Menopause is defined as the permanent cessation of ovulation and hence menstruation due to ovarian failure. The median age of menopause is 51 years. However, early menopause might occur at 40 years ...of age while late menopause might happen as late as 62 years of age. Premature menopause is defined as the cessation of ovulation prior to the age of 40 years, a condition generally referred to as primary ovarian insufficiency (POI). Menopause is also a highly heritable condition. Genetic variants are known to contribute to ∼50% of the variation in age at menopause. Several genetic studies have tried to unravel this genetic background making use of different genetic techniques in population studies as well as in animal models. Genome-wide linkage studies have identified only a limited amount of genetic variants that seem to be associated with menopause. Population-based studies as well as animal research into the genetic background of POI have identified several genetic variants that seem to be associated with POI. However, a lot of these studies suffer from methodological flaws because results are generally not replicated in different independent samples and most of these studies are underpowered. Hence, results are conflicting. Recent genome-wide association studies (GWAS) have identified several genetic variants that are associated with menopause and POI. Genes seem to be involved in DNA repair and maintenance as well as in immune function. Biological as well as epidemiological data seem to indicate that reproductive performance, age at menopause, and longevity are interlinked through common genetic factors involved in DNA repair and maintenance. In case these systems fail, cell death and accelerated aging occur. Consequently, it seems that the aging of the soma, as a result of dysfunctional DNA repair, is responsible for failure to reproduce and the subsequent occurrence of menopause. Hence, reproductive performance constitutes a good predictor for general health in later life.
Aims/hypothesis
Previous literature documents controversial results for the impact of dehydroepiandrosterone (DHEA) in glucose metabolism. We aimed to assess the associations between serum levels of ...DHEA and its main derivatives DHEA sulphate (DHEAS) and androstenedione, as well as the ratio of DHEAS to DHEA, and risk of type 2 diabetes.
Methods
We used data on serum levels of DHEA, DHEAS and androstenedione from 5189 middle-aged and elderly men and women from the prospective population-based Rotterdam Study. Type 2 diabetes was defined as a fasting blood glucose ≥7.0 mmol/l or a non-fasting blood glucose ≥11.1 mmol/l.
Results
During a median follow-up of 10.9 years, 643 patients with incident type 2 diabetes were identified. After adjusting for age, sex, cohort, fasting status, fasting glucose and insulin, and BMI, both serum DHEA levels (per 1 unit natural log-transformed, HR 0.76, 95% CI 0.67, 0.87) and serum DHEAS levels (per 1 unit natural log-transformed, HR 0.82, 95% CI 0.73, 0.92) were inversely associated with risk of type 2 diabetes in the total population. Further adjustment for alcohol, smoking, physical activity, prevalent cardiovascular disease, serum total cholesterol, use of lipid-lowering medications, systolic BP, treatment for hypertension, C-reactive protein, oestradiol and testosterone did not substantially affect the association between DHEA and incident type 2 diabetes (per 1 unit natural log-transformed, HR 0.80, 95% CI 0.65, 0.99), but abolished the association between DHEAS and type 2 diabetes. Androstenedione was not associated with risk of type 2 diabetes, nor was DHEAS to DHEA ratio.
Conclusions/interpretation
DHEA serum levels might be an independent marker of type 2 diabetes.
Objective To study associations between periconceptional dietary patterns and semen quality parameters. Design Prospective periconception cohort study. Setting Tertiary hospital. Patient(s) One ...hundred and twenty-nine male partners of pregnant women who participated in the Rotterdam Periconception Cohort (Predict study). Intervention(s) None. Main Outcome Measure(s) Semen quality parameters—ejaculate volume, sperm concentration, total sperm count, progressive motility, immotile sperm, and total motile sperm count (TMSC). Result(s) Men included in our study were on average 35 (±6 standard deviation) years old and had a body mass index of 26.4 ± 4 kg/m2 . Two dietary patterns were identified using principle component analysis, which were labeled as “healthy” and “unhealthy.” An increase of one factor score (stated as β) represented an increase of 1 standard deviation. Sperm concentration (β = 0.278; 95% CI, 0.112–0.444), total sperm count (β = 1.369; 95% CI, 0.244–2.495), progressive motility (β = 4.305; 95% CI, 0.675–7.936), and TMSC (β = 0.319; 95% CI, 0.113–0.526) were all positively associated with a strong adherence to the healthy dietary pattern. Subgroup analysis showed that these associations were mainly present in men with a TMSC <10 million spermatozoa. Although there was a trend toward a diminution in semen quality, we found no statistically significant associations with strong adherence to the unhealthy dietary pattern. Conclusion(s) The positive associations between strong adherence to a healthy dietary pattern and semen parameters in men with poor semen quality support the importance of preconceptional tailored nutritional counseling and coaching of couples who are trying to conceive.
Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in ...up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10(-8)), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10(-9)), higher insulin resistance (P=6 × 10(-4)) and lower serum sex hormone binding globulin concentrations (P=5 × 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10(-5)). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk.
The association between preconception dietary intake of the polyunsaturated fatty acids (LC-PUFAs) omega-6 and omega-3 and the E2 levels and IVF/intracytoplasmic sperm injection (ICSI) outcome were ...investigated in women in a prospective study. It revealed that high intakes of omega-3 LC-PUFA alpha-linolenic acid increase baseline E2 , high intakes of eicosapentaenoic acid and docosahexaenoic acid reduce E2 response and the number of follicles after ovarian stimulation, and total omega-3 intake, in particular alpha-linolenic acid and docosahexaenoic acid, improve embryo morphology.
In the past decades evidence has accumulated that women with reproductive and pregnancy-related disorders are at increased risk of developing cardiovascular disease (CVD) in the future. Up to now ...there is no standardised follow-up of these women becausee guidelines on cardiovascular risk management for this group are lacking. However, early identification of high-risk populations followed by prevention and treatment of CVD risk factors has the potential to reduce CVD incidence. Therefore, the Dutch Society of Obstetrics and Gynaecology initiated a multidisciplinary working group to develop a guideline for cardiovascular risk management after reproductive and pregnancy-related disorders.
The guideline addresses the cardiovascular risk consequences of gestational hypertension, preeclampsia, preterm delivery, small-for-gestational-age infant, recurrent miscarriage, polycystic ovary syndrome and premature ovarian insufficiency. The best available evidence on these topics was captured by systematic review. Recommendations for clinical practice were formulated based on the evidence and consensus of expert opinion. The Dutch societies of gynaecologists, cardiologists, vascular internists, radiologists and general practitioners reviewed the guideline to ensure support for implementation in clinical practice.
For all reproductive and pregnancy-related disorders a moderate increased relative risk was found for overall CVD, except for preeclampsia (relative risk 2.15, 95% confidence interval 1.76-2.61).
Based on the current available evidence, follow-up is only recommended for women with a history of preeclampsia. For all reproductive and pregnancy-related disorders optimisation of modifiable cardiovascular risk factors is recommended to reduce the risk of future CVD.
Abstract
BACKGROUND
The existence of an extensive microbiome in and on the human body has increasingly dominated the scientific literature during the last decade. A shift from culture-dependent to ...culture-independent identification of microbes has occurred since the emergence of next-generation sequencing (NGS) techniques, whole genome shotgun and metagenomic sequencing. These sequencing analyses have revealed the presence of a rich diversity of microbes in most exposed surfaces of the human body, such as throughout the reproductive tract. The results of microbiota analyses are influenced by the technical specifications of the applied methods of analyses. Therefore, it is difficult to correctly compare and interpret the results of different studies of the same anatomical niche.
OBJECTIVES AND RATIONALE
The aim of this narrative review is to provide an overview of the currently used techniques and the reported microbiota compositions in the different anatomical parts of the female and male reproductive tracts since the introduction of NGS in 2005. This is crucial to understand and determine the interactions and roles of the different microbes necessary for successful reproduction.
SEARCH METHODS
A search in Embase, Medline Ovid, Web of science, Cochrane and Google scholar was conducted. The search was limited to English language and studies published between January 2005 and April 2018. Included articles needed to be original microbiome research related to the reproductive tracts.
OUTCOMES
The review provides an extensive up-to-date overview of current microbiome research in the field of human reproductive medicine. The possibility of drawing general conclusions is limited due to diversity in the execution of analytical steps in microbiome research, such as local protocols, sampling methods, primers used, sequencing techniques and bioinformatic pipelines, making it difficult to compare and interpret results of the available studies. Although some microbiota are associated with reproductive success and a good pregnancy outcome, it is still unknown whether a causal link exists. More research is needed to further explore the possible clinical implications and therapeutic interventions.
WIDER IMPLICATIONS
For the field of reproductive medicine, determination of what is a favourable reproductive tract microbiome will provide insight into the mechanisms of both unsuccessful and successful human reproduction. To increase pregnancy chances with live birth and to reduce reproduction-related health costs, future research could focus on postponing treatment or conception in case of the presence of unfavourable microbiota and on the development of therapeutic interventions, such as microbial therapeutics and lifestyle adaptations.
Polycystic ovary syndrome (PCOS) is an endocrine condition associated with reproductive and psychiatric disorders, and with obesity. Eating disorders, such as bulimia and recurrent dieting, are also ...linked to PCOS. They can lead to the epigenetic dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis, thereby impacting on ovarian folliculogenesis. We postulate that PCOS is induced by psychological distress and episodes of overeating and/or dieting during puberty and adolescence, when body dissatisfaction and emotional distress are often present. We propose that upregulated activation of the central HPG axis during this period can be epigenetically altered by psychological stressors and by bulimia/recurrent dieting, which are common during adolescence and which can lead to PCOS. This hypothesis is based on events that occur during a largely neglected stage of female reproductive development. To date, most research into the origins of PCOS has focused on the prenatal induction of this disorder, particularly in utero androgenization and the role of anti-Müllerian hormone. Establishing causality in our peripubertal model requires prospective cohort studies from infancy. Mechanistic studies should consider the role of the gut microbiota in addition to the epigenetic regulation of (neuro) hormones. Finally, clinicians should consider the importance of underlying chronic psychological distress and eating disorders in PCOS.
Abstract
Context
The corpus luteum (CL) secretes prorenin, renin’s inactive precursor. It may thus contribute to the renin-angiotensin-aldosterone-system (RAAS) activation that is required for ...maternal adaptation in pregnancy. Whether this activation is disturbed in pregnancies lacking a CL is unknown.
Objective
The objective of this work is to investigate maternal RAAS determinants in early pregnancy.
Design and Setting
Two observational prospective cohort studies
took place at
2 tertiary referral hospitals.
Patients and Intervention(s)
Pregnancies (n = 277) were stratified by CL number and in vitro fertilization (IVF) protocol: 0 CL (programmed cycle frozen embryo transfer FET, n = 28), 1 CL (natural cycle FET, n = 41 and spontaneous conceptions, n = 139), and more than 1 CL (ovarian stimulation and fresh embryo transfer, n = 69).
Methods
Quantification was performed for maternal prorenin, renin, and aldosterone blood levels at 5, 9, and 11 weeks of gestation.
Results
Prorenin and renin were lower in the absence of a CL at all time points when compared to 1 CL, whereas prorenin, renin, and aldosterone were higher in the presence of more than 1 CL vs 1 CL (P < .05). Ovarian stimulation with menopausal gonadotropin resulted in higher prorenin, renin, and aldosterone concentrations during the late first trimester than recombinant follicle-stimulating hormone (P < .05). Prorenin, and to a lesser degree renin, correlated positively with serum progesterone and relaxin, but not serum estradiol. Total follicle diameter, body mass index (BMI), polycystic ovary syndrome (PCOS), and antimüllerian hormone (AMH) were additional determinants of circulating prorenin. Finally, pregnancies conceived in the absence of a CL were more disposed to develop preeclampsia.
Conclusions
CL number, IVF protocol, BMI, PCOS, and AMH affect maternal RAAS activation in early pregnancy, and may thus contribute to pregnancy complications.
Abstract
Context
Anti-Müllerian hormone (AMH) measured in adolescence as biomarker for prediction of adult polycystic ovary syndrome (PCOS) is doubtful but not substantiated.
Objective
To investigate ...whether serum AMH levels and other PCOS-associated features in adolescence can predict the presence of PCOS in adulthood.
Design and Setting
A long-term follow-up study based on a unique adolescent study on menstrual irregularities performed between 1990 and 1997.
Participants and interventions
AMH was assayed in 271 adolescent girls. Data on PCOS features were combined with AMH levels. In 160 of the 271 (59%) participants, we collected information in adulthood about their menstrual cycle pattern and presence of PCOS (features) by questionnaire 2 decades after the initial study.
Results
AMH was higher in adolescent girls with oligomenorrhea compared with girls with regular cycles, median (interquartile range): 4.6 (3.1-7.5) versus 2.6 (1.7-3.8) μg/L (P < 0.001). Women with PCOS in adulthood had a higher median adolescent AMH of 6.0 compared with 2.5 μg/L in the non-PCOS group (P < 0.001). AMH at adolescence showed an area under the receiver operating characteristic curve for PCOS in adulthood of 0.78. In adolescent girls with oligomenorrhea the proportion developing PCOS in adulthood was 22.5% (95% CI, 12.4-37.4) against 5.1% (95% CI, 2.1-12.0) in girls with a regular cycle (P = 0.005). Given adolescent oligomenorrhea, adding high AMH as factor to predict adult PCOS or adult oligomenorrhea was of no value.
Conclusions
Adolescent AMH either alone or adjuvant to adolescent oligomenorrhea does not contribute as prognostic marker for PCOS in adulthood. Therefore, we do not recommend routine its use in clinical practice.
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