Publicado em 08/12/2011 - Atualizado 26/07/2019

Atualizações científicas da semana – 28 de novembro a 02 de dezembro de 2011


Esta semana várias atualizações sobre Reprodução Humana foram publicadas pela comunidade acadêmica internacional. Confira.

Inotropic action of the puberty hormone kisspeptin in rat, mouse and human:cardiovascular distribution and characteristics of the kisspeptin receptor

Publicado em 22 de Novembro de 11 pela PLoS One, disponível no Oxfor Journal.


Kisspeptins, the ligands of the kisspeptin receptor known for its roles in reproduction and cancer, are also vasoconstrictor peptides in atherosclerosis-prone human aorta and coronary artery. The aim of this study was to further investigate the cardiovascular localisation and function of the kisspeptins and their receptor in human compared to rat and mouse heart. Immunohistochemistry and radioligand binding techniques were employed to investigate kisspeptin receptor localisation, density and pharmacological characteristics in cardiac tissues from all three species. Radioimmunoassay was used to detect kisspeptin peptide levels in human normal heart and to identifyany pathological changes in myocardium from patients transplanted for cardiomyopathy or ischaemic heart disease. The cardiac function of kisspeptin receptor was studied in isolated human, rat and mouse paced atria, with a role for the receptor confirmed using mice with targeted disruption of Kiss1r. The data demonstrated that kisspeptin receptor-like immunoreactivity localised to endothelial and smooth muscle cells of intramyocardial blood vessels and to myocytes in human and rodent tissue. [(125)I]KP-14 bound saturably, with subnanomolar affinity to human and rodent myocardium (K(D) = 0.12 nM, human; K(D) = 0.44 nM, rat). Positive inotropic effects of kisspeptin were observed in rat, human and mouse. No response was observed in mice with targeted disruption of Kiss1r. In human heart a decrease in cardiac kisspeptin level was detected in ischaemic heart disease. Kisspeptin and its receptor are expressed in the human, rat and mouse heart and kisspeptins possess potent positive inotropic activity.

The cardiovascular actions of the kisspeptins may contribute to the role of these peptides in pregnancy but the consequences of receptor activation must be considered if kisspeptin receptor agonists are developed for use in the treatment of reproductive disorders or cancer.


Investigation of systemic inflammatory response in first trimester pregnancy failure.

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


The contribution of local and systemic inflammation to the pathophysiology of sporadic first trimester miscarriages remains unclear. The objective of this study was to investigate the inflammatory response in the circulation of women presenting with first trimester miscarriage.

METHODS: Levels of tumour necrosis factor alpha (TNFα),TNF receptors 1 and 2, interferon gamma (IFNγ),interleukin (IL)-6 and IL-10 were assayed using cytometric bead arrays in plasma samples from 29 euploid and 21 aneuploid missed miscarriages, 35 normal pregnant controls and 31 non-pregnant women (NPW). Whole blood flow cytometry was carried out with samples from 17 euploid and 16 aneuploid miscarriages, 18 pregnant controls and 13 NPW.RESULTS: The plasma of women with euploid miscarriage  contained significantly higher circulating levels of TNFα (P < 0.005),IFNγ (P <  0.005),IL-6 (P < 0.005) and IL-10 (P < 0.01) than that of pregnant controls, irrespective of gestational age. Significantly (P < 0.05) higher TNF-R1 levels at 6-9 weeks, and significantly higher TNFα/IL-6 (P < 0.001) and significantly lower TNFα/IL-10 (P < 0.001) and IFNγ/IL-10 (P < 0.001) ratios at 10-14 weeks, were also found in euploid miscarriage cases compared with pregnant controls. TNFα/IL-10 ratio in plasma was significantly (P < 0.05) lower in miscarriages with an abnormal karyotype than those with normal karyotype. Normal pregnant women had a significantly higher plasma level of IFNγ (P < 0.01) and IFNγ/IL-10 ratio (P < 0.005),a significantly (P < 0.005) lower TNF-R1 level, and a significant (P < 0.05) increase in stimulated TNFα in monocytes, compared with NPW.

CONCLUSIONS: Our data confirm that there is an inflammatory reaction in normal pregnancy compared with the non-pregnant state, which may be disrupted during miscarriage.


Monitoring of ovarian activity by measurement of urinary excretion rates of estrone glucuronide and pregnanediol glucuronide using the Ovarian Monitor, Part II: reliability of home testing,

Publicado em 29 de Novembro de 11 pela Human Reproduction, disponível no Oxfor Journal.


The UNDP/WHO/World Bank/Special Programme of Research, Development and  Research Training in Human Reproduction (Geneva) set up a study to determine whether it is feasible for women to monitor their ovarian activity reliably by home testing. Daily self-monitoring of urinary hormone metabolites for menstrual cycle assessment was evaluated by comparison of results obtained with the Home Ovarian Monitor by untrained users both at home and in study centres.

METHODS: Women collected daily data for urinary estrone glucuronide (E1G) and pregnanediol glucuronide (PdG) for two cycles, then the procedure was repeated in the women’s local centre (in Chile, Australia or New Zealand) giving a total of 113 duplicate cycles. The tests were performed without the benefit of replicates or quality controls. The home and centre cycles were normalized and compared to identify assay errors, and the resulting home and centre menstrual cycle profiles were averaged.RESULTSReliable mean cycle profiles were obtained with the home and centre excretion rates agreeing to within 36 ± 21 nmol/24 h for E1G and 0.77 ± 0.28 µmol/24 h for baseline PdG values (1-5 µmol/24 h). The cycles had a mean length of 28.1 ± 3.1 days (n = 112; 5th and 95th percentiles: 24 and 35 days, respectively),a mean follicular phase of 14.8 ± 3.1 days (n = 107; 5th and 95th percentiles: 11 and 21 days) and a mean luteal phase length of 13.3 ± 1.5 days (n= 106; 5th and 95th percentiles: 11 and 17 days),calculated from the day of the LH peak.

CONCLUSIONS: The study confirmed that the Ovarian Monitor pre-coated assay tubes worked well even in the hands of lay users, without standard curves, quality controls or replicates. Point-of-care monitoring to give reliable fertility data is feasible.


The decline of fertility in male uremic patients is correlated with low expression of the cystic fibrosis transmembrane conductance regulator protein(CFTR) in human sperm

Publicado em 29 de Novembro de 11 pela Human Reproduction, disponível no Oxfor Journal.


The present study was designed to investigate the possible association between infertility of male uremic patients and expression of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in their sperm.

METHODS: Semen was collected and analyzed. Serum levels of FSH, LH and testosterone were measured by radioimmunoassay. The sperm CFTR expressions of 21 uremic patients and 15 renal transplant patients were measured and compared with those of 32 healthy and 33 infertile men.

RESULTS: Only 9 ± 5.9% of sperm from uremic patients expressed CFTR, significantly less than those of the renal transplant patients (29 ± 14.3%, P< 0.001),the infertile men (42 ± 20.7%, P< 0.001) and the healthy men (51 ± 20.5%, P< 0.001). Furthermore, significantly fewer sperm from renal transplant patients expressed CFTR than those of the infertile men (P< 0.05) and the healthy men (P< 0.01). LH levels in uremic patients were significantly higher than in all other groups, whereas FSH levels in uremic patients were only significantly higher than in infertile and healthy men. There was no significant difference in testosterone level among the four categories.

CONCLUSIONS: Sperm CFTR expression is depressed in uremic patients but recovers to some degree after renal transplant along with some improvement in fertility, indicating a ‘reversible’ change. These results suggest that the CFTR expression rate in sperm is correlated with the decline of uremic patients’ fertility, and may be considered as a potential marker to assess the fertility of male uremic patients.


Subfertility and risk of later life maternal cardiovascular disease

Publicado em 30 de Novembro de 11, pela Human Reproduction, disponível no Oxfor Journal.


Subfertility shares common pathways with cardiovascular disease (CVD),including polycystic ovarian syndrome, obesity and thyroid disorders. Women with prior 0-1 pregnancies are at an increased risk of incident CVD when compared with women with two pregnancies. It is uncertain whether history of subfertility among women eventually giving birth is a risk factor for CVD.

METHODS: Among Swedish women with self-reported data on subfertility in the Swedish Medical Birth Register (n= 863 324),we used Cox proportional hazards models to relate a history of subfertility to CVD risk after adjustment for age, birth year, highest income, education, birth country, hypertension, diabetes, preterm birth, small for gestational age (SGA),smoking and for BMI in separate models. In additional analyses, we excluded women with: (i) pregnancy-related or non-pregnancy-related hypertension and/or diabetes; and (ii) preterm births and/or SGA babies.

RESULTS: Among nulliparous women eventually having a childbirth (between 1983 and 2005, the median follow-up time 11.9; 0-23 years and 9 906 621 person-years of follow-up),there was an increased risk of CVD among women reporting ≥5 years of subfertility versus 0 years (hazard ratio 1.19, 95% confidence interval 1.02-1.39). There were not significantly elevated CVD risks for women with 1-2 or 3-4 years of subfertility versus 0 years. Accounting for BMI did not change results. Excluding women with hypertension and/or diabetes attenuated associations, whereas exclusion of women with preterm and/or SGA births did not change findings.

CONCLUSIONS: Subfertility among women eventually having a childbirth is a risk factor for CVD even upon accounting for cardiovascular risk factors and adverse pregnancy outcomes. Future studies should explore the mechanisms underlying this association.


Embryo culture media and neonatal birthweight following IVF

Publicado em 28 de Novembro de 11, pela Human Reproduction, disponível no Oxfor Journal.


Infants conceived from IVF are at increased risk for low birthweight. Animal studies suggest that embryo culture medium influences birthweight but it is unknown whether this association exists in humans. This study examines the relationship between culture medium and birthweight following IVF.

METHODS: We identified all IVF cycles with start dates between 1 January 1999 and 31 December 2008 that used autologous oocytes with resulting embryos cultured in G1.3, Global or G1.5 medium. The population was restricted to singleton deliveries following Day 3, fresh single embryo transfer, or twin deliveries following Day 3, fresh double embryo transfer, at a gestational age of ≥34 weeks. Only the first cycle during the study period was included for each woman. Women were excluded if the number of gestational sacs on ultrasound differed from the number of infants born. Variables were evaluated with the χ(2)-test or analysis of variance. Multiple linear regressions controlled for potential confounders.

RESULTS: Of the 198 women with singleton deliveries, 102 embryos were cultured in G1.3, 53 in Global and 43 in G1.5 medium. Of the 303 twin deliveries, 172 pairs of embryos were cultured in G1.3, 58 in Global and 73 in G1.5 medium. No significant association between culture medium and birthweight was observed, even when controlling for potential confounders.

CONCLUSIONS: This retrospective study demonstrated no significant association between embryo culture medium and birthweight following IVF. Although our careful selection of patients minimized the influence of potential confounders, further research is required to elucidate this issue with larger numbers of patients.


Human chorionic gonadotrophin treatment prior to microdissection testicular sperm extraction in non-obstructive azoospermia

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


Despite the improved success rate of sperm retrieval by microdissection testicular sperm extraction (micro-TESE),methods to stimulate spermatogenesis in men with non-obstructive azoospermia (NOA) remain unexplored. The aim of this study was to evaluate the effects of hCG-based hormonal stimulation in men with NOA on the success of sperm retrieval by micro-TESE.

METHODS: Forty-eight men with NOA who had negative sperm retrieval results by the micro-TESE procedure were included. A second micro-TESE was subsequently performed on these men: 20 were not treated by any hormonal therapy, and 28 subjects received daily subcutaneous injections of hCG for 4-5 months prior to the second micro-TESE. Recombinant FSH was added if endogenous gonadotrophin levels decreased during the hCG stimulation. The sperm retrieval rate at the second micro-TESE; the levels of gonadotrophins, testosterone and estradiol; and the effects of hormonal therapy on testicular histology were evaluated.

RESULTS: Among the 28 men with hCG stimulation, 15 (54%) showed decreased LH and FSH levels (0.67 ± 0.10 and 0.96 ± 0.14 mIU, mean ± SEM, respectively) due to elevated serum testosterone (9.5ng/dl). Sperm were obtained at the second micro-TESE from six men who had received hormonal therapy (21%),whereas no sperm were retrieved from untreated men (P < 0.05). Success at the second micro-TESE was more likely if histology at the first micro-TESE showed hypospermatogenesis.

CONCLUSIONS: The Leydig cells of the testis can respond positively to exogenous hCG even under hypergonadotropic conditions. HCG-based hormonal therapy prior to a second micro-TESE attempt is effective in men with hypospermatogenesisZ


Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study

Publicado em 28 novembro de 11, pela Human Reproduction, disponível no Oxfor Journal.


Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment.

METHODS: Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary  outcome was clinical PR.

RESULTS: Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95% confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03),LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04),cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031),within three cycles of OI.

CONCLUSIONS: Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.Clinical trials registration.


Effect of bacterial vaginosis on the pharmacokinetics of misoprostol in early pregnancy

Publicado em 28 novembro de 11, pela Human Reproduction, disponível no Oxfor Journal.


Misoprostol has been shown to be an effective agent for cervical ripening and termination of early pregnancy especially when administered vaginally. Our objective was to evaluate whether bacterial vaginosis (BV) affected the pharmacokinetics of vaginally administered misoprostol during early pregnancy.

METHODS: Ten women with BV and 10 healthy women requesting medical abortion up to 9 weeks of pregnancy were administered 200 mg mifepristone followed 24-48 h later by a single dose of 800 µg misoprostol vaginally. Blood samples were taken before (0 h) and 0.5, 1, 2, 3 and 4 h after misoprostol administration. Misoprostol acid was determined in serum samples using liquid chromatography/tandem mass spectrometry.

RESULTS: All women with BV had a vaginal pH > 4.7. The mean bioavailability measured as the area under the curve (AUC) and maximum concentration (C(max)) appeared higher in the control than in the BV group (1458.7 versus 878.1 pg h/ml) and (630.7 versus 342.5 pg/ml),respectively,but did not achieve statistical significance and there was no other significant difference in the pharmacokinetics between the two groups. However, if two women with vaginal pH > 4.7 were excluded from the control group the difference in AUC(240) (1359 versus 878.1 pgh/ml) reached statistical significance (P =0.048).

CONCLUSIONS: BV had an effect on pharmacokinetics of vaginally administered misoprostol in early pregnancy. However, the results should be interpreted with caution due to the small sample size and marked individual variations

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