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.

Endometriosis and pregnancy outcome : women with previously excised posterior DIE

Obstetric complications after laparoscopic excision of posterior deep infiltrating endometriosis: a case–control study

2018 Study Abstract

In this issue, Nirgianakis et al. present a retrospective analysis of the complications of pregnancy after laparoscopic excision of deep infiltrating endometriosis (DIE). Most important is that excision of DIE does not affect the increased risk of placenta previa, gestational hypertension, and intrauterine growth retardation (IUGR) associated with endometriosis. In addition, the risk of a vaginal delivery was not increased in the entire group or in the 26 women with a vaginal excision of endometriosis.

Read the full text (free access).
Fertility and Sterility, Volume 110, Issue 3, Pages 406–407, August 2018.

DES Exposure and Endometriosis

The impact of assisted reproductive technology on the offspring

Association of birth defects with the mode of assisted reproductive technology in a Chinese data-linkage cohort

2018 Study Abstract

Objective
To evaluate the impact of assisted reproductive technology (ART) on the offspring of Chinese population.

Design
Retrospective, data-linkage cohort.

Setting
Not applicable.

Patient(s)
Live births resulting from ART or natural conception.

Intervention(s)
None.

Main Outcome Measure(s)
Birth defects coded according to ICD-10.

Result(s)
Births after ART were more likely to be female and multiple births, especially after intracytoplasmic sperm injection (ICSI). ART was associated with a significantly increased risk of birth defects, especially, among singleton births, a significantly increased risk in fresh-embryo cycles after in vitro fertilization (IVF) and frozen-embryo cycles after ICSI. Associations between ART and multiple defects, between ART and gastrointestinal malformation, genital organs malformation, and musculoskeletal malformation among singleton births, and between ART and cardiac septa malformation among multiple births were observed.

Conclusion(s)
This study suggests that ART increases the risk of birth defects. Subgroup analyses indicate higher risk for both fresh and frozen embryos, although nonsignificantly for frozen embryos after IVF and for fresh embryos were presented with low power. Larger sample size research is needed to clarify effects from fresh- or frozen-embryo cycles after IVF and ICSI.