David L Kleinberg, M.D.

Pasireotide, an IGF-I action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia
Kleinberg, David L; Ameri, Pietro; Singh, Baljit
2011 Mar;14(1):44-52, Pituitary
Mammary hyperplasia increases breast cancer risk. Tamoxifen prevents breast cancer in women with atypical hyperplasia, but has serious side effects. As estradiol action requires IGF-I, direct inhibition of IGF-I action theoretically might be an efficacious alternative to tamoxifen. After hypophysectomy and oophorectomy, 21-day-old female rats were treated with GH and E(2.) After 7 days all terminal end buds (TEBs) and 75% of ducts became hyperplastic. Co-treatment with pasireotide, a somatostatin analog that blocks GH secretion and IGF-I action in the mammary gland, prevented hormone-induced hyperplasia. The number and size of TEBs and moderately or floridly hyperplastic ducts was reduced by pasireotide (P < 0.01). In contrast, the same concentration of octreotide, which has a more selective somatostatin receptor subtype binding profile, was less effective than pasireotide. Tamoxifen inhibited hyperplasia when used alone with GH + E(2), but did not add to the inhibitory effect of pasireotide when the two treatments were combined. Both pasireotide and tamoxifen acted via the IGF-I receptor signaling pathway and both were found to inhibit mammary cell proliferation and stimulate apoptosis. The number of epithelial cells expressing phosphorylated insulin receptor substrate (IRS)-1 in response to GH and E(2) was reduced by pasireotide, as was staining intensity. These results support the concept that IGF-I inhibition, in this case by pasireotide, inhibits E(2) and GH-induced mammary hyperplasia. As tamoxifen did not further increase the inhibitory effect of pasireotide, the peptide appears to be at least as effective as tamoxifen in preventing GH + E(2)-induced mammary hyperplasia
— id: 123203, year: 2011, vol: 14, page: 44, stat: Journal Article,

The pivotal role of insulin-like growth factor I in normal mammary development
Kleinberg, David L; Barcellos-Hoff, Mary Helen
2011 Sep;40(3):461-471, Endocrinology & metabolism clinics of North America
Mammary development begins in puberty in response to an estrogen (E(2)) surge. E(2) does not act alone. It relies on pituitary growth hormone (GH) to induce insulin-like growth factor I (IGF-I) production in the mammary stromal compartment. In turn, IGF-I permits E(2) (and progesterone) action. During puberty, E(2) and IGF-I synergize for ductal morphogenesis. During pregnancy, progesterone joins IGF-I and E(2) to stimulate secretory differentiation necessary to produce milk. Prolactin stimulates milk production, while transforming growth factor-beta inhibits proliferation. The orchestrated action of hormones, growth factors, and receptors necessary for mammary development and function are also critical in breast cancer
— id: 137076, year: 2011, vol: 40, page: 461, stat: Journal Article,

Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline
Melmed, Shlomo; Casanueva, Felipe F; Hoffman, Andrew R; Kleinberg, David L; Montori, Victor M; Schlechte, Janet A; Wass, John A H
2011 Feb;96(2):273-288, Journal of clinical endocrinology & metabolism
OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia. PARTICIPANTS: The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented
— id: 134162, year: 2011, vol: 96, page: 273, stat: Journal Article,

Moderate doses of hGH (0.64 mg/d) improve lipids but not cardiovascular function in GH-deficient adults with normal baseline cardiac function
Newman, Connie B; Frisch, Katalin A; Rosenzweig, Barry; Roubenoff, Ronenn; Rey, Mariano; Kidder, Teresa; Kong, Yuan; Pursnani, Amit; Sedlis, Steven P; Schwartzbard, Arthur; Kleinberg, David L
2011 Jan;96(1):122-132, Journal of clinical endocrinology & metabolism
CONTEXT: Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient (GHD) adults are limited. OBJECTIVES: The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults. DESIGN: The study was a 6-month double-blind, placebo-controlled randomized trial. SETTING: The study was conducted at the General Clinical Research Center. PARTICIPANTS: Thirty hypopituitary adults with GHD were studied. INTERVENTION: Subjects were randomized to recombinant human GH or placebo for 6 months, followed by open-label recombinant human GH for 12 months. MAIN OUTCOME MEASURES: Primary endpoints were exercise duration, maximal oxygen consumption, and left ventricular ejection fraction. Secondary endpoints were echocardiographic indices of systolic and diastolic function, left ventricular mass, lipids, and body composition. RESULTS: In the 6-month double-blind phase, mean GH dose was 0.64 mg/d. Mean IGF-I sd score increased from -4.5 to -1.0. Exercise duration, maximal oxygen consumption, left ventricular ejection fraction, and other echocardiographic parameters were normal at baseline and did not change. GH decreased total and low-density lipoprotein cholesterol by 7.5% (P = 0.016) and 14.7% (P = 0.002) (P = 0.04 vs. placebo). Mean lean body mass increased by 2.2 kg (P = 0.004), fat mass decreased by 1.7 kg (P = 0.21), and percent body fat decreased by 2.5% (P = 0.018), although between-group changes were not significant. CONCLUSIONS: Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol, increased IGF-I, and increased lean body mass. These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment
— id: 138237, year: 2011, vol: 96, page: 122, stat: Journal Article,

Prevention of breast cancer: the case for studying inhibition of IGF-1 actions
Smith, J; Axelrod, D; Singh, B; Kleinberg, D
2011 Jan;22 Suppl 1:i50-i52, Annals of oncology
Measures to prevent breast cancer are receiving particular attention by women at high risk from either clinico-pathologic findings or genetic susceptibility. Life-style and nutritional interventions have been difficult to quantify, but merit further study. Chemoprevention with tamoxifen and subsequently with the related raloxifene demonstrates some efficacy, but may be not be applicable to premenopausal women (with regard to raloxifene), or have low acceptance (with regard to tamoxifen). Based on the importance of the insulin-like growth factor-1 pathway in mammary gland development, and the availability of a potent inhibitor, pilot studies are ongoing to evaluate such an inhibitor in women with demonstrable high risk to develop breast cancer. Short-term interventions with the inhibitor have been completed, and subsequent interventions are planned
— id: 134119, year: 2011, vol: 22 Suppl 1, page: i50, stat: Journal Article,

Prevalence of metabolic syndrome in adult hypopituitary growth hormone (GH)-deficient patients before and after GH replacement
Attanasio, Andrea F; Mo, Daojun; Erfurth, Eva Marie; Tan, Meng; Ho, Ken Y; Kleinberg, David; Zimmermann, Alan G; Chanson, Philippe
2010 Jan;95(1):74-81, Journal of clinical endocrinology & metabolism
CONTEXT AND OBJECTIVE: Metabolic and body compositional consequences of GH deficiency (GHD) in adults are associated with a phenotype similar to the metabolic syndrome (MetS). PATIENTS: We assessed MetS prevalence in adult GHD patients (n = 2531) enrolled in the Hypopituitary Control and Complications Study. Prevalence was assessed at baseline and after 3 yr of GH replacement in a subset of 346 adult-onset patients. RESULTS: Baseline MetS crude prevalence was 42.3%; age-adjusted prevalence in the United States and Europe was 51.8 and 28.6% (P < 0.001), respectively. In the United States, age-adjusted prevalence was significantly higher (P < 0.001) than in a general population survey. Increased MetS risk at baseline was observed for age 40 yr or older (adjusted relative risk 1.34, 95% confidence interval 1.17-1.53, P < 0.001), females (1.15, 1.05-1.25, P = 0.002), and adult onset (1.77, 1.44-2.18, P < 0.001). In GH-treated adult-onset patients, MetS prevalence was not changed after 3 yr (42.5-45.7%, P = 0.172), but significant changes were seen for waist circumference (62.1-56.9%, P = 0.008), fasting glucose (26.0-32.4%, P < 0.001), and blood pressure (59.8-69.7%, P < 0.001). Significantly increased risk of MetS at yr 3 was associated with baseline MetS (adjusted relative risk 4.09, 95% confidence interval 3.02-5.53, P < 0.001) and body mass index 30 kg/m(2) or greater (1.53, 1.17-1.99, P = 0.002) and increased risk (with a P value < 0.1) for GH dose 600 microg/d or greater (1.18, 95% confidence interval 0.98-1.44, P = 0.088). CONCLUSION: MetS prevalence in GHD patients was higher than in the general population in the United States and higher in the United States than Europe. Prevalence was unaffected by GH replacement, but baseline MetS status and obesity were strong predictors of MetS after GH treatment
— id: 134971, year: 2010, vol: 95, page: 74, stat: Journal Article,

Development of an Acromegaly Registry To Follow Treatment
Sood, M.; Benaviv-Meskin, D.; Heron-Chaturvedi, D. C.; Lowy, N.; Narayan, N. R.; Lesser, M. L.; Escalon, L. B.; Martocci, A. S.; Levitt, H. B.; Kleinberg, D. L.
2010 JUN ;31(3):-, Endocrine reviews
— id: 128834, year: 2010, vol: 31, page: , stat: Journal Article,

Breast Cancer Chemoprevention in Pre-Neoplastic Lesions with a Somatostatin Analog in Nine Women: A Proof of Principle Trial
Axelrod, D; Smith, JA; Singh, B; Ruan, W; Lubitz, S; Kleinberg, DL
2009 DEC 15 ;69(24):552S-552S, Cancer research
— id: 106452, year: 2009, vol: 69, page: 552S, stat: Journal Article,

Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions
Kleinberg, David L; Wood, Teresa L; Furth, Priscilla A; Lee, Adrian V
2009 Feb;30(1):51-74, Endocrine reviews
Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer chemoprevention by preventing actions of both estrogen and progesterone, especially in women at extremely high risk for developing breast cancer such as BRCA gene 1 or 2 mutations
— id: 95722, year: 2009, vol: 30, page: 51, stat: Journal Article,

Guidelines for Acromegaly Management: An Update
Melmed, S; Colao, A; Barkan, A; Molitch, M; Grossman, AB; Kleinberg, D; Clemmons, D; Chanson, P; Laws, E; Schlechte, J; Vance, ML; Ho, K; Giustina, A
2009 MAY ;94(5):1509-1517, Journal of clinical endocrinology & metabolism
Objective: The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. Participants: The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. Evidence/Consensus Process: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. Conclusions: The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients. (J Clin Endocrinol Metab 94: 1509-1517, 2009)
— id: 99176, year: 2009, vol: 94, page: 1509, stat: Journal Article,

Evidence that SOM230 can prevent experimental mammary hyperplasia by blocking IGF-I and thus estrogen action in the mammary gland: preliminary evidence for an effect in humans
Ruan, W; Singh, B; Smith, J; Axelrod, D; Kleinberg, DL
2009 ;69(2):325S-326S, Cancer research
— id: 93515, year: 2009, vol: 69, page: 325S, stat: Journal Article,

Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study
Colao, Annamaria; Abs, Roger; Barcena, David Gonzalez; Chanson, Philippe; Paulus, Wolfgang; Kleinberg, David L
2008 Jan;68(1):66-71, Clinical endocrinology
OBJECTIVE: Cabergoline is a dopamine agonist used to treat hyperprolactinaemia. Because hyperprolactinaemia is a significant cause of infertility in women, cabergoline and other dopamine agonists are frequently prescribed to reduce prolactin levels and restore normal menses. They are usually discontinued shortly after the patient becomes pregnant. Although cabergoline has been used to treat hyperprolactinaemia since the mid-1990s, safety data related to maternal and foetal exposure to this agent are still limited. DESIGN: The current prospective, observational study reports on a total of 380 pregnancies. This extends by 154 pregnancies the results of a previously published interim report on the outcomes of 226 pregnancies in women treated with cabergoline up to 1994. MAIN OUTCOME MEASURES: Outcomes examined include the incidence of abortions and premature delivery and the number and types of foetal malformations or abnormalities. RESULTS: Follow-up data were available for 329 pregnancies, including 258 (78%) deliveries and 71 (22%) abortions. Of the 71 reported abortions, 31 (44%) were voluntary, 30 (42%) were spontaneous miscarriages, and nine (13%) were therapeutic. Of the 258 deliveries, 250 (97%) were live deliveries, four (2%) were stillbirths, and the status of delivery was unknown for the remaining four (2%). Of the 250 live deliveries, 193 (77%) were term deliveries (gestational period > 37 weeks), 45 (18%) were preterm deliveries (gestational period < or = 37 weeks), and 62% of the infants had normal birthweights (i.e. 3-4 kg). Neonatal abnormalities were recorded for 23 (9%) of the infants with no apparent pattern in type or severity. CONCLUSION: The results of this study suggest that foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation
— id: 95723, year: 2008, vol: 68, page: 66, stat: Journal Article,

IGF-I, GH, and sex steroid effects in normal mammary gland development
Kleinberg, David L; Ruan, Weifeng
2008 Dec;13(4):353-360, Journal of mammary gland biology & neoplasia
Although the pubertal surge of estrogen is the immediate stimulus to mammary development, the action of estrogen depends upon the presence of pituitary growth hormone and the ability of GH to stimulate production of IGF-I in the mammary gland. Growth hormone binds to its receptor in the mammary fat pad, after which production of IGF-I mRNA and IGF-I protein occurs. It is likely that IGF-I then works through paracrine means to stimulate formation of TEBs, which then form ducts by bifurcating or trifurcating and extending through the mammary fat pad. By the time pubertal development is complete a tree-like structure of branching ducts fills the rodent mammary fat pad. In addition to requiring IGF-I in order to act, estradiol also directly synergizes with IGF-I to enhance formation of TEBs and ductal morphogenesis. Together they increase IRS-1 phosphorylation and cell proliferation, and inhibit apoptosis. In fact, the entire process of ductal morphogenesis, in oophorectomized IGF-I(-/-) knockout female mice, can occur as a result of the combined actions of estradiol and IGF-I. IGF-I also permits progesterone action in the mammary gland. Together they have been shown to stimulate a form of ductal morphogenesis, which is anatomically different from the kind induced by IGF-I and estradiol. Although both progesterone and estradiol synergize with IGF-I by increasing IGF-I action parameters, there must be other, as yet unknown mechanisms that account for the anatomical differences in the different forms of ductal morphogenesis observed (hyperplasia in response to IGF-I plus estradiol and single layered ducts in response to IGF-I plus progesterone)
— id: 91490, year: 2008, vol: 13, page: 353, stat: Journal Article,

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. [Spanish]
Casanueva F.F.; Molitch M.E.; Schlechte J.A.; Abs R.; Bonert V.; Bronstein M.D.; Brue T.; Cappabianca P.; Colao A.; Fahlbusch R.; Fideleff H.; Hadani M.; Kelly P.; Kleinberg D.; Laws E.; Marek J.; Scanlon M.; Sobrinho L.G.; Wass J.A.H.; Giustina A.
2007 ;54(8):438.e1-438.e10, Endocrinologia y Nutricion
— id: 74878, year: 2007, vol: 54, page: 438.e1, stat: Journal Article,

Insulin-like growth factor (IGF)-I controls prostate fibromuscular development: IGF-I inhibition prevents both fibromuscular and glandular development in eugonadal mice
Kleinberg, David L; Ruan, Weifeng; Yee, Douglas; Kovacs, Kalman T; Vidal, Sergio
2007 Mar;148(3):1080-1088, Endocrinology
Although antiandrogen therapy has been shown effective in treating prostatic tumors, it is relatively ineffective in treating benign prostatic hyperplasia (BPH). In an attempt to understand better the role of androgens in the development of the normal prostate and BPH, we studied the relative effects of testosterone and IGF-I on the development of the two compartments of the prostate in castrated IGF-I((-/-)) male mice. Here we report that IGF-I stimulated the development of the fibromuscular compartment, but testosterone inhibited it (stromal epithelial ratio 2.17 vs. 0.83, respectively; P < 0.001). Testosterone also impaired IGF-I induced insulin receptor substrate-1 phosphorylation and cell division, and increased apoptosis in fibromuscular tissue. In sharp contrast IGF-I and testosterone both stimulated the development of the glandular compartment individually and together. The combined effects were either additive or synergistic on compartment size, cell division, insulin receptor substrate-1 phosphorylation, and probasin production. Together they also had a greater inhibitory effect on apoptosis in gland tissue. To determine whether IGF-I inhibition would inhibit both fibromuscular and glandular compartments, we tested the effect of IGF binding protein-1 on prostate development in two different models: castrated Ames dwarf mice and eugonadal normal male mice. IGF binding protein-1 blocked bovine GH-induced fibromuscular and glandular development in both. It also inhibited epithelial cell division and increased apoptosis in both prostate compartments in the eugonadal mice. The observed discordance between IGF-I and testosterone control of prostate compartment development might explain the relative failure of 5alpha-reductase inhibition in BPH and why testosterone inhibition might theoretically reduce gland volume but increase fibromuscular tissue. The work also provides a rationale for considering IGF-I inhibition as therapy for BPH to reduce the size of both prostate compartments
— id: 71336, year: 2007, vol: 148, page: 1080, stat: Journal Article,

GH peak response to GHRH-arginine: relationship to insulin resistance and other cardiovascular risk factors in a population of adults aged 50-90
Carmichael, John D; Danoff, Ann; Milani, Daniela; Roubenoff, Ronenn; Lesser, Martin L; Livote, Elayne; Reitz, Richard E; Ferris, Steven; Kleinberg, David L
2006 Aug;65(2):169-177, Clinical endocrinology
OBJECTIVE: To assess the GH response to GHRH-arginine in apparently healthy adults in relation to cardiovascular risk factors. DESIGN: Cross-sectional. PATIENTS: Eighty-six male and female volunteers aged 50-90. MEASUREMENTS: GH peak response to GHRH-arginine and cardiovascular risk factors, including obesity, insulin resistance, low levels of high density lipoprotein (HDL) cholesterol, elevated triglycerides, and hypertension. The primary outcome measurement was GH response to GHRH-arginine. The relationship between GH peak responses and cardiovascular risk factors was determined after data collection. RESULTS: GH peaks were highly variable, ranging from 2.3 to 185 microg/l (14% with GH peaks < 9 microg/l). An increasing number of cardiovascular risk factors were associated with a lower mean GH peak (P < 0.0001). By univariate analysis, fasting glucose, insulin, body mass index (BMI), HDL cholesterol and triglycerides were significantly associated with GH peak (all P < 0.0001). Multiple regression analysis revealed that fasting glucose, fasting insulin, BMI, triglycerides and sex accounted for 54% of GH peak variability. The role of abdominal fat as it relates to GH peak was explored in a subset of 45 subjects. Trunk fat and abdominal subregion fat measured by dual energy X-ray absorptiometry (DXA) were inversely related to GH peak (P < 0.008 and 0.001, respectively). Analysis of this subgroup by multiple regression revealed that subregion abdominal fat became the significant obesity-related determinant of GH peak, but still lagged behind fasting insulin and glucose. CONCLUSIONS: GH response to secretagogues was highly variable in apparently healthy adults aged 50-90 years. Peak GH was significantly related to fasting glucose, insulin, BMI, HDL cholesterol, triglycerides, trunk fat and abdominal subregion fat, with fasting glucose ranking first by multiple regression analysis. There was a strong relationship between cardiovascular risk factors and low GH, with individual risk factors being additive. Although these data do not differentiate between low GH being a cause or an effect of these cardiovascular risk factors, they indicate that the relationship between low GH and increased cardiovascular risk may be physiologically important in the absence of pituitary disease
— id: 95724, year: 2006, vol: 65, page: 169, stat: Journal Article,

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas
Casanueva, FF; Molitch, ME; Schlechte, JA; Abs, R; Bonert, V; Bronstein, MD; Brue, T; Cappabianca, P; Colao, A; Fahlbusch, R; Fideleff, H; Hadani, M; Kelly, P; Kleinberg, D; Laws, E; Marek, J; Scanlon, M; Sobrinho, LG; Wass, JAH; Giustina, A
2006 AUG ;65(2):265-273, Clinical endocrinology
In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data
— id: 98071, year: 2006, vol: 65, page: 265, stat: Journal Article,

SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3?
Ruan, Weifeng; Fahlbusch, Fabian; Clemmons, David R; Monaco, Marie E; Walden, Paul D; Silva, Antonio P; Schmid, Herbert A; Kleinberg, David L
2006 Feb;20(2):426-436, Molecular endocrinology
Somatostatin analogs (SAs) treat acromegaly by lowering pituitary GH secretion, which, in turn, lowers systemic IGF-I. The profound systemic effect is often greater than expected in the face of only partial GH suppression. Here we report that the SA SOM230 can also act by a nonpituitary-mediated inhibition of IGF-I action. SOM230 inhibited mammary development in intact and hypophysectomized female rats, a process requiring IGF-I. IGF-I overcame this inhibition. SOM230 also inhibited other actions of IGF-I (inhibition of apoptosis, phosphorylation of insulin receptor substrate-1, and cell division). SOM230 did not reduce IGF-I mRNA abundance in mammary gland but did stimulate IGF binding protein 5 (IGFBP5). IGFBP5 was 3.75 times higher in mammary epithelium of SOM230 than in placebo animals (P < 0.001). Administration of IGFBP-5 also inhibited GH-induced mammary development (P < 0.001). Measurement of sstr(1-5) (somatostatin subtype receptor) by real-time RT-PCR revealed that the mammary glands had an abundance of sstr(3) and lower amounts of sstr(4) and sstr(5) but no sstr(1) or sstr(2.) That mammary development was also inhibited to a lesser degree than SOM230 by octreotide, whose main action is through sstr(2), strongly suggests that sstr(3) is at least in part mediating the effects of the SAs. We conclude that 1) SAs inhibit IGF-I action in the mammary gland through a novel nonpituitary mechanism; 2) IGFBP-5, here shown to inhibit pubertal mammary development, might mediate the effect; and 3) Measurement of available sstr receptors in the mammary gland suggests that sstr(3) mediates the SA activity, but sstr(5) is also a possible mediator
— id: 64154, year: 2006, vol: 20, page: 426, stat: Journal Article,

New roles and challenges in neurosurgery of acromegaly
Kleinberg, D L
2005 ;28(5 Suppl):88-91, Journal of endocrinological investigation
Acromegaly is a disease that shortens life expectancy (1-3) and causes severe systemic problems during life (4). It can arise and be recognized quickly if the onset is rapid, as in gigantism. Unfortunately there is usually a delay in diagnosis, on average 9 yr (4). The longer the delay the more likely patients are to develop partially or completely irreversible systemic problems, such as sleep apnea (5) and arthritis. Although some of the signs and co-morbidities of acromegaly are permanent, there is good evidence that cure of the disease reverses early mortality (3, 6, 7). It has been estimated that life expectancy is shortened by about 10 yr overall, and longer when diabetes or heart disease are already present at the time of diagnosis
— id: 58982, year: 2005, vol: 28, page: 88, stat: Journal Article,

Primary therapy for acromegaly with somatostatin analogs and a discussion of novel peptide analogs
Kleinberg, David L
2005 Jan;6(1):29-37, Reviews in endocrine & metabolic disorders
— id: 56072, year: 2005, vol: 6, page: 29, stat: Journal Article,

A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly
Melmed, Shlomo; Sternberg, Richard; Cook, David; Klibanski, Anne; Chanson, Philippe; Bonert, Vivien; Vance, Mary Lee; Rhew, David; Kleinberg, David; Barkan, Ariel
2005 Jul;90(7):4405-4410, Journal of clinical endocrinology & metabolism
CONTEXT: Somatostatin analogs have been successfully used to treat patients with GH-secreting pituitary adenomas because they are safe, effective, and usually well tolerated. The results of studies evaluating acromegaly treatment with the somatostatin receptor ligands (SRLs), octreotide and lanreotide, have supported the use of these agents for primary medical therapy before or as an alternative to traditional interventions of surgery and radiotherapy in selected cases. EVIDENCE ACQUISITION: We therefore undertook a systematic literature overview to characterize the results of studies involving primary therapy with somatostatin analogs and their effects on pituitary tumor size. Because most studies in which pituitary tumor shrinkage has been assessed involve uncontrolled, open-label, prospective trials or retrospective case series, the lack of a control arm does not permit pooling of data in a metaanalytic fashion to determine tumor size reduction. Therefore, this systematic review was designed to document and stratify data by study design, summarize therapeutic regimens and patient characteristics, assess the percentage of patients showing changes in tumor size, and calculate the weighted average effect on size reduction. EVIDENCE SYNTHESIS: Overall, for patients who experience significant shrinkage, an approximately 50% decrease in pituitary mass is achieved when a somatostatin analog is used exclusively or before surgery or radiotherapy. Fourteen studies (n = 424) provided a definition of significant tumor shrinkage, and the results showed that 36.6% (weighted mean percentage) of patients receiving primary SRL therapy for acromegaly experienced a significant reduction in tumor size. The weighted mean percent reduction in tumor size was 19.4% for those studies in which all patients received SRLs and change in tumor size was reported for all patients. CONCLUSIONS: Clinical implications are discussed for patients in whom tumor size control with SRLs is an important objective, typically those who have failed surgery or are being treated with primary medical therapy with large tumors
— id: 63408, year: 2005, vol: 90, page: 4405, stat: Journal Article,

Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing insulin-like growth factor-I action
Ruan, Weifeng; Monaco, Marie E; Kleinberg, David L
2005 Mar;146(3):1170-1178, Endocrinology
Progestins have been implicated in breast cancer development, yet a role for progesterone (Pg) in ductal morphogenesis (DM) has not been established. To determine whether Pg could cause DM, we compared relative effects of Pg, estradiol (E2) and IGF-I on anatomical and molecular biological parameters of IGF-I-related DM in oophorectomized female IGF-I(-/-) mice. Pg had little independent effect on mammary development, but together with IGF-I, in the absence of E2, Pg stimulated an extensive network of branching ducts, occupying 92% of the gland vs. 28.3% with IGF-I alone, resembling pubertal development (P < 0.002). Its major effect was on enhancing duct length and branching (P < 0.002). Additionally, Pg enhanced phosphorylation of IRS-1, increased cell division, and increased the antiapoptotic effect of IGF-I. Pg action was inhibited by RU486 (P < 0.01). E2 also stimulated DM by enhancing IGF-I action but had a greater effect on terminal end bud formation and side branching (P < 0.002). In contrast to previous findings, long-term exposure to E2 alone, without IGF-I, caused formation of ducts and side branches, a novel finding. Both IGF-I and E2 were found necessary for Pg-induced alveolar development. In conclusion, Pg, through Pg receptor can enhance IGF-I action in DM, and E2 acts through a similar mechanism; E2 alone caused formation of ducts and side branches; there were differences in the actions of Pg and E2, the former largely affecting duct formation and extension, and the latter side branching; and both IGF-I and E2 were necessary for Pg to form mature alveoli
— id: 50630, year: 2005, vol: 146, page: 1170, stat: Journal Article,

AACE Medical Guidelines for Clinical Practice for the diagnosis and treatment of acromegaly
Cook, David M; Ezzat, Shereen; Katznelson, Laurence; Kleinberg, David L; Laws, Edward R Jr; Nippoldt, Todd B; Swearingen, Brooke; Vance, Mary Lee
2004 May-Jun;10(3):213-225, Endocrine practice
— id: 95725, year: 2004, vol: 10, page: 213, stat: Journal Article,

Growth hormone (GH) replacement therapy in adult-onset GH deficiency: Effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial
Hoffman, AR; Kuntze, JE; Baptista, J; Baum, HBA; Baumann, GP; Biller, BMK; Clark, RV; Cook, D; Inzucchi, SE; Kleinberg, D; Klibanski, A; Phillips, LS; Ridgway, EC; Robbins, RJ; Schlechte, J; Sharma, M; Thorner, MO; Vance, ML
2004 MAY ;89(5):2048-2056, Journal of clinical endocrinology & metabolism
Adult GH deficiency (AGHD) is characterized by an altered body composition, an atherogenic lipid profile, decreased exercise capacity, and diminished quality of life. We performed a randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD to assess the effects of GH on these outcomes. GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for 12 months. Primary measures of efficacy included body composition, strength and endurance, and quality of life. Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density. After 12 months, 79% of subjects remained on GH 0.0125 mg/kg.d, whereas 21% received 0.00625 mg/kg.d. GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean body mass over base-line. In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a smaller response in women. GH treatment was associated with significant improvements in total cholesterol and low-density lipoprotein (P < 0.05 for all). No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density. GH treatment was generally well tolerated. Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD and improve body composition and cardiovascular risk factors
— id: 46639, year: 2004, vol: 89, page: 2048, stat: Journal Article,

Variability and reliability of single serum IGF-I measurements: impact on determining predictability of risk ratios in disease development
Milani, Daniela; Carmichael, John D; Welkowitz, Joan; Ferris, Steven; Reitz, Richard E; Danoff, Ann; Kleinberg, David L
2004 May;89(5):2271-2274, Journal of clinical endocrinology & metabolism
In recent years, a number of investigators have studied the relationship between IGF-I and risk of developing cancer, diabetes or cardiovascular disease. Upper tertile, quartile, and quintile IGF-Is were associated with higher risk of developing cancer, and lowest quartile with cardiac disease and diabetes. As part of a study to correlate serum IGF-Is and growth hormone dynamics in aging, we measured fasting serum IGF-I at baseline and two weeks later in a group of 84 normal volunteers between the ages of 50 and 90 years. Although the correlation between the two IGF-Is was high (r=0.922; p<0.0001) there were substantial differences between the two IGF-I values ranging from -36.25 to +38.24% between individual IGF-I values at the two blood draws and a significant difference between the mean IGF-Is at visits I and 2 (mean 120.28+/-53.5 vs. 114.95+/-50.03; p=0.03). When considered in quartiles, IGF-I changed from one quartile to another in 34/84 (40.5%) of the volunteers. When the group was divided in halves, tertiles,quartiles, or quintiles there was an increasing number of subjects who changed from one subdivision to another as the number of gradations increased. These results suggest that the predictive outcomes of earlier studies that used single IGF-I samples for analysis of risk ratios according to tertiles, quartiles, or quintiles could have been different if a second IGF-I was used to establish the risk ratio. The results also suggest that variability in IGF-I should be taken into account when designing such studies
— id: 44925, year: 2004, vol: 89, page: 2271, stat: Journal Article,

Lipid metabolism in phosphatidylinositol transfer protein alpha-deficient vibrator mice
Monaco, Marie E; Kim, James; Ruan, WeiFeng; Wieczorek, Rosemary; Kleinberg, David L; Walden, Paul D
2004 Apr 30;317(2):444-450, Biochemical & biophysical research communications
Mice that are homozygous for the vibrator mutation express 65-85% less phosphatidylinositol transfer protein alpha (PITPalpha) than their wild type litter mates. By postnatal day 10-12 (P10-12) they exhibit signs of neurodegeneration and die prematurely by P40. In the present study, we examine the lipid content of brain, liver, and mammary glands from these animals. Lipid-mediated signal transduction is evaluated in primary fibroblast cultures. With respect to the lipid make-up of brain and liver, we report that there is a significant increase (2- to 4-fold) in the neutral lipids present in the livers of vb/vb animals when compared with wild type (+/+) litter mates. No significant changes are observed in the brains of these animals. The mammary glands of vb/vb mice are underdeveloped with respect to ductal and alveolar structures, and the fat pad is composed of predominantly brown adipose tissue rather than the white adipose tissue characteristic of age-matched wild type litter mates. No differences are observed in any aspect of lipid-mediated signal transduction
— id: 44926, year: 2004, vol: 317, page: 444, stat: Journal Article,

Workshop B: androgens for men and women - new insights
Allolio, B; Kleinberg, D L
2003 Aug;13 Suppl A(12):S62-S62, Growth hormone & IGF research
— id: 44928, year: 2003, vol: 13 Suppl A, page: S62, stat: Journal Article,

Somatostatin analogs as primary medical therapy for acromegaly
Danoff, Ann; Kleinberg, David
2003 Apr;20(3):291-298, Endocrine
Acromegaly is a debilitating disease usually caused by a growth-hormone secreting pituitary adenoma. Therapeutic goals include improvement of symptoms, reduction in tumor mass, biochemical normalization, and preservation of pituitary function. Treatment options include transsphenoidal surgery, radiation, and pharmacotherapy. In view of the good cure rate, surgery remains the therapeutic modality of choice for most patients with microadenomas or well-circumscribed macroadenomas. In contrast, >40% of patients with invasive macroadenomas (who make up the majority of patients with acromegaly) will have residual disease following surgery, and require additional therapeutic intervention. Somatostatin analogs result in biochemical normalization in >60% of non-operated patients, and are well tolerated. Therefore, somatostatin analogs have emerged as a rational first-line treatment for the appropriately selected patient with acromegaly
— id: 37966, year: 2003, vol: 20, page: 291, stat: Journal Article,

Diagnosis and treatment of acromegaly complications
Giustina, A; Casanueva, F F; Cavagnini, F; Chanson, P; Clemmons, D; Frohman, L A; Gaillard, R; Ho, K; Jaquet, P; Kleinberg, D L; Lamberts, S W J; Lombardi, G; Sheppard, M; Strasburger, C J; Vance, M L; Wass, J A H; Melmed, S
2003 Dec;26(12):1242-1247, Journal of endocrinological investigation
The Pituitary Society in conjunction with the European Neuroendocrine Association held a consensus workshop to develop guidelines for diagnosis and treatment of the co-morbid complications of acromegaly. Fifty nine pituitary specialists (endocrinologists, neurosurgeons and cardiologists) assessed the current published literature on acromegaly complications in light of recent advances in maintaining tight therapeutic control of GH hypersecretion. The impact of elevated GH levels on cardiovascular disease, hypertension, diabetes, sleep apnea, colon polyps, bone disease, reproductive disorders, and neuropsychologic complications were considered. Guidelines are proposed for effective management of these complications in the context of overall acromegaly control. When appropriate, requirements for prospective evidence-based studies and surveillance database development are enunciated. Effective management of co-morbid acromegaly complications will lead to improved morbidity and mortality in acromegaly
— id: 44927, year: 2003, vol: 26, page: 1242, stat: Journal Article,

Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency
Biller, Beverly M K; Samuels, Mary H; Zagar, Anthony; Cook, David M; Arafah, Baha M; Bonert, Vivien; Stavrou, Stavros; Kleinberg, David L; Chipman, John J; Hartman, Mark L
2002 May;87(5):2067-2079, Journal of clinical endocrinology & metabolism
Although the use of the insulin tolerance test (ITT) for the diagnosis of adult GH deficiency is well established, diagnostic peak GH cut-points for other commonly used GH stimulation tests are less clearly established. Despite that fact, the majority of patients in the United States who are evaluated for GH deficiency do not undergo insulin tolerance testing. The aim of this study was to evaluate the relative utility of six different methods of testing for adult GH deficiency currently used in practice in the United States and to develop diagnostic cut-points for each of these tests. Thirty-nine patients (26 male, 13 female) with adult-onset hypothalamic-pituitary disease and multiple pituitary hormone deficiencies were studied in comparison with age-, sex-, estrogen status-, and body mass index-matched control subjects (n = 34; 20 male, 14 female). A third group of patients (n = 21) with adult-onset hypothalamic-pituitary disease and no more than one additional pituitary hormone deficiency was also studied. The primary end-point was peak serum GH response to five GH stimulation tests administered in random order at five separate visits: ITT, arginine (ARG), levodopa (L-DOPA), ARG plus L-DOPA, and ARG plus GHRH. Serum IGF-I concentrations were also measured on two occasions. For purposes of analysis, patients with multiple pituitary hormone deficiencies were assumed to be GH deficient. Three diagnostic cut-points were calculated for each test to provide optimal separation of multiple pituitary hormone deficient and control subjects according to three criteria: 1) to minimize misclassification of control subjects and deficient patients (balance between high sensitivity and high specificity); 2) to provide 95% sensitivity for GH deficiency; and 3) to provide 95% specificity for GH deficiency. The greatest diagnostic accuracy occurred with the ITT and the ARG plus GHRH test, although patients preferred the latter (P = 0.001). Using peak serum GH cut-points of 5.1 microg/liter for the ITT and 4.1 microg/liter for the ARG plus GHRH test, high sensitivity (96 and 95%, respectively) and specificity (92 and 91%, respectively) for GH deficiency were achieved. To obtain 95% specificity, the peak serum GH cut-points were lower at 3.3 microg/liter and 1.5 microg/liter for the ITT and ARG plus GHRH test, respectively. There was substantial overlap between patients and control subjects for the ARG plus L-DOPA, ARG, and L-DOPA tests, but test-specific cut-points could be defined for all three tests to provide 95% sensitivity for GH deficiency (peak GH cut-points: 1.5, 1.4 and 0.64 microg/liter, respectively). However, 95% specificity could be achieved with the ARG plus L-DOPA and ARG tests only with very low peak GH cut-points (0.25 and 0.21 microg/liter, respectively) and not at all with the L-DOPA test. Although serum IGF-I levels provided less diagnostic discrimination than all five GH stimulation tests, a value below 77.2 microg/liter was 95% specific for GH deficiency. In conclusion, the diagnosis of adult GH deficiency can be made without performing an ITT, provided that test-specific cut-points are used. The ARG plus GHRH test represents an excellent alternative to the ITT for the diagnosis of GH deficiency in adults
— id: 44929, year: 2002, vol: 87, page: 2067, stat: Journal Article,

Guidelines for acromegaly management
Melmed, S; Casanueva, FF; Cavagnini, F; Chanson, P; Frohman, L; Grossman, A; Ho, K; Kleinberg, D; Lamberts, S; Laws, E; Lombardi, G; Vance, ML; Von Werder, K; Wass, J; Giustina, A
2002 Sep;87(9):4054-4058, Journal of clinical endocrinology & metabolism
— id: 32443, year: 2002, vol: 87, page: 4054, stat: Journal Article,

Hypogonadism in patients with acromegaly: data from the multi-centre acromegaly registry pilot study
Katznelson L; Kleinberg D; Vance ML; Stravou S; Pulaski KJ; Schoenfeld DA; Hayden DL; Wright ME; Woodburn CJ; Klibanski A
2001 Feb;54(2):183-188, Clinical endocrinology
OBJECTIVE: Because acromegaly is an uncommon disorder, epidemiological data regarding the demographics of the disease such as the prevalence of hypogonadism have been limited. In order to derive clinical and epidemiological information, including underlying hormonal factors, regarding hypogonadism in patients with acromegaly, we performed a pilot study designed to develop a multi-centre acromegaly patient registry. DESIGN AND MEASUREMENTS: Medical records of patients with acromegaly seen between 1976 and 1996 at three Institutions were reviewed, and data were entered into a database using a secure internet website. Hypogonadism was defined as amenorrhoea in women and testosterone deficiency in men. Subanalysis was performed in patients with microadenomas and women less than 50 years of age, to include women of reproductive age. RESULTS: Information was available on 363 patients, of whom 54% were women. The mean age at diagnosis was 41 +/- 13 years. In subjects less than 50 years of age, hypogonadism was present in 59%. Hyperprolactinaemia was present in 45% and 21% of hypogonadal and eugonadal patients of reproductive age, respectively (P = 0.0003). GH levels were higher in patients with hypogonadism (P = 0.03). In patients < 50 years of age with microadenomas, hypogonadism was present in nine of the 22 (41%) patients, including 55% of the women and 27% of the men (P = ns). Hyperprolactinaemia was present in three of the 10 and four of the 14 of microadenoma patients with hypogonadism and eugonadism, respectively. CONCLUSION: We developed a web-based acromegaly patient registry and used it to show that hypogonadism is a frequent consequence of acromegaly, even in patients with microadenomas, who are not at risk from hypopituitarism due to local mass effects. We also demonstrated that prolactin and GH hypersecretion contribute to the pathogenesis of hypogonadism in acromegaly, and that hypogonadism may occur in microadenoma patients even in the absence of hyperprolactinaemia
— id: 18388, year: 2001, vol: 54, page: 183, stat: Journal Article,

State-of-the-art strategies for the diagnosis and management of acromegaly
Klibanski, A; Ho, K; Freda, PU; Clemmons, DR; Barkan, AL; Kleinberg, DL; Trainer, PJ; Swearingen, B; Molitch, ME; Wass, JAH; Thorner, MO; Melmed, S; Strasburger, CJ; Frohman, LA
2001 MAY-JUN ;11(3):223-232, Endocrinologist
Elevation of blood levels of insulin-like growth factor I (IGF-I) is the most reliable diagnostic marker of growth hormone hypersecretion, and normalization of IGF-I levels is the principal criterion for documenting biochemical remission in patients with acromegaly. Levels of insulin like growth hormone-binding protein 3 also may be useful in the assessment of patients whose IGF-I levels are not definitively diagnostic of active disease. When surgical therapy for acromegaly is not curative, drugs such as the dopamine agonists and somatostatin analogues can be used to manage the disease; the somatostatin analogues are more effective than the dopamine agonists. In addition, a new class of agents for the medical management of acromegaly, the growth hormone receptor antagonists, may soon be available. The importance of biochemical control of acromegaly is suggested by a study of 149 acromegalic patients who had undergone transsphenoidal surgery; for those who were not cured, a 3.5-fold increase in the relative death risk was associated with each year of active disease compared with a year in biochemical remission. Moreover, primary drug therapy, rather than surgery, may be preferred in some circumstances; for example, when surgical cure is unlikely and no acute mass effects are present
— id: 55041, year: 2001, vol: 11, page: 223, stat: Journal Article,

Diagnosis and management of growth hormone deficiency in adults
Stavrou S; Kleinberg DL
2001 Sep;30(3):545-563, Endocrinology & metabolism clinics of North America
In adults, GHD is a clinical syndrome that occurs in patients with pituitary or hypothalamic disease. It may be asymptomatic or present with relatively nonspecific constitutional symptoms. Most patients have abnormal body composition, consisting of increased fat mass and decreased lean mass. Life expectancy is significantly decreased in hypopituitary patients with GHD, with cardiovascular disease a common cause of death. Treatment with growth hormone reverses abnormalities in body composition and may reduce cardiovascular risk factors; however, the long-term treatment outcomes regarding mortality, the incidence of cardiovascular disease, bone fractures, tumor development, and recurrence are not known. Longer prospective clinical studies are needed. The major manufacturers of growth hormone have initiated postmarketing surveillance databases to monitor the safety of growth hormone treatment
— id: 39481, year: 2001, vol: 30, page: 545, stat: Journal Article,

Rheumatic manifestations of pituitary tumors
Stavrou, S; Kleinberg, D L
2001 Oct;3(5):459-463, Current rheumatology reports
Pituitary tumors may cause rheumatologic problems as a result of under production or overproduction of one pituitary hormone. Excessive growth hormone causes destruction of cartilage by a direct action. Facial and acral changes and arthralgias may be some of the first symptoms of acromegaly. The arthritis associated with acromegaly is often devastating. Carpal tunnel syndrome is very common in patients with acromegaly. Adrenocorticotropin (ACTH) has indirect effects via the action of glucocorticoid on bones, muscles, and the immune system. Proximal muscle weakness is a characteristic feature of Cushing's syndrome. Patients with Cushing's syndrome commonly have osteopenia and osteoporosis that lead to an increase in bone fractures. Avascular necrosis is associated with exogenous steroid administration. The effects of too much glucocorticoid or too rapid withdrawal can be severe. Gonadotropins act via the gonadal steroids and protect bone mass from loss. Prolactin is less involved in rheumatologic disease; the data for which are limited in humans. Pituitary tumors can have manifestations similar to rheumatologic disorders and should be included in the differential diagnosis of these diseases
— id: 111711, year: 2001, vol: 3, page: 459, stat: Journal Article,

IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis
Kleinberg DL; Feldman M; Ruan W
2000 Jan;5(1):7-17, Journal of mammary gland biology & neoplasia
Growth hormone (GH) is essential for rodent mammary gland development during puberty. It binds to GH receptors in the stromal compartment of the mammary gland and stimulates IGF-I mRNA expression. These findings lead to the hypothesis that GH acts through locally produced IGF-I, which in turn, causes development of terminal end buds (TEBs), the structures that lead the process of mammary gland development during puberty. Subsequent studies have in large measure proven this hypothesis. They include the observations that mammary development was grossly impaired in female mice deficient in IGF-I (IGF-I(-/-) knockout mice), and treatment of these mice with IGF-I plus estradiol (E2) restored pubertal mammary development while treatment with GH + E2 did not. Thus, the full phenotypic action of GH in mammary gland development is mediated by IGF-I. We have demonstrated one effect of GH on the mammary gland that does not appear to be mediated by the action of IGF-I. GH increased the level of estrogen receptor (ER) mRNA and protein in the nuclei of mammary fat pad cells, but IGF-I did not. In addition to the critical role of the GH/IGF-I axis during pubertal mammary development, other data suggest that IGF-I might also be of importance during pregnancy and lactation. In summary, the earliest phase of pubertal mammary development (formation of TEBs) requires IGF-I or GH in IGF-I sufficient animals. No other hormones have been shown to stimulate formation of TEBs unless GH or IGF-I is present. GH-induced IGF-I is of major importance in ductal morphogenesis, and may, in fact, be necessary for later stages of mammary development, as well
— id: 11724, year: 2000, vol: 5, page: 7, stat: Journal Article,

Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant
Trainer, PJ; Drake, WM; Katznelson, L; Freda, PU; Herman-Bonert, V; van der Lely, AJ; Dimaraki, EV; Stewart, PM; Friend, KE; Vance, ML; Besser, GM; Scarlett, JA; Thorner, MO; Parkinson, C; Klibanski, A; Powell, JS; Barkan, AL; Sheppard, MC; Maldonado, M; Rose, DR; Clemmons, DR; Johannson, G; Bengtsson, BA; Stavrou, S; Kleinberg, DL; Cook, DM; Phillips, LS; Bidlingmaier, M; Strasburger, CJ; Hackett, S; Zib, K; Bennett, WF; Davis, RJ
2000 APR 20 ;342(16):1171-1177, New England journal of medicine
Background: Patients with acromegaly are treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone. Methods: We conducted a 12-week, randomized, double-blind study of three different daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. Results: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score for total symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P less/equal 0.05). The incidence of adverse effects was similar in all groups. Conclusions: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement. (N Engl J Med 2000;342:1171-7.) (C) 2000, Massachusetts Medical Society
— id: 54714, year: 2000, vol: 342, page: 1171, stat: Journal Article,

The effect of GH on estrogen receptor expression in the rat mammary gland
Feldman M; Ruan W; Tappin I; Wieczorek R; Kleinberg DL
1999 Dec;163(3):515-522, Journal of endocrinology
Both GH and insulin-like growth factor I (IGF-I) synergize with estrogen to induce normal mammary gland development. However, the nature of this synergy has not been explored. To gain insight into the mechanism of these interactions we have examined the effects of these substances on the estrogen receptor (ER). ER levels in the mammary gland cytosols from hypophysectomized and oophorectomized rats, were measured using two assay systems: a dextran-coated charcoal procedure to measure binding to radiolabeled steroid, and an immunologic assay employing a specific antibody to the receptor. In both assays, levels of ER were at or near baseline detection (approximately 1-2 ng/mg protein). Treating animals with either bovine or human GH significantly increased ER activity (P<0.001), whereas prolactin (PRL) and/or estradiol treatment had no effect. That this increase was at the level of transcription was demonstrated by reverse transcriptase/polymerase chain reaction. Following a single injection of GH (50 microgram), a substantial increase in ER mRNA was observed by 10 h, with levels returning to baseline within 24 h; a concomitant increase in ER itself was also observed at the 10 h time point. The effect of GH appeared to occur mainly in the mammary stroma, because there were no differences in GH stimulation of ER between gland-free and gland containing mammary fat pads. Furthermore, analysis of mammary gland ER by immunocytochemistry demonstrated that while ER was present in the epithelial cells of non-treated animals, only GH treated animals had ER clearly visible in both glandular and fat cells of the tissue. In contrast, treating animals with des(1-3)-IGF-I did not result in reproducible increases in ER, nor in the staining of fat cell nuclei for ER. These data demonstrate a specific GH effect on the ER in the mammary fat cell
— id: 8597, year: 1999, vol: 163, page: 515, stat: Journal Article,

Prolactin levels and adverse events in patients treated with risperidone
Kleinberg DL; Davis JM; de Coster R; Van Baelen B; Brecher M
1999 Feb;19(1):57-61, Journal of clinical psychopharmacology
Hyperprolactinemia is a common clinical disorder that may lead to sexual dysfunction or galactorrhea. It may arise from a variety of etiologies, including the use of antipsychotic agents, presumably because of a dopamine receptor blockade. This analysis was designed to characterize the relationship between risperidone, serum prolactin levels, and possible clinical sequelae. All data from randomized, double-blind studies of risperidone in patients with chronic schizophrenia were analyzed. The two largest studies (the North American and multinational trials) included 841 patients (259 women, 582 men) with paired prolactin level data and 1,884 patients (554 women, 1,330 men) with data on six adverse events possibly associated with increased prolactin levels (amenorrhea, galactorrhea, and decreased libido in women; erectile dysfunction, ejaculatory dysfunction, gynecomastia, and decreased libido in men). Both risperidone and haloperidol produced dose-related increases in plasma prolactin levels in men and women. Among women, the risperidone dose was not correlated with adverse events, nor were the adverse events correlated with endpoint prolactin levels. Among men, the incidence of adverse events was positively correlated with risperidone dose; however, at risperidone doses of 4 to 10 mg/day the incidence of adverse events was not significantly higher than that observed in patients receiving placebo. Furthermore, adverse events in men were unrelated to plasma prolactin levels. Risperidone-associated increase in serum prolactin levels was not significantly correlated to the emergence of possible prolactin-related side effects
— id: 7373, year: 1999, vol: 19, page: 57, stat: Journal Article,

Insulin-like growth factor I is essential for terminal end bud formation and ductal morphogenesis during mammary development
Ruan W; Kleinberg DL
1999 Nov;140(11):5075-5081, Endocrinology
Previous studies from this laboratory have emphasized the essential role of GH in pubertal mammary development and shown that insulin-like growth factor I (IGF-I) was capable of substituting for GH in this process in rats and mice. The present study shows that, even when GH is present, no mammary development is possible unless IGF-I is present. IGF-I(-/-) null female animals were found to have significantly less mammary development than age matched wild-type controls (P <0.006) using several endpoints including the number of terminal end buds or TEBs (1.3 vs. 7.3), percent of the fat pad occupied by glandular elements (6.5 vs. 100), and number of ducts (15 vs. too numerous to count). That the deficiency in mammary gland development was related to the absence of IGF-I was underscored by the observation that des (1-3) IGF-I administration to IGF-I(-/-) null animals for 5 days caused significant mammary gland development as measured by TEB formation and branching of ducts. The number of TEBs rose from a mean of 1.3 in controls to 20.5 without added E2 (P < 0.009), and from 1.7 to 21 when des (1-3) IGF-I was given together with E2 (P < 0.006). The number of ducts increased significantly from a mean of 12 to 27 in response to IGF-I and E2, and from 15 to 24.5 with IGF-I alone. In contrast, administration of human GH with E2 had no stimulatory effect on mammary development in these animals, indicating that the full effect of GH in this process is mediated by IGF-I. To determine whether IGF-I was also responsible for further ductal morphogenesis, we administered des (1-3) IGF-I + E2 to the knockout animals for 14 days and compared the effects of this combination of hormones on mammary development with those observed after 5 days. We found that there was a significant increase from 5 to 14 days in the number of TEBs (mean: 21 vs. 41) and the area of the mammary fat pad occupied by glands (mean: 10 vs. 20%). There was elongation and thickening of the ducts which accounted for the increased area that was occupied by ductal structures. There was no significant increase in the number of ducts. However, there was the appearance of a large number of buds along the length of the ductal structures, suggesting the beginning of side branching. These results suggest that IGF-I, when given along with E2, is responsible for ductal morphogenesis
— id: 11939, year: 1999, vol: 140, page: 5075, stat: Journal Article,

Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development
Ruan W; Powell-Braxton L; Kopchick JJ; Kleinberg DL
1999 May;140(5):1984-1989, Endocrinology
Insulin-like growth factor I (IGF-I) has been implicated as a factor that may predispose one to prostate cancer. However, no specific relationship between IGF-I and prostate development or cancer in vivo has been established. To determine whether IGF-I was important in prostate development, we examined prostate architecture in IGF-I(-/-) null mice and wild-type littermates. Glands from 44-day-old IGF-I-deficient animals were not only smaller than those from wild-type mice, but also had fewer terminal duct tips and branch points and deficits in tertiary and quaternary branching (P < 0.0001), indicating a specific impairment in gland structure. Administration of des(1-3)-IGF-I for 7 days partially reversed the deficit by increasing those parameters of prostate development (P < 0.006). That IGF-I production probably mediates an effect of GH in this process was indicated by the observations that GH antagonist transgenic mice also had significantly impaired prostate development (P < 0.0002) and that bovine GH had no independent effect on stimulating prostate development in IGF-I null animals. The data indicate that IGF-I deficiency is the proximate cause of impaired prostate development and give credence to the idea that, like testosterone, GH and IGF-I may be involved in prostate cancer growth as an extension of a normal process
— id: 12020, year: 1999, vol: 140, page: 1984, stat: Journal Article,

Role of IGF-I in normal mammary development
Kleinberg DL
1998 Feb;47(3):201-208, Breast cancer research & treatment
Growth hormone (GH) is now believed to be the pituitary factor that is responsible for mammary ductal morphogenesis. Mammary development at puberty occurs because of synergy between GH and estrogen on formation of terminal end buds (TEBs). TEBs extend into the substance of the mammary gland fat pad, resulting in ductal morphogenesis. Ultimately, the whole mammary fat pad accommodates a complex network of ducts. IGF-I or des(1-3) IGF-I mimic the actions of GH on TEB formation in hypophysectomized, gonadectomized rats. Since GH stimulates IGF-I mRNA within the mammary gland synergistically, we hypothesize that IGF-I partially mediates actions of GH in mammary gland development. Studies in transgenic mice overexpressing IGF-I, des(1-3) IGF-I, or IGFBP-3 show that IGF-I causes ductal hypertrophy in the lactating mouse and prevention of post-lactational mammary gland involution. One of the mechanisms for this effect involves apoptosis. The potential role of GH or IGF-I in mammary carcinogenesis, and the applicability of animal studies to humans, are discussed
— id: 57178, year: 1998, vol: 47, page: 201, stat: Journal Article,

Current treatment guidelines for acromegaly
Melmed, S; Jackson, I; Kleinberg, D; Klibanski, A
1998 AUG ;83(8):2646-2652, Journal of clinical endocrinology & metabolism
Acromegaly, an indolent disorder of growth hormone (GH) hypersecretion is most typically caused by a somatotroph cell adenoma and may be treated by several modalities. Transsphenoidal surgical resection of micro-adenomas by experienced neurosurgeons results in biochemical normalization (postglucose GH <2 ng/mL, assay-dependent, age- and sex-matched IGF-I levels) in 70% of patients. However, over 65% of GH-secreting adenomas are invasive or macroadenomas, and over 50% of these patients have persistent postoperative GH hypersecretion. Irradiation of adenomas results in attenuation of GH secretion to more than 5 ng/mL in 50% of subjects after 12 yr. However, the percent of parents who normalize IGF-I levels is less certain. Most of these patients develop associated pituitary failure and rarely develop other local adverse effects. About 60% of patients receiving somatostatin analogs achieve normalized IGF-I levels. Efficacy of medical management with somatostatin analogs may be improved by increasing injection frequency, changing delivery modes to depot preparations, and in the future, development of novel SRIF receptor subtype-specific analogs. An integrated approach to acromegaly management based upon relative risks and benefits of the currently available therapeutic modes is presented that allows for a national individualized strategy designed to achieve maximal biochemical control. of GH hypersecretion and elevated IGF-I levels
— id: 53393, year: 1998, vol: 83, page: 2646, stat: Journal Article,

Octreotide as primary therapy for acromegaly
Newman CB; Melmed S; George A; Torigian D; Duhaney M; Snyder P; Young W; Klibanski A; Molitch ME; Gagel R; Sheeler L; Cook D; Malarkey W; Jackson I; Vance ML; Barkan A; Frohman L; Kleinberg DL
1998 Sep;83(9):3034-3040, Journal of clinical endocrinology & metabolism
The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989-1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 micrograms octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient's individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range. In the second phase of the study, in which patients were randomized to either 100 or 250 micrograms octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 +/- 5.2 to 6.0 +/- 1.7 micrograms/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3-60 months). The mean final daily dose was 777 micrograms. In the patients receiving secondary treatment, mean GH fell from 30.2 +/- 7.6 to 5.6 +/- 1.1 micrograms/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 micrograms daily). Mean IGF-I concentrations fell from 5.2 +/- 0.5 x 10(3) U/L (primary treatment group) and 4.7 +/- 0.4 x 10(3) U/L (secondary treatment group) to a mean of 2.2 +/- 0.3 x 10(3) U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group. Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups. Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50-100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62-88%. Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH. In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. (AB
— id: 57219, year: 1998, vol: 83, page: 3034, stat: Journal Article,

Adult growth hormone deficiency
Newman, CB; Kleinberg, DL
1998 MAY ;8(3):178-186, Endocrinologist
Growth hormone (GH) deficiency should he suspected in adults with either hypothalamic or pituitary disease, a history of pituitary or whole brain radiation, or a history of GH treatment during childhood. Clinical manifestations include abnormal body composition (increased fat, decreased lean mass, and lo iv bone density), reduced exercise ca pacity, and unfavorable lipid profile thigh total and LDL cholesterol, low HDL). Although some GH-deficient adults are asymptomatic, others have nonspecific complaints of fatigue, low energy level, and impairment of memory and concentration. The diagnosis of GH deficiency should be confirmed by at least one provocative test. We define GH deficiency as the failure of GH to rise above 3 ng/mL in response to an appropriate stimulus, such as insulin-induced hypoglycemia, L-dopa, or arginine. GH replacement should be reserved for patients with documented GI-I deficiency who show no evidence of active malignancy and do not have severe edema or a history of carpal tunnel syndrome. GI-I treatment of the GH-deficient adult has been shown to have positive effects on body composition, exercise tolerance, and lipids. In nine placebo controlled studies in 392 adults using GH doses ranging between 2.6 and 26 mu g per kg per day, mean body fat decreased 4.4% and mean lean body mass increased 3.4 kp. These changes were seen after 6 months. increase in hip and spine bone mineral density required longer periods of treatment. GH replacement also has been found to increase maximal oxygen consumption, exercise capacity, ventricular ejection fraction, and cardiac output. Improvement in muscle strength has not been demonstrated convincingly, Most studies have shown reduction in total and LDL cholesterol and either increased or unchanged I-IDL, GH's effects on psychological parameters have been difficult to evaluate and require further study Adverse effects, which are more frequent in patients treated with higher doses of GH, include edema of the hands and feet, arthralgias, myalgias, and paresthesias of the fingers. These problems diminish or resolve with dose reduction. In conclusion, GH deficiency in adulthood is recognized as a syndrome that may benefit from treatment. GH replacement should, therefore, be considered in individuals with hypothalamic-pituitary disease who have an abnormal GH response during at least one provocative test. Additional studies are needed to determine the consequences of long-standing GH deficiency and whether the beneficial effects observed during the first 18 months of GH replacement diminish, plateau, or continue to improve during chronic treatment
— id: 53450, year: 1998, vol: 8, page: 178, stat: Journal Article,

Evidence that the mammary fat pad mediates the action of growth hormone in mammary gland development
Walden PD; Ruan W; Feldman M; Kleinberg DL
1998 Feb;139(2):659-662, Endocrinology
Recent evidence from our laboratory suggests that GH and insulin-like growth factor I (IGF-I) mediate glandular mammary development together with estrogen. It has also been well established that both stromal and epithelial elements must interact for mammary glandular development to occur. To determine whether the effect of GH is mediated by the stromal or epithelial tissue, we set up the following experiment. Bovine GH (bGH; 100 microg) or BSA (as a control), without or with estradiol (E2), was injected i.p. into sexually immature female rats that were hypophysectomized and oophorectomized. Mammary glands and subscapular fat pads were removed from the animals. The mammary glands were divided into two parts: a gland-free fat pad and remaining glandular tissue. The end point of bGH activity was induction of IGF-I messenger RNA (mRNA). This was determined quantitatively by solution hybridization and also by RT-PCR. We found that the effects of GH on stimulation of IGF-I mRNA in the gland-free mammary fat pad and the remainder of the mammary gland were similar (3.6- vs. 3.9-fold, respectively; P < 0.001). In both sorts of mammary tissue, bGH was found to synergize with E2 in the induction of IGF-I mRNA (5.8- vs. 5.3-fold; P < 0.001). There was also an increase in IGF-I mRNA in subscapular fat pads in response to 100 microg bGH (5.3-fold; P < 0.001); however, no synergism between bGH and E2 was found. These data indicate that bGH works as well on mammary stromal tissue as on tissue with glands and suggests that GH acts on the stromal compartment of the mammary gland to induce IGF-I mRNA and possibly IGF-I itself, which, in turn, causes differentiation of epithelial ducts into terminal end buds. These data also might explain why mammary epithelium is also able to differentiate in nonmammary fat pads when transplanted there
— id: 7840, year: 1998, vol: 139, page: 659, stat: Journal Article,

Early mammary development: growth hormone and IGF-1
Kleinberg DL
1997 Jan;2(1):49-57, Journal of mammary gland biology & neoplasia
The first step in pubertal mammary development is the appearance of terminal end buds arising from pleuropotent stem cells present in the immature ductal tree of the prepubertal animal. Work from this laboratory indicates that growth hormone is the pituitary hormone responsible for terminal end bud development. Growth hormone likely acts through the production of IGF-1. This minireview focuses on the hormonal control of early mammary development with special emphasis on the roles of growth hormone and IGF-1
— id: 11608, year: 1997, vol: 2, page: 49, stat: Journal Article,

Pharmacological therapies and surgical options in the treatment of hyperprolactinemia
Kleinberg, DL
1997 SEP-OCT ;7(5):379-384, Endocrinologist
In this paper we review causes of hyperprolactinemia. These include prolactinomas, nonprolactin secreting pituitary tumors, other tumors located in the area of the pituitary gland and hypothalamus, granulomatous diseases, hypothyroidism, and medications. Therapeutic options for hyperprolactinemia of the various causes also are discussed
— id: 53174, year: 1997, vol: 7, page: 379, stat: Journal Article,

A novel whey to study effects of insulin-like growth factor-I on mammary development
Kleinberg DL
1996 Jan;137(1):1-2, Endocrinology
— id: 18390, year: 1996, vol: 137, page: 1, stat: Journal Article,

Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men--a clinical research center study
Wang C; Eyre DR; Clark R; Kleinberg D; Newman C; Iranmanesh A; Veldhuis J; Dudley RE; Berman N; Davidson T; Barstow TJ; Sinow R; Alexander G; Swerdloff RS
1996 Oct;81(10):3654-3662, Journal of clinical endocrinology & metabolism
To study the effects of androgen replacement therapy on muscle mass and strength and bone turnover markers in hypogonadal men, we administered sublingual testosterone (T) cyclodextrin (SLT; 5 mg, three times daily) to 67 hypogonadal men (baseline serum T, < 8.4 nmol/L) recruited from 4 centers in the U.S.: Torrance (n = 34), Durham (n = 12), New York (n = 9), and Salem (n = 12). Subjects who had received prior T therapy were withdrawn from injections for at least 6 weeks and from oral therapy for 4 weeks. Body composition, muscle strength, and serum and urinary bone turnover markers were measured before and after 6 months of SLT. We have shown previously that this regimen for 60 days will maintain adequate serum T levels and restore sexual function. Total body (P = 0.0104) and lean body mass (P = 0.007) increased with SLT treatment in the 34 subjects in whom body composition was assessed. There was no significant change in total body fat or percent fat. The increase in lean body mass was mainly in the legs; the right leg lean mass increased from 8.9 +/- 0.3 kg at 0 months to 9.2 +/- 0.3 kg at 6 months (P = 0.0008). This increase in leg lean mass was associated with increased leg muscle strength, assessed by leg press (0 months, 139.0 +/- 4.0 kg; 6 months, 147.7 +/- 4.2 kg; P = 0.0038). SLT replacement in hypogonadal men led to small, but significant, decreases in serum Ca (P = 0.0029) and the urinary calcium/creatinine ratio (P = 0.0066), which were associated with increases in serum PTH (P = 0.0001). At baseline, the urinary type I collagen-cross linked N-telopeptides/creatinine ratio [75.6 +/- 7.9 nmol bone collagen equivalents (BCE/mmol] was twice the normal adult male mean (41.0 +/- 3.6 nmol BCE/mmol) and was significantly decreased in response to SLT treatment at 6 months (68.2 +/- 7.7 nmol BCE/mmol; P = 0.0304) without significant changes in urinary creatinine. Serum skeletal alkaline phosphatase did not change. In addition, SLT replacement caused significant increases in serum osteocalcin (P = 0.0001) and type I procollagen (P = 0.0012). Bone mineral density did not change during the 6 months of SLT treatment. We conclude that SLT replacement therapy resulted in increases in lean muscle mass and muscle strength. Like estrogen replacement in hypogonadal postmenopausal females, androgen replacement therapy led to decreased bone resorption and urinary calcium excretion. Moreover, androgen replacement therapy may have the additional benefit of increasing bone formation. A longer term study for several years duration would be necessary to demonstrate whether these changes in bone turnover marker levels will result in increased bone mineral density decreased fracture risks, and reduced frailty in hypogonadal men
— id: 18389, year: 1996, vol: 81, page: 3654, stat: Journal Article,

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
Ruan, W; Catanese, V; Wieczorek, R; Feldman, M; Kleinberg, D L
1995 Mar;136(3):1296-1302, Endocrinology
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
— id: 138562, year: 1995, vol: 136, page: 1296, stat: Journal Article,

Galactorrhea
Kleinberg DL
1994 ;5:360-364, Current therapy in endocrinology & metabolism
— id: 13040, year: 1994, vol: 5, page: 360, stat: Journal Article,

Visual loss in pregnant women with pituitary adenomas [see comments]
Kupersmith MJ; Rosenberg C; Kleinberg D
1994 Oct 1;121(7):473-477, Annals of internal medicine
OBJECTIVE: To investigate the potential risk for developing visual loss during single or multiple pregnancies in women with pituitary adenomas. DESIGN: Cohort study. SETTING: Referral center of a neuro-ophthalmology service. PATIENTS: 65 consecutive women with pituitary adenomas who had not been previously treated with surgery or radiation were monitored during 111 pregnancies. Sixty had increased levels of serum prolactin or growth hormone and 5 did not. MAIN OUTCOME MEASURES: Visual field or acuity loss was compared with the baseline size of the adenoma measured on the coronal view of the computed tomographic or magnetic resonance image. RESULTS: Computed tomography or magnetic resonance imaging showed a definitive tumor (> 0.3 cm, vertical height) in 57 patients, 8 of whom had macroadenomas (> or = 1.1 cm). Visual field loss occurred in 6 of 8 primiparous patients, all with adenomas greater than 1.1 cm (range, 1.2 to 2.5 cm). None of the 57 patients (95% CI, 0% to 6.3%) with a microadenoma or presumed microadenoma of 1 cm or smaller developed visual loss after as many as four full-term pregnancies. CONCLUSIONS: The risk for developing visual loss during single or multiple pregnancies in patients with microadenomas was small. Six of eight pregnant women with macroadenomas, however, developed visual field loss during pregnancy
— id: 6666, year: 1994, vol: 121, page: 473, stat: Journal Article,

Identification of rat liver phosphatidylinositol synthase as a 21 kDa protein
Monaco ME; Feldman M; Kleinberg DL
1994 Nov 15;304 ( Pt 1):301-305, Biochemical journal
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
— id: 56687, year: 1994, vol: 304 ( Pt 1), page: 301, stat: Journal Article,

P53 PROTEIN OVEREXPRESSION IN MALE BREAST-CANCER - CLINICOPATHOLOGICAL (CPC) CORRELATION
WIECZOREK, R; HELLER, P; FEINER, H; SIDHU, G; DEMOPOULOS, R; JAGIRDAR, J; KLEINBERG, D; FELDMAN, M; SUHRLAND, M
1994 ;70(Suppl 1):A24-A24, Laboratory investigation
— id: 52574, year: 1994, vol: 70, page: A24, stat: Journal Article,

Evidence that the growth hormone receptor mediates differentiation and development of the mammary gland
Feldman M; Ruan W; Cunningham BC; Wells JA; Kleinberg DL
1993 Oct;133(4):1602-1608, Endocrinology
We have shown that nonlactogenic rat (r) GH is far more potent than rPRL in inducing rat mammary development. To determine the relative roles of GH and PRL in mammary development and their mechanisms of action, we have compared the abilities of a group of native and mutant GHs, PRLs, and placental lactogens (PLs) to induce mammary development, bind to GH receptors, and activate lactogenic receptors. Mammary development was assessed histologically by counting terminal end buds and alveolar structures in glands from sexually immature, hypophysectomized, castrated, estradiol-treated rats. Hormones were implanted, in Elvax pellets, into the lumbar mammary gland. Significant increases in terminal end buds (P < 0.03) over internal control values were obtained with rGH, recombinant human GH (rhGH), rbGH, and one of two mutant rhGHs. These four hormones were also found to bind to GH receptors with high affinity. In contrast, little development occurred with hPRL, rPRL, rhPL, ovine PRL, mutant forms of rhPRL and rhPL, and a mutant of rhGH altered to reduce binding to GH and PRL receptors. All of these substances are more than 50-fold reduced in binding to the GH receptor, yet can bind and activate lactogenic receptors. Thus, only those natural or mutant pituitary or placental hormones with high binding affinity to GH receptors induce mammary development, suggesting that GH receptors play a central role in this process
— id: 8218, year: 1993, vol: 133, page: 1602, stat: Journal Article,

Intact and amino-terminally shortened forms of insulin-like growth factor I induce mammary gland differentiation and development
Ruan W; Newman CB; Kleinberg DL
1992 Nov 15;89(22):10872-10876, Proceedings of the National Academy of Sciences of the United States of America
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
— id: 18391, year: 1992, vol: 89, page: 10872, stat: Journal Article,

Ovarian control of pituitary hormone secretion in early human pregnancy
Emmi AM; Skurnick J; Goldsmith LT; Gagliardi CL; Schmidt CL; Kleinberg D; Weiss G
1991 Jun;72(6):1359-1363, Journal of clinical endocrinology & metabolism
To determine the influence of ovarian relaxin on the secretion of pituitary GH and PRL in vivo, we evaluated circulating serum hormone levels in 17 pregnant patients with functional corpora lutea (group I) and compared them to levels in 10 patients with premature ovarian failure (POF; group II) who became pregnant with egg donation and did not have corpora lutea. Group II patients had exogenous hormonal support. Serum relaxin (RLX), GH, PRL, estradiol (E2), and progesterone levels were measured weekly by RIA from weeks 4-8 of pregnancy. Analysis of variance and covariance were used to determine hormonal relationships. Serum RLX was present in the natural pregnancy group, with a mean of 1.94 micrograms/L over the study period. Serum RLX was undetectable in the POF patients (less than 0.16 micrograms/L). No significant difference in PRL or progesterone levels between the two groups was noted. E2 levels showed an upward trend in both groups with time and were significantly higher in patients of the POF group than in group I women (P = 0.001). GH levels were significantly higher in the natural cycle patients (P = 0.02) despite lower E2 levels. These data provide additional support for the concept that RLX production in early pregnancy originates from the corpus luteum. They suggest that a luteal product, probably RLX, stimulates GH secretion in early pregnancy. This is a previously undescribed role for RLX in pituitary physiology during human pregnancy
— id: 25517, year: 1991, vol: 72, page: 1359, stat: Journal Article,

FINE NEEDLE ASPIRATION (FNA) OF PRIMARY BREAST-CARCINOMA FOR FLOW CYTOMETRIC (FCM) DNA ANALYSIS
Eliasen, C; Opitz, L; Rizk, C; Vamvakas, E; Kleinberg, D; Roses, D; Harris, M; Feiner, H
1990 ;62(Suppl 1):A30-A30, Laboratory investigation
— id: 32017, year: 1990, vol: 62, page: A30, stat: Journal Article,

Non-lactogenic effects of growth hormone on growth and insulin-like growth factor-I messenger ribonucleic acid of rat mammary gland
Kleinberg DL; Ruan W; Catanese V; Newman CB; Feldman M
1990 Jun;126(6):3274-3276, Endocrinology
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
— id: 18392, year: 1990, vol: 126, page: 3274, stat: Journal Article,

GROWTH-HORMONE (GH) IS A MORE POTENT MAMMARY MITOGEN THAN PROLACTIN (PRL) INVIVO
RUAN, WF; FELDMAN, M; NEWMAN, CB; KLEINBERG, DL
1990 APR ;38(2):A343-A343, Clinical research
— id: 98508, year: 1990, vol: 38, page: A343, stat: Journal Article,

Growth of prolactinoma despite lowering of serum prolactin by bromocriptine
Kupersmith MJ; Kleinberg D; Warren FA; Budzilovitch G; Cooper P
1989 Mar;24(3):417-423, Neurosurgery
Four patients with macroprolactinomas treated with bromocriptine had tumor growth and visual loss despite marked reduction in their serum prolactin levels. Explanations for this dissociation of tumor growth and prolactin measurement might include noncompliance. Patients treated with bromocriptine require periodic examination by computed tomographic scan or magnetic resonance imaging and neuro-ophthalmological evaluation in addition to monitoring of serum prolactin
— id: 10699, year: 1989, vol: 24, page: 417, stat: Journal Article,

Effect of CV 205-502 in hyperprolactinaemic patients intolerant of bromocriptine
Newman CB; Hurley AM; Kleinberg DL
1989 Oct;31(4):391-400, Clinical endocrinology
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)
— id: 18393, year: 1989, vol: 31, page: 391, stat: Journal Article,

Isolation and characterization of monoclonal antibodies against ribonuclease inhibitor
Feldman M; Kohtz DS; Kleinberg DL
1988 Nov 30;157(1):286-294, Biochemical & biophysical research communications
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
— id: 10883, year: 1988, vol: 157, page: 286, stat: Journal Article,

PROLACTIN AND BREAST-CANCER
Kleinberg, DL
1987 Jan 29;316(5):269-271, New England journal of medicine
— id: 31285, year: 1987, vol: 316, page: 269, stat: Journal Article,

Evidence for a nonprolactin, non-growth-hormone mammary mitogen in the human pituitary gland
Newman CB; Cosby H; Friesen HG; Feldman M; Cooper P; De Crescito V; Pilon M; Kleinberg DL
1987 Nov;84(22):8110-8114, Proceedings of the National Academy of Sciences of the United States of America
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
— id: 18394, year: 1987, vol: 84, page: 8110, stat: Journal Article,

The pituitary gland in primate mammary development: evidence that prolactin is not essential
Kleinberg DL; Newman CB
1986 ;464(22):37-43, Annals of the New York Academy of Sciences
— id: 18395, year: 1986, vol: 464, page: 37, stat: Journal Article,

NOVEL HUMAN PITUITARY FACTORS STIMULATE GROWTH OF MAMMARY-CANCER CELLS AND NORMAL MAMMARY-GLAND
NEWMAN, CB; COSBY, H; FRIESEN, H; STAMPFER, M; MONACO, ME; KLEINBERG, DL
1986 APR ;34(2):A645-A645, Clinical research
— id: 41408, year: 1986, vol: 34, page: A645, stat: Journal Article,

Decreased prolactin secretion in childhood obesity
AvRuskin, T W; Pillai, S; Kasi, K; Juan, C; Kleinberg, D L
1985 Mar;106(3):373-378, Journal of pediatrics
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
— id: 122850, year: 1985, vol: 106, page: 373, stat: Journal Article,

Primate mammary development. Effects of hypophysectomy, prolactin inhibition, and growth hormone administration
Kleinberg DL; Niemann W; Flamm E; Cooper P; Babitsky G; Valensi Q
1985 Jun;75(6):1943-1950, Journal of clinical investigation
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
— id: 33566, year: 1985, vol: 75, page: 1943, stat: Journal Article,

COMPUTED-TOMOGRAPHY OF HYPERPROLACTINEMIA UNDER TREATMENT WITH PERGOLIDE
GEORGE, AE; KLEINBERG, DL; FRANTZ, AG; BOYD, AE; WARDLAW, S; GREISING, J; SELTZER, T
1983 ;7(1):193-193, Journal of computer assisted tomography
— id: 40744, year: 1983, vol: 7, page: 193, stat: Journal Article,

PERGOLIDE FOR THE TREATMENT OF PITUITARY-TUMORS SECRETING PROLACTIN OR GROWTH-HORMONE
Kleinberg, DL; Boyd, AE; Wardlaw, S; Frantz, AG; George, A; Bryan, N; Hilal, S; Greising, J; Hamilton, D; Seltzer, T; Sommers, CJ
1983 ;309(12):704-709, New England journal of medicine
— id: 30618, year: 1983, vol: 309, page: 704, stat: Journal Article,

ANTAGONISM OF PROLACTIN STIMULATED LACTOGENESIS IN PRIMATE MAMMARY TISSUE BY ESTRADIOL - A NEW FUNCTION FOR ESTROGENS IN MAMMARY PHYSIOLOGY
KLEINBERG, DL; TODD, J; BABITSKY, G
1983 JAN 20 ;31(2):A471-A471, Clinical research
— id: 98615, year: 1983, vol: 31, page: A471, stat: Journal Article,

INHIBITION BY ESTRADIOL OF THE LACTOGENIC EFFECT OF PROLACTIN IN PRIMATE MAMMARY TISSUE - REVERSAL BY ANTI-ESTROGENS LY- 156758 AND TAMOXIFEN
Kleinberg, DL; Todd, J; Babitsky, G
1983 ;80(13):4144-4148, Proceedings of the National Academy of Sciences of the United States of America
— id: 30635, year: 1983, vol: 80, page: 4144, stat: Journal Article,

ESTRADIOL INHIBITS PROLACTIN INDUCED ALPHA-LACTALBUMIN PRODUCTION IN NORMAL PRIMATE MAMMARY TISSUE INVITRO
Kleinberg, DL; Todd, J; Babitsky, G; Greising, J
1982 ;110(1):279-281, Endocrinology
— id: 30589, year: 1982, vol: 110, page: 279, stat: Journal Article,

Immunohistochemical and electron-microscopic studies of functional and non-functional pituitary adenomas including one TSH secreting tumor in a thyrotoxic patient
Cravioto, H; Fukaya, T; Zimmerman, E A; Kleinberg, D L; Flamm, E S
1981 ;53(4):281-292, Acta neuropathologica
— id: 118103, year: 1981, vol: 53, page: 281, stat: Journal Article,

A double-blind comparison of trebenzomine and thioridazine in the treatment of schizophrenia
Georgotas A; Gerbino L; Jordan B; McCarthy M; Gershon S; Kleinberg D; Lautin A; Stanley M; Rotrosen J
1981 ;73(3):292-294, Psychopharmacology
Forty inpatient volunteers with diagnoses of schizophrenia were randomly assigned to treatment either with trebenzomine or thioridazine in a double-blind study of clinical antipsychotic efficacy following a 1-week placebo treatment. Psychopathology was rated using the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI). There was a significant difference in therapeutic response to the two drugs in that psychopathology decreased significantly for the thioridazine group, but not for the trebenzomine group. Serum prolactin was elevated during treatment with thioridazine, but not with trebenzomine. Side effects were more frequently reported for the thioridazine group. These results fail to confirm previous reports of clinical antipsychotic efficacy for trebenzomine
— id: 23647, year: 1981, vol: 73, page: 292, stat: Journal Article,

Treatment of advanced Parkinson disease with pergolide
Lieberman, A; Goldstein, M; Leibowitz, M; Neophytides, A; Kupersmith, M; Pact, V; Kleinberg, D
1981 Jun;31(6):675-682, Neurology
Pergolide mesylate, a semisynthetic ergoline and a potent, long-acting central dopamine agonist, was tested in 13 patients with advanced Parkinson disease and diurnal oscillations in performance ('wearing-off' or 'on-off' phenomena or both) whose response to levodopa had diminished considerably. Among all nine patients who completed the initial clinical trial, pergolide alone (two patients) or combined with levodopa (seven patients) had a marked antiparkinson effect. There was a significant reduction (p less than 0.05) in rigidity, bradykinesia, gait disorder and total Parkinson disease disability score. Pergolide had a marked effect in all the patients with 'wearing-off' or 'on-off' phenomena or both, resulting in a significant increase (p less than 0.01) in the duration of the time patients were 'on.' the number of hours in which patients were 'on' increased from 3.8 +/- 0.5 (SEM) to 11.4 +/0 ).8 (SEM). The main daily dose of pergolide was 2.4 mg (range, 2 to 5 mg). Ten months later, all nine patients are doing well. Pergolide is an effective drug in patients with advanced Parkinson disease and reduces 'on-off' phenomena
— id: 122222, year: 1981, vol: 31, page: 675, stat: Journal Article,

Lisuride in Parkinson disease: efficacy of lisuride compared to levodopa
Lieberman, A; Goldstein, M; Neophytides, A; Kupersmith, M; Leibowitz, M; Zasorin, N; Walker, R; Kleinberg, D
1981 Aug;31(8):961-965, Neurology
Lisuride hydrogen maleate, a semisynthetic ergoline and potent central dopamine and serotonin agonist, was tested in 10 patients with moderate to marked Parkinson disease whose response to levodopa had diminished. In the group of 10 patients, there was a significant reduction (p less than or equal to 0.05) in bradykinesia, gait disorder, and total Parkinson disease disability score when levodopa was replaced with lisuride. The mean dose of lisuride was 3.6 mg per day. Among the 10 patients, 5 were better on lisuride than on levodopa, and 4 continue on lisuride 1 year later. A decline in efficacy was noted in all four after a mean of 45 months. Adverse effects necessitating discontinuing the drug were mental changes in three patients and nausea in one patient. Lisuride, when used alone, has definite antiparkinsonian activity and is a promising new drug
— id: 122221, year: 1981, vol: 31, page: 961, stat: Journal Article,

Pergolide mesylate: a potent day-long inhibitor of prolactin in rhesus monkeys and patients with Parkinson's disease
Kleinberg, D L; Lieberman, A; Todd, J; Greising, J; Neophytides, A; Kupersmith, M
1980 Jul;51(1):152-154, Journal of clinical endocrinology & metabolism
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
— id: 122225, year: 1980, vol: 51, page: 152, stat: Journal Article,

EVIDENCE THAT HUMAN GROWTH-HORMONE IS A POTENT LACTOGEN IN PRIMATES
Kleinberg, DL; Todd, J
1980 ;51(5):1009-1013, Journal of clinical endocrinology & metabolism
— id: 28060, year: 1980, vol: 51, page: 1009, stat: Journal Article,

EFFECT OF PRL INHIBITION BY PERGOLIDE ON MONKEY MAMMARY-GLANDS
Kleinberg, DL; Todd, J; Niemann, W; Greising, J
1980 ;28(2):A480-A480, Clinical research
— id: 28117, year: 1980, vol: 28, page: A480, stat: Journal Article,

Metoclopramide: antipsychotic efficacy of a drug lacking potency in receptor models
Stanley M; Lautin A; Rotrosen J; Gershon S; Kleinberg D
1980 ;71(3):219-225, Psychopharmacology
Metoclopramide is a substituted benzamide derivative, structurally similar to procainamide and sulpiride. In behavioral, biochemical, and neuroendocrine tests it displays classic neuroleptic dopamine (DA) antagonist properties; in contrast to other DA antagonists, it lacks potency in currently used DA receptor models. In clinical studies using low doses or dubious measures, it was considered not to be efficacious as an antipsychotic. We now find that it indeed has a clinical profile similar to known neuroleptics when used in a dose range predicted from animal models. The findings raise questions regarding the validity and universality of several predictive models, as well as hypotheses purporting to explain molecular mechanisms of action of neuroleptic agents. The drug's inactivity in receptor models suggests that an as yet unidentified DA receptor subpopulation may be important as the mediator of many DA dependent neurobiologic phenomena
— id: 23655, year: 1980, vol: 71, page: 219, stat: Journal Article,

PITUITARY-TUMORS AND FAILURE OF ENDOCRINE TARGET ORGANS
Kleinberg, DL
1979 ;139(9):969-970, Archives of internal medicine
— id: 30081, year: 1979, vol: 139, page: 969, stat: Journal Article,

PROLACTIN IS LACTOGENIC IN BREAST-TISSUE OF IMMATURE PRIMATES
Kleinberg, DL; Todd, J
1979 ;27(2):A450-A450, Clinical research
— id: 30123, year: 1979, vol: 27, page: A450, stat: Journal Article,

EVIDENCE THAT PROLACTIN STIMULATES ALPHA-LACTALBUMIN PRODUCTION IN MAMMARY TISSUES FROM PRE-MENARCHEAL RHESUS-MONKEYS
Kleinberg, DL; Todd, J; Niemann, W
1979 ;104(6):1569-1573, Endocrinology
— id: 29733, year: 1979, vol: 104, page: 1569, stat: Journal Article,

Pergolide and lisuride for Parkinson's disease
Lieberman, A N; Leibowitz, M; Neophytides, A; Kupersmith, M; Mehl, S; Kleinberg, D; Serby, M; Goldstein, M
1979 Nov 24;2(8152):1129-1130, Lancet
— id: 122227, year: 1979, vol: 2, page: 1129, stat: Journal Article,

PATHOPHYSIOLOGY OF HYPERPROLACTINEMIC STATES AND ROLE OF NEWER ERGOT COMPOUNDS IN THEIR TREATMENT
FRANTZ, AG; KLEINBERG, DL
1978 ;37(8):2192-2197, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 40041, year: 1978, vol: 37, page: 2192, stat: Journal Article,

STUDIES WITH LERGOTRILE MESYLATE IN ACROMEGALY
KLEINBERG, DL; SCHAAF, M; FRANTZ, AG
1978 ;37(8):2198-2201, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 40042, year: 1978, vol: 37, page: 2198, stat: Journal Article,

ALPHA-LACTALBUMIN IN HUMAN AND SUBHUMAN PRIMATE NORMAL MAMMARY TISSUE AND IN HUMAN BREAST-CANCER AS A MARKER FOR PROLACTIN ACTIVITY
KLEINBERG, DL; TODD, J
1978 ;38(11):4318-4322, Cancer research
— id: 40034, year: 1978, vol: 38, page: 4318, stat: Journal Article,

PROLACTIN STIMULATION OF ALPHA-LACTALBUMIN IN NORMAL PRIMATE MAMMARY-GLAND
KLEINBERG, DL; TODD, J; NIEMANN, W
1978 ;47(2):435-441, Journal of clinical endocrinology & metabolism
— id: 98678, year: 1978, vol: 47, page: 435, stat: Journal Article,

Dopaminergic agonist properties of ephedrine--theoretical implications
Angrist B; Rotrosen J; Kleinberg D; Merriam V; Gershon S
1977 Dec 19;55(2):115-120, Psychopharmacology
Reports of ephedrine-induced psychoses resembling amphetamine psychosis prompted studies of this classic sympathomimetic agent in systems that indicate central dopaminergic actions. Ephedrine induced dose-related stereotyped behavior in rats. This behavior was antagonized by haloperidol, but not by alpha- or beta-adrenergic blockers. Pretreatment with AMPT, but not reserpine, attenuated the stereotypy induced by ephedrine under one of two sets of conditions. Consistent prolactin suppression in humans was not seen. These findings are discussed in the context of clinical and pharmacologic data regarding other dopamine agonist drugs (the central nervous system stimulants, apomorphine, ET 495). These data suggest the possibility that synergistic noradrenergic and dopaminergic facilitation may be important in the induction of the stimulant psychoses
— id: 23669, year: 1977, vol: 55, page: 115, stat: Journal Article,

GALACTORRHEA - STUDY OF 235 CASES, INCLUDING 48 WITH PITUITARY TUMORS
Kleinberg, DL; Noel, GL; Frantz, AG
1977 ;296(11):589-600, New England journal of medicine
— id: 29550, year: 1977, vol: 296, page: 589, stat: Journal Article,

IMPLICATIONS OF CIRCULATING PROLACTIN - REPLY
KLEINBERG, DL; NOEL, GL; FRANTZ, AG
1977 ;297(1):55-56, New England journal of medicine
— id: 39954, year: 1977, vol: 297, page: 55, stat: Journal Article,

STUDIES ON HUMAN ALPHA-LACTALBUMIN - RADIOIMMUNOASSAY MEASUREMENTS IN NORMAL HUMAN BREAST AND BREAST-CANCER
KLEINBERG, DL; TODD, J; GROVES, ML
1977 ;45(6):1238-1250, Journal of clinical endocrinology & metabolism
— id: 50013, year: 1977, vol: 45, page: 1238, stat: Journal Article,

POSITIVE FEEDBACK OF ESTROGEN ON LH-SECRETION IN WOMEN ON NEUROLEPTIC DRUGS
Weiss, G; Schmidt, C; Kleinberg, DL; Ganguly, M
1977 ;7(5):423-427, Clinical endocrinology
— id: 29562, year: 1977, vol: 7, page: 423, stat: Journal Article,

EFFECT OF PROLACTIN ON ALPHA-LACTALBUMIN IN NORMAL HUMAN AND PRIMATE BREAST
Kleinberg, DL; Todd, J; Niemann, W
1976 ;24(3):A273-A273, Clinical research
— id: 28753, year: 1976, vol: 24, page: A273, stat: Journal Article,

HUMAN ALPHA-LACTALBUMIN - MEASUREMENT IN SERUM AND IN BREAST-CANCER ORGAN-CULTURES BY RADIOIMMUNOASSAY
KLEINBERG, DL
1975 ;190(4211):276-278, Science
— id: 98733, year: 1975, vol: 190, page: 276, stat: Journal Article,

HUMAN ALPHA-LACTALBUMIN BY RADIOIMMUNOASSAY - SERUM AND ORGAN- CULTURE MEASUREMENTS
Kleinberg, DL; Todd, J
1975 ;23(3):A238-A238, Clinical research
— id: 28536, year: 1975, vol: 23, page: A238, stat: Journal Article,

The sesamoid index. An aid in the diagnosis of acromegaly
Kleinberg, D L; Young, I S; Kupperman, H S
1966 May;64(5):1075-1078, Annals of internal medicine
— id: 125510, year: 1966, vol: 64, page: 1075, stat: Journal Article,