Towards a pituitary apoplexy classification based on clinical presentation and patient journey.

PURPOSE: The condition of pituitary apoplexia contains the clinical spectre from life-threatening emergency to asymptomatic self-limiting course, which partly determines diagnostic delay and management. Outcome evaluation of course and management of pituitary apoplexia is hampered by the diverse presentation of this condition and requires appraisal. This study aimed to describe the patient journey, clinical presentation, and management of various types of pituitary apoplexy in a new classification to facilitate future outcome evaluation and identify unmet needs in the care process. METHODS: A single-center retrospective patient chart study was conducted between 2005-2021 (N = 98). Outcome measures were clinical symptoms at first presentation in hospital, being headache, consciousness, visual acuity, visual field defects (VFD), ophthalmoplegia, nausea, vomiting, fever, and hypopituitarism and care process characteristics. RESULTS: Mean age was 47.6 ± 16.6 years (51.0% male). We describe their patient journey and identified three different types, differing in clinical presentation, in-hospital route, and final treatment, e.g., Acute (type A, 52%), Subacute (type B, 22.5%), and Non-acute (type C, 25.5%). Type A generally presents with acute onset headaches, VFD, or ophthalmoplegia emergency setting, with lowest mean visual acuity of both eyes and frequent hypocortisolism. CONCLUSIONS: Pituitary apoplexy can be approached as a spectrum of disease with 3 main subtypes, with a different initial presentation, different in-hospital route resulting in different management. Acknowledging subtypes with particular needs for (emergency) referrals to Pituitary Tumors Center of Excellence (PTCOE) will serve patient care improvements, outcome evaluations and address areas for improvement.

Variants of FOXO3 and RPA3 genes affecting IGF-1 levels alter the risk of development of primary osteoarthritis.

INTRODUCTION: Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the potential role of the GH/IGF-1 axis in primary osteoarthritis (OA). We aimed to disentangle the role of IGF-1 levels in primary OA pathogenesis. METHODS: Patients from the Genetics osteoARthritis and Progression (GARP) Study with familial, generalized, symptomatic OA (n = 337, mean age: 59.8 ± 7.4 years, 82% female) were compared to Leiden Longevity Study (LLS) controls (n = 456, mean age: 59.8 ± 6.8 years, 51% female). Subjects were clinically and radiographically assessed, serum IGF-1 levels were measured, and 10 quantitative trait loci (QTL) in the FOXO3, IGFBP3/TNS3, RPA3, SPOCK2 genes, previously related to serum IGF-1 levels, were genotyped. Linear or binary logistic generalized estimating equation models were performed. RESULTS: Serum IGF-1 levels were increased in OA patients, with male patients exhibiting the strongest effect (males OR = 1.10 (1.04-1.17), P=0.002 vs females OR = 1.04 (1.01-1.07), P = 0.02). Independent of the increased IGF-1 levels, male carriers of the minor allele of FOXO3 QTL rs4946936 had a lower risk to develop hip OA (OR = 0.41 (0.18-0.90), P = 0.026). Additionally, independent of IGF-1 levels, female carriers of the minor alleles of RPA3 QTL rs11769597 had a higher risk to develop knee OA (OR = 1.90 (1.20-2.99), P = 0.006). CONCLUSION: Patients with primary OA had significantly higher IGF-1 levels compared to controls. Moreover, SNPs in the FOXO3 and RPA3 genes were associated with an altered risk of OA. Therefore, altered IGF-1 levels affect the development of OA, and are potentially the result of the pathophysiological OA process.

Progression of vertebral fractures in long-term controlled acromegaly: a 9-year follow-up study.

OBJECTIVE: Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess results in both reversible and irreversible musculoskeletal damage, including increased vertebral fracture (VF) risk. The prevalence of VFs is approximately 60% in controlled acromegaly patients, and these VFs can progress in time. We aimed to identify the course of VFs in a cohort of acromegaly patients in long-term remission and their associated risk factors during prolonged follow-up. METHODS: Thirty-one patients with acromegaly (49% female, median age 60 years (IQR 53-66)), who were in remission for ≥2 years, were included in this longitudinal, prospective, follow-up study. Spine radiographs of vertebrae Th4 to L4 were assessed for VFs using the Genant score, at baseline, after 2.6 years and 9.1 years. Progression was defined as either a new fracture or a ≥1-point increase in Genant score. RESULTS: The prevalence of VF at baseline was 87% (27/31 patients). Progression of VFs was observed in eleven patients (35.5%) during the 9.1-year follow-up period, with a total incidence rate of 65.5 per 1000 person years (males 59.8 per 1000 person years vs females 71.6 per 1000 person years). Patients treated with surgery or radiotherapy had a higher risk of VF progression in this cohort (P = 0.030). CONCLUSIONS: In this cohort of long-term, well-controlled acromegalic patients, the prevalence and progression of VFs was high, showing that the deleterious effects of GH and IGF-1 excess on bone persist despite achievement of longstanding remission.

Acromegalic arthropathy in various stages of the disease: an MRI study.

BACKGROUND: Arthropathy is a prevalent and invalidating complication of acromegaly with a characteristic radiographic phenotype. We aimed to further characterize cartilage and bone abnormalities associated with acromegalic arthropathy using magnetic resonance imaging (MRI). METHODS: Twenty-six patients (23% women, mean age 56.8 ± 13.4 years), with active (n = 10) and controlled acromegaly (n = 16) underwent a 3.0 T MRI of the right knee. Osteophytes, cartilage defects, bone marrow lesions and subchondral cysts were assessed by the Knee Osteoarthritis Scoring System (KOSS) method. Cartilage thickness and cartilage T2 relaxation times, in which higher values reflect increased water content and/or structural changes, were measured. Twenty-five controls (52% women, mean age: 59.6 ± 8.0 years) with primary knee OA were included for comparison. RESULTS: Both in active and controlled acromegaly, structural OA defects were highly prevalent, with thickest cartilage and highest cartilage T2 relaxation times in the active patients. When compared to primary OA subjects, patients with acromegaly seem to have less cysts (12% vs 48%, P = 0.001) and bone marrow lesions (15% vs 80%, P = 0.006), but comparable prevalence of osteophytosis and cartilage defects. Patients with acromegaly had 31% thicker total joint cartilage (P < 0.001) with higher cartilage T2 relaxation times at all measured sites than primary OA subjects (P < 0.01). CONCLUSIONS: Patients with active acromegaly have a high prevalence of structural OA abnormalities in combination with thick joint cartilage. In addition, T2 relaxation times of cartilage are high in active patients, indicating unhealthy cartilage with increased water content, which is (partially) reversible by adequate treatment. Patients with acromegaly have a different distribution of structural OA abnormalities visualized by MRI than primary OA subjects, especially of cartilage defects.

Bone material strength index as measured by impact microindentation is altered in patients with acromegaly.

OBJECTIVE: Acromegaly is a rare disease caused by excess growth hormone (GH) production by the pituitary adenoma. The skeletal complications of GH and IGF-1 excess include increased bone turnover, increased cortical bone mass and deteriorated microarchitecture of trabecular bone, associated with a high risk of vertebral fractures in the presence of relatively normal bone mineral density (BMD). We aimed to evaluate tissue-level properties of bone using impact microindentation (IMI) in well-controlled patients with acromegaly aged ≥18 years compared to 44 controls from the outpatient clinic of the Centre for Bone Quality. DESIGN AND METHODS: In this cross-sectional study, bone material strength index (BMSi) was measured in 48 acromegaly patients and 44 controls with impact microindentation using the osteoprobe. RESULTS: Mean age of acromegaly patients (54% male) was 60.2 years (range 37.9-76.5), and 60.5 years (range 39.8-78.6) in controls (50% male). Patients with acromegaly and control patients had comparable BMI (28.2 kg/m2 ± 4.7 vs 26.6 kg/m2 ± 4.3, P = 0.087) and comparable BMD at the lumbar spine (1.04 g/cm2 ± 0.21 vs 1.03 g/cm2 ± 0.13, P = 0.850) and at the femoral neck (0.84 g/cm2 ± 0.16 vs 0.80 g/cm2 ± 0.09, P = 0.246). BMSi was significantly lower in acromegaly patients than that in controls (79.4 ± 0.7 vs 83.2 ± 0.7; P < 0.001). CONCLUSION: Our data indicates that tissue-level properties of cortical bone are significantly altered in patients with controlled acromegaly after reversal of long-term exposure to pathologically high GH and IGF-1 levels. Our findings also suggest that methods other than DXA should be considered to evaluate bone fragility in patients with acromegaly.

Abnormal metabolic phenotype in middle-aged GH-deficient adults despite long-term recombinant human GH replacement.

BACKGROUND: Adult GH deficiency (GHD) is associated with increased cardiovascular mortality. Recombinant human GH (rhGH) replacement has beneficial short-term metabolic effects. Although these positive effects sustain during longer follow-up, the prevalence of the metabolic syndrome (MS) remains increased in comparison with population data not adjusted for the higher mean BMI in GHD adults. OBJECTIVE: To explore whether middle-aged patients with proposed physiological rhGH replacement have been normalized with respect to MS and its individual components in comparison with the general population, adjusted for age, sex, and BMI. METHODS: One hundred and sixty-one GHD patients (aged 40-70 years) were studied before the start and after 5 years of rhGH replacement, and were compared with 1671 subjects (aged 45-66 years) from the general population (NEO Study). RESULTS: MS PROPORTION IN GHD PATIENTS WAS 41.0% BEFORE THE START OF RHGH SUPPLETION, INCREASING TO 53.4% AFTER 5 YEARS (P=0.007). DESPITE CHRONIC RHGH REPLACEMENT, GHD PATIENTS HAD A 1.3-TIMES HIGHER MS PROPORTION THAN THE GENERAL POPULATION, INDEPENDENTLY OF AGE, SEX, AND BMI (95% CI 1.11.5, P=0.008). THE GHD POPULATION SHOWED A DIFFERENT METABOLIC PROFILE THAN THE GENERAL POPULATION WITH SIMILAR BMI: an increased risk of hypertriglyceridemia (adjusted prevalence ratio (PR) 2.0, 95% CI 1.7-2.3) and low HDL-C (adjusted PR 1.8, 95% CI 1.5-2.2), but less hyperglycemia (adjusted PR 0.5, 95% CI 0.4-0.7). CONCLUSIONS: Despite 5 years of rhGH replacement, GHD patients still have a different metabolic profile and more frequently MS than the general population. These differences were independent of BMI, and resemble the unfavorable metabolic profile of untreated GHD patients, pointing to question the long-term benefits of rhGH replacement.

Relationship between the functional exon 3 deleted growth hormone receptor polymorphism and symptomatic osteoarthritis in women.

BACKGROUND: Several studies suggest a role of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity. OBJECTIVE: To study associations between the d3-GHR polymorphism and symptomatic OA. METHODS: In the GARP (Genetics, osteoARthritis and Progression) study, we compared the d3-GHR polymorphism between OA patients and controls. GARP patients were genotyped for seven single nucleotide polymorphisms encompassing the d3-GHR gene, using rs4590183 as proxy for d3-GHR (pairwise r(2)=1). Binary logistic regression models with robust SEs were performed, stratified by sex. For replication, rs4590183 was tested in three additional cohorts. Fixed- and random-effects combined analyses were performed. RESULTS: In female GARP patients with severe familial OA, d3-GHR was associated with OA (adjusted OR 1.36 (95% CI 1.01 to 1.83), p=0.043), independently of age and body mass index. Combined analysis of all studies showed suggestive evidence for association between d3-GHR and OA (OR=1.17 (95% CI 1.04 to 1.30), p=0.008). Evidence was strongest in hip OA cases, without any evidence for heterogeneity. CONCLUSIONS: In women, the d3-GHR polymorphism was associated with symptomatic OA, especially at the hip site.

Increased clinical symptoms of acromegalic arthropathy in patients with long-term disease control: a prospective follow-up study.

Arthropathy is an invalidating complication of acromegaly. This arthropathy deteriorates radiographically despite long-term disease control. However, the clinical course and its relationship to the radiographic course are currently unknown. We aimed to investigate the clinical course of arthropathy during follow-up and its relationship to radiographic progression in long-term controlled acromegaly patients. Prospective follow-up study. We studied 58 patients (mean age 62 years, women 41 %) with controlled acromegaly for a mean of 17.6 years. Clinical progression of joint disease was defined at baseline and after 2.6 years, by the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and Australian/Canadian Osteoarthritis Index (AUSCAN) questionnaires for lower limb and hand OA, respectively, and performance tests. Potential risk factors for progression were assessed. The clinical course of arthropathy was related to the radiographic course. On average, hand and lower limb function deteriorated during follow-up, despite large interindividual variations. Joint pain was stable over time. High levels of pain and functional impairment at baseline were related to clinical progression of hand pain and functional limitations. High baseline BMI was a risk factor for functional deterioration in the lower limb. The changes in symptoms and radiographic progression during follow-up were not related. In treated acromegaly patients, joint function deteriorates during prolonged follow-up, despite biochemical disease control, although there was interindividual variation. Clinical and radiographic course of arthropathy were not related. Therefore, in clinical practice, a combination of clinical and radiographic assessment is necessary to evaluate the course of acromegalic arthropathy.

Progression of vertebral fractures despite long-term biochemical control of acromegaly: a prospective follow-up study.

BACKGROUND: In active acromegaly, pathologically elevated GH and IGF-1 levels are associated with increased bone turnover and a high bone mass, the latter being sustained after normalization of GH values. In a cross-sectional study design, we have previously reported a high prevalence of vertebral fractures (VFs) of about 60% in patients with controlled acromegaly, despite normal mean bone mineral density (BMD) values. Whether these fractures occur during the active acromegaly phase or after remission is achieved is not known. OBJECTIVE: Our objective was to study the natural progression of VFs and contributing risk factors in patients with controlled acromegaly over a 2.5-year follow-up period. METHODS: Forty-nine patients (mean age 61.3 ± 11.1 years, 37% female) with controlled acromegaly for ≥ 2 years after surgery, irradiation, and/or medical therapy and not using bisphosphonates were included in the study. Conventional spine radiographs including vertebrae Th4-L4 were assessed for VFs according to the Genant method. VF progression was defined as development of new/incident fractures and/or a minimum 1-point increase in the Genant scoring of preexisting VFs. BMD was assessed by dual-energy x-ray absorptiometry (Hologic 4500). RESULTS: Prevalence of baseline VFs was 63%, being highest in men, and fractures were unrelated to baseline BMD. VF progression was documented in 20% of patients, especially in men and in case of ≥ 2 VFs at baseline. VF progression was not related to BMD values or BMD changes over time. CONCLUSION: Findings from this longitudinal study show that VFs progress in the long term in 20% of patients with biochemically controlled acromegaly in the absence of osteoporosis or osteopenia. These data suggest that an abnormal bone quality persists in these patients after remission, possibly related to pretreatment long-term exposure to high circulating levels of GH.

Two phenotypes of arthropathy in long-term controlled acromegaly? A comparison between patients with and without joint space narrowing (JSN).

BACKGROUND: Arthropathy is an invalidating complication of acromegaly, also in long-term controlled patients, and is radiographically characterized by osteophytes and preserved joint spaces. However, joint space narrowing (JSN) is observed in the minority of patients. It is unknown whether JSN is the end-stage of acromegalic arthropathy or whether this feature develops independently of acromegaly. OBJECTIVE: To gain insight into the pathophysiology of acromegalic arthropathy, and, more specifically, in the process of JSN, risk factors for radiographic JSN were studied in a cross-sectional study. METHODS: We studied hips and knees of 89 well-controlled acromegaly patients (mean age 58.3 yr, 51% female). Joints were divided into two groups based on the presence of JSN, defined as an Osteoarthritis Research Society (OARSI) score ≥ 1. Potential risk factors for JSN were assessed, and its relationship to joint complaints. Individual knees and hips were analyzed in a Generalized Estimating Equations model, adjusted for age, sex, BMI and intra-patient effect. RESULTS: In controlled acromegaly, JSN was found in, respectively, 10.3% and 15.4% of the hips and knees. Increasing age and female sex were associated with more JSN; acromegaly-specific risk factors for JSN were joint-site specific. In the hip, JSN was related to more active disease: higher pre-treatment GH/IGF-1, longer and more severe GH exposure and immediate postoperative cure was less frequently achieved. In the knee, especially previous knee surgery, not acromegaly-specific characteristics, was associated with JSN. The presence of JSN was associated with more joint complaints. CONCLUSIONS: JSN is an infrequent finding in patients with acromegalic arthropathy, but it is associated with more symptoms. This study indicates that, at least in the hip, early and ongoing GH/IGF-1 activity play a role in JSN development.

Progression of acromegalic arthropathy despite long-term biochemical control: a prospective, radiological study.

OBJECTIVE: Arthropathy is an invalidating complication of acromegaly, of which the prognosis and determinants are currently unknown in treated acromegaly. Therefore, the objective of the present study was to investigate the radiographic progression of arthropathy over a mean follow-up period of 2.6 years and determinants of outcome in patients with long-term, well-controlled acromegaly. DESIGN: Prospective follow-up study. METHODS: In a prospective cohort study we studied 58 patients (mean age 62, women 41%) with controlled acromegaly for a mean of 17.6 years. Radiographic progression of joint disease was defined by the Osteoarthritis Research Society International classification as a 1-point increase in joint space narrowing (JSN) or osteophyte scores on radiographs of the hands, knees, and hips obtained at the first study visit and after 2.6 years. Potential risk factors for progression were assessed. RESULTS: Progression of osteophytes and JSN was observed in 72 and 74% of patients respectively. Higher age predisposed for osteophyte progression. Patients with biochemical control by somatostatin (SMS) analogs had more progression of osteophytosis than surgically cured patients (odds ratio=18.9, P=0.025), independent of age, sex, BMI, baseline IGF1 SDS and exon 3 deletion of the GHR. This was also evident for JSN progression, as were higher age and higher baseline IGF1 SDS. CONCLUSIONS: Acromegalic patients have progressive JSN and osteophytosis, despite long-term biochemical control. Parameters reflecting GH/IGF1 activity were associated with progressive joint disease. Remarkably, biochemical control by SMS analogs was associated with more progression than surgical cure. Although the present study is not a randomized controlled trial, this may indicate insufficient GH control according to current criteria and the need for more aggressive therapy.

Automated image analysis of hand radiographs reveals widened joint spaces in patients with long-term control of acromegaly: relation to disease activity and symptoms.

OBJECTIVE: Arthropathy is an invalidating complication of acromegaly. Although acromegalic arthropathy shares features with primary osteoarthritis, joint spaces are widened rather than narrowed in patients with long-term cure of acromegaly. The late effects of acromegaly on hand joints have not been characterized. Therefore, the objective of the current study was to assess joint space widths (JSWs) of hand joints in patients with long-term control of acromegaly and to identify factors associated with JSW. METHODS: A cross-sectional study was carried out in 89 patients (age 58 ± 12 years, 49% women) with long-term controlled acromegaly and 471 controls without hand symptoms (age 46 ± 12 years, 42% women). Radiological JSWs of individual hand joints were measured by automated image analysis. RESULTS: Patients had wider mean joint spaces than controls: metacarpo-phalangeal (MCP) joints were ~24%, proximal interphalangeal joints ~21%, and distal interphalangeal joints were ~20% wider (patients vs controls; P < 0.001 for all joints). Mean JSW exceeded the 95th percentile of the values obtained in controls in 64% of patients. Higher IGF1 and GH concentrations at diagnosis were associated with larger JSWs (adjusted ß for pretreatment GH in tertiles: 0.09 (95% confidence interval (CI) 0.03-1.84) and for IGF1 in tertiles: 0.14 (95% CI 0.05-0.23) at the MCP joints in acromegalic patients. In male patients, but not in female patients, increased JSWs were associated with more self-reported pain (P = 0.02). CONCLUSIONS: Using a new semi-automated image analysis of hand radiographs, acromegalic patients with long-term disease control appeared to have increased joint spaces of all hand joints. JSWs were positively related to disease activity at diagnosis, but not to duration of follow-up, suggesting irreversible cartilage hypertrophy. Irreversible cartilage hypertrophy may partly explain persisting hand complaints despite long-term disease control.

Relationship between insulin-like growth factor-1 and radiographic disease in patients with primary osteoarthritis: a systematic review.

OBJECTIVE: To evaluate the association between radiographic osteoarthritis (OA) and either serum insulin-like growth factor-1 (IGF-1) levels or IGF-1 gene polymorphisms in patients with primary OA. METHODS: We conducted a systematic review of reported associations between circulating IGF-1 and/or IGF-1 gene polymorphisms and radiographic OA. Studies were eligible when: (1) investigating serum IGF-1 and/or IGF-1 gene polymorphisms in relation to prevalent or incident radiographic OA; (2) written in English; (3) full-text article or abstract; (4) patients had primary OA in knee, hip, hand or spine; (5) longitudinal, case-control or cross-sectional design. Quality assessment was done using a standardized criteria set. Best-evidence synthesis was performed based on guidelines on systematic review from the Cochrane Collaboration Back Review Group, using five evidence levels: strong, moderate, limited, conflicting and no evidence. RESULTS: We included 11 studies with more than 3000 primary OA cases. Data on the relationship between serum IGF-1 and radiographic OA were inconsistent. Adjustment for body mass index (BMI) was often omitted. Of four high-quality studies, three studies reported no association, one study found significantly higher IGF-1 levels in OA patients compared to controls. Patients with IGF-1 gene promoter polymorphisms and a genetic variation at the IGF-1R locus had an increased OA prevalence compared to controls. CONCLUSIONS: Observational data showed no association between serum IGF-1 and occurrence of radiographic OA (moderate level of evidence), and a positive relationship between IGF-1 gene polymorphisms and radiographic OA (moderate level of evidence); however the confounding effect of BMI was insufficiently addressed. Future well-designed prospective studies should further elaborate the role of the complex GH/IGF-1 system in primary OA.