AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF TESTOSTERONE AND CARDIOVASCULAR RISK.

This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

PITUITARY MRI FINDINGS IN PATIENTS WITH PITUITARY AND ECTOPIC ACTH-DEPENDENT CUSHING SYNDROME: DOES A 6-MM PITUITARY TUMOR SIZE CUT-OFF VALUE EXCLUDE ECTOPIC ACTH SYNDROME?

OBJECTIVE: Expert opinion and a consensus statement on Cushing syndrome (CS) indicate that in a patient with a clinical presentation and biochemical studies consistent with a pituitary etiology, the presence of a pituitary tumor ≥6 mm is highly suggestive of Cushing disease (CD). The purpose of the present study was to determine the optimal pituitary tumor size that can differentiate between patients with CD and ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) and obviate the need for inferior petrosal sinus sampling (IPSS). METHODS: We performed a retrospective study of 130 patients seen between 2000 and 2012 including 104 patients with CD and 26 patients with EAS. RESULTS: A pituitary lesion was reported in 6/26 (23%) patients with EAS and 71/104 (68.3%) patients with CD, with median (range) sizes of 5 mm (3-14) and 8 mm (2-31), respectively. All tumors in the EAS group measured ≤6 mm except for 1 that measured 14 mm. The presence of a pituitary tumor >6 mm in size had 40% sensitivity and 96% specificity for the diagnosis of CD. ACTH levels >209 pg/mL and serum potassium <2.7 mmol/L were found in patients with EAS. All patients with EAS had a 24-hour urine free cortisol (UFC) >3.4 times the upper limit of normal (×ULN) Conclusion: Pituitary incidentalomas as large as 14 mm in size can be seen in patients with EAS. However, the 6-mm tumor size cut-off value provided 96% specificity and may be a reasonable threshold to proceed with surgery without the need for IPSS when the biochemical data support a pituitary etiology.

Biochemical and radiological relationships in patients with pheochromocytoma: lessons from a case control study.

BACKGROUND: An elevation of fractionated plasma or urinary metanephrine (MN) or nor-metanephrine (NMN), collectively called metanephrines (MN and NMN), >4-fold above the upper limit of normal (ULN) is usually considered to be diagnostic for pheochromocytoma (PHEO). There are a greater number of false positive results when the elevations are more modest. AIM: To identify biochemical and radiological features in PHEOs with modest elevations (<4-fold above ULN) of metanephrines. METHODOLOGY: We retrospectively reviewed the charts of 112 patients with PHEO (10% extra-adrenal) and 208 patients with a non-PHEO adrenal mass operated from 1997-2011, who had metanephrines measured pre-operatively. We divided PHEO into group 1 (n = 90) with metanephrines ≥4-fold ULN and group 2 (n = 22) with metanephrines <4-fold ULN. The non-PHEO group was designated as group 3. RESULTS: The median (range) tumour size in group 1 and group 2 was 4·8 cm (1·7-22) and 3·0 cm (1·7-5) respectively (P < 0·001). All patients with PHEO in group 2 had a tumour <5 cm in size. The MN fraction was elevated in about 65% of groups 1 and 2; only 2 (1%) patients in group 3 had an elevated urinary MN fraction, and none were associated with an elevated plasma MN fraction. All PHEOs had a pre-contrast attenuation ≥17 Hounsfield Units (HU). CONCLUSIONS: Modest elevations (<4-fold ULN) of the NMN fraction in an adrenal mass >5 cm are almost always falsely positive. Elevations in plasma and urinary MN fraction are less likely to be false positive. The CT pre-contrast attenuation of PHEOs is >10 HU.

Is a stable or decreasing prolactin level in a patient with prolactinoma a surrogate marker for lack of tumor growth?

The optimal interval for follow-up imaging of patients with prolactinomas is unclear. We wish to determine the likelihood of tumor enlargement in patients with prolactinomas who have a stable or reduced prolactin (PRL) level over time, whether or not they are treated with a dopamine agonist (DA). We identified 80 patients with prolactinomas (34 men, 46 women) who had at least two paired sets of serum PRL levels and pituitary MRIs, 3 or more months apart. Patients with hyperprolactinemia due to drug or stalk effects were excluded. The median (range) age was 45 (25-77) years. Sixty-three patients (78.8%) were treated with DA. PRL levels (ng/mL) at the initial and latest sets were 114 (0.3-15,732) and 16 (0.3-1,204), respectively. In patients with identifiable tumors, the maximum tumor diameters (mm) at the initial and latest MRI studies were 12.5 (2-60) and 12.5 (2-39) respectively, with an interval of 2.9 (0.3-9.7) years. Sixty percent of patients (n = 48) had a macroadenoma. Forty-two (52.5%) patients had either disappearance of the tumor (n = 22) or reduction (n = 20) in tumor size. In the remainder, tumor size was stable in 35 but increased in 3 patients. One of these patients, observed off therapy had a concomitant rise in PRL level. The other 2 had evidence of pituitary hemorrhage with no PRL increase. Tumor growth in prolactinoma patients with a stable or decreasing PRL level, regardless of size, is a rare event. Repetitive pituitary imaging in these patients may not be warranted.

Mody-3: novel HNF1A mutation and the utility of glucagon-like peptide (GLP)-1 receptor agonist therapy.

OBJECTIVE: An estimated 1 to 2% of cases of diabetes mellitus have a monogenic basis; however, delayed diagnosis and misdiagnosis as type 1 and 2 diabetes are common. Correctly identifying the molecular basis of an individual's diabetes may significantly alter the management approach to both the patient and his or her relatives. We describe a case of mature onset diabetes of the young (MODY) with sufficient evidence to support the classification of a novel HNF1A (hepatocyte nuclear factor-1-α) mutation as a cause of MODY-3. METHODS: A 21-year-old Caucasian female presented to our office with a diagnosis of noninsulin-dependent diabetes mellitus (NIDDM) at age 10; glycemia was initially managed with oral antidiabetic (OAD) agents and insulin detemir. The patient reported a strong family history of early-onset NIDDM in both her mother and maternal grandmother, both of whom eventually required insulin therapy to control glycemia. The patient's medical and family history were highly suggestive of maturity-onset diabetes of the young (MODY), and genetic testing was performed. RESULTS: Genetic screening detected a mutation p. Arg200Trp in the HNF1A gene in the patient, her mother, and maternal grandmother, suggesting a diagnosis of MODY-3. This finding resulted in a change of antidiabetic therapy in all 3 patients, including the addition of once-daily liraglutide therapy, which helped improve their glycemic control. CONCLUSION: Our case report supports the classification of the p. Arg200Trp mutation as a cause of MODY-3. The findings also suggest that glucagon-like peptide-1 (GLP-1) receptor agonist therapy may be of value in managing glycemia in patients with MODY-3.

The clinical utility of free thyroxine in oral levothyroxine absorption testing.

OBJECTIVE: Original absorption studies for levothyroxine (LT4) were validated using total thyroxine (TT4) measurements. Free thyroxine (FT4) has largely supplanted TT4 in clinical practice. The objective of our study was to assess the clinical utility of FT4 in oral LT4 absorption testing. METHODS: In this retrospective electronic health record analysis, we recorded data of patients who underwent LT4 oral absorption testing between November 2010 and January 2012 because of persistent hypothyroidism despite a greater than anticipated weight-based dose of LT4. Patients included had primary hypothyroidism and an absorption test with assessment of both TT4 and FT4 measured at times 0, 30, 60, 90, 120, 180, 240, 300, and 360 minutes. The test was conducted with 1 mg (five 200-µg tablets) of Synthroid® after an overnight fast by a standard nonisotopic method. RESULTS: A total of 10 patients (3 men/7 women) underwent absorption testing. Prior to testing, the median daily LT4 dose was 250 µg (range, 150 to 350 µg). Three patients were also on liothyronine (10, 20, or 50 µg daily). Based on the calculated amount absorbed, 1 patient demonstrated subnormal absorption, and 9 patients were normal. Median body mass index was 33 kg/m2 (range, 21 to 50 kg/m2). Median calculated absorption was 105% (range, 3.7 to 195.6%). The correlation comparing FT4 and TT4 was 0.88 (95% confidence interval, 0.56 to 0.97; P<.001), a significant correlation. CONCLUSION: FT4 and TT4 correlated highly, even in patients who were severely hypothyroid; FT4 may be used interchangeably with TT4 as a qualitative assessment of suspected malabsorption using an oral LT4 absorption test.

Prolactin measurement during inferior petrosal sinus sampling improves the localization of pituitary adenomas in Cushing's disease.

OBJECTIVE: Inferior petrosal sinus sampling (IPSS) distinguishes pituitary-dependent Cushing's disease (CD) from ectopic ACTH syndrome with a high degree of certainty, but has not been reliable in predicting the location of an adenoma within the pituitary gland. We investigated whether prolactin measurements during IPSS would improve pituitary tumour localization. METHODS: Fifty-four patients with suspected ACTH-dependent Cushing's syndrome who underwent IPSS between 1997 and 2009 were studied retrospectively. Twenty-eight patients who had an identifiable tumour that stained for ACTH on histopathology are the subject of this study. Intersinus ACTH gradients before and after adjustment for prolactin were compared with surgical findings and pathology. RESULTS: Magnetic resonance imaging localized a pituitary adenoma in 17/28 (61%) patients. Using a maximum intersinus ACTH gradient of ≥1·4 before or after CRH stimulation, we could diagnose the tumour location correctly in 15/28 (54%) patients. By comparison, tumour lateralization by means of a dominant (≥1·4) prolactin-adjusted ACTH intersinus gradient was correct in 21/28 (75%) patients (P = 0·041). Tumour localization was correct in 23/28 (82%) patients when MRI and prolactin-adjusted ratio data were combined. Fourteen patients with proper bilateral IPS venous sampling (as determined by concurrent IPS to peripheral prolactin ratio ≥1·8) either had correct localization of the tumour (n = 12) or had a central lesion (n = 2). In none of these 14 patients was the dominant prolactin-adjusted ACTH ratio associated with a tumour on the opposite side of the gland. CONCLUSION: Prolactin measurement, during IPSS, improves our ability to correctly localize the pituitary adenoma site in CD.

Pregnancy and acromegaly: a review.

To review the literature regarding the diagnosis and management of acromegaly during pregnancy. A systematic literature search was performed using MEDLINE including hand-searching reference lists from original articles. The diagnosis of acromegaly during pregnancy is made difficult due to the physiologic changes in pituitary GH secretion and IGF-1 production resulting from placental GH secretion and the inability of commercial assays to discriminate between pituitary and placental GH. Most patients with acromegaly during pregnancy do not have an increase in tumor size, metabolic complications are uncommon, and neonatal outcome is largely unaffected. IGF-1 levels tend to be stable in such patients possibly due to the high estrogen levels causing GH resistance. Dopamine agonists, somatostatin analogues, and a GH receptor antagonist have been reported to be safe during pregnancy. Patients with visual field defects should be considered for surgery, but in most cases this can be safely postponed until after delivery. Overall, pregnancy in acromegaly is uneventful and newborns unaffected. Dopamine agonists and somatostatin analogues have not been associated with major adverse effects to the fetus; however, more data are needed to validate their safety.

Diabetes and Heart Failure: A Marriage of Inconvenience.

Type 2 diabetes and congestive heart failure are growing public health problems and are expected to worsen in the next decade. There is an inarguable link between diabetes and heart failure but only recently has there been an effort to elucidate the underlying pathophysiologic connection resulting in diabetic cardiomyopathy. Traditionally, diabetes and heart failure have been treated as 2 distinct disease entities, but recent advances in individual therapies have shown remarkable concomitant improvements in both diabetes and cardiovascular outcomes. This article aims to review the key connections in the epidemiology and etiopathophysiology of type 2 diabetes and heart failure.

Cyclic Cushing syndrome due to an ectopic pituitary adenoma.

BACKGROUND: A 39-year-old man was referred to an endocrinology clinic for evaluation of his Cushing syndrome. He had gained 20 kg over 5 years and complained of intermittent headaches and easy bruisability. His medical history included a left foot fracture associated with minimal trauma 2 years earlier, hypertension, and stable Crohn disease with no use of exogenous glucocorticoids for at least 10 years. INVESTIGATIONS: Measurements of plasma adrenocorticotropic hormone, 24 h urine free cortisol excretion, late-night salivary cortisol, serum cortisol levels before and after corticotropin-releasing hormone administration during a dexamethasone suppression/corticotropin-releasing hormone-stimulation test, pituitary MRI, and inferior petrosal sinus sampling. DIAGNOSIS: Cyclic Cushing syndrome secondary to an ectopic pituitary adenoma. MANAGEMENT: The cyclic nature of Cushing syndrome was suggested by the absence of hypercortisolemia during inferior petrosal sinus sampling, and was confirmed by multiple 24 h urine free cortisol measurements. The patient underwent transsphenoidal surgery, during which a 5 mm firm, round, midline sphenoid sinus lesion was identified and resected. In preoperative imaging studies, this lesion had been interpreted as being a mucosal polyp. At microscopic examination, the lesion was found to be a pituitary adenoma, which stained diffusely with antiadrenocorticotropic-hormone antibodies. Explorations of the sella and pituitary did not reveal any abnormalities. Postoperatively, the patient became hypocortisolemic and his cushingoid features resolved. His adrenal function normalized 3 months after surgery. At 18 months, the patient continued to be symptom-free with normal levels of urinary-free cortisol and midnight salivary cortisol.

Posttransplant diabetes mellitus in kidney transplant recipients receiving calcineurin or mTOR inhibitor drugs.

BACKGROUND: The aim of this study was to evaluate the incidence and risk factors for posttransplant diabetes mellitus (PTDM; defined as new insulin use and/or new hyperglycemia) in 528 kidney recipients using different immunosuppressive agents. METHODS: Maintenance therapy included mycophenolate mofetil or azathioprine plus glucocorticoids in combination with Group I cyclosporine (263); Group II tacrolimus (60); or Group III sirolimus (205). RESULTS: The mean follow-up was 39.2 (range 9.0-103.8) months. Overall, the number of patients needing insulin was 7.4% (39/528). The incidences for Groups I, II, and III of 7.6%, 11.7%, and 5.9%, respectively, were not statistically different. Characteristics of patients with PTDM included older age (P=0.007); greater body weight (kg) at transplant, 6 months, and 12 months, respectively (P<0.001); greater BMI (kg/m2) at transplant, 6 months, and 12 months, respectively (P<0.001); more acute rejection episodes 28.2% vs. 13.5% (P=0.012); and increased incidence in African Americans (P=0.03). Multivariable analysis demonstrated increased risk for PTDM (defined as new insulin use) for tacrolimus, (hazard ratio [HR] 3.794, P=0.007); treated rejections (HR 2.491, P=0.0115); age (HR 1.407, P=0.0116); and BMI (HR 1.153, P<0.0001). New insulin use occurred sooner and with less total glucocorticoid dose for tacrolimus patients. If PTDM is defined as all cases of new hyperglycemia, then no immunosuppressive drug group demonstrated an increased risk. CONCLUSION.: The risk for developing PTDM is greatest among older recipients, and those obese at the time of transplant; those given steroid pulse therapy were at exceptionally high-risk. PTDM risk reduction should focus on weight loss in the obese end-stage renal disease population prior to transplant.

Post-transplant diabetes mellitus: risk reduction strategies in the elderly.

New-onset diabetes mellitus in a previously non-diabetic transplant recipient is a serious adverse event that confers significant morbidity and mortality. The most significant consequences of post-transplant diabetes mellitus (PTDM) in solid organ transplant recipients include decreased patient and graft survival, an increased risk of infectious complications, and morbid cardiovascular events. The development of PTDM in the elderly is of particular concern because this group is already at increased risk of progression of cardiovascular disease. Because the elderly, especially those aged >65 years, are the fastest-growing segment of the renal transplant population, attention needs to be given to PTDM risk reduction and post-transplant management. PTDM develops as a consequence of both impaired insulin production and enhanced peripheral insulin resistance. A number of non-modifiable factors such as age, race, family history, hepatitis C, polycystic kidney disease and emerging genetic causes have been identified as risk factors for PTDM. However, a number of modifiable factors can be targets for intervention in high-risk patients, including bodyweight (through dietary restriction and exercise), hypertension, hyperlipidaemia and the effects of certain immunosuppressive agents. The two agents most responsible for PTDM are tacrolimus and corticosteroids, especially when used in combination. Attempts to modify doses and regimens designed to eliminate or avoid these drugs should be considered. Use of HMG-CoA reductase inhibitors ('statins') and ACE inhibitors is particularly helpful in controlling hypertension and hyperlipidaemia in the elderly because these agents confer protection against future adverse cardiovascular events. Bisphosphonates are also advantageous in controlling the progression of osteoporosis and possible increased risk of bone fractures. Future trials in the elderly should focus on such endpoints as PTDM, post-transplant neoplasia, cardiovascular events and bone fracture events in order to identify the safest regimens that provide the optimal control of rejection while limiting the morbidity from these secondary events.

Spontaneous Hypoglycemia After Islet Autotransplantation for Chronic Pancreatitis.

CONTEXT: Spontaneous hypoglycemia has been reported in patients after total pancreatectomy (TP) and islet autotransplantation (IAT) with maintained insulin independence. Details surrounding these events have not been well described. OBJECTIVE: The objective of the study was to determine the frequency and characteristics of spontaneous hypoglycemia in patients undergoing TP-IAT and/or to ascertain predictive or protective factors of its development. DESIGN: This was an observational cohort study in 40 patients who underwent TP-IAT from August 2008 to May 2014, with a median follow-up of 34 months. SETTING: The study was conducted at a single institution (Cleveland Clinic). PATIENTS: Patients included recipients of TP-IAT. INTERVENTION: The intervention included small, frequent meals in those patients who developed spontaneous hypoglycemia. MAIN OUTCOME MEASURES: Incidence of spontaneous hypoglycemia development, characteristics of the patients developing hypoglycemia, and their response to small, frequent meals were measured. RESULTS: Six of 12 patients, who maintained insulin independence, developed spontaneous hypoglycemia. The episodes could be fasting, postprandial, and/or exercise associated, with the frequency ranging from two to three times daily to once every 1-2 weeks. All patients experienced at least one episode that required external assistance, glucagon administration, and/or emergent medical attention. Patients who developed hypoglycemia had a lower median age and tended to have a lower median islet equivalent/kg body weight but a higher median total islet equivalent, body mass index, and homeostatic model assessment for insulin resistance score. All patients who received small, frequent meal intervention had improvement in severity and/or frequency of the hypoglycemic episodes. CONCLUSIONS: Spontaneous hypoglycemia is prevalent after TP-IAT. Although the underlying pathophysiology responsible for these hypoglycemia events remains to be elucidated, small, frequent meal intervention is helpful in ameliorating this condition.

Basal and postglucagon C-peptide levels in Ethiopians with diabetes.

OBJECTIVE: To study basal C-peptide (BCP) and postglucagon C-peptide (PGCP) levels in Ethiopians with diabetes. RESEARCH DESIGN AND METHODS: A total of 56 subjects with type 1 diabetes, 97 subjects with type 2 diabetes, and 50 control subjects were recruited from a hospital in Ethiopia. BCP was determined in all subjects and PGCP in 86 subjects. RESULTS: Mean (+/- SEM) BCP, PGCP, and the increment after glucagon in type 1 diabetic subjects (0.14 +/- 0.04, 0.22 +/- 0.11, and 0.08 +/- 0.05 nmol/l, respectively) were lower (P < 0.001) than those in type 2 diabetic subjects (0.66 +/- 0.04, 1.25 +/- 0.10, and 0.56 +/- 0.06 nmol/l, respectively) or control subjects (0.54 +/- 0.04, 1.52 +/- 0.26, and 1.11 +/- 0.24 nmol/l, respectively). The mean BCP level was higher in type 2 diabetic subjects than control subjects (P=0.015), whereas the mean increment was lower (P=0.005). Insulin-treated type 2 diabetic subjects, compared with non-insulin-treated type 2 diabetic subjects, had lower mean BCP (0.55 +/- 0.08 nmol/l [n=37] vs. 0.73 +/- 0.04 [n=60], P=0.001), lower PGCP (0.97 +/- 0.20 nmol/l [n=18] vs. 1.40 +/- 0.11 [n=35], P=0.010), and a lower C-peptide increment (0.34 +/- 0.06 [n=18] vs. 0.67 +/- 0.07 nmol/l [n=35], P=0.003). In both the type 1 and type 2 diabetic groups, those with BCP levels <0.2 nmol/l had lower BMI than those with higher BCP levels (P=0.023 and P < 0.001, respectively). CONCLUSIONS: Combined with clinical criteria, C-peptide levels are good discriminators between type 1 and type 2 diabetes in Ethiopians and may also be useful in identifying subjects with type 2 diabetes who require insulin therapy. There is a subgroup of type 2 diabetic subjects with features of type 1 diabetes.

Factors associated with islet yield and insulin independence after total pancreatectomy and islet cell autotransplantation in patients with chronic pancreatitis utilizing off-site islet isolation: Cleveland Clinic experience.

CONTEXT: Total pancreatectomy (TP) with islet cell autotransplantation (IAT) can reduce or prevent diabetes by preserving beta cell function and is normally performed with on-site isolation laboratory facilities. OBJECTIVE: We examined factors associated with islet yield and metabolic outcomes in patients with chronic pancreatitis undergoing TP-IAT. We report our experience of TP-IAT with an off-site islet isolation laboratory. PATIENTS AND METHODS: Data (August 2008 to February 2014) were obtained from a TP-IAT database which included information from medical records, clinic visits, questionnaires, and follow-up telephone calls. Each patient was assessed with pre- and postoperative 5-hour mixed-meal tolerance tests for metabolic measurements and with serial glycosylated hemoglobin (HbA1c) determinations. RESULTS: Thirty-six patients with a mean age of 38 years (range, 16-72 y) underwent TP-IAT for different etiologies. At a median follow-up time of 28 months (range, 3-66 mo), 12 patients were insulin independent and 24 patients were on at least one insulin injection a day. Postoperatively, C-peptide levels ≥0.3 ng/mL were present in 23/33 (70%) of the patients, with a median fasting C-peptide value of 0.8 ng/mL (range, <0.2-1.5 ng/mL). Those who were insulin independent were more likely to be female (P = .012), have normal morphology on pre-operative pancreatic imaging (P = .011), and have significantly higher median islet yield (6845 islet equivalent numbers [IEQ]/kg, n = 12 vs 3333 IEQ/kg, n = 24; P < .001). CONCLUSIONS: IAT after TP performed in our facility with an off-site islet isolation laboratory shows islet yield and rates of insulin independence that are comparable to other large centers with on-site laboratories.

Detection of thyrotropin-receptor messenger ribonucleic acid (mRNA) and thyroglobulin mRNA transcripts in peripheral blood of patients with thyroid disease: sensitive and specific markers for thyroid cancer.

Because thyroid cancer cells express functional TSH receptors (TSHR), TSHR-mRNA in peripheral blood might serve as a tissue-/cancer-specific marker. We measured circulating TSHR-mRNA by RT-PCR in 51 normal controls, 27 patients with benign thyroid disease, 67 patients with treated differentiated thyroid cancer (DTC), and eight patients with newly diagnosed DTC, preoperatively. Results were compared with thyroglobulin (Tg) mRNA and serum Tg levels. TSHR-mRNA signals were not detected in normal controls and in 24 of 27 (89%) patients with benign thyroid disease. All 19 patients with treated DTC with evidence of distant or local disease tested positive for TSHR-mRNA (sensitivity 100%). Among patients with no evidence of disease, TSHR-mRNA was detected in 1 in 48 (specificity 98%). Six of the eight newly diagnosed DTC patients tested preoperatively were positive for TSHR-mRNA. The concordance between TSHR-mRNA and Tg-mRNA and between TSHR-mRNA and serum Tg was 95%. Fourteen patients with DTC (21%) had Tg antibodies, three with local disease (all positive for TSHR-mRNA), and 11 with no evidence of disease (all negative for TSHR-mRNA). Our results indicate that TSHR-mRNA and/or Tg-mRNA in peripheral blood are both equally sensitive and specific markers for monitoring thyroid cancer patients. Their principal value resides in the Tg antibody-positive patients in whom a positive or a negative mRNA value might have indicated or obviated the need for a whole-body scan. Furthermore, the high specificity combined with their ability to predict thyroid cancer preoperatively suggests a potential role in detecting thyroid cancer in patients with thyroid nodules.

Gonadal dysgenesis with X-monosomy in a cynomolgus monkey (Macaca fascicularis).

A 3-year-old female cynomolgus monkey (Macaca fascicularis) was found to have inappropriately high circulating immunoassayable follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels compatible with primary gonadal failure. Hypergonadotropic hypogonadism was confirmed by the findings of persistently high serum gonadotropin levels by both LH bioassay and FSH and LH radioimmunoassays and low levels of serum estradiol. In addition, circhoral gonadotropin pulsatility and an exaggerated response to a gonadotropin-releasing hormone challenge were demonstrated. Both FSH and LH coeluted in a single peak on gel filtration column chromatography. Clinically, the animal showed the following features of Turner syndrome: small body size, sexual underdevelopment, gonadal streaks with absent follicles, and a chromosomal constitution of 41,X. A similar case has been reported previously in a rhesus monkey (Macaca mulatta). Considering the fetal and live birth prevalences in humans of aneuploidy in general and X-monosomy in particular, one would predict that this chromosomal aberration underlies a high number of pregnancy failures in nonhuman primates.

Postpartum infertility in common chimpanzees.

The endocrine profile during normal postpartum amenorrhea in chimpanzees (Pan troglodytes) closely resembles that of women, and its duration is similarly extended by nursing. However, when infant chimpanzees in our colony were removed at birth, excessively prolonged postpartum amenorrhea (7-26 months duration) occurred in 24% of cases. Our endocrine studies indicate that such prolonged postpartum amenorrhea (PPAm) is a pathological condition associated with chronically elevated serum prolactin levels and galactorrhea. In the absence of nursing, we sought an alternate behavioral basis for PPAm. Breast and genital auto- and partner-directed manipulation was compared in PPAm chimpanzees, normal 2-3 mo. postpartum chimpanzees (infants removed at birth), and regularly-menstruating chimpanzees. A statistically significant pattern of breast, but not genital, manipulation was observed in the PPAm group only, at levels comparable to normal suckling. In particular, a characteristic pattern of nipple auto-manipulation (spooling) occurred. Two partner-stimulated PPAm animals were also identified: when caged individually, they resumed cycling within a few days. In contrast, 2 self-stimulators did not resume cyclicity when isolated. These observations suggested that interruption of breast stimulation allowed cyclicity to resume. Treatment of PPAm chimpanzees with oral Bromocryptine Mesylate (Sandoz, 2.5-5.0 mg b.i.d.) was associated with depression of prolactin levels in most animals and resumption of cyclicity in 11/13 subjects within 4 months. Oral Pergolide (Eli Lilly, 200 µg once daily, 13-17 days), appeared much more effective, cyclicity resumed in 8/8 animals within 14 days of commencing treatment; both drugs significantly reduced postpartum amenorrhea duration.

Testicular "hyperstimulation" syndrome: a case of functional gonadotropinoma.

Gonadotropins secreting pituitary tumors tend to present as sellar mass with hypogonadism. Biologically active LH secretion by these tumors resulting in elevated testosterone is extremely rare. We report a case of a 48-year-old male patient who presented with giant pituitary tumor, elevated testosterone, and elevated levels of gonadotropins. Surgical resection of the tumor resulted in normalization of gonadotropins and fall in serum testosterone to subnormal levels in the postoperative period confirming that the tumor was secreting bioactive luteinizing hormone (LH).

Liraglutide effective in the severely insulin-resistant patient with type 2 diabetes requiring U-500 insulin: a case report.

BACKGROUND/OBJECTIVE: We describe the effectiveness of liraglutide therapy in a severely insulin-resistant patient with type 2 diabetes mellitus (DM-2) requiring U-500 insulin. SUBJECT AND METHODS: A 65-year-old morbidly obese man (body mass index, 67.3 kg/m(2); weight, 156.2 kg) presented with a 20-year history of DM-2; the glycemic control deteriorated to U-500 insulin requirement. He was inadequately controlled (hemoglobin A1c [HbA1c], 9.1%) on metformin plus U-500 insulin titrated to 575 units daily. Liraglutide was added and titrated to 1.8 mg once daily over 3 weeks. RESULTS: Insulin requirements decreased markedly (>50%) to 250 units daily after 5 months of added liraglutide, with a concurrent improvement in HbA1c from 9.1% to 6.9% and weight loss of 22.6 kg. CONCLUSIONS: The addition of once-daily liraglutide to the regimen of patients with uncontrolled DM-2 requiring U-500 insulin should be considered as it may help to reduce insulin requirements, improve glycemic control, and assist with weight management.