Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Syndrome

Polycystic Ovary Syndrome

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

All Drugs and Chemicals

Hypoglycemic Agents

Anti-Infective Agents

Hormones

Sitagliptin Phosphate

Incretins

Hormone Antagonists

Dipeptidyl-Peptidase IV Inhibitors

HIV Protease Inhibitors

Protease Inhibitors

Enzyme Inhibitors

Sitagliptin 100 mg by mouth daily for 30 days followed by Placebo daily for 30 days

Placebo daily for 30 days followed by Sitagliptin 100 mg daily for 30 days

Sitagliptin 100 mg by mouth daily for 30 Days

Sitagliptin

1 placebo pill by mouth per day for 30 days

Placebo

Jessica Devin, MD MSCI

Adults with abdominal obesity are at high risk for cardiovascular disease and also exhibit diminished growth hormone (GH) secretion; the latter further contributes to the development of visceral adiposity, impaired fibrinolysis and inflammation.Growth hormone releasing hormone (GHRH), the primary stimulus for endogenous GH secretion, is a substrate of dipeptidyl peptidase 4 (DPP4); inhibition of DPP4 with the currently available anti-diabetic therapy, sitagliptin, may therefore increase GH secretion by decreasing the degradation of GHRH. The proposed research will test the hypothesis that chronic sitagliptin therapy will enhance GH secretion and vascular function while improving glucose tolerance in patients with impaired GH secretion who are at risk for the development of diabetes mellitus and cardiovascular disease, specifically obese women with polycystic ovary syndrome.

Thirty-four obese (BMI ≥ 30 kg/m2) females (18-40 years old) with polycystic ovarian syndrome (PCOS) will participate in this randomized, double-blind, placebo-controlled crossover study. The use of oral contraceptives or metformin will be discontinued at least 30 days prior. In females experiencing monthly cycles, the outpatient visit will take place during the mid-luteal phase of the participant's menstrual cycle and the inpatient visit will take place during the late follicular phase.

Subjects will be randomized to treatment order (sitagliptin 100 mg daily vs placebo) using a block randomization algorithm with a block size of two. The dose of sitagliptin was chosen as it is currently the FDA-recommended dose of sitagliptin for type 2 diabetic patients with unimpaired renal function. Subjects will receive standardized dietary counseling throughout the study; visits will be standardized to the menstrual cycle when possible. Subjects will take each therapy for one month; a minimum one month wash-out will separate study treatments. Side effects and compliance with study medication will be assessed at each visit in the clinical research center (CRC).

Each subject will undergo one outpatient visit and one inpatient visit during each treatment. On each study day, subjects will report fasting to the CRC in the morning having abstained from exercise that morning. On each study day, subjects will receive an intravenous catheter. Subjects will undergo an oral glucose tolerance test (OGTT) during the outpatient study visit. During the inpatient study visit, endothelium-dependent and -independent vasodilation will be assessed using flow-mediated dilation technique with ultrasound. Standardized meals will be provided at lunch and dinner. Body composition will be determined in the afternoon. At 8 PM overnight frequent sampling for venous GH will begin every 10 minutes for 12 hours to determine overnight GH secretion.

The Effect of Dipeptidyl Peptidase 4 Inhibition on Growth Hormone Secretion in Women With Polycystic Ovarian Syndrome

Growth hormone levels were determined every 10 minutes from 8 PM until 8 AM during the inpatient visit on the last day of each treatment. A mean of the GH levels was calculated for each participant, and then the value from each participant was averaged across all participants.

Oral glucose tolerance testing was performed with 75 grams of glucose solution. Baseline venous blood samples of insulin were obtained prior to ingestion of oral glucose solution (time 0). Insulin levels were then obtained through a peripheral IV line every 15 minutes for 270 minutes after glucose solution is swallowed. Early insulin secretion was determined by calculating area under the curve using data (i.e. insulin levels) obtained at baseline (time 0), 15 minutes and 30 minutes.

Oral glucose tolerance testing was performed with 75 grams of glucose solution. Baseline blood glucose was obtained prior to ingestion of oral glucose solution (time 0). Blood glucose levels were then obtained through a peripheral IV line every 15 minutes from timepoint 0 until 120 minutes to calculate the area under the curve.

During the inpatient visit of each treatment (placebo and sitagliptin), visceral adipose tissue was determined by a certified densitometrist using dual-energy x-ray absorptiometry with enCore software (v. 13.6)

Endothelium-dependent vasodilation was evaluated by measuring the diameter of the brachial artery under basal (i.e. rest) condition and during reactive hyperemia. The percentage change in diameter (i.e. endothelium-dependent vasodilation) was calculated as percent change=\[(peak diameter-baseline diameter)/baseline diameter\]\*100. Endothelium-dependent vasodilation was determined twice during the study: at completion of 30 days of placebo treatment and at completion of 30 days of sitagliptin treatment.

National Heart, Lung, and Blood Institute (NHLBI)

Vanderbilt University

Principal Investigator

Safety population included all participants who received at least one dose of intervention.

Participants received Sitagliptin 100 mg by mouth daily for up to 30 days.

Participants received Placebo daily for up to 30 days.

Participants first received sitagliptin 100 mg by mouth daily for 30 days. After an 8 week washout period, they then received Placebo daily for 30 days.

Sitagliptin Then Placebo

Participants first received Placebo daily for 30 days. After an 8 week washout period, they then received Sitagliptin 100 mg daily for 30 days.

Placebo Then Sitagliptin

Total

Age, Continuous

Only Females were included in this study because Polycystic Ovarian Syndrome is a disorder limited to women.

Sex: Female, Male

Race (NIH/OMB)

All participants randomized to an intervention are included.

Dr. Jessica Devin

Null hypothesis is that there was no difference in change of mean growth hormone (GH) levels between sitagliptin and placebo. The test was performed with a significance level of 0.05 (two sided). A sample size of 16 participants was needed to provide 93% power to detect a difference in GH means of 0.5 mcg/L.

Participants who received Placebo tablet each morning in either the first 30 days or last 30 days of the study.

Participants who received Sitagliptin 100 mg daily each morning in either the first 30 days or last 30 days of the study.

All participants who received both interventions and completed both inpatient visits were included in the analysis. (1 participant was unable to complete their 2nd inpatient visit due to a family emergency. A 2nd participant was unable to complete the overnight portion of the inpatient visit due to illness in a family member.)

Mean Overnight Growth Hormone Levels

Null hypothesis is that there was no difference in change of early insulin secretion between sitagliptin and placebo. The test was performed with a significance level of 0.05 (two sided).

All participants who received both interventions and completed both outpatient study visits were included in the analysis.

Early Insulin Secretion During Oral Glucose Tolerance Test

Null hypothesis is that there was no difference in blood glucose levels between sitagliptin and placebo. The test was performed with a significance level of 0.05 (two sided).

All participants who received both interventions and completed both outpatient study visits were included in analysis.

Area Under the Curve (AUC) for Blood Glucoses During 75 Gram Oral Glucose Tolerance Test

Null hypothesis is that there was no difference in the mass of visceral adipose tissue after sitagliptin vs. placebo. The test was performed with a significance level of 0.05 (two sided).

Participants who received Sitagliptin 100 mg each morning in either the first 30 days or last 30 days of the study.

All participants who received both interventions and completed all study protocols during the daytime portion of the inpatient visits were included in the analysis. (1 participant was unable to complete their 2nd inpatient visit due to a family emergency.)

Visceral Adipose Tissue

Null hypothesis is that there was no difference in vascular function between sitagliptin and placebo treatments. The test was performed with a significance level of 0.05 (two sided).

Vascular Function (Endothelium-dependent Vasodilation)

Participants first received sitagliptin 100 mg by mouth daily for 30 days. After a washout period of 8 weeks, then then received Placebo daily for 30 days

Participants first received Placebo daily for 30 days. After a washout period of 8 weeks, they then received Sitagliptin 100 mg daily for 30 days

First Intervention (30 Days)

Washout (8 Weeks)

Second Intervention (30 Days)

Blood and Lymph Conditions

Musculoskeletal Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Dwarfism

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Bone Diseases

Bone Diseases, Developmental

Genetic Diseases, Inborn

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Growth Hormone Deficiency

Isolated Growth Hormone Deficiency

Chronic Myeloproliferative Disorders

Antineoplastic Agents

Imatinib Mesylate

0.3mg/kg/week GH in seven divided doses will be given subcutaneously for one year.

All GH deficient patients with bone age \<14 years will be treated with GH therapy for one year.Serum IGF-1 will be measured 4weekly and GH dose will be titrated till S.IGF-1 is in mid-normal range and then after every 3 months.

Growth parameters will be assessed after every 3 months.Serum T4, TSH will be done after every 3 months. Patients will be monitored for any side effects of GH therapy

Growth Hormone

ANIL BHANSALI, MBBS, MD,DM

anil bhansali, MBBS,MD,DM

CML is a myeloproliferative disorder defined by the presence of the Philadelphia chromosome, which arises from the reciprocal translocation of genes on chromosomes 9 and 22.It is rare in childhood and accounts for 2-3% of all leukemias in childhood.

BCR-ABL gene on Philadelphia chromosome results in a 210kd fused BCR-ABL protein with constitutive tyrosine kinase activity, and subsequent activation of cytoplasmic and nuclear signal transduction pathways including STAT, RAS, JUN, MYC, and phosphatidylinositol-3 kinase. The ultimate result of such activation is the myeloid proliferation and differentiation and suppressed apoptosis.

Children present with a higher WBC count, otherwise presentation is nearly identical to adults. Current treatment include tyrosine kinase inhibitors (TKI) and allogeneic stem cell transplant (SCT).Imatinibmesylate inhibits the tyrosine kinase (TK) activity of BCR-ABL1 and several related TKs, including c-kit and the platelet-derived growth factor receptor (PDGFR). Development of tyrosine kinase inhibitor (TKI) therapy has revolutionizedtreatment of CML. Imatinib or second generation TKIs (dasatinib or nilotinib) have become standard front-line therapy forchildren and adults with CML and are also important componentsof therapy for Ph+ acute lymphoblastic leukemia (ALL).

TKIs are administered orally and cause a number of side effects including fatigue, hypertension, rash, impaired wound healing, myelosuppression, and diarrhea . The overall toxicity of TKIs, while less life-threatening than conventional cytotoxic chemotherapy, nevertheless is common, and may require dose reduction.Recently, proposed endocrine-related side effects of these agents include alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, glucose metabolism and adrenal function.

Growth impairment is one of the major adverse effect of long-term imatinib treatment in children with CML. Multiple case reports have demonstrated growth retardation in children onimatinib.Imatinibmesylate inhibits the TK activity of BCR-ABL1 and several related TKs, including c-kit and theplatelet-derived growth factor receptor (PDGFR). It isthe inhibition of TK activity at the non-BCR-ABL sites that couldbe the likely cause for the adverse effect on growth. Severalstudies in adults have suggested that inhibition of c-kit,c-fms, and PDGF receptors results in modulation of bone metabolism. Other reports are focusing on disturbance of the growth hormone (GH) axis as a mechanism for growth impairment. Receptor and non receptor TK is expressed at multiple levels in GH-IGF-1 axis including GHRH-R, GH-R and IGF-1R. Inhibition of TKs with TKI, at any one of these level, might result in growth impairment.

Various studies are available to show that Imainib therapy may cause short stature in children on prolonged treatment but exact mechanism by which this occurs is still not clear. Further, no treatment modality has been tried so far, for short stature in these children.

So, the purpose of this study is to study GH-IGF1 axis in these children and to administer GH therapy to GH deficienct children in remission.

AIMS AND OBJECTIVES:

* To study GH-IGF1 axis in children with CML having short stature following Imatinib therapy.
* To administer growth hormone therapy to children with CML on Imatinib in remission having GH deficiency.

STUDY DESIGN: It is an interventional, non-randomized study. STUDY GROUP: one NUMBER OF PATIENTS: 20

ELIGIBILITY CRITERIA:

CML patients on Imatinib therapy for more than 6 months and in remission will be included in the study if there is:

* Severe short stature (height SDS \<-3 SD)
* Severe growth deceleration (height velocity SDS \<-2 SD over 12 months)
* Height \<-2 SD and height velocity \<-1.0 SD over 12 months
* Height \<-1.5 SD and height velocity \<-1.5 SD over 2 years

EXCLUSION CRITERIA:

* Patients with coexisting systemic illness (e.g. kidney disease, liver disease, celiac disease)
* Patients of CML not receiving Imatinib therapy as prescribed. (e.g. poor compliance)

MATERIALS AND METHODS:

Once eligibility criteria are confirmed, after having written informed consent, following parameters will be assessed:

* Chronological age
* Height
* Height for age
* Height SDS
* Target height
* Body proportion
* Weight
* Weight for age

Following investigations will be done in all patients:

* Complete blood count with peripheral smear.
* Liver function tests
* Renal function tests
* Calcium, phosphate, ALP, albumin.
* Fasting Blood glucose
* Thyroid function tests (T4, and TSH)
* Serum Cortisol
* Serum Prolactin
* Serum Follicular stimulating hormone (FSH) and Luteinizing hormone (LH)
* Serum Testosterone
* Serum Estrogen
* Serum IgA anti-tTG antibodies
* Serum IGF-1.
* Serum IGFBP-3.
* X-Ray of left hand and wrist
* MRI Brain focussing pituitary hypothalamic region. Two dynamic growth hormone provocation,GHRH + Arginine andGlucagon tests will be performed in all patients having no other cause for short stature.Minimum gap of one week will be kept between the two GHstimulationtests.Priming will be done prior to each GH stimulation test. IGF-1 generation test will be performed in all patients.Minimum gap of one week will be kept betweenGH stimulation and IGF-1 generation test.

X-ray of left hand and wrist for bone age and sexual maturity rating (SMR) by Tanners scale will be performed for all patients. All GH deficient patients with bone age \<14 years will be treated with GH therapy for one year. 0.3mg/kg/week GH in seven divided doses will be given subcutaneously. Serum IGF-1 will be measured 4weekly and GH dose will be titrated till S.IGF-1 is in mid-normal range and then after every 3 months.

Patients will be monitored for any side effects of GH therapy Growth parameters, Serum T4, TSH and complete blood count will be assessed after every 3 months.Cytogenetic and molecular remission will be assessed before and after completion of GH therapy.

Assessment Of Gh-Igf-1 Axis In Children With Chronic Myelogenous Leukemia (CML) In Remission

ASSESSMENT OF GH-IGF1 AXIS AND TO STUDY RESPONSE TO GH THERAPY IN CHILDREN WITH CML IN REMISSION HAVING GH DEFICIENCY

Growth impairment is one of the major adverse effect of long-term imatinib treatment in children with CML. Receptor and non receptor TK is expressed at multiple levels in GH-IGF-1 axis including GHRH-R, GH-R and IGF-1R. Inhibition of TKs with TKI, at any one of these level, might result in growth impairment.Various studies are available to show that Imainib therapy may cause short stature in children on prolonged treatment but exact mechanism by which this occurs is still not clear.So, the purpose of this study is to study GH-IGF1 axis in these children

Disturbance of the growth hormone (GH) axis has been shown as one of the mechanism for growth impairment. But, no treatment modality has been tried so far for short stature in these children. So, one of the outcome measure will be to study gain in height after administeration of GH therapy to these GH deficient children.

Post Graduate Institute of Medical Education and Research, Chandigarh

senior resident

Nervous System Diseases

Pituitary Diseases

Pituitary Neoplasms

Dwarfism, Pituitary

Bone Diseases, Endocrine

Hypopituitarism

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Estrogens

Stratified based on age and estrogen status from 3 to 6 mcg/kg/day

Somatropin

Dosage based on age and estrogen status ranging from 3 to 6 mcg/kg/day

Anne Klibanski, M.D

The purpose of the study is to evaluate the effects of growth hormone replacement on women with growth hormone deficiency. Growth hormone deficiency means the body no longer produces growth hormone due to a tumor or some kind of disease of the brain in an area called the pituitary/hypothalamic region. This is the area of the brain where growth hormone is normally produced. We, the researchers at Massachusetts General Hospital, will establish the effects of growth hormone replacement on cardiovascular parameters (laboratory tests, the flexibility of the arteries, changes in heart rate) in women with growth hormone deficiency. Our goal is to see if this therapy:

* has effects on women's cardiovascular risk markers (special blood tests which indicate how healthy the heart and arteries are)
* has effects on women's types and levels of various substances circulating in their blood
* in women affects the stiffness of their arteries and heart rate variability in parallel with changes in cardiovascular risk markers
* has different effects depending on whether women are pre or post menopausal.

Participation in this study is expected to last approximately 12 months.

The aim of the study is to evaluate the gender specific effects of physiologic Growth Hormone (GH) replacement in women with GH deficiency on the basis of pituitary/hypothalamic region tumors, radiation, or surgery on cardiovascular risk markers and arterial distensibility. Cardiovascular mortality in growth hormone (GH) deficient adults has been shown to be increased in a number of retrospective studies. Increased arterial intima-media thickness, increased prevalence of atherosclerotic plaques and endothelial dysfunction have been reported in growth hormone deficient adults both in childhood and adulthood onset forms.

The growth hormone deficiency (GHD) syndrome is associated with a cluster of cardiovascular-risk factors such as central adiposity, increased visceral fat, insulin resistance, dyslipoproteinemia and decreased plasma fibrinolytic activity. GH administration has effects on a number of these factors, but it is unknown which mechanisms are implicated in GH action on the process of atherosclerosis. In addition to alterations in atherosclerotic markers, abnormalities in cardiac function and structure have been reported among patients with GHD possibly contributing to the increased cardiovascular mortality. In addition, GHD is associated with cardiac autonomic dysfunction that may also contribute to cardiovascular mortality and improves with GH replacement therapy.

The vast majority of studies have focused primarily on men and the gender-specific effects of GH replacement on cardiovascular risk factors remain unknown. In addition to being of interest in terms of understanding the physiologic effects of GH therapy, there are important therapeutic implications regarding data in women. Cardiovascular disease is the leading cause of mortality in women. Effects of GH replacement on bone density may be less pronounced in women and because specific GH effects on cardiovascular risk factors in women are unknown, many adult women with GHD are untreated.

Long-term GH treatment decreases total body fat including visceral fat. Decreases in central fat as assessed by waist to hip ratio have been reported in some studies, but not in others. Administration of GH causes insulin resistance acutely but long-term therapy may restore glucose sensitivity. GH treatment increases lipoprotein (a) (Lp (a)) levels but its effects on other lipoproteins are still controversial. Some studies have reported decreases in LDL cholesterol with or without increases in HDL cholesterol with GH administration, while others have not. Twelve months of GH replacement improves left ventricular mass and cardiac performance in young adults with GHD. Key factors likely involved in the discrepant findings include heterogeneity of patients studied in terms of age of onset of the GH deficiency (childhood versus adulthood), gender, severity of GHD and methodologic issues such as dose and duration of GH administration. In addition, many of the studies have no control period.

Inflammation plays a central role in the pathophysiology of atherosclerosis. Each atherosclerotic lesion represents a different stage of a chronic inflammatory process in the arterial wall and different markers along the inflammatory cascade have been reported to predict cardiovascular risk \[34\]. Among those, high-sensitivity testing for C-reactive protein (CRP) is one of the best validated. Several prospective studies support a strong link between levels of CRP and future risk of coronary events. CRP adds considerable value to the total and HDL cholesterol measurement in the prediction of cardiovascular risk. Other distal indicators of inflammation such as serum-amyloid polypeptide A (SAA) likewise predict coronary risk. These distal markers reflect the consequences of elevated proinflammatory cytokines like interleukin-6 (IL-6). GH is known to have important immunomodulatory effects. We therefore hypothesized that the effects of GH on the process of atherosclerosis might be mediated through the cytokine-inflammatory pathway. We have recently investigated the effects of physiologic GH replacement in cardiovascular risk markers in men with GHD. In this study we found that CRP and IL-6 levels decreased in GH treated men compared to controls despite no significant change in serum lipid levels. We also recently have investigated levels of inflammatory markers in women with hypopituitarism compared with healthy controls. We found that women with hypopituitarism have increased levels of IL-6 and CRP suggesting that chronic inflammation may be involved in the pathogenesis of atherosclerosis in this population. It will be critical to determine whether physiologic GH replacement has beneficial effects in women, and whether these effects are influenced by estrogen.

We will investigate the effect of long-term physiologic GH administration on IL-6, CRP, SAA as well as other classic cardiovascular risk factors in women with GHD in a randomized, placebo-controlled study. In addition, we will evaluate structural/function correlates in women by measuring arterial wall distensibility and heart rate variability in parallel with cardiovascular risk markers.

We will establish the gender-specific effects of physiologic GH replacement on cardiovascular risk in women with GHD by investigating whether this therapy:

1. has gender-specific effects on cardiovascular risk markers
2. has gender-specific effects on lipid profiles
3. alters heart rate variability and arterial distensibility in parallel with changes in cardiovascular risk markers
4. has different effects depending upon gonadal status

Growth Hormone Administration and Its Effects on Cardiovascular Risk Factors in Growth Hormone Deficient Women

Gender-Specific Effects of Physiologic GH Administration on Cardiovascular Risk Factors in Women With Growth Hormone Deficiency

Massachusetts General Hospital

Anne Klibanski, MD

Nutritional and Metabolic Diseases

Immune System Diseases

Obesity

Hypersensitivity

Anti-Inflammatory Agents

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Insulin

Insulin, Globin Zinc

Growth hormone or Placebo 0.1 mg/day self-administrated once a day.

Nutropin 0.1 mg/day self-administered once a day

Nutropin

Kevin C. Yuen, MRCP(UK), MD

David M. Cook, MD

Study hypothesis:

Growth hormone (GH), through its generation of free 'bioavailable' insulin-like growth factor (IGF)-I, can improve insulin sensitivity and the metabolic profile of women with polycystic ovary syndrome.

Study aims:

To determine the mechanism of how low dose GH treatment affects the body's sensitivity to insulin actions and whether this low GH dose can affect the body's handling of steroid hormone levels (cortisol clearance) and testosterone (male hormones) in obese women with polycystic ovary syndrome.

Study design:

Obese women with polycystic ovary syndrome, but not recently been on GH treatment, and presently attending Outpatients Clinic will be invited to participate in this study. The subjects will be assessed at the initial visit to ascertain their suitability before further participating in the study. If suitable, an equal number of women will be randomized to receive either daily low dose GH or placebo injections first for 12 weeks, before exchanging over for another 12 weeks of treatment after a 4-week washout period. Before, during and after treatment, the subjects will be assessed at frequently with blood tests, scans and fat biopsies. During the study, the subjects will be studied 4 times at the Oregon Clinical and Translational Research Institute (OCTRI). At the first, second and final visit, testing will include scans to measure the amount of whole body fat and fat in the stomach area, muscle, and liver; blood tests to measure levels of cortisol, and fat tissue (taken from a biopsy) analysis to measure the density of insulin-like growth factor-I (a hormone stimulated by growth hormone in the body) in fat; whereas blood tests to examine how well insulin works in the body (insulin sensitivity) will be collected at all visits of the study.

The study will be a double-blinded cross-over study. Thirty subjects will be screened for eligibility initially, and the first 12 eligible subjects will be enrolled. Six subjects will be randomized to receive the low GH dose (0.1 mg/day) treatment and 6 subjects to receive Placebo treatment for 12 weeks, exchanging their treatment for a further 12 weeks after a 4-week washout period. The study drugs will be stored at the Oregon Health and Science University (OHSU) Research Pharmacy and following randomization, the subjects will be taught by our Endocrine Nurses to self-administer the subcutaneous GH and Placebo injections using Nutropin/Placebo vials and insulin syringes into the abdomen at 2200h. Randomization for treatment assignment will be performed by an investigator not directly involved in the patients' recruitment, treatment and follow-up care. The randomization process will be performed by computerized pre-assigned random codes by blocks, stratified by age and examined for possible differences in body mass index. During their in-patient stay at the Oregon Clinical and Translational Research Institute (OCTRI) at OHSU, subjects will only be allowed to eat the food provided to them by the OCTRI.

Initial Screening Assessment (outpatient)

The following assessments will be performed:

* Written informed consent
* Demographics (demographic information including the subject's birth date, and race)
* Physical exam and medical history
* Previous/significant medical history
* Concomitant medication review
* Vital signs, e.g., pulse and blood pressure measurements
* Height and weight
* Laboratory findings, e.g. CBC, electrolytes, and fasting glucose levels

  * Visit 1, Baseline Assessment for the First Treatment Phase (in-patient)

The following is a description of the assessments that will be performed after consent is obtained:

* Physical exam and medical history
* Vital signs, e.g., pulse and blood pressure measurements
* Height and weight
* Waist circumference measurement
* Concomitant medication review
* Urine pregnancy test
* Fasting blood assessments, e.g., hemoglobin, glucose, insulin, C-peptide, serum total and free IGF-I, IGFBP-3, C-reactive protein, non-esterified fatty acids (NEFAs), testosterone, albumin, sex hormone binding globulin and androstenedione
* A 3-hour one-step hyperinsulinemic euglycemic clamp
* MRS and DEXA scans
* Cortisol clearance rate assessments
* Fat biopsy
* Randomization to GH or Placebo
* Teach GH or Placebo self-administration

  * Visit 2, Final Assessment for the First Treatment Phase (Week 12 +/- 1 week) (outpatient)

The following is a description of the assessments that will be performed at the end of the first treatment phase with either GH or Placebo. Subjects will also be monitored for safety with the collection of the following:

* Physical exam and medical history
* Vital signs, e.g. pulse and blood pressure measurements
* Height and weight
* Waist circumference measurement
* Concomitant medication review
* Adverse event recording
* Urine pregnancy test
* Fasting blood assessments, e.g. hemoglobin, glucose, insulin, C-peptide, serum total and free IGF-I, IGFBP-3, C-reactive protein, adiponectin, ghrelin, non-esterified fatty acids (NEFAs), testosterone, albumin, sex hormone binding globulin and androstenedione
* A 3-hour one-step hyperinsulinemic euglycemic clamp
* MRS and DEXA scans
* Cortisol clearance rate assessments
* Fat biopsy

Washout Period and Crossover After the first treatment phase with GH or Placebo, the subjects will have a 4-week washout period and the treatment will be crossed over for another 12-week treatment phase with either GH or Placebo. During this time, the subjects will be advised to maintain a stable diet and weight.

Visit 3, Baseline Assessment for the Second Treatment Phase (Week 16 +/- 1 week) (as outpatient)

The following is a description of the assessments that will be performed:

* Physical exam and medical history
* Vital signs, e.g., pulse and blood pressure measurements
* Height and weight
* Waist circumference measurement
* Concomitant medication review
* Adverse event recording
* Urine pregnancy test
* Fasting blood assessments, e.g. hemoglobin, glucose, insulin, C-peptide, serum total and free IGF-I, IGFBP-3, C-reactive protein, adiponectin, ghrelin, non-esterified fatty acids (NEFAs), testosterone, albumin, sex hormone binding globulin and androstenedione
* Treatment exchanged to Placebo or GH

  * Visit 4, Final Assessment for the Second Treatment Phase (Week 28 +/- 1 week) (as inpatient)

The following is a description of the assessments that will be performed at the end of the second treatment phase with either GH or Placebo. Subjects will also be monitored for safety with the collection of the following:

* Physical exam and medical history
* Vital signs, e.g. pulse and blood pressure measurements
* Height and weight
* Waist circumference measurement
* Concomitant medication review
* Adverse event recording
* Urine pregnancy test
* Fasting blood assessments, e.g., hemoglobin, glucose, insulin, C-peptide, serum total and free IGF-I, IGFBP-3, C-reactive protein, adiponectin, ghrelin, non-esterified fatty acids (NEFAs), testosterone, albumin, sex hormone binding globulin and androstenedione
* A 3-hour one-step hyperinsulinemic euglycemic clamp
* MRS and DEXA scans
* Cortisol clearance rate assessments
* Fat biopsy

  * Because of the potentially long duration of Visits 1, 2 and 4, the studies can either be divided into two separate admissions upon prior arrangement or can be done all at once with one admission, depending on the subject's wishes and schedule.

Low Dose Growth Hormone in Obese PCOS Women

Effects of Low Dose Growth Hormone (GH) Therapy on Insulin Sensitivity, Metabolic Profile, Adipocyte IGF-I and Insulin Signaling, Intramyocellular Lipids, and Cortisol Metabolism in Obese Women With Polycystic Ovary Syndrome (PCOS)

Oregon Health and Science University

Associate Professor in Endocrinology

Acromegaly

Gastrointestinal Agents

Mitogens

Octreotide

Pasireotide

Lanreotide

Lactitol

Antineoplastic Agents, Hormonal

Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution)

If a patient is randomized to the open label arm the investigator will either:

* be instructed to contact a Novartis delegate to initiate shipment of either octreotide LAR 30 mg or lanreotide ATG 120 mg from a Novartis or designee depot to the site, or
* continue to dispense either octreotide LAR 30 mg or lanreotide ATG 120 mg available at the institution to the patient if permitted by local regulations.

* Double-blind pasireotide LAR 40 mg i.m. injection once every 28 ± 2 days for 24 weeks or
* Double-blind pasireotide LAR 60 mg i.m. injection once every 28 ± 2 days for 24 weeks

In an open-label, active control arm, continue on the same treatment with octreotide LAR 30 mg every 28 ± 2 days as received for at least 6 months prior to randomization

octreotide LAR 30mg

In an open-label, active control arm, continue on the same treatment with lanreotide ATG 120 mg every 28 ± 2 days as received for at least 6 months prior to randomization

lanreotide ATG 120mg

Novartis Pharmaceuticals

This study will evaluate the efficacy and safety of pasireotide LAR 40 and 60 mg versus octreotide LAR or lanreotide ATG in patients with inadequately controlled acromegaly.

Efficacy and Safety of Pasireotide Long Acting Release (LAR) Versus Octreotide LAR or Lanreotide Autogel (ATG) in Patients With Inadequately Controlled Acromegaly

A Phase III, Multicenter, Randomized, Parallel-group Study to Assess the Efficacy and Safety of Double-blind Pasireotide LAR 40 mg and Pasireotide LAR 60 mg Versus Open-label Octreotide LAR or Lanreotide ATG in Patients With Inadequately Controlled Acromegaly

The primary objective of this study was to compare the percentage of patients achieving biochemical control (defined as mean GH levels \<2.5 µg/L and normalization of sex- and age- adjusted IGF-1) at 24 weeks with pasireotide LAR 40 mg and pasireotide LAR 60 mg separately versus continued treatment with octreotide LAR 30 mg or lanreotide autogel (ATG) 120 mg. The primary efficacy variable is the proportion of patients with a reduction of mean GH levels to \< 2.5 µg/L and normalization of sex- and age-adjusted IGF-1 at 24 weeks.

The percentage of patients achieving mean growth hormone (GH) levels \< 2.5 μg/L and normalization of sex and age-adjusted IGF-1 was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Total insulin-like growth factor (IGF-1) levels were assessed with one pre-dose sample at the same visits as GH. Concomitant medication known to affect GH or IGF-1 levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (extension full analysis set)

The percentage of patients achieving normalization of sex and age-adjusted IGF-1 was calculated with two sided 95% confidence interval. Total insulin-like growth factor (IGF-1) levels were assessed with one pre-dose sample at the same visits as GH. Concomitant medication known to affect IGF-1 levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set)

The percentage of patients achieving mean growth hormone (GH) levels \< 2.5 μg/L was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Concomitant medication known to affect GH levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set)

The percentage of patients achieving mean growth hormone (GH) levels \< 1.0 μg/L and normalization of sex and age-adjusted IGF-1 was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Total insulin-like growth factor (IGF-1) levels were assessed with one pre-dose sample at the same visits as GH. Concomitant medication known to affect GH or IGF-1 levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set

The percentage of patients achieving mean growth hormone (GH) levels \< 1.0 μg/L was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Concomitant medication known to affect GH levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set)

Change from CORE baseline at each scheduled assessment was performed for patients randomized to pasireotide arms. Change from extension baseline at each scheduled assessment was performed for patients randomized to active control arm.

Standardized IGF-1 = IGF-1 value / ULN, where ULN is the upper limit of the normal range

Change from CORE baseline at each scheduled assessment was performed for patients randomized to pasireotide arms. Change from extension baseline at each scheduled assessment was performed for patients randomized to active control arm. Standardized IGF-1 = IGF-1 value / ULN, where ULN is the upper limit of the normal range

n is the number of patients achieving response criteria. The weeks correspond to duration of first response (in weeks) for patients achieving biomedical control. Median and 95% CI are derived from Kaplan-Meier curves. Kaplan-Meier estimates \[95% CI\] at each time point are estimates of probability of response.

Time to first response is defined as the time from the date of first dose to the date of first occurrence of a reduction of mean GH \< 2.5 µg/L and the normalization of IGF-1. The weeks correspond to time taken to achieve first mean GH \< 2.5 µg/L and the normalization of IGF-1.

Acromegaly Quality of Life questionnaire (AcroQoL) is a validated disease specific questionnaire. It contains 22 items divided into two scales: physical aspects (8 items) and psychological aspects (14 items) which is divided in two sub-scales: physical appearance and personal relationships of the patient (seven items each). The total score and sub-scores were calculated using the following formula: ((X -Y) / 4Y) x 100, X=sum of the scores for individual items (between 1 and 5 for each item), Y=number of individual items included in above sum (i.e. 22 for the total score, 8 for the physical sub-score, 14 for the psychological sub-score, 7 for the sub-score 'appearance' and 'personal relations'). The scoring of the questionnaire was performed as specified by the instrument developers. Total scores range from 0 to 100. Higher scores represent better quality of life. If more than 25% of items are not completed, results were considered invalid.

PK samples were collected for those patients treated with pasireotide LAR in the core study and who continued on pasireotide LAR in the extension phase. PK samples were collected before the injection of pasireotide LAR only at weeks 112 and 196. PK samples were also collected at weeks 48 and 132 only for all patients treated with octreotide LAR 30 mg or lanreotide ATG 120 mg in the core study who started treatment with pasireotide LAR in the extension study.

Blood samples (2.5 mL each sample) were collected to yield 1-mL plasma for analysis of pasireotide LAR oncentration.

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator. The adverse events were reported on the combined CORE and extension and there were 5 patients who never received drug and 1 with no post baseline safety assessment.

Pasireotide LAR 40 mg

Pasireotide LAR 60 mg

Cross-over to Pasireotide

Open label octreotide LAR 30 mg or lanreotide ATG 120 mg supplied either locally or from designated depot. Administered intramuscular every 28 days

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