Atualizações científicas da semana – 12 a 16 de dezembro de 2011

Publicado em: 20 de dezembro de 2011

Symmetrical division of mouse oocytes during meiotic maturation can lead to the development of twin embryos that amalgamate to form a chimeric hermaphrodite

Publicado em Dezembro de 11 pela Human Reproduction, disponível no Oxfor Journal.


Gentle compression of mouse oocytes during meiosis-1 prevented the usual extrusion of a small polar body and resulted in the symmetrical division of the ooplasm into two cells of similar size within the zona pellucida. The purpose of our study was to determine whether such cells, equivalent to two small oocytes, were capable of embryonic development and would result in birth following transfer to the uterus.

Methods: IVF of the 2-celled oocytes was performed and the twin intra-zonal embryos were observed. In each case, the two embryos that originated from fertilized cells with two pronuclei were observed to amalgamate and form a single morula and subsequent blastocyst that was transferred to the uterus of a recipient of a different mouse strain. FISH analysis was performed on sectioned paraffin-embedded tissue of the offspring.

Results: In symmetrically divided oocytes each cell contained a metaphase II spindle. Both cells were fertilizable and cleaved to form twin embryos within the same zona pellucida. Most twin embryos amalgamated to form a single compacted morula, which progressed to hatched blastocysts that contained a single inner cell mass. In total, 104 of these blastocysts were transferred to 19 mice, two of which became preg- nant, resulting in the birth of three offspring. FISH analysis showed that one newborn contained both XX and XY cells.

Conclusions: We found that two small oocytes fertilized within the same zona pellucida to form twin embryos that amalgamate to establish a single chimeric embryo. This may be one mechanism that leads to the formation of a chimeric hermaphrodite when an embryo containing XX cells mixes with its intra-zonal twin containing XY cells.

When and how should new technology be introduced into the IVF laboratory?

Publicado em Dezembro de 11 pela Human Reproduction, disponível no Oxfor Journal.


There are many examples in assisted reproduction technology, where new technology and methods have been introduced into the clinical setting without appropriate development and evidence-based medicine to show that the procedure is safe and beneficial to the patient. Examples include preimplantation genetic screening, assisted hatching, in vitro maturation, blastocyst transfer and vitrification. Changes to culture media composition, stimulation regimes and laboratory protocols are also often established internationally without ad- equate validation. More recently, novel equipment that needs to be validated before it enters routine clinical use is being developed for IVF. With technologies such as producing gametes from stem cells around the corner, it is vital to ensure that the necessary research and de- velopment is conducted before bringing new techniques into clinical practice. Ideally, this should include preliminary work on animal models, such as mice/rats/rabbits/larger mammals, followed by studies on human embryos donated for research and finally well-designed RCTs with a follow up of all children born from the procedure. If such preliminary studies are not performed and published, it is possible that technology bringing no clinical benefit or leading to adverse health outcomes in the children born by these practices may be introduced. All IVF clinics need to consider the safety and efficacy of new technologies before introducing them.

Can pubertal boys with Klinefelter syndrome benefit from spermatogonial stem cell banking?

Publicado em Dezembro de 11 pela Human Reproduction, disponível no Oxfor Journal.


Although early development of testes appears normal in boys with Klinefelter syndrome (KS), spermatogonial stem cell (SSC) depletion occurs in mid puberty, leading to infertility. Cryopreservation of SSCs prior to stem cell loss is an option that is currently offered to boys who have to undergo gonadotoxic treatments. This study aimed to explore the possibility of preserving SSCs in pubertal KS adolescents by testicular tissue banking.

Methods: A retrospective study was conducted in seven non-mosaic 47,XXY adolescents, aged 13–16 years, who were invited for an experimental testicular tissue banking programme during their follow-up at the Paediatric Endocrinology Department of the UZ Brussel between 2009 and 2011. Paraffin-embedded testicular tissue was sectioned and stained with haematoxylin-eosin, and immunostainings were performed for Mage-A4, anti-Mullerian hormone, Inhibin a and steroidogenic acute regulatory protein. The presence of spermatogen- esis and/or spermatogonia was evaluated.

Results: Massive fibrosis and hyalinization was observed in all but one KS patients. Although spermatogonia were seen in five patients, spermatogonia were only present in tubules showing normal architecture in the youngest patient who also had normal follicle-stimulating hormone and inhibin B concentrations.

Conclusions: Testicular tissue cryopreservation in KS adolescents should be recommended as soon as possible, probably before hormonal changes of failing Sertoli cell function are detected.

Trends in embryo disposition decisions: patients’ responses to a 15-year mailing program

Publicado em Dezembro de 11 pela Human Reproduction, disponível no Oxfor Journal.


This study examined the responses of patients of a Belgian fertility center to mailed requests to make or renew an embryo disposition decision (EDD), over a period of 15 years, to investigate trends in the decisions.

Methods: A retrospective analysis was performed on a mailing program from 1992 to 2006, for patients, of the Department of Repro- ductive Medicine, Ghent University Hospital (Belgium), from whom embryos had been cryopreserved at least 2 years.

Results: In 15 years, 3840 EDD forms were prepared for 2334 couples or female patients. The number of forms increased from 21 in 1992 to 558 in 2006. Each year, around a third of the forms were not returned. In general, a quarter of patients who received more than one form never answered. Donation to others for reproduction was overall the least popular option and decreased over the years. The rising trend in decisions to discard reversed into a negative trend from the introduction of donation for science (1997). Since then, donation for science has been the most popular option and its popularity increased with time. In 15 years, 2504 embryos were donated for science. More than a quarter of the patients who chose more than one final EDD in different years did not select the same EDD the second time.

Conclusions: This study showed a positive trend in donation for science and a negative trend in donation to others and discarding. A substantial number of individual patients chose different types of EDDs in consecutive mailings, which shows that advance EDD directives should be used with caution.

A Crucial Role in Fertility for the Oyster Angiotensin-Converting Enzyme Orthologue CgACE

Publicado em Dezembro de 11  pela Plos One, disponível no Oxfor Journal.


Angiotensin-converting enzyme (ACE) is a highly conserved metallopeptidase. In mammals, the somatic isoform governs blood pressure whereas the germinal isoform (tACE) is required for fertility. In Ecdysozoans, ACE-like enzymes are implicated in reproduction. Despite ACE orthologues being present from bacteria to humans, their function(s) remain(s) unknown in distant organisms such as Lophotrochozoans. In silico analysis of an oyster (Crassostrea gigas) EST library suggested the presence of an ACE orthologue in molluscs. Primer walking and 5′-RACE revealed that the 1.9 kb cDNA encodes CgACE, a 632 amino acid protein displaying a conserved single active site and a putative C-terminal transmembrane anchor, thus resembling human tACE, as supported by molecular modelling. FRET activity assays and Maldi-TOF spectrometry indicated that CgACE is a functional dipeptidyl-carboxypeptidase which is active on Angiotensin I and sensitive to ACE inhibitors and chloride ion concentration. Immunocytochemistry revealed that, as its human counterpart, recombinant CgACE is synthesised as a transmembrane enzyme. RT-qPCR, in-situ hybridization and immunohistochemistry shed light on a tissue, and development stage, specific expression pattern for CgACE, which is increased in the gonad during spermatogenesis. The use of ACE inhibitors in vivo indicates that the dipeptidase activity of CgACE is crucial for the oyster fertilization. Our study demonstrates that a transmembrane active ACE is present in the oyster Crassostrea gigas, and for the first time ascribes a functional role for ACE in Lophotrochozoans. Its biological function in reproduction is conserved from molluscs to humans, a finding of particular evolutionary interest especially since oysters represent the most important aquaculture resource worldwide.

Pregnancies beyond the human biological fecundity

Será publicado em Janeiro de 2012  pela Womens Health (Lond Engl), disponível no Oxfor Journal.


The maternal age at first delivery constantly rises in developed countries due to a social trend to postpone the age of parenting. Assisted reproduction technologies do extend the age of fecundity to some limit, but their success rate is inversely related to the patients’ age. The major factor limiting human fecundity in the fifth decade of life is the quality of the human oocyte. This problem can be readily bypassed using oocytes from young donors thus significantly extending the age limit in which conception and delivery are possible well into menopause. The ability to become pregnant and deliver at such an age raises serious medical, moral, social and legal concerns regarding the health and welfare of the mother, child and oocyte donor, which will be presented and discussed here.

Toward a Better Understanding of Functional Ovarian Reserve: AMH (AMHo) and FSH (FSHo) Hormone Ratios per Retrieved Oocyte

Publicado em 14 Dezembro de 11 pelo J Clin Endocrinol Metab. disponível no Pub Med.


Context:Functional ovarian reserve (FOR) has recently been demonstrated to differ with ovarian genotypes of the FMR1 gene and is currently routinely determined with anti-Müllerian hormone (AMH) and FSH. Both, however, reflect distinctively different stages of folliculogenesis.Objectives:To better understand how AMH and FSH reflect FOR, we evaluated both hormones in association with in vitro fertilization (IVF) by determining how they associate with oocyte yields, considered the most accurate available measure of FOR.Design and Setting:Using a series of logistic regressions, we assessed AMH and FSH per oocyte retrieved (AMHo and FSHo) in only first IVF cycles and determined whether at different ages and/or based on ovarian FMR1 genotypes and subgenotypes AMHo and/or FSHo are associated with clinical pregnancy chances in IVF.Patients:We investigated 392 consecutive IVF patients of all ages, with among them 60.7% suffering from diminished FOR.Interventions:Interventions included routine IVF cycles.Main Outcome Measure:Clinical pregnancy rate in IVF cycle was assessed.Results:FSHo, but not AMHo, was, overall, statistically associated with pregnancy chances in IVF. This association was further limited to women above age 38 yr. FSHo was also significantly associated with pregnancy chances in women with normal FMR1 genotype, although only almost reaching significance with heterozygous-normal/low. Normal-genotype patients also demonstrate significant interaction between FSHo and age in pregnancy outcome, although insignificant for all other FMR1 genotypes and subgenotypes and universally for AMHo.Conclusions:AMHo and FSHo are representative of distinctively different components of FOR, likely influenced by different ovarian FMR1 genotypes and subgenotypes.

Surgical management of metabolic dysfunction in PCOS

Publicado em 08 de Dezembro de 11 pela Human Reproduction disponível no Pub Med.


Metabolic disturbances are common in women with polycystic ovary syndrome (PCOS). Obesity is the major link in the association of PCOS with diabetes, metabolic syndrome, hypertension, low-grade chronic inflammation and increased body iron stores, among others. Metabolic prevention in PCOS women should start as early as possible, usually beginning at diagnosis. Among preventive strategies, those promoting a healthy life-style based on diet, regular exercising and smoking cessation are possibly the most effective therapies, but also are the most difficult to achieve. To this regard, every effort must be made to avoid weight gain and obesity, given the deleterious impact that obesity exerts on the metabolic and cardiovascular associations of PCOS. Unfortunately, classic strategies that address obesity by life-style modification and dieting are seldom successful on a long-term basis, especially in women with severe obesity. In selected cases, metabolic surgery in severely obese women may resolve signs and symptoms of PCOS restoring insulin sensitivity and fertility, and avoiding the long-term risks associated with PCOS and morbid obesity. Surgical techniques for bariatric surgery have evolved in the past decades and newer procedures do not longer carry the severe side effects associated with earlier bariatric procedures. The choice of bariatric procedure should consider both the severity of obesity and the possibility of future pregnancy, since fertility may be restored by the sustained and marked weight loss usually attained after bariatric surgery. Finally, avoidance of the risks associated with morbid obesity compensate for the possible residual risks for pregnancy derived from the previous bariatric procedure itself.

Conteúdo atualizado em: 17 de Abril de 2014

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