Measurement Of Growth Hormone Research Articles

Acromegaly in humans and cats: Pathophysiological, clinical and management resemblances and differences

ObjectiveAcromegaly is a disorder associated with excessive levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). In general, GH/IGF-1 excess leads to morphologic craniofacial and acral changes as well as cardiometabolic complications, but the phenotypic changes and clinical presentation of acromegaly differ across species. Here, we review the pathophysiology, clinical presentation and management of acromegaly in humans and cats, and we provide a systematic comparison between this disease across these different species. DesignA comprehensive literature review of pathophysiology, clinical features, diagnosis and management of acromegaly in humans and in cats was performed. ResultsAcromegaly is associated with prominent craniofacial changes in both species: frontal bossing, enlarged nose, ears and lips, and protuberant cheekbones are typically encountered in humans, whereas increased width of the head and skull enlargement are commonly found in cats. Malocclusion, prognathism, dental diastema and upper airway obstruction by soft tissue enlargement are reported in both species, as well as continuous growth and widening of extremities resulting in osteoarticular compromise. Increase of articular joint cartilage thickness, vertebral fractures and spine malalignment is more evident in humans, while arthropathy and spondylosis deformans may also occur in cats. Generalized organomegaly is equally observed in both species. Other similarities between humans and cats with acromegaly include heart failure, ventricular hypertrophy, diabetes mellitus, and an overall increased cardiometabolic risk. In GH-secreting pituitary tumours, local compressive effects and behavioral changes are mostly observed in humans, but also present in cats. Cutis verticis gyrata and skin tags are exclusively found in humans, while palmigrade/plantigrade stance may occur in some acromegalic cats.Serum IGF-1 is used for acromegaly diagnosis in both species, but an oral glucose tolerance test with GH measurement is only useful in humans, as glucose load does not inhibit GH secretion in cats. Imaging studies are regularly performed in both species after biochemical diagnosis of acromegaly. Hypophysectomy is the first line treatment for humans and cats, although not always available in veterinary medicine. ConclusionAcromegaly in humans and cats has substantial similarities, as a result of common pathophysiological mechanisms, however species-specific features may be found.

Pseudoacromegaly-A challenging entity in the endocrine clinic: A systematic review.

Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to review published pseudoacromegaly cases evaluated due to clinical suspicion of acromegaly. PubMed/Medline search was conducted to identify reported pseudoacromegaly cases, which were systematically reviewed to ensure they met eligibility criteria: (1) presentation suggestive of acromegaly; (2) acromegaly excluded based on normal GH, IGF-1 and/or GH suppression on oral glucose tolerance test (OGTT-GH); (3) diagnosis of the pseudoacromegaly condition was established. Data were retrieved from each case and analysed collectively. Of 76 cases, 47 were males, mean ages at presentation and at first acromegaloid symptoms were 28 ± 16 and 17 ± 10 years, respectively. Most common conditions were pachydermoperiostosis (47%) and insulin-mediated pseudoacromegaly (IMP) (24%). Acromegaloid facies (75%) and acral enlargement (80%) were the most common features. Measurement of random GH was reported in 65%, IGF-1 in 79%, OGTT-GH in 51%. GH excess was more frequently excluded based on two tests (53%). Magnetic resonance imaging (MRI) was performed in 30 patients, with pituitary adenoma or hyperplasia being reported in eight and three patients, respectively. Investigations differed between cases managed by endocrine and non-endocrine specialists, the former requesting more often IGF-1, OGTT-GH and pituitary MRI. Pseudoacromegaly is a challenging entity that may be encountered by endocrinologists. Pachydermoperiostosis and IMP are the conditions most often mimicking acromegaly. Adequate assessment of GH/IGF-1 is crucial to exclude acromegaly, which may be better performed by endocrinologists. Pituitary incidentalomas are common and require careful judgement to prevent unnecessary pituitary surgery.

Challenges Confounding Biochemical Diagnosis of Acromegaly.

Abstract:
 Acromegaly is a disorder caused by growth hormone (GH) hypersecretion resulting in excessive release of insulin like growth factor-1 (IGF-1). Both GH and IGF-1 measurements are crucial in its accurate diagnosis and in differentiating it from pseudoacromegaly. Early diagnosis is frequently restricted by its subtle, unnoticeable pathological changes; hence, clinical presentation is often late. Therefore, biochemical diagnosis is critical. However, the straightforward interpretation of these markers are hindered by factors that contribute to GH – IGF-1 discordance observed both in static and in dynamic function tests. These factors include both markers biological variation and their analytical assay limitations, which lead to false positive and negative results. This review is describing the pitfalls and challenges confounding the biochemical diagnosis of acromegaly. Despite these interpretive challenges, we strongly believe that interpretation of these results could be facilitated by effective clinician-laboratory professional communications which is the highlight of this review.
 
 Keywords: Acromegaly, growth hormone (GH), insulin like growth factor-1 (IGF-1), IGF-binding proteins (IGFBP)

Plasma Growth Hormone as a Prognostic Biomarker to Durvalumab and Tremelimumab in Patients with Advanced Hepatocellular Carcinoma.

In this study, we explored the potential of plasma growth hormone (GH) as a prognostic biomarker in patients with advanced HCC treated with durvalumab plus tremelimumab (D+T). In this study, we included 16 patients with advanced HCC who received D+T at MD Anderson Cancer Center between 2022 and 2023 and had plasma GH measurements recorded before treatment. Plasma GH levels were measured from prospectively collected blood samples and were correlated with progression-free survival (PFS) and overall survival (OS). The cutoff for normal GH levels in women and men was defined as ≤3.7 μg/L and ≤0.9 μg/L, respectively. The Kaplan-Meier method was employed to compute the median OS and PFS, while the Log rank test was applied to compare the survival outcomes between the GH-high and GH-low groups. Sixteen patients were included in this analysis, two female and fourteen male, with a median age of 65.5 years. At the time of the analysis, the 6-month OS rate was 100% among GH-low patients (6 patients) and 30% among GH-high patients (10 patients). OS was significantly longer in GH-low patients (not evaluable) compared to GH-high patients (3.94 months) (p = 0.030). PFS was also significantly longer in GH-low patients (not evaluable) compared to the GH-high patients (1.87 months) (p = 0.036). Plasma GH is a prognostic biomarker in patients with advanced HCC treated with D+T. Given the relatively small patient cohort size, this finding should be further validated in larger randomized clinical trials in advanced HCC patients.

Interpreting growth hormone and IGF-I results using modern assays and reference ranges for the monitoring of treatment effectiveness in acromegaly.

Standard treatment for acromegaly focuses on the achievement of target absolute levels of growth hormone (GH) and insulin-like growth factor (IGF-I). The appropriateness of these targets when measured using modern assay methods is not well defined. This paper reviews biochemical status assessed using methods available at the time and associated clinical outcomes. GH measurements were shown to provide an indication of changes in tumor size, and failure of GH suppression after glucose stimulation is associated with tumor recurrence. IGF-I levels were more closely associated with changes in symptoms and signs. Reduced GH and IGF-I concentrations were shown to be associated with increased longevity, although the degree of increase has only been analyzed for GH. Lowering of GH and IGF-I has consistently been associated with improved outcomes; however, absolute levels reported in previous studies were based on results from methods and reference ranges that are now obsolete. Applying previously described absolute thresholds as targets (e.g. "normal" IGF-I level) when using current methods is best applied to those with active acromegaly symptoms who could benefit from further lowering of biochemical markers. In asymptomatic individuals with mild IGF-I or GH elevations, targeting biochemical "normalization" would result in the need for combination pharmacotherapy in many patients without proven benefit. Measurement of both GH and IGF-I remains an essential component of diagnosis and monitoring the effectiveness of treatment in acromegaly; however, treatment goals based only on previously identified absolute thresholds are not appropriate without taking into account the assay and reference ranges being employed. Treatment goals should be individualized considering biochemical improvement from an untreated baseline, symptoms of disease, risks, burdens and costs of complex treatment regimens, comorbidities, and quality of life.

THU091 Hypopituitarism And The Finding Of Hyperprolactinemia Following Mild Traumatic Brain Injury In Female Athletes

Abstract Disclosure: L.Ó. Eggertsdóttir Claessen: None. H. Kristjánsdóttir: None. M.K. Jónsdóttir: None. S.H. Lund: Employee; Self; Amgen Inc. I.S. Kristensen: None. H.Á. Sigurjónsdóttir: None. Background Hypopituitarism (HP) following mild traumatic brain injury (mTBI) in sports can have serious consequences making prompt diagnosis and treatment essential. Studies have focused on male populations despite female athletes being more susceptible to mTBI. To the best of our knowledge, this study is the first all-female study reporting the prevalence of HP following mTBI. Subjects The study included 508 female athletes aged 18 to 45 years currently active in or retired from soccer, team handball, basketball, ice hockey, and martial arts who answered an online questionnaire regarding mTBI history. Women who reported one or more concussions (n = 308) were invited to participate in a medical interview and a physical examination with 151 accepting. Consequently, 133 women attended pituitary hormone screening blood tests (SBT). Methods SBT were taken at 8 a.m. and included S-IGF1, S-cortisol, S-prolactin, S-TSH, S-fT4, S-FSH, S-oestrogen, and S-progesterone measurements. When SBT were repeatedly outside reference value (O-RV), participants were referred to an endocrinologist for a medical interview and physical examination. Detailed endocrinological tests for possible HP were performed as indicated. When serum levels of TSH or fT4 were O-RV, anti-TPO antibodies were measured and when negative, an MRI was performed. If S-prolactin was repeatedly above reference value (RV) an MRI was performed. When S-cortisol was below 350 mmol/L, morning plasma ACTH was added and morning Synacthen test performed. When S-IGF1 was below median RV and clinical symptoms of GHD were present, a GHRH-arginine test was performed. An ITT was performed in one woman due to practical reasons and strong clinical symptoms indicating GHD. Results etailed endocrinological evaluation for possible HP was indicated in 86 women. Pituitary dysfunction (PD) was diagnosed in 16 women (12.0%). Six (4.5%) women had HP. One woman had GH measurements below RV in a GHRH-arginine test (peak GH levels ≤11.0 µg/L for BMI <25 kg/m2) and one had GH below <3µg/L in an ITT. Four women had low or normal TSH levels (reference range 0.270 - 4.20 mIU/L), low fT4 (reference range 12 - 22 pmol/L) and a negative anti-TPO measurement. Ten women (7.5%) had hyperprolactinemia (HPRL) (reference range 4.79 - 23.3 μg/L). Four of the 10 women with HPRL were diagnosed with a prolactinoma following an MRI. Medical treatment was initiated for 13 (9.8%) women as one woman had a prolactinoma but no clinical symptoms of HPRL. Conclusions PD is an important consideration in post-concussion care as 12.0% had PD following mTBI with 9.8% requiring medical treatment. Six women (4.5%) had HP following mTBI (GHD = 2 and central hypothyroidism n = 4). This is lower than previously reported and may be due to HP recovering with time. As six women had HPRL without a prolactinoma, HRPL may represent pituitary or hypothalamic injury following mTBI. Presentation: Thursday, June 15, 2023

FRI598 Evolving Growth Hormone Deficiency: A Proof Of Concept

Abstract Disclosure: S. Chimatapu: None. S. Sethuram: None. J. Samuels: None. M. Savage: None. R. Rapaport: None. Introduction: Most cases of growth hormone deficiency (GHD) in pediatric patients are idiopathic, isolated and acquired. All acquired conditions commence with a period during which the diagnosis maybe unapparent. We document here evidence for evolution of GHD in a group of adolescent males who tested sufficient on initial GH stimulation test (GST) but tested deficient upon reevaluation. The rationale for repeat GST was ongoing growth failure. Hypothesis: We hypothesize that GHD in some individuals evolves with time and can be diagnosed by repeat testing (EGHD). We also postulate that their response to GH therapy is similar to other patients with GHD. Methods: We performed an IRB-approved retrospective chart review of children who presented for short stature (height less < 2SD for mean or < 2SD for mid-parental height) to pediatric endocrinology at Kravis Children’s Hospital at Mount Sinai, New York and who had 2 GST. GST were performed using two different stimuli (arginine and glucagon) and highly sensitive assay serum GH measurements were processed by the same laboratory, Esoterix. No patient had obesity, chronic illnesses, or any genetic conditions affecting growth. Data were collected from electronic medical records and analyzed using SPSS v28.0 once at least half the population studied reached adult height. We defined adult height as bone age ≥ 16 years and growth velocity ≤ 2 cm/year. Results: Of 42 charts analyzed, all male, 25 had EGHD. Their average GH peak on initial GST was 15.48 ± 4.92 ng/ml, mean age 10.07 ± 2.65 years, mean height -1.68 ± 0.56 SD , IGF-1 -1.00 ± 0.88 SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height decreased to -1.82 ± 0.63 SD and IGF-1 was -1.08 ± 0.84 SD. At repeat GST, GH peak was 7.59 ± 2.12 ng/mL and 28% were in puberty. All patients had MRI before starting GH therapy; 40% had small anterior pituitary glands. 12 males who reached adult height had a height of -1.88 ± 0.64 SD, IGF-1 of -1.15 ± 0.81 SD, with 42% pubertal and peak GH of 7.33 ± 2.47 ng/mL at repeat GST. They had a mean height gain of 1.83 ± 0.56 SD(p<0.005), with an adult height of 0.09 ± 0.70 SD after 4.64 ± 1.4years of treatment. They were 2.10 ± 4.20 cm taller than their mid-parental target heights. Discussion/Conclusions: We provide proof of concept for the diagnosis of EGHD. The diagnosis could be established by repeat GST in children with ongoing growth deceleration despite pubertal progression and a non-diagnostic initial GST. Our patients who reached adult height had a height gain consistent with that reported by KIGS for patients with growth hormone deficiency (1.7SD; Cutfield,1999) and indeed better than patients with ISS (0.7SD; Maghnie,2022). Presentation: Friday, June 16, 2023

Association between pain, arthropathy and health-related quality of life in patients suffering from acromegaly. A cross-sectional study

Despite successful therapy, acromegalic patients have reduced health-related quality of life (HRQoL) compared to healthy controls. Finding predictors of poor HRQoL can be crucial to improving these patients' global health state. Aim: The primary objective of the study was to find out predictors of HRQoL. Secondary objectives were: (I) to determine correlations with AcroQoL subscales, and (II) to identify predictors for subscales. In this cross-sectional study conducted in 2019 at the Messina Policlinic Hospital, 45 acromegalic patients were assessed at the Physical and Rehabilitative Medicine Ambulatory. During routine outpatient clinic attendances, the following questionnaires were administered: Acromegaly Quality of Life Questionnaire (AcroQoL), Patient-Assessed Acromegaly Symptom Questionnaire (PASQ), and Western Ontario and McMaster Universities Arthritis Index (WOMAC). We furthermore included the following variables obtained by medical record review: age, BMI, disease duration, previous surgery (Yes/No), previous radiotherapy (Yes/No), use of GH lowering medications (Yes/No), hypertension (Yes/No), diabetes mellitus (Yes/No), and biochemical control of the disease (Yes/No): immunoradiometric assays were employed to serum GH and IGF-1 measurements to identify biochemical control of the disease. Correlation between outcome measures and AcroQoL has been performed. Pearson's r was calculated for continuous data following normal distribution (AcroQoL, PASQ, AcroQoL-B, AcroQoL-R, WOMAC-P), while Spearman's rank order correlation was calculated for non-normally distributed data (WOMAC, WOMAC-F, WOMAC-S, AcroQoL-P) and point-biserial correlation for binary variables (biochemically controlled disease, use of GH lowering medications, radiotherapy, surgery). The same correlation analysis was performed for the AcroQoL subscales. Multiple linear regression with backwards, stepwise analysis was used to assess the influence on AcroQoL of correlated variables. AcroQoL was strongly negatively correlated with PASQ (r=-0.700, p<0.001) and negatively correlated with WOMAC [rs (43)=-0.530, p<0.001] and among WOMAC subscales with WOMAC-Physical fitness [rs (43)=-0.518, p<0.001] WOMAC-Pain [r (43)=-0.428, p=0.003], WOMAC-Stiffness [rs (43)=-0.393, p=0.007], and radiotherapy [r (43) =-0.314, p=0.035]. After univariate stepwise regression, PASQ was the strongest independent predictor of AcroQoL, with R2 of 0.392 [F (1,43)=27.695, p<0.001]. This study shows that the severity of painful symptoms is the most important predictor of HRQoL in patients with acromegaly; at the same time, acromegalic arthropathy leads to pain and to a variable amount of functional impairment, exerting great impact on the patient's perception of his health status. Measure of the progression of arthropathy and symptomatic management could lead to a great HRQoL benefit.

Morphological Determination of Glenohumeral Joint and Acromioclavicular Joint with Computed Tomography

Although acute and chronic pathologies of the glenohumeral and acromioclavicular joints are frequently encountered in the population, the anatomy and morphometry are not fully known. The aim of this study is to determine the measurements of morphometric parameters according to age groups and sex in a large series of Turkish population. Nine hundred and forty-one shoulders computed tomography (CT) images were screened and those of subjects with healthy anatomical structure were included. Humeral head diameter (HDD) was measured on CT images. Measurements were made using 3D-CT images of: width (GW) and height (GH) of the glenoid cavity; width (CW) and height (CH) of the distal clavicular joint surface; and width (AW) and height (AH) of the acromial joint surface. Data were compared, stratified by age and sex. Images of 223 patients (118 men, 105 women) were analyzed. The following mean measurements were determined: HDD, 41.77±3.77 mm; GH, 34.66±3.26 mm; GW, 25.50±2.90 mm; CW, 14.85±3.51 mm; CH, 8.49±2.27 mm; AW, 12.97±2.94 mm; AH, 7.01±1.77 mm. When startified by sex, HDD (p<0.001), GH (p<0.001), GW (p<0.001), CW (p<0.001), CH (p=0.002), AW (p<0.001) and AH (p<0.001) measurements were significantly different and mean values were greater in men. Similarly for age, significant differences were found for GH (p=0.028), CW (p<0.001), AW (p<0.001), AH (p<0.001). The parametric values we have obtained in the Turkish population we measure differ from the measurements made in different populations according to age groups and sex. Knowing these features will contribute to treatment planning, implant and prosthesis applications.

Optimization of the follow-up and treatment of patients with acromegaly with the SAGIT&lt;sup&gt;®&lt;/sup&gt; tool

The condition of a patient with acromegaly is significantly influenced not only by growth hormone (GH) and insulin-like growth factor type 1 (IGF-1) levels, but also by specific characteristics of somatotropinoma, severity of the main symptoms of acromegaly, and concomitant disorders. After successful achievement of biochemical control (GH and IGF-1 goals) the expected life longevity in patients with acromegaly could be comparable with that in the general population. It is important to avoid therapeutic inertia, to achieve biochemical control within shortest time period and to carefully tailor the treatment of concomitant disorders.&#x0D; The cumulative experience of patient management has shown that therapeutic decisions should be based not only on measurement of GH and IGF-1 levels, but also on a unified multifactorial assessment of the patient's status. For this purpose, the SAGIT tool has been elaborated, which ensures a multifaceted standardized assessment of patients with acromegaly, taking into account clinical symptoms, hormonal parameters, tumor size and comorbidities. This paper is the first description of the SAGIT tool in Russian. The use of this tool allows for standardization of the patients assessment and for comparison of the status in patients both within one center and in different centers. The key unified information obtained with SAGIT could be the basis for making prompt decisions on the need in treatment optimization for a patient with acromegaly, including his/hers referral to an expert center for the choice of further treatment strategy.&#x0D; The SAGIT tool has been recommended for implementation into clinical practice by international professional associations. It is advisable to perform studies with participation of the Russian patients with acromegaly to assess the possibility of SAGIT implementation into clinical practice in Russia.

Intraoperative Prediction of Long-Term Remission in Acromegaly.

The features of long-term remission in acromegaly adenomectomy are incompletely understood. An intraoperative predictor for long-term outcome would be valuable for assessing resection of growth hormone (GH)-secreting tumors in real-time. To evaluate whether intraoperative GH measurement could predict long-term outcomes for acromegaly. In 47 patients, peripheral blood GH levels were measured thrice intraoperatively: once before tumor dissection, once during tumor dissection, and once after tumor dissection. Long-term remission was defined by age-appropriate, normalized insulin-like growth factor-1 at most recent follow-up and a random GH less than 1.0 ng/mL. Patients were only considered to be in long-term remission without the use of postoperative medical therapy for acromegaly or radiation therapy. The median length of follow-up was 4.51 (range: 0.78-9.80) years. Long-term remission was achieved in 61.7% (29/47) of operations. Like previous studies, cavernous sinus invasion (odds ratio [OR]: 0.060; 95% CI: 0.014-0.260; P value < .01), suprasellar extension (OR: 0.191; 95% CI: 0.053-0.681; P value<.01), and tumor size greater than 1 cm (OR: 0.177; 95% CI: 0.003-0.917; P value = .03) were associated with not being in long-term remission. The minimum GH measured intraoperatively predicted long-term outcome (area under the curve: 0.7107; 95% CI: 0.537-0.884; P value < .01). The odds ratio of remission in patients with the lowest quartile minimum intraoperative GH compared with patients with the highest quartile minimum intraoperative GH was 27.0 (95% CI: 2.343-311.171; P value < .01). Minimum intraoperative GH may predict long-term outcome for acromegaly, which in principle could provide the pituitary neurosurgeon with real-time feedback and inform intraoperative decision making.

PMON117 IGF-1 Testing: Diagnostic Pitfalls

Abstract Introduction Acromegaly is a rare endocrine disorder, with an incidence of 5.3/million/year, that results from persistent hypersecretion of growth hormone (GH), which stimulates hepatic secretion of insulin-like growth factor-1 (IGF-1). The best single test for the diagnosis of acromegaly is measurement of serum IGF-1; however, the result must be interpreted with caution, with understanding of potential pitfalls. Here we present a case of falsely elevated IGF-1 levels. Case Description A 43-year-old female with medical history of prediabetes, sleep apnea, and headaches was referred to endocrine clinic for evaluation of possible acromegaly. Patient had been evaluated by her primary care physician for frequent headaches, unintentional weight gain, and bilateral leg and hand swelling. Patient endorsed being unable to wear her wedding ring for a few years. Initial laboratory evaluation by primary care physician 3 months prior revealed normal thyroid function, prolactin, FSH, LH, random cortisol, but elevated IGF-1 of 310 ng/mL (normal 71-258 ng/mL), with negative pregnancy test. Brain MRI at that time revealed a pineal gland cyst but no pituitary abnormality. During her initial endocrine visit, IGF-1 was repeated, which was again elevated but improved to 283 ng/mL (normal 71-258 ng/mL). Other pertinent labs included a normal random ACTH of 18 pg/mL (normal &amp;lt;47 pg/mL), and pm cortisol of 2.4 mcg/dL (normal 2.9-17.3 mcg/dL). Physical examination was notable for a few light purple striae on abdomen, acanthosis nigricans, and mild limb edema, but no macrognathia, enlarged hands or feet. Given patient's lack of typical features of acromegaly, normal pituitary imaging, and spontaneous IGF-1 improvement, it was decided to postpone GH measurements with oral glucose tolerance test but repeat IGF-1 in 6 months. Patient was able to follow up 11 months after initial visit at which patient denied any worsening symptoms. At that time, repeat laboratory study showed normal IGF-1 of 231. Given spontaneous normalization of IGF-1 levels, no further laboratory testing or imaging studies were recommended, and patient was instructed to follow up in 11-12 months. Discussion Prompt diagnosis of acromegaly is crucial. However, it is important to note IGF-1 could be falsely elevated. A retrospective review by Erickson et. al of 2747 unique patients with IGF-1 elevation, 117 (4%) were found to have false-positive results following a review of the clinical data. In addition to acromegaly, other causes of elevated IGF-1 levels include high protein and high glycemic-index diet, pregnancy, hyperthyroidism, IGF-1 assay problems, and some rare tumors (carcinoids) secreting IGF-1. Discovery of "falsely" elevated IGF-1 may lead to unnecessary testing and physician visits. Therefore, clinicians should consider retesting patients after some time interval if spurious IGF-1 is suspected, before aggressively pursuing more extensive investigations. Presentation: No date and time listed

Optimal timing of blood samplings to detect GH inhibition during oral glucose tolerance test.

In patients with suspected acromegaly, evaluation of IGF-I is recommended as first-line test, while the assessment of GH-nadir during oral glucose tolerance test (OGTT) is advised as confirmatory test. The procedure of this test generally involves GH measurement every 30min (30') from baseline to +120' or +180'. However, the optimal timing of samplings for the distinction between patients with or without active acromegaly is still a matter of debate. Sixty-seven healthy subjects and 46 acromegalic patients who achieved documented and persistent long-term cure were enrolled. A greedy algorithm was used to identify the minimal subset of time-points that sufficed to correctly detect GH suppression. The sampling at 90' was the one in which a GH level < 1μg/L was most frequently achieved (i.e., in 91.3% of cured acromegalic patients and in 91.0% of healthy subjects). Considering the whole cohort, the best combination of 2 time-points was +90' and +150' and achieved 95.6% accuracy; the best combination of 3 time-points was +60', +90' and +150' and achieved 99.1% accuracy. The minimal subset of GH determinations that demonstrated perfect accuracy (100%) needed the inclusion of 4 time-points, namely +60', +90', +120' and +150'. A subset of 4 time-points (60' - 90' - 120' - 150') was identified as the most relevant to detect GH suppression at OGTT, with a perfect classification of 100% of subjects. This supports the possibility to restrict the blood samplings to these time-points when assessing disease cure, with possible advantages in terms of saving time and lowering costs.

Discordant parameters of insulin-like growth factor 1 and growth hormone in the diagnosis and monitoring of acromegaly

Acromegaly is a rare endocrine disorder associated with multiple complications and increased mortality. Timely diagnosis and adequate treatment can bring the life expectancy of patients with acromegaly closer to the general population level. The tests for the diagnosis of acromegaly are measurement of both serum GH, and GH after oral glucose administration; serum insulin-like growth factor-1 (IGF-1). However, in clinical practice, up to 39% of patients with discordant results are found. The patients with discordant GH and IGF-1levels, are the most difficult to manage. This review discusses the prevalence of discordant GH and IGF-1 outcomes in patients with acromegaly; factors causing this discrepancy; the impact of hormone levels on treatment outcomes. Although endocrinologists are used to dealing with this discrepancy in clinical practice for many years, discordant patients'outcome remains uncertain and undefined The optimal treatment should be individually tailored for each patient, taking into account all clinical parameters.

Preoperative prediction of granulation pattern subtypes in GH-secreting pituitary adenomas.

The aim of this study was to establish a preoperative prediction method for sparsely granulated (SG) growth hormone (GH)-secreting pituitary adenoma, an aggressive tumour subtype with high recurrence risk, in acromegaly patients. Eighty-three patients with GH-secreting pituitary adenomas were included in this study. GH measurements, cytokeratin immunostaining and electron microscopy were performed to detect granulation patterns. Preoperative factors, including general, radiological and endocrinological features and acute octreotide suppression test outcomes, were compared between SG and densely granulated (DG) groups. The predictive capabilities of these features were analysed using a receiver operating characteristic (ROC) curve, and the most predictive features were combined to establish a grading scale. Thirty-nine of the 83 patients had SG GH-secreting pituitary adenomas; 44 had DG tumours. SG tumours tended to occur in younger patients and have larger diameters and volumes, higher Knosp grades, lower GH indexes and normalized insulin-like growth factor-1 (IGF-1) level, and a lower ∆GH% after octreotide treatment. The tumour size, Knosp grade, GH index and ∆GH% after octreotide treatment had good predictive performance, with area under the curve (AUC) values ranging from 0.70 to 0.80. Combining four parameters, including diameter, Knosp grade, GH index and ∆GH% after octreotide treatment, we established a grading scale for predicting SG GH-secreting pituitary adenomas with an AUC of 0.84 and relatively high sensitivity and specificity. We propose a predictive method for distinguishing SG and DG GH-secreting pituitary adenomas preoperatively. This method will help physicians identify candidates for presurgical medical treatment and neurosurgeons determine radical surgical strategies for high-risk tumours.

Provocative growth hormone testing in children: how did we get here and where do we go now?

Provocative growth hormone (GH) tests are widely used for diagnosing pediatric GH deficiency (GHD). A thorough understanding of the evidence behind commonly used interpretations and the limitations of these tests is important for improving clinical practice. To place current practice into a historical context, the supporting evidence behind the use of provocative GH tests is presented. By reviewing GH measurement techniques and examining the early data supporting the most common tests and later studies that compared provocative agents to establish reference ranges, the low sensitivity and specificity of these tests become readily apparent. Studies that assess the effects of patient factors, such as obesity and sex steroids, on GH testing further bring the appropriateness of commonly used cutoffs for diagnosing GHD into question. Despite the widely recognized poor performance of provocative GH tests in distinguishing GH sufficiency from deficiency, limited progress has been made in improving them. New diagnostic modalities are needed, but until they become available, clinicians can improve the clinical application of provocative GH tests by taking into account the multiple factors that influence their results.

Insulin‐like growth factor‐1, growth hormone and disease outcomes in acromegaly: A population study

A lack of consensus remains about the relative importance of insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in predicting adverse outcomes in patients with acromegaly. To describe the differing association between IGF-1 and GH and major disease outcomes in acromegaly. Retrospective cohort study. United Kingdom National Health Service patients with acromegaly who had an IGF-1 and/or a GH measurement recorded following diagnosis, prior to December 2019. A composite endpoint including all-cause mortality (ACM), type 2 diabetes (DM), major adverse cardiovascular events (MACE) or cancer was the primary outcome. These outcomes were also analysed individually. Follow-up period was capped at 5years. A maximum of 417 cases and 332 cases were eligible for the IGF-1 and GH analyses, respectively, comprising 1041.5 and 938.9years of follow-up. There was a direct association between increased IGF-1 concentration and adjusted event risk for the composite endpoint (hazard ratio [HR]=1.2; 95% confidence interval [CI]=1.02-1.5); in GH, the HR was 1.1 (1.0-1.2). For the individual endpoints in relation to IGF-1 level, the HRs were ACM (1.2; 0.93-1.5), MACE (1.2; 0.64-2.1), DM (1.53; 1.09-2.2) and cancer (1.3; 0.95-1.7). For GH, the HRs were ACM (1.1; 0.97-1.2), MACE (0.99; 0.73-1.3), DM (1.1; 0.99-1.2) and cancer (0.90; 0.66-1.2). In this contemporary data set with extended follow-up, IGF-1 and GH concentrations showed an association with major adverse outcomes from acromegaly.

Pulse wave velocity is decreased in acromegaly compared to non-acromegaly study participants with similar cardiovascular risk profile

ObjectiveAcromegaly patients were reported to have an increased arterial stiffness that could contribute to the frequent cardiovascular complications in this population. The chronic excess of GH and IGF-1 may lead to arterial stiffening via different mechanisms, including hypertension, impaired glucose tolerance and dyslipidemia, however, it is not known whether the activation of GH/IGF-1 axis might influence arterial stiffening independently of cardiovascular risk factors. The objective of this prospective case-control study was to compare arterial stiffness assessed with pulse-wave velocity (PWV) in acromegaly versus non-acromegaly group with similar cardiovascular risk profile. DesignThis prospective case-control study included 27 patients with active acromegaly, who underwent the assessment of clinical, physiological, biochemical parameters and the evaluation of PWV with applanation tonometry. We used “The epidemiology of cardiovascular disease in different regions of the Russian Federation” study database (n = 522) to establish a non-acromegaly control group with similar cardiovascular risk profile (n = 54). Non-acromegaly control participants underwent the same assessment as acromegaly patients except for the measurement of serum GH and IGF-1 levels. We compared PWV in acromegaly patients to the general non-acromegaly cohort and its subset, matched with acromegaly patients for cardiovascular risk factors. We also investigated the associations of PWV with clinical, physiological and biochemical parameters in acromegaly and non-acromegaly group using correlation and regression analysis with adjustment for age and sex. ResultsAcromegaly patients had lower PWV (6.70 (5.75–7.65) m/s) compared to unmatched non-acromegaly control cohort (7.50 (6.70–8.57) m/s, p = 0.01) and to the non-acromegaly control group matched for cardiovascular risk factors (7.45 (6.73–8.60), p < 0.01). In non-acromegaly control group PWV was associated with BMI (ρ = 0.40, p < 0.01; β = 0.09, p < 0.01), obesity (r = 0.46, p < 0.01; β = 1.36, p < 0.01), systolic blood pressure (ρ = 0.60, p < 0.01; β = 0.05, p < 0.01), diastolic blood pressure (ρ = 0.62, p < 0.01; β = 0.07, p < 0.01), triglycerides (ρ = 0.55, p < 0.01; β = 0.58, p = 0.04), glucose (ρ = 0.54, p < 0.01; β = 0.70, p < 0.01) and diabetes (r = 0.40, p < 0.01; β = 1.10, p = 0.03), while in acromegaly group PWV was associated with IGF-1 expressed in mcg/ml (ρ = −0.49, p ≤0.01; β = −0.002, p ≤0.01) and in percentage of the upper limit of the normal (ρ = −0.47, p = 0.01; β = −0.005, p ≤0.01) as well as with diuretics treatment (β = −1.17, p = 0.03). ConclusionsPWV is decreased in acromegaly patients compared to non-acromegaly control participants with similar cardiovascular risk profile. Future studies need to explore the role of GH/IGF-1 axis in the regulation of arterial wall properties and the reliability of PWV as a prognostic marker of cardiovascular complications in acromegaly.

Discordant GH and IGF-1 Results in Treated Acromegaly: Impact of GH Cutoffs and Mean Values Assessment.

Discordant growth hormone (GH) and insulin-like growth factor-1 (IGF-1) values are frequent in acromegaly. To evaluate the impact of different GH cutoffs on discordance rate. To investigate whether the mean of consecutive GH measurements impacts discordance rate when matched to the last available IGF-1 value. Retrospective study. Referral center for pituitary diseases. Ninety acromegaly patients with at least 3 consecutive evaluations for GH and IGF-1 using the same assay in the same laboratory (median follow-up 13 years). Multimodal treatment of acromegaly. Single fasting GH (GHf) and IGF-1 (IGF-1f). Mean of 3 GH measurements (GHm), collected during consecutive routine patients' evaluations. At last evaluation GHf values were 1.99 ± 2.79 µg/L and age-adjusted IGF-1f was 0.86 ± 0.44 × upper limit of normality (mean ± SD). The discordance rate using GHf was 52.2% (cutoff 1 µg/L) and 35.6% (cutoff 2.5 µg/L) (P = 0.025). "High GH" discordance was more common for GHf <1.0 µg/L, while "high IGF-1" was predominant for GHf <2.5 µg/L (P < 0.0001). Using GHm mitigated the impact of GH cutoffs on discordance (GHm <1.0 µg/L: 43.3%; GHm <2.5 µg/L: 38.9%; P = 0.265). At receiver-operator characteristic curve (ROC) analysis, both GHf and GHm were poor predictors of IGF-1f normalization (area under the curve [AUC] = 0.611 and AUC = 0.645, respectively). The prevalence of disease-related comorbidities did not significantly differ between controlled, discordant, and active disease patients. GH/IGF-1 discordance strongly depends on GH cutoffs. The use of GHm lessen the impact of GH cutoffs. Measurement of fasting GH levels (both GHf and GHm) is a poor predictor of IGF-1f normalization in our cohort.

The prevalence of silent acromegaly in prolactinomas is very low.

The aim of this study was to evaluate the somatotroph axis in a large series of patients with prolactinoma to verify the prevalence of silent acromegaly in this population. A hundred and forty-four patients were enrolled in a multicenter study: 90 were already on cabergoline (CAB) and enrolled in a cross-sectional arm (group A) with random PRL, GH and IGF-I determination on treatment (≥3months), whereas 54 untreated patients were enrolled at diagnosis in a prospective arm (group B) with PRL, GH and IGF-I measurement before and after 6 and 12months of treatment. In the presence of high IGF-I, CAB was withdrawn for 3months and GH, IGF-I, PRL and GH during an oral Glucose Tolerance Test (OGTT) were obtained. High IGF-I levels (ULN 1.01-1.56) were observed in 9 patients (6.25%, 5F). After CAB withdrawal, IGF-I levels normalized in 5/9 patients, GH was<0.4ng/ml after OGTT in 7/9 cases or at random GH determination in one case. After CAB re-introduction, IGF-I levels re-increased in a single case. Overall, a single young female patient harboring a macroadenoma in group A was diagnosed with silent acromegaly and underwent successful transsphenoidal removal of a GH/PRL-secreting adenoma. The prevalence of silent acromegaly in prolactinomas (0.7%) is lower than previously reported and OGTT is helpful to recognize silent acromegaly. We suggest that the somatotroph axis should be evaluated at diagnosis in all cases and not systematically during follow-up.