[Management of adverse effects related to human immunoglobulin therapy: Recommendations for clinical practice]. / Prise en charge des événements indésirables chez les patients sous traitement par immunoglobulines : recommandations pour la pratique clinique.

Both intravenous and subcutaneous immunoglobulins are therapeutic modalities approved in various conditions, including primary and secondary immune deficiencies and autoimmune disorders. To date, immunoglobulins have more often been considered as a safe medication, with minor adverse effects such as hypertension, fever and chills, nausea, myalgia or headache. However, with the wider use of immunoglobulins in the treatment of autoimmune diseases, severe side effects have also been reported to occur in immunoglobulin-treated patients, especially anaphylaxis, aseptic meningitis, acute renal impairment, thrombotic events as well as haematological manifestations. This paper reviews all the potential adverse events related to immunoglobulin therapy and establishes a comprehensive guideline for the management of these events.

Does the route of immunoglobin replacement therapy impact quality of life and satisfaction in patients with primary immunodeficiency? Insights from the French cohort "Visages".

BACKGROUND: IgG replacement therapy (IgRT) in primary immunodeficiencies (PID) is a lifelong treatment which may be administered intravenously (IVIg) or subcutaneously (SCIg), at hospital or at home. The objective of the VISAGE study was to investigate if route and/or place for IgRT impact patients' satisfaction regarding IgRT and quality of life (QoL) in real-life conditions. METHODS: The study enrolled PID patients at least 15 years old receiving IgRT for at least 3 months. Satisfaction and QoL were evaluated at enrollment and over a 12-month follow-up period by Life Quality Index (LQI) which measures 3 dimensions of satisfaction: treatment interference, therapy related problems and therapy settings (factors I, II and III) and SF-36 v2 questionnaire. RESULTS: The study included 116 PID patients (mean age 42 ± 18 years, 44 % males, 58 % with scholar or professional occupation) receiving IgRT for a mean of 8.5 ± 8.4 years. At enrollment they were receiving either home-based SCIg (51 %), hospital-based IVIg (40 %) or home-based IVIg (9 %). Patients exhibited a high degree of satisfaction regarding IgRT whatever the route and place for administration. LQI factor I was higher for home-based SCIg (86 ± 2) than for hospital-based IVIg (81 ± 3) and home-based IVIg (73 ± 5; p = 0.02 versus home-based SCIg); no difference was found for LQI factor II; LQI factor III was higher for home-based SCIg (92 ± 2) than for hospital-based IVIg (87 ± 5) and hospital-based IVIg (82 ± 3; p = 0.005 versus home-based SCIg). By contrast, every dimension of QoL was impaired. Over the follow-up period, 10 patients switched from hospital-based IVIg to home-based SCIg and improved LQI factor I (p = 0.004) and factor III (p = 0.02), while no change was noticed in LQI factors II and QoL. Meanwhile, no change in satisfaction or QoL was found in patients with stable route of IgRT. When asked on their preferred place of treatment all but one patient with home-based treatment would choose to be treated at home and 29 % of patients treated at hospital would prefer home-based IgRT. CONCLUSION: PID patients expressed a high degree of satisfaction regarding IgRT, contrasting with impaired QoL. In real-life conditions awareness of patient's expectations regarding the route or place of IgRT may be associated with further improvement of satisfaction.

Corticosteroid-binding globulin synthesis regulation by cytokines and glucocorticoids in human hepatoblastoma-derived (HepG2) cells.

Plasma corticosteroid-binding globulin (CBG) concentrations decrease dramatically in patients with septic shock or burn injury. This decrease suggests that mediators of the acute phase response, such as cytokines and glucocorticoid hormones, might influence clearance as well as liver synthesis of CBG in humans. The present study investigated the effects of interleukin-6 (IL-6), IL-1 beta, and dexamethasone on CBG synthesis by a clone of human hepatoblastoma-derived (HepG2) cell line. In culture medium from HepG2 cells, the immunoconcentration of CBG and the levels of CBG messenger ribonucleic acid (mRNA) were dose dependently decreased in the presence of IL-6 concentrations ranging from 0.1-10 ng/mL. The percent decrease in CBG immunoconcentration was quantitatively similar to the percent decrease in CBG mRNA levels (29 +/- 6% and 39 +/- 15%, respectively, of control values). In contrast, and as expected, IL-6 dose dependently increased the mRNA levels (164 +/- 22% of control values) of alpha 1-antitrypsin, a positive acute phase protein, but did not affect the immunoconcentration of sex hormone-binding globulin, another liver protein. Dexamethasone alone did not significantly affect CBG secretion or mRNA levels, but did dose-dependently increase tyrosine amino-transferase mRNA levels, which increased to 252 +/- 16% of the control values. However, in combination with IL-6, dexamethasone had a significant additive effect on IL-6 inhibition of CBG secretion and mRNAs in HepG2 cells. IL-1 beta dose-dependently stimulated CBG secretion (156 +/- 10% of control values) with no significant effect on CBG mRNA levels. In addition, IL-1 beta significantly decreased the inhibitory effect of IL-6 on CBG secretion, but had no effect on the inhibitory effect of IL-6 on CBG mRNA levels. These results suggest that IL-1 beta acts on the posttranslation processing and/or secretion mechanisms of CBG in HepG2 cells. Together, the present results strongly support the hypothesis that the decrease in plasma CBG concentrations is associated with the increase in IL-6 and glucocorticoid levels reported in patients with septic shock and burn injury.

Clinical utility of sex hormone-binding globulin measurement.

The high-affinity binding of the sex hormone-binding globulin (SHBG) for testosterone and to a lesser extent for estradiol influences the circulating levels of these sex steroid hormones, their biodisposal to target cells as well as their mutual balance. Although the regulation of SHBG is still not completely understood, in vitro studies performed with human hepatocarcinoma (Hep G2) cells have shown that estrogens and thyroxine stimulate SHBG secretion, by increasing the steady state of its mRNA concentrations. These observations are in good agreement with studies showing that SHBG levels increase during oral administration of estrogens as well as in patients with thyrotoxicosis. Interestingly, SHBG levels are normal in syndromes such as the abnormal transport of thyroid hormones and/or the syndrome of thyroid hormone resistance, which can be confused with thyrotoxicosis. By contrast, the effects of androgens are controversial. In many patients with hirsutism, SHBG concentrations are low and correlate negatively with both body mass index and fasting insulin levels. Because of the inhibitory effect of both insulin and insulin-like growth factor-1 on SHBG secretion by Hep G2 cells in vitro, it has been proposed that SHBG levels could be a marker of insulin resistance and/or hyperinsulinism in humans. Furthermore, an increased risk for either noninsulin-dependent diabetes and/or the overall mortality are associated with decreased SHBG levels in postmenopausal women. Finally, in men, SHBG levels are positively correlated with the concentration of high-density lipoprotein cholesterol. Therefore, the measurement of SHBG in clinical practice can be a useful diagnostic tool for: (1) correctly interpretating testosterone and estradiol serum concentrations; (2) investigating androgen-estrogen balance in gonadal and sexual dysfunctions; (3) assessing the peripheral effect of the hormones which regulate SHBG productions, and (4) evaluating insulin resistance and cardiovascular risk.

Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women.

Evidence suggests that hyperinsulinemic insulin resistance may increase serum levels of ovarian androgens and reduce sex hormone-binding globulin (SHBG) levels in humans. The present study was conducted to assess the effect of administration of the biguanide metformin, a drug commonly used in the treatment of diabetes mellitus, on androgen and insulin levels in 24 hirsute patients. The patients selected for the study were obese, with a body mass index higher than 25 kg/m2 and high fasting insulin (> 90 pmol/L) and low SHBG levels (< 30 nmol/L). All patients were given a low calorie diet (1500 Cal/day) and randomized for either metformin administration at a dose of 850 mg or a placebo, twice daily for 4 months, in a double blind study. In the placebo group, diet resulted in a significant decrease in body mass index (30.8 +/- 1.0 vs. 32.7 +/- 1.5 kg/m2; P < 0.0001), fasting insulin (127 +/- 11 vs. 156 +/- 14 pmol/L; P < 0.01), non-SHBG-bound testosterone (0.19 +/- 0.02 vs. 0.28 +/- 0.03 nmol/L; P < 0.02), androstenedione (5.8 +/- 0.5 vs. 9.0 +/- 1.1 nmol/L; P < 0.03), and 3 alpha-diolglucuronide (8.6 +/- 1.1 vs. 11.7 +/- 1.9; P < 0.005) plasma concentrations and a significant increase in the glucose/insulin ratio (0.047 +/- 0.005 vs. 0.035 +/- 0.003; P < 0.001) and plasma concentrations of SHBG (26.0 +/- 3.3 vs. 19.1 +/- 1.9 nmol/L; P < 0.001) and dehydroepiandrosterone sulfate (8.7 +/- 1.5 vs. 8.4 +/- 1.3; P < 0.05). Beneficial effects of diet were not significantly different in the patients who were given metformin instead of placebo. These results confirm that weight loss induced by a low calorie diet is effective in improving hyperinsulinemia and hyperandrogenism in obese and hirsute women. With our study design, metformin administration had no additional benefit over the effect of diet.

Interrelations between sex hormone-binding globulin (SHBG), plasma lipoproteins and cardiovascular risk.

The incidence of coronary artery disease is significantly higher in men than in women, at least until menopause. This gender difference could be explained by the action of sex steroids on the lipoprotein profile. In prepubertal children, high-density lipoprotein (HDL) cholesterol and triglyceride levels are similar between sexes, while adult men have generally lower HDL cholesterol and higher triglyceride levels than premenopausal adult women. Most cross-sectional studies have reported that sex hormone binding globulin (SHBG) and testosterone levels correlate positively with HDL cholesterol levels between sexes. Thus SHBG by modulating the balance in the biodisposal of testosterone and estradiol, might have a profound effect on the risk of cardiovascular disease. However, adjustment for body weight and body fat distribution weakens the association between SHBG, testosterone and HDL cholesterol. The negative correlation of fasting insulin with SHBG and HDL cholesterol levels in both sexes, and some evidence that insulin is an inhibitor of SHBG production in vitro, has suggested that hyperinsulinism might negatively regulate SHBG and HDL levels. It remains to be determined whether the inverse relationship between SHBG and insulin levels is coincidental or has a causal effect on the increase of atherosclerosis. Decreased SHBG has been shown to be predictive of the incidence of non-insulin-dependent diabetes mellitus in women but not in men, and of subsequent development of cardiovascular disease and overall mortality in postmenopausal women. SHBG is an index of androgenism in women and of insulin-resistance in both sexes, and might be useful in epidemiological studies of cardiovascular risk. However, in men, SHBG is not predictive of the occurrence of cardiovascular disease. Whether SHBG might have an intrinsic protective effect on the arterial wall through SHBG-receptors is still highly speculative.

Differential effects of insulin and insulin-like growth factor I on the production of plasma steroid-binding globulins by human hepatoblastoma-derived (Hep G2) cells.

Changes in the plasma levels of corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG) from birth to adulthood suggest that growth factors might influence clearance and/or hepatic secretion of CBG and SHBG in humans. The effects of insulin-like growth factor I (IGF-I) and insulin on CBG and SHBG synthesis by a clone of human hepatoblastoma-derived (Hep G2) cell lines were therefore investigated. The results showed that the immunoconcentrations of CBG and SHBG, as well as total protein concentration in culture medium from Hep G2 cells, were decreased by IGF-I and insulin. However, although the CBG-to-total protein ratio was decreased dose dependently by IGF-I and insulin, IGF-I and insulin did not dose-dependently decrease the SHBG-to-total protein ratio. The steady state levels of CBG and SHBG messenger RNAs (mRNAs) were reduced dose dependently by IGF-I with a half-effect at 5.4 +/- 1.9 and 4.6 +/- 1.6 nmol/L, respectively, and by insulin with a half-effect at 4.3 +/- 1.1 and 4.3 +/- 1.4 nmol/L, respectively. The maximum inhibitory effect of IGF-I on CBG mRNA level was 48 +/- 17% of control values and 60 +/- 13% for SHBG mRNA level. The changes in CBG mRNA levels were quantitatively similar to the changes in CBG immunoconcentration in the Hep G2 medium. In contrast, the inhibitory effects of insulin were only 17 +/- 8% and 31 +/- 12% of control values on CBG and SHBG mRNAs and 37 +/- 4% and 43 +/- 4% on CBG and SHBG concentrations, respectively. These results demonstrate that IGF-I reduces CBG and SHBG production by Hep G2 cells by decreasing mRNA steady state levels. The discrepancy between the inhibitory effects of insulin on CBG and SHBG mRNAs and protein secretion suggests that insulin exercises its inhibitory effects mainly on the mechanism(s) of translation and/or excretion of CBG and SHBG. The respective effects of IGF-I and insulin in the regulation of CBG and SHBG levels during fetal life and pubertal development in humans merit further study.

Hormonal substitution in older men.

The biological bases of endocrine alterations in ageing men are now well identified: progressive impairment of testicular function, decline in growth hormone (GH) secretion with decreased insulin-like growth factor-I (IGF-I) levels, and reduced adrenal androgen secretion. Insulin resistance and glucose intolerance also accompany male ageing. The mechanisms of these age-related changes are still unknown. There are preliminary results on the effects of hormonal replacement therapy in older males with mild hypogonadism or decreased IGF-I levels. Controlled placebo studies will in the future define the risks and benefits of long-term administration of androgens, GH or GH-releasing hormone in these patients. In view of the severe potential side effects, the generalized use of hormonal substitution in elderly men cannot, for the moment, be recommended.

[Hyperandrogenism in hirsute and obese women. Effects of a low calorie diet]. / Hyperandrogénie de la femme hirsute et obèse. Effets d'un régime hypocalorique.

To investigate the relationship between overweight and hyperandrogenism, a 1500 kcal/day diet was prescribed for 4 months to 23 hirsute and obese patients. This diet decreased body mass index from 29.9 +/- 4.9 to 27.2 +/- 4.4 kg/m2 (P < 0.008), but had no significant effect on fasting insulin levels (18.9 +/- 14.2 vs. 21.1 +/- 9.6 mlU/l). Weight lost increased significantly (P < 0.008) the plasma concentration of sex-hormone binding-globulin (SHBG) from 21.2 +/- 10.6 to 26.2 +/- 13.5 nmol/l and decreased significantly (P < 0.04) the SHBG-unbound testosterone concentration from 9.3 +/- 6.2 to 7.2 +/- 4.8 ng/dl, without changing the concentrations of the main androgens measured in this study. Moreover, during diet 5 patients in amenorrhea and 8 among 13 patients with irregular menstrual cycle recovered regular menses. We concluded that the control of excess body weight in hirsute women is effective but not sufficient to improve hyperandrogenism.

Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin.

In humans, the plasma level of sex hormone binding globulin (SHBG) is regulated by several hormones. We have now accumulated evidence that SHBG is also intimately related to nutritional state. However, we do not yet know what specific signal, if any, may be the regulator of SHBG. There is a strong and negative correlation between fasting insulin level and SHBG in obese as in hyperandrogenic women. Under such circumstances, a high fasting insulin level, normal glycemia and a low SHBG level suggest insulin resistance in terms of glucose disposal but not in terms of SHBG inhibition. This is a rather complex situation. It is too early to judge the importance of IGF-I in the regulation of SHBG. But it may turn out that IGF-I is the main regulator of SHBG and that, by interaction with the IGF-I receptors, insulin carries on its inhibitory activity on SHBG.

[Inverse relationship between body mass index and fasting insulinemia with testosterone-binding protein in hirsutism]. / Relation inverse de l'index de masse corporelle et de l'insulinémie à jeun avec la protéine de liaison de la testostérone au cours de l'hirsutisme.

To identify the factor(s) involved in the decreased of sex steroid binding-protein (SBP) in hirsute women, we have investigated which parameters were in correlation with SBP in a population of 90 hirsute women. We found no significant correlation of SBP binding capacity with the plasma concentrations of the main androgens. Conversely, SBP was in inverse and significant correlation with body mass index and with the fasting insulin plasma level. These findings confirm that nutritional status must be considered in the physiopathology of hyperandrogenism in women. The control of overweight may be a goal for treating hirsutism in some patients.