Ann Danoff, M.D.

Effect of autoimmune thyroid disease in older euthyroid infertile woman during the first 35 days of an IVF cycle
Reh, Andrea; Chaudhry, Sonal; Mendelsohn, Felicia; Im, Shelly; Rolnitzky, Linda; Amarosa, Alana; Levitz, Mortimer; Srinivasa, Suman; Krey, Lewis; Berkeley, Alan S; Grifo, James A; Danoff, Ann
2011 Mar 1;95(3):1178-1181, Fertility & sterility
In this case-control study of euthyroid first-cycle IVF patients >/= 38 years old with singleton baby, miscarriage, biochemical pregnancy, and no pregnancy outcomes from 2005-2008, we assayed frozen serum for autoimmune thyroid disease (AITD) and thyroid function at cycle start, trigger, and 4 and 5 weeks' gestation. AITD prevalence in older infertile women was similar across clinical outcomes, and although AITD was associated with a higher baseline TSH, TSH remained within acceptable ranges, suggesting that T(4) supplementation may not affect maternal outcomes in older euthyroid AITD patients through 5 weeks gestation
— id: 138179, year: 2011, vol: 95, page: 1178, stat: Journal Article,

Energy, evolution, and human diseases: an overview
Roth, Jesse; Szulc, Alessandra L; Danoff, Ann
2011 Apr;93(4):875S-8783, American journal of clinical nutrition
In the symposium entitled 'Transcriptional controls of energy sensing,' the authors presented recent advances on 1) AMP kinase, an intracellular energy sensor; 2) PGC-1alpha (peroxisome proliferator-activated receptor gamma co-activator 1alpha), a transcriptional co-activator that has powerful effects on mitochondria; 3) methylation and demethylation in response to metabolic fluctuations; and 4) FGF21 (fibroblast growth factor 21) as an emerging hormone-like intercellular metabolic coordinator. This introduction places these advances within a broad overview of energy sensing and energy balance, with a focus on human evolution and disease. Four key elements of human biology are analyzed: 1) elevated body temperature; 2) complex prolonged reproductive pathways; 3) emergence of 4 large, well-defined fat depots, each with its own functional role; and 4) an immune system that is often up-regulated by nutrition-related signals, independent of the actual presence of a pathogen. We propose that an overactive immune system, including the 'metabolic syndrome,' was adopted evolutionarily in the distant past to help hold out against unconquerable infections such as tuberculosis, malaria, and trypanosomiasis. This immune activation is advantageous in the absence of other disease management methods, especially under conditions in which life expectancy is short. The inflammation has become a major agent of pathology in wealthy populations in whom the pathogens are a minor threat and life expectancy is long. The 'Conclusions' section sketches cautiously how understanding the molecules involved in energy sensing and energy balance may lead to specific therapies for obesity and diabetes and for their complications
— id: 134220, year: 2011, vol: 93, page: 875S, stat: Journal Article,

Can 'personalized diagnostics' promote earlier intervention for dysglycaemia? Hypothesis ready for testing
Dankner, Rachel; Danoff, Ann; Roth, Jesse
2010 Jan;26(1):7-9, Diabetes/metabolism research & reviews
The risk associated with progression to diabetes as well as for cardiovascular complications increases along a continuum, rather than being threshold-dependent. How can we identify those with glucose levels in the upper reaches of normal who are most in need of a preventive intervention? With present criteria, we are likely excluding many individuals who have heightened risk. We introduce here the possibility of using a 'personalized' glucose profile to encourage early intervention in subjects in whom glucose metabolism is deteriorating (on an individual level) but not yet abnormal on a population-based norm. We further suggest that 'personalized profiles' of hemoglobin A1c and basal plasma insulin may also help encourage appropriately early intervention. That the first line therapies are so effective, safe and simple make these more sensitive approaches very attractive
— id: 149789, year: 2010, vol: 26, page: 7, stat: Journal Article,

Glycated haemoglobin in diabetic women with and without HIV infection: data from the Women's Interagency HIV Study
Glesby, Marshall J; Hoover, Donald R; Shi, Qiuhu; Danoff, Ann; Howard, Andrea; Tien, Phyllis; Merenstein, Dan; Cohen, Mardge; Golub, Elizabeth; Dehovitz, Jack; Nowicki, Marek; Anastos, Kathryn
2010 ;15(4):571-577, Antiviral therapy
BACKGROUND: Limited data suggest that glycated haemoglobin (haemoglobin A1c; A1C) values might not reflect glycaemic control accurately in HIV-infected individuals with diabetes. METHODS: We evaluated repeated measures of paired fasting glucose and A1C values in 315 HIV-infected and 109 HIV-uninfected diabetic participants in the Women's Interagency HIV Study. Generalized estimating equations used log A1C as the outcome variable, with adjustment for log fasting glucose concentration in all models. RESULTS: An HIV-infected woman on average had 0.9868 times as much A1C (that is, 1.32% lower; 95% confidence interval 0.9734-0.9904) as an HIV-uninfected woman with the same log fasting glucose concentration. In multivariate analyses, HIV serostatus was not associated, but White, other non-Black race, and higher red blood cell mean corpuscular volume (MCV) were statistically associated with lower A1C values. Use of diabetic medication was associated with higher A1C values. In multivariate analyses restricted to HIV-infected women, White and other race, higher MCV, and HCV viraemia were associated with lower A1C values, whereas older age, use of diabetic medications and higher CD4(+) T-cell count were associated with higher A1C values. Use of combination antiretroviral therapy, protease inhibitors, zidovudine, stavudine or abacavir was not associated with A1C values. CONCLUSIONS: A1C values were modestly lower in HIV-infected diabetic women relative to HIV-uninfected diabetic women after adjustment for fasting glucose concentration. The difference was abrogated by adjustment for MCV, race and diabetic medication use. Our data suggest that in clinical practice A1C gives a reasonably accurate refection of glycaemic control in HIV-infected diabetic women
— id: 119249, year: 2010, vol: 15, page: 571, stat: Journal Article,

WHAT IS A NORMAL THYROID STIMULATING HORMONE (TSH) LEVEL? EFFECTS OF STRICTER TSH THRESHOLDS ON PREGNANCY OUTCOMES AFTER IVF
Reh, A.; Danoff, A.; Grifo, J.
2010 SEP ;94(4):S188-S188, Fertility & sterility
— id: 113772, year: 2010, vol: 94, page: S188, stat: Journal Article,

EFFECT OF AUTOIMMUNE THYROID DISEASE (AITD) IN OLDER, EUTHYROID INFERTILE WOMEN UNDERGOING IN VITRO FERTILIZATION (IVF)
Reh, A.; Im, S.; Amarosa, A.; Rolnitzky, L.; Grifo, J.; Danoff, A.
2010 SEP ;94(4):S189-S190, Fertility & sterility
— id: 113773, year: 2010, vol: 94, page: S189, stat: Journal Article,

What is a normal thyroid-stimulating hormone (TSH) level? Effects of stricter TSH thresholds on pregnancy outcomes after in vitro fertilization
Reh, Andrea; Grifo, James; Danoff, Ann
2010 Dec;94(7):2920-2922, Fertility & sterility
Using a thyroid-stimulating hormone (TSH) cutoff of 2.5 mIU/L or 4.5 mIU/L, no differences in the rates of clinical pregnancy, delivery, or miscarriage were observed in this large, retrospective cohort study of first-cycle IVF patients from 2005 through 2008, after controlling for age. Although lowering the TSH threshold to 2.5 mIU/L would result in a nearly fivefold increase in the number of women being classified as hypothyroid, the lack of differences in maternal clinical outcomes must be considered in the current controversy regarding the relative merits of lowering the upper limit of normal of TSH
— id: 149782, year: 2010, vol: 94, page: 2920, stat: Journal Article,

Adenomatoid Tumor of the Adrenal Gland Case Report of a Rare Adrenal Lesion
Chaudhry, S; Lubitz, S; Newman, K; Pei, ZH; Shepard, T; Danoff, A
2009 SEP-OCT ;19(5):233-236, Endocrinologist
Objective: To report a rare case of an adenomatoid tumor (AT) of the adrenal gland. Methods: We present a case report, including clinical, radiologic, and pathologic findings, and review the relevant literature. Results: We describe a 60-year-old man in whom an AT of the adrenal gland was discovered incidentally, and review the literature. Fewer than 20 cases of these tumors are reported. The tumors range in size from 0.5 to 11 cm, are more common in men, and are more frequently located in the left adrenal gland. A specific imaging phenotype has not been characterized. Histologic features, including infiltration into the surrounding tissue, and presence of signet ring cells, may raise concern of a more aggressive neoplasm. Immunologic staining for mesothelial and endothelial markers may be necessary to establish a definitive diagnosis. Conclusion: ATs of the adrenal gland are rare benign lesions. They are difficult to differentiate from more common adrenal tumors by computerized tamography (CT) or magnetic resonance imaging (MRI). Pathologic findings also can present challenges in distinguishing these lesions from more aggressive neoplasms. ATs should be considered in the differential diagnosis of adrenal masses, whether discovered as incidental radiologic, surgical, or pathologic findings, or at autopsy, so that the potential consequences of misdiagnosis may be avoided
— id: 102951, year: 2009, vol: 19, page: 233, stat: Journal Article,

Elevated Sex Hormone Binding Globulin Levels May Contribute to Sexual Dysfunction in Men With Chronic Hepatitis C Virus Infection
Rao, Jyoti; Danoff, Ann; Bini, Edmund J
2009 Jan;43(1):94-95, Journal of clinical gastroenterology
— id: 95144, year: 2009, vol: 43, page: 94, stat: Journal Article,

Health care utilization, barriers to care, and hormone usage among male-to-female transgender persons in New York City
Sanchez, Nelson F; Sanchez, John P; Danoff, Ann
2009 Apr;99(4):713-719, American journal of public health. AJPH
OBJECTIVES: We investigated health care utilization, barriers to care, and hormone use among male-to-female transgender persons residing in New York City to determine whether current care is in accord with the World Professional Association for Transgender Health and the goals of Healthy People 2010. METHODS: We conducted interviews with 101 male-to-female transgender persons from 3 community health centers in 2007. RESULTS: Most participants reported having health insurance (77%; n = 78) and seeing a general practitioner in the past year (81%; n = 82). Over 25% of participants perceived the cost of medical care, access to specialists, and a paucity of transgender-friendly and transgender-knowledgeable providers as barriers to care. Being under a physician's care was associated with high-risk behavior reduction, including smoking cessation (P = .004) and obtaining needles from a licensed physician (P = .002). Male-to-female transgender persons under a physician's care were more likely to obtain hormone therapies from a licensed physician (P < .001). CONCLUSIONS: Utilization of health care providers by male-to-female transgender persons is associated with their reduction of some high-risk behaviors, but it does not result in adherence to standard of care recommendations for transgender individuals
— id: 96286, year: 2009, vol: 99, page: 713, stat: Journal Article,

Metabolic syndrome does not impact survival in patients treated for coronary artery disease
Shah, Binita; Kumar, Nidhi; Garg, Parveen; Kang, Eunice; Grossi, Eugene; Lorin, Jeffrey D; Schwartzbard, Arthur Z; Mass, Howard; Danoff, Ann; Sedlis, Steven P
2008 Mar;19(2):71-77, Coronary artery disease
OBJECTIVES: We evaluated the effect of metabolic syndrome (a risk factor for the development of coronary artery disease) on survival in patients with established coronary artery disease. METHODS: Survival was determined for 2886 patients with coronary artery disease diagnosed by cardiac catheterization performed between 1990 and 2005 at a Department of Veterans Affairs hospital. Variables obtained from the computerized medical record were evaluated in multivariate analysis by Cox regression. The analysis was performed for the entire population; separate analyses were performed for patient cohorts treated with percutaneous coronary intervention and medication (n=1274), coronary artery bypass grafting and medication (n=1096), or medication alone (n=516). RESULTS: Although age (odds ratio 0.948; P<0.000), left ventricular function (odds ratio 0.701; P<0.000), serum creatinine (odds ratio 0.841; P<0.000), and smoking (odds ratio 0.873; P=0.019) were all strong predictors of mortality. Metabolic syndrome had no independent effect irrespective of diabetic status. CONCLUSION: Metabolic syndrome does not impact survival patients with coronary artery disease treated by revascularization and/or medical therapy
— id: 78361, year: 2008, vol: 19, page: 71, stat: Journal Article,

Association between chronic hepatitis B virus infection and diabetes among Asian Americans and Pacific Islanders
Li-Ng, M; Tropp, S; Danoff, A; Bini, E J
2007 Jun;39(6):549-556, Digestive & liver disease
BACKGROUND: Asians have a higher prevalence of both diabetes (diabetes mellitus) and chronic hepatitis B virus infection compared to Caucasians. The aim of this study was to investigate whether hepatitis B virus infection was associated with diabetes mellitus among Asian Americans and Pacific Islanders. METHODS: We reviewed the electronic medical records of 411 Asian and 424 Pacific Islanders seen at our medical centre over a 5-year period. Diabetes mellitus was defined by the presence of two or more random blood glucose levels >/=200mg/dL, an ICD-9 diagnostic code of diabetes mellitus, or use of medications for diabetes mellitus. Hepatitis B virus infection was defined by a positive HBsAg test. RESULTS: Diabetes mellitus was diagnosed in 223 of the 835 subjects (26.7%), whereas hepatitis B virus infection was diagnosed in 56 (13.8%) of the 407 subjects tested for HBsAg. Overall, the prevalence of diabetes mellitus was significantly higher in patients with hepatitis B virus than in those without hepatitis B virus (58.9% vs. 33.3%, P<0.001), and this remained significant after adjustment for potential confounding variables (OR=3.17; 95% CI, 1.58-6.35). When Asians and Pacific Islanders were analysed separately, the prevalence of diabetes mellitus in patients with hepatitis B virus was significantly higher than in those without hepatitis B virus among Asians (65.0% vs. 27.5%, P<0.001) but not in Pacific Islanders (43.8% vs. 37.1%, P=0.60). Among the 390 subjects who were tested for both hepatitis B virus and hepatitis C virus, the prevalence of diabetes mellitus was 29.4% in uninfected subjects, 44.4% in patients with hepatitis B virus monoinfection, 47.2% in patients with hepatitis C virus monoinfection and 85.0% in patients with hepatitis B virus and hepatitis C virus coinfection (P<0.001). CONCLUSIONS: Hepatitis B virus infection is strongly associated with diabetes mellitus among Asian Americans, but not in Pacific Islanders, whereas hepatitis C virus infection was associated with diabetes mellitus in both ethnic groups
— id: 72435, year: 2007, vol: 39, page: 549, 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,

HIV and the thyroid--what every practicing endocrinologist needs to know
Danoff, Ann
2006 Nov;2(11):602-603, Nature clinical practice. Endocrinology & metabolism
— id: 96287, year: 2006, vol: 2, page: 602, stat: Journal Article,

Sexual dysfunction is highly prevalent among men with chronic hepatitis C virus infection and negatively impacts health-related quality of life
Danoff, Ann; Khan, Oona; Wan, David W; Hurst, Lainie; Cohen, Daniel; Tenner, Craig T; Bini, Edmund J
2006 Jun;101(6):1235-1243, American journal of gastroenterology
OBJECTIVES: Although sexual dysfunction has been reported in patients with hepatitis C virus (HCV) infection, little is known about this association. The aims of this study were to determine the prevalence of sexual dysfunction among men with chronic HCV infection and to evaluate the impact of sexual dysfunction on health-related quality of life (HRQOL). METHODS: We prospectively enrolled 112 HCV positive men and 239 HCV negative controls, and all patients completed validated questionnaires to assess sexual function (Brief Male Sexual Function Inventory [BMSFI]), depression (Beck Depression Inventory), and HRQOL (Medical Outcomes Study Short Form-36). The BMSFI assessed sexual drive, erection, ejaculation, sexual problem assessment, and overall sexual satisfaction. RESULTS: HCV positive men had significantly more sexual dysfunction than control subjects across all five domains of the BMFSI. In addition, HCV-infected men were significantly more likely than controls to not be sexually satisfied (53.6% vs 28.9%, p<0.001) and this remained statistically significant after adjusting for age, race, and other potential confounding variables (OR=3.36; 95% CI, 1.59-7.13). In the 241 individuals without depression, HCV positive men were significantly more likely to not be sexually satisfied as compared with control subjects (47.5% vs 11.0%, p<0.001). HCV-infected men who were not sexually satisfied scored significantly worse in six of eight domains of HRQOL as compared with HCV-infected men who were sexually satisfied. CONCLUSIONS: Sexual dysfunction is highly prevalent in men with chronic HCV infection, is independent of depression, and is associated with a marked reduction in HRQOL
— id: 67005, year: 2006, vol: 101, page: 1235, stat: Journal Article,

Assessment of adrenal function in patients with chronic hepatitis C and severe fatigue
Gaslightwala, I; Danoff, A; Leong, J; Bini, EJ
2006 SEP ;101(9):S186-S186, American journal of gastroenterology
— id: 69309, year: 2006, vol: 101, page: S186, stat: Journal Article,

Oral glucose tolerance and insulin sensitivity are unaffected by HIV infection or antiretroviral therapy in overweight women
Danoff, Ann; Shi, Qiuhu; Justman, Jessica; Mulligan, Kathleen; Hessol, Nancy; Robison, Esther; Lu, Dalian; Williams, Tania; Wichienkuer, Paula; Anastos, Kathryn
2005 May 1;39(1):55-62, Journal of acquired immune deficiency syndromes. JAIDS
OBJECTIVE: To assess the frequency of diabetes, prediabetes, and insulin resistance among a subset of participants in the Women's Interagency HIV Study (WIHS). DESIGN: Cross-sectional substudy nested within a prospective multicenter cohort study. Women underwent 75 g oral glucose tolerance testing. Diagnoses of diabetes and prediabetes were made according to the American Diabetes Association criteria, and insulin resistance was determined by area under the curve insulin and homeostasis model assessment values. SETTING: Six urban clinical sites in the United States (Brooklyn, NY; Bronx, NY; Washington, DC; Chicago, IL; San Francisco, CA; Los Angeles, CA) participate in the entire WIHS. The Bronx, NY, and San Francisco, CA, WIHS sites participated in this substudy. PARTICIPANTS: A total of 258 women, 88 HIV negative, 74 HIV positive not on highly active antiretroviral therapy (HAART), and 96 HIV positive taking HAART were enrolled in the study. MAIN OUTCOMES: Prevalence of diabetes, prediabetes, and insulin resistance was compared among the HIV-uninfected and HIV-infected women. RESULTS: The frequency of diabetes, prediabetes, or insulin resistance was unrelated to HIV status or antiretroviral treatment. Increasing body mass index was the only characteristic associated with the combined endpoints of diabetes and prediabetes (odds ratio = 1.104, P = 0.0002). CONCLUSIONS: Routine oral glucose tolerance testing of HIV-infected women is not supported by these findings. Elucidation of putative perturbations from HIV or antiretroviral medications requires direct studies of insulin resistance and beta-cell function
— id: 56014, year: 2005, vol: 39, page: 55, stat: Journal Article,

Relation of elevated periprocedural blood glucose to long-term survival after percutaneous coronary intervention
Shah, Binita; Liou, Michael; Grossi, Eugene; Mass, Howard; Lorin, Jeffrey D; Danoff, Ann; Sedlis, Steven P
2005 Aug 15;96(4):543-546, American journal of cardiology
Strict glycemic control improves outcomes in critically ill patients. We evaluated the hypothesis that strict glycemic control might be similarly beneficial after percutaneous coronary intervention. This study reports the correlation of periprocedural blood glucose with long-term survival in 1,746 patients who underwent percutaneous coronary intervention from 1990 to 2003 in a Department of Veterans Affairs hospital
— id: 57864, year: 2005, vol: 96, page: 543, stat: Journal Article,

Sexual dysfunction is highly prevalent among men with chronic hepatitis C virus infection and negatively impacts health-related quality of life
Wan, D; Danoff, A; Khan, O; Hurst, L; Cohen, D; Tenner, CT; Bini, EJ
2005 OCT ;42(4):422A-422A, Hepatology
— id: 59264, year: 2005, vol: 42, page: 422A, stat: Journal Article,

The Endocrine Society Ethics Advisory Committee: ethical aspects of conflicts of interests, October 2003
Komesaroff, Paul A; Bach, Mark A; Danoff, Ann; Grumbach, Melvin M; Kaplan, Selna; Lakoski, Joan M; Leitman, Dale; Mellon, Synthia; Underwood, Louis E; Leupen, Sarah
2004 Jun;145(6):3032-3041, Endocrinology
— id: 96288, year: 2004, vol: 145, page: 3032, 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,

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,

Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women
Justman, Jessica E; Benning, Lorie; Danoff, Ann; Minkoff, Howard; Levine, Alexandra; Greenblatt, Ruth M; Weber, Kathleen; Piessens, Eva; Robison, Esther; Anastos, Kathryn
2003 Mar 1;32(3):298-302, Journal of acquired immune deficiency syndromes. JAIDS
OBJECTIVE: To assess the association between protease inhibitor (PI) use and the incidence of diabetes mellitus (DM) among participants in the Women's Interagency HIV Study. DESIGN: Prospective multicenter cohort study. The diagnosis of DM was based on self-report at semiannual interviews conducted from 1994 to 1998. SETTING: Six inner-city clinical sites in the United States (Brooklyn, NY; Bronx, NY; Washington, DC; Chicago, IL; San Francisco, CA; and Los Angeles, CA). PARTICIPANTS: A total of 1785 nonpregnant women who had no history of prior DM. The women made up four groups: 1) PI users (n = 609, person-years [PY] at risk = 707); 2) reverse transcriptase inhibitor (RTI)-only users (n = 932, PY = 1486); 3) HIV-infected women reporting no antiretroviral therapy (ART) ever (n = 816, PY = 1480); and 4) HIV-uninfected women (n = 350, PY = 905). MAIN OUTCOMES: Incidence of DM and median body mass index (BMI) from 1995 to 1998 were compared among the four groups. RESULTS: Sixty-nine incident cases of DM occurred among 1785 women (1.5 cases per 100 PY; 95% CI: 1.2-1.9). The incidence of DM among PI users was 2.8 cases per 100 PY (2.8%) versus 1.2% among both RTI users and women on no ART (95% CI: 1.6-4.1 [PI]; 0.7-1.8 [RTI and no ART]; P = 0.01 for comparison of the PI group with the RTI group) and 1.4% among HIV-uninfected women (95% CI: 0.7-2.2, P = 0.06 for comparison with PI group). Weight gain was not associated with either PI or RTI use. Multivariate models identified PI use (hazard ratio [HR] = 2.90 [95% CI: 1.50-5.60]; P = 0.002), age (HR = 1.75 per 10 years [95% CI: 1.31-2.34]; P = 0.0002) and BMI as independent risk factors for DM. CONCLUSIONS: PI use was associated with a threefold increase in the risk of reporting incident DM. Routine screening for diabetes, particularly among older and heavier patients using PI therapy, is advisable
— id: 37967, year: 2003, vol: 32, page: 298, stat: Journal Article,

Protease inhibitors do not interfere with prohormone processing
Danoff A; Ling WL
2000 Feb 15;132(4):330-330, Annals of internal medicine
— id: 37968, year: 2000, vol: 132, page: 330, stat: Journal Article,

The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection
Dobs AS; Cofrancesco J; Nolten WE; Danoff A; Anderson R; Hamilton CD; Feinberg J; Seekins D; Yangco B; Rhame F
1999 Aug;107(2):126-132, American journal of medicine
PURPOSE: Weight loss is a strong predictor of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. Men with acquired immunodeficiency syndrome (AIDS) lose body cell mass. Hypogonadism is also common. This study tested the efficacy of a testosterone transscrotal patch (6 mg/day) in improving body cell mass and treating hypogonadism in these patients. SUBJECTS AND METHODS: This multicenter, randomized, double-blinded, placebo-controlled trial was conducted from August 1995 to October 1996 in 133 men, 18 years of age and older, who had AIDS, 5% to 20% weight loss, and either a low morning serum total testosterone level (<400 ng/dL) or a low free testosterone level (<16 pg/mL). Outcomes included weight, body cell mass as measured using bioelectrical impedance analysis, quality of life, and morning measurements of serum testosterone and dihydrotestosterone levels, lymphocyte subsets, and HIV quantification. RESULTS: There were no significant differences in baseline weight, CD4 cell counts, or HIV serum viral quantification between treatment arms. Morning total and free testosterone levels increased in those treated with testosterone, but not with placebo. Following 12 weeks of treatment there were no differences (testosterone-placebo) in mean weight change (-0.3 kg [95% confidence interval (CI): -1.4 to 0.8]) or body cell mass (-0.2 kg [95% CI: -1.0 to 0.6]) in the two groups. There were also no changes in quality of life in either group. CONCLUSION: Hypogonadal men with AIDS and weight loss can achieve adequate morning serum sex hormone levels using a transscrotal testosterone patch. However, this system of replacement does not improve weight, body cell mass, or quality of life
— id: 37969, year: 1999, vol: 107, page: 126, stat: Journal Article,

Endocrinologic complications of HIV infection
Danoff A
1996 Nov;80(6):1453-1469, Medical clinics of North America
A variety of endocrine disorders occur in HIV-infected patients. The abnormalities may be a consequence of HIV infection, or may result from opportunistic infections, associated malignancies, illness-associated cytokine production, or use of therapeutic agents. Observations and controversies concerning adrenal, gonadal, thyroidal, and metabolic abnormalities are discussed. Heightened awareness of problems that might otherwise be overlooked will permit timely diagnosis and treatment of identified problems, which will enhance and potentially prolong the lives of people infected with HIV
— id: 37970, year: 1996, vol: 80, page: 1453, stat: Journal Article,

The propeptide of anglerfish preprosomatostatin-I rescues prosomatostatin-II from intracellular degradation
Chen YG; Danoff A; Shields D
1995 Aug 4;270(31):18598-18605, Journal of biological chemistry
Polypeptide hormones and neuropeptides are initially synthesized as precursors possessing one or several domains that constitute the propeptide. Previous work from our laboratory demonstrated that expression of anglerfish prosomatostatin-I (proSRIF-I) in rat anterior pituitary GH3 cells resulted in efficient and accurate cleavage of the prohormone to generate the mature 14-amino acid peptide, SRIF-I. We also implicated the propeptide in mediating intracellular sorting to the trans Golgi network where proteolytic processing is initiated. In contrast, expression of a second form of the precursor, proSRIF-II in GH3 cells resulted in its intracellular degradation in an acidic, post-trans Golgi network compartment, most probably lysosomes. To further investigate the positive sorting signal present in proSRIF-I, we constructed a chimera comprising the signal peptide and proregion of SRIF-I fused to proSRIF-II and expressed the cDNA in GH3 cells. Here we demonstrate that the propeptide of SRIF-I rescued proSRIF-II from intracellular degradation quantitatively and diverted it to secretory vesicles. Furthermore, the chimera was processed to SRIF-28, an amino-terminally extended form of the hormone that is the physiological cleavage product of proSRIF-II processing in vivo. Most significantly, the SRIF-I propeptide functioned only in cis as part of the fusion protein and not in trans when expressed as a separate polypeptide. These data suggest that the SRIF-I propeptide may possess a sorting signal for sequestration into the secretory pathway rather than functioning as an intramolecular chaperone to promote protein folding
— id: 37971, year: 1995, vol: 270, page: 18598, stat: Journal Article,

Intracellular degradation of prohormone-chloramphenicol-acetyl-transferase chimeras in a pre-lysosomal compartment
Danoff A; Mai XP; Shields D
1993 Dec 15;218(3):1063-1070, European journal of biochemistry
Small peptide hormones (less than 50 amino acids) are synthesized as larger inactive precursors. Work from several laboratories, including our own, has implicated the propeptide of various precursors in mediating intracellular transport and targeting to secretory granules. We previously demonstrated that the proregion of prosomatostatin, one of the simplest peptide hormone precursors, when fused to alpha-globin, enabled the globin polypeptide to be transported to the regulated secretory pathway. To identify sorting motifs in this propeptide, we have now constructed a chimera comprising the somatostatin signal peptide and proregion fused to chloramphenicol acetyl transferase (CAT) and a control protein consisting of the signal peptide fused to CAT, both of which were expressed in rat anterior-pituitary GH3 cells. Both molecules were translocated into the endoplasmic reticulum (ER) efficiently and core-glycosylated on the single cryptic N-linked glycosylation site present in CAT. Surprisingly, the glycosylated propeptide-CAT and signal without CAT were degraded intracellularly with half-lives of 30 min and 90 min, respectively. Based on the kinetics of degradation, temperature sensitivity, and resistance to lysosomotrophic agents, we suggest that degradation occurred in the ER. Our data imply that the pro-region is not an a priori universal sorter, but only directs heterologous peptides to the secretory pathway when the passenger peptide assumes a secretion-competent conformation
— id: 37972, year: 1993, vol: 218, page: 1063, stat: Journal Article,

Heterologous expression of peptide hormone precursors in the yeast Saccharomyces cerevisiae. Evidence for a novel prohormone endoprotease with specificity for monobasic amino acids
Bourbonnais Y; Danoff A; Thomas DY; Shields D
1991 Jul 15;266(20):13203-13209, Journal of biological chemistry
The peptide somatostatin (SRIF) exists as two different molecular species. In addition to the most common form, which is a 14-residue peptide, there is also a 14-amino acid amino-terminally extended form of the tetradecapeptide, SRIF-28. Both peptides are synthesized as larger precursors containing paired basic and monobasic amino acids at their processing sites, which, upon cleavage, generate either SRIF-14 or -28, respectively. In mammals a single prepro-SRIF molecule undergoes tissue-specific processing to generate the mature hormone whereas in some species of fish separate genes encode two distinct but homologous precursors prepro-SRIF-I and -II that give rise to SRIF-14 and -28, respectively. To investigate the molecular basis for differential processing of the prohormones we introduce their cDNAs into yeast cells (Saccharomyces cerevisiae). The signal peptides of both precursors were poorly recognized by the yeast endoplasmic reticulum translocation apparatus, consequently only low levels of SRIF peptides were synthesized. To circumvent this problem a chimeric precursor consisting of the alpha-factor signal peptide plus 30 residues of the proregion was fused to pro-SRIF-II. This fusion protein was efficiently transported through the yeast secretory pathway and processed to SRIF-28 exclusively, which is identical to the processing of the native precursor in pancreatic islet D-cells. Most significantly, cleavage of the precursor to SRIF-28 was independent of the Kex 2 endoprotease since processing occurred efficiently in a kex 2 mutant strain. We conclude that in addition to the Kex 2 protease, yeast possess a distinct prohormone converting enzyme with specificity toward monobasic processing sites
— id: 37973, year: 1991, vol: 266, page: 13203, stat: Journal Article,

Heterologous expression of preprosomatostatin. Intracellular degradation of prosomatostatin-II
Danoff A; Cutler DF; Shields D
1991 May 25;266(15):10004-10010, Journal of biological chemistry
Somatostatin (SRIF) is a peptide hormone that is synthesized as part of a larger precursor, prepro-SRIF, consisting of a signal peptide and a proregion of 80-90 amino acids. The mature hormone exists as two different bioactive species. In addition to the most common form, which is a 14-residue peptide, there is also a 14-amino acid NH2-terminally extended form of the tetradecapeptide, SRIF-28. In mammals a single prepro-SRIF molecule undergoes tissue-specific processing to generate the mature hormone, whereas in some species of fish separate genes encode two distinct but homologous precursors, prepro-SRIF-I and -II, that give rise to SRIF-14 and -28, respectively. To investigate the molecular basis for differential processing of the prohormones, we have expressed their cDNAs in heterologous cells. Previously, we demonstrated that prepro-SRIF-I was efficiently and accurately processed in rat pituitary growth hormone (GH3) cells to generate the same hormone as synthesized in pancreatic islet D-cells, namely SRIF-14 (Stoller, T., and Shields, D. (1989) J. Biol. Chem. 264, 6922-6928). We have now compared the proteolytic processing of pro-SRIF-II to that of pro-SRIF-I in these cells. In contrast to pro-SRIF-I, pro-SRIF-II was neither processed nor secreted. Instead, greater than 70% of the precursor was degraded intracellularly in a post-trans Golgi network compartment which was inhibited by weak bases. Brefeldin A treatment prevented degradation, suggesting that turnover of the remaining pro-SRIF-II occurred after exit from the endoplasmic reticulum/intermediate compartment and prior to arrival at the trans Golgi network. The intracellular degradation of the precursor was unexpected, since heterologous cells which do not cleave prohormones generally secrete the unprocessed precursor. We speculate that unique structural domains within each precursor are recognized by the sorting apparatus in GH3 cells, thereby targeting the molecules to different intracellular organelles
— id: 37974, year: 1991, vol: 266, page: 10004, stat: Journal Article,

Differential translation of two distinct preprosomatostatin messenger RNAs
Danoff A; Shields D
1988 Nov 5;263(31):16461-16466, Journal of biological chemistry
Somatostatin (SRIF) is a 14-amino acid peptide hormone that is present in pancreatic islets and the brain where it is synthesized as a larger precursor, preprosomatostatin. In pancreatic islets of the anglerfish (Lophius americanus), there are two separate precursors, preproSRIF I and preproSRIF II, which give rise to SRIF-14 or an N-terminally extended form SRIF-28, respectively. Significantly higher levels of preproSRIF I compared to preproSRIF II are synthesized in pancreatic islets. We show here that preproSRIF II mRNA possesses an eight-nucleotide repeat (CCAGCAGA) which is present three times in its 5'-noncoding region; this sequence is absent from preproSRIF I mRNA. Progressive deletion of these octameric repeats results in the concomitant enhancement of preproSRIF II mRNA translation in vitro. Furthermore, expression of native or 5'-truncated preproSRIF II mRNA in non-islet tissue culture cells, using a retroviral expression vector, gave identical results to those obtained in vitro, indicating that differential translation was a function of the mRNA rather than the translation system. We propose that the octameric repeat sequence, or a subset of it, is responsible for attenuation of preproSRIF II mRNA translation. Since the differential translation of preproSRIF II mRNA was reproduced in widely divergent systems, this suggests that our results are not related to islet cell gene expression per se. Rather, it is possible they have general significance in that the 5'-repeat sequences may be recognized by putative trans-acting factors involved in the translational regulation of protein synthesis
— id: 37975, year: 1988, vol: 263, page: 16461, stat: Journal Article,

Adrenocortical micronodular dysplasia, cardiac myxomas, lentigines, and spindle cell tumors. Report of a kindred
Danoff A; Jormark S; Lorber D; Fleischer N
1987 Mar;147(3):443-448, Archives of internal medicine
In a family encompassing three generations, six of 11 evaluated members have two or three elements of a triad comprising adrenocortical micronodular dysplasia, mucocutaneous lentigines, and cardiac myxomas. Evaluation of the adrenals in affected members revealed characteristic pathologic lesions of micronodular adrenal hyperplasia and corticotropin-independent steroidogenesis that correlated with age, suggesting a progressive lesion that begins in early childhood. Since all subjects with micronodular hyperplasia and/or cardiac myxomas also had mucocutaneous lentigines, the skin lesions were markers for affected subjects. This family is one of the larger reported with this syndrome. Of special note was the finding of rare visceral tumors in affected family members, including melanocytic schwannomas and a fibrolamellar hepatoma, signaling another feature of the syndrome. Since 60% of this family encompassing three contiguous generations were affected, the syndrome appears to be inherited as an autosomal or X-linked dominant gene
— id: 37978, year: 1987, vol: 147, page: 443, stat: Journal Article,

Properties of p19, a novel cAMP-dependent protein kinase substrate protein purified from bovine brain
Schubart UK; Alago W Jr; Danoff A
1987 Aug 25;262(24):11871-11877, Journal of biological chemistry
We report the purification from bovine brain and describe some of the properties of a 19-kDa protein, p19, which we have previously shown to undergo hormone-dependent, cAMP-mediated phosphorylation in several peptide hormone-producing tumor cells. The procedure for purifying p19 to apparent homogeneity utilized ammonium sulfate fractionation, sequential chromatography on DEAE-cellulose and phenyl-Sepharose, followed by fast protein liquid chromatography using a Mono Q and, finally, a C8 reverse-phase column. The yield was 0.3-0.5 mg of p19/kg of brain. The molecular weight (Mr = 19,000) and frictional ratio (f/f0 = 1.87) of p19, which were derived from its Stokes radius (33 A) and sedimentation constant (s20,w = 1.4), suggest that the native form of p19 is an asymmetrically shaped monomer. We provide evidence to suggest that p19 is isolated as a mixture of molecular forms consisting of an unphosphorylated form and of three phosphoforms indicative of multisite phosphorylation. These forms cosedimented on sucrose density gradients and coeluted on gel filtration, hydrophobic chromatography, and reverse-phase fast protein liquid chromatography. They were resolved from each other by anion-exchange chromatography. The unphosphorylated form (pI 6.2) was phosphorylated by catalytic subunit of cAMP-dependent protein kinase to a stoichiometry of 0.5 mol of P/mol of p19, thereby giving rise to the three phosphoforms (pI 5.8, pI 5.6, and pI 5.2, respectively). We conclude that p19 is a novel cAMP-dependent protein kinase substrate protein that is present in brain and in peptide hormone-producing tumor cells. Its function remains to be identified
— id: 37976, year: 1987, vol: 262, page: 11871, stat: Journal Article,

Identification in rat brain of a 19-kDa protein that comigrates on two-dimensional electrophoresis with p19, a hormonally regulated phosphoprotein of insulinoma cells
Schubart UK; Danoff A
1987 Jul 31;146(2):410-415, Biochemical & biophysical research communications
We have previously shown that a set of 19-kDa cytosolic proteins, p19, undergoes hormone-dependent phosphorylation in several peptide hormone-producing tumor cells. Here we show, using comigration on two-dimensional electrophoresis with RIN-1122 rat insulinoma cell p19, that an identical set of 19-kDa proteins is present in rat brain but not in liver or skeletal muscle. We have partially purified p19 from rat brain and have compared the apparent isoelectric variants by tryptic peptide mapping. The data suggest that p19 is a novel phosphoprotein consisting of an unphosphorylated form and of three phosphoforms
— id: 37977, year: 1987, vol: 146, page: 410, stat: Journal Article,

P19, a hormonally regulated phosphoprotein of peptide hormone-producing cells: secretagogue-induced phosphorylation in AtT-20 mouse pituitary tumor cells and in rat and hamster insulinoma cells
Pasmantier R; Danoff A; Fleischer N; Schubart UK
1986 Sep;119(3):1229-1238, Endocrinology
P19, a group of 19,000 mol wt cytosolic proteins, with apparent isoelectric points of pI 5.9, pI 5.7, and pI 5.4, respectively, was identified in three peptide hormone-producing cell types: AtT20 mouse pituitary tumor cells, RIN-1122 rat insulinoma cells, and hamster insulinoma cells. Secretagogue-dependent phosphorylation of P19 was analyzed in 32P-labeled cells by two-dimensional electrophoresis and autoradiography. The results were quantitated by computer-assisted densitometry. Cellular levels of cAMP and hormone release were measured in parallel incubations. In addition to stimulating ACTH release, CRF raised the cellular level of cAMP and increased the 32P labeling of all three 19,000 mol wt proteins in AtT20 cells. Other agents known to act through cAMP, which included isoproterenol, forskolin, and 8-bromo-cAMP, mimicked the effect of CRF on both ACTH release and phosphorylation of P19. 12-O-Tetra-decanoylphorbol-13-acetate, a tumor-promoting phorbol ester, also stimulated both ACTH release and phosphorylation of P19. In contrast, although 40 mM K+ promoted ACTH release, it did not affect the phosphorylation of P19. Analogous findings were observed in insulinoma cells. Glucagon stimulated insulin release, increased cellular cAMP and promoted phosphorylation of P19 in RIN 1122 cells. 12-O-Tetradecanoylphorbol-13-acetate also enhanced insulin release and the phosphorylation of P19 in these cells. The results obtained with hamster insulinoma cells closely resembled the observations in RIN-1122 cells. In conclusion, P19, an apparently homologous set of cytosolic proteins, undergoes phosphorylation in three peptide hormone-producing cells in response to two groups of secretagogues, the effect of which is probably mediated, in one case, by cAMP-dependent protein kinase and, in the other, by protein kinase C. The data suggest the possibility that P19 participates in a secretory pathway activated by these two effector systems
— id: 37979, year: 1986, vol: 119, page: 1229, stat: Journal Article,