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THE ADRENOGENITAL SYNDROME IN CHILDREN

H. Andersen, C. Hansted, M. Sprechler, and E. Thamdrup

Although the adrenogenital syndrome has been known for about 150 years, it was not until 1950 when Wilkins et al. succeeded in suppressing the excessive adrenal androgen production with cortisone, that a better understanding of the abnormal adrenal function and its treatment was obtained.

This syndrome is caused by hyperplasia of the adrenal cortex or an adrenal cortical tumour. Sometimes nests of adrenal cortical cells situated anywhere from renal to gonad levels, even in the liver, may produce this clinical picture.

As to the frequency of the adrenogenital syndrome, a recent survey (Russel, 1954) gives a total of 275 cases, 215 of which were due to hyperplasia (10 of postnatal origin) and 60 of which were due to tumour (all postnatal). Around 75 % of the cases occurred in females.

All the clinical manifestations can, in the true adrenogenital syndrome, be traced back to an abnormal androgen production, and may be

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Development of acromegaly in patients with prolactinomas

M Andersen, C Hagen, J Frystyk, and HD Schroeder

OBJECTIVES: Patients with prolactinomas and patients with acromegaly often have heterogenous adenomas. In this study we have focused on patients with prolactinomas who developed acromegaly and acromegalic patients with hyperprolactinaemia. Our hypothesis is that some patients with hyperprolactinaemia may develop clinical acromegaly. METHODS: We have included patients examined at department M, Odense University Hospital between 1996 and 2001. Seventy-eight patients with prolactinomas, 65 females and 13 males, with a median age (range) of 30 Years (14-74) and 47 Years (20-66), respectively, were included in the study. RESULTS: In females and males the median prolactin (PRL) levels were 90 microg/l (27-4700; normal values (NV) <or=23) and 1075 microg/l (24-6500; NV <or=14), respectively. The PRL levels were significantly higher in males compared with females (P<0.002). Fifty-nine patients with acromegaly, 24 females and 35 males, with a median age (range) of 45 Years (24-70) and 53 Years (19-70), respectively, were included. Seven of the 24 females had hyperprolactinaemia, with PRL levels of 90 microg/l (27-494). Thirteen of the 35 males had hyperprolactinaemia with PRL levels of 47 microg/l (17-251). Three females with prolactinomas developed acromegaly clinically and biochemically. These patients had a normal low GH level and/or a normal IGF-I level at first diagnosis. CONCLUSIONS: Our findings suggest that there is a common group of patients with a pituitary adenoma who secrete PRL and GH unsynchronously. Some of these patients have clinical acromegaly at diagnosis and some patients diagnosed as prolactinomas will develop acromegaly. We suggest an annual IGF-I measurement as a screening test.

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Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy

C Hagen, H D Schroeder, S Hansen, and M Andersen

Objective

Aggressive pituitary tumours may be difficult to treat. Temozolomide (TMZ) is an alkylating cytostaticum. In a small number of cases, TMZ therapy has been reported to reduce pituitary tumour size and hormone hypersecretion.

Design

We present three patients with pituitary tumours treated with TMZ. One tumour was initially a macroprolactinoma that developed into a mixed GH- and prolactin-secreting carcinoma (patient A). To our knowledge, this is the first published in English literature. Two adenomas, a macroprolactinoma (patient B) and a clinically non-functioning pituitary adenoma (patient C), were highly invasive. The three patients suffered from extensive tumour mass effects, and all tumours were resistant to conventional treatment.

Method

TMZ, 150–200 mg/m2 of body surface area was administered orally for 5 days during each 28-day cycle.

Result

During TMZ therapy, tumour sizes were significantly reduced, hormone levels normalized and symptoms of mass effects decreased in all three cases. The carcinoma was treated from 2004 to 2006 (23 months). Three years after the terminating treatment, the tumour has not regrown and hormone levels are normalized. Immunohistochemical staining for methylguanine DNA methyltransferase (MGMT) was negative in two patients (A and B), and in one patient (C) a few nuclei stained positive.

Conclusion

TMZ therapy significantly decreased tumour volume, hormone hypersecretion and symptoms in all three patients, corresponding to the pathological findings regarding MGMT. TMZ therapy may be a new option for the treatment of resistant pituitary adenomas.

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MR spectroscopy of hepatic fat and adiponectin and leptin levels during testosterone therapy in type 2 diabetes: a randomized, double-blinded, placebo-controlled trial

L V Magnussen, P E Andersen, A Diaz, J Ostojic, K Højlund, D M Hougaard, A N Christensen, T L Nielsen, and M Andersen

Background

Men with type 2 diabetes mellitus (T2D) often have lowered testosterone levels and an increased risk of cardiovascular disease (CVD). Ectopic fat increases the risk of CVD, whereas subcutaneous gluteofemoral fat protects against CVD and has a beneficial adipokine-secreting profile.

Hypothesis

Testosterone replacement therapy (TRT) may reduce the content of ectopic fat and improve the adipokine profile in men with T2D.

Design and methods

A randomized, double-blinded, placebo-controlled study in 39 men aged 50–70 years with T2D and bioavailable testosterone levels <7.3 nmol/L. Patients were randomized to TRT (n = 20) or placebo gel (n = 19) for 24 weeks. Thigh subcutaneous fat area (TFA, %fat of total thigh volume), subcutaneous abdominal adipose tissue (SAT, % fat of total abdominal volume) and visceral adipose tissue (VAT, % fat of total abdominal volume) were measured by magnetic resonance (MR) imaging. Hepatic fat content was estimated by single-voxel MR spectroscopy. Adiponectin and leptin levels were measured by in-house immunofluorometric assay. Coefficients (b) represent the placebo-controlled mean effect of intervention.

Results

TFA (b = −3.3 percentage points (pp), P = 0.009), SAT (b = −3.0 pp, P = 0.006), levels of adiponectin (b = −0.4 mg/L, P = 0.045), leptin (b = −4.3 µg/mL, P < 0.001), leptin:adiponectin ratio (b = −0.53, P = 0.001) and HDL cholesterol (b = −0.11 mmol/L, P = 0.009) decreased during TRT compared with placebo. Hepatic fat content and VAT were unchanged.

Conclusions

The effects of TRT on cardiovascular risk markers were ambiguous. We observed potentially harmful changes in cardiovascular risk parameters, markedly reduced subcutaneous fat and unchanged ectopic fat during TRT and a reduction in adiponectin levels. On the other hand, the decrease in leptin and leptin:adiponectin ratio assessments could reflect an amelioration of the cardiovascular risk profile linked to hyperleptinaemia in ageing men with T2D.

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Effect of testosterone on markers of mitochondrial oxidative phosphorylation and lipid metabolism in muscle of aging men with subnormal bioavailable testosterone

Stine J Petersson, Louise L Christensen, Jonas M Kristensen, Rikke Kruse, Marianne Andersen, and Kurt Højlund

Objective

Recent studies have indicated that serum testosterone in aging men is associated with insulin sensitivity and expression of genes involved in oxidative phosphorylation (OxPhos), and that testosterone treatment increases lipid oxidation. Herein, we investigated the effect of testosterone therapy on regulators of mitochondrial biogenesis and markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels.

Methods

Skeletal muscle biopsies were obtained before and after treatment with either testosterone gel (n=12) or placebo (n=13) for 6 months. Insulin sensitivity and substrate oxidation were assessed by euglycemic–hyperinsulinemic clamp and indirect calorimetry. Muscle mRNA levels and protein abundance and phosphorylation of enzymes involved in mitochondrial biogenesis, OxPhos, and lipid metabolism were examined by quantitative real-time PCR and western blotting.

Results

Despite an increase in lipid oxidation (P<0.05), testosterone therapy had no effect on insulin sensitivity or mRNA levels of genes involved in mitochondrial biogenesis (PPARGC1A, PRKAA2, and PRKAG3), OxPhos (NDUFS1, ETFA, SDHA, UQCRC1, and COX5B), or lipid metabolism (ACADVL, CD36, CPT1B, HADH, and PDK4). Consistently, protein abundance of OxPhos subunits encoded by both nuclear (SDHA and UQCRC1) and mitochondrial DNA (ND6) and protein abundance and phosphorylation of AMP-activated protein kinase and p38 MAPK were unaffected by testosterone therapy.

Conclusion

The beneficial effect of testosterone treatment on lipid oxidation is not explained by increased abundance or phosphorylation-dependent activity of enzymes known to regulate mitochondrial biogenesis or markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels.

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Ipamorelin, the first selective growth hormone secretagogue

K Raun, BS Hansen, NL Johansen, H Thogersen, K Madsen, M Ankersen, and PH Andersen

The development and pharmacology of a new potent growth hormone (GH) secretagogue, ipamorelin, is described. Ipamorelin is a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2), which displays high GH releasing potency and efficacy in vitro and in vivo. As an outcome of a major chemistry programme, ipamorelin was identified within a series of compounds lacking the central dipeptide Ala-Trp of growth hormone-releasing peptide (GHRP)-1. In vitro, ipamorelin released GH from primary rat pituitary cells with a potency and efficacy similar to GHRP-6 (ECs) = 1.3+/-0.4nmol/l and Emax = 85+/-5% vs 2.2+/-0.3nmol/l and 100%). A pharmacological profiling using GHRP and growth hormone-releasing hormone (GHRH) antagonists clearly demonstrated that ipamorelin, like GHRP-6, stimulates GH release via a GHRP-like receptor. In pentobarbital anaesthetised rats, ipamorelin released GH with a potency and efficacy comparable to GHRP-6 (ED50 = 80+/-42nmol/kg and Emax = 1545+/-250ng GH/ml vs 115+/-36nmol/kg and 1167+/-120ng GH/ml). In conscious swine, ipamorelin released GH with an ED50 = 2.3+/-0.03 nmol/kg and an Emax = 65+/-0.2 ng GH/ml plasma. Again, this was very similar to GHRP-6 (ED50 = 3.9+/-1.4 nmol/kg and Emax = 74+/-7ng GH/ml plasma). GHRP-2 displayed higher potency but lower efficacy (ED50 = 0.6 nmol/kg and Emax = 56+/-6 ng GH/ml plasma). The specificity for GH release was studied in swine. None of the GH secretagogues tested affected FSH, LH, PRL or TSH plasma levels. Administration of both GHRP-6 and GHRP-2 resulted in increased plasma levels of ACTH and cortisol. Very surprisingly, ipamorelin did not release ACTH or cortisol in levels significantly different from those observed following GHRH stimulation. This lack of effect on ACTH and cortisol plasma levels was evident even at doses more than 200-fold higher than the ED50 for GH release. In conclusion, ipamorelin is the first GHRP-receptor agonist with a selectivity for GH release similar to that displayed by GHRH. The specificity of ipamorelin makes this compound a very interesting candidate for future clinical development.

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Testosterone therapy decreases subcutaneous fat and adiponectin in aging men

L Frederiksen, K Højlund, D M Hougaard, T H Mosbech, R Larsen, A Flyvbjerg, J Frystyk, K Brixen, and M Andersen

Objective

Testosterone therapy increases lean body mass and decreases total fat mass in aging men with low normal testosterone levels. The major challenge is, however, to determine whether the metabolic consequences of testosterone therapy are overall positive. We have previously reported that 6-month testosterone therapy did not improve insulin sensitivity. We investigated the effect of testosterone therapy on regional body fat distribution and on the levels of the insulin-sensitizing adipokine, adiponectin, in aging men with low normal bioavailable testosterone levels.

Design

A randomized, double-blinded, placebo-controlled study on 6-month testosterone treatment (gel) in 38 men, aged 60–78 years, with bioavailable testosterone <7.3 nmol/l, and a waist circumference >94 cm.

Methods

Central fat mass (CFM) and lower extremity fat mass (LEFM) were measured by dual X-ray absorptiometry. Subcutaneous abdominal adipose tissue (SAT), visceral adipose tissue (VAT), and thigh subcutaneous fat area (TFA) were measured by magnetic resonance imaging. Adiponectin levels were measured using an in-house immunofluorometric assay. Coefficients (b) represent the placebo-controlled mean effect of intervention.

Results

LEFM was decreased (b=−0.47 kg, P=0.07) while CFM did not change significantly (b=−0.66 kg, P=0.10) during testosterone therapy. SAT (b=−3.0%, P=0.018) and TFA (b=−3.0%, P<0.001) decreased, while VAT (b=1.0%, P=0.54) remained unchanged. Adiponectin levels decreased during testosterone therapy (b=−1.3 mg/l, P=0.001).

Conclusion

Testosterone therapy decreased subcutaneous fat on the abdomen and lower extremities, but visceral fat was unchanged. Moreover, adiponectin levels were significantly decreased during testosterone therapy.

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Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

M Frost, T L Nielsen, K Wraae, C Hagen, E Piters, S Beckers, F De Freitas, K Brixen, W Van Hul, and M Andersen

Objective

Both animal and human studies have associated the endocannabinoid system with obesity and markers of metabolic dysfunction. Blockade of the cannabinoid receptor 1 (CB1) caused weight loss and reduction in waist size in both obese and type II diabetics. Recent studies on common variants of the CB1 receptor gene (CNR1) and the link to obesity have been conflicting. The aim of the present study was to evaluate whether selected common variants of the CNR1 are associated with measures of obesity and fat distribution.

Design and methods

The single nucleotide polymorphisms (SNPs) rs806381, rs10485179 and rs1049353 were genotyped, and body fat and fat distribution were assessed by the use of dual-energy X-ray absorptiometry and magnetic resonance imaging in a population-based study comprising of 783 Danish men, aged 20–29 years.

Results

The rs806381 polymorphism was significantly associated with visceral fat mass (FM) only, whereas the rs1049353 was significantly and directly associated with visceral and intermuscular FM. None of the SNPs analysed were associated with total body FM or subcutaneous FM.

Conclusion

The results point towards a link between common variants of the CNR1 and fat distribution in young men.

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Thyroid stimulating immunoglobulins in Graves' disease with goitre growth, low thyroxine and increasing triiodothyronine during PTU treatment

Laszlo Hegedüs, Jens M. Hansen, Karine Bech, Jens P. Kampmann, Keld Jensen, Elo Andersen, Palle Hansen, Steen Karstrup, and Henning Bliddal

Abstract. In 50 consecutive patients with Graves' disease treated with PTU, 7 (group 1) developed increasing goitre in spite of unmeasurable TSH. Thyroid variables were compared with those from 10 controls with an ordinary response to PTU (group 2). Serum T4 decreased in group 1 from 246 ± 47 nmol/l (mean ± sd) to 40 ± 9 nmol/l after 6 weeks of PTU treatment and continued to be below the normal range during the next 4 months. In group 2 serum T4 decreased from 190 ± 35 to 88 ± 47 nmol/l and stayed in the normal range. Serum T3 was normalized in both groups after 6 weeks but increased to values above the normal range in group 1 after that time. In spite of unmeasurable TSH during the 6 months of treatment in group 1, thyroid volume, determined ultrasonically, increased significantly from 60 ± 29 to 93 ± 68 ml (P < 0.05), but was unaltered in group 2 about 25 ml.

Thyroid stimulating antibodies (TSAb) measured by adenylate cyclase activation (normal below 109%) decreased in group 2 from 117 ± 23 to 90 ± 17% (P <0.01) (6 months of therapy), but increased significantly in group 1, from 201 ± 47% to a maximum value of 234 ± 69% (P < 0.05). TSH binding inhibitory immunoglobulins (TBII) (given as per cent inhibition, normal below 26%) decreased in group 2 from 43 ± 29 to 29 ± 27% (P < 0.05) but were unaltered high in group 1,66 ± 25% before therapy and 57 ± 26% after 6 months of therapy. A positive correlation was found between thyroid volume and TSAb and TBII levels (P < 0.05, P < 0.05) before treatment as well as during the treatment period of 6 months. In 5 of 7 patients of group 1 either 131I therapy or subtotal thyroidectomy were necessary to control the disease.

It is proposed that TSAb and TBII remaining abnormal in this subgroup of patients with Graves' disease, might in part explain the unusual response to PTU-treatment.

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Thyroglobulin in smoking mothers and their newborns at delivery suggests autoregulation of placental iodide transport overcoming thiocyanate inhibition

Stine L Andersen, Susanne B Nøhr, Chun S Wu, Jørn Olsen, Klaus M Pedersen, and Peter Laurberg

Background

Placental transport of iodide is required for fetal thyroid hormone production. The sodium iodide symporter (NIS) mediates active iodide transport into the thyroid and the lactating mammary gland and is also present in placenta. NIS is competitively inhibited by thiocyanate from maternal smoking, but compensatory autoregulation of iodide transport differs between organs. The extent of autoregulation of placental iodide transport remains to be clarified.

Objective

To compare the impact of maternal smoking on thyroglobulin (Tg) levels in maternal serum at delivery and in cord serum as markers of maternal and fetal iodine deficiency.

Methods

One hundred and forty healthy, pregnant women admitted for delivery and their newborns were studied before the iodine fortification of salt in Denmark. Cotinine in urine and serum classified mothers as smokers (n=50) or nonsmokers (n=90). The pregnant women reported on intake of iodine-containing supplements during pregnancy and Tg in maternal serum at delivery and in cord serum were analyzed.

Results

In a context of mild-to-moderate iodine deficiency, smoking mothers had significantly higher serum Tg than nonsmoking mothers (mean Tg smokers 40.2 vs nonsmokers 24.4 μg/l, P=0.004) and so had their respective newborns (cord Tg 80.2 vs 52.4 μg/l, P=0.006), but the ratio between Tg in cord serum and maternal serum was not significantly different in smokers compared with nonsmokers (smoking 2.06 vs nonsmoking 2.22, P=0.69).

Conclusion

Maternal smoking increased the degree of iodine deficiency in parallel in the mother and the fetus, as reflected by increased Tg levels. However, placental iodide transport seemed unaffected despite high thiocyanate levels, suggesting that thiocyanate-insensitive iodide transporters alternative to NIS are active or that NIS in the placenta is autoregulated to keep iodide transport unaltered.