BACKGROUND

Nomegestrol acetate/17β-estradiol (NOMAC/E₂) is a new monophasic oral contraceptive combining NOMAC (2.5 mg), a highly selective progesterone-derived progestogen, with E₂ (1.5 mg), which is structurally identical to endogenous estrogen. The objective of this study was to compare the effects on ovarian activity of two different NOMAC/E₂ regimens.

METHODS

This was a double-blind, randomized study. Healthy, premenopausal women (aged 18–38 years, previous menstrual cycle length 28 ± 7 days) were randomized by computer-generated code to once-daily NOMAC/E₂ for three consecutive 28-day cycles: either 24 days with a 4-day placebo interval (n = 40) or 21 days with a 7-day placebo interval (n = 37) per cycle. Follicular growth (primary outcome measure), plasma hormone profiles and bleeding patterns were assessed.

RESULTS

There was no evidence of ovulation during treatment with either NOMAC/E₂ regimen. The largest follicle diameter was significantly smaller in the 24-day group than in the 21-day group [mean (SD) mm in cycle 2: 9.0 (3.0) versus 11.3 (5.3) (P = 0.02); in cycle 3: 9.2 (3.0) versus 11.5 (6.0) (P = 0.04)]. Mean FSH plasma levels were significantly lower in the 24-day versus the 21-day group on Day 24 of cycles 1 and 2. Withdrawal bleeding duration was significantly shorter in the 24-day than in the 21-day group [mean (SD) days after cycle 1: 3.5 (1.3) versus 5.0 (2.6) (P = 0.002); after cycle 2: 3.9 (1.6) versus 4.8 (1.7) (P = 0.03)].

CONCLUSIONS

The 24-day NOMAC/E₂ regimen was associated with greater inhibition of follicular growth and shorter duration of withdrawal bleeding than the 21-day regimen, suggesting the shorter pill-free interval results in a greater margin of contraceptive efficacy and tolerability, and fewer withdrawal symptoms.

BACKGROUND

Multidisciplinary laparoscopic treatment is the standard of care for radical treatment of deep infiltrating pelvic endometriosis. If bowel resection is necessary, a muscle-split or Pfannenstiel incision is also required. The avoidance of any laparotomy could decrease surgical stress response, give a faster return to normal bowel function, decrease post-operative pain and reduce wound complications and incisional hernias. We assessed post-operative outcome after a full laparoscopic sigmoid resection for bowel endometriosis.

PATIENTS AND METHODS

Twenty-one patients who underwent elective full laparoscopic sigmoid resection for bowel endometriosis from September 2009 to September 2010 were matched for age, American Society of Anesthesiologists class and BMI to 21 patients who underwent a conventional laparoscopic sigmoid resection. Groups were compared for peri-operative factors, complications, length of hospital stay, post-operative pain (Visual Analog Scale: VAS), analgesics consumption and inflammatory response (plasma C-reactive protein: CRP).

RESULTS

Median operating time was 15 min shorter with transrectal specimen extraction (P = 0.003). VAS-scores and use of analgesics were higher in the conventional laparoscopic group (P = 0.0005). Mean CRP-level tended to be higher in the transrectal specimen extraction group (38%, P = 0.054) but there was no difference in increase in CRP level between groups (P = 0.15). There were no anastomotic leaks or reinterventions in either group, and the median hospital stay was similar. At follow-up, no wound infections or incisional hernias were observed and no patients reported anal dysfunction.

CONCLUSION

Full laparoscopic sigmoid resection reduced operating times and decreased post-operative VAS-scores and analgesic requirements compared with the conventional laparoscopic sigmoid resection for bowel endometriosis.

BACKGROUND

CD56+ cells in peripheral blood or the endometrium may be increased in women with reproductive failure. However, the relationship between numbers of peripheral blood CD56+ and endometrial CD56+ cells is uncertain. The aim of this study was (i) to compare the numbers of CD56+ cells in peripheral blood and endometrium in samples taken simultaneously and (ii) to compare measurements by flow cytometry and immunohistochemistry of CD56+ cells in the same endometrial biopsy.

METHOD

Endometrial biopsies and blood were obtained from women with recurrent miscarriage (n= 25) on days LH+7–LH+9 of the cycle. The total number of CD56+, CD56+ CD16– and CD56+CD16+ cells in blood was measured by flow cytometry; the number of CD56+ cells in the endometrium was determined by immunohistochemistry. Endometrial samples were also obtained from fertile women (n= 20) and used to measure CD56+ and CD45+ cells, by both flow cytometry and immunostaining.

RESULTS

There was no correlation between the numbers of total CD56+, CD56+CD16– or CD56+CD16+ in peripheral blood and the number of endometrial CD56+ cells in the same women. In endometrium from fertile women, a significant correlation was found between the numbers of CD56+ cells measured by flow cytometry and immunohistochemistry (correlation= 0.497, P= 0.026, when expressed as % total cells; correlation= 0.570, P= 0.009 when expressed as % CD45+ cells).

CONCLUSIONS

Measurements of CD56+ cells in peripheral blood do not correlate with endometrial CD56+ cell numbers and therefore should not be extrapolated to events in the endometrium. In contrast, measurements of endometrial CD56+ cells by flow cytometry and immunostaining correlate well.

BACKGROUND

There is a growing consensus that ovarian reserve is reduced after surgical excision of ovarian endometriomas. However, it remains to be fully clarified whether this damage precedes or follows surgery. In order to further elucidate this aspect, we evaluated ovarian responsiveness to hyperstimulation in women selected for IVF with unilateral unoperated endometriomas. The main aim of this study was to compare the number of developing follicles in the affected ovary with that in the contralateral intact gonad as a control.

METHODS

Patients selected for IVF who were diagnosed with one or more monolateral endometriomas (diameter <4 cm) and who did not undergo previous ovarian surgery were retrospectively identified. We compared the number of follicles (diameter ≥11 mm) and the number of co-dominant follicles (diameter >15 mm) on the day of hCG administration in the affected and intact ovaries.

RESULTS

Among the 84 women selected, the median interquartile range (IQR) number of follicles ≥11 mm in the affected and intact ovaries was 5 (3–7) and 5 (3–8), respectively (P= 0.36). The median (IQR) number of co-dominant follicles in the affected and intact ovaries was 3 (2–4) and 3 (2–5), respectively (P= 0.48). The number of co-dominant follicles was lower in the affected ovary in 36 cases (43%, 95% confidence interval: 32–53%). We also failed to identify any statistically significant difference between the two ovaries when evaluating data according to the number of cysts, their dimension, the dose of gonadotrophins used or the number of oocytes retrieved.

CONCLUSIONS

In women selected for IVF, the presence of an endometrioma does not markedly affect responsiveness to hyperstimulation.

BACKGROUND

Treatment decisions should ideally be based on well-designed randomized controlled trials (RCTs). Here we determine the rate of full publication of RCTs presented at annual meetings of the European Society of Human Reproduction and Embryology (ESHRE), identify potential bias against publishing non-significant results and results not favoring the experimental arm, quantify this bias in case it exists, and identify factors associated with time to publication.

METHODS

RCTs presented at ESHRE meetings 2003 and 2004 were recorded. Subsequent search in Medline, Cochrane Library and EMBASE was performed through December 2010 to identify full-text publication in a peer-review journal.

RESULTS

Among 155 abstracts describing RCTs 89 (57%) were published in full-text in a peer-review journal. Median time from presentation to publication was 15 months (range: 0–75). In bivariate analysis, only type of presentation and presence of outcomes favoring the experimental arm were related to publication rate. Studies presented orally or reporting a positive outcome in favor of the experimental arm were more likely to be published (P = 0.018 and 0.014, respectively). Results were consistent in a multivariable logistic regression, with odds ratio (OR) 2.51 [95% confidence interval (CI), 1.25–5.03] for oral versus poster presentations and OR 2.46 (95% CI, 1.23–4.95) for trials favoring versus not favoring the experimental arm. Kaplan–Meier curves revealed time to publication was shorter for oral presentations (log-rank test = 0.013) and trials favoring the experimental arm, compared with all others (log rank = 0.007).

CONCLUSIONS

RCTs with significant results in favor of the experimental arm are more likely to be published and are published sooner. Publication bias in reproductive medicine is a fact.

BACKGROUND

Steroid sulfatase (STS) is involved in estrogen biosynthesis and expressed in eutopic and ectopic endometrium of disease-free and endometriosis patients. The present study was designed to investigate its role in endometriosis development.

METHODS

Human endometrial explants were cultured on inserts for 24 h to assess the effectiveness of an STS inhibitor (STS-I), estradiol-3-O-sulfamate (E2MATE), on STS activity in endometrial tissue. Endometriosis was induced in mice, and E2MATE (or vehicle alone) was given orally for 21 days. Plasma estradiol levels were measured, and STS activity was assessed in murine organs (uterus, liver and leukocytes) and in lesions. Lesion number, weight and size (morphometry) were quantified. Lesion STS and progesterone receptor (PR) expression, proliferation and apoptosis rates were determined by immunohistochemistry.

RESULTS

In vitro, addition of 1 µM E2MATE to the culture medium resulted in decreased STS activity in endometrial explants (P < 0.001). Treatment of mice with E2MATE (1.0 and 0.5 mg/kg) did not modify plasma estradiol levels, but inhibited STS activity in murine uterus (P < 0.05), liver (P < 0.001) and leukocytes (P < 0.001), as well as in induced lesions (P < 0.05). E2MATE reduced lesion weight (P < 0.01) and size (P < 0.05), but had no impact on proliferation or apoptosis rates, nor STS protein expression. Stromal edema was observed in the uterus of animals treated with E2MATE, but not in the stroma of lesions. Increased PR expression was detected in endometriotic lesions (P < 0.001).

CONCLUSIONS

E2MATE was shown to effectively inhibit STS activity in endometrial tissue in vitro. In vivo, E2MATE decreased endometriosis development without affecting systemic estradiol levels. Use of STS-I could therefore be of potential interest in endometriosis treatment.

BACKGROUND

Ultrasound-guided transvaginal oocyte retrieval is often performed under local anaesthesia on an outpatient basis. The objective of this study was to compare the overall pain experience of a newly designed reduced needle (RN) compared with a thicker standard needle (SN).

METHODS

A prospective, randomized, multi-centre study was performed at four different clinics from June to December 2009. The oocyte aspiration was performed under local anaesthesia, either with a needle with a reduced diameter (0.9 mm) for the last 50 mm from the tip (RN) or with a SN (1.4 mm). A total of 257 patients were randomized (RN: n = 129; SN: n = 128). The primary endpoint was the overall pain experience self-assessed and registered by the patient on a visual analogue scale (VAS 0 mm = no pain to 100 mm = unbearable pain) immediately after the oocyte retrieval. Secondary end-points such as vaginal bleeding and several embryological parameters were also registered.

RESULTS

The overall pain during the oocyte retrieval procedure was significantly lower in the RN group than in the SN group (mean 21.0 mm, SD 17.5 mm and median 19.0 mm versus mean 26.0 mm, SD 19.9 mm and median 24.0 mm; P = 0.040, difference between groups mean–5.0 mm, 95% CI: 9.7 to–0.4). This was also true when adjusting for baseline characteristics such as number of follicles, number of previous oocyte pick-up, body mass index and age, by a multiple linear regression analysis. Significantly more patients (40 of 126) had less than expected vaginal bleeding in the RN group when compared with the SN group (24 of 124; 32 versus 19%; P = 0.03 and 95% CI 1.7–23.0%). No differences were found between the two needles with regard to additional i.v. analgesia, aspiration time, oocyte recovery, fertilization, cleavage rate, number of good quality embryos, number of embryos for freezing and pregnancy rate.

CONCLUSIONS

Oocyte aspiration performed with the newly designed thinner-tipped needle resulted in significantly less overall pain and less vaginal bleeding, without prolonging the retrieval procedure or influence the oocyte recovery rate, when compared with a SN.

Clinicaltrials.gov: NCT00924885

Aggressive chemotherapy generally results in the loss of both endocrine and reproductive functions. If the patient has not undergone previous oocyte, embryo or ovarian tissue cryopreservation, orthotopic allotransplantation of fresh ovarian tissue from a genetically non-identical sister may be considered. Here, we describe a case report. The patient, aged 15 years and presenting with homozygous sickle cell anemia, underwent chemotherapy (busulfan, cyclophosphamide) and total body irradiation before bone marrow transplantation, the donor being her HLA-compatible sister. HLA group analysis later revealed complete chimerism. When the patient was 32 years old, ovarian allografting was performed, with the ovarian tissue donor being the same sister who had already donated bone marrow. The goal was to restore ovarian activity and natural fertility. No immunosuppressive therapy was administered. No sign of rejection was observed. Restoration of ovarian function was achieved 3.5 months after transplantation, as proved by the first estradiol peak and follicular development detected by ultrasound. After 9 months of regular ovulatory cycles, IVF was attempted because proximal tubal stenosis (unknown at the time of grafting) could not be repaired by tubal reanastomosis. After stimulation, three oocytes were retrieved. Two embryos were obtained. One embryo was frozen and the other was transferred, resulting in an ongoing pregnancy. The patient delivered a healthy baby girl weighing 3.150 g at 37 2/7 weeks of gestation.

BACKGROUND

It is increasingly common for women in high-income countries to delay childbearing. We aimed to describe the context of pregnancy for first-time mothers of different ages and examine relationships among maternal age at first birth, mode of conception and psychosocial wellbeing in pregnancy.

METHODS

Using stratified sampling, we recruited similar numbers of women conceiving through assisted reproductive technology (ART; n = 297) or spontaneously (n = 295) across three age groups: younger, ≤20–30 years; middle, 31–36 years; older, ≥37 years. Women participated in a structured interview and completed validated questionnaires assessing socio-economic status, personality, quality of partner relationship, state and trait anxiety, pregnancy-focused (P-F) anxiety and maternal–fetal attachment.

RESULTS

Older maternal age was associated with lower depression and anxiety symptoms, lower maternal–fetal attachment (P< 0.05), greater psychological hardiness (resilience) (P< 0.001) and lower ratings of control in the partner relationship (P< 0.05) at a univariate level. ART conception, but not older maternal age, was associated with more P-F anxiety. Although most main effects of age and mode of conception became non-significant after controlling for contextual/reproductive history variables, a significant association between ART conception and more intense fetal attachment emerged (P< 0.05).

CONCLUSIONS

Women having their first baby when older appear to have some psychological advantages over their younger counterparts; they are more resilient, report their partners as less controlling and report lower symptoms of depression and anxiety during pregnancy. However, women conceiving through ART have a more complex experience of pregnancy, simultaneously experiencing more P-F anxiety and more intense emotional attachment to the fetus.

BACKGROUND

The impact of metabolic and reproductive features of polycystic ovary syndrome (PCOS) compromises psychological functioning. We investigated factors associated with negative psychological functioning to determine whether they were predictive of anxiety and depression in PCOS.

METHODS

A cross-sectional study was performed by questionnaire in 177 women with PCOS (mean ± SD age 32.8 ± 7.8 years) and 109 healthy controls (mean age 41.9 ± 15.4 years). Main outcome measures were anxiety and depression, measured using the Hospital Anxiety Depression Scale (HADS) and Multidimensional Body-Self Relations Questionnaire (MBSRQ), respectively.

RESULTS

Women with PCOS, compared with control women, had a higher mean anxiety HADS score (9.5 ± 3.9 versus 6.5 ± 3.6; P < 0.001), a higher mean depression score (5.7 ± 3.7 versus 3.3 ± 3.1; P < 0.001) and more negative body image in 7 out of 10 subscales of the MBSRQ. Multivariate regression analysis in PCOS showed that anxiety was predicted by self-worth (P < 0.0001), health evaluation (P = 0.005), time taken to diagnose PCOS (P = 0.003) and age (P = 0.02), while in control women, anxiety was predicted by self-worth (P = 0.009), health evaluation (P = 0.001) and rural living (P = 0.03). Depression in PCOS was predicted by self-worth (P = 0.0004), quality of life (QOL) (P = 0.004), fitness orientation (P = 0.002), appearance evaluation (P = 0.001) and time to diagnosis (P = 0.03) and in women without PCOS, by self-worth (P < 0.0001), QOL (P < 0.0001), illness orientation (P = 0.001) and appearance orientation (P = 0.02).

CONCLUSIONS

Women with PCOS have increased anxiety, depression and negative body image compared with women without PCOS. In women with or without PCOS, body image and self-worth are predictors of both anxiety and depression, while QOL also predicts only depression. Time taken to diagnose PCOS is associated with poor psychological functioning.

BACKGROUND

The fifth leading cause of cancer deaths among women is ovarian cancer (OC), which originates primarily in the ovarian surface epithelium (OSE) that surrounds the ovary. Permanent removal of the OSE could provide a novel strategy to substantially reduce OC risk, while retaining the benefits of ovarian function, including gameto- and steroidogenesis. It must be determined whether ovarian surface epitheliectomy (OSEx) carries deleterious side effects, including loss of menstrual cyclicity, infertility or scarring (e.g. adhesions), prior to any clinical application of this strategy. To achieve this, we selected the non-human primate, rhesus macaque, for long-term (12 month) studies on the effects of OSEx.

METHODS

Rhesus macaque females underwent OSEx by detergent treatment and were then monitored for menstrual cyclicity (menstruation, steroidogenesis and follicle development) and adverse side effects (tissue scarring or adhesions). Ovaries were collected at 6 or 12 months and examined for evidence of tissue damage, follicle rupture and regression of the corpus luteum. The ovarian surface was examined immunohistologically for signs of epithelial replacement, using markers for OSE and fimbrial epithelium (FE), a possible alternative source of pelvic tumors diagnosed as OC.

RESULTS

After OSEx, menstrual cycle length, estrogen and progesterone production, follicle rupture and luteal regression appeared normal. No evidence of adhesions was seen. At 6 and 12 months post-OSEx, the ovarian surface was sparsely populated by cells expressing OSE and FE markers. Proliferative activity in this population was notably low.

CONCLUSIONS

OSEx may provide a novel method to reduce the risk of OC, without sacrificing ovarian function, although the effects on fertility remain to be tested. The absence of epithelial replacement via enhanced proliferation suggests OSEx does not increase malignant potential. Complete and permanent OSEx may be feasible.

BACKGROUND

Epithelial ovarian cancer (EOC) risk correlates strongly with the number of ovulations that a woman experiences. The primary source of EOC in women is the ovarian surface epithelium (OSE). Mechanistic studies on the etiology of OSE transformation to EOC cannot be realistically performed in women. Selecting a suitable animal model to investigate the normal OSE in the context of ovulation should be guided by the model's reproductive similarities to women in natural features that are thought to contribute to EOC risk.

METHODS

We selected the non-human primate, rhesus macaque, as a surrogate to study the normal OSE during the natural menstrual cycle. We investigated OSE morphology and marker expression, plus cell proliferation and death in relation to menstrual cycle stage and ovulation.

RESULTS

OSE cells displayed a morphological range from squamous to columnar. Cycle-independent parameters and cycle-dependent changes were observed for OSE histology, steroid receptor expression, cell death, DNA repair and cell adhesion. Contrary to findings in non-primates, primate OSE cells were not manifestly cleared from the site of ovulation, nor were proliferation rates affected by ovulation or stage of the menstrual cycle. DNA repair proteins were more highly expressed in OSE than in other ovarian cells.

CONCLUSIONS

This study identifies significant differences between primate and non-primate OSE. In contrast to established views, ovulation-induced death and proliferation are not indicated as prominent contributors to EOC risk, but disruption of OSE cadherin-mediated adhesion may be, as could the loss of ovary-mediated chronic suppression of proliferation and elevation of DNA repair potential.

BACKGROUND

Grafting of isolated follicles represents an approach to prevent the risk of reimplanting malignant cells with cryopreserved ovarian fragments. Optimal conditions and cell types required to sustain human follicular growth need to be identified. To help improve the grafting technique, we investigated whether short-term xenografting of a suspension containing ovarian stromal and endothelial cells without follicles could enhance graft survival and revascularization.

METHODS

In human ovary, CD34 selectively labels endothelial cells of blood vessels. A CD34-replete ovarian stromal cell group, including stromal and endothelial cells, was obtained after enzymatic digestion of fresh human ovarian cortex. Magnetic-activated cell sorting was used to establish a CD34-depleted ovarian stromal cell group. Proportions of CD34-positive cells were evaluated by flow cytometry and immunocytochemistry. Cell suspensions were embedded in human plasma clots and grafted (n = 10 for each group, 7 days) to the ovarian bursa of nude mice. Angiogenesis was quantified after human/mouse CD34 immunostaining.

RESULTS

CD34-replete grafts had a well-organized and vascularized stromal structure, containing tubular components staining for human CD34 and corresponding to functional vessels, as evidenced by intraluminal red blood cells. CD34-depleted grafts tended to be smaller than CD34-replete grafts and poorly vascularized with central necrosis. Global microvessel density was higher in the CD34-replete than depleted group (337.9 versus 187.3 vessels/mm², P < 0.05), with a greater proportion of human vessels (68.02 versus 6.95%, respectively, P < 0.05).

CONCLUSIONS

We demonstrated the importance of co-transplanting ovarian endothelial and stromal cells to ensure the formation of a well-vascularized and structured ovarian-like stroma after short-term xenografting, for future application in the transplantation of isolated follicles.

BACKGROUND

The aims of this study were to establish whether individual differences exist in the frequency and size of vacuoles found in human sperm and to ascertain whether such vacuoles are involved in causing DNA damage.

METHODS

Morphologically normal sperm were obtained from 15 IVF and 2 ICSI patients and 3 fertile donors. (i) Sperm heads were analyzed for the presence of vacuoles under a 1000x differential interference contrast microscope. (ii) In three patients and two donor samples, structural chromosomal damage was evaluated in normal sperm containing large vacuoles and selected at 1000x magnification for injection into mouse oocytes. (iii) In 10 patients and two donor samples, confocal laser microscopy detected DNA damage in sperm-exhibiting large vacuoles and stained with an in situ cell death detection kit.

RESULTS

(i) Vacuoles were observed in almost all normal sperm from patient and donor ejaculates and were mainly located at the tip or middle area of the sperm heads. However, average incidence of normal sperm exhibiting large vacuoles was 4.6 and 4.2% in the patient and donor groups, respectively. (ii) Sperm chromosome assays did not reveal any differences in the incidence of structural chromosome aberrations between sperm exhibiting large vacuoles and those without them (9.1 versus 4.1%). (iii) No significant difference in frequency of TUNEL-positive cells was found between normal sperm with large vacuoles and those without them in the samples examined. Among 227 sperm exhibiting large vacuoles, only 7 cells were TUNEL positive.

CONCLUSION

The results showed that large vacuoles were not responsible for DNA damage, suggesting that intra-cytoplasmic injection of morphologically selected sperm may not be required for patients who produce high-quality semen.

BACKGROUND

During the process of fertilization, human spermatozoa are confronted with phagocytic cells of the female reproductive tract. Part of this host mucosal barrier are immature dendritic cells (DCs), which play an important role in the defense of invading microbial pathogens. In the present study, we investigated the potential interaction of spermatozoa with DCs and raised the question of whether seminal plasma impacts the interaction of DCs with spermatozoa or pathogenic microbes.

METHODS AND RESULTS

Flow cytometry and microscopy detected a strong association between spermatozoa and human monocyte-derived DCs, which was partly mediated by the DC-specific adhesion receptor, DC-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN). Coincubation assays also showed that capture of spermatozoa by DCs was blocked in the presence of increasing concentrations of seminal plasma. This inhibitory effect of seminal plasma was accompanied by altered DC maturation, revealed by flow cytometry analysis of maturation-specific DC surface markers. Phalloidin-staining of the DC cytoskeleton further visualized an impact of seminal plasma on DC morphology. To elucidate the molecular nature of the inhibitory activity of seminal plasma on sperm–DC -association, binding assays were performed in the presence of individual seminal plasma components. This approach identified specific prostaglandins—in particular, PGE_l, 19-OH-PGE_l and PGE₂, which are present in seminal plasma at high concentrations—as likely inhibitory factors. In contrast to glass beads, the yeast Candida albicans, a common commensal organism and frequent pathogen of the genital tract, was also found to be protected from capture by DCs in the presence of seminal plasma or the specific prostaglandins.

CONCLUSIONS

The immunomodulatory power of seminal plasma may help spermatozoa to circumvent the attack of DCs of the female reproductive tract, thereby supporting successful fertilization. At the same time, however, such protective effects of seminal plasma may also modulate DC action during host–pathogen interactions.

INTRODUCTION

Based on historical data, a decline in sperm counts during the years 1940–1990 has been suggested and aetiologically linked to a concomitant increase in the incidence of testicular cancer. This study, focusing on possible changes in sperm parameters among young Swedish men, during the past 10 years, was specifically designed in order to answer the question of whether there is a continuing decline in sperm counts.

METHODS

During the period 2008–2010, 295 young (17–20 years; median 18) men born and raised in Sweden were recruited at the age they were supposed to undergo medical examination prior to military service. The participants filled in questionnaires, underwent andrological examination and delivered an ejaculate. Their semen parameters were compared with those of a similar cohort of men (n = 216) recruited in the year 2000–2001.

RESULTS

No significant changes (means; 2000–2001 versus 2008–2010) in sperm concentration (78 x 10⁶/ml versus 82 x 10⁶/ml; P = 0.54), semen volume (3.1 ml versus 3.0 ml; P = 0.26) or total sperm counts (220 x 10⁶ versus 250 x 10⁶; P = 0.18) were found. The proportion of progressively motile spermatozoa also remained unchanged.

CONCLUSIONS

Between the years 2000 and 2010 we found no evidence of time-related deterioration of semen parameters among young Swedish men from the general population. This finding does not exclude that such a decrease may have taken place before year 2000. If the risk of testicular cancer is linked to the sperm counts, the increase in incidence of this malignancy should be levelling off in southern Sweden in the next 10–15 years.

BACKGROUND

The aim of this study was to assess whether the cessation of progesterone (P) supplementation during early pregnancy after GnRH antagonist cycles is not inferior to its continuation in terms of pregnancy rates beyond 12 weeks of gestation

METHODS

There were 200 patients, with a positive β-hCG test (followed by a doubling in β-hCG levels 48 h later) after a fixed recombinant FSH (recFSH)/GnRH antagonist protocol for IVF/ICSI and a Day-3 fresh embryo transfer (ET), participated in this randomized controlled study. All patients received luteal support, with 200 mg vaginal P being administered three times daily for 14 days, beginning on the day of ET until the second β-hCG test, 16 days post-ET. In the control group (n = 100) the administration of P was continued until 7 weeks of gestation. In the study group (n = 100), vaginal P was discontinued on the 16th day post-ET

RESULTS

The ongoing pregnancy rate beyond 12 weeks, the primary outcome measure, did not differ between the study and control groups (82 versus 73%, P = 0.175; difference 9%, 95% CI: –2.6 to 20.3). There were also no significant differences observed between the study and control group in terms of abortion before or after 7 weeks of gestation [(9 versus 12%, P = 0.645) and (8 versus 10%, P = 0.806), respectively]. The same was true for bleeding episodes (14 versus 19%, P = 0.446).

CONCLUSIONS

After recFSH/GnRH antagonist cycles, the withdrawal of P supplementation in early pregnancy, with normally increasing β-hCG levels on the 16th day post-ET, had no significant clinical impact in terms of ongoing pregnancy rates beyond 12 weeks.

BACKGROUND

Exposure to tobacco smoking prenatally is a risk factor for reduced semen quality, but whether the exposure has adverse effects on reproductive hormones, pubertal development or adult BMI remain largely unexplored. The aim of this study was to investigate the associations between these factors while controlling for the effects of current smoking in young adulthood.

METHODS

This cross-sectional study (1996–2006) included 3486 Danish men (median age: 19 years), participating in a semen-quality study. Data were obtained from questionnaires, physical examinations, semen analyses and assessments of reproductive hormones. The main outcome measures were markers of pubertal onset, BMI, reproductive hormones and semen variables.

RESULTS

Maternal smoking during pregnancy was associated with earlier onset of puberty (e.g. early pubic hair development in 25.2 versus 18.9% of unexposed subjects), lower final adult height (median: 1.80 versus 1.82 cm), higher BMI (22.9 versus 22.4), smaller testicles (14.0 versus 14.5 ml), lower total sperm counts (119 versus 150 million), reduced spermatogenesis-related hormones (e.g. inhibin-B/FSH 66 versus 73 pg/mU) and higher calculated free testosterone (free-T, 2.38 versus 2.33 nmol/l). If not exposed prenatally, men's own smoking was associated with increased total testosterone but unchanged free-T. For smokers who had been exposed prenatally, total testosterone was increased but free-T was reduced (2.30 versus 2.38 nmol/l, P = 0.003) due to higher levels of sex hormone-binding globulin.

CONCLUSIONS

Prenatal exposure to tobacco may lead to faster pubertal development possibly caused by a higher free-T, and to higher adult BMI and impairment of testicular function. The findings may not be clinical relevant for the individual but are of public health importance, and add to the knowledge of effects of tobacco smoking.

BACKGROUND

Cumulus cell (CC) gene expression is suggested as a non-invasive analysis method to predict oocyte competence. There are, however, important between-patient differences in CC gene expression. These can be compensated when expression results are combined with patient and cycle characteristics using a multiple regression analysis model.

METHODS

From ICSI patients stimulated with GnRH antagonist and recombinant FSH (n= 25) or GnRH agonist and highly purified menotrophin (n= 20), CC were collected and oocytes were individually fertilized and cultured. CC were analyzed for the expression of Syndecan 4 (SDC4), Prostaglandin-endoperoxide synthase 2 (PTGS2), Versican (VCAN), Activated leukocyte cell adhesion molecule, Gremlin 1, transient receptor potential cation channel, subfamily M, member 7 (TRPM7), Calmodulin 2 and Inositol 1,4,5-trisphosphate 3-kinase A (ITPKA) using quantitative PCR. Results were analyzed in relation to the stimulation protocol. Within-patient variation in gene expression was related to oocyte maturity and developmental potential. Models predictive for normal embryo or blastocyst development and pregnancy in single embryo transfer cycles were developed.

RESULTS

Mature oocytes have higher PTGS2 and lower VCAN expression in their cumulus. All genes except VCAN had a positive correlation with good embryo or blastocyst morphology and were used to develop predictive models for embryo or blastocyst development (P< 0.01). Specific models were obtained for the two stimulation protocols. In both groups, better cleavage-stage embryo prediction relied on TRPM7 and ITPKA expression and pregnancy prediction relied on SDC4 and VCAN expression. In the current data set, the use of CC expression for pregnancy prediction resulted in a sensitivity of >70% and a specificity of >90%.

CONCLUSIONS

Multivariable models based on CC gene expression can be used to predict embryo development and pregnancy.

BACKGROUND

Severe pre-eclampsia (sPE) causes significant maternal morbidity and intrauterine growth restriction as a result of severe placental dysfunction. Defects in the formation of both extra-villous and villous trophoblast are characteristic of this disease. The outer syncytiotrophoblast layer covering the placental villi develops syncytial knots and focal necrosis while reduced invasion of the extra-villous trophoblast results in a reduced maternal blood supply and ischemia of the placental villi. The transcription factor glial cell missing-1 (GCM1) regulates formation of both types of trophoblast. GCM1 expression is reduced in placental villi of women with sPE but the functional downstream consequences of reduced GCM1 expression are unknown.

METHODS AND RESULTS

In floating first trimester villous explants we demonstrated increased mRNA (2.5-fold, n = 12) and protein level (9.8-fold) of tissue inhibitor of metalloproteinase-4 (TIMP4) following repression of GCM1 (70 ± 7%) by small interfering-RNA, using RT–PCR and western blot, respectively. Similar increases in TIMP4 mRNA (4.2-fold, n = 7, P< 0.001 versus control) and protein levels were found following gene silencing of GCM1 in BeWo cells (<90% knock down of protein). TIMP4 protein was increased in placenta from women with sPE (3.5 ± 0.4 pg/µg, n = 8), compared with preterm (1.7 ± 0.17 pg/µg, n = 9) and term controls (1.6 ± 0.16 pg/µg, n = 9; P< 0.01; quantified by enzyme-linked immunosorbent assay and visualized using immunohistochemistry) with reduced GCM1 expression, mostly in the pathologic syncytial knots.

CONCLUSIONS

TIMP4 is a downstream target of GCM1 that may link the consequences of reduced GCM-1-directed trophoblast differentiation to histologic and functional components of disordered placentation in sPE.