Metformin therapy increases insulin-like growth factor binding protein-1 in hyperinsulinemic women with polycystic ovary syndrome

OBJECTIVES: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, insulin resistance, compensatory hyperinsulinemia, and increased levels of free insulin-like growth factor-I (IGF-I), presumably due to a decline in IGF binding protein 1 (IGFBP-1). This study was designed to evaluate effects of metformin therapy on serum levels of IGFBP-1 and IGF-I. STUDY DESIGN: Twenty-seven obese, hyperandrogenic PCOS women with elevated fasting insulin were treated for 12 weeks with metformin (500 mg p.o., t.i.d.). Serum levels of insulin, testosterone, sex hormone binding globulin (SHBG), IGF-I, and IGFBP-1 were measured before and after treatment. Body mass index (BMI) and waist-to-hip ratio (WHR) were assessed at baseline and at the end of therapy. RESULTS: Metformin therapy significantly increased IGFBP-1 concentration by 38% (P = 0.05) but had no demonstrable effect on the total IGF-I levels. Fasting insulin levels declined by 38% (P = 0.0001) while the glucose/insulin ratio increased by 72% (P = 0.0001) and quantitative insulin sensitivity check index (QUICKI) increased by 8% (P = 0.0001). Metformin treatment also significantly decreased testosterone (by 37%, P = 0.0001) and increased SHBG concentration (by 16%, P = 0.04). Multiple linear regression analysis revealed that baseline IGFBP-1 levels correlated inversely and independently with two baseline parameters: WHR (P = 0.003) and free testosterone index (P = 0.04). CONCLUSIONS: The present study shows that metformin therapy not only restores normal levels of insulin and testosterone, but also decreases the pool of free-bioactive IGF-I by increasing the levels of circulating IGFBP-1. We provide further arguments in favor of metformin therapy in hyperinsulinemic women with PCOS.     

Leptin,VEGF, IGF-1, and IGFBP-3 concentrations in serum and follicular fluid of women undergoing in vitro fertilization

We studied the influence of recombinant follicle-stimulating hormone (rFSH) stimulation on the concentration of leptin, vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) in serum and follicular fluid (FF) in women undergoing assisted reproduction. To test the hypothesis that these hormones could predict successful implantation and that the levels correlate with pregnancy rate. Sequential serum samples were drawn at the beginning of stimulation and on the day of embryo transfer (ET) from 84 women undergoing IVF. The follicular fluid (FF) obtained during oocyte retrieval was collected and the concentration of leptin, VEGF, IGF-1 and IGFBP-3 were measured in all samples. The hormones were measured by commercially available IRMA, RIA or EIA. Patients' characteristics and results of the assisted reproductive cycles were registered. Serum concentrations of VEGF, IGF-1 and IGFBP-3 significantly decreased during rFSH treatment. In contrast, serum leptin significantly increased after rFSH treatment. A strong correlation was found between the FF - levels of IGF-1, IGFBP-3, leptin and respective serum levels. With regard to IVF outcome, higher serum concentrations of IGF-1, IGFBP-3 and VEGF on the day of oocyte retrieval were observed in conception cycles vs. non-conception cycles. No such difference, however, was apparent at the beginning of the stimulation cycle. There was no association between FF levels of any of these hormones and IVF outcome. Our results demonstrate that VEGF, IGF-1, IGFBP-3 and leptin levels are affected by rFSH during controlled ovarian hyperstimulation and that there is a direct association between serum and FF levels, albeit without clinical implications     

Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome

OBJECTIVE: To evaluate the effects of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective study. SETTING: Women with PCOS attending as outpatients of the Endocrine Division, Hospital Durand, Buenos Aires. PATIENT(S): Twenty-four insulin-resistant women with PCOS. INTERVENTION(S): Hormonal evaluations and a standardized oral glucose tolerance test before and after a 3-month trial of 4 mg of rosiglitazone daily. MAIN OUTCOME MEASURE(S): Serum LH, FSH, T, IGF-1, IGFBP-1, IGFBP-3, leptin, 17alpha-hydroxyprogesterone, insulin, and glucose concentrations. The area under insulin curve (AUC-insulin), the HOMA index (insulin resistance), the QUICKI index (insulin sensitivity), and the beta-cell function were calculated. Body mass index (BMI) and the waist/hip ratio were evaluated. RESULT(S): A significant decrease was observed in serum fasting insulin, AUC insulin, HOMA index, beta-cell function, IGF-1, LH, and waist/hip ratio. The QUICKI index and IGFBP-1 increased significantly. Serum sex hormone-binding globulin, androgens, leptin, IGFBP-3, and BMI remained unchanged. Twenty-two of 23 females had their menses restored, and three patients became pregnant. One patient was excluded because she became pregnant at the second month. CONCLUSION(S): Associated with the decrease in LH, rosiglitazone improved insulin-resistance parameters and normalized the menstrual cycle, which suggests that this drug could improve the endocrine-reproductive condition in insulin-resistant women with PCOS.     

Increased frequency of the G972R variant of the insulin receptor substrate-1 (irs-1) gene among girls with a history of precocious pubarche

To test the hypothesis that lower sex hormone-binding globulin (SHBG) concentrations are associated with heterozygosity for the G972R variant of the IRS-1 gene among adolescent girls with a history of precocious pubarche (PP) and hyperinsulinemic ovarian hyperandrogenism.Association study.Academic research environment.Adolescent girls with a history of PP and healthy adolescent female control subjects.Determine body mass index; measure serum androgen, insulin-like growth factor (IGF)-binding protein 1, lipids, IGF-1, and SHBG concentrations; perform glucose tolerance tests; and assay for G972R variant of the IRS-1 gene.Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes.Twenty-five of 54 (45%) girls with a history of PP developed hyperinsulinemic ovarian hyperandrogenism at adolescence. Frequency of heterozygosity for G972 was 31% among girls with a history of PP, 40% among girls with hyperinsulinemic ovarian hyperandrogenism, and 19% among healthy control subjects. Sex hormone-binding globulin concentrations were lower among girls heterozygous for G972R variant. Predictors of progression from PP to hyperinsulinemic ovarian hyperandrogenism included chronological age, insulin, low-density lipoprotein cholesterol, and IGFBP-1 concentrations.The low mean SHBG concentration found among G972R carriers suggests that this variant may be a minor locus associated with development of hyperinsulinemic insulin resistance and ovarian androgen excess in girls with a history of PP.     

Maternal and fetal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3, and their relationship to fetal acidosis at delivery

OBJECTIVE: To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2), and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and in fetal cord blood at delivery. METHODS: Prospective cohort study of 1650 low-risk Caucasian women in a University teaching hospital in London. Statistical analysis was performed using commercial software (SPSS for Windows, version 6.1, SPSS, Chicago, Illinois, USA), with p<0.05 as significant. Maternal IGF 1, IGF 2 and IGF BP-3 were assessed on maternal blood at booking and in fetal blood by cord blood analysis at delivery. Cord pH was also recorded. RESULTS: There was no significant correlation between maternal IGF-1, IGF-2, or IGFBP-3 levels and fetal acidosis. However, a significant correlation does exist between cord IGF-1 levels and fetal acidosis. CONCLUSION: Fetal cord IGF-1 has a significant correlation with fetal acidosis at delivery.     

Serum levels of insulin, IGF-1, and IGFBP-1 in pre-eclampsia and eclampsia.

OBJECTIVES: To investigate whether the serum concentrations of insulin, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-1 (IGFBP-1) were altered in women with mild pre-eclampsia, severe pre-eclampsia, and eclampsia. METHODS: In this prospective study, we investigated 20 mild pre-eclamptic, 20 severe pre-eclamptic, and 20 eclamptic patients in the third trimester. The control group consisted of 20 healthy pregnant women. Serum levels of insulin, IGF-1, and IGFBP-1 were measured. RESULTS: In patients with eclampsia, serum levels of IGF-1 were lower, and IGFBP-1 were higher, respectively, than control and other study groups (P<0.001) The values of IGF-1 in mild pre-eclampsia and severe pre-eclampsia were lower compared with control groups (both P<0.01), but there were no differences between mild and severe pre-eclampsia. The serum levels of IGFBP-1 in severe pre-eclampsia were higher compared with control groups (P<0.01), but there was no statistical difference between mild pre-eclampsia and other groups. CONCLUSIONS: IGF-1 was lower, and IGFBP-1 was higher in pre-eclamptic and eclamptic patients than controls, these alterations were related to the severity of pre-eclampsia.     

Maternal zinc and cord blood zinc, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels in small-for-gestational-age newborns

PURPOSE: To determine the relationship between maternal serum zinc (Zn) levels and birth weight of the offspring and their correlation with cord blood Zn, insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels. METHOD: 22 term small-for-gestational-age (SGA) and 34 term appropriate-for-gestational-age (AGA) infants and their mothers were included. Maternal and cord blood Zn levels and cord blood IGF-1 and IGFBP-3 levels were measured. RESULTS: Eighteen percent of mothers had Zn deficiency (< 75 mcg/dl). No significant difference between IGF-1 and IGFBP-3 levels and birth weight of infants of the mothers with and without Zn deficiency was found. Maternal and neonatal Zn levels correlated (r = 0.38, p < 0.01). Mean IGF-1 and IGFBP-3 levels were significantly lower in the SGA group compared to the AGA group (42.3 +/- 16.8 ng/ml, 1.2 +/- 0.2 mcg/ml, and 62.4 +/- 22.7 ng/ml, 1.5 +/- 0.4 mcg/ml, p < 0.001). A correlation was found between birth weight, IGF-1 and IGFBP-3 levels, and weight gain of the mother during pregnancy (p < 0.01). CONCLUSIONS: Zn deficiency was not observed to be a risk factor for low birth weight. The significant difference between the SGA and AGA babies' IGF-1 and IGFBP-3 levels emphasizes function of the IGF system in intrauterine growth.     

Correction of insulin resistance and hyperandrogenism in polycystic ovary syndrome by combined rosiglitazone and clomiphene citrate therapy

OBJECTIVE: To investigate the effects of combined rosiglitazone and clomiphene citrate versus clomiphene citrate monotherapy on serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) levels in polycystic ovary syndrome (PCOS) and to evaluate these therapeutic interventions in the link between hyperinsulinemia and hormonal perturbations in PCOS. METHODS: We performed a randomized clinical study at the King Abul-Aziz and Cairo University Hospitals. We studied 50 women with PCOS. Clinical diagnosis was based on hyperandrogenism; hyperinsulinism; oligomenorrhea; or amenorrhea, anovulatory cycles, and ultrasonographic findings. They were randomly assigned to two groups of 25 women each. One group was treated with rosiglitazone and clomiphene citrate; the other was treated only with clomiphene citrate. Serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, dehydroepiandrosterone sulfate (DHEAS), free testosterone, IGF-1, and IFGBP-3 were measured by specific radioimmunoassays before and after treatment. RESULTS: Combined rosiglitazone and clomiphene treatment led to a significant reduction in area under the insulin curve (AUC insulin), whereas clomiphene monotherapy did not lead to this reduction. Both types of treatment induced a significant decrease in LH, LH:FSH ratio, free testosterone, and IGF1:IGBP-3 ratio and were associated with a significant increase in IGFBP-3 levels. These changes were more pronounced in PCOS patients treated with combined rosiglitazone and clomiphene than in those treated with clomiphene monotherapy. Regular menstrual cycles occurred in 72% of the former group and 48% of the latter. CONCLUSION: Combined rosiglitazone and clomiphene was an effective therapeutic regimen for correcting insulin resistance in patients with PCOS, possibly by reducing IGF1 bioavailability to the ovaries, thus modifying the hyperandrogenic intrafollicular milieu that occurs in PCOS. In addition, the clinical and hormonal responses were better than with clomiphene alone.     

Maternal insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and IGF BP-3 and the hypertensive disorders of pregnancy

Objective.?To investigate the relationship between levels of insulin-like growth factors 1 and 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in antenatal maternal serum and gestational hypertension and pre-eclampsia (PET).

Methods.?Prospective cohort study of 1650 low-risk Caucasian women in a University teaching hospital in London. Statistical analysis was performed using commercial software (SPSS for Windows, version 6.1, SPSS, Chicago, IL), with P?<?0.05 as significant. Maternal IGF 1, IGF 2 and IGF BP-3 were assessed on maternal blood at booking. Blood pressure was checked at each visit in conjunction with urine analysis. The Davey & MacGillivray 1988 classification system was used in making the diagnosis of PET.

Results.?There was no significant correlation between maternal IGF-1 or IGFBP-3 levels and gestational hypertension or PET. However, a significant positive correlation does exist between maternal IGF-2 levels and PET.

Conclusions.?Maternal IGF-2 has a significant positive correlation with PET.     

The Role of Serum Testosterone in Early Pregnancy Outcome: A Comparison in Women With and Without Polycystic Ovary Syndrome

ObjectiveHyperandrogenic conditions in women are associated with increased rates of miscarriage. However, the specific role of maternal testosterone in early pregnancy and its association with pregnancy outcome is unknown. The purpose of this study was to compare serum testosterone levels during early pregnancy in women with and without polycystic ovary syndrome (PCOS) who either had successful pregnancies or miscarried.MethodWe collected serum samples from women attending a university-based fertility centre at the time of their first positive serum beta human chorionic gonadotropin pregnancy test. The samples were subsequently assayed for total testosterone level. We used logistical regression modelling to control for PCOS diagnosis, BMI, and age.ResultsTotal testosterone levels were available for 346 pregnancies, including 286 successful pregnancies and 78 first trimester miscarriages. We found no difference in total testosterone levels between women who subsequently had an ongoing pregnancy (mean concentration 3.6 ± 2.6 nmol/L) and women with a miscarriage (mean 3.6 ± 2.4 nmol/L). Using the Rotterdam criteria to identify women with PCOS, we also found no differences in serum testosterone between women who had ongoing pregnancies or miscarriages, either with PCOS (P = 0.176) or without PCOS (P = 0.561).ConclusionsOur findings show that early pregnancy testosterone levels do not predict pregnancy outcome, and they call into question the role of testosterone in causing miscarriage in populations of women with PCOS. Further research is needed to elucidate the normal progression of testosterone levels during pregnancy and to investigate further the relationship between PCOS and miscarriage.     

Raised serum levels of matrix metalloproteinase-9 in women with polycystic ovary syndrome and its association with insulin-like growth factor binding protein-1

Background.?It has been suggested in recent studies that matrix metalloproteinases (MMPs) may be implicated in the pathogenesis of polycystic ovary syndrome (PCOS) through regulating ovarian tissue remodeling. In addition to degrading the extracellular matrix, MMPs exhibit the ability to cleave insulin-like growth factor binding protein-1 (IGFBP-1), the major regulator of insulin-like growth factor-I (IGF-I) in serum. The present study aimed to investigate the possible role of MMPs in the pathophysiology of PCOS.

Methods.?Serum levels of MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), IGF-I and IGFBP-1 were measured in 42 patients with PCOS and 30 healthy women with regular menstruation, matched for age and body mass index. Correlation between IGFBP-1 and other parameters in the PCOS group was analyzed by Pearson's linear correlations.

Results.?Serum MMP-9 concentrations and MMP-9/TIMP-1 ratios were significantly higher in PCOS women than in controls. Serum levels of IGFBP-1 were markedly lower in the PCOS group. There was a negative correlation between serum IGFBP-1 and MMP-9 in women with PCOS.

Conclusion.?Our results raise the possibility that MMPs may be implicated in the pathophysiology of PCOS either by regulating ovarian tissue remodeling or indirectly by facilitating IGF-I bioavailability through proteolysis of IGFBP-1.     

Chlamydia1 antibodies in women who suffer miscarriage

Objective To ascertain the relation between previous chlamydial infection and miscarriage.
Design A prospective study of 349 women who had a miscarriage.
Participants Women surgically treated for spontaneous pregnancy loss on an outpatient basis at a hospital.
Subjects Three hundred and forty-nine women who miscarried, of whom 91 had at least one previous miscarriage and 33 had had two or more miscarriages previously. Age-matched women who had a normal pregnancy served as controls.
Interventions Blood samples were drawn from patients and controls for antibody determination.
Main outcome measures Patients and controls were compared regarding the frequency of Chlamydia trachomatis IgG antibodies (titre 2 1/32). Antibodies to C. pneumoniae were also analysed to study cross reactivity.
Results The frequency of IgG antibodies among the patients was 137/349 (39.3%) which was not statistically different from that among controls (116/349; 33.2%). Even among those who had miscarried previously the antibody frequencies did not differ significantly between patients and controls. The rate of C. trachomatis antibodies was about the same whether or not antibodies to C. pneumoniae were present in both patients and controls.
Conclusion No association was found serologically between previous chlamydial infection and miscarriage and no significant cross reactivity between C. pneumoniae and C. trachomatis could be detected.     

Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors

OBJECTIVE: To determine if metformin therapy improves in vitro fertilization (IVF) outcomes in patients with clomiphene-resistant polycystic ovarian syndrome (PCOS). DESIGN: Retrospective data analysis of selective groups of patients. SETTING: A private IVF unit. PATIENT(S): Forty-six women with clomiphene citrate-resistant PCOS underwent 60 cycles of IVF embryo transfer with intracytoplasmic sperm injection. INTERVENTION(S): In half of the cycles, patients received metformin (1000 to 1500 mg) daily, starting the cycle prior to gonadotropin treatment. MAIN OUTCOME MEASURE(S): Total number of follicles; serum estradiol (E2) on the day of hCG administration and the cycle's E2 maximum; total number of oocytes, mature oocytes, embryos, fertilization, and pregnancy rates; and follicular fluid levels of insulin-like growth factors (IGF-I, IGF-II) and IGF-binding proteins (IGFBP-1, IGFBP-3). RESULT(S): In patients treated with metformin, the total number of follicles on the day of hCG treatment was decreased (23 +/- 1.2 vs. 33 +/- 2.6) with no change in follicles > or = 14 mm in diameter (21 +/- 1.2 vs. 25 +/- 1.7). Metformin treatment did not affect the mean number of oocytes retrieved (22 +/- 1.9 vs. 20.3 +/- 1.5). However, the mean number of mature oocytes (18.4 +/- 1.5 vs. 13 +/- 1.5) and embryos cleaved (12.5 +/- 1.5 vs. 5.9 +/- 0.9) were increased after metformin treatment. Fertilization rates (64% vs. 43%) and clinical pregnancy rates (70% vs.30%) were also increased. Metformin led to modulation of preovulatory of follicular fluid IGF levels with increases of IGF-I (140 +/- 8 vs. 109 +/- 7ng/mL) and decreased of IGFBP-1 (133 +/- 8 vs.153 +/- 9ng/mL). CONCLUSION(S): Metformin use appears to improve IVF outcomes in patients with clomiphene citrate-resistant PCOS.     

The effects of somatostatin in the polycystic ovary syndrome.

Eighteen obese women (body mass index 30 +/- 6.1 kg/m2) with hyperinsulinaemia and with the polycystic ovary syndrome took octreotide at the dose of 100 mug s.c. The effect of the drug was assessed on plasma levels of gonadotropins luteinising hormone (LH), follicle stimulating hormone (FSH), of insulin, insulin-like growth factor-1 (IGF-1), androstenedione, testosterone, dehydroepiandrosterone sulphate (DHEAS), sex hormone binding globulin (SHBG) and insulin-like growth factor-binding protein-3 (IGFBP-3). Octreotide significantly reduced LH (31.8%), insulin (52%), IGF-1 (14%), androstenedione (22.6%) and testosterone (20%) and increased IGFBP-3 (25%).     

IGF-1、IGF-2、IGFBP-3与非糖尿病孕妇巨大儿发生的相关性研究

目的探讨胰岛素样生长因子1、2（IGF-1、IGF-2）、胰岛素样生长因子结合蛋白3（IGFBP-3）与非糖尿病孕妇巨大儿发生的关联性。方法选择2010年1月至2011年5月于上海市浦东新区人民医院产前检查并分娩的初产妇,孕期纵向观察,抽取妊娠中期（26～28周）和妊娠足月（38～41周）的母血及孕妇分娩时新生儿出生体重≥4000g30例（巨大儿组）、2500～3500g30例（正常组）的脐血,应用放射免疫法检测IGF-1、IGF-2、IGFBP-3的水平,并进行对比分析。结果①两组孕妇妊娠足月IGF-1水平均高于妊娠中期,差异有高度统计学意义（分别为P〈0.0001、P〈0.001）,但妊娠中期和足月时,巨大儿组与正常组二组间比较差异均无统计学意义（P〉0.05）。巨大儿组脐血IGF-1水平高于正常组,差异有高度统计学意义（P〈0.0001）;②孕妇血清IGF-2水平巨大儿组与正常组比较差异无统计学意义（P〉0.05）;③孕妇妊娠中期、妊娠足月血清IG-FBP-3水平巨大儿组明显高于正常组,差异有高度统计学意义（分别为P〈0.001、P〈0.01）;④母血IGFBP-3水平、脐血IGF-1水平与新生儿出生体重正相关。结论 IGF-1参与了胎儿生长发育的调节;胎儿自身循环中的IGF-1与新生儿出生体重有关;非糖尿病孕妇血清IGFBP-3水平与巨大儿形成有关。     

Effects of laparoscopic ovarian drilling on young adult women with polycystic ovarian syndrome

STUDY OBJECTIVE: To assess changes in serum hormone levels and ovarian stromal blood flow after laparoscopic ovarian drilling (LOD) in young adult women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, nonrandomized study (Canadian Task Force classification II-1). SETTING: Tertiary care, major teaching hospitals. PATIENTS: Anovulatory young women with PCOS who were resistant to clomiphene citrate. INTERVENTION: Laparoscopic ovarian drilling. MEASUREMENTS AND MAIN RESULTS: To evaluate the endocrinological effects of LOD, serum leptin, insulin-like growth factor-1, estrone (E1), and estradiol were measured before and after ovarian drilling in the early follicular phase. Three-dimensional transabdominal power Doppler examinations were performed to determine the effects of LOD. Serum leptin was correlated with body mass index (BMI) before LOD. Levels of BMI, fasting blood sugar, and leptin were higher and LH, LH/FSH, and the sugar/insulin ratio were lower in the obese group. There were significant decreases in the free androgen index, and total testosterone, luteinizing hormone (LH), and LH/follicle-stimulating hormone (FSH) levels, and a significant increase in sex hormonebinding globulin (SHBG) concentration in the 3 months after the operation. The vascularization index and vascularization flow index of the intraovarian stroma significantly decreased after treatment. Reversed correlations between leptin and LH, LH/FSH, E1, thyroid-stimulating hormone, and SHBG were noted 3 months after the operation compared with levels obtained before the operation. CONCLUSIONS: Treatment of young adult women with PCOS using LOD did not influence leptin levels but changed the ovarian stromal blood flow dynamics during short-term follow-up. The surgical procedure may be beneficial both to endocrine profiles and to intraovarian stromal flow in patients with PCOS.     

胰岛素样生长因子1及胰岛素样生长因子结合蛋白1表达与妊娠期高血压疾病发病的关系

目的探讨胰岛素样生长因子1(IGF-1)与胰岛素样生长因子结合蛋白1(IGFBP-1)在妊娠期高血压疾病发病中的作用。方法采用酶联免疫吸附法(ELISA)及免疫组化方法检测60例妊娠期高血压疾病患者(妊娠期高血压疾病组,其中妊娠期高血压20例、轻度子痫前期19例、重度子痫前期21例)及18例正常妊娠妇女(对照组)的血清及胎盘组织中IGF-1及IGFBP-1的水平,并分析妊娠期高血压疾病组患者血清中IGF-1水平与胎盘组织中IGFBP-1的相关性。结果(1)血清IGF-1水平:妊娠期高血压疾病组为(229±100)μg/L,明显低于对照组的(336±120)μg/L,两组比较,差异有统计学意义(P<0.01)。妊娠期高血压患者血清中IGF-1水平为(303±80)μg/L,轻度子痫前期患者为(233±77)μg/L,重度子痫前期患者为(155±73)μg/L。3者间比较,差异有统计学意义(P<0.05)。(2)胎盘组织中IGF-1阳性率:妊娠期高血压疾病组为48%(29/60),明显低于对照组的83%(15/18),两组比较,差异有统计学意义(P<0.01);轻、重度子痫前期患者明显低于对照组(P<0.05,P<0.01)。(3)血清中IGFBP-1水平:妊娠期高血压疾病组为(161±90)μg/L,明显高于对照组的(98±75)μg/L,两组比较,差异有统计学意义(P<0.01)。妊娠期高血压患者为(97±73)μg/L,轻度子痫前期患者为(157±69)μg/L,重度子痫前期患者为(225±81)μg/L。3者间比较,差异有统计学意义(P<0.05)。(4)胎盘组织中IGFBP-1阳性率:妊娠期高血压疾病组为77%(46/60),明显高于对照组的39%(5/18),两组比较,差异有统计学意义(P<0.01);轻、重度子痫前期患者明显高于对照组(P<0.05,P<0.01)。(5)相关性:妊娠期高血压疾病组患者血清及胎盘组织中IGF-1水平分别与相应部位的IGFBP-1水平均呈负相关(r=-0.269,P<0.05;r=-0.396,P<0.01)。血清中IGFBP-1水平与胎盘组织中IGFBP-1表达水平呈正相关(r=0.388,P<0.01)。结论孕妇血清及胎盘组织中IGF-1、IGFBP-1水平变化与妊娠期高血压疾病发病及病情发展有关。     

Sperm DNA fragmentation is a novel biomarker for early pregnancy loss

Research questionSpontaneous pregnancy loss affects 10–15% of couples, with 1–2% suffering recurrent pregnancy loss and 50% of miscarriages remaining unexplained. Male genomic integrity is essential for healthy offspring, meaning sperm DNA quality may be important in maintaining a pregnancy. Does sperm DNA fragmentation measured by alkaline Comet assay act as a biomarker for early pregnancy loss?DesignSperm DNA fragmentation was measured by alkaline Comet test in 76 fertile donors and 217 men whose partners had recently experienced miscarriage. Couples were divided into five groups for analysis: one miscarriage after spontaneous conception; two or more miscarriages after spontaneous conception; one miscarriage after fertility treatment; two or more miscarriages after fertility treatment and biochemical pregnancy.ResultsReceiver operator characteristic curve analysis was used to determine ability of the average Comet score (ACS), low Comet score (LCS) and high Comet score (HCS) to diagnose miscarriage and develop clinical thresholds comparing men whose partners have miscarried with men with recently proven fertility. Male partners of women who had miscarried had higher sperm DNA damage (ACS 33.32 ± 0.57%) than fertile men (ACS 14.87 ± 0.66%; P < 0.001). Average Comet score, HCS and LCS all have promise as being highly predictive of sporadic and recurrent miscarriage using clinical thresholds from comparisons with fertile men's spermatozoa: receiver operating characteristic curve AUC for ACS ≥26%, 0.965; LCS ≤70%, 0.969; HCS ≥2%, 0.883; P <0.0001.ConclusionsSperm DNA damage measured by the alkaline Comet has promise as a robust biomarker for sporadic and recurrent miscarriage after spontaneous or assisted conception, and may provide novel diagnoses and guidance for future fertility pathways.