How well are the optimal serum 25OHD concentrations reached in high-dose intermittent vitamin D therapy? a placebo-controlled study on comparison between 100 000 IU and 200 000 IU of oral D3 every 3 months in elderly women.

OBJECTIVE: Intermittent dosing may improve adherence to vitamin D therapy. Dosing regimen should maintain optimal serum 25-hydroxyvitamin D (25OHD) levels over all the year. We compared two dosing regimens, the primary outcome being the percentage of 25OHD measurements reaching the targets of 75 nmol/l or 50 nmol/l after baseline. DESIGN: Randomized, placebo-controlled parallel group comparison. PATIENTS: Sixty women aged 75·0 ± 2·9 years. INTERVENTIONS: 100 000 IU (group 1D) or 200 000 IU (2D) of vitamin D3 or placebo orally every 3 months plus calcium 1 g daily for 1 year. MEASUREMENTS: Serum 25OHD, 1,25-dihydroxyvitamin D, PTH, sclerostin, ionized calcium, urinary calcium, renal function, bone turnover markers. RESULTS: Serum 25OHD increased, but the difference between two doses was of borderline significance (P = 0·0554; area under curve analysis). Immediate postadministrative increases were higher in the 2D vs 1D group (P < 0·05) after 3 and 6 months' dosing. In the 1D and 2D groups, 51·2% and 57·7% of all on-treatment measurements reached the target of 75 nmol/l. PTH levels differed marginally (P = 0·0759) due to tendency to lowering immediately after vitamin D boluses. Urinary calcium differed between the groups (P = 0·0193) due to increases 1 week after vitamin D dosing. CONCLUSIONS: The doses of 100 000 or 200 000 IU of oral cholecalciferol every 3 months were not capable of stabilizing 25OHD levels over the target of 75 nmol/l over the year. To improve the efficacy of high-dose vitamin D therapy, the interval between boluses has to be shortened instead of increasing their size.

Unusually severe hypophosphatemic rickets caused by a novel and complex re-arrangement of the PHEX gene.

X-linked hypophosphatemia (XLH) is caused by mutations in PHEX. Several other genetic forms of hypophosphatemia have also been described. These disorders share variable clinical presentation ranging from mild hypophosphatemia to severe lower extremity bowing. We report on a 43-year-old woman with short stature, painful leg deformities, and poor dentation. Her biochemical profile showed hypophosphatemia with renal phosphate wasting. Due to unusually severe clinical presentation and absence of mutations in Sanger sequencing of the PHEX gene, quantitative multiplex ligation-dependent probe amplification was performed. A large deletion within the PHEX gene encompassing exons 8 to 11 was identified. We generated a specific junction fragment using long-range PCR and sequenced the junction fragment to determine the exact deletion breakpoints. We found a heterozygous novel complex re-arrangement involving gross deletions, insertions, and inversion of PHEX (hg19:g.22,115,003_22,141,395del;g:22,145,536_22,150,789delinsCins22,114,640_22,114,698invinsA). Thus, the complex re-arrangement including a deletion of coding exons 8 to 11 of the PHEX can be regarded as the cause of XLH in the patient reported here. Phosphate and active vitamin D treatment was initiated with subsequent relief in bone pain and physical improvement. This report expands the spectrum of clinical severity underlying genetic defects in XLH and highlights the importance of conventional medical therapy even at adult age. Furthermore, our findings underscore the importance of search for gene deletions in patients with suspected XLH.

[The effect of gastric sleeve and bypass surgery on the use and costs of medications for type 2 diabetes]. / Mahalaukun kavennus- ja ohitus- leikkauksen vaikutus tyypin 2 diabeetikon lääikkeiden käyttöön ja kustannuksiin--kahden vuoden seurantatutkimus.

The study group consisted of 96 patients who had used a medication for type 2 diabetes; of them, 33 had undergone gastric sleeve surgery and 63 bypass surgery. Both surgical methods resulted in a similar weight loss among the patients. In follow-up 39 out of 88 patients were able to manage without antidiabetic drugs two years after surgery. The costs of antidiabetic drugs two years after surgery were 79% lower than before the operation. Weight reduction surgery decreases the need for antidiabetic drugs. The greatest cost-efficiency is achieved by targeting weight-loss operations to patients using insulin therapy.

Physiology of Calcium Homeostasis: An Overview.

Calcium plays a key role in skeletal mineralization and several intracellular and extracellular homeostatic networks. It is an essential element that is only available to the body through dietary sources. Daily acquisition of calcium depends, in addition to the actual intake, on the hormonally regulated state of calcium homeostasis through three main mechanisms: bone turnover, intestinal absorption, and renal reabsorption. These procedures are regulated by a group of interacting circulating hormones and their key receptors. This includes parathyroid hormone (PTH), PTH-related peptide, 1,25-dihydroxyvitamin D, calcitonin, fibroblast growth factor 23, the prevailing calcium concentration itself, the calcium-sensing receptor, as well as local processes in the bones, gut, and kidneys.

Characteristics and outcomes of the Finnish ectopic ACTH syndrome cohort.

PURPOSE: Ectopic ACTH syndrome (EAS) is rare. We established a national cohort to increase awareness and address unmet needs. METHODS: The Finnish national EAS cohort includes 60 patients diagnosed in 1997-2016. We assessed clinical features, diagnostic work-ups, treatments, incidence, and outcomes of subgroups occult tumor (OT), well-differentiated neuroendocrine tumor G1/G2 (NETG1/G2) and NET G3/neuroendocrine carcinoma (NETG3/NEC). RESULTS: The distribution of OT, NETG1/G2, and NETG3/NEC was 10 (17%), 20 (33%), and 30 (50%), respectively; and median follow-up 22 months (0-249). Annual incidence (0.20-0.93 per million inhabitants) and tumor subgroups (OT vs. NEC) varied across the country. The longest diagnostic delay from EAS onset to radiological tumor identification was 48 months. In NET/NEC, 6/50 (12%) were diagnosed 1-24 years before EAS onset. Osteoporotic fractures (32%) and severe infections (55%) were common. The CRH stimulation test accurately diagnosed EAS in 25/31 (81%). Metyrapone (≤6 g daily, prescribed in 88%) was well tolerated. In NETG1/G2, 13/20 (65%) underwent curative resection of the primary tumor; four experienced recurrence within 2-12 years. In OT, 70% underwent bilateral adrenalectomy. Five-year overall survival in OT, NETG1/G2, and NETG3/NEC was 90%, 55%, and 0%, respectively (P < 0.001). Morning cortisol, hypokalemia, infections, metastatic disease, and acute onset were negative, whereas resection of the primary tumor and bilateral adrenalectomy were positive predictors of survival. CONCLUSIONS: NET/NEC may precede EAS onset by several years. In NETG1/G2, recurrences may occur > 10 years after successful primary surgery. Tumor subgroup (OT, NETG1/G2, NEC) was an independent predictor of survival.

The same annual dose of 292000 IU of vitamin D (cholecalciferol) on either daily or four monthly basis for elderly women: 1-year comparative study of the effects on serum 25(OH)D concentrations and renal function.

OBJECTIVE: Daily dosing of vitamin D supplements may be difficult among older people. Infrequent administration of 'megadoses' controlled by health care personnel may overcome adherence problem. We compared the efficacy and safety of two oral dosages (800 IU daily or 97333 IU four monthly) of vitamin D(3) resulting in the equal annual dose of 292000 IU. DESIGN: Randomized, double-blind, double-dummy parallel group comparison. Patients Forty women aged 69.3-78.8 years. INTERVENTIONS: Vitamin D(3) 400 IU twice daily (D group) or vitamin D(3) oil 97333 IU every 4 months (4 M group) for 1 year. All received 1 g of calcium daily. MEASUREMENTS: Serum 25-hydroxyvitamin D(3) [25(OH)D(3)] in relation to the target levels of 50-75 nmol/l, PTH, serum type I procollagen aminoterminal propeptide (PINP), serum and urine calcium, renal function. RESULTS: A quantity of 25OHD(3) increased more in D group than in 4 M group (P < 0.0001). All participants in D group and 67% in 4 M group had 25(OH)D(3) above 50 nmol/l at 12 months; the target level of 75 nmol/l was reached by 47% and 28% respectively. PTH did not show any seasonal perturbation in either group. PINP declined and urinary calcium rose similarly in the study groups over time (P < 0.0001). Renal function did not worsen in either group. CONCLUSIONS: In terms of serum 25(OH)D(3) concentrations, 800 IU daily was more efficient than a 97333 IU every 4 months. However, to increase adherence, the latter is still worth developing. Both treatments increased urinary excretion of calcium, but did not worsen renal function.

Two-Year Nutrition Data in Terms of Vitamin D, Vitamin B12, and Albumin After Bariatric Surgery and Long-term Fracture Data Compared with Conservatively Treated Obese Patients: a Retrospective Cohort Study.

INTRODUCTION: Nutritional deficiencies may occur after bariatric surgery despite supplementation. Fracture risk may also be elevated after bariatric surgery. OBJECTIVES: To compare 25-hydroxyvitamin D [25(OH)D], vitamin B12, and albumin serum concentrations in severely obese patients who had undergone either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Fracture data was compared with data for a conservatively treated group of severely obese patients. METHODS: We considered 253 RYGB and 142 SG performed between 2007 and 2010. At 1- and 2-year control follow-ups, weight was measured and blood samples were drawn. The control group of 199 obese patients received lifestyle intervention and weight was measured at 1 and 2 years post-intervention between 2002 and 2006. We retrospectively collected fracture data for all patients through the end of 2016. RESULTS: At follow-ups, the mean serum 25(OH)D and albumin levels were within reference ranges and were similar between the RYGB and SG groups. Serum median vitamin B12 level was significantly higher in the SG group compared with the RYBG group, 319 versus 286 pmol/L at 2 years, respectively, p = 0.04. The cumulative risk for fracture was higher in the bariatric groups compared with the control group. The Cox multivariate model showed higher age, bariatric surgery, and lower body mass index (BMI) at the 2-year control increased the risk for fracture after obesity treatment. CONCLUSION: Vitamin 25(OH)D, B12, and albumin levels were mainly within recommended levels during the 2 years after bariatric surgery. The cumulative fracture risk was higher in bariatric patients.

The effect of hormone therapy on the health-related quality of life in elderly women.

OBJECTIVES: The purpose of this study was to compare the health-related quality of life (HRQoL) of elderly users and non-users of hormone therapy (HT). SUBJECTS AND METHODS: Subjects were participants in an ongoing intervention study, which is aimed at elucidating the effectiveness of an educational program in the prevention of osteoporosis. A random sample (n=4200) of the female population in Southern Finland within the age group of 60-70 years was drawn from the population register and invited to take part in the trial; 2181 (52%) accepted the invitation and were randomized either to the educational program or to a control group. In 2002 all 2181 participants were asked by a postal survey about HRQoL (generic15D), education, profession, climacteric symptoms, use of HT, chronic diseases and medication. Of the 1663 respondents (76% of the participants; 40% of the original cohort) 585 (mean age 67.5 years) were HT users and 1078 (mean age 68.9 years) non-users. RESULTS: After standardizing for age, education, number of continuous medication and ongoing diseases HRQoL of HT users was significantly better on the dimensions of usual activities, vitality and sexual activity. The effect of HT on overall HRQoL on a 0-1 scale was positive, but neither statistically significant nor clinically important. The number of medication and diseases had a statistically significant negative effect, but higher education a positive, but statistically non-significant effect on HRQoL overall. CONCLUSIONS: Among elderly women HT use has a statistically significant positive effect on some dimensions of HRQoL, but not on HRQoL overall. To improve HRQoL is not an indication for elderly postmenopausal women to use HT.

Gender has to be taken into account in diagnosing adult growth hormone deficiency by the GHRH plus arginine test.

OBJECTIVE: Data on the effect of gender on the interpretation of the GHRH plus arginine stimulation test (GHRH+ARG test) is controversial. We validated the GHRH+ARG stimulation test in control subjects and patients with organic or idiopathic pituitary disease and a suspicion of adult growth hormone deficiency (AGHD) using the Immulite 2000 XPi GH assay. DESIGN: We studied 126 apparently healthy adults (median age 38.8years) and 34 patients with a suspicion of AGHD (median age 42.2years). Identification of AGHD with the GHRH+ARG test was investigated with commonly accepted BMI-related consensus cut-off limits for peak GH concentrations. Serum samples collected during the GHRH+ARG test were analysed for GH in 2014-2015. Serum IGF-1 concentrations were studied as a reference. RESULTS: In 14 of 65 (22%) control males the GH peak value was below the BMI-related cut-off limits for GH sufficiency indicating a false diagnosis of AGHD. All control females had a normal GHRH+ARG response. Median peak GH response was significantly (p<0.001) higher in female (39.3µg/L) than in male controls (21µg/L). According to consensus cut-offs all but one young female patient had a deficient response compatible with a diagnosis of AGHD. CONCLUSIONS: The GH response to stimulation by GHRH+ARG is gender-dependent, being lower in healthy males than in females. Gender should be considered when defining cut-off limits for peak GH concentrations in the GHRH+ARG test. The presently used BMI-related cut-off levels will lead to a significant misclassification of males as GH deficient.

Long-Term Effect of Gastric Bypass and Sleeve Gastrectomy on Severe Obesity: Do Preoperative Weight Loss and Binge Eating Behavior Predict the Outcome of Bariatric Surgery?

BACKGROUND: Few studies have examined weight loss sustainability after sleeve gastrectomy (SG). The purpose of this study was to determine long-term outcome after SG and gastric bypass (GBP) and learn whether preoperative weight loss and binge eating behavior can be used to predict outcome. MATERIALS AND METHODS: Together, 257 patients (64 % women) were operated, 163 by GBP and 94 by SG. Binge eating was assessed by binge eating scale (BES) and preoperative weight loss was advised to all, including very low-calorie diet for 5 weeks. Postoperative visits took place at 1 and 2 years, and long-term outcome was at median 5 years (range 2.29-6.85). Multivariate linear regression analysis was used to predict outcome at 2-year and long-term control. RESULTS: Median age was 48 years, weight 141.1 kg, and BMI 48.2 kg/m(2). Preoperative weight loss was median 4.9 % before GBP and 3.8 % before SG, P = 0.04. Total weight loss at year one was 24.1 % in GBP and 23.7 % in SG (P = 0.40), at year two 24.4 and 23.4 % (P = 0.26), and at long-term control 23.0 and 20.2 % (P = 0.006), respectively. Weight was analyzed in 93, 88, and 89 % of those alive, respectively. BES did not predict weight outcome, but larger preoperative weight loss predicted less postoperative weight loss at 2 years. CONCLUSION: On long term, weight loss was better maintained after GBP compared with SG. Binge eating behavior was not a significant predictor, but larger preoperative weight loss predicted less postoperative weight loss for the next 2 years.

Long-term weight maintenance after a 17-week weight loss intervention with or without a one-year maintenance program: a randomized controlled trial.

BACKGROUND: Weight lost by obese patients is almost always regained over time. Extended treatment may improve maintenance, but solid evidence is lacking. PURPOSE: We determined effectiveness of maintenance therapy after a weight loss program. METHODS: Together 201 patients (mean age 47 years and BMI 42 kg/m(2), 71% women) were randomly assigned to either a 17-week weight loss program followed by a one-year maintenance program or to a weight loss program without subsequent maintenance intervention. The weight loss program included behavior modification and a very-low-calorie diet, and maintenance program behavior modification. The primary outcome measure was percentage of patients with 5% or more weight loss at the end of maintenance (week 69) and one year later (week 121). Secondary outcomes were weight related changes in lifestyle and quality of life. RESULTS: At week 69, 52% of the patients with and 44% of those without maintenance program had lost weight ≥5%, P = 0.40, and, at week 121, 33% and 34%, P = 0.77, respectively. At week 121 secondary outcomes did not differ between the groups among those successfully followed up. CONCLUSIONS: This one-year maintenance program was not effective in preventing weight regain in severely obese patients. Trial Registration. This trial is registered under clinicaltrials.gov Identifier: NCT00590655.

Comparison of two growth hormone stimulation tests and their cut-off limits in healthy adults at an outpatient clinic.

OBJECTIVE: A peak GH less than 3 µg/L to insulin tolerance test (ITT) is commonly used as a threshold indicating severe adult GH deficiency (GHD). This cut-off is based on results obtained by polyclonal radioimmunoassays preferably under standard conditions at hospital. Our aim was to evaluate the validity of this cut-off limit using two currently used immunometric GH assays and to compare GH responses in the ITT and the GH releasing hormone + arginine (GHRH + ARG) test in healthy adults at our outpatient endocrine unit. DESIGN: ITT was performed on 73 subjects and the GHRH + ARG test on those 28 who showed insufficient response to the ITT. METHODS: GH was measured by an immunofluorometric and immunochemiluminometric assay. RESULTS: GH peak above 3 µg/L was observed in 56% of the healthy volunteers with adequate hypoglycemia in the ITT. Among the 28 subjects with a peak GH below 3 µg/L, only two overweight men had a GH peak response below the commonly used cut-off limit of 9.1 µg/L in the GHRH + ARG test. CONCLUSIONS: Lean healthy adults could erroneously be classified as GH deficient by the ITT while their results in the GHRH + ARG test were normal. The GH results are highly dependent on the immunoassay used, but false positive results in the ITT are often obtained even if lower cutoff limits determined on the basis on the calibration of the GH assay are used. Confounding factors seemed to blunt the GH response to the ITT more than to the GHRH + ARG test at our outpatient clinic.

Serum 25(OH)D3 vitamin status of elderly Finnish women is suboptimal even after summer sunshine but is not associated with bone density or turnover.

OBJECTIVE: Concentrations of 50 and 75 nmol/l are proposed as serum 25-hydroxyvitamin D (25(OH)D) target for older people from the view of bone health. We evaluated vitamin D status of elderly Finnish women in light of these definitions, its relationship to bone mineral density (BMD) and turnover, and improvement by summer sunshine. DESIGN: Population-based study. METHODS: A total of 1604 ambulatory women aged 62-79 years were studied; 66% used vitamin D supplements. Serum 25(OH)D(3) was measured with HPLC before and after summer, and heel BMD in spring. In subgroups, serum parathyroid hormone (PTH) and type I procollagen aminoterminal propeptide (PINP) were analyzed. RESULTS: In spring, 60.3% of the women had 25(OH)D(3)

Effect of sex and assay method on serum concentrations of growth hormone in patients with acromegaly and in healthy controls.

BACKGROUND: Diagnosis and follow-up of acromegaly is based on measurements of serum growth hormone (GH) concentrations during an oral glucose tolerance test (OGTT). A nadir value <1 microg/L is commonly used to define a normal response, but some authors suggest lower cutoff values. METHODS: To compare the results and subsequent patient classification obtained with 3 GH assays, we obtained basal serum samples from 78 apparently healthy adult controls (43 women and 35 men; median age, 32.5 years) and from 71 treated (44 women and 27 men; median age, 55.2 years) and 7 untreated acromegaly patients (4 women and 3 men; median age, 54.6 years), and OGTT was performed on all patients and on 72 of the 78 controls. GH was determined by 2 immunometric assays-a double monoclonal (AutoDELFIA; Wallac) and a monopolyclonal (Immulite 2000; DPC) assay-and in a limited set of samples by an RIA (Spectria RIA; Orion). RESULTS: There was a strong correlation (r = 0.995; P < 0.001) between the 2 immunometric methods, but the results obtained with the Immulite 2000 were, on average, 1.4-fold higher than those obtained with the AutoDELFIA. At concentrations around the cutoff (1 microg/L), however, the difference was approximately 2-fold. Overall, the Orion RIA method also showed a good correlation (r = 0.951-0.959) with the other methods, but it did not measure concentrations <2 microg/L. Women had higher basal and OGTT nadir GH concentrations than men. CONCLUSION: Reference intervals should be determined separately for each method, and the need for establishing sex-specific reference values should be investigated.

Sex hormones and sexual function in obese men losing weight.

OBJECTIVE: To study the impact of a weight-loss program on sex hormones and sexual function among 38 middle-aged obese men (BMI >or=35 kg/m(2)). RESEARCH METHODS AND PROCEDURES: A randomized controlled clinical trial was conducted. The treatment group (n = 19) participated in a 4-month weight-loss program including 10 weeks on a very-low-energy diet (VLED) and 17 behavior modification visits. There was no intervention in the control group (n = 19). Both groups were followed for 8 months, i.e., 22 weeks after the active weight loss in the treatment group. The outcome measures (weight, sex hormones, sexual function, leptin, and metabolic variables) were obtained at baseline and at three time-points during follow-up. RESULTS: The mean weight loss in the treatment group was 21 kg at the end of the 10-week VLED. At the end of follow-up, the maintained weight loss was 17 kg of baseline weight. The control group was weight stable throughout the study. In the treatment group, increases in sex hormone-binding globulin, testosterone, and high-density lipoprotein-cholesterol, as well as decreases in insulin and leptin, were maintained until the end of follow-up, although with VLED, the level of several hormones and metabolic variables improved transiently during the rapid weight loss. There were no significant changes in the questionnaire scores on sexual function in either group. DISCUSSION: We conclude that obese men lose weight and increase their serum testosterone level on a weight-loss program with VLED and behavior modification. However, they do not change their sexual function scores.