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Biomedical subjects

Francis de Zegher

Publications and source records attributed to Francis de Zegher.

11 recordsLinked to original sources
PubMed2003

Functional polymorphisms in the paternally expressed XLalphas and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation.

The paternally expressed extra-large stimulatory G protein gene (XLalphas) is a splice variant of the stimulatory G-protein gene (Gsalpha) consisting of XL-exon1 and exons 2-13 of Gsalpha. A second open reading frame (ORF) in XL-exon1, that completely overlaps the XL-domain ORF, encodes ALEX, which is translated from the XLalphas mRNA and binds the XL-domain of XLalphas. We previously demonstrated that a paternally inherited functional polymorphism in XL-exon1, consisting of a 36 bp insertion and two nucleotide substitutions, is associated with Gs hyperfunction in platelets, leading to an increased trauma-related bleeding tendency and is accompanied by neurological problems and brachydactyly in two families. Here, we describe eight additional patients with brachydactyly, who inherited the same XLalphas polymorphism paternally and who show Gs hyperfunction in their platelets and fibroblasts. All carriers also have an elongated ALEX protein, as a consequence of the paternally inherited insertion. The in vitro interaction between the two elongated XLalphas and ALEX proteins is markedly reduced. Moreover, XLalphas or ALEX can be co-immunoprecipitated with an antibody against either ALEX or XLalphas in platelets from a control but hardly from patients with the XLalphas/ALEX insertion. In contrast to the strong interaction between the two wild-type proteins, we suggest that this defective association results in unimpeded receptor-stimulated activation of XLalphas. The paternally inherited double XLalphas/ALEX functional polymorphism is also associated with elevated platelet membrane Gsalpha protein levels. Both phenomena contribute to increased Gs signaling in patients with platelet hypersensitivity towards Gs-agonists and may be accompanied by neurological problems or growth deficiency.

Blood Platelets↗
PubMed2003

Fat distribution in non-obese girls with and without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche.

OBJECTIVE: Precocious pubarche (PP) in girls is associated with hyperinsulinaemia and dyslipidaemia of prepubertal onset, and with ovarian hyperandrogenism and ovulatory dysfunction in adolescence, particularly if they also had prenatal growth restraint and postnatal growth acceleration. Hyperinsulinaemia may be the pathogenic key factor, possibly amplified by hyperandrogenaemia. While such PP girls do not have increased body mass index (BMI), we hypothesized that body fat mass and fat distribution may differ between PP girls and matched controls, and may relate to insulin and androgen levels. PATIENTS AND DESIGN: Sixty-seven PP girls (age range 6.0-18.0 years) and 65 control girls matched for age and pubertal stage (5.9-18.0 years) had height, weight, waist and hip circumferences measured, and dual-energy X-ray absorptiometry (DXA) assessment of total body fat mass, and fat mass in abdominal and truncal regions. All girls had fasting plasma glucose, serum insulin, lipids, testosterone and SHBG levels measured; PP girls also had a standard 2-h oral glucose tolerance test (oGTT). RESULTS: Despite no differences in BMI, PP girls had significantly larger waist circumference, waist-to-hip ratio, total fat mass, percentage fat mass, abdominal fat mass, and truncal fat mass vs. controls in each pubertal stage. Overall, fasting insulin levels, free androgen index (FAI) and blood lipid levels were more closely related to central fat than to total body fat mass. In a multiple regression analysis, truncal fat mass was independently related to both fasting insulin (P = 0.009) and FAI (P < 0.0001). Abdominal fat mass was inversely related to birthweight (r = -0.25, P = 0.001). In PP girls, central fat mass was positively related to insulin levels after oGTT (truncal fat vs. 30 min insulin; r = 0.46, P < 0.0005). CONCLUSIONS: Precocious pubarche girls had excess total body and central fat mass throughout all pubertal stages, and increased central fat was related to hyperinsulinaemia and hyperandrogenaemia. It remains to be verified whether body composition in PP girls can be normalized by insulin-sensitization and/or antiandrogen therapy.

Adolescent↗
PubMed2003

Low-dose combination of flutamide, metformin and an oral contraceptive for non-obese, young women with polycystic ovary syndrome.

BACKGROUND: The endocrine-metabolic status of non-obese, young women with polycystic ovary syndrome (PCOS) is normalized more effectively by combined treatment with flutamide and metformin than by either of these drugs in monotherapy. In this follow-up study, we assess whether the endocrine-metabolic benefits of combined flutamide-metformin treatment are maintained in the presence of a low-dose oral contraceptive (OC). METHODS: To a population of non-obese, young PCOS women already receiving flutamide-metformin (125 mg/day and 1275 mg/day), a low-dose OC (ethinyl estradiol 20 microg + gestodene 75 microg) was administered to reduce the risk of pregnancy. A total of 12 women elected to receive the OC and this subgroup (OC+) was matched to a subgroup continuing on flutamide-metformin alone (OC-), for a total study population of 24 women (mean age +/- SEM 18.7 +/- 0.3 years; body mass index, 21.8 +/- 0.5 kg/m(2)). Endocrine-metabolic indices were assessed before any treatment (0 months), on flutamide-metformin (12 months), and again after a further 6 months with or without additional OC (18 months). RESULTS: In OC- and OC+ women, the beneficial effects of flutamide-metformin on hyperandrogenaemia, hyperinsulinaemia and dyslipidaemia were maintained. In OC+ women, there was an additional increase in sex hormone-binding globulin (SHBG), and thus a further drop in the free androgen index. CONCLUSION: When a low-dose OC is administered with a low-dose flutamide-metformin combination in women with PCOS, the beneficial effects are maintained on hyperinsulinaemia-dyslipidaemia, which are key determinants of long-term complications. Hence, in daily practice, such a low-dose quatuor may become a therapeutic option of first choice for young women with PCOS.

Adult↗
PubMed2003

Hypergonadotrophinaemia with reduced uterine and ovarian size in women born small-for-gestational-age.

BACKGROUND: Fetal growth restraint has been associated with FSH hypersecretion in early infancy and in early post-menarche, and with reduced uterine and ovarian size in adolescence. It is unknown whether these reproductive anomalies persist, respectively, into late infancy and into the reproductive age range. METHODS: We report follow-up findings in two age groups of girls. A cohort of infants [n=26; n=10 born appropriate-for-gestational-age (AGA) and n=16 born small-for-gestational-age (SGA)], who had been studied at the age of approximately 4 months, was assessed again at the age of 12 months. A cohort of teenagers (n=28), who had been studied at the age of approximately 14 years, was assessed again at the age of approximately 18 years; this group was complemented by a transversal cohort of similar age (n=19) for a total of 47 young women (n=27 AGA; n=20 SGA). In infants, only serum FSH was measured; adolescents underwent endocrine-metabolic screening, ultrasound assessment of uterine-ovarian size, and evaluation of body composition by dual X-ray absorptiometry. RESULTS: Serum FSH levels were higher in SGA than AGA infant girls at 4 and 12 months, and higher in SGA than AGA adolescents at 14 and 18 years (all P<0.01). Longitudinal ultrasound assessments disclosed a late-adolescent increment of uterine size that was less obvious in SGA than AGA girls. In contrast, ovarian volume remained stable in both subgroups. Compilation of longitudinal and transversal results at 18 years of age corroborated the persistent reduction in the uterine size of SGA girls (by approximately 20%; P<0.005) and in their ovarian volume (by approximately 40%; P<0.0001); moreover, SGA girls displayed not only a persistent elevation of FSH (by approximately 50%; P<0.001), but also a rise of LH and fasting insulin, as well as an excess of abdominal fat (all P<0.01). CONCLUSIONS: The gynaecology of young women born SGA was found to be characterized by hypergonadotrophinaemia and by a reduced uterine and ovarian size.

Adolescent↗
PubMed2003

Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism.

Ovarian hyperandrogenism is a common disorder often presenting post menarche with anovulatory oligomenorrhea and signs of androgen excess. Associated hyperinsulinemic insulin resistance, dyslipidemia, and central fat excess herald long-term disease risk. Combined antiandrogen (flutamide 250 mg/d) and insulin-sensitizing (metformin) therapy has beneficial effects, in particular on dyslipidemia and androgen excess in young women. We studied the effects of low-dose flutamide-metformin combination on metabolic variables and body composition in adolescent girls with ovarian hyperandrogenism. Thirty teenage girls (age range, 13.6-18.6 yr) with hyperinsulinemic hyperandrogenism participated in a 12-month pilot study with a 3-month off-treatment phase and a 9-month treatment phase (randomized sequence) on combined flutamide (125 mg/d) and metformin (1275 mg/d). Body composition was assessed by dual-energy x-ray absorptiometry; endocrine-metabolic state and ovulation rate were screened every 3 months. Insulin sensitivity was assessed by homeostasis model assessment (HOMA). Overnight GH and LH profiles were obtained pretreatment and after 6 months on treatment (n = 8). Over the 3-month pretreatment control phase (n = 14) all study indices were unchanged. Flutamide-metformin treatment (n = 30) was followed within 3 months by marked decreases in hirsutism score and serum androgens, by a more than 50% increase in insulin sensitivity and by a less atherogenic lipid profile (all P < 0.0001). After 9 months on flutamide-metformin, body fat decreased by 10%, with a preferential 20% loss of abdominal fat; conversely lean body mass increased, and total body weight remained unchanged; ovulation rate increased from 7-87% after 9 months. Baseline GH hypersecretion and elevated serum IGF-1 normalized after 6 months on flutamide-metformin. Within 3 months post treatment (n = 16), a rebound was observed for all assessed indices. In conclusion, in teenage girls with ovarian hyperandrogenism, low-dose combined flutamide-metformin therapy attenuated a spectrum of abnormalities, including insulin resistance and hyperlipidemia. Improved insulin sensitivity and reduced androgen activity led to a marked redistribution of body fat and lean mass, resulting in a more feminine body shape.

Adipose Tissue↗
PubMed2002

The somatotropic axis in short children born small for gestational age: relation to insulin resistance.

To determine whether hyperinsulinemia and reduced insulin sensitivity in individuals born small for gestational age (SGA) could be related to persisting abnormalities of the GH/IGF-I axis, we assessed overnight GH secretory profiles and measured fasting glucose, insulin, intact and 32,33 split proinsulin, and IGF-I levels in 16 short SGA children (age range 2.3-8.0 y) and in controls. Insulin sensitivity was calculated using the homeostasis model. Compared with short normal-birthweight controls (n = 7, age range 2.3-5.0 y), short SGA children had higher fasting insulin levels (means: 26.8 vs 20.6 pmol/L, p = 0.02), lower insulin sensitivity [means: 204 vs 284 %homeostasis model assessment (HOMA), p = 0.01], and higher beta cell function (112 vs 89 %HOMA, p = 0.04). SGA children also had lower levels of IGFBP-1 (87.0 vs 133.8, p = 0.04), but similar IGF-I levels (IGF-I SDS: -1.1 vs -1.7, p = 0.4). Compared with normal-height controls (n = 15, age range 5.6-12.1 y), SGA children had higher overnight GH secretion (GH maximum: 55.9 vs 39.6 mU/L, p = 0.01; mean: 13.1 vs 8.9, p = 0.004; minimum: 1.2 vs 0.6, p = 0.02). Interestingly, among SGA children, fasting insulin levels and insulin sensitivity were significantly related to overnight GH secretion (insulin sensitivity vs maximum GH: r = -0.68, p = 0.01; vs GH pulse amplitude r = -0.71, p = 0.007). The only hormone level significantly related to current height velocity was C-peptide (r = 0.75, p = 0.008). In conclusion, elevated fasting insulin levels and reduced insulin sensitivity in short SGA children was related to elevated levels of overnight GH secretion. We hypothesize that resistance to the somatotropic actions of GH and IGF-I in short SGA children may contribute directly to reduced insulin sensitivity.

Child↗
PubMed2002

Plasminogen activator inhibitor-1 in girls with precocious pubarche: a premenarcheal marker for polycystic ovary syndrome?

In both obese and nonobese women, polycystic ovary syndrome (PCOS) is essentially a disorder of hyperinsulinemic insulin resistance, and it may be heralded by precocious pubarche (PP; appearance of pubic hair in girls aged <8 y). The risk of progression from PP to PCOS is related to low birth weight, but there are no early biochemical markers of this risk. As increased plasminogen activator-inhibitor type 1 (PAI-1) activity (act) is an early marker of cardiovascular risk in PCOS, we have sought abnormalities in young girls with PP. In 33 young PP girls (age range 6-11 y), PAI-1-act was increased (mean + SEM: 15.6 +/- 1.5 IU/mL) compared with age-, sex-, and pubertal stage-matched controls (n = 13, 10.7 +/- 1.9, p < 0.05). PAI-1-act levels were inversely related to birth weight SD score (r = -0.33, p < 0.05), and PAI-1-act levels were therefore higher in PP girls with low birth weights (n = 14, 19.5 +/- 2.5 IU/mL) than normal birth weights (n = 19, 12.8 +/- 1.5, p < 0.01). During longitudinal observation in 10 PP girls (mean time interval 2.7 y), PAI-1-act levels in early puberty were positively related to postmenarcheal insulin levels (mean serum insulin SDS postoral glucose, r = 0.65, p < 0.05), and showed a similar relationship to postmenarcheal testosterone levels (r = 0.61, p = 0.06). Together with low birth weight, increased plasma PAI-1-act levels in early pubertal PP girls may indicate those girls with greater risk of developing hyperinsulinemic-hyperandrogenism features of PCOS.

Biomarkers↗
PubMed2002

High-dose growth hormone (GH) treatment in non-GH-deficient children born small for gestational age induces growth responses related to pretreatment GH secretion and associated with a reversible decrease in insulin sensitivity.

GH therapy variably reduces the height deficit of short children born small for gestational age (SGA) but is associated with hyperinsulinemia. Intermittent, higher-dose GH regimens may be alternatives to continuous, lower-dose treatment. We examined whether the growth response to GH therapy is related to pre-treatment indices of endogenous somatotropic activity, and studied the reversibility of the insulin resistant state induced by GH. 13 non-GH deficient short SGA children were randomised to high-dose GH (100 mcg/kg/day) by daily sc injection (n = 9), or no GH treatment (n = 4) for 2 years (2/4 controls subsequently received GH treatment). Overnight GH profiles were performed at baseline; intravenous glucose tolerance tests were performed at baseline, yearly on GH treatment, and 3 months post-GH treatment. Fasting glucose, insulin and proinsulin levels were measured, insulin sensitivity estimated using Bergman's minimal model, and glucose tolerance calculated from rate of glucose disappearance. In all GH-treated children, gain in height SDS (mean gain yr 1 = +1.2 SDS) was inversely related to baseline peak overnight GH (r = -0.88, n = 10, p = 0.0008), IFG-I (r = -0.74, n = 11, p = 0.009), and fasting insulin levels (r = -0.71, n = 11, p = 0.014). GH treatment increased fasting glucose (means: baseline vs. yr 2: 3.7 vs. 4.4 mmol/l, p = 0.005), insulin (3.8 vs. 13.9 mU/l, p = 0.0002), and proinsulin levels (1.7 vs. 4.5 pmol/l, p = 0.004), and decreased insulin sensitivity (26.9 vs. 4.0 per min/mU/1 x 10(4), p = 0.002). Glucose tolerance initially decreased (baseline: 2.62 min(-1); yr 1: 2.18, p = 0.02; yr 2: 2.39, p = 0.12). However, by 3 months post-GH treatment significant improvements were seen in fasting insulin (post-GH: 5.2 mU/1, p = 0.0003 vs. yr 2), proinsulin (1.7 pmol/l, p = 0.002), and insulin sensitivity (17.6 per min/mU/1 x 10(4), p = 0.0001). Post-GH treatment, fasting glucose levels (4.1 mmol/l, p = 0.04) and glucose tolerance (2.49 min(-1), p = 0.4) were similar to baseline, and the slight increase in fasting insulin levels (5.2 mU/1, p = 0.04) was similar to that observed in non-GH treated children over the 2 yr study period (baseline vs. 2 years: 3.9 vs. 5.9 mU/1, n = 4). In conclusion, in this study of 13 short non-GH-deficient SGA children, high-dose GH therapy induced growth responses that were associated with reversible decreases in insulin sensitivity, and that were predicted by pretreatment markers of endogenous, but not stimulated, somatotropic activity.

Blood Glucose↗
PubMed2002

Reduced ovulation rate in adolescent girls born small for gestational age.

FSH and insulin are key hormones involved in spontaneous ovulation. Adolescent girls born small for gestational age (SGA) are at risk for FSH and insulin resistance. We have assessed whether ovulation rate is reduced in SGA girls. Ovulatory function was assessed by weekly filter paper progesterone measurements, obtained by finger-stick auto-sampling for 3 consecutive months in matched populations of asymptomatic, nonobese girls (mean age, 15.5 yr; > or =3 yr postmenarche) who were either born with an appropriate weight for gestational age (AGA; n = 24; mean birthweight, 3.3 kg) or born small for gestational age (SGA; n = 25; mean birthweight, 2.3 kg). The prevalence of anovulation was higher among SGA than AGA girls (40% vs. 4%; P = 0.002). Moreover, in the relatively small fraction of ovulating SGA girls, the ovulation rate was lower than in AGA adolescents (average number of ovulations during the study, 1.4 vs. 1.9; P < 0.01). In conclusion, the endocrine correlates of prenatal growth restraint are herewith extended to include oligo-ovulation and anovulation in adolescence. It remains to be verified whether this SGA-related phenomenon persists into the reproductive age range. If it does, then fetal growth restraint may prove to be one of the enigmatic components underpinning hitherto unexplained female subfertility.

Adolescent↗