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D L Kleinberg

Publications and source records attributed to D L Kleinberg.

At least 19 recordsLinked to original sources
PubMed1995

Estradiol enhances the stimulatory effect of insulin-like growth factor-I (IGF-I) on mammary development and growth hormone-induced IGF-I messenger ribonucleic acid.

Pubertal mammary development in the rat is largely dependent upon GH and estrogen. We recently showed that insulin-like growth factor-I (IGF-I) can substitute for GH in inducing mammary development in male rats, suggesting that IGF-I mediates GH action. The present study investigated whether IGF-I, like GH, required estradiol (E2) to act or whether IGF-I could substitute for both GH and E2. The effects of IGF-I were tested in the presence and absence of E2. Elvax pellets containing IGF-I or des(1-3) IGF-I were implanted into right lumbar mammary glands of sexually immature, hypophysectomized, oophorectomized female rats, with control BSA-containing pellets in the contralateral glands. After 5 days, both lumbar mammary glands were removed and examined in whole mounts for mammary development by counting terminal end buds and alveolar structures. E2, administered in SILASTIC brand capsules, had no independent effect on mammary development. In the absence of E2, des(1-3) IGF-I had a small, but significant, independent effect on mammary development; native IGF-I was ineffective. The addition of E2 significantly enhanced the effects of IGF-I and des(1-3) IGF-I on mammary development, similar to that noted when E2 was given along with GH. We also studied the effects of E2 and/or hGH on mammary gland IGF-I messenger RNA (mRNA) in hypophysectomized castrated male animals. E2 alone did not increase mammary gland IGF-I mRNA concentrations, but E2 enhanced the effect of hGH on IGF-I mRNA by 4- to 6-fold. These studies indicate that IGF-I can have a small independent effect on mammary development, but like GH, E2 is required for a full effect. They also indicate that E2 is capable of synergizing with GH in the production or expression of IGF-I mRNA, and that the action of E2 on mammary development may take place at multiple sites. If locally produced IGF-I does indeed mediate the action of GH in mammary development, then although E2 is capable of enhancing the effect of GH on IGF-I mRNA, its major effect in mammary development occurs after IGF-I is produced.

Animals↗
PubMed1994

Identification of rat liver phosphatidylinositol synthase as a 21 kDa protein.

Substantial purification of rat liver phosphatidylinositol (PtdIns) synthase has been achieved by a combination of Hecameg extraction, heat treatment, affinity chromatography and chromatography on PBE-94. The activity chromatographs as a single peak which has an apparent molecular mass between 150 and 200 kDa on Sepharose 4B. When analysed by SDS/PAGE, two major bands are seen. The enzyme activity is correlated with a protein band of 21 kDa. A second band, at 51 kDa, is eluted from a PBE-94 column slightly ahead of the activity. Manganese is an absolute requirement for stabilization of activity in the presence of detergent. The effect of manganese is optimal at 0.5 mM; magnesium at a concentration of 10 mM is only minimally effective. Substrate Kms are 1.3 mM and 9.5 microM for inositol and CDP-diacylglycerol respectively. The activity eluting from the PBE-94 column is purified 5000-fold over the post-mitochondrial supernatant.

Animals↗
PubMed1994

Galactorrhea.

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Butyrophenones↗
PubMed1992

Intact and amino-terminally shortened forms of insulin-like growth factor I induce mammary gland differentiation and development.

Growth hormone (GH) plays a role in regulating growth and differentiation of immature glandular structures in the mammary gland, but the mechanisms by which the hormone exerts these effects are unknown. We have previously found that GH stimulates insulin-like growth factor I (IGF-I) I mRNA production within the mammary glands of hypophysectomized rats. In this study we set out to determine if IGF-I administration could mimic the action of GH in initiating mammary gland differentiation and development. Two forms of IGF-I, intact and amino-terminally shortened [des-(1-3)-IGF-I], were found to induce the development of terminal end buds and the formation of alveolar structures in the mammary glands of hypophysectomized, castrated, and estradiol-treated sexually immature male rats. The effect of both forms of IGF-I was similar to that obtained with human GH, but the truncated form was at least 5 times more potent than intact IGF-I. These findings suggest that the inductive effect of GH on glandular differentiation is mediated by the GH-induced production of IGF-I or a related molecule within the mammary gland itself.

Animals↗
PubMed1990

Non-lactogenic effects of growth hormone on growth and insulin-like growth factor-I messenger ribonucleic acid of rat mammary gland.

In contrast to established dogma that PRL is central in mammary development, and GH mimics PRL in affecting growth because of structural similarities, we found that both hGH, which is lactogenic, and rGH, which is non-lactogenic, were significantly more potent than hPRL and rPRL in stimulating mammary growth in rats. Additionally, hGH was more potent than hPRL in increasing mammary IGF-I mRNA content. These data indicate that GH has separate effects on parameters of mammary gland growth, suggesting an independent role for GH in mammary growth.

Animals↗
PubMed1989

Effect of CV 205-502 in hyperprolactinaemic patients intolerant of bromocriptine.

CV 205-502 (Sandoz), an octahydrobenzol [g]quinoline, is a long-acting dopamine agonist which inhibits prolactin secretion. We conducted a phase 2 clinical study in 10 hyperprolactinaemic women (nine of whom were previously intolerant of bromocriptine) in order to determine (1) the dose at which CV 205-502 exerted its prolactin-lowering effect; (2) the nature of adverse reactions associated with long-term therapy; and (3) whether patients who were intolerant of bromocriptine could tolerate CV 205-502. At first patients were randomized to take initial doses of either 0.02 or 0.05 mg daily at bedtime. Thereafter these doses of medication were gradually increased either to the point of normalizing serum prolactin (to 0.70 IU/l or 20 ng/ml) or to a maximum dose of 0.14 mg daily. The lower initial dose was ineffective and had to be increased in all patients. The higher initial dose (0.05 mg) normalized prolactin in three of five women within 24 h. During chronic administration of the final dose of CV 205-502 (mean 0.09 mg a day), serum prolactin decreased from a mean level of 9.19 +/- 4.9 (SEM) IU/l to a mean level of 1.55 +/- 0.49 IU/l (n = 10 patients). Prolactin was normalized in five patients. Two patients, one of whom had been previously unresponsive to bromocriptine, and another unresponsive to pergolide with regard to prolactin inhibition, were also unresponsive to CV 205-502. Nausea, the side-effect responsible for these patients' previous intolerance of bromocriptine, occurred in six of 10 patients taking CV 205-502 but was much less disabling and did not cause any of the patients to stop this medication. Only one patient taking CV 205-502 discontinued treatment because of adverse effects (light-headedness).

Adult↗
PubMed1988

Isolation and characterization of monoclonal antibodies against ribonuclease inhibitor.

Mouse monoclonal antibodies were generated against human ribonuclease inhibitor, an intracellular regulatory protein. A total of four antibodies were isolated, all of which were of the immunoglobulin G1 subtype. Western blot analysis of the antibodies suggested monospecificity. Based on immunoradiometric competition assays two of the antibodies were determined to be directed against the same antigenic epitope, while the other two were against a second and possibly third epitope. None of the antibodies appeared to be directed against the ribonuclease binding site of the antigen. Data is presented suggesting that ribonuclease inhibitor is present in normal human serum. The potential significance of these findings is discussed.

Animals↗
PubMed1987

Evidence for a nonprolactin, non-growth-hormone mammary mitogen in the human pituitary gland.

To determine whether the human pituitary contains a previously unidentified, nonprolactin (non-hPRL), non-growth-hormone (non-hGH) factor capable of stimulating mammary development, we tested the effects of whole human pituitary extract (hPE) and pituitary extracts depleted of hPRL and hGH ("stripped hPE") in hypophysectomized, castrated estradiol (E2)-treated male rats and rhesus monkeys. Both whole and stripped hPE significantly stimulated rat mammary development (mean scores = 3.3 and 2.0, respectively, on a scale ranging from 0 to 4) in comparison with controls (mean score = 1.0). Mammary development was not due to minute concentrations of hGH or hPRL remaining in stripped hPE because 30- to 100-fold higher concentrations of hGH (Genentech) and 1000-fold higher concentrations of hPRL were required to stimulate significant mammary development. Non-pituitary extracts of human ovary, muscle, and serum, and bovine serum albumin did not stimulate rat mammary gland growth. Trypsin destroyed the mammary mitogenic activity of whole hPE, indicating that the unidentified factor is likely a protein. Mammary growth and development were also stimulated in hypophysectomized, E2-treated monkeys by stripped hPE (mean histological score = 3.25 vs. 1.35 in control animals). Monkeys receiving stripped hPE had undetectable levels of hGH and hPRL in serum sampled over a 24-hr period. These findings suggest that the human pituitary contains a non-hPRL, non-hGH factor that stimulates mammary growth and may be important in normal mammary growth and development and perhaps in breast cancer.

Animals↗
PubMed1985

Decreased prolactin secretion in childhood obesity.

Twelve obese patients and 7 control subjects, age and sex matched, whose weights were greater than 200% of ideal weight and 100% of ideal body weight, respectively, underwent intravenous insulin and thyroid releasing hormone (TRH) tests. Serial prolactin growth hormone, insulin, blood sugar, cortisol, glucagon, thyrotropin stimulating hormone, thyroxine, and triiodothyronine were obtained by RIA. Obese patients showed no significant differences from controls in basal and nadir glucose, basal and peak glucagon, cortisol, and thyroid responses to both tests. Basal insulin levels were higher (36 +/- 9.4 vs 10 +/- 2.3 microU/ml, P less than 0.05) and peak growth hormone responses after insulin were lower in the obese group (6.1 +/- 1.1 vs 12.7 +/- 3.7 ng/ml, P less than 0.05) than in controls. Whereas all control subjects had prolactin responses to both tests, five of 12 obese patients had no responses to insulin. Obese patients had lower prolactin responses at 30 minutes after insulin (5.4 +/- 0.7 vs 12.9 +/- 3.7 ng/ml, P less than 0.05) and lower prolactin responses at 60 minutes after TRH (9.9 +/- 1.7 vs 20.4 +/- 5.9 ng/ml, P less than 0.05). Maximum prolactin responses after TRH were lower in obese patients (9.9 +/- 2.0 vs 28.8 +/- 10.9 ng/ml, P less than 0.05). Maximum prolactin responses after insulin were lower in obese patients (6.2 +/- 4.1 vs 28.9 +/- 18.3 ng/ml). Thus prolactin secretion in childhood obesity is decreased after both stimuli, but more so after IV insulin that TRH, and suggests that, as in adult hypothalamic obesity, neuroendocrine regulation of prolactin release in obese children is impaired.

Adolescent↗
PubMed1985

Primate mammary development. Effects of hypophysectomy, prolactin inhibition, and growth hormone administration.

The pituitary gland has been found to be an important factor in mammary development in primates. Hypophysectomy in 12 sexually immature monkeys caused significant inhibition of estradiol (E2)-induced mammary growth and development. A histological index of mammary development in sexually immature hypophysectomized animals was lower (0.82) than in intact E2-treated controls (3.4; P less than 0.008). Hypophysectomy also inhibited growth of the mammary gland as judged by a size index. Despite the hypophysectomy, E2 stimulated some, albeit blunted, mammary growth and development, which may have been due to incomplete hypophysectomy. Selective inhibition of prolactin by ergot drugs in intact animals did not prevent full mammary development, suggesting that there may be pituitary mammogens other than prolactin, or that very low or unmeasurable concentrations of prolactin were sufficient to synergize with E2 to cause full acinar development. The mean histological index was 3.08 in E2-treated animals and 3.16 in animals treated with E2 plus pergolide. There was also no difference in the size of the glands. We evaluated the effect of growth hormone on mammary development by treating three hypophysectomized animals with pure 22,000 mol wt human growth hormone (hGH) (Genentech, Inc., South San Francisco, CA). We found that physiological or slightly supraphysiological concentrations of hGH in animals with unmeasurable prolactin were incapable of restoring the capacity of E2 to induce full mammary growth. These findings suggest that, if growth hormone is a mammary mitogen, that physiological concentrations are insufficient to synergize with E2 to induce full mammary growth or that other forms of hGH are mammogenic. Our studies suggest that the role of the pituitary gland in mammary mitogenesis in primates is more complicated than previously thought. They also raise the possibility that heretofore unidentified pituitary substances may be mammogenic.

Animals↗
PubMed1983

Pergolide for the treatment of pituitary tumors secreting prolactin or growth hormone.

We gave pergolide mesylate, a new long-acting ergot derivative with dopaminergic properties, to 47 patients with hypersecretion of prolactin or growth hormone. Single doses produced long-lasting reductions of serum prolactin levels; after 24 hours, the values remained depressed at a mean of 28.8 per cent of the base-line value. Among 41 patients (22 women and 19 men) with hyperprolactinemia who took pergolide for three months or more, prolactin levels fell to normal in 37 and remained slightly elevated in 2. In the two patients in whom the levels fell to only 38 to 52 per cent of base line, treatment was regarded as a failure. The level of growth hormone fell to a mean of 52.8 per cent of base line in patients with acromegaly who were taking 100 micrograms of pergolide per day. Among patients for whom adequate CT scans were available, definite tumor shrinkage occurred in 10 of 13 with macroadenomas and definite or probable shrinkage in 5 of 9 with microadenomas. Menses returned in 76 per cent of treated women and testosterone levels rose in 10 of 14 men. We conclude that pergolide reduces hypersecretion and shrinks most prolactin-secreting macroadenomas. In some patients long-term pergolide therapy may be superior to surgery and x-ray treatment.

Acromegaly↗
PubMed1983

Inhibition by estradiol of the lactogenic effect of prolactin in primate mammary tissue: reversal by antiestrogens LY 156758 and tamoxifen.

Increasing concentrations of estradiol (E2) ranging from 0.01 to 10 nM were found to inhibit partially but significantly the lactogenic effect of ovine prolactin (oPRL) on alpha-lactalbumin production in primate mammary tissues maintained in organ culture for 9 days. E2 at 10 nM inhibited by 38% (mean) PRL-stimulated alpha-lactalbumin production measured by radioimmunoassay. E2 antagonized the effect of oPRL by reducing new alpha-lactalbumin synthesis as determined by specific immunoprecipitation of alpha-lactalbumin and by analysis with NaDodSO4 gel electrophoresis. In immunoprecipitation studies, the mean inhibition of alpha-lactalbumin production was 57.6%. E2 in the absence of oPRL had no effect on alpha-lactalbumin production. In contrast to previous observations in rodents, progesterone was found to be a much weaker inhibitor of PRL-induced alpha-lactalbumin production than was E2 in primate breast tissues. Mean inhibition of oPRL-stimulated alpha-lactalbumin production was 32.3% with 10 microM progesterone and 8.3% with 10 nM. The inhibitory effect of E2 on oPRL-stimulated alpha-lactalbumin production was significantly reversed by both tamoxifen and a new antiestrogen, LY 156758. Although exact comparison of the effects of these two antiestrogens was not possible, it was apparent that LY 156758 was more potent in blocking the E2 inhibitory effect. In summary, these studies provide evidence that physiologic concentrations of estradiol partially block the lactogenic effect of PRL in primate mammary glands, suggesting a new role for estrogen in mammary physiology. The inhibitory effect of estrogen treatment on milk production in women after parturition may possibly be explained by this direct antagonism between E2 and PRL.

Animals↗
PubMed1982

Estradiol inhibits prolactin induced alpha-lactalbumin production in normal primate mammary tissue in vitro.

The effect of estradiol on prolactin induced alpha-lactalbumin production in normal primate mammary tissue was studied by maintaining tissues in organ culture with or without various combinations of oPRL and 17 beta-estradiol. As expected alpha-lactalbumin was increased byoPRL. 17 Beta-estradiol was found to have a significant inhibitory effect on oPRL-induced alpha-lactalbumin production. By 9 days in culture estradiol (10(-11) M) caused a mean 31% inhibition of prolactin-induced alpha-lactalbumin; with estradiol (10(-8) M) the inhibition was 40%. In the absence of oPRL, estradiol did not inhibit alpha-lactalbumin production. Thus it appears that estradiol directly antagonizes the lactogenic effect of prolactin on the normal primate mammary gland.

Animals↗
PubMed1980

Pergolide mesylate: a potent day-long inhibitor of prolactin in rhesus monkeys and patients with Parkinson's disease.

The effect of a new synthetic ergot alkaloid, pergolide mesylate, on the inhibition of PRL during 24-h periods was evaluated in four rhesus monkeys and three patients with Parkinson's disease. In the monkeys, the mean PRL level during the 24-h period fell to 24% of control in response to 50 micrograms. With 1000 micrograms pergolide daily and to 6.6% of control with 200 micrograms pergolide daily, PRL was unmeasurable in the great majority of samples over 24 h. In addition, the marked episodic fluctuation in PRL occurring in controls was not observed in treated animals. In three patients with Parkinson's disease, treatment with pergolide also resulted in uniform 24-h suppression of PRL. In one patient on pergolide (100 micrograms/day), the mean 24-h PRL level fell to 18% of control, and in two other patients on 200 and 600 micrograms pergolide, respectively, whose mean PRL levels were 4.1 and 7.4 ng/ml, respectively, before treatment, no PRL was detected in any of the blood samples obtained during the 24-h periods. These data provide evidence that pergolide is a potent inhibitor of PRL in rhesus monkeys and in patients with Parkinson's disease; the effect is iniform over 24-h periods.

Animals↗
PubMed1980

Evidence that human growth hormone is a potent lactogen in primates.

To help determine if human GH (hGH) plays a physiological role in normal mammary function or diseases of the human breast, a study was undertaken to examine the lactogenic potency of hGH in a subhuman primate system. hGH was previously considered a relatively weak lactogen when tested in avian crop sac and rodent mammary assays. The effect of hGH on the production of alpha-lactalbumin in organ cultures of primate mammary tissue was compared with the effect of equal concentrations of ovine PRL (oPRL). Mammary tissues from seven adult rhesus monkeys were maintained in culture for 9 days (medium changed every 3 days) without and with oPRL or hGH in doses ranging from 30-1000 ng/ml. hGH was consistently more effective than oPRL in the stimulation of alpha-lactalbumin production in over 90% of the cases. For example, mean (+/- SEM) alpha-lactalbumin production at the 6-day time period in response to 1000 ng/ml hormone was 12.9 +/- 3.3 ng/ml for oPRL and 61.9 +/- 18 ng/ml for hGH. Overall, it was calculated that hGH had 328% the potency of oPRL in adult rhesus monkey mammary tissue. In pigtail macaques, hGH was also a more potent stimulant of alpha-lactalbumin production than oPRL, but the differences wer not as great as in rhesus monkeys. alpha-Lactalbumin in medium was higher in hGH-containing dishes than in those containing oPRL in over 85% of the cases. It was calculated that the lactogenic potency of hGH in macaque tissue was 160.5% that of oPRL. The differences between species were significant. These results indicate that hGH is a more effective lactogen in subhuman primates than oPRL and suggest the possibility of GH may be a lactogen which has physiological importance.

Animals↗