Germán Iñiguez

Anti-Müllerian hormone and inhibin B levels as markers of premature ovarian aging and transition to menopause in type 1 diabetes mellitus

BACKGROUND Serum anti-Müllerian hormone (AMH) levels decrease early during the transition to menopause and women with type 1 diabetes mellitus (DM1) experience menopause at a younger age. We hypothesized that older women with DM1 will have lower AMH levels than controls. METHODS We studied ovarian function in women with DM1 (n = 66) and healthy controls (n = 58), all <45 years old. Steroids, gonadotrophins, AMH and inhibin B levels were measured during the follicular phase. RESULTS Piece-wise regression analysis demonstrated that AMH levels begin to decrease at 33 years of age in both groups. This age limit was used to compare data in both groups. AMH levels were lower in DM1 women than in controls >33 years (4.1 +/- 4.2 versus 9.5 +/- 7.9 pmol/l, mean +/- SD, P = 0.006). A higher proportion of women with DM1 showed AMH levels in the menopausal range compared with controls (16.7% versus 3.4%, respectively, P = 0.02). For all patients, those with DM1 exhibited lower inhibin B levels than controls (89.3 +/- 51.7 versus 113.2 +/- 76.0 ng/ml, P < 0.05). FSH and estradiol were similar in both groups. Regression analysis showed an earlier decline in AMH levels in women with DM1 than controls. Even after age adjustment, DM1 was a significant factor for the determination of inhibin B and AMH levels. CONCLUSIONS Lower AMH levels in women with DM1 during the fourth decade of life suggest the presence of an earlier decline in the ovarian follicle pool in these women. Further studies are needed to evaluate the mechanism of this complication.

Polycystic ovarian morphology in adolescents with regular menstrual cycles is associated with elevated anti-Müllerian hormone

BACKGROUND The significance of polycystic ovarian morphology (PCOM) during adolescence is not clear. The aim of this study was to determine the relationship between PCOM and anti-Müllerian hormone (AMH), inhibin B, testosterone and insulin levels in healthy girls during the second decade of life. We also determined whether AMH could be used as a surrogate marker of PCOM during adolescence. METHODS Seventy-four non-obese adolescents (age range: 13.5-19.75 years old) with regular menstrual cycles participated in this study. Transabdominal ultrasound and blood samples were obtained during the follicular phase. RESULTS PCOM was present in 33.8% of the subjects. Girls with PCOM had higher AMH levels than girls without PCOM (72.5 ± 6.1 versus 33.4 ± 2.6 pmol/l; P < 0.0001) and lower FSH levels (5.4 ± 0.3 versus 6.2 ± 0.2 mUI/ml; P < 0.036). Similar levels of inhibin B, androgens and LH were observed in girls with and without PCOM. PCOM prevalence and AMH levels were not associated with age (P = 0.745 and 0.2, respectively) or BMI-SDS (P = 0.951 and 0.096, respectively). AMH levels positively correlated with the of 2-5 mm follicle number. AMH levels ≥ 60.15 pmol/l had a sensitivity and specificity of 64.0 and 89.8%, respectively, to diagnose PCOM (area under the curve = 0.873). CONCLUSIONS These data confirm that PCOM in healthy non-hyperandrogenic girls with regular menstrual cycles is prevalent and is not associated with hyperandrogenism. The elevated AMH and lower FSH levels observed in healthy girls with regular menses and PCOM suggest that this ovarian pattern is secondary to a larger number of 2-5 mm follicles. An elevated AMH level is suggestive of the presence of PCOM during adolescence.

Bone mass and sex steroids in postmenarcheal adolescents and adult women with Type 1 diabetes mellitus

OBJECTIVE The aim of this study was to compare the bone mass in young adolescents and adult women with Type 1 diabetes mellitus (T1DM) and determine its relationship with sex steroid and sex hormone-binding globulin (SHBG) levels. DESIGN Cross-sectional study. PATIENTS We studied a group of adolescents and adult women with T1DM (n=45) and 50 healthy controls (C) matched by gynecological age and body mass index in a case-control study. Girls with menarche within the last 18-40 months (n=17 T1DM and 32 C) and adult women (age=30.4+1.4 years; n=28 T1DM and 18 C) were recruited. MEASUREMENTS Bone mass was evaluated with a GE Lunar Prodigy densitometer. Sex steroid levels were measured by radioimmunoassay. RESULTS Bone mass was lower in adolescents with T1DM than in control adolescents, but was similar in both groups of postmenarcheal girls after adjusting for age, lean, and fat mass. However, adult T1DM women exhibited lower adjusted and unadjusted (P<.05) Z-femoral neck (-0.2±0.2 vs. 0.4±0.2) and bone mineral content (BMC) (2306±61 vs. 2645±79 g) than adult controls. Adult controls and T1DM adults showed higher whole body BMC than adolescent controls and T1DM adolescents, respectively. Bone mass in T1DM did not correlate with estradiol, free estradiol, testosterone, SHBG, or HbA1c levels. CONCLUSIONS The diminished bone mass observed in adult T1DM women does not appear to be related to sex steroid levels. In young adolescents with T1DM, the observed decrease in bone mass appears to be related to differences in body composition and age.

Gonadal function in low birth weight infants: a pilot study.

OBJECTIVE To evaluate gonadal function and anti-Müllerian hormone (AMH) serum concentrations during the first 3 months of life in low birth weight (low-BW) and normal birth weight (normal-BW) infants. INFANTS: Twenty low-BW and 29 normal-BW infants were studied. METHODS The pituitary-gonadal axis was evaluated by a GnRH agonist test (leuprolide acetate, 10 microg/kg s.c.). Circulating concentrations of gonadotropins, steroid hormones, sex hormone binding globulin, inhibin B and AMH were determined by specific assays. RESULTS In both sexes, basal concentrations of gonadotropins, sex steroids, sex hormone binding globulin and inhibin B were similar between low-BW and normal-BW infants. However, AMH concentrations were significantly higher in low-BW compared to normal-BW females (p = 0.004). This was not observed in males. After leuprolide administration, estradiol concentrations were higher in low-BW compared to normal-BW females (p = 0.043). In males, post-stimulated sex steroid concentrations were similar in both groups except for 17-OHP, which was significantly higher after leuprolide in the low-BW group (p = 0.023). CONCLUSIONS An increase in AMH and post-stimulated estradiol serum concentrations suggests altered follicular development in low-BW girls. In contrast, the normal circulating levels of AMH and inhibin B seem to indicate that Sertoli cell function is normal in low-BW boys. We suggest that ovarian function seems to be more vulnerable than testicular function in infants with intrauterine growth restriction.

Expression and protein content of IGF-I and IGF-I receptor in placentas from small, adequate and large for gestational age newborns.

In humans, a direct relationship between IGF-I cord blood levels and birth weight has been demonstrated. To determine the placental IGF-I, IGF-II and IGF-IR mRNA and protein contents in full-term pregnancies from appropriate for gestational age (AGA), small for gestational age (SGA) and large for gestational age (LGA) newborns, we studied the placentas from 35 AGA, 30 SGA and 28 LGA pregnancies. The IGF-I, IGF-II and IGF-I receptor (IGF-IR) placental mRNA and protein contents were determined in the basal and chorionic plates of the placenta. IGF1 and IGF1R mRNA was higher in SGA compared to AGA and LGA placentas and lower in LGA compared with AGA placentas. In addition, a higher protein content of IGF-I and IGF-IR was observed in SGA compared with AGA and LGA placentas and lower contents in LGA compared with AGA placentas. These results suggest that the higher IGF-I and IGF-IR contents observed in SGA placentas and the lower contents observed in LGA placentas compared with AGA placentas may be influencing human fetal growth.

Effects of Prenatal Ethanol Exposure on Postnatal Growth and the Insulin-Like Growth Factor Axis

Aims: To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation. Methods: We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (≧48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age. Results: IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects. Conclusion: Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure.

Long-term metabolic risk among children born premature or small for gestational age

Accumulating evidence suggests that both the intrauterine environment and growth during early life can influence the development of chronic noncommunicable diseases, such as type 2 diabetes mellitus and cardiovascular disease, in adulthood. Here, we review the available human data supporting increased metabolic risk among children born premature or small for gestational age; the adrenal and pubertal modifications that contribute to this risk; metabolic changes that occur during adolescence and early adulthood; and approaches to potentially modify or decrease risk of metabolic disease. The risks associated with delivery at term or preterm are compared for each period of life. Knowledge of these associations is fundamental for the paediatric community to develop preventive strategies early during postnatal life.

Elevated anti-Müllerian hormone (AMH) and inhibin B levels in prepubertal girls with type 1 diabetes mellitus

Objective  Elevated anti‐Müllerian hormone (AMH) and adrenal androgen levels have been observed during childhood in girls at risk of developing polycystic ovarian syndrome (PCOS). The aim of this study was to evaluate ovarian function and adrenal steroid levels in prepubertal girls with type 1 diabetes mellitus (T1D).

GH-IGF axis during catch up growth in small for gestational age (SGA) infants.

The hormonal profile in 47 small for gestational age (SGA) term newborns during their first year of life was studied. The newborns had a mean birth weight of 2290 +/- 230 g and a length of 45.5 +/- 2.0 cm, and they were followed up every month. Serum IGF-I, IGF-II, and urinary growth hormone (u-GH) concentrations were measured at 3 days of age and every 3 months during one year. Serum IGFBP-3 levels were measured at 3 and 6 months of age. Catch up growth (CUG) was defined as an increase in length z score greater than 1 SD between birth and 6 months of age. According to this definition, 27 infants (57.4%) experienced CUG. We compared the hormonal profile of the infants who demonstrated evidence of CUG [CUG(+)] with those who did not [CUG(-)]. Serum IGF-II levels were significantly higher in CUG(+) infants compared to CUG(-) infants at 3 months of age. We did not find any differences in serum IGF-I, IGFBP-3 and urinary GH between CUG(+) and CUG(-) infants at any time during the study.

Relationship between Nocturnal Growth Hormone Concentrations, Serum IGF-I/IGFBP-3 Levels, Insulin Sensitivity and GH Receptor Allelic Variant in Small for Gestational Age Children

Growth hormone may help to increase final height in patients with short stature, but its efficacy is variable. It has been recently reported that the isoform of the GH receptor (GHR) that lacks exon 3 (d3-GHR) is associated with a greater growth response to GH therapy. We hypothesized that nocturnal growth hormone concentrations, basal IGF-I and IGFBP-3 levels, and insulin sensitivity might show variations among individuals depending on their GHR allelic variant. To test this hypothesis, we studied 38 prepubertal LBW children with nocturnal GH concentrations, IGF-I and IGFBP-3 levels and insulin sensitivity during OGTT and Insulin test. The GHR allelic variant was analyzed through multiplex PCR analysis in DNA from peripheral leukocytes. Characteristics of the overnight GH secretion [(mean GH: 6.8 ± 0.6 vs. 6.2 ± 0.5 ng/ml), (AUC: 3,227 ± 280 vs. 2,908 ± 212 ng/ml·min), (peak number: 4.4 ± 0.3 vs. 4.4 ± 0.2), (amplitude: 12 ± 1.1 vs. 10.8 ± 1.1 ng/ml)] did not differ between groups (f1/f1 vs. f1/d3 plus d3/d3). In addition, we did not observe any significant differences in serum IGF-I SDS (–0.49 ± 0.26 vs. –0.40 ± 0.35) or IGFBP-3 SDS (–1.21 ± 0.24 vs. –0.89 ± 0.21) nor in insulin sensitivity (WIBSI: 12 ± 1.2 vs. 10.8 ± 1.1) in LBW children with full length GHR compared to children carrying at least one GHRd3 allele. The distribution of the f1/f1 allelic variant and fi/d3 or d3/d3 was similar in the LBW children with or without catch-up growth. These results suggest that the GHR allelic variant does not play a significant role in the regulation of GH-IGF-I/BP3 axis or in insulin sensitivity in prepubertal LBW children.