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Marja Thorén, Kerstin Hall and Tiit Rähn

Abstract.

The serum levels of immunoreactive somatomedin A (SMA) in 23 patients with Cushing's disease, aged 6–61 years, were within the range of healthy subjects for their ages. No correlation was found between SMA and the excretion of cortisol. After im administration of hGH (8 IU = 4 mg) daily for 3 days there was a significant rise in SMA, both determined by radioimmunoassay and radioreceptor assay. Thus no impairment was found in the GH-dependent SMA levels or the ability of hGH to generate somatomedin, which indicates that the growth retarding effect of cortisol is most likely due to a direct effect on the tissue. After treatment with stereotactic radiation to the hypophysis there was a significant decrease in cortisol excretion without any change in SMA levels, indicating the possibility to achieve a selective impairment of the ACTH-cortisol axis.

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Henrik Falhammar, Helena Filipsson Nyström, Anna Wedell and Marja Thorén

Objective

Lifelong glucocorticoid therapy in patients with congenital adrenal hyperplasia (CAH) or the disease per se may result in increased cardiovascular risk. We therefore investigated cardiovascular and metabolic risk profiles in adult CAH males.

Subjects and methods

We compared CAH males (n=30), 19–67 years old, with age- and sex-matched controls (n=32). Subgroups of different ages (<30 years or older) and CYP21A2 genotypes (null, I2splice, and I172N as the mildest mutation) were studied. Anthropometry, fat and lean mass measured by dual-energy X-ray absorptiometry, lipids, liver function tests, homocysteine, lipoprotein-(a), glucose and insulin during an oral glucose tolerance test (OGTT), urine albumin, adrenal hormones, and 24 h ambulatory blood pressure measurements were studied.

Results

CAH males were shorter. Waist/hip ratio and fat mass were higher in older patients and the I172N group. Heart rate was faster in older patients, the I2splice, and I172N groups. Insulin levels were increased during OGTT in all patients and in the I172N group. γ-glutamyl transpeptidase was increased in older patients and in the I172N group. Testosterone was lower in older patients. Homocysteine was lower in younger patients, which may be cardioprotective. The cardiovascular risk seemed higher with hydrocortisone/cortisone acetate than prednisolone. Urinary epinephrine was lower in all groups of patients except in I172N.

Conclusions

Indications of increased risk were found in CAH males ≥30 years old and in the I172N group. In contrast, younger CAH males did not differ from age-matched controls. This is likely to reflect a better management in recent years.

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Marie Degerblad, Nabil Elgindy, Kerstin Hall, Hans-Erik Sjöberg and Marja Thorén

Six patients (21–50 years) with growth hormone deficiency and panhypopituitarism were given recombinant growth hormone, somatropin, 0.04–0.1 U·kg·body wt−1·day−1, for 12 months. All patients reported improved well-being with increased working capacity. Bone mineral density, as measured by single photon absorptiometry at two sites on the forearm, showed increased values in 5/6 patients after 12 months when measured at the most distal site (predominantly trabecular bone) and in 4/6 at the more proximal site (predominantly cortical bone). Five patients continued therapy for an additional year and after 18 months a significant increase in bone mineral density was seen at both the distal and proximal sites. The mean annual increase in bone mineral density was 12.0±0.6 (sem)% and 3.8±1.3% at the distal and proximal sites, respectively. In a growth hormone deficient control group without growth hormone therapy, the corresponding values were −2.4±0.6% and −1.9±0.4%, respectively. Lean body mass, estimated anthropometrically, increased significantly after 12 months and total body potassium, measured by whole body counting technique, increased in 4/6 patients. During growth hormone treatment, the IGF-1 values were above the mean values for age and 50% of the values were above the mean + 2 SD. B-glucose, P-insulin, serum IGF-2, procollagen-III peptide and phosphate increased and urea, creatinine and IGF-binding protein-1 decreased during treatment. The beneficial effects of growth hormone substitution, especially on bone mineral density, indicate that growth hormone substitution should be considered in all patients with hypopituitarism and growth hormone deficiency, irrespective of age.

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Marie Degerblad, Ove Almkvist, Roland Grunditz, Kerstin Hall, Lennart Kaijser, Evert Knutsson, Hans Ringertz and Marja Thorén

Abstract.

In a double-blind cross-over study with recombinant methionyl growth hormone (GH) and placebo during 12 weeks, the effect of GH substitution therapy (0.5-0.6 IU · kg−1 · week−1) on physical performance, muscle strength, bone mineral density, and mood and cognitive functions was investigated in 6 GH-deficient adults. During GH substitution serum concentrations of insulin-like growth factor-I and procollagen-III peptide increased in all 6 patients, whereas concentrations of serum urea decreased. Five of the patients identified the GH period and reported improved well-being with increased mental alertness and vitality and improved physical capacity and muscle strength. There was, however, no change of the isokinetic muscle strength during GH substitution therapy, and the working capacity on the bicycle ergometer was just slightly improved in some patients. The bone mineral density was low and unchanged in all patients. Mood and cognitive functions did not change during GH therapy. A reversible fluid retention was observed in one patient during the GH period. In conclusion, short-term GH substitution therapy to GH-deficient adults induced a subjective improvement of general wellbeing. Longer treatment periods will be necessary to establish the effect on physical capacity, muscle strength, bone mineral density, and mood and cognitive functions.

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Marie Degerblad, Bengt-Åke Bengtsson, Margareta Bramnert, Olof Johnell, Per Manhem, Thord Rosén and Marja Thorén

Degerblad M, Bengtsson B-Å, Bramnert M, Johnell O, Manhem P, Rosén T, Thorén M. Reduced bone mineral density in adults with growth hormone (GH) deficiency: increased bone turnover during 12 months of GH substitution therapy. Eur J Endocrinol 1995;133:180–8. ISSN 0804–4643

To evaluate the consequences of growth hormone (GH) deficiency on bone mineral density and to evaluate the effects of GH substitution therapy, 68 adults (25 females and 43 males) aged 22–61 (mean 44.2 ± 1.2) years with GH deficiency (GHD) were studied. Fifty-eight patients had panhypopituitarism, three had isolated GHD and in seven patients at least one additional pituitary function was affected. Twenty-one patients had childhood onset GHD. The patients were randomized to receive either GH in daily injections (0.125 IU · kg−1 · week−1 for the first 4 weeks and subsequently 0.25 IU · kg−1 · week−1) or placebo for 6 months. The trial continued as an open study with GH treatment for 6 or 12 months, with data presented as compiled data of 12 months of GH treatment in 64 patients. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry and bone turnover was assessed by serum markers of bone metabolism (osteocalcin, procollagen I peptide, crosslinked telopeptide of type I collagen and alkaline phosphatase activity). In women with adult onset GHD (N = 19) and in men with childhood onset GHD (N = 15), total body, spine and hip BMD was significantly reduced at baseline compared to Swedish age- and sex-matched control material. In men with adult onset of GHD (N = 28), BMD did not differ from male controls. During the placebocontrolled period, GH induced decreased total body and spine BMD, probably due to an expansion of the remodelling space, whereas all serum markers of bone turnover increased. Compiled GH data showed similar results after 6 months of treatment. After 12 months of GH treatment, BMD did not differ from basal values except for total body BMD, which was lower, whereas the serum markers of bone metabolism were still increased as compared to basal values. Two-thirds of the patients experienced fluid retention with peripheral oedema and arthralgias on the higher GH dosage. One obese patient developed non-insulin-dependent diabetes mellitus and was withdrawn from the study. These results demonstrate that GHD has negative effects on BMD and that GH substitution induces increased bone turnover. Continued long-term observations will reveal if there is a positive effect of GH substitution on bone mass in the adult GHD patient.

Marie Degerblad, Department of Endocrinology and Diabetology, Karolinska Hospital, S-17176 Stockholm, Sweden

Open access

Henrik Falhammar, Helena Filipsson Nyström, Urban Ekström, Seth Granberg, Anna Wedell and Marja Thorén

Objective

Fertility in males with congenital adrenal hyperplasia (CAH) is reported from normal to severely impaired. Therefore, we investigated fertility/fecundity, social/sexual situation, and pituitary–gonadal function in CAH males.

Subjects and methods

The patient cohort comprised 30 males, aged 19–67 years, with 21-hydroxylase deficiency. Their fertility was compared with age-matched national population data. For the evaluation of social/sexual factors and hormone status, age-matched controls were recruited (n=32). Subgroups of different ages (<30 years and older) and CYP21A2 genotypes (null (severe salt-wasting (SW)), I2splice (milder SW), and I172N (simple virilizing)) were also studied. Patients underwent testicular ultrasound examination (n=21) and semen analysis (n=14).

Results

Fertility was impaired in CAH males compared with national data (0.9±1.3 vs 1.8±0.5 children/father, P<0.001). There were no major differences in social and sexual factors between patients and controls apart from more fecundity problems, particularly in the I172N group. The patients had lower testosterone/estradiol (E2) ratio and inhibin B, and higher FSH. The semen samples were pathological in 43% (6/14) of patients and sperm concentration correlated with inhibin B and FSH. Testicular adrenal rest tumors (TARTs) were found in 86% (18/21). Functional testicular volume correlated positively with the testosterone/E2 ratio, sperm concentration, and inhibin B. Patients with pathological semen had increased fat mass and indications of increased cardiometabolic risk.

Conclusions

Fertility/fecundity was impaired in CAH males. The frequent occurrence of TARTs resulting in testicular insufficiency appears to be the major cause, but other factors such as elevated fat mass may contribute to a low semen quality.

Free access

Henrik Falhammar, Helena Filipsson Nyström, Anna Wedell, Kerstin Brismar and Marja Thorén

Objective

The aim of this study was to determine bone mineral density (BMD), markers of bone metabolism, fractures, and steroids reflecting hormonal control in adult males with congenital adrenal hyperplasia (CAH).

Subjects, methods, and design

We compared CAH males with 21-hydroxylase deficiency (n=30), 19–67 years old, with age- and sex-matched controls (n=32). Subgroups of CYP21A2 genotypes, age, glucocorticoid preparation, poor control vs overtreatment, and early vs late (>36 months) diagnosis were studied. BMD measured by dual energy X-ray absorptiometry and markers of bone metabolism and androgens/17-hydroxyprogesterone levels were investigated.

Results

All, including older (>30 years), CAH patients had lower BMD in all measured sites compared with control subjects. The null group demonstrated lower BMD in more locations than the other groups. Osteoporosis/osteopenia was present in 81% of CAH patients compared with 32% in controls (≥30 years). Fracture frequency was similar, osteocalcin was lower, and fewer patients than controls had vitamin D insufficiency. IGF1 was elevated in the milder genotypes. In patients, total body BMD was positively correlated to weight, BMI, total lean body mass, and triglycerides, and negatively to prolactin. Patients on prednisolone had lower BMD and osteocalcin levels than those on hydrocortisone/cortisone acetate. Patients with poor control had higher femoral neck BMD. There were no differences in BMD between patients with an early vs late diagnosis.

Conclusions

CAH males have low BMD and bone formation markers. BMD should be monitored, adequate prophylaxis and treatment established, and glucocorticoid doses optimized to minimize the risk of future fractures.

Free access

Birgitta Bülow, Svante Jansson, Claes Juhlin, Lars Steen, Marja Thorén, Hans Wahrenberg, Stig Valdemarsson, Bo Wängberg and Bo Ahréen

Group-author : on behalf of the Swedish Research Council Study Group of Endocrine Abdominal Tumours

Objectives: To examine the risk of developing adrenal carcinomas and clinically overt hypersecreting tumours during short-term follow-up in patients with adrenal incidentalomas.

Design: 229 (98 males and 131 females) patients with adrenal incidentalomas were investigated in a prospective follow-up study (median time 25 months; range 3–108 months). The patients were registered between January 1996 and July 2001 and followed until December 2004. Twenty-seven Swedish hospitals contributed with follow-up results.

Methods: Diagnostic procedures were undertaken according to a protocol including reinvestigation with computed tomography scans after 3–6 months, 15–18 months and 27–30 months, as well as hormonal evaluation at baseline and after 27–30 months of follow-up. Operation was recommended when the incidentaloma size increased or if there was a suspicion of a hypersecreting tumour.

Results: The median age at diagnosis of the 229 patients included in the follow-up study was 64 years (range 28–84 years) and the median size of the adrenal incidentalomas when discovered was 2.5 cm (range 1–8 cm). During the follow-up period, an increase in incidentaloma size of ≥0.5 cm was reported in 17 (7.4%) and of ≥1.0 cm was reported in 12 (5.2%) of the 229 patients. A decrease in size was seen in 12 patients (5.2%). A hypersecreting tumour was found in 2% of the hormonally investigated patients: Cushing’s syndrome (n = 2) and phaeochromocytoma (n = 1). Eleven patients underwent adrenalectomy, but no cases of primary adrenal malignancy were observed.

Conclusions: Patients with adrenal incidentaloma had a low risk of developing malignancy or hormonal hypersecretion during a short-term follow-up period.