Endocrine disruptors have an impact on reproduction for several generations

Endocrine disruptors transgenerationally alters pubertal timing through epigenetic reprogramming of the hypothalamus

2019 Study Abstract

Endocrine disruptors are a rising concern for public health due to their ubiquitous presence affecting reproductive development throughout generations.

We aim at studying the transgenerational effect of an EDC mixture on female sexual development and reproduction.

Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. The mixture was composed of plasticizers (BPA, DBP, DEHP), fungicides/pesticides (Vinclozolin, Procymidon, Prochloraz, Epoxynazole, Linurone, p-p’-DDT), UV filters (4-MBC, OMC), Butylparaben and the analgesic Acetaminophen. Doses were in the human exposure range (μg/kg).

Sexual development and reproductive parameters (vaginal opening, GnRH secretion, estrous cyclicity and folliculogenesis) were studied from F1 to F3 generations. Maternal behavior was measured from F0 to F2 generations. At PND21, mediobasal hypothalamus of the F1 and F3 were removed for gene expression analysis (RNAseq, RT-PCR) as well as for Chromatin Immunoprecipitation of histone modifications at regulatory regions of target genes.

The results show multiple multi- and transgenerational effects after ancestral EDC exposure. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles, decreased GnRH interpulse interval and altered folliculogenesis, no such changes were detected in F1 animals. These alterations were accompanied with transcriptional and histone posttranslational modifications of key hypothalamic genes involved in puberty and reproduction. We observed a downregulation of estrogen signaling (Esr1), genes involved in the GnRH network (Kisspeptin, Grin2d, Tac3R), maternal behavior (Th, Oxt, Avp, Drd1, Drd2) and stress responsiveness (Nr3c1). Upregulated gens involved glucocorticoid activity (Crh) and metabolism (Pomc, Cart). Concomitantly with transcriptional levels, while downregulated genes present higher levels of repressive histone marks (H3K9me3, H3K27me3) and decreased levels of activational histone marks (H3K4me3, H3K9ac), upregulated genes present the opposite pattern. Such histone marks related to changes in the polycomb/thritorax group of protein balance, involved in the control of female puberty. F1 and F2 females displayed decreased licking while spending more time resting alone. F1 RNAseq showed a reduction in Th, Drd1 and Drd2 mRNA expression. These alterations on maternal behavior are known to cause transgenerational alterations of the development of the corticotropic and gonadotropic axis.

In conclusion, exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development and reproduction throughout epigenetic reprogramming of the hypothalamus. While not yet clear, such effects could be mediated by alterations of maternal behavior caused by exposure to the first generation.

ReferenceImage.

DES and the GENES

Developmental Origins of Endometriosis

a Swedish cohort study, Journal of epidemiology and community health, 2019

Abstract

Background
Endometriosis is a chronic condition affecting women of reproductive age and is associated with multiple health burdens. Yet, findings regarding its ‘developmental origins’ are inconsistent. We aimed to investigate the associations of birth characteristics with endometriosis. We also explored potential mediation by adult social and reproductive factors.

Methods
This cohort study consisted of 3406 women born in Uppsala, Sweden, between 1933 and 1972. We used data from archived birth records and endometriosis diagnoses at ages 15–50 recorded in the national patient registers. Socioeconomic and reproductive characteristics were obtained from routine registers. HRs were estimated from Cox regression.

Results
During the follow-up, 111 women have been diagnosed with endometriosis, and most cases are external endometriosis (ie, outside the uterus, n=91). Lower standardised birth weight for gestational age was associated with increased rate of endometriosis (HR 1.35 per standard deviation decrease; 95% CI 1.08 to 1.67). This increased rate was also detected among women with fewer number of live births (HR 2.38; 95% CI 1.40 to 4.07 for one child vs ≥2 children; HR 6.09; 95% CI 3.88 to 9.57 for no child vs ≥2 children) and diagnosed infertility problem (HR 2.00; 95% CI 1.10 to 3.61) prior to endometriosis diagnosis. All the observed associations were stronger for external endometriosis. However, no evidence was found that number of births was the mediator of the inverse association between standardised birth weight and endometriosis.

Conclusion
This study supports the developmental origins theory and suggests that exposure to growth restriction during the fetal period is associated with increased risk of endometriosis during reproductive years.
Image credit hellomagazine.

DES Exposure and Endometriosis

Effect of environmental and pharmaceutical exposures on fetal testis development and function

A systematic review of human experimental data, 2019

Abstract

BACKGROUND
Overall, the incidence of male reproductive disorders has increased in recent decades. Testicular development during fetal life is crucial for subsequent male reproductive function. Non-genomic factors such as environmental chemicals, pharmaceuticals and lifestyle have been proposed to impact on human fetal testicular development resulting in subsequent effects on male reproductive health. Whilst experimental studies using animal models have provided support for this hypothesis, more recently a number of experimental studies using human tissues and cells have begun to translate these findings to determine direct human relevance.

OBJECTIVE AND RATIONALE
The objective of this systematic review was to provide a comprehensive description of the evidence for effects of prenatal exposure(s) on human fetal testis development and function. We present the effects of environmental, pharmaceutical and lifestyle factors in experimental systems involving exposure of human fetal testis tissues and cells. Comparison is made with existing epidemiological data primarily derived from a recent meta-analysis.

SEARCH METHODS
For identification of experimental studies, PubMed and EMBASE were searched for articles published in English between 01/01/1966 and 13/07/2018 using search terms including ‘endocrine disruptor’, ‘human’, ‘fetal’, ‘testis’, ‘germ cells’, ‘testosterone’ and related search terms. Abstracts were screened for selection of full-text articles for further interrogation. Epidemiological studies involving exposure to the same agents were extracted from a recent systematic review and meta-analysis. Additional studies were identified through screening of bibliographies of full-texts of articles identified through the initial searches.

OUTCOMES
A total of 25 experimental studies and 44 epidemiological studies were included. Consistent effects of analgesic and phthalate exposure on human fetal germ cell development are demonstrated in experimental models, correlating with evidence from epidemiological studies and animal models. Furthermore, analgesic-induced reduction in fetal testosterone production, which predisposes to the development of male reproductive disorders, has been reported in studies involving human tissues, which also supports data from animal and epidemiological studies. However, whilst reduced testosterone production has been demonstrated in animal studies following exposure(s) to a variety of environmental chemicals including phthalates and bisphenol A, these effects are not reproduced in experimental approaches using human fetal testis tissues. Image credit academic.oup.

WIDER IMPLICATIONS
Direct experimental evidence for effects of prenatal exposure(s) on human fetal testis development and function exists. However, for many exposures the data is limited. The increasing use of human-relevant models systems in which to determine the effects of environmental exposure(s) (including mixed exposures) on development and function of human tissues should form an important part of the process for assessment of such exposures by regulatory bodies to take account of animal-human differences in susceptibility.

FIGO Cancer Report 2018

Presention of the management of gynecological cancers

The FIGO Committee for Gynecologic Oncology is pleased to present the third edition of the FIGO Cancer Report. Since 2012, this report has been presented triennially in the current format, which aims to present the state of the art management of gynecological cancers in our endeavor to ensure women worldwide receive an acceptable standard of care. The excellent readership of the previous edition encouraged us to produce an updated edition. A series of carefully reviewed and presented articles covers each of the gynecologic cancers. Chapters on pathology, targeted therapy, psychosexual health, and end‐of‐life care have been updated. New chapters have been added on surgical anatomy in gynecologic oncology, essential surgical skills for gynecologic oncologists, enhanced recovery after surgery, role of imaging in endometrial cancer, and cancer in pregnancy. This edition is Open Access to ensure wide dissemination. The 2015 edition of the Cancer Report was translated into Portuguese and Spanish, and the 2018 edition will also be translated to ensure greater readership.

Undeniably, this does not do away with the need for data. The situational analysis done during the tenure of the previous committee had indicated the need to position dedicated data entry managers to get good quality data from low‐ and middle‐income countries (LMICs). However, this project could not find funding. It is apparent that in these days of widespread internet use and mobile health, new methods will have to be found. The Committee initiated a survey to understand changing practices, the results of which will be presented at the XXII FIGO World Congress, held in Rio de Janeiro, Brazil, October 14–19, 2018. It is hoped that increased use of these techniques will bring more insights.

In the last three years, FIGO Gynecologic Oncology Committee members have been actively engaged in organizing and participating in several educational activities including conferences, workshops, and training programs in various countries. They have developed educational aids including handbooks and slide sets. An e‐learning course in collaboration with the Catalan Institute of Oncology (ICO) has been implemented. Cadaver training programs have been initiated for skills development in open and laparoscopic surgery. A smartphone mobile application (free to download and use ofline) for staging and resource‐based management of gynecologic cancers was developed in collaboration with the International Atomic Energy Agency (IAEA).

One of the major objectives of the Committee has been to work with governments to inform policy regarding the implementation of the HPV vaccine program. Members have been engaged in advising various governments during this period. The Committee has collaborated with international and nongovernmental organizations to support this cause in different regions.

By far one of the most challenging tasks undertaken by the Committee was the revision of the staging of cervical cancer. Hitherto staged by clinical methods only, it was insensitive to the advances in technology that had improved the quality of imaging and brought in minimally invasive surgery to facilitate access. However, being a disease largely confined to LMICs, there was widespread belief that a revision would not be applicable where it was needed most. Various rounds of discussions, extensive literature review, interaction, face‐to‐face meetings with the major gynecologic oncology societies internationally, in collaboration with the International Union for Cancer Control (UICC) and the American Joint Commission on Cancer (AJCC), finally resolved the impasse and the 2018 revision now allows the use of imaging and pathology in a way that can be practiced at all levels of resources. The revised staging has been endorsed by the FIGO Executive Board and will be published in the International Journal of Gynecology and Obstetrics (IJGO).

The members of the FIGO Committee for Gynecologic Oncology during this term were: Neerja Bhatla (Chair), India; Kanishka Karunaratne (Co‐Chair), Sri Lanka; Lynette Denny (Immediate Past Chair), South Africa; Seija Grenman (Vice President FIGO, Ex officio member), Finland; Jonathan Berek, USA; Mauricio Cuello Fredes, Chile; Sean Kehoe, UK; Ikuo Konishi, Japan; Alexander Olawaiye, USA; Jaime Prat, Spain; Rengaswamy Sankaranarayanan, France.

Going forward, the Committee will continue its work on FIGO staging, the next cancer to be updated will be cancer of the vulva. FIGO also hopes to work closely with WHO in response to the call for elimination of cervical cancer. Collaboration with the International Agency for Research on Cancer (IARC) will help to gain insights on incidence and survival statistics from different regions to understand the inequities and direct our efforts to promote appropriate education and skills training as we work together to lessen the burden of gynecologic cancers.

Reference. FIGO Cancer Report 2018.

La contraception chez les adolescents canadiens

Les adolescentes devraient choisir le stérilet avant la pilule, dit la Société canadienne de pédiatrie

Les craintes liées à l’utilisation du stérilet sont des vestiges du siècle dernier, expliquent les pédiatres.

Résumé

Chez les adolescents, la santé sexuelle et reproductive est un aspect important des soins de santé complets. Le présent document de principes fournit des conseils afin de sélectionner des contraceptifs à l’intention des adolescentes et de leur en prescrire, y compris les contraceptifs hormonaux courants (pilule, timbre, anneau et progestatif injectable) et les contraceptifs réversibles à longue durée d’action (CRLDA).

Tel qu’on les utilise habituellement, les CRLDA, qui incluent les implants sous-cutanés (non offerts au Canada) et les contraceptifs intra-utérins, sont beaucoup plus efficaces que les contraceptifs hormonaux.

Le présent document de principes recommande les CRLDA comme contraception de première intention chez les adolescentes canadiennes, tout en soulignant que les dispensateurs de soins doivent collaborer avec les jeunes dans le choix d’un moyen de contraception que celles-ci trouvent acceptable, sécuritaire, efficace et pratique. Des stratégies sont proposées pour éliminer les obstacles à l’adoption et au maintien de la contraception.

Référence. Interview HuffPost Québec. Image Ben White.

Medically assisted reproduction and birth outcomes

A within-family analysis using Finnish population registers

Large registry study finds lighter birth weight and higher prematurity rates observed after IVF largely attributable to factors other than treatment.

Summary

Background
Children born after medically assisted reproduction are at higher risk of adverse birth outcomes than are children conceived naturally. We aimed to establish the extent to which this excess risk should be attributed to harmful effects of treatment or to pre-existing parental characteristics that confound the association.

Methods
We used data from Finnish administrative registers covering a 20% random sample of households with at least one child aged 0–14 years at the end of 2000 (n=65 723). We analysed birthweight, gestational age, risk of low birthweight, and risk of preterm birth among children conceived both by medically assisted reproduction and naturally. First, we estimated differences in birth outcomes by mode of conception in the general population, using standard multivariate methods that controlled for observed factors (eg, multiple birth, birth order, and parental sociodemographic characteristics). Second, we used a sibling-comparison approach that has not been used before in medically assisted reproduction research. We compared children conceived by medically assisted reproduction with siblings conceived naturally and, thus, controlled for all observed and unobserved factors shared by siblings.

Findings
Between 1995 and 2000, 2776 (4%) children in our sample were conceived by medically assisted reproduction; 1245 children were included in the sibling comparison. Children conceived by medically assisted reproduction had worse outcomes than did those conceived naturally, for all outcomes, even after adjustments for observed child and parental characteristics—eg, difference in birthweight of −60 g (95% CI −86 to −34) and 2·15 percentage point (95% CI 1·07 to 3·24) increased risk of preterm delivery. In the sibling comparison, the gap in birth outcomes was attenuated, such that the relation between medically assisted reproduction and adverse birth outcomes was statistically and substantively weak for all outcomes—eg, difference in birthweight of −31 g (95% CI −85 to 22) and 1·56 percentage point (95% CI −1·26 to 4·38) increased risk of preterm delivery.

Interpretation
Children conceived by medically assisted reproduction face an elevated risk of adverse birth outcomes. However, our results indicate that this increased risk is largely attributable to factors other than the medically assisted reproduction treatment itself.

Uterus transplantation is still highly experimental in 2018, ASRM committee says

American Society for Reproductive Medicine position statement on uterus transplantation: a committee opinion

Following the birth of the first child from a transplanted uterus in Gothenburg, Sweden, in 2014, other centers worldwide have produced scientific reports of successful uterus transplantation, as well as more recent media reports of successful births.

The American Society for Reproductive Medicine recognizes uterus transplantation as the first successful medical treatment of absolute uterus factor infertility, while cautioning health professionals, patient advocacy groups, and the public about its highly experimental nature.

Read American Society for Reproductive Medicine position statement on uterus transplantation: a committee opinion on Fertility and Sterility, September 2018.

Sadly for many DES daughters having their own children is not possible! Many of us who have experienced miscarriages, want to have kids but are struggling or unable to… Find out more about DES pregnancy risks and DES studies on fertility and pregnancy.

Childhood obesity before 12 years of age appears to increase the risk of female infertility in later life

Association of childhood obesity with female infertility in adulthood: a 25-year follow-up study

2018 Study Abstract

Objective
To evaluate whether childhood obesity is associated with infertility in women’s reproductive-aged life.

Design
Prospective longitudinal study.

Setting
Not applicable.

Intervention(s)
None.

Patient(s)
A total of 1,544 girls, aged 7–15 years in 1985, and who completed questionnaires at follow-up in 2004-2006 and/or 2009-2011.

Main Outcome Measure(s)
Infertility was defined as having difficulty conceiving (had tried for ≥12 months to become pregnant without succeeding) or having seen a doctor because of trouble becoming pregnant.

Result(s)
At ages from 7–11 years, girls at both the lower and upper end of the body mass index (BMI) z score had increased risk of infertility. Compared with normal weight girls, those with obesity at ages 7–11 years were more likely in adulthood to report infertility (adjusted relative risk [aRR] = 2.94, 95% confidence interval [CI] 1.48–5.84), difficulty conceiving (aRR = 3.89, 95% CI 1.95–7.77), or having seen a doctor because of trouble becoming pregnant (aRR = 3.65, 95% CI 1.90–7.02) after adjusting for childhood age, follow-up length, highest parental education, and marital status.

Conclusion(s)
Childhood obesity before 12 years of age appears to increase the risk of female infertility in later life.

Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy

The Practice Committee of the American Society for Reproductive Medicine Opinion, 2018

“Patients preparing to undergo gonadotoxic medical therapy or radiation therapy or gonadectomy should be provided with prompt counseling regarding available options for fertility preservation. Fertility preservation can best be provided by comprehensive programs designed and equipped to confront the unique challenges facing these patients.

Over 100,000 individuals less than 45 years of age are diagnosed with cancer annually in the United States. Over the past 4 decades, advancements in cancer therapies, particularly chemotherapeutics, have led to dramatic improvements in survival. Given the reproductive risks of cancer therapies and improved long-term survival, there has been growing interest in expanding the reproductive options for cancer patients. Indeed, both cancer survivors and the medical community have acknowledged the importance of patient counseling” …

continue reading on the American Society for Reproductive Medicine practice guidelines.

Failures in reproductive health policy: overcoming the consequences and causes of inaction

Inaction and its consequences in Reproductive Health

Achieving safer pregnancies and thriving babies is within reach here and now. The key is finally taking robust action on these public health measures. The next generation deserves no less.

The focus of this Journal of Public Health article, published 18 August 2018, is on public health actions that should have been implemented in Scotland (and the rest of the UK) years ago, but were not.

Overview

  • Profiles in procrastination
    1. Case 1: Not fortifying flour with vitamin B9
    2. Case 2: Minimizing the existence and importance of foetal alcohol harm
    3. Case 3: Failing to control access to, and gain informed consent about, valproate prescribing for women of reproductive age
  • The price of passivity
  • The causes of inaction
  • Replacing inaction with accomplishment
  • Replacing inaction with accomplishment

Abstract

It is assumed that long-established research findings and internationally accepted evidence should, and will, be translated into policy and practice. Knowledge about what prevents harm and promotes health has, in fact, guided and resulted in numerous beneficial public health actions. However, such is not always the case.

The authors examine three notable, and unwelcome, exceptions in the UK—all in the field of reproductive health and all focused on the period prior to pregnancy. The three examples of counterproductive inaction discussed are:

  1. fortifying flour with Vitamin B9 (folic acid);
  2. preventing foetal alcohol spectrum disorders;
  3. and reducing risks and better regulating a highly teratogenic medication (valproate).

The adverse consequences, as well as the causes, of inaction are analysed for each example. Reasons for optimism, and recommendations for overcoming inaction, are also offered, in particular, greater priority should be accorded to preconception health, education and care.