Birth weight and age at menarche in patients with polycystic ovary syndrome or diminished ovarian reserve, in a retrospective cohort

BACKGROUND: Few studies have investigated the association between subfertility in women and factors in early life such as birth weight and age at menarche, and most have produced contradictory results. In the present study, this association was investigated among women undergoing artificial reproductive techniques (ART), including IVF for reason of polycystic ovary syndrome (PCOS) or diminished ovarian reserve. Herein, PCOS included oligomenorrhoea and at least one additional symptom such as hyperandrogenism, hirsutism or polycystic ovaries on ultrasound. In most patients this was concomitant with elevated serum LH levels. Diminished ovarian reserve was defined as receiving a donated oocyte or having a low response to ovarian hyperstimulation. METHODS: Among a retrospective cohort of 26 428 women diagnosed with subfertility between 1980 and 1995, three study groups and one reference group were defined using data from medical records. Women were included in the first group if diagnosed as having PCOS (n = 265). In order to define diminished ovarian reserve capacity, two groups were selected: (i) women receiving a donated oocyte (n = 98); and (ii) women having a low response (three follicles or less) to ovarian hyperstimulation in both their first and second IVF cycles (n = 351). Women with tubal obstruction formed the reference group (n = 957). In a logistic regression model, the effect of birth weight and age at menarche was examined. Information on both variables was obtained from mailed questionnaires. RESULTS: Birth weight did not differ significantly between the study groups and the reference group. However, PCOS patients were significantly older at menarche [OR 3.31 (2.18-5.04)]. Women receiving a donated oocyte and low responders were significantly younger at menarche [OR 2.67 (1.35-5.29) and OR 2.01 (1.26-3.20) respectively]. CONCLUSION: The fetal origins hypothesis, the association between intrauterine growth retardation and disease in adult life, could not be confirmed, though a relationship between timing of menarche and PCOS and a diminished ovarian reserve was identified. Further investigation of the effect of birth weight on fertility outcome in a prospective setting is strongly advised.     

Estrogen-metabolizing gene polymorphisms and age at natural menopause in Caucasian women

BACKGROUND: Lifestyle parameters, personal history and genetic factors are thought to affect the timing of natural menopause in humans. Based on their biological function, estrogen-metabolizing gene polymorphisms have been regarded as candidate genes for early menopause. METHODS: In the present cross-sectional, multi-centre study, we analysed nine single nucleotide polymorphisms of six estrogen-metabolizing genes [three estrogen-synthesizing genes, i.e. 17-beta-hydroxysteroid dehydrogenase type 1 (17-beta HSD), cytochrome P-450 (CYP) 17 and CYP19; and three estrogen-inactivating genes, i.e. catechol-O-methyltransferase (COMT), CYP1A1 and CYP1B1] by sequencing-on-chip-technology in 1360 Caucasian women with natural menopause. Women's lifestyle parameters, reproductive and personal histories were ascertained. RESULTS: Carriage of at least one mutant allele of the CYP1B1-4 Asn453Ser A--> G polymorphism (P = 0.004) and the number of full-term pregnancies (P < 0.001) were found to be independently associated with age at natural menopause. Women with at least one polymorphic allele of CYP1B1-4 experienced natural menopause earlier than non-carriers of the polymorphism [mean (SD) 48.6 (5.0) versus 49.4 (4.3) years]. Women with no, one, two and three or more full-term pregnancies experienced natural menopause at 48.5 (5.0), 48.8 (4.8), 49.5 (4.2) and 49.6 (4.6) years, respectively. CONCLUSION: We present the most comprehensive data on estrogen-metabolizing gene polymorphisms and timing of natural menopause to date. The number of full-term pregnancies and the CYP1B1-4 polymorphism are significant predictors of timing of natural menopause in Caucasian women.     

Birth weight in pre-eclamptic and normotensive twin pregnancies: an analysis of discordance and growth restriction

The aim of this study was to verify whether twin pregnancies complicated by pre-eclampsia were associated with a higher rate of inter-twin weight discordance or an increased prevalence of small for gestational age (SGA) neonates than in normotensive twin pregnancies. A 17 year retrospective study was undertaken by examining 76 twin pregnancies complicated by pre-eclampsia and comparing them with 400 normotensive twin pregnancies. The case notes were reviewed in reference to birth weight differences, birth order, pregnancy outcome and inter-twin birth weight discordance. Statistical analyses were performed with t-test, contingency tables, regression curves, rank sum test and non-parametric survival plots. Power analysis was also carried out. Pre-eclamptic twin pregnancies were delivered at similar weeks of gestation to normotensive. They resulted in a smaller size for the second twin the earlier the delivery week, while in normotensive twin pregnancies no significant difference occurred at any week. Twin pregnancies complicated by pre-eclampsia showed higher rates of SGA neonates among second twins than those with normal pressure. The >25% discordance was associated with lower gestational age at delivery in each group [mean (range) 33 weeks (27-38) versus 37 (29-41), P < 0.005 pre-eclampsia and 35 weeks (25-41) versus 38 (25-42), P < 0.001 normotensive]. In pre-eclampsia the concomitant occurrence of SGA second twin and the discordance >25% was associated with shorter gestation while the presence of SGA second twin alone was not.     

Ovary and ovulation: A model conforming the decline in follicle numbers to the age of menopause in women

The store of primordial follicles in the ovary is fixed beforebirth and dwindles with age until it is unable to provide enoughGraafian stages to sustain menstrual cyclicity. According toa simple bi-exponential model of ageing, the rate of follicledisappearance increases at age 37.5 years (or when 25 000 folliclesremain) so that the numbers fall to approximately 1000 at 51years, the median age of menopause in the population. This studyattempts to produce a biologically more realistic model of fofficledisappearance and harmonizes follicle dynamics with the distributionof menopausal ages from an American survey. The step-changein the rate of fofficle attrition was replaced by a model whichassumed that this rate changes more gradually with the sizeof the follicle store. This produced a distribution of predictedmenopausal ages (based on an assumed threshold of 1000 follicles)which was closer to observed data. The fit further improvedwhen the model was modified by having a threshold that variedacross the population. Using such a stochastic threshold modelfor menopause, the number of fertile years remaining could beforecast with an acceptable margin of uncertainty if it everbecomes possible to estimate the size of the follicle storein vivo.     

Birth weight in offspring of mothers with polycystic ovarian syndrome

BACKGROUND: A relationship between reduced fetal growth and the polycystic ovary syndrome (PCOS) has been proposed in girls with PCOS. However, the birth weight in the offspring of PCOS mothers has not been systematically investigated. The aim of this study was to establish the birth weight of newborns of mothers with PCOS and to compare it with a control group of newborns of normal women matched by age and weight at the beginning of pregnancy. METHODS: The birth weight of 47 infants born from singleton pregnancies in women with well-documented PCOS was compared with 180 infants born from singleton pregnancies in healthy controls. RESULTS: The prevalence of small for gestational age (SGA) infants was significantly higher in the PCOS group compared to the control group (12. 8% versus 2.8%, respectively, P<0.02). Moreover, SGA infants born to PCOS mothers were smaller than those born to control mothers (P<0.05). The prevalence of large for gestational age infants (LGA) was similar in both groups, but birth length of LGA newborns was greater in PCOS women than controls (P<0.05). CONCLUSIONS: PCOS mothers showed a significantly higher prevalence of SGA newborns which cannot be completely attributed to pregnancy complications, and seems to be more related to the PCOS condition of the mother.     

Risks of preterm delivery and association with maternal age, birth order, and fetal gender.

The risk of preterm delivery in a recent sample (1990-1994) of Italian liveborns was examined, taking into account child birth order, and maternal age and education in addition to the fetal gender. Univariate analyses showed that a higher risk was associated with male than female babies, with first- than second-born children, with older mothers, and with less educated mothers. The relative weights of the factors examined were evaluated through logistic regression analyses and the highest and the lowest risks were found to be associated with advanced maternal age and male fetal gender respectively. Our findings therefore suggest that biological factors associated more with advanced maternal age than with the male gender of the fetus may influence premature onset of labour.     

Genetic and environmental variation in the birth weight of twins

Two novel approaches to the analysis of twin data are illustrated with data from birth weight in twins. First, two possible covariates of birth weight are fitted to the data simultaneously, allowing for linear effects of these variables, and their correlation. Second, information on chorionicity is used to estimate the effects of chorion type on birth weight. The data were collected from a large sample of twins born in East Flanders, Belgium. Variation and covariation in twins were considered as a function of sex, chorionicity, maternal age, gestational age, and genotype. No evidence for sex differences in causes of variation was found. As expected, the largest source of variation in birth weight was associated with gestational age. Other common environmental influences were nonsignificant. Heritability was significant, constituting approximately 40% of variation not associated with maternal and gestational age. A small but significant effect of chorionicity was found, such that dichorionic twins show a greater similarity than monochorionic.The theoretical work and data analysis described in this paper were made possible by NATO Grant 86/0823 and grants from the Belgian National Research Fund, the State University of Gent, and the Catholic University of Leuven. Dr. Neale was supported by NIH Grants MH-40828. We are also grateful to Drs. R. Vlietinck and R. Derom for excellent organization of the successful workshop.     

Predicting age at onset of menopause: Testing the “adaptive onset” hypothesis

This study tests the “adaptive onset” hypothesis (AOH) proposed by Kuhle and explores the potential adaptive origins of menopause (Kuhle (2007) [3]). The AOH posits that both menopause and the timing of its onset are adaptive, and that age at onset may be mediated according to the likelihood of successful continued reproduction. Twelve factors were hypothesized to predict whether continued reproduction would be successful. Eight factors were tested using data extracted from the NLS Mature Women cohort. Statistical analyses reveal no support for predictions of the AOH; in fact, a majority of analyses suggest trends opposite from those predicted.     

A comparison of the merits of using birth weight,or appropriateness of birth weight to gestational age,in the assessment of subsequent growth in twin children

Background: Size at birth has an important relationship to subsequent growth. Many reports subgroup subjects according to birth weight or birth weight in relation to the duration of gestation, and it is not clear whether one of these methods is more relevant to subsequent growth or if in fact they are comparable.

Aim: The present study compared the outcome of twins in terms of pre-pubertal weight and height when sub-grouped according to birth weight (BW), or the appropriateness of birth weight for the duration of gestation (BW-SDS).

Subjects and methods: The birth weights of 1533 twins were graded into four subgroups according to BW or BW-SDS. The relationship of birth weight to subsequent weight and height standard deviation scores, obtained between the ages of 2 and 9 years, were compared on the basis of these two methods.

Results: There was a marked difference in identity of the twins who fell into each of the four subgroups by the two methods. Despite this, no difference was found in the subsequent weight and height of the twins.

Conclusions: Analysis of data relating BW-SDS to subsequent growth shows no significant difference to those groups using BW alone.     

Comparison of fetal growth in singleton, twin, and triplet pregnancies.

The objective of this longitudinal retrospective study was to evaluate differences of the fetal growth and fetal organ growth among singleton small for gestational age (S-SGA), singleton appropriate for gestational age (S-AGA), twin (Tw-AGA), and triplet (Tri-AGA) infants. Ultrasonographic examinations were performed on 35 S-AGA, 18 S-SGA, 52 Tw-AGA and 12 Tri-AGA fetuses. Circumferences of head (HC), abdomen (AC), spleen (SC) and adrenal gland (AGC) and lengths of femur diaphysis (FDL), liver (LL), estimated weight (EWT) were measured every 2 weeks after 15 weeks of menstrual age until delivery. There was no significant difference in predicted HC values in S-AGA, Tw-AGA and Tri-AGA fetuses; these values were lowest in S-SGA fetuses. As the number of fetuses in the uterus increased with advancing menstrual age, the slope of the growth curve for predicted AC value became lower, but there was no significant difference between Tri-AGA and S-SGA fetuses. There was no significant difference in predicted FDL values among Tw-AGA, Tri-AGA and S-SGA fetuses; those values were significantly lower than that in S-AGA fetuses. There was no significant difference in predicted EWT value between Tw-AGA and Tri-AGA fetuses, which were intermediate between those for S-AGA and S-SGA fetuses. There were no significant differences in predicted SC and AGC values between S-AGA and Tw-AGA fetuses, respectively. However, in S-SGA fetuses, the slopes of the growth curve for SC and AGC were lower than those in the other two groups with advancing menstrual age. There were slight differences in predicted LL values between S-AGA, S-SGA and Tw-AGA fetuses. These results suggest that in AGA fetuses, there was a slight difference in growth pattern among singleton, twin, and triplet pregnancies.     

Age at menopause and determinants of hysterectomy and menopause in a multi-ethnic community: The Hilo Women's Health Study

Objectives

A lifespan approach was used to evaluate age at menopause, and determinants of surgical and natural menopause, in the multi-ethnic community of Hilo, Hawaii.

Study design

Participants aged 40–60 years (n = 898) were drawn from a larger, randomly generated sample recruited by postal questionnaires. Median age at natural menopause was computed by probit analysis. Logistic regression analysis was applied to examine determinants of hysterectomy, and Cox regression analysis was used to examine risk factors for an earlier age at menopause.

Main outcome measures

History of hysterectomy, age at menopause.

Results

Frequency of hysterectomy was 19.2% at a mean age of 40.5 years. The likelihood of hysterectomy increased with older ages, lower education, mixed ancestry, having been overweight at age 30, and married 20 years prior to survey. Median age at natural menopause was 53.0 years. Smoking and not being married 10 years before survey were associated with an earlier age at menopause.

Conclusions

Median age at menopause was later than the national average. Ethnicity and education were determinants of hysterectomy, but not associated with age at natural menopause. Events later in the lifespan (e.g., smoking and not being married 10 years prior to the survey) were more important than earlier events (e.g., childhood residence) in relation to age at menopause. The timing of weight gain and marital status appear to be important in relation to surgical menopause, and the timing of marital status appears to be important in relation to the timing of natural menopause.     

No association of estrogen receptor alpha and cytochrome P450c17alpha polymorphisms with age at menopause in a Dutch cohort

BACKGROUND: Age at menopause is under strong genetic control. So far, genetic variations of only one gene, the PvuII polymorphism of the estrogen receptor alpha (ERalpha) gene, have been shown to be associated with age at onset of menopause. This study aims to investigate whether PvuII, XbaI and B-variant polymorphisms of the ERalpha gene, and the MspAI polymorphism of the cytochrome P450c17alpha (CYP17) gene are associated with age at menopause in a Dutch cohort. METHODS: DNA was isolated from urine samples of 385 Caucasian women with natural menopause and the genotypes of the four polymorphisms were determined. A questionnaire was used for background characteristics. The genotypes of PvuII, XbaI, MspAI were obtained by PCR restriction fragment length polymorphism analysis. The B-variant was determined with an allele-specific oligonucleotide hybridization method. Two-sided t-tests were performed to assess the association between the four polymorphisms and menopausal age. The PvuII and XbaI polymorphisms were analysed separately as well as in a combined score. RESULTS: The results show that none of the polymorphisms independently, nor the combined genotypes for PvuII and XbaI, were associated with age at natural menopause. CONCLUSION: No evidence was found for a relationship between common variants of the ERalpha gene and the CYP17 gene with age at natural menopause.     

单相抑郁症父母育龄及胎次效应的研究

为了了解单相抑郁症有否父母育龄及胎次效应，用Haldane和Smith方法对此进行了研究。结果表明单相抑郁症有父母育龄及胎次效应，这种效应为父母育龄越小或胎次早者易患单相抑郁症，提示适龄婚育对防止这种疾病的发生具有重要意义。     

Impaired fetal growth decreases the risk of childhood atopic eczema: a Swedish twin study

Background Studies have found associations between birth weight and risk of atopic eczema or allergic rhinitis (AR), although this could be due to confounding. Objective We sought to evaluate associations between fetal growth and the risk of atopic eczema or AR in childhood, controlling for gestational age (GA), shared (familial) environmental and genetic factors. Methods Data on atopic eczema, AR, birth characteristics and confounders were collected from registers and telephone interviews with the parents of 9‐ and 12‐year‐old twins. Firstly, cohort analyses on all twins (eczema n=10 132 and AR n=10 896) were performed. Secondly, to control for genetic and shared environment, co‐twin‐control analyses were performed in twin pairs discordant for atopic eczema (n=480) and AR (n=332). Results The rate of atopic eczema increased with birth weight, from 12.6% in twin children <2000 g to 17.3% in children 3500 g. The rate of AR varied between 7.8% and 8.8%. In the cohort analyses, the odds ratio (OR) for atopic eczema was 1.62 (95% CI: 1.27–2.06) for 500 g increase in birth weight and 1.00 (95% CI: 0.75–1.33) for AR. In co‐twin‐control analyses on atopic eczema, OR was 3.93 (95% CI: 1.55–9.98) for 500 g increase in birth weight, with no significant difference between monozygotic and dizygotic twins (P=0.84). Conclusions We found a positive association between fetal growth and childhood atopic eczema, but not AR, independent of GA, shared environmental and genetic factors. This indicates fetal growth affects the immune system, and supports further studies on early mechanisms. Cite this as: C. Lundholm, A. K. Örtqvist, P. Lichtenstein, S. Cnattingius and C. Almqvist, Clinical & Experimental Allergy, 2010 (40) 1044–1053.     

Physiology: Morphology and ultrastructure of Fallopian tube epithelium at different stages of the menstrual cycle and menopause

The Fallopian tube has been reported to undergo cyclical changes.However, many studies of tubal ultrastructure have either examinedone segment of the tube only or studied animal oviducts. Theaim of this study was to document in detail the combined morphologicaland ultrastructural features of the epithelial lining alongthe length of the tube in women at different stages of the menstrualcycle. We report an increase in the proportion of ciliated cellsalong the tube, being highest in the fimbriae, but no substantialdifference between the follicular and luteal phases of the menstrualcycle. In the late follicular phase, fragments of cytoplasmicand cellular material were seen in the isthmic lumen but notin the outer tubal segments. Similarly, surface domes and secretorygranules were more prominent in the mid-tube and ampullary sectionsthan in the fimbriae. This surface activity was followed byrelative quiescence in the early/mid luteal phase with reversionto a more active surface but with little secretory activityin the late luteal phase. These findings along the Fallopiantube substantiate the concept of functional differentiationbetween the different segments and necessitate further studiesto determine its clinical relevance.     

Gestational age and occurrence of atopy at age 31—a prospective birth cohort study in Finland

BACKGROUND: It has been suggested that main risk factors for development of allergic diseases operate already during pregnancy and in early childhood. OBJECTIVE: To study the association between gestational age, birth weight, parity and parental farming with the risk of atopy and asthma in young adults. METHODS: In a prospective birth cohort study, 5192 subjects born in Northern Finland in 1966 were followed up at the age of 31. Skin prick tests were done to three of the most common allergens in Finland and to house dust mite. Data on doctor-diagnosed asthma was obtained from questionnaires. Perinatal data had already been collected during pregnancy. RESULTS: The risk of atopy increased linearly with increasing length of pregnancy among babies born in the 35th weak of gestation or later. Gestational age equal to, or over 40 weeks compared with less than 36 weeks was associated with an increased risk of atopy (multivariate odds ratio 1.65, 95% CI 1.16, 2.34). The association was stronger among farmers' children (P for interaction 0.01). High parity and being a farmer's child (multivariate odds ratio 0.50, 95% CI 0.42-0.60) was associated with decreased risk of atopy. In contrast, no associations were observed for doctor-diagnosed asthma. CONCLUSIONS: The results underline the importance of pregnancy and very early childhood in the development of atopy, and suggest that timing of the environmental exposure is of importance for the immune system. No association was observed for asthma, which may be due to the multifactorial origins of asthma.     

The effect of age on the cyclical patterns of plasma LH, FSH, oestradiol and progesterone in women with regular menstrual cycles

Luteinizing hormone (LH), follicle-stimulating hormone (FSH),oestradiol and progesterone concentrations in plasma were obtaineddaily throughout the menstrual cycles of 94 regularly cyclingwomen, aged between 24 and 50 years. Although mean LH concentrationschanged little with advancing age, mean FSH concentrations weresignificantly (P< 0.001) elevated from the age of 39 years.FSH concentrations in the oldest women studied (48–50years) were 3-fold greater than in the younger controls (womenaged 23–35 years). LH concentrations rose slightly (P< 0.05) during the last 5 years only. The increase in FSHconcentration was not, however, uniform across the cycle, butwas confined predominantly to the mid-follicular and post-ovula-toryphases (i.e. those times in the normal menstrual cycle whencirculating inhibin concentrations appear to be minimal). Despitethe clear increases in FSH concentration, there was little alterationin the mean steroid profiles which remained within the normalfertile range throughout the last decade of reproductive life.The only exception to this was a small, transient, but significant(P< 0.05) decrease in pre-ovulatory oestradiol concentrationbetween the ages of 36 and 38 years, which was followed by atransient increase (P< 0.01) in oestradiol concentrationbetween 39 and 44 years. However, no corresponding significantchanges in mean progesterone concentrations were observed.     

A randomized double-blind controlled study on the efficacy of laser zona pellucida thinning on live birth rates in cases of advanced female age

BACKGROUND: It is conceivable that defective embryo hatching plays a part in the mechanisms involved in the decrease of embryo implantation rates with advancing age. In an effort to test this hypothesis, we tested the effectiveness of assisted hatching (AH) in women > or =37 years of age. METHODS: We prospectively studied 103 IVF-embryo transfer patients undergoing 103 embryo transfers. All of them were > or =37 years of age and had <3 previous IVF-embryo transfer attempts. Laser-AH of transferred embryos was either performed (AH group, n = 49) or not (control group, n = 54) according to randomized and double-blind methodology. Primary outcome was live birth rate. RESULTS: Population characteristics were comparable in AH and control groups as well as the mean number of embryos transferred (2.7 +/- 0.6 versus 2.7 +/- 0.6) and the prevalence of top quality embryos transferred (65 versus 59%, respectively). We failed to find any statistically significant difference between AH and control groups with regard to implantation (16.1 versus 16.7%, respectively) and live birth rates (22.4 versus 29.6%, respectively). CONCLUSION: The present study indicates that AH does not improve IVF-embryo transfer outcome in women aged > or =37 years.     

Physiology: A comparative morphological and ultrastructural study of endometrial gland and Fallopian tube epithelia at different stages of the menstrual cycle and the menopause

Cyclical ultrastructural changes in the endometrium and Fallopiantube have been reported previously but in different subjects.The aim of this study is to compare cyclical changes in endometrialgland and tubal (isthmic, mid-tube, ampulla, and fimbria) epitheliain the same subjects with a view to identifying any similaritiesor differences which may have clinical implications for assistedreproduction treatment. Endometrial and Fallopian tube sampleswere obtained from women undergoing hysterectomy and salpingectomy.We report similar epithelial surface changes taking place inthe endometrial glandular and endosalpingeal epithelia withthe exception of the fimbriae. Secretions within endometrialgland lumen and the isthmus increase throughout the late follicularphase and before ovulation, then dissipate in these two regionssimultaneously in the early/mid luteal phase. Similarly, inthe late follicular and pre-ovulatory phases, the process ofgranule secretion is similar in the glandular epithelium, isthmusand ampulla. In the fimbriae, no comparable activity is notedduring these phases of the menstrual cycle. The differencesreflect the functional differentiation between these regions.Equally, the observed similarities highlight the need for furthercomparative studies to determine the role of these secretionsin early embryonic development and their clinical relevance.