James Gibney

Frequent Misdiagnosis and Mismanagement of Hyperprolactinemic Patients before the Introduction of Macroprolactin Screening: Application of a New Strict Laboratory Definition of Macroprolactinemia

BACKGROUND Macroprolactin (big big prolactin) has reduced bioactivity and is measured by immunoassays for prolactin when it accumulates in the plasma of some individuals. We applied normative data for serum prolactin after treatment of sera to remove macroprolactin to elucidate the contribution of macroprolactin to misleading diagnoses, inappropriate investigations, and unnecessary treatment. METHODS We reviewed records of women attending a tertiary referral center who had prolactin >1000 mIU/L. Application of a reference interval to polyethylene glycol (PEG)-treated hyperprolactinemic sera identified 21 patients in whom hyperprolactinemia was accounted for entirely by the presence of macroprolactin. Presenting clinical features, diagnoses, and treatment were compared in these patients and 42 age-matched true hyperprolactinemic patients. RESULTS Prolactin concentrations in sera of 110 healthy individuals ranged from 78 to 564 mIU/L. The range of values for the sera after PEG treatment was 70-403 mIU/L. For macroprolactinemic samples, PEG treatment decreased mean (SD) prolactin from 1524 (202) mIU/L to 202 (27) mIU/L but decreased it only from 2096 (233) mIU/L to 1705 (190) mIU/L in true hyperprolactinemic patients (P <0.01 between groups). Oligomenorrhea or amenorrhea and galactorrhea were the most common clinical features in both groups, although they occurred more frequently in true hyperprolactinemic patients (P <0.05). Serum estradiol and luteinizing hormone concentrations were significantly higher in participants with macroprolactinemia than in those with true hyperprolactinemia (P <0.05). Among participants with retrospectively identified macroprolactinemia, pituitary imaging was performed in 93% and treatment with dopamine agonist was prescribed in 87%. CONCLUSIONS Macroprolactin is a significant cause of misdiagnosis, unnecessary investigation, and inappropriate treatment. The use of an appropriate reference interval for the PEG immunoprecipitation procedure may be of particular importance in those patients who have an excess of both macroprolactin and monomeric prolactin.

The Growth Hormone/Insulin-Like Growth Factor-I Axis in Exercise and Sport

The syndrome of adult GH deficiency and the effects of GH replacement therapy provide a useful model with which to study the effects of the GH/IGF-I axis on exercise physiology. Measures of exercise performance including maximal oxygen uptake and ventilatory threshold are impaired in adult GH deficiency and improved by GH replacement, probably through some combination of increased oxygen delivery to exercising muscle, increased fatty acid availability with glycogen sparing, increased muscle strength, improved body composition, and improved thermoregulation. In normal subjects, in addition to the long-term effects of GH/IGF-I status, there is evidence that the acute GH response to exercise is important in regulating substrate metabolism after exercise. Administration of supraphysiological doses of GH to athletes increases fatty acid availability and reduces oxidative protein loss, particularly during exercise, and increases lean body mass. Despite a lack of evidence that these metabolic effects translate to improved performance, GH abuse by athletes is widespread. Tests to detect GH abuse have been developed based on measurement in serum of 1) indirect markers of GH action, and 2) the relative proportions of the two major naturally occurring isoforms (20 and 22kDa) of GH. There is evidence that exercise performance and strength are improved by administration of GH and testosterone in combination to elderly subjects. The potential benefits of GH in these situations must be weighed against potential adverse effects.

Clinical relevance of macroprolactin

The anterior pituitary hormone PRL was identified in animal species as early as 1933 1 but only purified in humans in 1972. 2 Since then, the clinical syndrome of hyperprolactinaemia has been characterized extensively, the predominant symptoms being galactorrhoea, oligomenorrhoea or amenorrhoea and infertility in women and reduced libido, impotence and galactorrhoea in men. 3–8 Hyperprolactinaemia has an estimated prevalence of 15% in women with secondary amenorrhoea, 9,10 a condition that affects at least 3% of women of reproductive age. 11

Evidence for a Specific Defect in Hippocampal Memory in Overt and Subclinical Hypothyroidism

CONTEXT Declarative memory largely depends upon normal functioning temporal lobes (hippocampal complex) and prefrontal cortex. Animal studies suggest abnormal hippocampal function in hypothyroidism. OBJECTIVE The aim of the study was to assess declarative memory in overt and subclinical (SCH) hypothyroid patients before and after l-T(4) (LT4) replacement and in matched normal subjects. DESIGN AND SETTING A prospective, open-labeled interventional study was conducted at a teaching hospital. PARTICIPANTS AND INTERVENTION Hypothyroid (n = 21) and SCH (n = 17) patients underwent neuropsychological tests at baseline and 3 and 6 months after LT4 replacement. Normal subjects were studied at the same time-points. MAIN OUTCOME Tests of spatial, verbal, associative, and working memory; attention; and response inhibition and the Hospital Anxiety and Depression Scale were administered. RESULTS Baseline deficits in spatial, associative, and verbal memory, which rely upon the integrity of the hippocampal and frontal areas, were identified in patients with overt hypothyroidism. Spatial and verbal memory were impaired in SCH patients (P < 0.05). TSH levels correlated negatively (P < 0.05) with these deficits. After LT4 replacement, verbal memory normalized. Spatial memory normalized in the SCH group but remained impaired in the hypothyroid group. Associative memory deficits persisted in the overt hypothyroid group. Hospital Anxiety and Depression Scale scores did not correlate with cognitive function. Measures of attention and response inhibition did not differ from control subjects. CONCLUSION Cognitive impairment occurs in SCH and more markedly in overt hypothyroidism. These impairments appear predominantly mnemonic in nature, suggesting that the etiology is not indicative of general cognitive slowing. We propose that these deficits may reflect an underlying disruption of normal hippocampal function and/or connectivity.

The Effect of Growth Hormone Replacement on Exercise Capacity in Patients with GH Deficiency: A Metaanalysis

CONTEXT/OBJECTIVES GH replacement in GH-deficient adults exerts clear effects on body composition, but there is a lack of high-quality evidence concerning its functional effects, which are more clinically important. This metaanalysis was carried out to determine the effects of GH replacement on exercise performance. DESIGN/METHODS A Medline search and examination of reference lists of included studies and relevant review articles identified 11 studies with utilizable, robust data, involving a total of 268 patients. All included studies were randomized, double blind, placebo controlled, and of either parallel or crossover design. Information was retrieved in uniform format, with data pertaining to patient numbers, study design, GH dose, age, IGF-I levels, and the exercise variables maximal oxygen uptake and maximal power output recorded. The data were analyzed using a fixed-effects model, using continuous data measured on different scales. A summary effect measure (ds) was derived for the individual exercise parameters, whereas an overall summary effect was derived from the sum of all studies across different variables; 95% confidence intervals were calculated from the weighted variances of individual study effects. RESULTS GH replacement was associated with significant improvement with all studies combined (ds=+0.32, 0.08-0.56), for maximal power output (ds=+0.4, 0.06-0.74), and maximal oxygen uptake (ds=+0.34, 0.07-0.62). There was no association between age or GH dose on the degree of improvement. CONCLUSIONS There is strong evidence that GH replacement improves exercise performance in GH-deficient patients. This evidence should be considered when decisions are made regarding prescription of GH.

High-Molecular-Weight Adiponectin Is Selectively Reduced in Women with Polycystic Ovary Syndrome Independent of Body Mass Index and Severity of Insulin Resistance

CONTEXT High-molecular-weight (HMW) adiponectin contributes to insulin resistance (IR), which is closely associated with the pathophysiology of polycystic ovary syndrome (PCOS). Abnormalities in adipocyte function have been identified in PCOS and potentially contribute to lower adiponectin concentrations. OBJECTIVE Our objective was to determine which variables in plasma and adipose tissue influence HMW adiponectin in a well characterized cohort of women with PCOS. DESIGN This was a cross-sectional study. SETTINGS AND PARTICIPANTS A teaching hospital. Women with PCOS (n = 98) and body mass index (BMI)-matched controls (n = 103) (including 68 age-, BMI-, and IR-matched pairs). INTERVENTIONS A standard 75-g oral glucose tolerance test was performed for each participant. Subcutaneous adipose tissue samples were taken by needle biopsy for a subset of PCOS women (n = 9) and controls (n = 8). MAIN OUTCOME MEASURES Serum levels of HMW adiponectin and their relation to indices of insulin sensitivity, body composition, and circulating androgens as well as adipose tissue expression levels of ADIPOQ, TNFalpha, PPARgamma, and AR were assessed. RESULTS HMW adiponectin was significantly lower in women with PCOS compared with both BMI- and BMI- and IR-matched controls (P = 0.009 and P = 0.027, respectively). Although BMI and IR were the main predictors of HMW adiponectin, an interaction between waist to hip ratio and plasma testosterone contributed to its variance (P = 0.026). Adipose tissue gene expression analysis demonstrated that AR and TNFalpha (P = 0.008 and P = 0.035, respectively) but not ADIPOQ mRNA levels were increased in PCOS compared with controls. CONCLUSIONS HMW adiponectin is selectively reduced in women with PCOS, independent of BMI and IR. Gene expression analysis suggests that posttranscriptional/translational modification contributes to reduced HMW adiponectin in PCOS.

Psychological effects of withdrawal of growth hormone therapy from adults with growth hormone deficiency

objective  Growth hormone (GH) is known to be required for physical well‐being. Although it is also widely believed to be important for quality of life (QoL) and psychological health, there is less supportive evidence. The objective of this study was to investigate the psychological effects of discontinuation of GH replacement from adults with severe GH deficiency (GHD).

Characterization of the metabolic phenotypes of Cushing's syndrome and growth hormone deficiency: a study of body composition and energy metabolism

Objective  A comparison of the severity and distribution of perturbations in body composition and their relationship to energy metabolism in glucocorticoid excess and GH deficiency (GHD) has not been undertaken before. The aim of this study was to investigate the impact of Cushings syndrome (CS) and GHD on whole and regional body composition and energy metabolism.

Hormonal and metabolic effects of polyunsaturated fatty acids in young women with polycystic ovary syndrome: results from a cross-sectional analysis and a randomized, placebo-controlled, crossover trial

BACKGROUND Polycystic ovary syndrome (PCOS) is characterized by an adverse metabolic profile. Although dietary changes are advocated, optimal nutritional management remains uncertain. Polyunsaturated fatty acids (PUFAs), particularly long-chain (LC) n-3 (omega-3) PUFAs, improve metabolic health, but their therapeutic potential in PCOS is unknown. OBJECTIVES We aimed to determine the associations between plasma PUFAs and metabolic and hormonal aspects of PCOS to investigate the efficacy of LC n-3 PUFA supplementation and to support the findings with mechanistic cellular studies. DESIGN We selected a cross-sectional PCOS cohort (n = 104) and conducted a principal component analysis on plasma fatty acid profiles. Effects of LC n-3 PUFA supplementation on fasting and postprandial metabolic and hormonal markers were determined in PCOS subjects (n = 22) by a randomized, crossover, placebo-controlled intervention. Direct effects of n-6 (omega-6) compared with n-3 PUFAs on steroidogenesis were investigated in primary bovine theca cells. RESULTS Cross-sectional data showed that a greater plasma n-6 PUFA concentration and n-6:n-3 PUFA ratio were associated with higher circulating androgens and that plasma LC n-3 PUFA status was associated with a less atherogenic lipid profile. LC n-3 PUFA supplementation reduced plasma bioavailable testosterone concentrations (P < 0.05), with the greatest reductions in subjects who exhibited greater reductions in plasma n-6:n-3 PUFA ratios. The treatment of bovine theca cells with n-6 rather than with n-3 PUFAs up-regulated androstenedione secretion (P < 0.05). CONCLUSIONS Cross-sectional data suggest that PUFAs modulated hormonal and lipid profiles and that supplementation with LC n-3 PUFAs improves androgenic profiles in PCOS. In bovine theca cells, arachidonic acid modulated androstenedione secretion, which suggests an indirect effect of n-3 PUFAs through the displacement of or increased competition with n-6 PUFAs. This trial was registered at clinicaltrials.gov as NCT01189669.

Characterization of macroprolactin and assessment of markers of autoimmunity in macroprolactinaemic patients.

Objective  It has been reported that macroprolactin is a complex of PRL and an immunoglobulin G (IgG). This study further characterizes macroprolactin and evaluates for other markers of autoimmunity using a cohort of macroprolactinaemic sera.