Liner type has no impact on bone mineral density changes around a 3D printed trabecular titanium acetabular component.

BACKGROUND: Three-dimensional printing of implants allows the ability to produce implants and interfaces which theoretically better mimic "normal" bone behaviour, leading to a possible reduction in stress shielding thus maintaining bone mineral density (BMD). This issue was not investigated in vivo using bone scan and different bearings; therefore, we did a prospective study aiming to answer: 1) is there a loss of BMD around the 3D printed trabecular titanium cup, when compared to the native hip?; 2) does liner type influence the BMD changes around the acetabulum when a 3D printed trabecular titanium cup is used? HYPOTHESIS: BMD changes around the acetabulum are not influenced by the liner type, and the cup will be associated with a reduction in BMD when compared to the native hip. MATERIAL AND METHODS: This is a prospective observational study of patients receiving a primary total hip arthroplasty. A 3D printed trabecular titanium uncemented acetabular component was used in all cases. All patients received a ceramic femoral head, with either a ceramic or polyethylene acetabular liner. BMD measurements using DXA were performed at 6 weeks, 6, 12 and 24 months after surgery to evaluate remodeling changes. The 3 acetabular regions of interest (ROI) of DeLee and Charnley were used for serial comparisons of peri-acetabular BMD. The study was powered as a non-inferiority study with the principle variables compared using a two-step repeated analysis of variance. RESULTS: A total of 48 consecutive patients were included in the study, with all patients completing their 2 year follow-up. There were no failures, revisions or complications within this cohort. We found no statistically significant difference in the BMD change scores between the operated and the native hip in any of the 3 ROI zones. We found no differences in BMD scores when comparing ceramic to polyethylene acetabular liners, head sizes and BMI. DISCUSSION: This study shows a similar pattern of BMD behaviour around a 3D printed cup when compared to the contralateral native hip. We were unable to show a clinical or radiological difference between the bearing material, head size, or BMI when used with this type of acetabular component. LEVEL OF EVIDENCE: III; prospective comparative study.

An unusual case of Cushing's syndrome due to bihormonal ACTH-prolactin secreting pituitary macroadenoma with rapid response to cabergoline.

A 23-year-old man presenting with florid Cushing's syndrome was found to have high plasma ACTH and very high serum prolactin. Pituitary MRI showed a large invasive macroadenoma. Low-dose cabergoline promptly suppressed both ACTH and prolactin levels within 2 weeks, with unexpected clinical and biochemical hypocortisolism requiring hydrocortisone replacement. Secondary hypogonadism was reversed. Clinical and biochemical remission of his Cushing's syndrome together with significant shrinkage of his macroadenoma has been maintained for 1 year on cabergoline 0.5 mg twice weekly. Reduction in pituitary tumour volume and brisk fall in serum prolactin in response to low-dose cabergoline is regularly observed in patients with macroprolactinomas, but the concurrent fall in the plasma ACTH level and hypocortisolism was a pleasant surprise. We assume that he most likely has a single bihormonal adenoma that is enriched with dopamine-2 receptors.

Mortality in patients with Cushing's disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study.

BACKGROUND: No agreement has been reached on the long-term survival prospects for patients with Cushing's disease. We studied life expectancy in patients who had received curative treatment and whose hypercortisolism remained in remission for more than 10 years, and identified factors determining their survival. METHODS: We did a multicentre, multinational, retrospective cohort study using individual case records from specialist referral centres in the UK, Denmark, the Netherlands, and New Zealand. Inclusion criteria for participants, who had all been in studies reported previously in peer-reviewed publications, were diagnosis and treatment of Cushing's disease, being cured of hypercortisolism for a minimum of 10 years at study entry, and continuing to be cured with no relapses until the database was frozen or death. We identified the number and type of treatments used to achieve cure, and used mortality as our primary endpoint. We compared mortality rates between patients with Cushing's disease and the general population, and expressed them as standardised mortality ratios (SMRs). We analysed survival data with multivariate analysis (Cox regression) with no corrections for multiple testing. FINDINGS: The census dates on which the data were frozen ranged from Dec 31, 2009, to Dec 1, 2014. We obtained data for 320 patients with 3790 person-years of follow-up from 10 years after cure (female:male ratio of 3:1). The median patient follow-up was 11·8 years (IQR 17-26) from study entry and did not differ between countries. There were no significant differences in demographic characteristics, duration of follow-up, comorbidities, treatment number, or type of treatment between women and men, so we pooled data from both sexes for survival analysis. 51 (16%) of the cohort died during follow-up from study entry (10 years after cure). Median survival from study entry was similar for women (31 years; IQR 19-38) and men (28 years; 24-42), and about 40 years (IQR 30-48) from remission. The overall SMR for all-cause mortality was 1·61 (95% CI 1·23-2·12; p=0·0001). The SMR for circulatory disease was increased at 2·72 (1·88-3·95; p<0·0001), but deaths from cancer were not higher than expected (0·79, 0·41-1·51). Presence of diabetes, but not hypertension, was an independent risk factor for mortality (hazard ratio 2·82, 95% CI 1·29-6·17; p=0·0095). We noted a step-wise reduction in survival with increasing number of treatments. Patients cured by pituitary surgery alone had long-term survival similar to that of the general population (SMR 0·95, 95% CI 0·58-1·55) compared with those who were not (2·53, 1·82-3·53; p<0·0001). INTERPRETATION: Patients with Cushing's disease who have been in remission for more than 10 years are at increased risk of overall mortality compared with the general population, particularly from circulatory disease. However, median survival from cure is excellent at about 40 years of remission. Treatment complexity and an increased number of treatments, reflecting disease that is more difficult to control, appears to negatively affect survival. Pituitary surgery alone is the preferred treatment to secure an optimum outcome, and should be done in a centre of surgical excellence. FUNDING: None.

Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients.

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

Is IGSF1 involved in human pituitary tumor formation?

IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.

Late primary autoimmune hypothyroidism in a patient with postdelivery autoimmune hypopituitarism associated with antibodies to growth hormone and prolactin-secreting cells.

BACKGROUND: Pituitary and thyroid autoimmunity can be triggered by pregnancy. We report the first association of combined growth hormone (GH) and prolactin secretion deficiency due to autoimmune damage to GH- and prolactin-secreting cells in a patient with postdelivery lactation failure, presenting subsequently with primary autoimmune hypothyroidism. PATIENT FINDINGS: A 34-year-old woman presented with lactation failure following the delivery of her first child. She had a family history of hypothyroidism without a history of pituitary dysfunction. Physical examination did not show any abnormal findings. Laboratory investigations showed normal gonadotropin levels after the restoration of normal menstrual cycles following pregnancy, normal basal and stimulated cortisol levels, but an impaired GH response to insulin-induced hypoglycemia, and low basal prolactin and insulin-like growth factor-1 concentrations. Thyroid function was normal when initially investigated three months after delivery, but five months later, marked primary hypothyroidism (thyrotropin levels >100 mIU/L) occurred. Immunological investigation revealed the presence of antipituitary antibodies, identified by double immunofluorescence and targeting GH- and prolactin-secreting cells. Antithyroid antibodies, in the normal range three months postpartum, became significantly elevated when the hypothyroidism appeared. Autoimmune hypophysitis is responsible for selective or multiple pituitary-hormone deficiencies, sometimes involving thyrotropin secretion and causing secondary hypothyroidism, but usually associated with hyperprolactinemia. To our knowledge, this is the first observation of autoimmune hypopituitarism involving deficient growth hormone and prolactin secretion in a patient with lactation failure after delivery, subsequently followed by severe primary autoimmune hypothyroidism, thus falling into an unusual constellation of autoimmune polyendocrine syndrome type 3. CONCLUSIONS: Considering the well-known relationship between pregnancy and autoimmunity, an early postdelivery immunological and functional investigation in women presenting with disorders of lactation may be useful to detect potential pituitary and thyroid dysfunction even at a subclinical stage.

Pioglitazone in acromegaly - an open-label, prospective study.

OBJECTIVE: Preclinical studies demonstrate that thiazolidinediones (TZDs) decrease growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, suggesting that they might be effective treatments for acromegaly. This study investigated the effect of pioglitazone on biochemical indices of disease activity in acromegaly. DESIGN AND PARTICIPANTS: This was a 4-month open-label prospective study in 16 patients with active acromegaly who were attending public hospital endocrinology clinics. METHODS: The intervention was pioglitazone 45 mg/day. The primary outcome was change in serum IGF-1; the secondary outcome was change in area under the curve of glucose-suppressed GH. RESULTS: Serum IGF-1 did not change during treatment with pioglitazone (P = 0·95). After 4 months, the mean (95% CI) change from baseline was -1 µg/l (-51, 49). GH levels following oral glucose loading were unchanged during pioglitazone therapy. After 4 months, the mean (95% CI) change from baseline in area under curve for glucose-suppressed GH was 31 µg/l (-75, 138, P = 0·54). CONCLUSIONS: Short-term treatment with conventional doses of pioglitazone did not improve biochemical measures of disease activity in acromegaly.

Unmasking of undiagnosed pre-existing central diabetes insipidus after renal transplantation.

Acquired central diabetes insipidus (CDI) often occurs abruptly after a cranial event causing hypothalamic or pituitary damage. We present a case of a patient with pre-existing and clinically unapparent CDI which was unmasked after renal transplantation. A 60 year old woman with end-stage renal failure due to autosomal dominant polycystic kidney disease (ADPKD) underwent renal transplantation. She was noted to be markedly polyuric and polydipsic after the transplant. A fluid deprivation test was unequivocally positive for CDI, and desmopressin treatment resulted in immediate symptom relief. Neuroimaging revealed a midline defect in the region of the hypothalamus. She had a history of an intracerebral aneurysm that had ruptured, requiring extensive neurosurgery many years previously. This case demonstrates a rare instance of pre-existing but clinically unapparent CDI unmasked by renal transplantation. It is likely that renal failure due to ADPKD disguised her CDI prior to transplantation. A previous intracerebral insult from an aneurysmal bleed is the likely cause of her vasopressin deficiency.

Mortality and morbidity in Cushing's syndrome in New Zealand.

OBJECTIVE: Untreated Cushing's syndrome (CS) is associated with significant morbidity and mortality. However, recent operative series suggest low morbidity and mortality for CS, whereas population-based surveys report elevated mortality rates. We investigated the mortality and morbidity of CS in New Zealand. DESIGN: A nationwide retrospective survey of patients with CS between 1960 and 2005 managed at the four main endocrinology services. PATIENTS: A total of 253 patients with CS were identified, excluding adrenal carcinoma and malignant ectopic CS. MEASUREMENTS; The primary outcome was the standardized mortality ratio (SMR), comparing the observed number of deaths with the expected number for the population matched for age, sex and duration of follow-up. Secondary outcomes were the change in prevalence of co-morbidities at presentation and at final follow-up. RESULTS: The approximate prevalence and incidence of CS was 79/million and 1·8/million/y. The mean age at presentation was 39 year, and median duration of follow-up was 6·4 year (range 0-46). Overall, 89% achieved biochemical cure at last follow-up, with >90% achieving biochemical cure for CS from adrenal adenoma and pituitary causes. Thirty-six patients died during follow-up compared with 8·8 expected deaths (SMR 4·1, 95%CI 2·9-5·6). While hypertension, sexual dysfunction, myopathy and mild psychiatric illness were significantly reduced after treatment, hypertension, diabetes mellitus, moderate or major psychiatric illness, and osteoporosis were common at final follow-up. CONCLUSION: CS is associated with both high mortality and a high prevalence of co-morbidities, even when biochemical cure rates are between 80% and 90%.

Aggressive pituitary adenomas occurring in young patients in a large Polynesian kindred with a germline R271W mutation in the AIP gene.

OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) were recently shown to confer a pituitary adenoma predisposition in patients with familial isolated pituitary adenomas (FIPA). We report a large Samoan FIPA kindred from Australia/New Zealand with an R271W mutation that was associated with aggressive pituitary tumors. DESIGN AND METHODS: Case series with germline screening of AIP and haplotype analyses among R271W families. RESULTS: This previously unreported kindred consisted of three affected individuals that either presented with or had first symptoms of a pituitary macroadenoma in late childhood or adolescence. The index case, a 15-year-old male with incipient gigantism and his maternal aunt, had somatotropinomas, and the maternal uncle of the index case had a prolactinoma. All tumors were large (15, 40, and 60 mm maximum diameter) and two required transcranial surgery and radiotherapy. All three affected subjects and ten other unaffected relatives were found to be positive for a germline R271W AIP mutation. Comparison of the single nucleotide polymorphism patterns among this family and two previously reported European FIPA families with the same R271W mutation demonstrated no common ancestry. CONCLUSIONS: This kindred exemplifies the aggressive features of pituitary adenomas associated with AIP mutations, while genetic analyses among three R271W FIPA families indicate that R271W represents a mutational hotspot that should be studied further in functional studies.

Occult nasal sinus tumours causing oncogenic osteomalacia.

Oncogenic osteomalacia (OOM) is a rare but curable cause of metabolic bone disease. We report 9 patients with OOM, including 2 patients with occult nasal sinus tumours and 1 in whom a progressive increase in the post-operative FGF23 level heralded the development of metastatic pulmonary disease. The median duration of symptoms before definitive surgical treatment was 6 years, and in one patient was more than 10 years. This series demonstrates that careful imaging of the nasal sinuses should be part of the work-up of cases of oncogenic osteomalacia, that serum FGF23 can be helpful in both diagnosis and monitoring treatment outcomes, and emphasizes that serum phosphate should be measured in patients with metabolic bone disease and/or unexplained musculoskeletal symptoms.

Variable presentation of post-traumatic hypopituitarism.

Post-traumatic hypopituitarism (PTHP) is defined as pituitary hormonal deficiency occurring after head injury. PTHP has recently been increasingly recognised as an important medical condition among survivors of head trauma. It can be fatal if undiagnosed, and may contribute to the morbidity and mortality associated with traumatic brain injury (TBI). Although about 75% of PTHP cases are diagnosed within a year of TBI,1 delayed development of PTHP can also occur.

Treatment of acromegaly.

Mortality is increased in individuals with acromegaly unless serum growth hormone (GH) levels are below 2 microg/l and serum insulin-like growth factor (IGF)-I levels are normal following treatment. These combined criteria have been used to define remission of the disorder in this review. Transsphenoidal surgery achieves remission targets in an average of 55% of patients. For those not in remission following surgery, options include repeat surgery or use of adjuvant therapy. Fractionated external beam pituitary radiotherapy achieves 10-year remission rates of 47% but leaves patients exposed to excess GH until remission occurs. Stereotactic radiotherapy and gamma knife radiosurgery achieve remission rates of 40% over 3 years, and dopamine agonists produce remission in about 20% of patients. Somatostatin analogues induce remission in 59% of patients within the first year of treatment. The GH receptor antagonist pegvisomant leads to remission in 90% of patients, using IGF-I levels for assessment. Optimal treatment for a patient with acromegaly thus depends on the likely efficacy of treatment, cost, surgical skill, severity of side effects, tolerability, control of tumour growth, and improvement in complications related to tumour mass. A primary surgical approach, followed by medical therapy for those not in remission, remains the preferred option in most centres.

Factors influencing mortality in acromegaly.

Studies of acromegaly have shown a doubling of mortality compared with the general population. With the development of new modalities of treatment, it has become important to identify prognostic factors relating to mortality. Between 1964 and 2000, 208 acromegalic patients were followed for a mean of 13 yr at Auckland Hospital. Treatment was by surgery or radionuclide pituitary implantation, and all except 27 patients received pituitary radiation. Over the duration of the study, 72 patients died at a mean age of 61 +/- 12.8 yr. Those dying were significantly older at diagnosis, had a higher prevalence of hypertension and diabetes, and were more likely to have hypopituitarism. The observed to expected mortality ratio (O/E ratio) fell from 2.6 (95% confidence interval, 1.9-3.6) in those with last follow-up GH greater than 5 microg/liter to 2.5 (1.6-3.8), 1.6 (0.9-3), and 1.1 (0.5-2.1) for those with GH less than 5, less than 2, and less than 1 microg/liter, respectively (P < 0.001). Serum IGF-I, expressed as an SD score, was significantly associated with mortality, with O/E mortality ratios of 3.5 (95% confidence interval, 2.8-4.2) for those with an SD score greater than 2, 1.6 (0.6-2.6) for those with an SD score less than 2 (normal or low levels), and 1.0 (0.1-3) for those with an SD score less than zero. When assessed by multivariate analysis, last serum GH (P < 0.001), age, duration of symptoms before diagnosis (P < 0.03), and hypertension (P < 0.04) were independent predictors of survival. If IGF-I was substituted for GH, then survival was independently related to last IGF-I SD score (P < 0.02), indicating that GH and IGF-I act equivalently as predictors of mortality. These findings indicate that reduction of GH to less than 1 microg/liter or normalization of serum IGF-I reduces mortality to expected levels.

Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome.

The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. The C-terminal zinc finger (ZnF2) binds DNA, whereas the N-terminal finger (ZnF1) stabilizes this DNA binding and interacts with other zinc finger proteins, such as the Friends of GATA (FOG). We have investigated seven HDR probands and their families for GATA3 abnormalities and have identified two nonsense mutations (Glu-228 --> Stop and Arg-367 --> Stop); two intragenic deletions that result in frameshifts from codons 201 and 355 with premature terminations at codons 205 and 370, respectively; one acceptor splice site mutation that leads to a frameshift from codon 351 and a premature termination at codon 367; and two missense mutations (Cys-318 --> Arg and Asn-320 --> Lys). The functional effects of these mutations, together with a previously reported GATA3 ZnF1 mutation and seven other engineered ZnF1 mutations, were assessed by electrophoretic mobility shift, dissociation, yeast two-hybrid and glutathione S-transferase pull-down assays. Mutations involving GATA3 ZnF2 or adjacent basic amino acids resulted in a loss of DNA binding, but those of ZnF1 either lead to a loss of interaction with specific FOG2 ZnFs or altered DNA-binding affinity. These findings are consistent with the proposed three-dimensional model of ZnF1, which has separate DNA and protein binding surfaces. Thus, our results, which expand the spectrum of HDR-associated GATA3 mutations and report the first acceptor splice site mutation, help to elucidate the molecular mechanisms that alter the function of this zinc finger transcription factor and its role in causing this developmental anomaly.

Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 following chemotherapy for advanced breast cancer.

BACKGROUND: Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) appear to influence the growth of breast cancer cells in vitro, and epidemiological studies suggest higher serum IGF-I levels increase the risk of breast cancer. IGF-I and IGFBP-3 have therefore been measured in women with advanced breast cancer to determine if changes in serum levels predict the response to treatment by chemotherapy. METHODS: Serum IGF-I and IGFBP-3 levels were measured in 14 patients before and after 1 week of chemotherapy. Changes in serum levels were compared with duration of survival. RESULTS: Mean basal serum levels of IGF-I and IGFBP-3 were not significantly different between patients with advanced breast cancer and controls or women with early breast cancer. Serum IGFBP-3 fell significantly 1 week after initiation of chemotherapy. Patient survival was not significantly related to baseline IGF-I or IGFBP-3 levels, but when the fall in serum levels 1 week after starting treatment was expressed either as absolute change or as a percentage of baseline, those individuals with a decrease in IGFBP-3 greater than the median had significantly poorer survival (median survival 5.5 months vs 18 months). These results were independent of other prognostic variables such as previous disease-free survival, and were also unaffected by the change in serum albumin with treatment. The fall in IGF-I and IGFBP-3 with chemotherapy mainly occurred in those with hepatic metastases, but prediction of survival was explained solely by the extent of the fall in IGFBP-3. CONCLUSIONS: This preliminary study has shown that serum IGFBP-3 falls significantly following initiation of chemotherapy and the extent of reduction significantly predicts the response to treatment.

Melanocortin-3 receptor gene variants in a Maori kindred with obesity and early onset type 2 diabetes.

Genetic studies suggest a diabetes susceptibility locus on human chromosome 20, near the melanocortin receptor-3 (MC3-R) gene. We examined the MC3-R as a candidate gene for type 2 diabetes in 12 members of a large Maori kindred with multiple affected members. The coding region of the MC3-R gene was sequenced for both diabetic and non-diabetic individuals. Two separate single base pair substitutions were found in the MC3-R coding sequence and these resulted in amino acid changes, Lysine6Threonine and Isoleucine81Valine. Neither of these MC3-R variants tracked with the presence of diabetes. Furthermore, the variant and wild type MC3-R showed similar functional coupling to adenylyl cyclase. A polymorphic marker (D20S32e) close to the human MC3-R (hMC3-R) coding sequence was investigated in a 60-member pedigree for association with diabetes and other metabolic parameters. There was an association between D20S32e genotype and fasting insulin (P=0.0085) and the insulin resistance index, HOMA-R (P=0.0042). An association was also found between genotype and HDL levels during oral glucose tolerance testing (P=0.0037). These associations were independent of BMI, age, gender and diabetes. Our data do not support a role for variations in the coding region of the hMC3-R in the development of type 2 diabetes in this Maori kindred, but suggest that a locus on chromosome 20 q, close to D20S32e, may contribute to both insulin secretion and action in the Maori kindred.