Publicado em 30/01/2012

Atualizações científicas – 23 a 27 de janeiro de 2012


Novos artigos, sobre Reprodução Humana e Andrologia, foram publicados nesta última semana pela comunidade científica. O resumo dos principais artigos está disponível a seguir:

A novel application of cell-free seminal mRNA: non-invasive identification of the presence of germ cells or complete obstruction in men with azoospermia

Publicado em 26 de Janeiro de 12 pela Human Reproduction, disponível no Oxfor Journal.


Cell-free seminal mRNA (cfs-mRNA) exists in human ejaculate at high concentrations and with high stability, and contains many tissue-specific transcripts secreted from the male reproductive system. Owing to the sensitivity of RNA technology, cfs-mRNAs are ideal candidates for non-invasive biomarkers of physiopathological conditions. This study applied cfs-mRNA in identifying the presence of either germ cells or complete obstruction in men with azoospermia.

METHODS RT–PCR was performed to amplify the germ cell-specific (DDX4),seminal vesicle-specific (SEMG1) and prostate-specific (TGM4) mRNAs from cfs-mRNAs, which were isolated from the seminal plasma of men with non-obstructive azoospermia (NOA) or obstructive azoospermia (OA). The 39 patients with NOA, diagnosed by testicular biopsy, included 8 men with maturation arrest (MA),3 men with incomplete sertoli cell only (iSCO) syndrome and 28 men with complete SCO (cSCO). The 29 patients with OA, confirmed by the presence of sperm in the testis or epididymis, included 8 men with congenital bilateral absence of the vas deferens (CBAVD) and 21 men with non-CBAVD. Healthy individuals and vasectomized men were enrolled as controls.

RESULTS TGM4 was detected in all participants. Consistent with their diagnosis, DDX4 was detected in all patients with MA or iSCO but was absent in most cases of cSCO (n = 21, 75.0%) or non-CBAVD (n = 18, 85.7%),and in all men with vasectomy or CBAVD. The presence of DDX4 in the other seven men with cSCO and three patients with non-CBAVD suggests the presence of germ cells in the testis, and incomplete obstruction, respectively. SEMG1 was undetectable in three patients with CBAVD with bilateral absence of the seminal vesicles, and in two non-CBAVD cases with low ejaculate volume.

CONCLUSIONS These results suggest that, with high sensitivity and representativity, cfs-mRNA could be non-invasive biomarkers for identifying the presence of germ cells or complete obstruction in azoospermia.

Antral follicle responsiveness to follicle-stimulating hormone administration assessed by the Follicular Output RaTe (FORT) may predict in vitro fertilization-embryo transfer outcome

Publicado em 24 de Janeiro de 12 pela Human Reproduction, disponível no Oxfor Journal.


Looking for a qualitative marker of ovarian function, we aimed to verify whether responsiveness of antral follicles to FSH administration, as reflected by the Follicular Output RaTe (FORT),is related to their reproductive competence.

METHODS: We studied 322 IVF-ET candidates aged 25–43 years who underwent controlled ovarian hyperstimulation with similar initial FSH doses. Antral follicle (3–8 mm) count (AFC) and pre-ovulatory follicle (16–22 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH treatment) and on the day of hCG administration. The FORT was calculated by PFC × 100/AFC. FORT groups were set according to tercile values: low (,42%; n 1⁄4 102),average (42–58%; n 1⁄4 123) and high (.58%; n 1⁄4 97).

RESULTS: The average FORT was 50.6% (range, 16.7–100.0%). Clinical pregnancy rates per oocyte retrieval increased progressively from the low to the high FORT groups (33.3, 51.2 and 55.7%, respectively, P , 0.003) and such a relationship assessed by logistic regression was independent of the confounding covariates, women’s ages, AFC and PFC.

CONCLUSIONS: The observed relationship between IVF-ET outcome and the percentage of antral follicles that effectively respond to FSH administration reaching pre-ovulatory maturation suggests that FORT may be a qualitative reflector of ovarian follicular competence. Further studies with broader inclusion criteria and more personalized protocols are needed to validate these results.

The role of melatonin as an antioxidant in the follicle

Publicado em 29 de Janeiro de 12 pelo Journal of Ovarian Research, disponível no Pub Med.


Melatonin is secreted during the dark hours at night by pineal gland, and it regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It has been believed that melatonin regulates ovarian function by the regulation of gonadotropin release in the hypothalamus-pituitary gland axis via its specific receptors. In addition to the receptor mediated action, the discovery of melatonin as a direct free radical scavenger has greatly broadened the understanding of melatonin’s mechanisms which benefit reproductive physiology. Higher concentrations of melatonin have been found in human preovulatory follicular fluid compared to serum, and there is growing evidence of the direct effects of melatonin on ovarian function especially oocyte maturation and embryo development. Many scientists have focused on the direct role of melatonin on oocyte maturation and embryo development as an antioxidant to reduce oxidative stress induced by reactive oxygen species, which are produced during ovulation process. The beneficial effects of melatonin administration on oocyte maturation and embryo development have been confirmed by in vitro and in vivo experiments in animals. This review also discusses the first application of melatonin to the clinical treatment of infertile women and confirms that melatonin administration reduces intrafollicular oxidative damage and increase fertilization rates. This review summarizes our recent works and new findings related to the reported beneficial effects of melatonin on reproductive physiology in its role as a reducer of oxidative stress, especially on oocyte maturation and embryo development.

Vitamin D and fertility-a systematic review

Publicado em 24 de Janeiro de 12 pelo European Journal of Endocrinology, disponível no Pub Med.


Vitamin D has been well-known for its function in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. There is some evidence, that in addition to sex steroid hormones, the classic regulators of human reproduction, vitamin D also modulates reproductive processes in women and men.Aim: The aim of this review was to assess studies that evaluated the relationship between vitamin D and fertility in women and men as well as in animals.

METHODS: We performed a systematic literature search in Pubmed for relevant English language publications published until October 2011.

RESULTS AND DISCUSSION: The vitamin D receptor (VDR) and vitamin D metabolizing enzymes are found in reproductive tissues of women and men. VDR knockout mice have significant gonadal insufficiency, decreased sperm count and motility, and histological abnormalities of testis, ovary and uterus. Moreover, we present evidence that vitamin D is involved in female reproduction including in-vitro fertilization (IVF) outcome (clinical pregnancy rates) and polycystic ovary syndrome (PCOS). In PCOS women, low 25-hydroxyvitamin D (25(OH)D) levels are associated with obesity, metabolic and endocrine disturbances and vitamin D supplementation might improve menstrual frequency and metabolic disturbances in those women. Moreover, vitamin D might influence steroidogenesis of sex hormones (estradiol and progesterone) in healthy women and high 25(OH)D levels might be associated with endometriosis. In men, vitamin D is positively associated with semen quality and androgen status. Moreover, vitamin D treatment might increase testosterone levels. Testiculopathic men show low CYP21R expression, 25(OH)D levels and osteoporosis despite normal testosterone levels.

Cumulative parenthood rates in 1735 couples: impact of male factor infertility

Publicado em 23 de Janeiro de 12 pela Human Reproduction disponível no Pub Med.


Most studies assessing the outcome of assisted reproductive technologies (ARTs) have reported live birth rates in couples by taking mainly the female factor into account. However, infertility is a couple’s concern, and the majority of publications do not take into consideration the true impact of male infertility on having the desired number of children.

METHODS: We carried out a follow-up study to evaluate the probability of having a child during treatments at the Toulouse Male Sterility Centre and after discontinuation from 2000 through 2008. Couples were followed for at least 4 years until discontinuation of treatment or delivery of a live infant.

RESULTS: We were able to contact 65% of the 1735 male partners by telephone. Of the 1131 respondents, 56% had become parents (60% if adoption is included),28% after ART, 16% by natural pregnancy, 8% after non-ART treatment and 4% after ART in another centre. The cumulative rates of success reached 64% [95% confidence interval (CI),60-67] for men ≤35 years and women ≤35 years after 9 years, and 31% (95% CI, 24-39) in older patients. With optimistic analysis, which assumes that patients for whom no information was available have the same chance of success in having a child as those whose reproductive outcome was known, the cumulative rate of success was 48% (95% CI, 45-50) in the 1735 couples.

CONCLUSIONS: More than half of couples consulting for male infertility succeeded in having a child. Male age over 35 years old appears as a key risk factor as well as the woman’s age, and these findings should encourage couples to attempt parenthood earlier.

The Emerging Role of Estrogen Receptor-β in Human Reproduction 

Publicado em 23 de Janeiro de 12 pela Seminars in Reproductive Medicine, disponível no Pub Med.


Knowledge surrounding estrogen and estrogen receptor biology continues to evolve, and the diversity of their actions and complexity of their mechanisms are becoming increasingly evident. Estrogen receptor (ER) regulation of reproduction is no exception. Although it is well established that estrogen and ERα play key roles in mediating several reproductive biological processes, such as myometrial and endometrial growth, increasing evidence suggests that ERβ is also an important factor. ERβ is a key mediator in folliculogenesis and may also play a role in stimulating ovulation and regulating aspects of luteinization. ERβ is also expressed in higher quantities than ERα in the human myometrium and cervix during pregnancy, and thus it may play a part in the initiation of labor and parturition. Finally, ERβ is the sole ER expressed within the endothelium of the endometrium and the fetoplacental vasculature, and studies suggest that its role may contribute to angiogenic and vasomotor changes that play a role in both implantation and regulation of fetoplacental blood flow.

Placental mesenchymal dysplasia: can early diagnosis ensure a good materno-foetal outcome? A case report

Publicado em 22 de Janeiro de 12 pela Archives of Gynecology and Obstetrics,  disponível no Pub Med.


Placental mesenchymal dysplasia is a rare disorder characterized by an increased size placenta with cystic villi and ectasic vessels. The correct diagnosis is very important, because placental mesenchymal dysplasia is usually compatible with a normal foetal morphology and a good materno-foetal outcome. An accurate ultrasound evaluation can help in the identification of characteristic patterns associated to this trophoblastic disease, particularly to distinguish it from its main differential diagnosis, i.e. hydatidiform mole. We report an early second-trimester ultrasound diagnosis of placental mesenchymal dysplasia complicated by foetal growth restriction, but with normal female karyotype and good healthy baby.

Assisted reproduction treatment and epigenetic inheritance

Publicado em 19 de Janeiro de 12 pela Human Reproduction Update,  disponível no Pub Med.


The subject of epigenetic risk of assisted reproduction treatment (ART),initiated by reports on an increase of children with the Beckwith-Wiedemann imprinting disorder, is very topical. Hence, there is a growing literature, including mouse studies.

METHODS: In order to gain information on transgenerational epigenetic inheritance and epigenetic effects induced by ART, literature databases were searched for papers on this topic using relevant keywords.

RESULTS: At the level of genomic imprinting involving CpG methylation, ART-induced epigenetic defects are convincingly observed in mice, especially for placenta, and seem more frequent than in humans. Data generally provide a warning as to the use of ovulation induction and in vitro culture. In human sperm from compromised spermatogenesis, sequence-specific DNA hypomethylation is observed repeatedly. Transmittance of sperm and oocyte DNA methylation defects is possible but, as deduced from the limited data available, largely prevented by selection of gametes for ART and/or non-viability of the resulting embryos. Some evidence indicates that subfertility itself is a risk factor for imprinting diseases. As in mouse, physiological effects from ART are observed in humans.In the human, indications for a broader target for changes in CpG methylation than imprinted DNA sequences alone have been found. In the mouse, a broader range of CpG sequences has not yet been studied. Also, a multigeneration study of systematic ART on epigenetic parameters is lacking.

CONCLUSIONS:The field of epigenetic inheritance within the lifespan of an individual and between generations (via mitosis and meiosis, respectively) is growing, driven by the expansion of chromatin research. ART can induce epigenetic variation that might be transmitted to the next generation.

Endocrine-disrupting chemicals in human follicular fluid impair in vitro oocyte developmental competence

Publicado em 20 de Janeiro de 12 pela Human Reproduction,  disponível no Oxfor Journal.


Increased global industrial activity has exposed humans to a wide variety of chemical substances some of which, called ‘endocrine-disrupting chemicals’ (EDCs) or ‘endocrine disruptors’, can disrupt the endocrine system in the body. The ovarian follicle is a very fragile micro-environment where interactions between hormones, growth factors, the oocyte and its surrounding somatic cells are essential to generate a fully competent oocyte. In vitro experiments suggest that EDCs can disturb this finely tuned balance, but very scarse in vivo data are available to confirm this assumption. Therefore, we have investigated if the presence of EDCs in human follicular fluid is a risk factor for the developmental competence of an in vivo exposed oocyte. Furthermore, because of the limited access to human follicular fluid, we verified if follicular fluid contamination can be predicted based on EDC levels in serum.

METHODS: Follicular fluid (n = 40) and serum (n = 20) samples from women undergoing assisted reproductive technology (ART) were analyzed by means of gas chromatography combined with mass spectrometry to examine the presence of different EDCs, such as polychlorinated biphenyls, polybrominated diphenyl ethers and organochlorine pesticides. Statistical models were used to investigate the relation between the characteristics and ART results of the patients and the contamination status of their follicular fluid and to assess the capacity of serum samples to predict follicular fluid contamination.

RESULT: Chlorinated biphenyl 153 (72 ± 44 and 201 ± 106 pg/ml) and p,p’-DDE (392 ± 348 and 622 ± 406 pg/ml) were the compounds found in the highest concentrations in follicular fluid and serum samples, respectively. A new variable principal component 1, representing the overall contamination status of the follicular fluid samples, is strongly associated with fertilization rate (P < 0.00001) and the proportion of high-quality embryos relative to the amount of retrieved oocytes (P < 0.05),even when the analysis is adjusted for age, estradiol concentration, BMI, fertilization procedure and male subfertility as explanatory variables. The strong correlations between the EDC concentrations in serum and follicular fluid (r ≥ 0.93) allowed us to build regression models, which accurately predict EDC concentrations in the follicular fluid based on serum samples.

CONCLUSIONS: An overall higher EDC contamination in the follicular micro-environment was associated with a decreased fertilization rate and consequently with a lower chance of an oocyte to develop into a high-quality embryo. In addition, EDC concentrations in serum were reliable predictors of the contamination status of the follicular micro-environment.

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