STUDY QUESTION

How patient-centered are two included specialized endometriosis clinics relative to each other and how can they improve the patient-centeredness of their care?

SUMMARY ANSWER

The validated ENDOCARE questionnaire (ECQ) reliably concluded that the adjusted overall patient-centeredness did not differ between the clinics, that each clinic was significantly more patient-centered for 2 out of 10 dimensions of patient-centered endometriosis care and that clinics 1 and 2 had to improve 8 and 13 specific care aspects, respectively.

WHAT IS KNOWN ALREADY

Patient-centered endometriosis care is essential to high-quality care and is defined by 10 dimensions. The ECQ was developed, validated and proved to be reliable in a European setting of self-reported endometriosis patients but had not yet been used at a clinic level for quality management.

STUDY DESIGN, SIZE, DURATION

A cross-sectional survey was disseminated in 2011 to all 514 women diagnosed with endometriosis during a laparoscopy indicated for pain and/or infertility during a retrospective 2-year period (2009–2010) in two university clinics from two different European countries.

PARTICIPANTS/MATERIALS, SETTING, METHODS

In total 337 patients completed the ECQ (216 and 121 per clinic). Respondents had a mean age of 34.3 years. Three in four reported a surgical diagnosis of moderate or severe endometriosis and the majority reported surgical treatment by a multidisciplinary team. The ECQ assessed the 10 dimensions of patient-centeredness, more specifically whether the health-care performance, as perceived by patients, measured up to what is important to patients in general.

MAIN RESULTS

The ECQ was completed by 337 respondents (response rate = 65.6%). Reliability and validity of the ECQ for use on clinic level were confirmed. Clinics did not differ in overall mean importance scores; importance rankings of the ECQ dimensions were almost identical. The overall patient-centeredness scores (PCS), adjusted for education level, did not discriminate between the clinics. However, the adjusted PCS for the dimensions ‘clinic staff’ and ‘technical skills’ were significantly better in clinic 1, whereas the dimensions ‘physical comfort’ and ‘access to care’ were significantly better in clinic 2. There were 8 (clinic 1) and 13 (clinic 2) targets identified for joint and cross-clinic improvement.

LIMITATIONS, REASONS FOR CAUTION

Response rates were relatively high. Recall bias was the most important limitation and research in more clinics is needed to define the statistical discriminative value of the ECQ.

WIDER IMPLICATIONS OF THE FINDINGS

European endometriosis clinics can use the validated ECQ for reliable assessment of their ‘patient-centeredness’, for comparison with others and for setting specific targets to improve the patient-centeredness of their endometriosis care, to plan interventions, and to evaluate their effectiveness.

STUDY FUNDING/COMPETING INTEREST

This work was funded by KU Leuven and European Network of Endometriosis (ENE), supported by the European Commission (Public Health Executive Agency). No competing interests are declared.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3168?rss=1

STUDY QUESTION

How is the expression of nectins and nectin-like molecules (Necls) detected by immunostaining altered by endometriosis?

SUMMARY ANSWER

Our results suggest that Nectin-1, -3, -4 and Necl-2 may contribute to the pathogenesis of endometriosis. Immunostaining of nectins and Necls varies according to the anatomical location of endometriosis.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

Nectin and Necl molecules are immunoglobulin-like cell adhesion molecules involved in apoptosis, cell proliferation and in metastases. Previous studies have demonstrated the involvement of adhesion molecules in the development of endometriotic lesions but no data exist on immunostaining of nectins and Necls molecules in endometriosis.

DESIGN, PARTICIPANTS AND SETTING

This retrospective study was conducted in a tertiary-care hospital (Tenon Hospital, Paris, France). Samples were collected from 55 women undergoing endometrial biopsy or surgery for endometriosis and 20 controls having hysterectomy or endometrial biopsy for other reasons; multiple samples were collected from 15 women. We studied the immunostaining of Nectin-1, -3, -4 and Necl-2 in secretory and proliferative endometrium from women with (n = 20) or without endometriosis (i.e. control group, n = 20), and in peritoneal (n = 20), ovarian (n = 20) and colorectal endometriosis (n = 20).

MAIN RESULTS

Semi-quantitative immunostaining demonstrated that (1) Necl-2 staining was stronger in all types of endometriotic lesions than in the eutopic endometrium from patients with endometriosis (P < 0.0125) and in ovarian endometriotic cysts compared with other locations (P < 0.001); (2) Nectin-3 staining was stronger in the eutopic endometrium of patients with endometriosis compared with controls (P = 0.03) and in all endometriotic lesions compared with the eutopic endometrium from patients with endometriosis (P < 0.0125); (3) Nectin-4, staining was stronger in the eutopic endometrium of patients with endometriosis compared with controls (P = 0.04) and (4) Nectin-1 staining was significantly increased in colorectal endometriosis compared with other locations (P = 0.004).

BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION

We did not assess the pattern of expression in endometriosis of all nectins and Necl molecules. Indeed, Necl-5 is implicated in many pathophysiological processes such as cell movement and proliferation with potential relevance to endometriosis.

GENERALISABILITY TO OTHER POPULATIONS

At present, few data on implication of nectins and Necl molecules in endometriosis exist. Hence, our results should be confirmed by further quantitative studies at protein or RNA levels.

STUDY FUNDING/COMPETING INTEREST(S)

No funding source. All the authors declare no conflict of interest.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3179?rss=1

BACKGROUND

Endometriosis is a multifactorial gynecological disease characterized by the presence of functional endometrium-like tissue in ectopic sites. Several studies have focused on elucidating the immunological, endocrine, environmental and genetic factors involved in endometriosis. However, its pathogenesis is still unclear.

METHODS

High-resolution comparative genomic hybridization was applied to screen for genomic imbalances in laser microdissected stromal and epithelial cells from 20 endometriotic lesions and three samples of eutopic endometrium derived from eight patients. The expression of seven stemness-related markers (CD9, CD13, CD24, CD34, CD133, CD117/c-Kit and Oct-4) in endometrial tissue samples was evaluated by immunohistochemistry.

RESULTS

Samples of eutopic endometrium showed normal genomic profiles. In ectopic tissues, an average of 68 genomic imbalances was detected per sample. DNA losses were more frequently detected and involved mainly 3p, 5q, 7p, 9p, 11q, 16q, 18q and 19q. Many of the genomic imbalances detected were common to endometriotic stroma and epithelia and also among different endometriotic sites from the same patient. These findings suggested a clonal origin of the endometriotic cells and the putative involvement of stem cells. Positive immunostaining for CD9, CD34, c-Kit and Oct-4 markers was detected in isolated epithelial and/or stromal cells in eutopic and ectopic endometrium in the majority of cases.

CONCLUSIONS

The presence of shared genomic alterations in stromal and epithelial cells from different anatomical sites of the same patient and the expression of stemness-related markers suggested that endometriosis arises as a clonal proliferation with the putative involvement of stem cells.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3187?rss=1

STUDY QUESTION

Is the cytoskeletal and chromosomal organization of failed fertilized oocytes from severely obese patients (BMI ≥ 35 kg/m²) altered compared with that in patients with normal BMI (BMI 18.5–24.9 kg/m²)?

SUMMARY ANSWER

Compared with normal BMI patients, severe obesity was associated with a greater prevalence of spindle anomalies and non-aligned chromosomes in failed fertilized oocytes.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

Obesity is associated with poor reproductive outcomes, but little is known regarding the underlying mechanisms. To address potential mechanisms, our study compared the cytoskeletal and chromosome organization in failed fertilized oocytes from severely obese and normal BMI patients.

DESIGN

The study population was drawn from IVF patients treated in a hospital-based infertility clinic between February 2010 and July 2011. The prevalence of meiotic spindle and chromosome alignment anomalies in failed fertilized oocytes from patients with severe obesity (i.e. Class II and III; BMI 35.0–50.1 kg/m²) was compared with those from patients with normal BMI (BMI 18.5–24.9 kg/m²). Oocytes were fixed and then labeled for tubulin, actin and chromatin. Spindle number and integrity, as well as chromosome alignment, were assessed using immunofluorescence microscopy and, in some cases, confocal microscopy. Generalized estimating equations were applied, which account for the correlation among oocytes from the same patient to estimate odds ratio (OR), 95% confidence intervals (CIs) and two-sided Wald P-values. Models were adjusted for continuous age at cycle start, cycle type (IVF or ICSI) and polycystic ovarian syndrome (PCOS) a priori.

PARTICIPANTS AND SETTING

University-affiliated infertility clinic. A total of 276 oocytes that failed to fertilize from 137 patients were evaluated: 105 oocytes from severely obese women (n = 47) and 171 oocytes from normal BMI patients (n = 90).

MAIN RESULTS AND THE ROLE OF CHANCE

(i) Significantly more oocytes from the severely obese group exhibited two spindles compared with those from the normal BMI group (58.9 versus 35.1%; OR = 2.68, CI = 1.39–5.15, P-value = 0.003).

(ii) Among oocytes with a single spindle, those from severely obese patients showed a significantly higher prevalence of disarranged spindles with non-aligned chromosomes compared with those from normal BMI patients (28.6 versus 8.6%; OR = 4.58, CI = 1.05–19.86, P-value = 0.04).

BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION

Inclusion of only failed fertilized oocytes, small sample size, unknown factors such as non-PCOS comorbidity.

GENERALIZABILITY TO OTHER POPULATIONS

For this study, by design, it is unclear whether the findings are generalizable to successfully fertilized oocytes, and whether this oocyte-level influence of obesity is generalizable to infertile women who do not undergo stimulation or, more broadly, to spontaneous conceptions in fertile women.

STUDY FUNDING/COMPETING INTEREST(S)

none.

TRIAL REGISTRATION NUMBER

n/a.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3198?rss=1

BACKGROUND

Before human MII oocytes are vitrified they are usually denuded from their cumulus cells. In this study we wanted to investigate the effects of an intact corona radiata on the vitrification and fertilization of human oocytes.

METHODS

The study comprised two different parts. In Part 1, 36 MII stage oocytes, from 6 patients, were randomly assigned into a control group, a group of vitrified-warmed oocytes without a corona radiata and a group of vitrified-warmed oocytes with an intact corona radiata. In each group of 12, 6 oocytes were used for evaluation of the zona pellucida solubility (hardening) and another 6 oocytes were used for the analysis of their ultrastructure. In addition, six polyspermically fertilized oocytes were used as positive controls for zona pellucida hardening. In Part 2, 16 patients in total produced 107 fresh and 98 vitrified-warmed oocytes, with or without an intact corona radiata. All oocytes were fertilized via conventional IVF and embryos were transferred according to our standard ET routines. The oocyte survival and fertilization rates, embryo quality and pregnancy and implantation rates were evaluated.

RESULTS

There were no differences in oocyte survival, zona pellucida solubility (hardening) or the number of cortical granules between the vitrified-warmed and fresh oocytes. There were also no differences in the zona pellucida solubility and the number of cortical granules between vitrified-warmed oocytes with or without an intact corona radiata. However, the oocytes with an intact corona radiata had a higher fertilization rate after conventional IVF insemination. No differences were seen in the survival and cleavage rates, the percentage of high-quality embryos or the clinical outcome.

CONCLUSIONS

Zona hardening and ultrastructural damage do not seem to occur in vitrified human oocytes. An intact corona radiata in vitrified-warmed oocytes retains their fertilization capacity in conventional IVF, but does not improve the embryo quality. Poor fertilizing capacities of vitrified-warmed oocytes without an intact corona radiata seem to have been due to the complete removal of the cumulus cells.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3208?rss=1

STUDY QUESTION

Are attachment anxiety and avoidance dimensions in female and male partners in couples seeking infertility treatment associated with her and his infertility-related stress?

SUMMARY ANSWER

Attachment dimensions are significantly associated with several aspects of infertility stress in couples undergoing IVF treatment.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

Attachment dimensions of anxiety and avoidance (where highly anxious individuals fear rejection and are preoccupied with maintaining proximity to their partner and highly avoidant individuals are uncomfortable with intimacy and prefer to maintain distance from their partner) may influence the well being of individuals undergoing IVF/ICSI treatment. This study showed that one partner's attachment dimensions had a direct effect on the infertility-related stress of the other partner.

DESIGN

Cross-sectional study of consecutive couples before starting their first IVF/ICSI treatment in 2009–2011 at the ANDROS clinic in Palermo, Italy.

PARTICIPANTS AND SETTING

Three hundred and fifty-nine couples undergoing fertility treatments were invited to participate in the research. The final sample comprised 316 females and 316 males who filled out the psychological questionnaires (Experiences in Close Relationships; Fertility Problem Inventory; State scale of State-Trait Anxiety Inventory). The participants included patients who had a primary infertility diagnosis and were about to undergo their first IVF or ICSI treatment.

DATA ANALYSIS METHOD

Paired t-tests were used to examine gender differences on the study variables (attachment anxiety, attachment avoidance, infertility stress, state anxiety, etc.). Associations between infertility-related stress and the study variables were explored using hierarchical stepwise multivariate linear regression analyses.

MAIN RESULTS AND THE ROLE OF CHANCE

Attachment anxiety and attachment avoidance were significantly associated with global infertility stress in both women (β = 0.24, P < 0.01 and β = 0.27, P < 0.01) and men (β = 0.23, P < 0.01 and β = 0.37, P < 0.01). Regarding the cross-partner effects, men's infertility stress and relationship concerns were associated with their partners' attachment avoidance (β = 0.10 P < 0.05 and β = 0.12, P < 0.05); and the infertility stress of women and the scores for need of parenthood were associated with their partners' attachment anxiety (β = 0.14 P < 0.05 and β = 0.16, P < 0.05).

BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION

The study data are cross sectional, and specifically focus on associations between adult attachment style and infertility stress. Treating the data from couples as independent observations may be a limitation of the analysis. Potential moderators of such relationships (e.g. coping strategies, stress appraisal) are not included in this study.

STUDY FUNDING/COMPETING INTEREST(S)

This research was supported by funds provided by Centro Andros S.r.l., Palermo, Italy. The authors declare no financial or commercial conflicts of interest in this study.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3215?rss=1

BACKGROUND

Little is known about the long-term course taken in life by couples who had undergone medically assisted reproduction (MAR). The aim of this study was to find out in a large sample whether, in comparison with parents, involuntarily childless couples have a different subjective perception of overall and specific quality of life over a period of >10 years.

METHODS

Between 1994 and 1997, 564 couples participated in the initial Heidelberg Fertility Consultation Service study of psychosocial aspects of infertility. In March 2008, a follow-up questionnaire was sent to all of these couples. Both partners were asked about the current status of their desire for a child and their satisfaction with life, their self-esteem, partnership, sexuality and career, as well as their current attitude towards the MAR they had undergone and experience of the process.

RESULTS

The final sample consisted of 148 couples and 60 women (response rate: 41% of the women and 31% of the men contacted). Fifty-nine percent of the women had at least one genetically related child, 11% had a foster or adopted child and 30% remained childless. Comparisons of psychological variables between parents and childless couples were done for the 148 couples only. Post-MAR parents indicated significantly higher self-esteem than childless couples (P < 0.01) and were more inclined to go through the infertility treatment again than childless couples (P < 0.001 for women, P < 0.05 for men). Positive aspects of infertility were seen more often by childless couples than by parents (P < 0.001). Childless women reported more occupational satisfaction than mothers (P < 0.01), while no such difference was identified in the male partners. Concerning overall life satisfaction, satisfaction with friendships and the partnership, and sexual satisfaction there were no statistically significant differences between childless women/men and mothers/fathers.

CONCLUSIONS

Overall, our 10-year follow-up survey indicated good psychological adjustment both in childless couples and in post-MAR parents. A decline of sexual satisfaction in childless couples (often reported in the literature) was not observed in this large sample. Quality of life in the long-term can safely be said to be high, both in the definitively childless couples and the post-MAR parents. These findings should be integrated into the information and counselling for would-be parents prior to infertility treatment. A major limitation of this study is that the majority of women and men from the initial study did not respond in our follow-up study.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3226?rss=1

BACKGROUND

Mammalian spermatogenesis is a process that involves a complex expression program in both somatic and germ cells present in the male gonad. A number of studies have attempted to define the transcriptome of male meiosis and gametogenesis in rodents and primates. Few human transcripts, however, have been associated with testicular somatic cells and germ cells at different post-natal developmental stages and little is known about their level of germline-specificity compared with non-testicular tissues.

METHODS

We quantified human transcripts using GeneChips and a total of 47 biopsies from prepubertal children diagnosed with undescended testis, infertile adult patients whose spermatogenesis is arrested at consecutive stages and fertile control individuals. These results were integrated with data from enriched normal germ cells, non-testicular expression data, phenotype information, predicted regulatory DNA-binding motifs and interactome data.

RESULTS

Among 3580 genes for which we found differential transcript concentrations in somatic and germ cells present in human testis, 933 were undetectable in 45 embryonic and adult non-testicular tissues, including many that were corroborated at protein level by published gene annotation data and histological high-throughput protein immunodetection assays. Using motif enrichment analyses, we identified regulatory promoter elements likely involved in germline development. Finally, we constructed a regulatory disease network for human fertility by integrating expression signals, interactome information, phenotypes and functional annotation data.

CONCLUSIONS

Our results provide broad insight into the post-natal human testicular transcriptome at the level of cell populations and in a global somatic tissular context. Furthermore, they yield clues for genetic causes of male infertility and will facilitate the identification of novel cancer/testis genes as targets for cancer immunotherapies.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3233?rss=1

STUDY QUESTION

Is decorin (DCN), a putative modulator of growth factor (GF) signaling, expressed in the primate ovary and does it play a role in ovarian biology?

SUMMARY ANSWER

DCN expression in the theca, the corpus luteum (CL), its presence in the follicular fluid (FF) and its actions revealed in human IVF-derived granulosa cells (GCs), suggest that it plays multiple roles in the ovary including folliculogenesis, ovulation and survival of the CL.

WHAT IS KNOWN ALREADY

DCN is a secreted proteoglycan, which has a structural role in the extracellular matrix (ECM) and also interferes with the signaling of multiple GF/GF receptors (GFRs). However, DCN expression and action in the primate ovary has yet to be determined.

STUDY DESIGN, SIZE, DURATION

Archival human and monkey ovarian samples were analyzed. Studies were conducted using FF and GC samples collected from IVF patients.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Immunohistochemistry, western blotting, RT–PCR, quantitative RT–PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) studies were complemented by cellular studies, including the measurements of intracellular Ca²⁺, reactive oxygen species (ROS), epidermal GF receptor (EGFR) phosphorylation by DCN and caspase activity.

MAIN RESULTS AND THE ROLE OF CHANCE

Immunohistochemistry revealed strong DCN staining in the connective tissue and follicular thecal compartments, but not in GCs of pre-antral and antral follicles. Pre-ovulatory follicles could not be studied, but DCN was associated with connective tissue of CL samples and the cytoplasm of luteal cells. DCN expression in monkey CL doubled (P < 0.05) towards the end of the luteal lifespan. DCN was found in human FF obtained from IVF patients (mean: 12.9 ng/ml; n = 20) as determined by ELISA. DCN mRNA and/or protein were detected in freshly isolated and cultured, luteinized human GCs. In the latter, exogenous human recombinant DCN increased intracellular Ca²⁺ levels and induced the production of ROS in a concentration-dependent manner. DCN, like epidermal GF, phosphorylated EGFR significantly (P < 0.05) and reduced the activity of caspase 3/7 in cultured GCs. The data indicate the expression of DCN in the theca of growing follicles, in FF of ovulatory follicles and in the CL. Therefore, DCN may exert paracrine actions via GF/GFR systems in multiple ovarian compartments.

LIMITATIONS, REASONS FOR CAUTION

Functional studies were performed in cultures of human luteinized GCs, which are an apt model but may not fully mirror the pre-ovulatory GC compartment or the CL. Other human ovarian cells, including the thecal cells, were not available.

WIDER IMPLICATIONS OF THE FINDINGS

In accordance with its evolving roles in other organs, ovarian DCN is an ECM-associated component, which acts as a multifunctional regulator of GF signaling in the primate ovary. DCN may thus be involved in folliculogenesis, ovulation and the regulation of the CL survival in primates.

STUDY FUNDING/COMPETING INTEREST(S)

This study was supported by Deutsche Forschungsgemeinschaft (DFG) MA1080/17-3 and in part DFG MA1080/21-1 (to AM), NIH grants HD24870 (S.R.O. and R.L.S.), the Eunice Kennedy Shriver NICHD/NIH through cooperative agreement HD18185 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research (S.R.O.) and 8P51OD011092-53 for the operation of the Oregon National Primate Research Center (G.A.D., J.D.H., S.R.O. and R.L.S).

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3249?rss=1

STUDY QUESTION

Do differences in endometrial gene expression exist after ovarian stimulation with four different regimens of triggering final oocyte maturation and luteal phase support in the same patient?

SUMMARY ANSWER

Significant differences in the expression of genes involved in receptivity and early implantation were seen between the four protocols.

WHAT IS KNOWN ALREADY

GnRH agonist triggering is an alternative to hCG triggering in GnRH antagonist co-treated cycles, resulting in an elimination of early ovarian hyperstimulation syndrome. Whereas previous studies have revealed a low ongoing clinical pregnancy rate after GnRH agonist trigger due to a high early pregnancy loss rate, despite supplementation with the standard luteal phase support, more recent studies, employing a ‘modified’ luteal phase support including a bolus of 1500 IU hCG on the day of oocyte aspiration, have reported ongoing pregnancy rates similar to those seen after hCG triggering.

STUDY DESIGN, SIZE DURATION

A prospective randomized study was performed in four oocyte donors recruited from an oocyte donation program during the period 2010–2011.

PARTICIPANTS, MATERIALS, SETTING, METHODS

Four oocyte donors in a university IVF center each prospectively underwent four consecutive stimulation protocols, with different modes of triggering final oocyte maturation and a different luteal phase support, followed by endometrial biopsy on Day 5 after oocyte retrieval. The following protocols were used: (A) 10 000 IU hCG and standard luteal phase support, (B) GnRH agonist (triptorelin 0.2 mg), followed by 1500 IU hCG 35 h after triggering final oocyte maturation, and standard luteal phase support, (C) GnRH agonist (triptorelin 0.2 mg) and standard luteal phase support and (D) GnRH agonist (triptorelin 0.2 mg) without luteal phase support. Microarray data analysis was performed with GeneSpring GX 11.5 (RMA algorithm). Pathway and network analysis was performed with the gene ontology software Ingenuity Pathways Analysis (Ingenuity^® Systems, http://www.ingenuity.com, Redwood City, CA, USA). Samples were grouped and background intensity values were removed (cutoff at the lowest 20th percentile). A one-way ANOVA test (P< 0.05) was performed with Benjamini–Hochberg multiple testing correction.

MAIN RESULTS

Significant differences were seen in endometrial gene expression, related to the type of ovulation trigger and luteal phase support. However, the endometrial gene expression after the GnRH agonist trigger and a modified luteal phase support (B) was similar to the pattern seen after the hCG trigger (A).

LIMITATIONS, REASONS FOR CAUTION

The study was performed in four oocyte donors only; however, it is a strength of the study that the same donor underwent four consecutive stimulation protocols within 1 year to avoid inter-individual variations.

WIDER IMPLICATIONS OF THE FINDINGS

These endometrial gene-expression findings support the clinical reports of a non-significant difference in live birth rates between the GnRH agonist trigger and the hCG trigger, when the GnRH agonist trigger is followed by a bolus of 1500 IU hCG at 35 h post trigger in addition to the standard luteal phase support.

STUDY FUNDING/ COMPETING INTERESTS

This study was supported by an un-restricted research grant by MSD Belgium.

TRIAL REGISTRATION NUMBER

EudraCT number 2009-009429-26, protocol number 997 (P06034).

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3259?rss=1

STUDY QUESTION

Are self-reported menstrual disorders associated with hyperandrogenaemia and metabolic disturbances as early as in adolescence?

SUMMARY ANSWER

Menstrual disorders at the age 16 are a good marker of hyperandrogenaemia, and an adverse lipid profile was associated with higher androgen levels.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

Hyperandrogenism per se has been suggested to be a significant metabolic risk factor in women and a cause of physical and psychological morbidity in adolescent girls. A weak positive correlation has been described between hyperandrogenaemia and obesity in adolescent girls, but the clinical consequences are still poorly understood. Hyperandrogenism and insulin resistance are also key features of polycystic ovary syndrome (PCOS), and women with PCOS are consequently at an increased risk of developing type 2 diabetes mellitus and/or metabolic syndrome, and may have increased cardiovascular morbidity.

Our findings confirm that the association between menstrual disorders, hyperandrogenism, obesity and metabolic risks is already evident in adolescence.

STUDY DESIGN

This population-based, cross-sectional study used postal questionnaires to targeting 15–16-year-old girls in the Northern Finland Birth Cohort 1986 (n= 4567).

PARTICIPANTS AND SETTING

There were 3669 girls who answered the postal questionnaire and out of 3373 girls who also underwent clinical examinations and blood tests, 2448 were included in the analyses. The questionnaire included one question about the regularity and length of the menstrual cycle: ‘Is your menstrual cycle (the interval from the beginning of one menstrual period to the beginning of the next period) often (more than twice a year) longer than 35 days?’ The girls who answered ‘yes’ to this question were considered to be suffering from menstrual disorders and were classified as ‘symptomatic’. The girls who answered ‘no’ were defined as ‘non-symptomatic’.

MAIN RESULTS AND THE ROLE OF CHANCE

There were 709 (29%) girls who reported menstrual disorders (symptomatic girls) and 1739 who had regular periods (non-symptomatic girls). In the whole population and in both study groups, there were significant correlations between body mass index (BMI) (and waist-to-hip ratio), hyperandrogenaemia and metabolic parameters. Symptomatic girls exhibited significantly higher serum concentrations of testosterone (P= 0.010), lower levels of sex hormone-binding globulin (P =0.042) and higher free androgen indices [FAIs; geometric mean 3.38 (interquartile range (IQR): 2.27, 5.18) versus 3.08 (IQR: 2.15, 4.74), P= 0.002]. The two groups had comparable BMI and insulin sensitivity, and serum levels of glucose, insulin and lipids. There was a significant linear trend towards higher FAI values in the higher BMI quartiles in both symptomatic and non-symptomatic girls. In the whole population, there was a statistically significant linear decrease in high-density lipoprotein concentrations (P < 0.001) and higher triglyceride concentrations (P =0.004) in the upper FAI quartile.

IMPLICATIONS

Information regarding menstrual disorders in adolescence is a good marker of hyperandrogenaemia and may be an early risk factor for the development of PCOS in adulthood. The association between obesity, hyperandrogenism and metabolic risks is already evident in adolescence, which strengthens the importance of noting menstrual disorders at an early stage.

BIAS, LIMITATIONS, GENERALIZABILITY

The cross-sectional nature of the study does not allow us to draw conclusions concerning the metabolic risks of this population in later life. The diagnosis of menstrual disorders was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. This study was not designed to diagnose PCOS, as ultrasonography was not available and there was no clinical evaluation of hyperandrogenism (i.e. hirsutism). However, we were able to take into account potential confounding factors in the analyses.

STUDY FUNDING/COMPETING INTERESTS

This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 104781, 120315, 129269, 1114194, SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643) and the Medical Research Council, UK (PrevMetSyn/SALVE). None of the authors have any conflict of interest to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3279?rss=1

BACKGROUND

For decades androgens have been considered detrimental to follicle maturation. Animal studies now suggest that they are essential for normal folliculogenesis. Especially in women with premature ovarian aging (POA), recent IVF data in humans are supportive. The literature also suggests an association between recently reported ovarian genotypes of the FMR1 gene and ovarian aging patterns. We, therefore, attempted to determine a potential difference in androgen concentrations and androgen interactions in women with POA who do or do not become pregnant while undergoing androgen supplementation, and whether androgen concentrations and pregnancy chances are affected by FMR1 genotypes.

METHODS

We longitudinally assessed androgen metabolism in 91 women with POA, following pre-supplementation with micronized dehydroepiandrosterone (DHEA) prior to IVF. IVF outcomes were assessed based on androgen levels and ovarian FMR1 genotypes.

RESULTS

The mean age of the women was 39.8 ± 4.4 years; the clinical pregnancy rate was 25.3%. Total androgen concentrations were not associated with pregnancy; however, in women with abnormal FMR1 genotypes, but not those with the normal genotype, free testosterone significantly affected clinical pregnancy potential (β = 1.101, SE ± 0.508, P = 0.03). At the start of the IVF cycle, interactions of DHEA with total and free testosterone also significantly affected subsequent pregnancy rates (β = –0.058, SE ± 0.023, P = 0.01 and β = –0.496, SE ± 0.197, P = 0.012).

CONCLUSIONS

Androgen interactions significantly influence IVF pregnancy rates in women with POA, with the impact of total androgens on cycle outcomes varying according to FMR1 genotypes. These observations suggest that the effectiveness of androgen supplementation in women with POA varies based on FMR1 genotypes, and defines androgen deficiency as a subset of diminished ovarian reserve.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3287?rss=1

STUDY QUESTION

Are anti-Müllerian hormone (AMH) levels lower in women with endometriosis, notably those with endometriomas (OMAs) and deep infiltrating lesions, compared with controls without endometriosis?

SUMMARY ANSWER

Endometriosis and OMAs per se do not result in lower AMH levels. AMH levels are decreased in women with previous OMA surgery independently of the presence of current OMAs.

WHAT IS KNOWN ALREADY

The impact of endometriosis and OMAs per se on the ovarian reserve is controversial. Most previous studies have been conducted in infertile women. The strength of our study lies in the following points: (i) the selection of women undergoing surgery and not only according to the presence of infertility, (ii) the classification of women with endometriosis and controls based on strict surgical and histological criteria.

STUDY DESIGN, SIZE, DURATION

Cross-sectional study using data prospectively collected in all non-pregnant <42-year-old patients, who were surgically explored for a benign gynaecological condition at a university tertiary referral centre between 2004 and 2008. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. AMH levels were measured in serum samples drawn in the month preceding surgery, without regard to menstrual phase or hormonal therapy.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Operations were done on 1262 women between 2004 and 2008, of which 1133 signed the informed consent. Of the 566 women with a visual diagnosis of endometriosis, 411 had histologically proven endometriosis. Frozen serum samples for the AMH measurement were available in 313 of them. Out of the 554 women without visual endometriosis and without past endometriosis surgery, 413 had a frozen serum sample for the AMH measurement. Univariate analysis examined AMH levels according to baseline patient characteristics, the presence and type of endometriosis (superficial lesion, OMA, deep infiltrating lesion) and previous OMA surgery. Analysis of variance–covariance then examined the effects of co-variables on AMH levels. Finally, logistic regressions were conducted to examine the odds ratio (OR) of having AMH levels <1 ng/ml according to the same co-variables.

MAIN RESULTS AND THE ROLE OF CHANCE

The difference in AMH levels between women with endometriosis and controls did not reach significance (3.6 ± 3.1 versus 4.1 ± 3.4 ng/ml, P = 0.06). Analysis of variance–covariance demonstrated that AMH levels significantly decreased with age (P < 0.001) and in women with prior OMA surgery irrespective of whether OMAs were present or not at the time of study (P < 0.05). Logistic regression revealed that two major factors were related to AMH levels <1 ng/ml: (i) age (compared with <29 years; 30–34 years OR = 3.1, 95% CI: 1.5–6.4, P = 0.01; 35–39 years OR = 7.0, 95% CI: 3.5–14.1, P = 0.001; ≥40 years OR = 20.8, 95% CI: 9.1–47.4, P = 0.001) and (ii) prior OMA surgery (OR = 3.0, 95% CI: 1.4–6.41, P = 0.01).

LIMITATIONS, REASONS FOR CAUTION

The selection of our study population was based on a surgical diagnosis. Women with an asymptomatic form of endometriosis are therefore not included in our study. We cannot exclude that infertile women with OMAs associated with a diminished ovarian reserve, as assessed during their infertility work-up, were less likely to be referred for surgery and might therefore be underrepresented.

WIDER IMPLICATIONS OF THE FINDINGS

Our findings suggest that OMAs per se do not diminish the ovarian reserve reflected by AMH levels but that alterations seen in women with endometriosis are a deleterious consequence of OMA surgery. These findings should be taken into account in the decision to operate OMAs in women with a desire for future pregnancy.

STUDY FUNDING/COMPETING INTERESTS

Study funding: none. Potential competing interests: none.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3294?rss=1

BACKGROUND

Metformin is a drug used in the treatment of diabetes and of some disorders related to insulin resistance, such as polycystic ovary syndrome. Gestational diabetes can cause complications for both mother and child, and some studies have shown a beneficial effect of metformin during pregnancy without an increase in perinatal complications. However, the effects on the gonads have not been properly studied. Here we investigated the effect of metformin administered during pregnancy on the development and function of the fetal testis.

METHODS

A dual approach in vitro and in vivo using human and mouse models was chosen. Cultures of human and murine organotypic testes were made and in vivo embryonic testes were analysed after oral administration of metformin to pregnant mice.

RESULTS

In human and mouse organotypic cultures in vitro, metformin decreased testosterone secretion and mRNA expression of the main factors involved in steroid production. In vitro, the lowest observed effect concentration (LOEC) on testosterone secretion was 50 µM in human, whereas it was 500 µM in mouse testis. Lactate secretion was increased in both human and mouse organotypic cultures with the same LOEC at 500 µM as observed in other cell culture models after metformin stimulation. In vivo administration of metformin to pregnant mice reduced the testicular size of the fetal and neonatal testes exposed to metformin during intrauterine life. Although the number of germ cells was not affected by the metformin treatment, the number of Sertoli cells, the nurse cells of germ cells, was slightly yet significantly reduced in both periods (fetal period: P = 0.007; neonatal period: P = 0.03). The Leydig cell population, which produces androgens, and the testosterone content were diminished only in the fetal period at 16 days post-coitum.

CONCLUSIONS

This study showed a potentially harmful effect of metformin treatment on the development of the fetal testis and should encourage future human epidemiological studies.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3304?rss=1

STUDY QUESTION

What is the health-related quality of life (HRQoL) in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction with clomifene citrate (CC) combined with metformin compared with those using CC combined with placebo?

SUMMARY ANSWER

Overall quality of life in women with PCOS treated with CC plus metformin was significantly lower than in women treated with CC plus placebo.

WHAT IS KNOWN ALREADY

There are no data on HRQoL in adult women who receive ovulation induction with the purpose of conceiving. Women with PCOS have higher scores on depression and anxiety scales and lower QoL scores than women without PCOS.

STUDY DESIGN, SIZE AND DURATION

This study was a secondary analysis of a multi-centre RCT completed between June 2001 and May 2004. The randomization was stratified per centre, and the centres received blinded, numbered containers with medication. There were172 women available for the HRQoL assessment: 85 were allocated to metformin and 87 were allocated to placebo.

PARTICIPANTS, SETTING AND METHODS

The Rotterdam Symptom Checklist (RSCL), a standard self-administered questionnaire, was used to assess physical symptoms, psychological distress, activity levels and overall HRQoL.

MAIN RESULTS AND THE ROLE OF CHANCE

In the intention to treat analysis, we found differences between the treatment groups with respect to physical symptoms and overall HRQoL. Physical well-being was significantly impaired in women allocated to metformin but not in women allocated to placebo. The increase in physical symptoms in the metformin group was caused by side-effects typical of metformin, and was most pronounced at Week 1 (mean difference 12 [95% confidence interval (CI): 8–16] and still apparent at Week 16 [mean difference 7 (95% CI 2–12]. Overall well-being was significantly impaired in the metformin group compared with the placebo group [mean difference 13 (95% CI 6–20)].

LIMITATIONS AND REASONS FOR CAUTION

RSCL measurements were available only for three quarters of the participants. Although the number of missing questionnaires and the baseline measurements, were comparable between the treatment groups, some form of selection bias cannot be ruled out.

WIDER IMPLICATIONS OF THE FINDINGS

Our finding that metformin was more burdensome than placebo, strengthens the recommendation that CC only and not CC plus metformin should be the drug of choice in this patient population.

STUDY FUNDING/COMPETING INTEREST(S)

None of the authors declared a conflict of interest. There was no study funding.

Trial Registration Number

ISRCTN55906981.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/27/11/3273?rss=1