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Biomedical subjects

Hans P F Koppeschaar

Publications and source records attributed to Hans P F Koppeschaar.

17 recordsLinked to original sources
PubMed2006

Efficacy of needle-free administration of recombinant human growth hormone in adults with growth hormone deficiency.

AIM: Needle-free administration of recombinant human growth hormone (rhGH) is effective in the treatment of growth hormone deficiency (GHD) in children, but has not been studied in adult patients. Therefore, we evaluated the efficacy of needle-free administration of rhGH in adults with GHD. METHODS: Insulin-like growth factor-I (IGF-I) concentrations were compared in newly diagnosed patients with GHD (n = 21) and in patients previously treated by subcutaneous injection of rhGH (switchers, n = 34), at baseline, 12 months and 24 months. RESULTS: In the new patients, IGF-I standard deviation scores (SDS) increased from - 1.82 +/- 0.46 to + 0.75 +/- 0.33 at 12 months and to + 0.65 +/- 0.41 at 24 months (P < or = 0.001 vs. baseline). In switchers, IGF-I SDS remained unchanged with values of + 0.98 +/- 0.32 at baseline, + 0.87 +/- 0.23 at 12 months and + 0.73 +/- 0.29 at 24 months (P = 0.696 vs. baseline). In new patients, the rhGH dose was 0.46 +/- 0.03 mg day(-1) at 12 months and 0.47 +/- 0.03 mg day(-1) at 24 months. In switchers, the rhGH dose was 0.53 +/- 0.04 mg day(-1) at baseline (s.c. injection), 0.52 +/- 0.03 mg day(-1) at 12 months and 0.48 +/- 0.03 mg day(-1) at 24 months (NS between the different time points). There was no difference in the dose of rhGH at 12 and 24 months between the two groups. Side-effects were generally minor and consisted of local tissue reactions. CONCLUSION: Administration of rhGH by needle-free, transdermal injection is effective in maintaining IGF-I concentrations in the normal range for age in adults with GHD, and is as effective as traditional subcutaneous injection of rhGH.

Adult↗
PubMed2006

Effect of obesity and morbid obesity on the growth hormone (GH) secretion elicited by the combined GHRH + GHRP-6 test.

OBJECTIVE: Obesity is characterized by low basal levels of growth hormone (GH) and impeded GH release. However, the main problem arises in the diagnosis of GH deficiency in adults, as all accepted cut-offs in the diagnostic tests of GH reserve are no longer valid in obese subjects. In this work, the role of obesity in the GH response elicited by the GHRH + GHRP-6 test was assessed in a large population of obese and nonobese subjects. PATIENTS: GHRH + GHRP-6-induced GH peaks were evaluated in 542 subjects. One hundred and five were healthy obese, 50 were morbid obese, and 261 were nonobese (both normal weight and overweight). One hundred and seventy-six GH-deficient patients (obese and nonobese) were also studied. RESULTS: A regression analysis of the 366 subjects with normal pituitary function indicated that adiposity had a negative effect on the elicited GH peak (r = -0.503, P < 0.0001). A receiver operating characteristic (ROC) curve analysis showed that in subjects with a BMI < or =35, the currently accepted cut-offs of the GHRH + GHRP-6 test (GH peaks > or =20 microg/l: normal secretion; GH peaks < or =10 microg/l: GH deficiency), were fully operative. However, in subjects with a BMI > 35, normality was indicated by GH peaks > or =15 microg/l and GH deficiency by peaks < or =5 microg/l (1 microg/l = 2.6 mU/l). CONCLUSIONS: This study confirms: (a) that the combined provocative test is adequate to separate normal and GH-deficient subjects; (b) the negative effect of obesity on GH secretion; (c) that obesity accounts for 25% of the reduction of GH release; and (d) that present cut-off values are applicable to normal weight, overweight and grade I obesity subjects, whereas in obese subjects with a BMI exceeding 35, all the normative limits of the GHRH-GHRP +6 test must be reduced by 5 microg/l.

Adolescent↗
PubMed2006

Does long-term GH replacement therapy in hypopituitary adults with GH deficiency normalise quality of life?

OBJECTIVE: To determine whether impaired quality of life (QoL) in adults with GH deficiency (GHD) is reversible with long-term GH therapy and whether the responses in QoL dimensions differ from each other. METHODS: QoL was measured by the Quality of Life-Assessment for Growth Hormone Deficiency in Adults (QoL-AGHDA) in general population samples in England & Wales, The Netherlands, Spain and Sweden (n = 892, 1038, 868 and 1682 respectively) and compared with corresponding patients' data from KIMS (Pfizer International Metabolic Database) (n = 758, 247, 197 and 484 respectively) for 4-6 years a follow-up. The subsets of patients from England and Wales, and Sweden with longitudinal data for 5 years' follow-up were also analysed. The change of the total QoL-AGHDA scores and responses within dimensions were evaluated. Subanalyses were performed to identify any specificity in response pattern for gender, age, disease-onset and aetiology. RESULTS: Irrespective of the degree of impairment, overall QoL improved dramatically in the first 12 months, with steady progress thereafter towards the country-specific population mean. Problems with memory and tiredness were the most serious burden for untreated patients, followed by tenseness, self-confidence and problems with socialising. With treatment, these improved in the reverse order, normalising for the latter three. CONCLUSIONS: Long-term GH replacement results in sustained improvements towards the normative country-specific values in overall QoL and in most impaired dimensions. The lasting improvement and almost identical pattern of response in each patient subgroup and independent of the level of QoL impairment support the hypothesis that GHD may cause these patients' psychological problems.

Adult↗
PubMed2005

Childhood-onset growth hormone deficiency, cognitive function and brain N-acetylaspartate.

Cognitive deficits have been reported in adults with childhood-onset growth hormone (GH) deficiency. We evaluated cognitive deficits simultaneously with parameters for neuronal integrity using (1)H magnetic resonance spectroscopy (MRS) in a cross-sectional design. We studied 11 adults (mean age 24.5 years) with childhood-onset GH deficiency, which persisted after reaching final height. All subjects were evaluated after interruption of GH supplementation for at least 3 months. We performed neuropsychological assessment (NPA) using tests evaluating memory, mental processing speed, reading ability and executive functioning. MRS was used to assess brain N-acetylaspartate (NAA)/choline ratios. Data were compared with an age-, sex- and education-matched control group (n=9, mean age 27.3 years). NPA demonstrated attenuated performance of the patients in the delayed verbal memory recall score (P<0.05) and the trail making A test (P<0.05), a measure of planning of behavior, processing speed and attention. Other neuropsychological tests were not affected. NAA/choline ratios were significantly reduced (P<0.01) in GH deficient subjects. Specific cognitive defects indicating affected memory and attention were found in patients with childhood-onset GH deficiency. These defects occur simultaneously with reduced neuronal integrity.

Adolescent↗
PubMed2005

Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency.

OBJECTIVE: Untreated GH-deficient adults are predisposed to insulin resistance and excess cardiovascular mortality. We showed previously that short-term treatment with a very low GH dose (LGH) enhanced insulin sensitivity in young healthy adults. The present study was therefore designed to explore the hypothesis that LGH, in contrast to the standard GH dose titrated to normalize serum IGF-I levels (SGH), may have differing effects on insulin sensitivity, body composition, and cardiovascular risk markers [lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and adiponectin] in adults with severe GH deficiency. PATIENTS AND METHODS: In this 12-month open, prospective study, 25 GH-deficient adults were randomized to receive either a fixed LGH (0.10 mg/day, n = 13) or SGH (mean dose 0.48 mg/day, n = 12), and eight age- and body mass index (BMI)-matched GH-deficient adults acted as untreated controls. Fasting blood samples were collected at baseline and at months 1, 3, 6, 9 and 12. Assessments of insulin sensitivity, using the hyperinsulinaemic euglycaemic clamp technique, and body composition, using dual-energy X-ray absorptiometry, were performed at baseline and at month 12. RESULTS: The LGH decreased fasting glucose levels (P < 0.01) and enhanced insulin sensitivity (P < 0.02), but body composition, nonesterified fatty acid (NEFA) levels and cardiovascular risk markers were unchanged. The SGH did not modify insulin sensitivity, decreased truncal fat mass (P < 0.05), CRP (P < 0.05) and IL-6 (P < 0.05) levels, and increased NEFA levels (P < 0.05). No changes were observed with the untreated controls. CONCLUSION: Our data indicate that, in contrast to the SGH, fixed administration of the LGH enhances insulin sensitivity with no apparent effects on body composition, lipolysis and other surrogate cardiovascular risk markers in adults with severe GH deficiency. Thus, the LGH may potentially be a beneficial replacement dose in reducing type 2 diabetes risk in adults with severe GH deficiency.

Adult↗
PubMed2005

Administration of testosterone increases functional connectivity in a cortico-cortical depression circuit.

Increasing evidence suggests that the steroid hormone testosterone (T) enhances libido and decreases depression. Even a single administration of T (0.5 mg sublingually) in healthy young women is sufficient to enhance physiological sexual responsiveness. Such physiological evidence is not yet available for the link between T and depression. Recent research has revealed that lowered functional connectivity in a specific cortico-cortical pathway may be a sensitive physiological index for depression. This pathway, comprised of the left prefrontal and right parietal cortex, has been named a cortical depression circuit. In the present study, a single dose of T was administered to healthy young women to investigate the effects on the functional connectivity in this cortico-cortical depression circuit. It was hypothesized that administration of T would lead to an increase of functional connectivity. In a double-blind placebo-controlled, crossover design, fourteen healthy females received (sublingually) a single dose of 0.5 mg T or placebo in a randomly assigned fashion. Three hours after drug administration the functional coupling between the left prefrontal and right parietal cortex was established by measuring the interhemispheric electroencephalogram (EEG) coherence for the different frequency bands. Compared to placebo, T administration significantly increased the functional connectivity in the sigma (1-3 Hz) frequency range between the left prefrontal and right parietal cortex. Reductions in interhemispheric coherence in the sigma frequency range have been observed in clinically depressed patients. Thus the present findings may provide a first insight into the neurobiological mechanism by which T decreases depression. The fact that only a single dose of T was able to induce the effect in healthy female subjects suggests that the mechanism is highly sensitive. A feasible application of T treatment in the struggle against depression is discussed.

Adult↗
PubMed2005

The GHRH/GHRP-6 test for the diagnosis of GH deficiency in elderly or severely obese men.

OBJECTIVE AND DESIGN: Ageing and obesity result in decreased activity of the GH/IGF-I axis and concomitant impaired GH responses to secretory stimuli. We therefore determined the validity of the GH cut-off value of 15.0 microg/l in the GH-releasing hormone (GHRH)/GH releasing peptide-6 (GHRP-6) test for the diagnosis of GH deficiency in elderly or severely obese men. METHODS: We performed a combined GHRH/GHRP-6 test in ten elderly men (mean age 74 years; mean body mass index (BMI) 24.6 kg/m(2)), nine obese men (mean age 47 years; mean BMI 40.6 kg/m(2)) and seven healthy male controls (mean age 51 years, mean BMI 24.3 kg/m(2)). After assessment of fasting plasma GH, IGF-I and IGF-binding protein-3 (IGFBP-3), GHRH (100 microg) and GHRP-6 (93 microg) were given intravenously as a bolus injection. Repeated GH measurements were performed for two hours. RESULTS: Both peak GH levels and areas under the curve (AUC) were significantly lower in the obese than in the controls (peak 13.2 vs 53.4 microg/l, P = 0.001; AUC 707 vs 3250 microg/l x 120 min; P = 0.001). Mean GH response in the elderly was lower than in the controls (peak 35.0 microg/l; AUC 2274 microg/l x 120 min), but this was not statistically significant. In contrast, GH peak levels in seven obese men remained below the cut-off level of 15.0 microg/l associated with severe GH deficiency. All others had GH peak levels exceeding this threshold. IGFBP-3 levels were significantly lower in the elderly than in the controls (1.35 vs 2.05 mg/l, P = 0.001). Baseline GH or IGF-I did not differ significantly between groups. CONCLUSIONS: GH responses following GHRH/GHRP-6 administration were significantly reduced in severely obese men, but were not significantly reduced in elderly men, despite a negative trend. Our data indicate that the cut-off GH level of 15.0 microg/l after GHRH + GHRP-6 administration for the diagnosis of severe GH deficiency cannot be used in severely obese men.

Aged↗
PubMed2004

Salivary cortisol and short and long-term memory for emotional faces in healthy young women.

Elevated levels of the stress hormone cortisol are associated with increased episodic memory for emotional events. Elevated levels of cortisol are also seen in anxiety and depression disorders. Because it is well documented how both depression and anxiety are related to valence-specific biases in attention and memory, the present study sought to establish relations between basal cortisol levels and episodic memory for neutral, positive and negative stimuli. Thirty-nine healthy young women performed an immediate recall and long-term (20 min) version of a task measuring spatial memory for neutral, happy and fearful faces. The sample as a whole showed a valence-specific better performance for happy faces than for neutral faces in the immediate recall condition, and a better performance for all emotional faces in the long-term condition. Salivary cortisol measures were found to be related to better memory for emotional faces in the long-term condition. This relation to cortisol was not valence-specific and is similar to effects predicted by a model on long-term consolidation and the influence of cortisol in this process.

Adolescent↗
PubMed2004

Sex differences for selective forms of spatial memory.

In the present study, a systematic comparison of sex differences for several tests of spatial memory was conducted. Clear evidence for more accurate male performance was obtained for precise metric positional information in a wayfinding task and in an object location memory task. In contrast, no sex difference characterized topological information processing (object-to-position assignment). Together, these findings provide further insight in the specificity of sex differences in spatial memory and in the functional architecture of spatial memory. Implications for the relevant evolutionary basis are discussed.

Adult↗
PubMed2004

A single administration of testosterone improves visuospatial ability in young women.

Previous research has documented correlations between endogenous testosterone levels and visuospatial cognitive function. Some causal relations have also been established in treatment designs in which testosterone was administered to elderly subjects for a number of weeks. Particularly, one study reported a selective effect of a single administration of testosterone on some aspects of spatial memory in 15 women. The present study tested the hypothesis whether a single administration of 0.5 mg of sublingual testosterone would improve visuospatial ability in healthy young women on a test that has consistently been associated with male superiority. Twenty-six women participated in a double-blind placebo-controlled cross-over trial of single administration of testosterone and placebo. Subjects were tested in the same phase of the menstrual-cycle. Four to five hours after both administrations, subjects completed a standardized measure of visuospatial ability (3-D Mental Rotations Test). Visuospatial ability improved significantly after testosterone administration compared to placebo, after controlling for learning effects due to repeated testing. Testosterone is suggested to be causally related to visuospatial ability in young women.

Adult↗
PubMed2004

Growth hormone (GH) peaks versus areas under the curve in the diagnosis of adult GH deficiency: analysis of the variables provided by the GHRH + GHRP-6 test.

BACKGROUND: The diagnosis of growth hormone deficiency (GHD) relies on provocative tests of GH reserve. The aim in these tests is to obtain an objective, biochemical-based, measure of gland function, but clinicians and researchers rely on the GH peak, as a surrogate of the 24-hour pituitary secretion. However, on a mathematical basis the area under the secretory curve (AUC) should be more valid for this evaluation. OBJECTIVES: To validate which variable provided by a provocative test of GH secretion is mathematically more robust for supporting the clinical diagnosis. Adult normal subjects and GHD patients were challenged with the combined stimulus GHRH + GHRP-6. The diagnostic efficacy of the GH peak, and the AUC were compared by the receiver operating characteristic (ROC) curve methodology. PATIENTS AND METHODS: 146 patients with GH deficiency due to organic pituitary disease and 184 healthy subjects were administered GHRH 1 microg/Kg iv, plus GHRP-6 1 microg/Kg iv, and GH was determined. Four variables were studied: (a) the GH peak; (b) the "standard" AUC, (c) the "stimulated" AUC and (d) the basal value, used as internal control. RESULTS: Under ROC curve analysis, the basal variable was devoid of diagnostic capability, while the other variables performed strikingly well, the ROC curve area for the GH peak was 0.9997; and for the AUC 0.9993, with no statistical differences. CONCLUSIONS: The variables provided by measuring the GH peak and the area under the curve were similarly effective for diagnosis, although on clinical grounds, the peak was more convenient as needed no calculation. If results for other test were similar the time-honored method of measuring the GH peak could be considered mathematically validated.

Adult↗
PubMed2004

The role of the somatotropic system in cognition and other cerebral functions.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) receptors can be found in several areas of the brain. GH receptors are mainly found in the choroid plexus, thalamus, hypothalamus, pituitary, putamen, and hippocampus, whereas IGF-1 receptors are mainly concentrated in the hippocampus and parahippocampal areas. In early life, GH and IGF-1 have an important role in the development and differentiation of the central nervous system. In the more developed central nervous system, GH and IGF-1 are thought to have a variety of functions such as a neuroprotective function, an appetite increasing function, various cognitive functions, and perhaps a blood flow-regulating function. In GH-deficient children and adults, improvement of cognitive functions was observed after the administration of GH. Furthermore, specific cognitive functions in healthy older subjects may improve after increasing GH or IGF-1 levels.

Affect↗
PubMed2003

Diagnosis of growth hormone deficiency after pituitary surgery: the combined acipimox/GH-releasing hormone test.

OBJECTIVE: Reduction of plasma free fatty acids leads to enhanced GH response after stimulation by GH-releasing hormone (GHRH). We studied the clinical usefulness of combined administration of acipimox and GHRH for the diagnosis of GH deficiency. DESIGN: We evaluated 35 patients [mean age 53.0 years; mean body mass index (BMI) 26.7 kg/m2] after pituitary surgery. We compared GH responses after acipimox and GHRH with the GH response during an insulin tolerance test (ITT) and, in a subgroup of 12 patients, with the GHRH/arginine test. The acipimox/GHRH test was additionally performed in 21 control subjects (mean age 53.8 years; mean BMI 24.7 kg/m2). RESULTS: In the patients, the mean (+/- SEM) peak GH was almost four-fold higher after acipimox/GHRH (6.94 +/- 1.07 microg/l, range 0.46-23.1; P < 0.001) and after GHRH/arginine (8.32 +/- 1.23 microg/l, range 1.1-49.2; P < 0.001) than after ITT (1.84 +/- 0.46 microg/l, range 0.01-11.9). According to the ITT, 29 patients were severely GH deficient (peak GH < 3.0 microg/l). Peak GH levels after acipimox/GHRH in controls ranged from 7.5 to 78.4 microg/l (mean 29.3 +/- 3.5). GH peak values during the acipimox/GHRH test were significantly correlated with values from the ITT (r = 0.63, P < 0.01) and GHRH/arginine test (r = 0.87, P < 0.001). Areas under the curve were also correlated. According to generally accepted cut-off peak GH levels for the ITT and GHRH/arginine test, a GH peak exceeding 11.2 micro g/l excludes severe GH deficiency after acipimox/GHRH. Our control data indicate that the cut-off level is lower at older age. CONCLUSIONS: The acipimox/GHRH test leads to GH responses similar to those of the GHRH/arginine test, and to higher peak GH values if compared with the ITT. The acipimox/GHRH test is a potential additional tool to detect GH deficiency in patients with pituitary disease, in particular in patients with a perturbation of fatty acid metabolism.

Adenoma↗
PubMed2002

Tumour dosimetry and response in patients with metastatic differentiated thyroid cancer using recombinant human thyrotropin before radioiodine therapy.

The development of recombinant human thyrotropin (rhTSH) has given clinicians new options for diagnostic follow-up and treatment of patients with differentiated thyroid cancer (DTC). This paper evaluates the tumour dosimetry and response following -iodine-131 treatment of metastatic thyroid cancer patients after rhTSH stimulation instead of classical hormone withdrawal-induced hypothyroidism. Nineteen consecutive (131)I treatments in 16 patients were performed after rhTSH stimulation. All patients had undergone a near-total thyroidectomy followed by an ablative dosage of (131)I. They all suffered from metastatic or recurrent disease showing tumoral (131)I uptake on previous post-treatment scintigraphy. Dosimetric calculations were performed using (131)I tumour uptake measurements from post-treatment (131)I scintigrams and tumour volume estimations from radiological images. Response was assessed by comparing pre-treatment serum thyroglobulin (Tg) level with the Tg level 3 months post treatment. In 18 out of 19 treatments, uptake of (131)I in metastatic or recurrent lesions was seen. The median tumour radiation dose was 26.3 Gy (range 1.3-368 Gy), and the median effective half-life was 2.7 days (range 0.5-6.5 days). Eleven of 19 treatments (10/16 patients) were evaluable for response after 3 months. (131)I therapy with rhTSH resulted in a biochemical partial response in 3/11 or 27% of treatments (two patients), biochemical stable disease in 2/11 or 18% of treatments and biochemical progressive disease in 6/11 or 55% of treatments. Our study showed that although tumour doses in DTC patients treated with (131)I after rhTSH were highly variable, 45% of treatments led to disease stabilisation or partial remission when using rhTSH in conjunction with (131)I therapy, without serious side-effects and with minimal impact on quality of life. RhTSH is therefore adequately satisfactory as an adjuvant tool in therapeutic settings and is especially suitable in advanced recurrent or metastatic DTC patients who may be intolerant to TSH stimulation by levothyroxine withdrawal.

Adenocarcinoma, Follicular↗
PubMed2002

Serotonergic functioning in children with oppositional defiant disorder: a sumatriptan challenge study.

BACKGROUND: Several studies support the notion that disturbances in the central serotonergic function are related to impulsive aggression. There is recent evidence from studies on 5-HT(1B) knock-out mice that this specific receptor is involved in impulsive aggressive behavior. The aim of the present study was to investigate 5-HT(1B/1D) receptor functioning in normal intelligent hospitalized children with oppositional defiant disorder (ODD). METHODS: The growth hormone (GH) response to a challenge with the 5-HT(1B/1D) agonist sumatriptan was examined in 20 children with an ODD, of whom 13 had an attention-deficit/hyperactivity disorder comorbidity, and 15 normal control subjects (NC). Blood samples for growth hormone were collected repeatedly between 8:30 and 12:00 AM. Sumatriptan was administered at 10 AM. The effect of stress due to this procedure was assessed by measuring salivary cortisol. RESULTS: The GH response was significantly stronger in the children with ODD. After sumatriptan injection NC children showed a significant increase in cortisol; no such pattern was present in the ODD group. CONCLUSIONS: The results suggest that the postsynaptic 5-HT(1B/1D) receptor is functionally more sensitive in children with ODD.

Aggression↗
PubMed2002

Complete inhibition of hypothalamic somatostatin activity is only partially responsible for the growth hormone response to strenuous exercise.

The aim of this study was to investigate whether growth hormone (GH) release during strenuous exercise (EX) is due to complete inhibition of hypothalamic somatostatin (SS) activity. Eight healthy male subjects (age, 22.1 +/- 2.2 years; body mass index [BMI], 22.2 +/- 2.5 kg/m(2); maximum oxygen consumption [Vo(2)max], 52.2 +/- 1.5 mL/min/kg [mean +/- SD]) were exposed to strenuous EX on a cycle ergometer, with and without administration of pyridostigmine (PD), and to administration of PD alone. PD is an acetylcholine-esterase inhibitor that stimulates GH secretion by suppressing hypothalamic SS secretion and unmasking endogenous GH-releasing hormone (GHRH) tone. Serial blood samples in the fasted state were taken immediately before the start of each trial, and at appropriate intervals over 2 hours. GH responses were calculated as area under the response curve (AUC) by trapezoidal integration. The mean peak serum GH level to PD alone was 18.3 microg/L (range, 0.3 to 40.9), which was significantly lower than to EX alone: 64.1 microg/L (range, 30.5 to 90.5), and to the combined administration of PD and EX (PD+EX): 79.8 microg/L (range, 37.7 to 98.2) (P <.05). The arithmetic sum of the individual peak levels of 82.4 microg/L was not different from the mean peak level to PD+EX: 79.8 microg/L. AUC (mean +/- SEM) to PD alone (1,721 +/- 358 microg/L x 180 min) was not significantly different from that to EX alone (2,472 +/- 408 microg/L x 120 min), but was significantly lower than that to PD+EX: 3,526 +/- 752 (P <.05). Although the latter AUC was 6% smaller than the AUC obtained by arithmetic addition (3,747 +/- 706), this difference was not statistically significant. In conclusion, the additive effect between PD and EX indicates that PD and EX act independently in evoking GH responses to strenuous EX. Therefore, GH responses to strenuous EX are only partially due to complete inhibition of hypothalamic SS. Additional potentiating factors, such as activation of endogenous GHRH and ghrelin must be operative.

Adult↗