Felipe F. Casanueva

Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia. PARTICIPANTS The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer. EVIDENCE This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented.

A consensus on criteria for cure of acromegaly

OBJECTIVE The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000. PARTICIPANTS Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. EVIDENCE/CONSENSUS PROCESS: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated. CONCLUSIONS Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.

Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans

An endogenous ligand for the GH secretagogue-receptor (GHS-R) has been recently purified from rat and human stomach and named Ghrelin. It has been demonstrated that Ghrelin specifically stimulates GH secretion from rat pituitary cells in culture as well as in rats in vivo. In this preliminary study, in 4 normal adults [age (mean±SE): 28.6±3.5 yr; body mass index (BMI): 22.3±2.1 kg/m2] we administered 1.0 μg/kg Ghrelin or GHRH-29 to compare their GH-releasing activities in humans. In all subjects Ghrelin induced a prompt, marked and long-lasting increase in circulating GH levels (peak: 107.9±26.1 μg/l; AUC: 6503.1±1632.7 μg/l/h). The GH response to Ghrelin was clearly higher (p<0.05) than that after GHRH (peak: 22.3±4.5 μg/l; AUC: 1517.5±338.4 μg/l/h). In conclusion, this preliminary study shows that Ghrelin exerts a strong stimulatory effect on GH secretion in humans releasing more GH than GHRH.

Leptin, from fat to inflammation: old questions and new insights

Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro‐inflammatory cytokine that belongs to the family of long‐chain helical cytokines and has structural similarity with interleukin‐6, prolactin, growth hormone, IL‐12, IL‐15, granulocyte colony‐stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory‐immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T‐helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro‐inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses.

Regulation of in Vivo Growth Hormone Secretion by Leptin

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes that regulates food intake and energy expenditure. Growth hormone (GH) secretion is markedly influenced by body weight being markedly suppressed in obesity and underweight. The aim of the present study was to study whether leptin can act as a metabolic signal connecting the adipose tissue with the growth hormone axis. We administered leptin antiserum (10 ul, i.c.v.) or normal rabbit serum (NRS; 10 ul, i.c.v.) to freely moving fed rats. Furthermore we assessed the effect of leptin administration (10 ug, i.c.v.) on fed and fasted rats. Spontaneous GH secretion was assessed over 6 hours with blood samples taken every 15 min. Administration of leptin antiserum led to a decrease in spontaneous GH secretion as assessed by the area under the curve (AUC) (168 ± 72 ng/ml/6h) in comparison to NRS-treated rats (813 ± 179 ng/ml/6 h, p < 0.01). While leptin administration (10 ug/rat; i.c.v.) to normal fed rats did not modify sp...

Novel Expression and Functional Role of Ghrelin in Rat Testis

Ghrelin, the endogenous ligand for the GH-secretagogue receptor (GHS-R), is a recently cloned peptide, primarily expressed in the stomach and hypothalamus, that acts at central levels to elicit GH release and, notably, to regulate food intake. However, the possibility of additional, as yet unknown, peripheral effects of ghrelin cannot be ruled out. In the present communication, we provide evidence for the novel expression of ghrelin and its functional receptor in rat testis. Testicular ghrelin gene expression was demonstrated throughout postnatal development, and ghrelin protein was detected in Leydig cells from adult testis specimens. Accordingly, ghrelin mRNA signal became undetectable in rat testis following selective Leydig cell elimination. In addition, testicular expression of the gene encoding the cognate ghrelin receptor was observed from the infantile period to adulthood, with the GHS-R mRNA being persistently expressed after selective withdrawal of mature Leydig cells. From a functional standpoint, ghrelin, in a dose-dependent manner, induced an average 30% inhibition of human CG- and cAMP-stimulated T secretion in vitro. This inhibitory effect was associated with significant decreases in human CG-stimulated expression levels of the mRNAs encoding steroid acute regulatory protein, and P450 cholesterol side-chain cleavage, 3beta-hydroxy steroid dehydrogenase, and 17beta-hydroxy steroid dehydrogenase type III enzymes. Overall, our data are the first to provide evidence for a possible direct action of ghrelin in the control of testicular function. Furthermore, the present results underscore an unexpected role of ghrelin as signal with ability to potentially modulate not only growth and body weight homeostasis but also reproductive function, a phenomenon also demonstrated recently for the adipocyte-derived hormone, leptin.

Synthesis of Leptin in Human Placenta

Gender-based differences in serum leptin levels have been reported in umbilical cord blood, and leptin has been detected in human amniotic fluid. In order to understand if leptin may be directly synthesized by human placentae an analysis made up of several steps was performed. First at all RT-PCR analysis from placenta-derived RNA was used to detect human leptin mRNA. The leptin-like immunoradioactivity detected in placentae extracts was identical to human leptin according to the criteria of charge, immunorecognition, SDS-PAGE analysis and blotting, indicating that intact leptin was found and no variants in size, charge or immunoactivity were present in the placentae. Finally an immunohistochemical analysis showed the presence of leptin in the cytoplasm of syncytiotrophoblast cells but not in the core of villi. In conclusion: leptin is synthesized as a single molecular variant identical to human recombinant leptin in human placentae at delivery.

Expert consensus document: A consensus on the medical treatment of acromegaly

In March 2013, the Acromegaly Consensus Group met to revise and update guidelines for the medical treatment of acromegaly. The meeting comprised experts skilled in the medical management of acromegaly. The group considered treatment goals covering biochemical, clinical and tumour volume outcomes, and the place in guidelines of somatostatin receptor ligands, growth hormone receptor antagonists and dopamine agonists, and alternative modalities for treatment including combination therapy and novel treatments. This document represents the conclusions of the workshop consensus.

A consensus on the diagnosis and treatment of acromegaly complications.

In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed.

Growth Hormone Secretagogues: Physiological Role and Clinical Utility

Growth hormone secretagogues (GHSs) are artificial compounds developed to release GH in vitro. GHSs mimic an unknown endogenous factor that activates the GHS receptor in the pituitary and the hypothalamus. With the cloning of the human GHS receptor it has been demonstrated that GHS is a new physiological system that regulates GH secretion along with growth hormone-releasing factor (GHRH) and somatostatin. GHSs administered alone or in combination with GHRH are the most potent and reproducible GH releasers, and are useful tools for the diagnosis of GH deficiency when tested in a variety of pathological conditions, both in children and in adults. As therapeutic agents, they show clinical effectiveness in enhancing GH release after short-term treatment.