Growth hormone replacement therapy in adults with growth hormone deficiency improves vascular reactivity

Patients with adult growth hormone (GH) deficiency are thought to be of increased risk of cardiovascular disease. Impaired vascular reactivity to endothelium derived nitric oxid (NO) is an early event in the development of atherosclerosis. In order to detect a possible effect of GH on vascular endothelium we examined forearm vasodilator responses in 8 patients with adult GH-deficiency before and after 3 months GH replacement therapy.

Effects of growth hormone (GH) replacement therapy on very low density lipoprotein apolipoprotein B100 kinetics in patients with adult GH deficiency: a stable isotope study

Patients with adult GH deficiency are often dyslipidemic and may have an increased risk of cardiovascular disease. The secretion and clearance of very low density lipoprotein apolipoprotein B 100 (VLDL apoB) are important determinants of plasma lipid concentrations. This study examined the effect of GH replacement therapy on VLDL apoB metabolism using a stable isotope turnover technique. VLDL apoB kinetics were determined in 14 adult patients with GH deficiency before and after 3 months GH or placebo treatment in a randomized double blind, placebo-controlled study using a primed constant [1-(13)C]leucine infusion. VLDL apoB enrichment was determined by gas chromatography-mass spectrometry. GH replacement therapy increased plasma insulin-like growth factor I concentrations 2.9 +/- 0.5-fold (P < 0.001), fasting insulin concentrations 1.8 +/- 0.6-fold (P < 0.04), and hemoglobin A1C from 5.0 +/- 0.2% to 5.3 +/- 0.2% (mean +/- SEM; P < 0.001). It decreased fat mass by 3.4 +/- 1.3 kg (P < 0.05) and increased lean body mass by 3.5 +/- 0.8 kg (P < 0.01). The total cholesterol concentration (P < 0.02), the low density lipoprotein cholesterol concentration (P < 0.02), and the VLDL cholesterol/VLDL apoB ratio (P < 0.005) decreased. GH therapy did not significantly change the VLDL apoB pool size, but increased the VLDL apoB secretion rate from 9.2 +/- 2.0 to 25.9 +/- 10.3 mg/kg x day (P < 0.01) and the MCR from 11.5 +/- 2.7 to 20.3 +/- 3.2 mL/min (P < 0.03). No significant changes were observed in the placebo group. This study suggests that GH replacement therapy improves lipid profile by increasing the removal of VLDL apoB. Although GH therapy stimulates VLDL apoB secretion, this is offset by the increase in the VLDL apoB clearance rate, which we postulate is due to its effects in up-regulating low density lipoprotein receptors and modifying VLDL composition.

The consequences of growth hormone deficiency in adulthood, and the effects of growth hormone replacement

The availability of recombinant human growth hormone (GH) has resulted in investigation of the role of GH in adulthood and the effects of GH replacement in the GH-deficient adult. These studies have led to the recognition of a specific syndrome of GH-deficiency, characterized by symptoms, signs and investigative findings. Adults with long-standing growth hormone deficiency are often overweight, have altered body composition, with reduced lean body mass (LBM), increased fat mass (FM), reduced total body water and reduced bone mass. In addition, there is reduced physical and cardiac performance, altered substrate metabolism and an abnormal lipid profile predisposing to the development of cardiovascular disease. Adults with GH deficiency report reduced psychological well-being and quality of life. These changes may contribute to the morbidity and premature mortality observed in hypopituitary adults on conventional replacement therapy. GH treatment restores LBM, reduces FM, increases total body water and increases bone mass. Following GH therapy, increases are recorded in exercise capacity and protein synthesis, and "favourable" alterations occur in plasma lipids. In addition, psychological well-being and quality of life improve with replacement therapy. GH is well tolerated; adverse effects are largely related to fluid retention and respond to dose adjustment. It is likely that GH replacement will become standard therapy for the hypopituitary adult in the near future. The benefits of GH replacement in the GH-deficient adult have been unequivocally demonstrated in studies lasting up to 3 years. The results of longer term studies are awaited to determine whether these benefits are sustained over a lifetime.

How well do radiographic absorptiometry and quantitative ultrasound predict osteoporosis at spine or hip? A cost-effectiveness analysis

Dual energy X-ray absorptiometry (DXA) is widely accepted as the reference method for diagnosis and monitoring of osteoporosis and for assessment of fracture risk, especially at hip. However, axial-DXA is not suitable for mass screening, because it is usually confined to specialized centers. We propose a two-step diagnostic approach to postmenopausal osteoporosis: the first step, using an inexpensive, widely available screening technique, aims at risk stratification in postmenopausal women; the second step, DXA of spine and hip is applied only to potentially osteoporotic women preselected on the basis of the screening measurement. In a group of 110 healthy postmenopausal woman, the capability of various peripheral bone measurement techniques to predict osteoporosis at spine and/or hip (T-score < -2.5SD using DXA) was tested using receiver operating characteristic (ROC) curves: radiographic absorptiometry of phalanges (RA), ultrasonometry at calcaneus (QUS. CALC), tibia (SOS.TIB), and phalanges (SOS.PHAL). Thirty-three women had osteoporosis at spine and/or hip with DXA. Areas under the ROC curves were 0.84 for RA, 0.83 for QUS.CALC, 0.77 for SOS.PHAL (p < 0.04 vs RA) and 0.74 for SOS.TIB (p < 0.02 vs RA and p = 0.05 vs QUS.CALC). For levels of sensitivity of 90%, the respective specificities were 67% (RA), 64% (QUS.CALC), 48% (SOS.PHAL), and 39% (SOS.TIB). In a cost-effective two-step, the price of the first step should not exceed 54% (RA), 51% (QUS.CALC), 42% (SOS.PHAL), and 25% (SOS.TIB). In conclusion, RA, QUS.CALC, SOS.PHAL, and SOS.TIB may be useful to preselect postmenopausal women in whom axial DXA is indicated to confirm/exclude osteoporosis at spine or hip.

Bone mineral density in young women with long-standing amenorrhea: limited effect of hormone replacement therapy with ethinylestradiol and desogestrel

To assess bone mineral density (BMD) at different skeletal sites in women with hypothalamic or ovarian amenorrhea and the effect of estrogen-gestagen substitution on BMD we compared BMD of 21 amenorrheic patients with hypothalamic or ovarian amenorrhea with that of a control population of 123 healthy women. All amenorrheic patients were recruited from the outpatient clinic of the Division of Gynecological Endocrinology at the University of Berne, a public University Hospital. One hundred and twenty-three healthy, regularly menstruating women recruited in the Berne area served as a control group. BMD was measured using dual-energy X-ray absorptiometry (DXA). At each site where it was measured, mean BMD was lower in the amenorrheic group than in the control group. Compared with the control group, average BMD in the amenorrheic group was 85% at lumbar spine (p < 0.0001), 92% at femoral neck (p < 0.02), 90% at Ward's triangle (p < 0.03), 92% at tibial diaphysis (p < 0.0001) and 92% at tibial epiphysis (p < 0.03). Fifteen amenorrheic women received estrogen-gestagen replacement therapy (0.03 mg ethinylestradiol and 0.15 mg desogestrel daily for 21 days per month), bone densitometry being repeated within 12-24 months. An annual increase in BMD of 0.2% to 2.9% was noted at all measured sites, the level of significance being reached at the lumbar spine (p < 0.0012) and Ward's triangle (p < 0.033). In conclusion BMD is lower in amenorrheic young women than in a population of normally menstruating, age-matched women in both mainly trabecular (lumbar spine, Ward's triangle, tibial epiphysis) and mainly cortical bone (femoral neck, tibial diaphysis).(ABSTRACT TRUNCATED AT 250 WORDS)

Medical treatment of vertebral osteoporosis

Although osteoporosis is a systemic disease, vertebral fractures due to spinal bone loss are a frequent, sometimes early and often neglected complication of the disease, generally associated with considerable disability and pain. As osteoporotic vertebral fractures are an important predictor of future fracture risk, including at the hip, medical management is targeted at reducing fracture risk. A literature search for randomized, double-blind, prospective, controlled clinical studies addressing medical treatment possibilities of vertebral fractures in postmenopausal Caucasian women was performed on the leading medical databases. For each publication, the number of patients with at least one new vertebral fracture and the number of randomized patients by treatment arm was retrieved. The relative risk (RR) and the number needed to treat (NNT, i.e. the number of patients to be treated to avoid one radiological vertebral fracture over the duration of the study), together with the respective 95% confidence intervals (95%CI) were calculated for each study. Treatment of steroid-induced osteoporosis and treatment of osteoporosis in men were reviewed separately, based on the low number of publications available. Forty-five publications matched with the search criteria, allowing for analysis of 15 different substances tested regarding their anti-fracture efficacy at the vertebral level. Bisphosphonates, mainly alendronate and risedronate, were reported to have consistently reduced the risk of a vertebral fracture over up to 50 months of treatment in four (alendronate) and two (risedronate) publications. Raloxifene reduced vertebral fracture risk in one study over 36 months, which was confirmed by 48 months' follow-up data. Parathormone (PTH) showed a drastic reduction in vertebral fracture risk in early studies, while calcitonin may also be a treatment option to reduce fracture risk. For other substances published data are conflicting (calcitriol, fluoride) or insufficient to conclude about efficacy (calcium, clodronate, etidronate, hormone replacement therapy, pamidronate, strontium, tiludronate, vitamin D). The low NNTs for the leading substances (ranges: 15-64 for alendronate, 8-26 for risedronate, 23 for calcitonin and 28-31 for raloxifene) confirm that effective and efficient drug interventions for treatment and prevention of osteoporotic vertebral fractures are available. Bisphosphonates have demonstrated similar efficacy in treatment and prevention of steroid-induced and male osteoporosis as in postmenopausal osteoporosis. The selection of the appropriate drug for treatment of vertebral osteoporosis from among a bisphosphonate (alendronate or risedronate), PTH, calcitonin or raloxifene will mainly depend on the efficacy, tolerability and safety profile, together with the patient's willingness to comply with a long-term treatment. Although reduction of vertebral fracture risk is an important criterion for decision making, drugs with proven additional fracture risk reduction at all clinically relevant sites (especially at the hip) should be the preferred options.

Differential impact of conventional oral or transdermal hormone replacement therapy or tibolone on body composition in postmenopausal women

To compare the effects on body composition and body weight of tibolone vs two different sequential oral or transdermal oestrogen-progestogen hormone replacement therapies versus no therapy.

Long-term influence of different postmenopausal hormone replacement regimens on serum lipids and lipoprotein(a): a randomised study

To assess the influence of three different postmenopausal hormone replacement therapies on levels of serum lipids and lipoprotein(a) [Lp(a)].

Prevention of postmenopausal bone loss using tibolone or conventional peroral or transdermal hormone replacement therapy with 17beta-estradiol and dydrogesterone

Postmenopausal bone loss can be prevented by continuous or intermittent estradiol (E2) administration. Concomitant progestogen therapy is mandatory in nonhysterectomized women to curtail the risk of endometrial hyperplasia or cancer. However, the recurrence of vaginal bleeding induced by sequential progestogen therapy in addition to continuous estrogen administration is one of the reasons for noncompliance to hormone replacement therapy (HRT). Tibolone, a synthetic steroid with simultaneous weak estrogenic, androgenic, and progestational activity, which does not stimulate endometrial proliferation, has recently been proposed for the treatment of climacteric symptoms. To compare the efficacy of conventional oral and transdermal HRT with that of tibolone in the prevention of postmenopausal bone loss, 140 postmenopausal women (age, 52 +/- 0.6 years; median duration of menopause, 3 years) were enrolled in an open 2-year study. Volunteers had been offered a choice between HRT and no therapy (control group, CO). Patients selecting HRT were randomly allocated to one of the following three treatment groups: TIB, tibolone, 2.5 mg/day continuously, orally; PO, peroral E2, 2 mg/day continuously, plus sequential oral dydrogesterone (DYD), 10 mg/day, for 14 days of a 28-day cycle; TTS, transdermal E2 by patch releasing 50 microg/day, plus DYD as above. Bone densitometry of the lumbar spine, upper femur, and whole body was performed using dual-energy X-ray absorptiometry at baseline, and then 6, 12, 18, and 24 months after initiation of therapy. One hundred and fifteen women (82%) completed the 2 years of the study. The dropout rate was similar in each group. Over 2 years, bone preservation was observed in all three treatment groups as compared with controls, without significant differences among treatment regimens. In conclusion, tibolone can be regarded as an alternative to conventional HRT to prevent postmenopausal bone loss.

Valgus Hip With High Antetorsion Causes Pain Through Posterior Extraarticular FAI

BACKGROUND: Valgus hips with increased antetorsion present with lack of external rotation and posterior hip pain that is aggravated with hip extension and external rotation. This may be the result of posterior femoroacetabular impingement (FAI). QUESTIONS/PURPOSES: We asked whether (1) the range of motion (ROM); (2) the location of anterior and posterior bony collision zones; and (3) the prevalence of extraarticular impingement differ between valgus hips with increased antetorsion compared with normal hips and hips with idiopathic FAI. METHODS: Surface models based on CT scan reconstructions of 13 valgus hips with increased antetorsion, 22 hips with FAI, and 27 normal hips were included. Validated three-dimensional collision detection software was used to quantify the simulated hip ROM and the location of impingement on the acetabular and the femoral sides. RESULTS: Hips with coxa valga and antetorsion showed decreased extension, external rotation, and adduction, whereas internal rotation in 90° of flexion was increased. Impingement zones were more anteroinferior on the femur and posteroinferior on the acetabular (pelvic) side; and the zones were more frequently extraarticular, posterior, or to a lesser degree anterior against the inferior iliac spine. We found a higher prevalence of extraarticular impingement for valgus hips with increased antetorsion. CONCLUSIONS: Valgus hips with increased antetorsion predispose to posterior extraarticular FAI and to a lesser degree anteroinferior spine impingement. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Prevalence of cam and pincer-type deformities on hip MRI in an asymptomatic young Swiss female population: a cross-sectional study

OBJECTIVES Femoroacetabular impingement is proposed to cause early osteoarthritis (OA) in the non-dysplastic hip. We previously reported on the prevalence of femoral deformities in a young asymptomatic male population. The aim of this study was to determine the prevalence of both femoral and acetabular types of impingement in young females. METHODS We conducted a population-based cross-sectional study of asymptomatic young females. All participants completed a set of questionnaires and underwent clinical examination of the hip. A random sample was subsequently invited to obtain magnetic resonance images (MRI) of the hip. All MRIs were read for cam-type deformities, increased acetabular depths, labral lesions, and impingement pits. Prevalence estimates of cam-type deformities and increased acetabular depths were estimated, and relationships between deformities and signs of joint damage were examined using logistic regression models. RESULTS The study included 283 subjects, and 80 asymptomatic females with a mean age of 19.3 years attended MRI. Fifteen showed some evidence of cam-type deformities, but none were scored to be definite. The overall prevalence was therefore 0% [95% confidence interval (95% CI) 0-5%]. The prevalence of increased acetabular depth was 10% (95% CI 5-19). No association was found between increased acetabular depth and decreased internal rotation of the hip. Increased acetabular depth was not associated with signs of labral damage. CONCLUSIONS Definite cam-type deformities in women are rare compared to men, whereas the prevalence of increased acetabular depth is higher, suggesting that femoroacetabular impingement has different gender-related biomechanical mechanisms.

Operative treatment of congenital hip osteoarthritis with high hip luxation (Crowe type IV)

OBJECTIVE The aim of the therapy is mechanical and functional stabilization of high dislocated hips with dysplasia coxarthrosis using total hip arthroplasty (THA). INDICATIONS Developmental dysplasia of the hip (DDH) in adults, symptomatic dysplasia coxarthrosis, high hip dislocation according to Crowe type III/IV, and symptomatic leg length inequality. CONTRAINDICATIONS Cerebrospinal dysfunction, muscular dystrophy, apparent disturbance of bone metabolism, acute or chronic infections, and immunocompromised patients. SURGICAL TECHNIQUE With the patient in a lateral decubitus position an incision is made between the anterior border of the gluteus maximus muscle and the posterior border of the gluteus medius muscle (Gibson interval). Identification of the sciatic nerve to protect the nerve from traction disorders by visual control. After performing trochanter flip osteotomy, preparation of the true actetabulum if possible. Implantation of the reinforcement ring, preparation of the femur and if necessary for mobilization, resection until the trochanter minor. Test repositioning under control of the sciatic nerve. Finally, refixation of the trochanteric crest. POSTOPERATIVE MANAGEMENT During hospital stay, intensive mobilization of the hip joint using a continuous passive motion machine with maximum flexion of 70°. No active abduction and passive adduction over the body midline. Maximum weight bearing 10-15 kg for 8 weeks, subsequently, first clinical and radiographic follow-up and deep venous thrombosis prophylaxis until full weight bearing. RESULTS From 1995 to 2012, 28 THAs of a Crow type IV high hip-dislocation were performed in our institute. Until now 14 patients have been analyzed during a follow-up of 8 years in 2012. Mid-term results showed an improvement of the postoperative clinical score (Merle d'Aubigné score) in 86 % of patients. Good to excellent results were obtained in 79 % of cases. Long-term results are not yet available. In one case an iatrogenic neuropraxia of the sciatic nerve was observed and after trauma a redislocation of the arthroplasty appeared in another case. In 2 cases an infection of the THA appeared 8 and 15 months after index surgery. No pseudoarthrosis of the trochanter or aseptic loosening was noticed.