Damaging legacy: maternal cigarette smoking has long-term consequences for male offspring fertility Sobinoff AP, Sutherland JM, Beckett EL, Stanger SJ, Johnson R, Jarnicki AG,McCluskey A, John JC, Hansbro PM, McLaughlin EA. in Hum Reprod. 2014;29:2719-2736.
Maternal cigarette smoke exposure during the gestational/weaning period causes long-term defects in male offspring fertility. That is the worrying conclusion of a study we publish this month. The study, by Alexander Sobinoff and colleagues from Newcastle, Australia, was performed in mice, but the findings were clear. Maternal cigarette smoke exposure caused increased gonocyte and meiotic spermatocyte apoptosis as well as germ cell depletion in the seminiferous tubules of neonatal and juvenile offspring. Aberrant testicular development characterized by abnormal Sertoli and germ cell organization, a depleted spermatogonial stem cell population, atrophic seminiferous tubules and increased germ cell DNA damage persisted in adult offspring 11 weeks after exposure. Microarray analysis of adult offspring testes associated these defects with meiotic germ cell development, sex hormone metabolism, oxidative stress and Sertoli cell signalling. Next generation sequencing also revealed a high mitochondrial DNA mutational load in the testes of adult offspring. Adult maternal smoke-exposed offspring also had reduced sperm counts with spermatozoa exhibiting morphological abnormalities, affecting motility and fertilization potential. Odf2, a spermatozoa flagellum component required for coordinated ciliary beating, was also significantly down-regulated in maternal smoke-exposed adult offspring, with aberrant localization along the spermatozoa flagellum. Adult maternal smoke-exposed offspring took significantly longer to impregnate control females and had a slight but significant reduction in litter size. So, if smoking mice come anywhere close to humans (and why shouldn’t they?), we have a problem. The study strengthens the current literature suggesting that maternal exposure impairs male offspring fertility. This is the first comprehensive animal model of maternal smoking on male offspring reproductive function, suggesting that exposure during the gestational/weaning period causes long-term defects in male offspring fertility. The study shows that this is due to a compromised spermatogonial stem cell population resulting from gonocyte apoptosis and impaired spermatogenic development. This results in significant germ cell damage and Sertoli cell dysfunction, impacting germ cell number, tubule organization, DNA damage and spermatozoa in adult offspring.
The effect of endometrial injury on ongoing pregnancy rate in unselected subfertile women undergoing in vitro fertilization: a randomized controlled trial
Yeung TW, Chai J, Li RH, Lee VC, Ho PC, Ng EH in Hum Reprod. 2014;29:2474-81
In the November issue of the journal we publish an important article. Tracy Yeung and her group from Hong Kong publish an exemplary RCT of the effect (on IVF ongoing pregnancy rate) of endometrial injury performed in the cycle preceding IVF treatment. The study was registered before inclusion of the first patient. They included the number of patients that the sample size calculation required, and they had one well-defined primary endpoint, ongoing pregnancy rate. Their analysis of the data showed that ‘scratching’ the endometrium did not result in significant improvement in the ongoing pregnancy rate among unselected subfertile women undergoing IVF. On the contrary! It is such a genuine (but unfortunately also rare) pleasure to review a well-designed, meticulously performed, and carefully reported study like the one by Yeung and colleagues. Of course, it is costly and labour-intensive to do an RCT. But imagine what the world-wide costs would have been if this group from Hong Kong would not have done the study, and all ART practitioners would have switched to endometrial “scratching”. Just because of some appealing findings in a few small, underpowered, mostly observational studies (although each coming with an elaborate explanation for the putative effect of tissue injury on endometrial receptivity).
The role of the cervix in fertility: is it time for a reappraisal? F. Martyn, F.M. McAuliffe and M. Wingfield in Hum Reprod. 2014;29(10):2092-2099
The seemingly contrary role of the uterine cervix is to keep bacteria out while allowing sperm cells in. The “father of American Gynaecology”, J. Marion Sims, was the first to draw attention to the fertility function of the uterine cervix (Sterility and the value of microscope in its diagnosis and treatment. Transact Am Gynecol Soc, 1888, 13: 291). A well-timed postcoital test provides information on the quality of the cervical mucus, its hormonal milieu (i.e. follicle maturation and ovulation), the most important features of the sperm cells, their interaction with the female factors, and on the technical proficiency of performing the conjugal sexual act. Furthermore, it “prevented the embarrassment of the husband having to provide a sperm sample”. His work earned him a life-size bronze statue at Fifth Avenue, near 103rd Street, in New York, opposite the Academy of Sciences. In fact, Sims is the first gynaecologist worldwide to be honoured with a public statue. With the exception of some clinical work by Max Hühner, a New York urologist, 25 years later (The value of the spermatozoa test in sterility. Urol Cutan Rev, 1914, 18: 587), the fertility function of the uterine cervix has been a fairly neglected field of research. In the current issue of Human Reproduction, Fiona Martyn, Fionnuala McAuliffe and the venerated Mary Wingfield from Dublin, Ireland, offer a reappraisal of this important interface between male and female fertility factors. They review the anatomy and physiology of the cervix and the vaginal ecosystem that it inhabits, the role of the cervical mucus and the effect of hormonal changes during the ovulatory menstrual cycle. They shed their light on the enigmatic sperm-mucus interaction, the fertile mucus window, and its significance for the occurrence of a pregnancy. They assess the soluble and cellular biomarkers of the lower female genital tract and the effects of exposure to semen during sexual intercourse. Finally they discuss the negative impact on a woman’s fertility of cervical surgery for (pre)neoplastic reasons, more and more an issue with reproductively ageing women. For a long time scant attention has been paid to the (frequently forgotten) cervical factor. This message from Ireland opens up tantalizing new research opportunities. Their review will allow our readers to familiarize themselves with recent developments and with a bit of luck will stimulate young investigators to enter this promising field of reproductive research.
Preimplantation genetic screening: back to the future Mastenbroek S, Repping S in Hum Reprod. 2014 Sep;29(9):1846-50
Let me start by stating how proud we are at Human Reproduction that our journal now has reached the number 2 position in the impact factor ratings for both categories in which we figure, Obstetrics & Gynecology AND Reproductive Biology. On both occasions after our sister journal Human Reproduction Update. The ESHRE journals now truly are the two “Top-Rated Journals in Obstetrics and Gynecology”. In the May issue of Human Reproduction we published the traditional PGD Data Collection XII. On that occasion I mentioned “the rather disturbing news that the application of PGD to spot aneuploidies in embryos, so-called PGS, now constitutes more than half (58%) of all cycles performed, notwithstanding the fact that the scientific foundation for PGS as a tool to improve pregnancy chances is not very robust - to say the least (...)”. Sebastiaan Mastenbroek and Sjoerd Repping co-authored a practice-changing New England Journal of Medicine publication in 2007 that, for a short while, diminished the use of PGS in the world. In the current issue of Human Reproduction they comment on what happened ever since their publication. They conclude that we are on the doorstep of the introduction of PGS 2.0 into the IVF clinics and state: “All agree that in hindsight the rapid adoption of preimplantation genetic screening (PGS) using cleavage stage biopsy and fluorescence in situ hybridization (FISH) in routine clinical practice without proper evaluation of (cost)effectiveness basically resulted in couples paying more money for a less effective treatment. Now, almost 20 years later, we are on the verge of a new era of PGS. But have things really changed (...)?”
Excess mortality in mothers of patients with polycystic ovary syndrome Y.V. Louwers, M.E. Roest-Schalken, N. Kleefstra, J. Roeters van Lennep, M. van den Berg, B.C.J.M. Fauser, H.J.G. Bilo, E.J.G. Sijbrands and J.S.E. Laven in Hum. Reprod. (2014) 29 (8): 1780-1786. doi: 10.1093/humrep/deu107
Insulin resistance is a conspicuous issue in polycystic ovary syndrome (PCOS) patients. In an elegant and original attempt to unravel some of the hereditary constituents of PCOS, Yvonne Louwers and co-workers from Rotterdam, Zwolle, Groningen and Utrecht asked the question whether diabetic parents of patients with PCOS show excess mortality compared to the mortality in a group of men and women with type 2 diabetes, but recruited without selection for PCOS. From their findings they conclude that type 2 diabetes among mothers of PCOS patients results in excess mortality compared to women with diabetes from the general population. Mothers (of PCOS daughters) with diabetes had two-times higher mortality risk compared to control women with diabetes (RR 2.0, 95% CI 1.19 to 3.41). No excess mortality among fathers of PCOS patients was noted. The authors conclude that their findings justify screening for type 2 diabetes among mothers with a daughter suffering from PCOS to ensure that timely preventive and therapeutic measures according to the appropriate guidelines can be taken. In the “Too Much Medicine” campaign initiated by The BMJ this form of screening might provide an inspiring issue for debate; however Human Reproduction considered this manuscript too important to deny it a wide circulation.
International Committee for Monitoring Assisted Reproductive Technologies (ICMART) world report: Assisted Reproductive Technology 2006, R. Mansour, O. Ishihara, D. Adamson, Hum. Reprod. (2014) 29 (7): 1536-1551. doi: 10.1093/humrep/deu084
Sometimes scientific papers attract our attention for more than one reason. In this case it concerns the ART World Report by ICMART in the current issue of Human Reproduction, reporting data (in 2014!) on the worldwide ART results of 2006 (!) from 2352 clinics in 56 countries. The findings trouble me. Not because of the fact that it took eight years to collect them, but because of the fact that humankind seems to be hit by an appalling outbreak of male infertility. In 2006, over 585,719 replacement cycles of fresh IVF or ICSI have been performed in the world at large. Of these, more than 199,174 concerned IVF, and over 386,545 were ICSI cycles, so in roughly 2 of every 3 ART cycles ICSI was performed. Should we thank our Lord (and Palermo, Devroey and Van Steirteghem) for introducing ICSI just in time to save our species from extinction? Or are perhaps not all ICSI treatments performed on the indication for which ICSI has been developed, i.e. severe male infertility? Bhattacharya and co-workers showed, already in 2001, in a robust RCT, that in case of non-male infertility ICSI performs worse than regular IVF (Lancet 2001;357:2075). This ICMART world report seems to confirm this: 22.8% deliveries per retrieval following IVF, and only 20.0% after ICSI. The Bhattacharya study has not been discredited by subsequent research. What’s happening? Wherefore all these ICSI’s? Why are we harming our patients by not giving them the best treatment available? Why did we prevent 10,000 pregnancies?
ESHRE PGD Consortium data collection XII: cycles from January to December 2009 with pregnancy follow-up to October 2010, Hum. Reprod. (2014) 29 (5): 880-903. doi: 10.1093/humrep/deu012, C. Moutou, V. Goossens, E. Coonen, M. De Rycke, G. Kokkali, P. Renwick, S.B. SenGupta, K. Vesela and J. Traeger-Synodinos, on behalf of the ESHRE PGD Consortium
In the May issue of Human Reproduction we publish Data Collection XII of the ESHRE PGD Consortium: 60 centres from all over the world provide data from 6160 cycles with oocyte retrieval (OR). A total of 870 ORs were performed for chromosomal abnormalities, 113 ORs for sexing for X-linked diseases, 1597 ORs for monogenic diseases, 3551 ORs for preimplantation genetic screening and 29 ORs for social sexing. The good news is that to date, including all cycles from Data Collection I to XII, misdiagnosis has been extremely rare: it occurred in only 12/7759 PCR-based cycles (0.15%) and in 19/30965 FISH-based PGD cycles (0.06%). In contrast, the rather disturbing news is that the application of PGD to spot aneuploidies in embryos, so-called PGS, now constitutes more than half (58%) of all cycles performed: 3551 cycles of PGS are reported on a total of 6160 cycles in Data Collection XII. Notwithstanding the fact that the scientific foundation for PGS as a tool to improve pregnancy chances is not very robust - to say the least - PGS was applied in women of advanced maternal age, in those who had suffered from repeated implantation failures or from repeated miscarriages, in women who had experienced a previous abnormal pregnancy, in couples with severe male factor subfertility and in some cases for more than one indication. A landmark paper by Sebastiaan Mastenbroek and co-workers in 2007 had already shown unequivocally that PGS does not work in older women (by deferring the transfer of aneuploid embryos). PGS did not increase, but instead significantly reduced the rates of live births after IVF in women of advanced maternal reproductive age. The publication of this paper resulted in a small but short-lived dip in the world-wide PGS numbers. In PGD Data Collection I-III however, 787 PGS cycles constituted again 36% of all reported PGD cycles, and now, with PGS 2.0 at the doorstep (an as yet unproven new alternative to PGS 1.0 by FISH and PCR), we are back at 58% again. Astonishing figures, that will be commented upon by Sebastiaan Mastenbroek and Sjoerd Repping in the July issue of Human Reproduction. And if you cannot wait that long I refer you to Hippocrates of Kos, the illustrious advocate of modern Medicine against the strong resistance by the self-interested Greek medical establishment: primum non nocere, first do no harm.
Pre-implantation Genetic Screening (PGS) of embryos by whole-genome sequencing: now, in the future or never?, Hum. Reprod. (2014) 29 (4): 842-851. doi: 10.1093/humrep/deu005, R. Winand, K. Hens, W. Dondorp, G. de Wert, Y. Moreau, J.B. Vermeesch, I. Liebaers, J. Aerts
How close have we come to Aldous Huxley’s "hatcheries and conditioning centres"? How far are the technical developments and do the developments of our ethical insight keep pace? In the ART clinic, PGD and PGS techniques such as FISH and PCR have been around from the mid-nineties. New techniques have been introduced, such as array-based single cell analysis and WGS, Whole Genome Sequencing. Application of WGS, which documents the entire DNA sequence of an individual, is now technically feasible at the single cell level. Raf Winand, Kristien Hens and their co-workers from Leuven, Maastricht and Brussels, asked the question whether the analytical and clinical validity and the clinical utility of WGS are already such that it can be used with confidence in PGS to select embryos for transfer. They discovered that more than 40% of us harbour mutations that are predicted to be damaging in genes associated with severe Mendelian disorders, or even marked as the cause of a disease. Yet, these individuals are perfectly healthy. Now that PGS 2.0 seems to be following the same unfortunate path of introduction into our IVF clinics as the original PGS ten years ago, this is a finding that should make us stop and think again. For me, the answer to the question posed by these authors in the title is: not now. Not without more research evidence. Predicting protein damage based on exonic sequence information alone will need to improve before it can be applied in selecting the best embryo to transfer. But, even then, also in this article the authors hint at ethical problems: how to make a meaningful choice between embryos with different health profiles? Whose decision should it be anyway? WGS-based screening may lead to conflicts between stakeholders. This again leads to a clinical problem: if we discard all embryos with a positive WGS-based screen, we may end up with no embryo to transfer. While there may be some beautiful ones among them, predestined to lead a perfectly healthy life. “How many goodly creatures are there here! How beauteous mankind is! O brave new world” (Shakespeare, The Tempest, Act V, Scene I).
The relationship between male BMI and waist circumference on semen quality: data from the LIFE study in Hum. Reprod. (2014) 29 (2): 193-200 doi:10.1093/humrep/det428 by Michael L. Eisenberg et al.
Fat men have poor sperm. We know that in infertile people a correlation exists between body weight and the outcome of semen analysis. Figures from ‘normal’ couples setting out to achieve a pregnancy were lacking however. Since infertile couples attend a fertility clinic because of fertility problems the association between sperm count and body weight may be an epiphenomenon. Michael Eisenberg and co-workers, from Stanford, USA, performed semen analysis in men from ‘normal’ couples who started to try becoming pregnant. They found that moderate and severe overweight (obesity) are associated with low ejaculate volumes and low sperm concentrations. Their findings are the first to show a relationship between waist circumference and sperm quality in men without known infertility. In their study there was no correlation with physical activity. The authors conclude that “given the worldwide obesity epidemic, further study of the role of weight loss to improve semen parameters is warranted”. Another good reason to go to the gym.
Is precarious employment associated with women remaining childless until age 35 years? Results from an Australian birth cohort study Hum. Reprod. (2014) 29: 155-161 by E.J. Steele, et al.
In my Department, in Maastricht, the average tenured professor has a median of 2.0 children, which is more than professors off the tenure track (1.0). The difference is statistically significant (p<0.05), but disappears if you correct for age. Only large scale observational studies may bring an answer to the question whether occupation and family building are interrelated. Theoretically, delaying her first pregnancy will increase the chance that a woman eventually will have no children. It is therefore of pivotal importance to understand whether the lack of secure, long-term employment constitutes an obstacle to starting a family, or at least to starting it early enough. Emily Steele and co-authors, from Adelaide, Australia, present results from an Australian birth cohort study showing that duration of time spent in temporary employment is associated with an increased likelihood of childlessness at age 35 years, irrespective of socio-economic background. They conclude that barriers to childbearing may occur in this group. Since all socioeconomic groups were implicated, the authors suggest that upstream labour market reforms could be considered in order to remove barriers to childbearing.
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