. Active ileal transport was not demonstrable in the newborn until at least 2 wk after birth.
Three persons in a kindred of 43 had variable expression of a syndrome consisting of immunoglobulin A deficiency, diabetes mellitus, malabsorption, and a common HLA haplotype. Findings from the proband included life-threatening malabsorption; idiopathic intestinal mucosal atrophy with infalmmation; IgA deficiency and antibodies to multiple endocrine organs; insulin-dependent diabetes mellitus; and the major histocomptability antigens HLA-A2, B8, and DW3. In addition to the described syndrome other conditions present in the family include Graves' disease, vitiligo, hypocomplementemia, rheumatic fever, multiple sclerosis, and a high frequency of antibodies to endocrine tissue. Since Graves' disease, diabetes mellitus, and idiopathic Addison's disease have all been described in association with HLS-B8 and DW3, we believe that the occurrence of these diseases in this family suggests that a single immune response gene or gene complex is linked with HLA-B8 and DW3.
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A case of an adult with chronic active hepatitis associated with giant multinucleated liver cells is presented. The giant liver cells in this case are widespread and the picture resembles neonatal hepatitis. The morphology, pathogenesis, and epidemiology of giant hepatocytes found in human neonates and adults and in experimental animals is discussed. Because the proliferative phase of giant hepatic cells is transient, this reaction may be more common than generally believed.
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A new technique has been developed in which mammalian fetal liver can be maintained in organ culture for prolonged periods with intact structure and function. Near-term rat fetal liver explants were incubated in vitro for periods of up to 3 wk with preservation of normal cellular morphology and intercellular (organ) relationships. [14C]cholate was incorporated into tissue and medium conjugates at a constant rate during 21 days in vitro. During a 24-h incubation with radioactively labeled cholic acid, bile acid conjugates accumulated in tissues to a maximum value by 6 h and maintained this value through 24 h. During the same 24-h incubation with [14C]cholate, conjugates were secreted into the medium at a constant rate. Addition of 8 X 10(-4) M taurine to the medium during a 4-day incubation produced a threefold enhancement in the rate of conjugate formation in tissues and medium. Enhanced conjugation in the presence of additional taurine was due almost entirely to increased taurocholate formation and no significant difference was observed in the amount of glycocholate formed. Exposure of explants to 3.6 X 10(-4) M cycloheximide for prolonged periods resulted in inhibition of conjugate formation, but when this concentration of cycloheximide was maintained for only 24 h a significantly (P less than 0.001) increased rate of conjugate formation was observed. The results indicate that metabolic processes in the organ-culture system are in a state of dynamic equilibrium and that morphologic integrity and specific hepatocytic function are maintained after 21 days in vitro. Preferential taurocholate formation was demonstrated in rat fetal liver, and the data suggest that glycine and taurine interact with separate enzymatic systems in bile acid conjugation. The possible mechanisms that mediate the effect of cycloheximide are discussed.