Further studies on the inhibition of Leydig cell testosterone production by cannabinoids.
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Biomedical subjects
Publications and source records attributed to S Burstein.
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Of fourteen boys with microphallus who were studied consecutively, nine had hypopituitarism that might otherwise have not been recognised. All fourteen were treated with low-dose, intramuscular testosterone enanthate administered in one or two 3-month courses. In each case, penile size was increased into the normal range without evoking either a significant increase in height velocity or an advancement of skeletal maturation. Before considering surgical sex reversal in infants and young children with microphallus, it is essential to assess whether treatment with intramuscular testosterone will induce clinically significant growth of the microphallus.
This study examined the relationship involving children's level of anxiety, defensiveness, and play patterns 1 week prior to, during, and 1 week after hospitalization for minor surgery. A 7-month follow-up was also conducted in order to assess the children's recall for hospital events and coping style. The results suggested that two classes of children could be identified. The children in one group distinguished themselves in terms of their disposition to engage in the "work of worrying" (i.e., were low defensive prior to hospitalization, actively played with stress-related toys prior to hospitalization, and reported minimal distress and anxiety following surgery). Those in the second group were highly defensive, avoided playing with stress-related toys, and reported most anxiety following surgery. The parallel between children and adults patterns of dealing with surgery was considered in terms of Janis's (1978) model of coping with psychological stress.
The recombinant resulting from the noncovalent interaction of a natural amino-terminal fragment of reduced and carbamoylmethylated human GH (residues 1-134) with a synthetic carboxyl-terminal fragment of reduced and carbamoyl-methylated human GH (residues 141-191) reacts in seven immunoassay systems and two receptor assay systems in a similar manner and with comparable potency to its naturally occurring analog, but with less avidity overall than does the native hormone. This similarity of reactivity is strong evidence for similarity of conformation among these molecules. The demonstration that a synthetic fragment can restore radioligand-binding properties to a proteolytic fragment of human GH implies that partially synthetic variant GH molecules have biological activity.
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Progesterone production by isolated rat luteal cells was inhibited by exposure to various cannabinoids in concentrations from 3.0--16.0 microM. The available evidence points to the cleavage of cholesterol esters as the site of inhibition.
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The behavior in six radioligand assays of the recombinant obtained by the noncovalent complementation of the reduced and carbamoylmethylated 134-residue amino-terminal fragment of human growth hormore with the reduced and carbamoylmethylated 51-residue carboxyl-terminal fragment of human chorionic somatomammotropin was compared to that of the analogous recombinant of the 133-residue amino-terminal fragment of human chorionic somatomammotropin and the 51-residue carboxyl-terminal fragment of human growth hormone. The determinants for the hepatic growth hormone receptor binding and for the lactogenic receptor binding of human growth hormone are on the amino-terminal fragments. The antigenic determinants for both a monospecific antiserum to human growth hormone and a monospecific antiserum to human chorionic somatomammotropin also are on the amino-terminal fragments of their respective antigens. The mixed recombinant of the amino-terminal fragment of human growth hormone with the carboxyl-terminal fragment of human chorionic somatomammotropin retains full radioimmuno- and radioreceptor activity after lyophilization.
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Addition of delta-9-tetrahydrocannabinol or cannabinol to an incubation medium containing decapsulated mouse testes caused a significant reduction in the accumulation of testosterone in the medium. This result suggests that the reported effects of cannabis on male sexual and reproductive function may result from direct inhibition of testicular steroidogenesis by both psychoactive and nonpsychoactive constituents of marihuana.
Incubation of lanosta-8, 24-dien-3beta-o1-1,2-3H and lanost-8-en-3beta-o1-1,2-3H with an adrenocortical bovine mitochondrial acetone-dried preparation did not yield any significant (less than 0.01%) 3beta-hydroxy-4, 4, 14-trimethyl-5alpha-pregn-8-en-20-one. Under the same conditions cholesterol-1,2-3H yielded 8.3% pregnenolone. Incubation of (20S)-17alpha, 20-di-hydroxycholesterol-7-3H yielded 0.6 to 1.6% (20S,22R)-17alpha, 20, 22-trihydroxycholesterol, 1.0 to 3.2% of 17alpha-hydroxy-pregnenolone, but no significant (less than 0.02%) (20S,22S)-17alpha,20,22-trihydroxycholesterol. In another experiment incubation of cholesterol-1,2-3H yielded 5% pregnenolone, 0.5% 17alpha-hydroxypregnenolone, 0.2% (20R,22R)-20,22-dihydroxy-cholesterol, but no significant ( less than 0.01%) 17alpha-hydroxy-cholesterol, (20S)-17alpha, 20-dihydroxycholesterol or (20S,22R)-17alpha, 20,22-trihydroxycholesterol.
Arachidonic acid causes a sharp transient increase in cyclic AMP levels in primary epithelial cell cultures obtained from C3H mouse mammary tumors. The effect is evident within two minutes and is enhanced by theophylline or 3-isobutyl-1-methylxanthine. Maximum increase in cyclic AMP levels are observed with a dose of 100 mug/ml of arachidonic acid (AA). At higher dose levels the increase in cyclic AMP levels is reduced. Naproxen, an inhibitor of prostaglandin synthesis in this system markedly reduces the stimulation of cyclic AMP by arachidonic acid but it does not affect the increase in cyclic AMP levels observed after the addition of prostaglandin E's, epinephrine or cholera enterotoxin. Arachidonic acid, under the same conditions, also causes a significant elevation of PGE and PGF media levels which is slower and more sustained than the cAMP response. The data strongly suggest that a metabolic of arachidonic acid is responsible for the cyclic rise, however, it is not certain whether this is due to PGE2 or some other product.
Antibodies with specificity for an experimental ovarian carcinoma were coupled to methotrexate by two procedures. Water-soluble carbodiimide gave effective coupling, but a large proportion of the conjugate was rendered insoluble, presumably due to alteration or aggregation of the antibodies. A modification of the mixed anhydride procedure gave rise to products which were completely soluble and allowed a high degree of coupling to be achieved. In vivo testing of the conjugates revealed a significant increase in survival time in treated mice when compared to a variety of control groups; these included groups receiving antiserum or drug alone, mixtures of the two, and conjugates of normal gamma-globulin with methotrexate. Our results provide added support for the concept that tumor-associated antibodies coupled to cytotoxic agents are more effective than single agents or noncoupled mixtures of agents.
7 alpha-Hydroxycholesterol, (22R)-22-hydroxycholesterol and 26-hydroxycholesterol have been quantitated in human meconium. The method used tetrahydrofuran for extraction and solvolysis of the sulfate esters, liquid partition chromatography for the separation of the hydroxysterols, gas-liquid chromatography for quantitation, gas-liquid chromatography-mass spectrometry for identification, and tritiated and 14C-labeled tracers for overall recovery standards. (22R)-22-Hydroxycholesterol and 26-hydroxycholesterol were present almost entirely, ( greater than 93%) in the sulfate fraction at concentrations of 3.8-6.4 and 0.4-0.8 mg per 100 g meconium, respectively. Since free tritiated (22R)-22-hydroxycholesterol was used as the tracer to assess recovery of this hydroxysterol, the concentrations found for this compound may be minimal. Tritiated 26-hydroxycholesterol 3,26-disulfate was used as tracer to determine the levels of this compound, and the solvolysis procedure was optimized for recovery of 26-hydroxycholesterol and least decomposition of 7 alpha-hydroxycholesterol. No significant amounts of 7 alpha-hydroxycholesterol were found based on the tracer-free hydroxysterol as recovery standard.
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The inhibition of the conversion of [4-14C] cholesterol to [4-14C] pregnenolone by a number of steroids has been studied in bovine adrenocortical mitochondrial acetonedried preparations. At equimolar substrate and inhibitor concentrations (3.3 muM) the most potent inhibitors were cholesterol derivatives containing a nitrogen function at c-22, followed by derivatives containing oxygen functions at c-22 or c-20 or both. The presence of a hydroxyl group at c-17 or the replacement of the 3beta-hydroxyl group by fluorine reduced the inhibitory efficacy. In the presence of inhibitors that were also relatively good substrates of the cholesterol side-chain cleavage system, such as some cholesterol derivatives hydroxylated in the side-chain,the rate of [4-14C] pregnenolone formation increased with time as the inhibitor was consumed. (20S)-20,21-Dihydroxycholesterol exerted such an effect on the kinetics of [4-14C]pregnenolone formation, and yielded 21-hydroxypregnenolone which was identified by gas chromatography-mass spectrometry. The synthesis of (20R)-22-ketocholesterol, of (20R,22R)-22hydroxycholesterol, (20R,22S)-hydroxycholesterol, and of (20S)-desmosterol is described.