Translocator protein expression and localization in human endometrium and endometriosis: A potential target for a noninvasive diagnosis?

The limitations of current imaging methods to detect small or superficial endometriotic lesions prompt the search for new molecular targets. TSPO is an 18 KDa protein located in the outer mitochondrial membrane, which can be traced by positron emission tomography (PET) using specific ligands. TSPO is located mostly in neurons and inflammatory sites outside the brain. We hypothesized that it might also be expressed in the human endometrium and endometrial-like tissue, being a target for molecular imaging of endometriosis. This prospective cross-sectional study included 28 women with endometriosis and 11 endometriosis-free controls. Endometriotic lesions (n = 49) and normal peritoneum (n = 13) from endometriosis patients were obtained during laparoscopy, while samples of eutopic endometrium from patients with endometriosis (n = 28) and from control women (n = 11) were collected in the operating room using a flexible device. TSPO mRNA expression was evaluated by quantitative reverse-transcription real-time PCR while protein expression was evaluated by immunohistochemistry with a monoclonal antibody antihuman TSPO. TSPO mRNA expression was detected in an invariable fashion in all tissue types evaluated; however, TSPO protein was found to be more abundant in the glandular epithelium than in the stroma, both in the endometrium and in the endometriotic lesions. Interestingly, hormone therapies did not alter the expression of TSPO, and its presence was mostly negative in tissues adjacent to endometriotic implants. As a proof of concept, the protein expression pattern of TSPO in endometriotic tissue and along the adjacent areas suggests that TSPO-based molecular imaging might be used for noninvasive endometriosis detection.

Impact of endometriosis on the ovarian follicles.

A significant body of evidence has supported a negative impact of endometriosis on ovarian follicles; however, the origin and relevance of this ovarian impairment in endometriosis is still a matter of debate. The ovarian damage can be caused by endometriosis itself or by surgeries aiming to remove endometriotic lesions. In this review, we summarized the existing knowledge on the mechanisms by which endometriosis can impact the ovarian follicles, from molecular to clinical points of view. From a molecular standpoint, the presence of endometriosis or its consequences can induce oxidative stress, inflammation, aberrant mitochondrial energy metabolism and inappropriate steroid production in granulosa cells, phenomena that may impair the quality of oocytes to variable degrees. These alterations may have clinical relevance on the accelerated exhaustion of the ovarian reserve, on the ovarian response to gonadotrophin stimulation in IVF cycles and on the competence of the oocytes. Critical points to be considered in current clinical practices related to fertility issues in endometriosis are discussed.

Live Birth After Oocyte Donation In Vitro Fertilization Cycles in Women With Endometriosis: A Systematic Review and Meta-Analysis.

Importance: Although multiple mechanisms have been proposed to explain the infertility related to endometriosis, there are no conclusive data on the association of endometriosis with endometrial receptivity. The oocyte donation model in assisted reproduction technology (ART) cycles can clarify this issue. Objective: To explore the association of a history of endometriosis with ART outcomes in recipients of oocyte donation. Data Sources: In this systematic review and meta-analysis, electronic databases were searched from inception until August 31, 2023, using combinations of relevant keywords. Moreover, we retrieved data from the databases of the Society for Assisted Reproductive Technology (SART) in the US and the Human Fertilization and Embryology Authority (HFEA) in the United Kingdom. Study Selection: Observational studies were included if they investigated the impact of endometriosis on ART outcomes with donor oocytes. Data Extraction and Synthesis: Publicly available data related to ART from various sources were gathered, and a retrospective aggregate and nonaggregate analysis using registries of in vitro fertilization cycles with oocyte or embryo donation was conducted. Main Outcomes and Measures: The primary outcome was live birth rate (LBR) following oocyte donor cycles. The effect measures of comparisons between groups are presented as odds ratios (ORs) with a 95% CI. Results: This study analyzed 7212 oocyte donation cycles from 4 studies for the meta-analysis, along with 162 082 cycles from 2 registries (137 182 from SART and 24 900 from HFEA). No significant differences between the groups were observed in the meta-analysis of published data after adjusting for confounding factors (OR, 0.54; 95% CI, 0.19-1.57). A statistically significant lower LBR was identified in women with endometriosis when analyzing the aggregate data from SART and HFEA databases (OR, 0.89; 95% CI, 0.81-0.97). Conclusions and Relevance: This study found a modest decrease in LBR among women with a history of endometriosis, although only results from the pooled analysis of registry data and not those from the meta-analysis reached statistical significance. These findings suggest that a marginal impairment of uterine receptivity may contribute to infertility mechanisms in women affected by endometriosis.

Seminal glucose levels: a prognostic factor of sperm survival to cryopreservation?

OBJECTIVE: Considering that glucose is an important component of seminal plasma and is a cryoprotectant at high concentrations, the aim of this study was to investigate the possible association of glucose levels in fresh semen with the sperm survival and motility rates following cryopreservation. METHODS: This was a prospective study including 149 men undergoing semen analysis due to male and/or female infertility. The seminal samples were analyzed according to the World Health Organization standards and glucose concentrations were measured using a dipstick glucometer. Samples were cryopreserved with Test Yolk Buffer-Gentamicine freezing medium under liquid nitrogen for an average of 120 days. The frozen aliquots were thawed at 37°C for 10 minutes and analyzed using the same methods and protocols used pre-freezing. RESULTS: Glucose levels ranged from 14 to 99 mg/dL and were similar in individuals with normal (n=100) vs. abnormal (n=49) semen analysis. The rates of sperm recovery (total, alive or motile sperm) in the cryopreserved samples did not change among samples with different glucose levels (p>0.05, Kruskal-Wallis ANOVA and Spearman's correlation coefficient). CONCLUSIONS: There appears to be no association between glucose levels in human semen samples and their resistance to cryopreservation.

Is endometrial receptivity affected in women with endometriosis? Results from a matched pair case-control study of assisted reproductive technology treatments.

RESEARCH QUESTION: Is endometriosis detrimental to embryo implantation? DESIGN: A retrospective matched case-control study of women with a surgical or ultrasound diagnosis of endometriosis at Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico di Milano between 2015 and 2021. Women with endometriosis who underwent a 'freeze-all' cycle during an IVF treatment were eligible to be included. They were matched to patients without the disease, who also underwent cryopreserved blastocyst transfer cycles, in a 1:1 ratio by age (±1 year), and number (=) and quality (±1 top versus low) of cryopreserved blastocysts. All women underwent single frozen embryo transfer, and assisted reproductive technology outcomes suggested by the Core Outcome Measure for Infertility Trials initiative were evaluated. The main outcome was the cumulative live birth rate per cycle. RESULTS: One hundred and one women with endometriosis and 101 matched unaffected women were included. Cumulative live birth rate per cycle did not vary between women with and without endometriosis (50% versus 58%, respectively; P = 0.32). On the basis of the Kaplan-Meier analysis, the predicted success rates over four embryos transferred were also similar (74% versus 82%, respectively; P = 0.67). CONCLUSION: In women with moderate or severe endometriosis, these retrospective results seem to indicate no or a limited effect of the disease on endometrial receptivity.

"Shadow of a Doubt"-The Pathogenic Role of Endometrial Defects in Endometriosis Development and Endometriosis-Associated Infertility: Robust Demonstration of Clinical Relevance Is Still Urgently Needed.

Endometriosis is an estrogen-dependent chronic inflammatory disease characterized by the presence of endometrial glands and stroma associated with fibrosis outside the uterine cavity [...].

Characteristics, prevalence and sources of stress in individuals who discontinue assisted reproductive technology treatments: a systematic review.

By considering the reasons behind discontinuing assisted reproductive technology (ART) treatment, several studies have indicated that 'stress' is an important issue, but the prevalence of stressors and stress responses, either acute or chronic, remains unclear. In this systematic review, we evaluated the characteristics, prevalence and causes of what was perceived and reported as 'stress' by couples who discontinued ART treatment. Electronic databases were systematically searched, and studies were considered eligible if they evaluated stress as a possible reason for ART discontinuation. Twelve studies were included, with 15,264 participants from eight countries. In all studies, 'stress' was assessed through generic questionnaires or medical records, not by validated stress questionnaires or biomarkers. The prevalence of 'stress' ranged from 11-53%. When the results were pooled, 'stress' was cited as a reason for ART discontinuation by 775 out of 2507 participants (30.9%). Clinical factors associated with worse prognosis, physical discomfort due to treatment procedures, family demands, time pressure and economic burden were identified as sources of 'stress' that contributed to ART discontinuation. Precisely knowing the characteristics of the stress associated with infertility is essential to devise preventive or supportive interventions to help patients to cope and endure the treatments. Further studies are necessary to investigate whether the mitigation of stress factors can reduce ART discontinuation rates.

Conventional IVF performs similarly in women with and without endometriosis.

PURPOSE: A reduced oocyte competence has been claimed as one of the factors underlying infertility in women with endometriosis. This idea has justified the hypothesis that intracytoplasmic sperm injection (ICSI), rather than conventional IVF (c-IVF), may overcome oocyte impairment and ensure better assisted reproduction technology (ART) outcomes; however, data from the literature are controversial. Thus, the aim of this study was to compare ART success rates following (c-IVF) between women with and without endometriosis in the presence of normozoospermic partners. METHODS: This is a retrospective, matched case-control study of 314 patients who underwent c-IVF cycles between January 2014 and December 2020. Women with endometriosis were matched in a 1:1 ratio with patients undergoing ART for other indications, considering age (± 6 months), number of oocytes retrieved (± 1), and study period. The main outcome measures included total fertilization failure, fertilization rate, embryo quality, cumulative clinical pregnancy, and live birth rates. RESULTS: The fertilization rate and the proportion of women with total fertilization failure did not differ between women with and without endometriosis. Similarly, all other embryological variables did not also differ, except for the number of top-quality cleavage stage embryos which was higher in the endometriosis group. Cumulative clinical pregnancy and live birth rates were similar between women with and without endometriosis. CONCLUSION: A diagnosis of endometriosis does not negatively affect the performance of c-IVF; thus, c-IVF can be efficiently used in women affected, unless a male factor is also involved. This issue holds clinical relevance to help operators on their insemination technique decision-making.

Altered Endometrial Expression of α-Inhibin Subunit and Its Co-Receptor Betaglycan in Infertile Women with Endometriosis.

BACKGROUND: Inhibins and their co-receptor betaglycan are members of the transforming growth factor ß superfamily, a group of signaling molecules that control the differentiation of human endometrium in the secretory phase of the menstrual cycle. OBJECTIVE: Since endometriosis is associated with endometrial dysfunction and infertility, this study aimed at evaluating the expression of α-inhibin and betaglycan mRNA and proteins in endometrial samples of infertile women with and without endometriosis. DESIGN: This was a cross-sectional study. Participants/Materials: Endometrial samples of women with (n = 17) and without (n = 22) endometriosis were subdivided according to the menstrual cycle phase into proliferative and secretory. SETTING: University hospital. METHODS: We used real-time RT-PCR to quantify mRNA levels and immunohistochemistry to localize the proteins. RESULTS: α-inhibin mRNA levels were significantly increased in the secretory phase (p < 0.01 vs. proliferative phase) only among women with endometriosis. Conversely, betaglycan mRNA levels were downregulated in the secretory endometrium of controls (p < 0.01 vs. proliferative) but failed to change between cycle phases of patients with endometriosis. Both proteins were present in the glandular epithelium and stroma in the endometrium of women with and without endometriosis. Immunostaining analysis showed that while α-inhibin protein expression did not vary significantly, the intensity of betaglycan immunostaining decreased in the secretory phase in the control group (p = 0.038 vs. proliferative phase) but not in the endometriosis group. LIMITATIONS: We cannot determine whether endometriosis causes the abnormal expression of α-inhibin and betaglycan in the eutopic endometrium or if this alteration already existed before the establishment of endometriotic lesions. CONCLUSION: Our findings suggest an abnormally increased expression of α-inhibin mRNA (not protein) and betaglycan (mRNA and protein) in the secretory-phase endometrium of women with endometriosis.

Immunolocalization of stem/progenitor cell biomarkers Oct-4, C-kit and Musashi-1 in endometriotic lesions.

BACKGROUND: Human endometrium harbors stem/progenitor cells (SPCs) that may contribute to the establishment of endometriosis when seeded outside the uterus. Oct-4, C-kit and Musashi-1 are some of the many proteins used to characterize SPCs, but their association with endometriosis is uncertain. OBJECTIVE AND DESIGN: In this study, specimens of normal endometrium (n = 12), eutopic endometrium from women with endometriosis (n = 9), superficial peritoneal endometriosis (SUP, n = 12) and deep endometriosis (DE, n = 13) lesions were evaluated for localization and intensity of immunostaining for Oct-4, C-kit and Musashi-1. RESULTS: The three markers were abundantly expressed in normal endometrium, eutopic endometrium from endometriosis patients, SUP and DE specimens. Oct-4 and C-kit expression did not vary across groups as regards intensity or frequency. C-kit staining signal was seldom detected in vascular endothelium of normal or eutopic endometrium from endometriosis patients; however, it was positive in 67% of the SUP lesions and in 25% of the DE lesions (p = 0.042). Musashi-1 was expressed in some endometriotic glands as cell clusters, but its signal was similar between the four types of tissue (p = 0.971) CONCLUSION: The wide distribution of Oct-4, C-kit and Musashi-1 in endometria of patients with and without endometriosis and in SUP and DE endometriotic lesions suggests that these markers are not suitable for the in situ characterization of endometrial SPCs and should not be taken as surrogates for the study of SPCs in the pathogenesis of endometriosis.

Cryoprotectant agents for ovarian tissue vitrification: Systematic review.

Studies on the cryopreservation of ovarian tissue usually compare slow freezing versus vitrification and aim to optimize protocols, evaluate combinations or concentrations of cryoprotectant agents (CPAs), exposure time, and the addition of synthetic polymers. This systematic review aimed to identify the different CPAs used for the vitrification of human or primate ovarian tissue and to compare their results in terms of follicular survival and functional preservation. We searched Pubmed and EMBASE for randomized clinical trials or cohort studies comparing CPAs for human and/or primate ovarian vitrification. The highest rate of morphologically normal follicles after cryopreservation was 98% and was obtained with a combination of 27% ethylene glycol (EG) plus 27% glycerol, in addition to non-permeable synthetic polymers. The use of dimethyl sulfoxide (DMSO) in relatively low concentrations combined with EG and other CPAs yielded more than 90% of intact follicles after vitrification. The methods and outcomes varied largely among studies, making it difficult to combine their results. While there is no definite answer to what is the best combination of CPAs for vitrification of human ovarian tissue, the data reviewed here suggest that current vitrification techniques are able to preserve the integrity of most follicles.

Serum and urine levels of activin A in primigravidae and multigravidae: a prospective cross-sectional study.

The aim of the present study was to investigate serum and urine levels of activin A in different moments of gestation, in primigravidae and in multigravidae, to understand whether these variables (biological sample and first gestation) affect activin A as a biomarker in pregnancy. We prospectively included 43 pairs of serum and urine samples from 25 women examined at different gestational ages (range 45 to 268 days). In the group of primigravidae (n = 16 samples from 9 participants), there was no significant change in serum activin A levels across gestation. Conversely, the group of multigravidae (n = 27 samples from 16 women) had higher serum activin A levels in the third trimester (2676 ± 840 pg/ml) compared to the first (583 ± 408 pg/ml) and second (1040 ± 384) trimesters (p = .025). Urine activin A concentrations did not differ between the two groups and did not change according to the gestation phase. There was no correlation between serum and urinary levels of activin A (r = 0.149, p = .359). These data suggest that activin A secretion may vary less during the first pregnancy, while urine activin A is unlikely to be a surrogate for the systemic levels of this hormone in pregnant women.

Angiotensin-converting enzyme 2, the SARS-CoV-2 cellular receptor, is widely expressed in human myometrium and uterine leiomyoma.

OBJECTIVE: Angiotensin-converting-enzyme 2 (ACE2), the cell surface receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is found in a variety of reproductive tissues. The present study evaluated whether uterine fibroids and normal myometrium express ACE2 and, if so, at which tissue compartments. METHODS: We included 13 premenopausal women (age range 33-50 years, median 40 years) with uterine fibroids undergoing elective hysterectomy or myomectomy. Samples of leiomyoma (n = 12) and normal myometrial tissue (n = 8) were analyzed by immunohistochemistry for protein localization or by real time PCR for mRNA detection. RESULTS: In normal myometrium, ACE2 immunoreactivity was localized in smooth muscle fibers, arteriolar walls, and endothelial cells. In uterine leiomyoma, ACE2 staining was more intense in smooth muscle cells than in the extracellular matrix, and was also present in vascular endothelium. ACE2 mRNA was detected in myometrium as well as in fibroid samples. CONCLUSION: Human myometrium and uterine leiomyoma express ACE2 mRNA and have abundant distribution of ACE2 protein in their smooth muscle cells and microvasculature.

Endometriosis and related pelvic pain: association with stress, anxiety and depressive symptoms.

Endometriosis is a chronic inflammatory disease affecting 10% of women in reproductive age and manifested as infertility and pelvic pain, which may be severe and incapacitating. This review aims to address the latest evidence on the association of endometriosis with chronic stress, anxiety and depression, and to find out whether the effective treatment of endometriosis has the additional benefit of attenuating these psychological comorbidities. Studies have found that women with endometriosis, especially those with painful symptoms, have higher levels of stress and a decreased quality of life compared to healthy women. Importantly, depression and anxiety are more prevalent in women with endometriosis, and the presence of psychiatric disorders correlates more to the severity of the endometriosis-related pain than to other disease characteristics. Considering therapeutic implications, controlled clinical trials found that medical and surgical treatments of endometriosis also ameliorated perceived stress, anxiety and depressive symptoms. In conclusion, current evidence indicates that women with endometriosis have an increased prevalence of psychological disorders which correlate more with pain itself than with endometriosis per se. In addition, the effective treatment of endometriosis may reduce the psychological burden of the disease.

Angiotensin-(1-7), Angiotensin-Converting Enzyme 2 and Mas Receptor in Rat Polycystic Ovaries.

BACKGROUND: Hyperandrogenism is a pivotal mediator in the pathogenesis of the polycystic ovary syndrome (PCOS), but the mechanisms of androgen excess in this condition are not fully understood. Angiotensin (Ang)-(1-7) is an active peptide of the renin-angiotensin system (RAS) that stimulates ovarian follicular growth and testosterone release in vitro. OBJECTIVE: To investigate whether Ang-(1-7), its receptor Mas and angiotensin-converting enzyme 2 (ACE2), the enzyme that converts Ang II into Ang-(1-7), are expressed in rat polycystic ovaries (PCO) and thus if this peptide system might be associated with excess androgen production in PCO. METHODS: A rat model that shares some features of PCOS such as disruption of folliculogenesis and multiple ovarian cyst formation was used in the study. RESULTS: We found reduced levels of Ang-(1-7) and Mas receptor in PCO compared to normal ovaries. Also, ACE2 mRNA expression was reduced in PCO compared to ovaries of control rats (p < 0.05). PCO had high levels of estrogen and testosterone and increased mRNA for upstream enzymes of the steroidogenic cascade, but not of P450 aromatase. CONCLUSION: These findings suggest that the ovarian ACE2-Ang-(1-7)-Mas receptor axis is inhibited and therefore may not be a co-factor of excess testosterone production in rat PCO.

Localization of angiotensin-(1-7) and Mas receptor in the rat ovary throughout the estrous cycle.

We have previously demonstrated the presence of Angiotensin (Ang)-(1-7) in rat ovary homogenates and its stimulatory effect on estradiol and progesterone production. The present study was undertaken to identify the cellular localization of Ang-(1-7) and its receptor Mas in the rat ovary in the different phases of the estrous cycle. Ang-(1-7) and Mas were localized by immunohistochemistry and Mas mRNA expression was assessed by RT-PCR. Immunostaining for both Ang-(1-7) and Mas was found in all phases of the estrous cycle, particularly in the thecal and interstitial cells, as well as in regressing corpora lutea. However, granulosa cells were positive only in antral and preovulatory follicles at proestrus and estrus phases. This pattern contrasted with the distribution of the octapeptide Ang II, which was abundant in granulosa but not in theca cells. In addition, the expression of Mas mRNA was demonstrated in all estrous cycle phases. Angiotensin-converting enzyme activity did not vary between estrous cycle phases, whereas prolyl endopeptidase activity was significantly higher in diestrus and neutral endopeptidase activity was significantly higher in metestrus. These data provide the first evidence that new RAS components are dynamically expressed in the ovary across the rat estrous cycle. Further functional studies should clarify the role of Ang-(1-7) signaling through Mas receptor in the regulation of ovarian physiology.

Seminal protein levels assessed with dipstick test correlate with sperm recovery after cryopreservation.

The process of freezing/thawing causes structural and functional damage to sperm samples, which can be mitigated by seminal plasma proteins. This study investigated the proposition that seminal protein measurements using a urinary dipstick prior to freezing could help predict the post-thaw recovery of live spermatozoa. This was a prospective study including 149 men undergoing semen analysis due to male and/or female infertility. The seminal samples were analysed according to World Health Organisation standards and protein concentrations were measured using a commercially available urinary dipstick following quantitative validation. The median live sperm recovery rates were 79%, 81% and 94%, respectively, in samples with protein concentrations of ≤1.0 g/L (+/++), 3.0 g/L (+++) and ≥20.0 g/L (++++) measured in fresh specimen dipstick analysis (p < 0.05) indicating that the probability of recovering at least 50% of frozen spermatozoa increased progressively with higher protein concentrations in the fresh sample (chi-square for linear association = 7.17. p = 0.007). In conclusion, fresh seminal protein concentration levels assessed with a dipstick test correlate with the proportion of live spermatozoa recovered from cryopreserved samples. This simple, low-cost test may add prognostic information to baseline semen analysis prior to sperm banking.

C-type natriuretic peptide signaling in human follicular environment and its relation with oocyte maturation.

Studies in mice have shown that C-type natriuretic peptide (CNP) is produced by granulosa cells and contributes to ovarian follicle growth and oocyte meiotic arrest until the preovulatory LH surge. In humans, the relationship between intraovarian CNP levels and oocyte meiotic resumption is unknown. The aim of this study was to investigate whether CNP and its receptor NPR2 are expressed in human ovarian follicles and if their levels change according to the meiotic phase of oocytes. We collected follicular fluid (FF) and luteinized granulosa cells (LGC) from follicle pools (n = 47), and FF, LGC and cumulus cells (CC) from individual follicles (n = 96) during oocyte pickup for in vitro fertilization. There was a positive linear correlation between CNP levels in FF pools and basal antral follicle counting (rs = 0.458; p = 0.002), number of preovulatory follicles >16 mm (rs = 0.361; p = 0.016) and number of oocytes retrieved (rs = 0,378; p = 0.011) and a negative correlation between CNP levels in FF pools and the percentage of mature (MII) oocytes retrieved (rs = -0.39; p = 0.033). FF CNP levels in follicles containing MII oocytes were significantly lower than in follicles containing immature (MI) oocytes (median = 0.44 vs. 0.57 ng/mL, p < 0.05). Accordingly, the CNP precursor gene NPPC was 50% less expressed in LGC from follicles containing MII oocytes than in follicles containing MI oocytes (p < 0.01). In addition, NPR2 mRNA was down-regulated in CC surrounding MII oocytes (60% reduction, p < 0.01). CNP signaling is downregulated in human ovarian follicles containing mature oocytes. Further studies should clarify whether CNP signaling is essential to keep oocyte meiotic arrest in humans.

Caspase-3 gene expression in human luteinized granulosa cells is inversely correlated with the number of oocytes retrieved after controlled ovarian stimulation.

Granulosa cells control oocyte maturation through paracrine signalling and changes to the microenvironment around the oocyte. Apoptosis occurs as a physiological mechanism of granulosa cell renewal, but how it relates with the ovarian response to induced ovulation is still unclear. Therefore, this study evaluated apoptosis-related gene expression levels in granulosa cells of patients undergoing controlled ovarian stimulation. We enrolled prospectively 59 consecutive IVF patients referred to a tertiary academic hospital for couple infertility treatment. Luteinized granulosa cells were isolated from follicular fluid and the RNA was extracted, reverse-transcribed and the gene expression of apoptosis inducers (caspase-3, caspase-8 and bax) and inhibitor (Bcl-2) was quantified by real-time polymerase chain reaction. Caspase-3 gene expression correlated negatively with the number of pre-ovulatory follicles (Spearman's r = -0.308), the number of collected oocytes (r = -0.451), the number of mature oocytes (r = -0.526), the number of fertilized oocytes (r = -0.439) and the number of viable embryos (r = -0.443, all statistically significant at p < 0.02 level). No such associations were found with caspase-8, bax or bcl-2. These preliminary findings suggest that increased caspase-3 gene expression in granulosa cells is associated with a worse ovulatory response in humans.

Mindfulness-based program for stress reduction in infertile women: Randomized controlled trial.

Infertile women often experience chronic stress, which may have a negative impact on general well-being and may increase the burden of infertility. In this open-label, parallel, randomized controlled trial, infertile women aged 18-50 years (median 37 years) were assigned to an 8-week mindfulness-based program (MBP) or no intervention. The primary outcome was stress severity measured by the Lipp's Stress Symptoms Inventory (ISSL). Data were analyzed by modified intent-to-treat principle, which included all cases available to follow-up regardless of adherence to the intervention (62 participants from the MBP group and 37 from the control group). The median number of symptoms of chronic stress recorded in the past month decreased from six (interquartile range 2 to 9) before the MBP to two (interquartile range 1 to 4) after the intervention (p < 0.001, repeated measures analysis of variance with Time × Group interaction). Depressive symptoms also decreased after MBP, whereas general well-being improved (p < 0.01 for both outcomes). Hair cortisol and serum brain-derived neurotrophic factor (BDNF) did not change significantly between preintervention and postintervention. None of the outcomes changed significantly in the control group. MBP was effective in reducing stress and depressive symptoms while increasing general well-being in infertile women.