Acquired hypothalamic obesity: A clinical overview and update.

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.

Diagnosis, Background, and Treatment of Hypothalamic Damage in Craniopharyngioma.

Craniopharyngiomas (CP) are rare brain tumors managed primarily with surgery and radiotherapy. There are 2 phenotypes of CP, i.e., one with a rather good outcome without hypothalamic damage and another with hypothalamic damage. With hypothalamic damage, progressive disease with recurrent operations and additional cranial radiotherapy often result in hypothalamic obesity, an affected psychosocial life, and cognitive dysfunction. The morbidity and mortality are increased for particularly cerebrovascular diseases. Preoperative hypothalamic involvement to predict hypothalamic damage is important for decision making for hypothalamus-sparing surgery. Also a postoperative hypothalamic damage evaluation with the use of hypothalamus volume measurement can predict hypothalamic obesity, which is important for early treatment options. The morbidity of CP includes cognitive dysfunction with attention deficits and impaired episodic memory and processing speed. Again patients with hypothalamic damage are more affected. Treatment options of hypothalamic obesity in the chronic phase are scarce and not convincingly successful. The most optimal situation is to try to hinder or stop the evolution of hypothalamic obesity. Prevention of hypothalamic damage is recommended, with special regard to hypothalamus-sparing therapeutic approaches that respect the integrity of essential nuclei located in both the medial and the posterior hypothalamic areas.

Posterior pituitary dysfunction following traumatic brain injury: review.

Neurohypophysial dysfunction is common in the first days following traumatic brain injury (TBI), manifesting as dysnatremia in approximately 1 in 4 patients. Both hyponatremia and hypernatremia can impair recovery from TBI and in the case of hypernatremia, there is a significant association with excess mortality. Hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIAD) is the commonest electrolyte disturbance following TBI. Acute adrenocorticotropic hormone (ACTH)/cortisol deficiency occurs in 10-15% of TBI patients and can present with a biochemical picture identical to SIAD. For this reason, exclusion of glucocorticoid deficiency is of particular importance in post-TBI SIAD. Cerebral salt wasting is a rare cause of hyponatremia following TBI. Hyponatremia predisposes to seizures, reduced consciousness, and prolonged hospital stay. Diabetes insipidus (DI) occurs in 20% of cases following TBI; where diminished consciousness is present, appropriate fluid replacement of renal water losses is occasionally inadequate, leading to hypernatremia. Hypernatremia is strongly predictive of mortality following TBI. Most cases of DI are transient, but persistent DI is also predictive of mortality, irrespective of plasma sodium concentration. Persistent DI may herald rising intracranial pressure due to coning. True adipsic DI is rare following TBI, but patients are vulnerable to severe hypernatremic dehydration, exacerbation of neurologic deficits and hypothalamic complications, therefore clinicians should be aware of this possible variant of DI.

The frequency and the diagnosis of pituitary dysfunction after traumatic brain injury.

PURPOSE: Clinical research studies over the last 15 years have reported a significant burden of hypopituitarism in survivors of traumatic brain injury (TBI). However, debate still exists about the true prevalence of hypopituitarism after head injury. METHODS: We have reviewed the literature describing the frequency of post-traumatic hypopituitarism and discuss the factors which may explain the variable frequency of the reported deficits in clinical studies including research methodology and the natural history of the disease. RESULTS: Pituitary hormone perturbations in the acute phase following injury are frequent but are difficult to attribute to traumatic pituitary damage due to physiological hormonal changes in acute illness, the confounding effect of medications, other co-morbidities and lack of appropriate control subjects. Nevertheless, a small number of studies have emphasised the clinical importance of acute, dynamic disturbance of the hypothalamic-pituitary-adrenal axis. There is a much larger evidence base examining the frequency of hypopituitarism in the chronic, recovery phase following head injury. These studies report a very broad prevalence of long-term pituitary hormone dysfunction in survivors of TBI. However, systematic review suggests the prevalence to be between 27 and 31%. CONCLUSION: Survivors of head injury are at risk of pituitary hormone dysfunction and we suggest an approach to the diagnosis of post-traumatic hypopituitarism in routine clinical practice.

Targeted therapy for infants with diencephalic syndrome: A case report and review of management strategies.

Young children with emaciation caused by a hypothalamic glioma are considered to have diencephalic syndrome (DS), which is often poorly controlled with conventional treatment. We describe an infant with DS whose tumor progressed following chemotherapy. Biopsy was performed for molecular testing and demonstrated a BRAF fusion. Treatment with the MEK inhibitor trametinib for 18 months resulted in reduction of tumor size, normalization of his weight curve, and marked neurodevelopmental improvement. Our results build on earlier reports of using targeted agents for low-grade glioma, and we review the evolving management strategy for such patients in the era of precision medicine.

The role of hypothalamic inflammation, the hypothalamic-pituitary-adrenal axis and serotonin in the cancer anorexia-cachexia syndrome.

PURPOSE OF REVIEW: In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. RECENT FINDINGS: The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1ß-induced activation of the hypothalamic-pituitary-adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin-proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. SUMMARY: Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic-pituitary-adrenal axis and serotonin pathway activation.

Jean Camus and Gustave Roussy: pioneering French researchers on the endocrine functions of the hypothalamus.

At the beginning of the twentieth century, the hypothalamus was known merely as an anatomical region of the brain lying beneath the thalamus. An increasing number of clinicopathological reports had shown the association of diabetes insipidus and adiposogenital dystrophy (Babinski-Fröhlich's syndrome), with pituitary tumors involving the infundibulum and tuber cinereum, two structures of the basal hypothalamus. The French physicians Jean Camus (1872-1924) and Gustave Roussy (1874-1948) were the first authors to undertake systematic, controlled observations of the effects of localized injuries to the basal hypothalamus in dogs and cats by pricking the infundibulo-tuberal region (ITR) with a heated needle. Their series of surgical procedures, performed between 1913 and 1922, allowed them to claim that both permanent polyuria and adiposogenital dystrophy were symptoms caused by damage to the ITR. Their results challenged the dominant doctrine of hypopituitarism as cause of diabetes insipidus and adiposogenital dystrophy that derived from the experiments performed by Paulescu and Cushing a decade earlier. With their pioneering research, Camus and Roussy influenced the experimental work on the hypothalamus performed by Percival Bailey and Frederic Bremer at Cushing's laboratory, confirming the hypothalamic origin of these symptoms in 1921. More importantly, they provided the foundations for the physiological paradigm of Neuroendocrinology, the hypothalamus' control over the endocrine secretions of the pituitary gland, as well as over water balance and fat metabolism. This article aims to credit Camus and Roussy for their groundbreaking, decisive contributions to postulate the hypothalamus being the brain region in control of endocrine homeostasis and energy metabolism.

Hypothalamic hamartoma with neurofibrillary tangles.

Hypothalamic hamartomas are rare tumors that typically present in childhood, often with gelastic seizures, precocious puberty, or as a manifestation of Pallister-Hall syndrome. Neurofibrillary tangles are cytoplasmic aggregates of hyperphosphorylated tau that are best recognized in Alzheimer disease, other tau-associated neurodegenerative diseases, or as part of aging, but occasionally may be seen in low-grade neoplasms with a ganglion cell component as gangliocytoma or ganglioglioma. Herein, we report a case of hypothalamic hamartoma with neurofibrillary tangles.

Metabolic role of lipid peroxidation processes and antioxidant defense system in the pathogenesis of hypothalamic syndrome.

LPO processes and blood antioxidant status were studied in reproductive-age women with the hypothalamic syndrome. The control group consisted of somatically healthy women without reproductive disorders. Female patients with the hypothalamic syndrome were characterized by an imbalance in the LPO-antioxidant defense system, which aggravated the course of the underlying disease.

Comparison of body composition, basal metabolic rate and metabolic outcomes of adults with Prader Willi syndrome or lesional hypothalamic disease, with primary obesity.

CONTEXT: The care of patients with hypothalamic obesity is challenging. OBJECTIVE: To compare body composition, basal metabolic rate (BMR) and metabolic outcomes of adults, with lesional or genetic hypothalamic obesity, with obese patients suffering from primary obesity, once matched for body mass index (BMI). DESIGN AND PATIENTS: Adults with hypothalamic obesity of genetic origin (Prader Willi syndrome (PWS)) or acquired hypothalamic damage (HD), such as craniopharygioma, were compared with obese control candidates awaiting bariatric surgery (C), with a BMI between 35 and 65 kg m(-)(2), and aged between 18 and 50 years. MAIN OUTCOME MEASURES: Body composition measured by whole-body dual-energy X-ray absorptiometry scanning, BMR using indirect calorimetry, hormonal and metabolic assessments. RESULTS: A total of 27 adults with a genetic diagnosis of PWS, 15 obese subjects with HD and 206 obese controls with similar BMI were studied. Compared with the control group, PWS patients had an increased percentage of fat mass (FM), and a decreased percentage of android FM. The BMR of PWS patients was significantly lower than controls and highly correlated with lean body mass in PWS and C patients. Body composition of HD was similar with those of obese patients. A trend toward an increased prevalence of diabetes in HD patients and of cytolysis in PWS was observed in comparison with primary obese patients. CONCLUSION: Genetic and lesional hypothalamic obesities have different consequences for phenotypic features such as body composition or BMR compared with primary obese patients. The mechanisms of adipose tissue development and metabolic complications may be different between genetic and lesional obesities.

Resumption of menstruation and pituitary response to gonadotropin-releasing hormone in functional hypothalamic amenorrhea subjects undertaking estrogen replacement therapy.

BACKGROUND: Functional hypothalamic amenorrhea (FHA) refers to a functional menstrual disorder with various causes and presentations. Recovery of menstrual cyclicity is common in long-term follow-up but the affecting factors remain unknown. AIM: To explore factors affecting the menstrual resumption and to evaluate the pituitary response to gonadotropin-releasing hormone (GnRH) in FHA. MATERIALS AND METHODS: Thirty cases with FHA were recruited. All subjects were put on continuous 1 mg/day estradiol valerate orally and followed up monthly. Recovery was defined as the occurrence of at least three consecutive regular cycles. Responder referred to those who recovered within two years of therapy. Gonadotropin response to the 50 µg GnRH challenge was tested every three months. RESULTS: Nineteen (63.3%) subjects recovered with a mean time to recovery of 26.8 months. Time to recovery was negatively correlated with body mass index (BMI) before and by amenorrhea. Twentyone cases had undertaken therapy for more than two years and 10 of them recovered. BMI before and by amenorrhea were negatively correlated with the recovery. Significant increase of serum luteinizing hormone (LH) and LH response to GnRH were noted after recovery. CONCLUSIONS: Menstrual resumption was common in FHA undertaking estrogen replacement therapy (ERT). The likelihood of recovery was affected by their BMI before and by amenorrhea but not by the weight gain during therapy. Low serum LH and attenuated LH response to GnRH were the main features of pituitary deficiency in FHA. The menstrual resumption in FHA was accompanied by the recovery of serum LH and the LH response to GnRH.

Inflammation of the hypothalamus leads to defective pancreatic islet function.

Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic ß-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic ß-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor α leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-γ coactivator Δα and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1α expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.

Functional rundown of gamma-aminobutyric acid(A) receptors in human hypothalamic hamartomas.

OBJECTIVE: Human hypothalamic hamartomas (HHs) are highly associated with treatment-resistant gelastic seizures. HHs are intrinsically epileptogenic, although the basic cellular mechanisms responsible for seizure activity are unknown. Altered gamma-aminobutyric acid (GABA) function can contribute to epileptogenesis in humans and animal models. Recently, functional GABA(A) receptor (GABA(A) R) rundown has been described in surgically resected human temporal lobe epilepsy tissue. We asked whether functional GABA(A) R rundown also occurs in human HH neurons. METHODS: GABA(A) R-mediated currents were measured using perforated patch-clamp recordings in single neurons acutely dissociated from surgically resected HH tissue. In addition, functional GABA(A) Rs were expressed in Xenopus oocytes after microinjection with membrane fractions from either HH or control hypothalamus, and were studied with 2-electrode voltage-clamp recordings. RESULTS: Perforated patch-clamp recordings in dissociated HH neurons showed that repetitive exposure to GABA (5 consecutive exposures to 0.1 mM GABA with 1-second duration and at 20-second intervals) induced a time-dependent rundown of whole-cell currents in small HH neurons, whereas large HH neurons showed much less rundown using the same protocol. Functional rundown was not observed in HH neurons with repetitive exposure to glycine or glutamate. Two-electrode voltage-clamp recordings (6 consecutive exposures to 1 mM GABA with 10-second duration and at 40-second intervals) induced GABA current rundown in Xenopus oocytes microinjected with HH membrane proteins, but not in the oocytes expressing hypothalamic membrane proteins derived from human autopsy controls. Functional rundown of GABA currents was significantly attenuated by intracellular application of adenosine triphosphate or the nonspecific phosphatase inhibitor, okadaic acid. INTERPRETATION: Neurons from surgically resected human HH demonstrate functional rundown of GABA(A) R-mediated transmembrane currents in response to GABA agonist exposure. Rundown may be a marker for impaired GABAergic function and a contributing mechanism for seizure genesis within HH tissue.

Concordant and discordant adrenocorticotropin (ACTH) responses induced by growth hormone-releasing peptide-2 (GHRP-2), corticotropin-releasing hormone (CRH) and insulin-induced hypoglycemia in patients with hypothalamopituitary disorders: evidence for direct ACTH releasing activity of GHRP-2.

The insulin-induced hypoglycemia test (insulin tolerance test: ITT) and corticotropin-releasing hormone (CRH) test are used to examine the activities of the hypothalamo-pituitary-adrenal (HPA) axis. Growth hormone-releasing peptide-2 (GHRP-2), a potent GH secretagogue, also stimulates adrenocorticotropin (ACTH) secretion. To evaluate the role of GHRP-2 in assessing the HPA axis, we examined 6 patients with various hypothalamo-pituitary disorders, and measured ACTH and cortisol responses during provocative tests (ITT, CRH, and GHRP-2 test). None of the 6 patients showed any significant ACTH or cortisol responses to ITT, but significant ACTH release was observed during CRH and GHRP-2 tests. These findings suggest GHRP-2 may directly stimulate ACTH secretion in patients with hypothalamo-pituitary disorders.

Microglia, neurodegeneration and loss of neuroendocrine control.

Microglia, the primary regulators of inflammatory responses in the brain, suffer deterioration during aging culminating in their inability to generate adequate adaptive responses to maintain physiological homeostasis in brain tissue. Microglia affect the function of other glial cells and neurons, including those involved in the hypothalamic control of body homeostasis. Microglial dysfunction with aging in cognitive areas such as the hippocampus is known to associate with cognitive decline; more recently, microglial alterations in the hypothalamus during midlife was suggested to participate in changes in the endocrine and metabolic control exerted by this brain region. Consequently, the feed-back loops between endocrine glands and the hypothalamus are altered. This generates a vicious circle in which the plasma levels of key neuroprotective hormones, such as gonadal hormones, insulin-like growth factor-1, growth hormone and leptin and their hypothalamic signaling are decreased, which further enhances microglial alterations and deterioration of hypothalamic function. Hypothalamic dysfunction is a risk factor for neurodegenerative diseases and these diseases in turn promote additional alterations in hypothalamic microglial cells, which are unable to cope with the neurodegenerative process, resulting in permanent damage of the neuronal-glial circuits controlling endocrine homeostasis, food intake and body metabolism. Thus, a "vicious cycle" may such be initiated.

Discriminating hypothalamic oligomenorrhea/amenorrhea from hyperandrogenic oligomenorrhea/amenorrhea in exercising women.

The mechanism underlying oligo/amenorrhea in exercising women is often presumed as hypothalamic inhibition secondary to energy deficiency; however, hyperandrogenism may provide an alternative mechanism in some exercising women. Our purpose was to compare reproductive, metabolic, and androgen profiles of exercising women with eumenorrheic, ovulatory menstrual cycles (n = 91), oligo/amenorrhea without evidence of hyperandrogenism (Oligo/Amen; n = 83), and oligo/amenorrhea with evidence of hyperandrogenism (Oligo/Amen-HA; n = 17), and determine the prevalence of oligo/amenorrhea with evidence of hyperandrogenism in exercising women. Self-reported menstrual history and quantification of daily estrogen and progesterone urinary metabolites determined reproductive status. Resting energy expenditure, body composition, and metabolic hormone concentrations determined metabolic status. Serum androgens and calculated free androgen index (FAI) determined androgen status. Groups were similar in age (22.4 ± 0.3 years), height (165.1 ± 0.5 cm), resting energy expenditure (1198.4 ± 12.0 kcal/day), and total triiodothyronine (85.0 ± 1.5 ng/dL) concentration. Oligo/Amen-HA had greater weight (60.0 ± 1.6, 56.1 ± 0.7 kg), body mass index (22.3 ± 0.4, 20.6 ± 0.2 kg/m2), percentage body fat (27.3% ± 1.4%, 24.4% ± 0.6%), fat mass (16.2 ± 1.0, 13.8 ± 0.4 kg), insulin (5.8 ± 0.7, 4.2 ± 0.3 µIU/mL), leptin (12.2 ± 2.3, 6.6 ± 0.7 ng/mL), FAI (6.1 ± 0.3, 1.7 ± 0.1), and luteinizing hormone/follicle-stimulating hormone (1.9 ± 0.3, 1.3 ± 0.2) compared with Oligo/Amen, respectively. In our sample, 17% of those with oligo/amenorrhea had concurrent hyperandrogenism. This study supports that oligo/amenorrhea in some exercising women is related to hyperandrogenism. Novelty Caution must be utilized when discriminating hypothalamic oligo/amenorrhea from hyperandrogenic oligo/amenorrhea. In our sample, 17% of those with presumed hypothalamic oligo/amenorrhea had concurrent hyperandrogenism. Exercise and/or mild energy deficiency may be protective against developing severe hyperandrogenic symptoms.

Metabolic features and changes in glucose-induced serum glucagon-like peptide-1 levels in children with hypothalamic obesity.

Background Hypothalamic damage may alter glucagon-like peptide-1 (GLP-1) secretion and be involved in the pathogenesis of obesity. We aim to evaluate the metabolic features and the dynamic changes of GLP-1 levels during an oral glucose tolerance test (OGTT) in children with hypothalamic obesity (HO) compared with simple obesity controls. Methods Subjects included eight patients (six females, aged 9-16 years) with hypothalamo-pituitary tumors who later developed obesity and eight controls with simple obesity matched for age, body mass index (BMI), gender and puberty. We assessed the metabolic syndrome features, fat mass, severity of hyperphagia using a standardized questionnaire, and measured glucose, insulin and GLP-1 levels during a standard 75 g OGTT. Results Age, gender distribution, pubertal status and BMI-Z scores were not significantly different. Subjects with HO had higher fasting triglycerides (TG) than controls (128 vs. 94 mg/dL; p=0.05). Four HO subjects and three controls met the criteria for the metabolic syndrome. Fasting and 120 min post-glucose load GLP-1 levels were significantly higher in HO patients than in controls (21.9 vs. 19.7 pg/mL; p=0.025, 22.1 vs. 17.7 pg/mL; p=0.012). Patients with HO had significantly higher hyperphagia scores than in simple obese controls (13 vs. 2.5; p=0.012). Conclusions Patients with HO appear to have more metabolic complications and hyperphagia than controls with simple obesity. Impaired satiety may play an important role in HO. Fasting and glucose-induced serum GLP-1 concentrations seem to be altered in HO patients and could be a part of the pathogenesis of HO.

ACTH-dependent precocious pseudopuberty in an infant with DAX1 gene mutation.

DAX1 gene (Xp21) expression is involved in the development of the hypothalamo-pituitary-gonadal and adrenal axes, and acts as a negative regulator of steroidogenesis. Mutations of this gene determine adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism. We report the case of a 9-month-old boy referred for the study of macrogenitosomia and pubic hair development. He had presented acute adrenal crises in the neonatal period and, later, a clinical picture of peripheral precocious puberty. A mutation in the DAX1 gene was found (Trp291Arg) and a diagnosis of AHC was made. Replacement doses of hydrocortisone (HC) (10 mg/m2/day) failed to produce a feedback inhibition of adrenocorticotropic hormone (ACTH), and testosterone levels remained high. Testosterone and ACTH values normalized after HC was progressively increased to 18 mg/m2/day. In conclusion, peripheral precocious puberty in patients with DAX1 gene mutations appears to be secondary to the stimulus exerted by ACTH on melanocortin receptors in Leydig cells and to the overexpression of testicular steroidogenesis activators by the loss of transcriptional repression.

Circulating levels of the components of the GH/IGF-1/IGFBPs axis total and intact IGF-binding proteins (IGFBP) 3 and IGFBP 4 and total IGFBP 5, as well as PAPPA, PAPPA2 and Stanniocalcin-2 levels are not altered in response to energy deprivation and/or metreleptin administration in humans.

OBJECTIVE: It remains unclear whether food deprivation induces changes in components of the GH/IGF-1/IGFBPs axis and if yes, which ones are mediated by leptin, an adipocyte secreted hormone regulating neuroendocrine response to energy deprivation in animals and humans. We aimed to investigate components of the axis that have not been studied to date, i.e. IGF-binding proteins (IGFBPs) and related proteases (total and intact IGFBP 3 and IGFBP 4, total IGFBP 5, PAPPA, PAPPA2 and Stanniocalcin-2), during acute (short-term fasting in healthy subjects) and chronic (women with hypothalamic amenorrhea [HA] due to excessive exercise) energy deprivation and whether metreleptin administration, in replacement, supraphysiologic or pharmacologic levels, may mediate any changes of circulating levels of the above molecules in healthy individuals and in women with hypothalamic amenorrhea. METHODS: We studied: 1) 11 healthy men and women during three four day admissions i.e. a baseline admission in the fed isocaloric state and two admissions in the complete food deprivation state for 72-h with either placebo (resulting in a hypoleptinemic state) or metreleptin administration in doses designed to normalize circulating leptin levels for the duration of the study, 2) 15 healthy men and women during three 72-hour long admissions in a complete food deprivation state receiving three escalating doses of metreleptin designed to bring circulating leptin levels to physiologic, supraphysiologic, or pharmacologic levels, and 3) 18 women with HA randomized to either metreleptin treatment in replacement doses or placebo for nine months. RESULTS: There were no significant changes in the circulating profiles of the above molecules in the fasting vs. fed state and/or with metreleptin administration during acute and chronic energy deprivation. CONCLUSIONS: The studied components of the GH/IGF-1/IGFBPs axis are not affected by energy deprivation, leptin deficiency associated with energy deprivation, or by metreleptin administration in physiologic, supraphysiologic or pharmacologic doses.

Investigating the Hypothesis of Stress System Dysregulation as a Risk Factor for Central Serous Chorioretinopathy: A Literature Mini-Review.

Background: This mini-review addressed the question "what do we know about the association between the dysregulation of stress systems (HPA axis and SAM) and the onset and prognosis of CSC in adult populations?" Methods: The literature mini-review was conducted through electronic searches using the PubMed, Web of Science, and Scopus databases. All published human and animal studies with both observational and experimental designs from 1966 to October 2018 were included. Results: Our search identified 229 reports, of which 32 articles were ultimately identified to be reviewed in this paper. Among these key articles, twenty-three were related to exogenous and/or endogenous high glucocorticoids as risk factors for CSC, seven were related to Type-A behavior and chronic psychological distress as risk factors for idiopathic CSC, and two were related to stress-induced animal models of CSC. Nineteen out of twenty-three studies in the first group reported a consistent association between high circulating corticosteroids and the onset and prognosis of CSC. Six out of seven studies in the second group reported a consistent association between stress-induced allostatic (over)load and the appearance of more- or less-severe CSC disorders, assuming that elevated circulating steroids may constitute a kind of risk factor for the eye through dysregulation of the HPA axis. All the selected studies reported HPA axis dysregulation as a possible common factor to explain the association between high circulating corticosteroids and CSC. In contrast, the involvement of the SAM system is only indirectly taken into consideration through the PA and HR measures and/or plasma and 24-h urinary catecholamine levels. Therefore, information regarding the involvement of SAM system dysregulation in the onset and prognosis of CSC is lacking. This observation is particularly relevant in view of the fact that animal models of CSC in monkeys are primarily induced by adrenergic hypertonia and that the course of experimental CSC is not further exacerbated by the administration of corticosteroids.