Risk assessment for aortic dissection in Turner syndrome: The role of the aortic growth rate.

OBJECTIVE: The risk of aortic dissection (AoD) is increased in Turner syndrome (TS) but predicting those at risk is difficult. Based on scarce evidence, preventive aortic surgery is recommended when aortic diameter increases >5 mm/year. To investigate the aortic growth rate in TS and TS-related conditions associated with aortic growth. We also reported our experience of women who suffered aortic dissection (AoD), and who had preventive aortic replacement. METHODS: 151 adult TS were retrospectively identified. Women who had more than one transthoracic echocardiogram (TTE) after age 16 years were included in the aortic growth study. Aortic diameters at sinuses of Valsalva (SoV) and ascending aorta (AA) were analysed by two experts. RESULTS: 70/151 women had more than one TTE (interscan interval 4.7 years). Mean aortic growth was 0.13 ± 0.59 mm/year at SoV and 0.23 ± 0.82 mm/year at AA. Known risk factors for aortic dilatation and TS-related conditions were not associated with aortic growth. 4/151 women experienced AoD (age 25±8 years): two had paired scans for aortic growth, which was 0.67 mm/year at both SoV and AA in the first woman, and 11 mm/year (SoV) and 4 mm/year (AA) in the second. Only 1/4 of women with AoD survived; she used a TS cardiac-alert card to inform emergency personnel about her risk of AoD. 5/151 had a preventive aortic replacement, but one died post-operatively. CONCLUSIONS: Mean aortic growth in our TS population was increased compared to non-TS women and was not associated with currently known risk factors for AoD, suggesting that aortic growth rate itself could be a useful variable to stratify who is at risk for AoD.

Analysis of a streamlined pathway for aortic surveillance for Turner syndrome in a single centre.

BACKGROUND AND OBJECTIVE: The risk of aortic dissection (AoD) is increased in women with Turner syndrome (TS) but predicting those with this heightened risk is difficult. In response to this, we sought to create a pathway to monitor TS patients to improve efficiency and resource utilisation in our dedicated TS clinic, and to monitor more closely those women thought to be at increased risk of AoD. DESIGN AND PATIENTS: Our pathway was designed based on evidence derived from International Guidelines for the management of aortic disease in women with TS. Women were divided according to those with known risk factors for AoD, and those with no known risk factors. These groups were further subdivided into 4 pathways depending on ascending aortic size which in-turn determined the frequency of outpatient appointments and imaging. RESULTS: Out of the 168 patients included in the analysis, 7 have had ascending aorta replacements, all in the highest risk group. Of the remaining 4 patients in the highest risk groups: 1 dissected whilst awaiting planned aortic surgery, 1 is currently awaiting surgery, 1 has low body mass index, therefore, making her aorta proportionally larger but not necessitating surgery and one has declined surgery. No women changed pathways. CONCLUSION: The risk-stratified pathway safely allowed consolidation of resources to women perceived to be at highest risk of AoD (excluding pregnancy), supporting the efficacy of the pathway and allowing the diversion of resources to those most at risk of AoD.

Tumour occurrence in women with Turner syndrome: A narrative review and single-centre case series.

BACKGROUND: Population studies suggest cancer morbidity may be different in Turner syndrome (TS) compared to the background female population. However, significant variability is observed in cancer associations likely due to heterogeneity in patient cohorts. We explored the prevalence and patterns of cancer amongst a cohort of women with TS attending a dedicated TS clinic. METHODS: Retrospective analysis of the patient database was performed to identify TS women who developed cancer. Population data (available before 2015) from the National Cancer Registration and Analysis Service database were used for comparison. RESULTS: Out of 156 TS women, median age of 32 (range 18-73) years, 9 (5.8%) had a recorded cancer diagnosis. Types of cancers were, bilateral gonadoblastoma, type 1 gastric neuroendocrine tumour (NET), appendiceal-NET, gastrointestinal stromal tumour, plasma cell dyscrasia, synovial sarcoma, cervical cancer, medulloblastoma and aplastic anaemia. Median age at cancer diagnosis was 35 (range 7-58) years and two were detected incidentally. Five women had 45,X karyotype, three received growth hormone treatment and all except one received oestrogen replacement therapy. The cancer prevalence of the background age-matched female population was 4.4%. CONCLUSIONS: We confirm the previous observations that women with TS do not appear to be at overall increased risk of common malignancies. Our small cohort showed a spectrum of rare malignancies that are not typically associated with TS, except for a single patient with a gonadoblastoma. The slightly higher prevalence of cancer in our cohort might simply represent increased cancer prevalence in the background population, or might be related to small sample size and regular monitoring of these women due to TS per se.

Society for Endocrinology UK Guidance on the initial evaluation of a suspected difference or disorder of sex development (Revised 2021).

It is paramount that any child or adolescent with a suspected difference or disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD and is discussed with the regional DSD service. In most cases, the paediatric endocrinologist within this service acts as the first point of contact but involvement of the regional multidisciplinary service will also ensure prompt access to specialist psychology and nursing care. The underlying pathophysiology of DSD and the process of delineating this should be discussed with the parents and affected young person with all diagnostic tests undertaken in a timely fashion. Finally, for rare conditions such as these, it is imperative that clinical experience is shared through national and international clinical and research collaborations.

Early low-dose rituximab for active thyroid eye disease: An effective and well-tolerated treatment.

BACKGROUND: Thyroid eye disease (TED) is an autoimmune inflammatory disease that can be disfiguring and potentially sight threatening. Suppression of inflammation in active disease can reduce the risk of visual loss and limit long-term sequelae. Current management involves inflammation suppression using glucocorticoids. The aim of this study was to evaluate the efficacy of early disease intervention with targeted immunomodulatory therapy to alter disease course. This paper reports the efficacy of low-dose rituximab in reducing clinical activity in TED in a small population. METHODS: A retrospective audit of consecutive patients with active TED managed primarily with a 100 mg rituximab infusion. Further glucocorticoid or steroid-sparing agents were prescribed if clinically indicated. Clinical activity score, VISA overall severity score and Oxford Quality of Life score were recorded at each visit as well as TSH receptor antibody levels (TRAb), B cell subsets and adverse reactions. RESULTS: Twelve patients had mean follow-up of 6.3 months. Clinical activity scores significantly decreased (mean score 5.08 to 1.58; P < 0.001), VISA overall severity scores reduced by 50% from 12 to 6, P < 0.001 and the mean cumulative dose of IV methylprednisolone was 2.3 g. 100 mg rituximab induced significant CD19+ B cell depletion (n = 8, P < 0.001). There was no significant reduction in serum TRAb (n = 8, P = 0.06). A transient infusion-related rash was the only adverse effect, n = 4. QoL scores did not differ markedly before and after treatment. CONCLUSION: Low-dose rituximab is an efficacious, well-tolerated and safe treatment for active TED; reducing disease activity and allowing reduced administration of systemic steroid.

Early use of steroid-sparing agents in the inactivation of moderate-to-severe active thyroid eye disease: a step-down approach.

OBJECTIVES: The current first-line treatment for management of active thyroid eye disease (TED) is high-dose intravenous corticosteroids, which have the potential for serious adverse effects. Our aim was to evaluate the effect of steroid-sparing agents (SSAs) in patients with moderate-to-severe active TED, using methotrexate as first-line. METHODS: Presented is a retrospective, four-year, single-centre, consecutive case series of patients with moderate-to-severe TED treated using the Oxford protocol. Treatment modality, disease activity, and adverse effects are reported at presentation, 6- and 12-month follow-up. RESULTS: 104 consecutive TED patients treated by the Oxford TED team were reviewed. 24 patients with moderate-to-severe active disease were identified (mean age 46.8 years;12 female) with a mean pretreatment VISA inflammatory index score of 5.5/10 (SD = 1.98; range 1-9). Intravenous methyl-prednisolone (IVMP) and an SSA was commenced in all patients. Mean total steroid dose was 2.72 g (SD = 1.4;1.0-6.9). 38% of patients (n = 9) received ≤1.5 g of IVMP. Only two patients required >4.5 g of IVMP equating to the EUGOGO treatment protocol dose for this patient group. There was significant improvement in inflammatory index score both at the intermediate review (mean score 2.7; SD = 2.8; P < 0.001; mean follow up 25.2 weeks) and at one year or last follow-up (mean score 1.4; SD = 1.5; P < 0.001; mean follow up 48.0 weeks). No serious or long-term adverse effects were reported. CONCLUSION: This study suggests that the initiation of an SSA, using methotrexate as first-line, with limited adjuvant IVMP is an effective and safe treatment for moderate-to-severely active TED, resulting in a significant reduction in both disease activity and total steroid load.

Liver biochemical abnormalities in Turner syndrome: A comprehensive characterization of an adult population.

OBJECTIVE: Abnormal liver function tests (LFTs) are frequent in Turner syndrome (TS). The causes and clinical significance are unclear. AIMS: To investigate the prevalence of elevated LFTs in adult TS; secondly, to analyse the associations between elevated LFTs, TS-karyotypes and TS-related conditions; and thirdly, to evaluate liver stiffness and histological assessment. METHODS: A total of 125 TS women were retrospectively studied. Karyotypes, clinical and biochemical details and aortic measurements were recorded. Fibroscan and liver biopsy results were noted. RESULTS: Elevated LFTs were found in 49.6%: gamma-glutamyltransferase (GGT) in 88.7%, ALK in 45.2%, ALT in 40.3% and AST in 29%. A FIB-4 index >1.3 was found in 11.8%. Women with isochromosome of the X long arm, iso[X](q), had a higher prevalence of elevated LFTs. A lower prevalence of abnormal GGT was found in patients with 45,X/46,XX, 45,X/47,XXX or 45,X/46,XX/47,XXX. Subjects with raised GGT were older, shorter and more likely to have higher triglyceride levels. There was no association with HRT duration after adjusting for age. Among patients with elevated aminotransferases, no differences were noted, except for higher HDL-cholesterol levels. The sinuses and ascending aorta diameter were greater in the elevated LFTs group. Fibroscan was suggestive of significant liver fibrosis in 38.1%. Among 11 biopsies, liver architectural changes were reported in 45.4%, including two with cirrhosis. CONCLUSIONS: Elevated LFTs in TS are common and important to detect given the possible progression towards severe liver disease. An association between raised LFTs and karyotype iso[X]q was demonstrated. We have also shown a new association between abnormal LFTs and aortic dilatation.

Fertility issues and pregnancy outcomes in Turner syndrome.

OBJECTIVE: To study fertility issues and pregnancy outcomes in Turner syndrome (TS). DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): One hundred fifty-six TS patients, median age 32 years, 23 mosaic 45,X/46,XX, 45,X/47,XXX, 45,X/46,XX/47,XXX. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fertility choices, spontaneous pregnancy, and oocyte donation (OD) outcomes. Conditions associated with aortic dissection and poor pregnancy outcomes at preconception were considered. Pregnancy-related aortic dimension changes and the long-term impact of pregnancy on TS-related comorbidities were assessed. RESULTS(S): In all, 13.5% had spontaneous pregnancies, resulting in a pregnancy with live birth in 18 patients (37 newborns); 16% considered OD, one adopted, and one underwent fertility preservation. Spontaneous pregnancy predictive factors were a karyotype with a second or third cell line with more than one X and spontaneous menarche. In all, 47.6% had miscarriages, two experienced preeclampsia, and two had gestational diabetes. One daughter was diagnosed with TS in adulthood. Seven of 14 who attempted OD had a pregnancy with live birth; two of seven had gestational diabetes; 64.3% attempting OD had risk factors associated with poor pregnancy outcomes, including four who had double embryo transfer. Cardiac status at preconception was evaluated in 12 of 25 women who had a pregnancy. The aortic diameters during pregnancy increased. The aortic growth at sinuses was 0.51 ± 0.71 mm/year and at ascending aorta 0.67 ± 0.67 mm/year, reaching a significant difference at sinuses compared with the growth in nulliparous TS. Among women who had a pregnancy, none experienced aortic dissection during and in the years after pregnancy. CONCLUSION(S): This study highlights the importance of a TS-dedicated multidisciplinary management of pregnancy, before and during pregnancy and in the postpartum period.

Angiogenesis in endocrine tumors.

Angiogenesis is the process of new blood vessel development from preexisting vasculature. Although vascular endothelium is usually quiescent in the adult, active angiogenesis has been shown to be an important process for new vessel formation, tumor growth, progression, and spread. The angiogenic phenotype depends on the balance of proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and inhibitors, as well as interactions with the extracellular matrix, allowing for endothelial migration. Endocrine glands are typically vascular organs, and their blood supply is essential for normal function and tight control of hormone feedback loops. In addition to metabolic factors such as hypoxia, the process of angiogenesis is also regulated by hormonal changes such as increased estrogen, IGF-I, and TSH levels. By measuring microvascular density, differences in angiogenesis have been related to differences in tumor behavior, and similar techniques have been applied to both benign and malignant endocrine tumors with the aim of identification of tumors that subsequently behave in an aggressive fashion. In contrast to other tumor types, pituitary tumors are less vascular than normal pituitary tissue, although the mechanism for this observation is not known. A relationship between angiogenesis and tumor size, tumor invasiveness, and aggressiveness has been shown in some pituitary tumor types, but not in others. There are few reports on the role of microvascular density or angiogenic factors in adrenal tumors. The mechanism of the vascular tumors, which include adrenomedullary tumors, found in patients with Von Hippel Lindau disease has been well characterized, and clinical trials of antiangiogenic therapy are currently being performed in patients with Von Hippel Lindau disease. Thyroid tumors are more vascular than normal thyroid tissue, and there is a clear correlation between increased VEGF expression and more aggressive thyroid tumor behavior and metastasis. Although parathyroid tissue induces angiogenesis when autotransplanted and PTH regulates both VEGF and MMP expression, there are few studies of angiogenesis and angiogenic factors in parathyroid tumors. An understanding of the balance of angiogenesis in these vascular tumors and mechanisms of vascular control may assist in therapeutic decisions and allow appropriately targeted treatment.

Molecular pathology shows p16 methylation in nonadenomatous pituitaries from patients with Cushing's disease.

PURPOSE: The majority of cases of Cushing's disease are due to the presence of a corticotroph microadenoma. Less frequently no adenoma is found and histology shows either corticotroph hyperplasia, or apparently normal pituitary. In this study we have used molecular pathology to determine whether the tissue labeled histologically as "normal" is indeed abnormal. EXPERIMENTAL DESIGN: Tissue from 31 corticotroph adenomas and 16 nonadenomatous pituitaries were subject to methylation-sensitive PCR to determine the methylation status of the p16 gene CpG island. The proportion of methylated versus unmethylated CpG island was determined using combined bisulphite restriction analysis. Methylation status was correlated with immunohistochemical detection of p16. RESULTS: Seventeen of 31 adenomas (54.8%), 4 of 6 cases of corticotroph hyperplasia, and 7 of 10 apparently normal pituitaries showed p16 methylation. Ten of 14 (71%; P = 0.01) adenomas and 2 of 3 cases of corticotroph hyperplasia, which were methylated, failed to express p16 protein. However, only 2 of 7 apparently normal pituitaries that were methylated failed to express p16 protein. Quantitative analysis of methylation using combined bisulphite restriction analysis showed only unmethylated CpG islands in postmortem normal pituitaries; however, in adenomas 80-90% of the cells within a specimen were methylated. The reverse was true for corticotroph hyperplasia and apparently normal pituitaries where only 10-20% of the cells were methylated. Thus, the decreased proportion of cells that were methylated, particularly in those cases of apparently normal pituitary, is the most likely explanation for the lack of association between this change and loss of cognate protein in these cases. CONCLUSIONS: To our knowledge this is the first report that describes an intrinsic molecular change, namely methylation of the p16 gene CpG island, common to all three histological patterns associated with Cushing's disease. Thus, the use of molecular pathology reveals abnormalities undetected by routine pathological investigation. In cases of "apparently" normal pituitaries it is not possible to determine whether the change is associated with adenoma cells "scattered" throughout the gland, albeit few in number, or with the ancestor-clonal origin of these tumor cells.

The impact of centrifugation in primary care on pseudohyperkalaemia: a retrospective evaluation.

BACKGROUND: Spurious hyperkalaemia is a relatively common occurrence in samples originating from primary care. Failure to identify spurious hyperkalaemia carries a significant risk of patient mismanagement. We have carried out a retrospective evaluation to review the impact of the use of centrifuges in primary care for biochemistry blood samples on the management of hyperkalaemia. METHODS: Serum potassium concentrations in samples received from primary care were reviewed for six months prior to and after the implementation of on-site centrifugation. Samples exhibiting significant hyperkalaemia (serum potassium >6.0 mmol/L) were further investigated to ascertain the degree of patient follow-up. RESULTS: There was a significant decrease in the number of samples exhibiting marked hyperkalaemia following the implementation (2244 versus 524; P < 0.0001). In terms of patient follow-up, we observed a reduction in the number of patients exhibiting pseudohyperkalaemia that previously had led to inappropriate hospital admissions over the same time period (6 cases postimplementation versus 22 cases preimplementation). We also observed an increase in the number of patients exhibiting true hyperkalaemia during the six-month period postimplementation (33 cases postimplementation versus 6 cases preimplementation). CONCLUSIONS: The centrifugation of serum samples in primary care improves the sample quality and the integrity of the potassium results reported. We have also demonstrated evidence of an improvement in patient management and quality of care.

The effect of electronic ordering on pre-analytical errors in primary care.

BACKGROUND: Pre-analytical variables are common across all laboratories and can negatively impact on patient care. The aim of this study was to review the impact of electronic requesting in Primary Care on the number of pre-analytical errors seen by the laboratory. METHOD: Error data were reviewed during two six-month periods, pre- and post-implementation of Primary Care electronic requesting. The outcome measures related to: the correct information on the sample tube (patient name, unique patient ID number, date of collection); the correct sample received and the availability of a clinical history. RESULTS: There was a marked decrease in the number of pre-analytical errors following the introduction of electronic requesting (2764 pre-implementation vs. 498 post-implementation, P < 0.001). There was an improvement in the quality of information provided with each request in the forms of clinical history, date and time of sample collection. CONCLUSIONS: The introduction of electronic requesting in Primary Care can reduce the number of pre-analytical errors and can improve the quality of information received with each request.

Seasonal pseudohyperkalaemia: no longer an issue?

BACKGROUND: Spurious hyperkalaemia is a well-recognized problem when reporting potassium results in samples originating from Primary Care. This is particularly relevant in laboratories serving large geographical areas where sample transport can cause significant delays in sample centrifugation. We have carried out a retrospective audit comparing serum potassium results on samples centrifuged at the general practice (GP) with those centrifuged on arrival at the clinical laboratory. METHODS: Potassium results were reviewed on serum samples received from 87 GPs in the Grampian region between August 2010 and March 2011. Potassium results were compared between samples centrifuged at the practice versus those centrifuged on arrival at the clinical laboratory. RESULTS: In the period between November 2010 and February 2011, median monthly serum potassium results were significantly different between samples centrifuged at practices and those centrifuged on arrival at the laboratory. Median potassium concentrations were 10.2% higher in January 2011 (4.8 mmol/L; interquartile range [IQR]: 4.5-5.1) compared with August 2010 (4.3 mmol/L; IQR: 4.0-4.6). A similar trend in monthly median potassium concentrations was not evident in samples centrifuged at source over the same period. CONCLUSIONS: The introduction of centrifuges into all GPs across NHS Grampian has significantly reduced the effect of seasonal variation in serum potassium results. There has also been a concurrent reduction in the number of cases of spurious hyperkalaemia. This exercise has significantly improved the overall quality of potassium results reported to Primary Care.

Comparison of sample types for N-terminal pro-B-type natriuretic peptide measured on the Siemens Immulite 2500 and Dimension Vista LOCI methods.

BACKGROUND: Measurement of serum natriuretic peptides is recommended in patients with suspected heart failure. Assays for N-terminal pro-B-type natriuretic peptide (NT-proBNP) are available on several platforms and can be measured in serum or heparinized plasma. Siemens Healthcare Diagnostics do not recommend the use of serum for the Immulite NT-proBNP assay. Serum offers some practical advantages over plasma. We investigated the suitability of serum for use with the Immulite and Dimension Vista LOCI methods. METHODS: Paired serum and heparinized plasma samples were drawn from patients in the Cardiology Department over a 48-h period. Samples spanning the NT-proBNP concentration range 50-60,000 ng/L were analysed using the Siemens Immulite 2500 and Dimension Vista LOCI methods. RESULTS: There was no significant difference between serum NT-proBNP concentrations on either platform (P = 0.0665). Plasma NT-proBNP measured using the Immulite were moderately higher than on Vista (P < 0.0001). There was a small but statistically significant difference between plasma and serum NT-proBNP measured using the Immulite (P = 0.0002) with plasma values higher than serum. A similar comparison between plasma and serum NT-proBNP measured using the Vista showed no difference (P = 0.3662). CONCLUSIONS: We have demonstrated the suitability of serum for use on the Immulite 2500. Bland-Altman comparative analysis indicated minimal bias between both serum methods near the clinical cut-off level below which heart failure is considered unlikely (400 ng/L) up to the highest concentration tested (60,000 ng/L).

GH replacement does not increase the risk of recurrence in patients with craniopharyngioma.

BACKGROUND: A significant number of patients with craniopharyngioma are GH deficient. The safety of GH replacement in these subjects has not been established. OBJECTIVE: To assess the effect of GH replacement upon recurrence in patients with craniopharyngioma. PATIENTS AND METHODS: All the patients with craniopharyngioma followed-up at the Departments of Endocrinology or Paediatrics in Oxford and treated or not with GH were studied retrospectively. These were recruited from the databases of the departments consisting of subjects diagnosed between January 1964 and July 2005. The impact of GH replacement upon recurrence was evaluated after adjusting for possible confounding factors. RESULTS: Forty-one subjects received GH replacement. Nine of them did not have follow-up imaging during GH therapy and were not included in the statistical analyses. The remaining 32 (22 males/10 females) received GH for a mean period of 6.3 +/- 4.6 years (median 5.1, range 0.8-22); 21 started during childhood (13 of them continued after the achievement of final height with an adult dose) and 11 during adult life. The mean duration of their follow-up (from surgery until last assessment) was 10.8 +/- 9.2 years (range 1.9-40). Fifty-three subjects had not received GH therapy (30 men/23 women). The mean duration of their follow-up (from surgery until last assessment) was 8.3 +/- 8.8 years (range 0.5-36). During the observation period, 4 patients treated with GH and 22 non-GH treated ones developed tumour recurrence. After adjusting for sex, age at tumour diagnosis and type of tumour therapy (gross total removal, partial removal, surgery + irradiation), GH treatment was not a significant independent predictor of recurrence (P = 0.06; hazard ratio = 0.309). Similar results were obtained when the impact of GH replacement was assessed according to its duration (P = 0.18; hazard ratio = 0.991/month of treatment). None of the nine patients with insufficient imaging data for inclusion in the statistical analyses [5 men/4 women, 3 treated with GH during childhood/6 during adult life, mean duration of GH therapy 2.9 +/- 2.4 years (median 1.8, range 0.4-7)] showed clinical features suggestive of recurrence during the period of GH replacement. CONCLUSION Based on the data of the craniopharyngiomas database in Oxford, there is no evidence that GH replacement is associated with an increased risk of tumour recurrence.

Do the limits of serum prolactin in disconnection hyperprolactinaemia need re-definition? A study of 226 patients with histologically verified non-functioning pituitary macroadenoma.

BACKGROUND: The differentiation of a pituitary non-functioning macroadenoma from a macroprolactinoma is important for planning appropriate therapy. Serum PRL levels have been suggested as a useful diagnostic indicator. However, values between 2500 and 8000 mU/l are a grey area and are currently associated with diagnostic uncertainty. OBJECTIVE: We wished therefore, to investigate the serum PRL values in a large series of patients presenting with apparently non-functioning pituitary macroadenomas. PATIENTS AND METHODS: All patients presenting to the Department of Endocrinology in Oxford with clinically non-functioning pituitary macroadenomas (later histologically verified) between 1990 and 2005 were studied. Information documented in the notes on the medications and on the presence of conditions capable of affecting the serum PRL levels at the time of blood sampling was also collected. RESULTS: Two hundred and twenty-six patients were identified (median age at diagnosis 55 years, range 18-88 years; 146 males/80 females; 143 gonadotroph, 46 null cell, 25 plurihormonal and 12 silent ACTH adenomas). All tumours had suprasellar extension. At the time of blood sampling 41 subjects were taking medications capable of increasing serum PRL. Hyperprolactinaemia was found in 38.5% (87/226) of the patients. The median serum PRL values in the total group were 386 mU/l (range 16-3257) (males: median 299 mU/l, range 16-1560; females: median 572 mU/l, range 20-3257) and in those not taking drugs capable of increasing serum PRL 363 mU/l (range 16-2565) (males: median 299 mU/l, range 16-1560; females: median 572 mU/l, range 20-2565). Serum PRL < 2000 mU/l was found in 98.7% (223/226) of the total group and in 99.5% (184/185) of those not taking drugs. Among the three subjects with serum PRL > 2000 mU/l, two were taking oestrogen preparations. CONCLUSIONS: Based on a large series of histologically confirmed cases, serum PRL > 2000 mU/l is almost never encountered in nonfunctioning pituitary macroadenomas. Values above this limit in the presence of a macroadenoma should not be surrounded by diagnostic uncertainty (after acromegaly or Cushing's disease have been excluded); a prolactinoma is the most likely diagnosis and a dopamine agonist should be considered as the treatment of choice.

The value of an acute octreotide suppression test in predicting long-term responses to depot somatostatin analogues in patients with active acromegaly.

BACKGROUND: The long-acting depot somatostatin analogues [octreotide LAR (LAR) and lanreotide (LAN)] are among the most effective available medical therapies for acromegaly. However, published data on a biochemical test suitable for predicting the responsiveness to these depot agents are lacking. AIM: To investigate the value of an acute octreotide suppression test (OST) in predicting the responses to treatment with long-acting somatostatin analogues in patients with active acromegaly. PATIENTS AND METHODS: Thirty patients with active acromegaly [mean GH in GH day curve (GHDC) > 5 mU/l] were subjected to an OST [hourly GH measurements for 6 h following 100 microg subcutaneous (s.c.) octreotide]. Subsequently, 14 patients were treated with LAR, 10 with LAN and 6 received both drugs at different times. The final response to treatment was evaluated when the subjects had achieved 'safe' GH levels (mean GH < 5 mU/l) or after receiving the maximal dose of each drug (maximum duration of treatment 6 months). RESULTS: The nadir GH values during the OST were 2.6 +/- 2.5 mU/l (mean +/- SD, range 0.2-8.7) with a percentage fall of 84.8 +/- 15.7% (mean +/- SD, range 26-99%) from the baseline levels (26.2 +/- 31.5 mU/l, mean +/- SD). All the patients except one showed a decrease of greater than 50%. The mean time to achieve the nadir GH value was 3.8 +/- 1.6 h (mean +/- SD, range 1-6). The nadir GH levels showed a positive correlation with both pre-treatment (i.e. before commencing LAN or LAR) GH values during the GHDC (r = 0.63, P < 0.01) and IGF-I levels (r = 0.56, P < 0.05). The nadir GH values during the OST showed a positive correlation with the achieved mean GH levels in patients treated with LAR (r = 0.66, P < 0.01) but not in the ones treated with LAN. The criterion of GH < 5.25 mU/l during the OST had sensitivity 100%, specificity 80%, positive predictive value (PPV) 94% and negative predictive value (NPV) 100% in predicting achievement of 'safe' GH levels in patients treated with LAR. A less optimal prognostic profile was obtained for subjects treated with LAN with the criterion of GH < 6.05 mU/l during the OST providing sensitivity 92%, specificity 67%, PPV 92% and NPV 67%. The above cut-off GH levels had a PPV of only 77% and 60% in predicting normalization of IGF-I on treatment with LAR or LAN, respectively. CONCLUSIONS: The OST is a reliable tool for the selection of patients with active acromegaly who will achieve 'safe' GH levels on therapy with LAR. Its prognostic profile is less optimal for patients treated with LAN. If GH values during the test fall < 5.25 mU/l (in case of LAR treatment) or < 6.05 mU/l (in case of LAN treatment), there is a 92-94% chance of subsequently achieving 'safe' GH levels after up to 6 months treatment with either of these agents.

Systematic dose-extension of octreotide LAR: the importance of individual tailoring of treatment in patients with acromegaly.

OBJECTIVE: The depot long-acting somatostatin analogue octreotide LAR (LAR) provides effective and well-tolerated treatment for acromegaly. Despite a 4-weekly recommended injection frequency, prolonged duration of GH suppression has been observed in some patients following treatment with long-acting somatostatin analogues. The aim of our study was to perform a prospective systematic study to determine whether extending the interval between doses of LAR allows maintenance of 'safe' GH in selected patients with acromegaly. PATIENTS AND METHODS: Twenty-two patients (15 men, seven women), mean age 58.9 years (35-81 years) with active acromegaly (mGH > 5 mU/l), requiring treatment were selected to receive treatment with LAR. Eleven patients had received previous treatment with both transsphenoidal surgery and radiotherapy, while six had received surgery alone. All patients were commenced on treatment with 20 mg LAR intramuscularly (i.m.) every 4 weeks. Mean GH (mGH) was measured after three consecutive injections immediately prior to the fourth injection. The dose frequency was systematically reduced after every four injections if mGH < 5 mU/l. Once mGH > 5 mU/l, the dose frequency was increased and mGH reassessed. RESULTS: The dosing interval was successfully increased to greater than 4 weeks in 20/22 patients (90.9%). Six of 22 (27.3%) were receiving injections every 8 weeks and 3/22 (13.6%) every 12 weeks. GH and IGF-I were lower on treatment compared with baseline (P < 0.01). There was no difference in individual mGH and IGF-I between the values on 4-weekly dosing and those at final dose frequency. There was no relationship between final dose frequency and either mean GH or IGF-I prior to LAR, patient age, or previous treatment. The percentage suppression following 100 micro g octreotide subcutaneously did not predict subsequent dose frequency of LAR. The drug cost if patients had continued at 4-weekly intervals would be UK pound 187 850, compared with UK pound 101 065 for the individually titrated dose frequency (P < 0.01). This represents a final cost of 53.8% of the 4-weekly injection price. CONCLUSION: Individual tailoring of LAR administration maintains control of acromegaly, with reduced injection frequency and improved cost-effectiveness.