Hum. Reprod. Update [JOURNAL]
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200 papers
The impact of primary ciliary dyskinesia on female and male fertility: a narrative review.
Newman L, Chopra J, Dossett C … +6 more , Shepherd E, Bercusson A, Carroll M, Walker W, Lucas JS, Cheong Y
Hum Reprod Update · 2023 May · PMID 36721921 · Full text
BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetic condition affecting the structure and function of sperm flagellum and motile cilia including those in the male and female reproductive tracts. Infertility is a co...
BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetic condition affecting the structure and function of sperm flagellum and motile cilia including those in the male and female reproductive tracts. Infertility is a commonly reported feature of PCD, but there is uncertainty as to how best to counsel patients on their fertility prognosis. OBJECTIVE AND RATIONALE: This review aimed to summarize the prevalence of subfertility, possible underlying mechanisms, and the success of ART in men and women with PCD. The efficacy of ART in this patient group is relatively unknown and, hence, the management of infertility in PCD patients remains a challenge. There are no previous published or registered systematic reviews of fertility outcomes in PCD. SEARCH METHODS: Systematic literature searches were performed in Medline, Embase, Cochrane Library, and PubMed electronic databases to identify publications between 1964 and 2022 reporting fertility outcomes in men and women with PCD. Publications were excluded if they reported only animal studies, where gender was not specified or where subjects had a medical co-morbidity also known to impact fertility. Quality of evidence was assessed by critical appraisal and application of an appraisal tool for cross-sectional studies. The primary outcomes were natural conception in men and women with PCD, and conception following ART in men and women with PCD. OUTCOMES: A total of 1565 publications were identified, and 108 publications were included after screening by two independent researchers. The quality of available evidence was low. The exact prevalence of subfertility in PCD is unclear but appears to be higher in men (up to 83% affected) compared to women (up to 61% affected). Variation in the prevalence of subfertility was observed between geographic populations which may be explained by differences in underlying genotype and cilia function. Limited evidence suggests subfertility in affected individuals is likely caused by abnormal cilia motion in the fallopian tubes, endometrium and efferent ductules, and dysmotile sperm. Some men and women with PCD benefited from ART, which suggests its use should be considered in the management of subfertility in this patient group. Further epidemiological and controlled studies are needed to determine the predictors of fertility and optimal management in this patient group. WIDER IMPLICATIONS: It is important that patients with PCD receive evidence-based counselling about the potential impact of their condition on their fertility prognosis and what management options may be available to them if affected. Understanding the pathophysiology and optimal management of subfertility in PCD will increase our understanding of the role of cilia and the impact of wider secondary ciliopathies on reproduction.
Obstetric, neonatal, and child health outcomes following embryo biopsy for preimplantation genetic testing.
Alteri A, Cermisoni GC, Pozzoni M … +3 more , Gaeta G, Cavoretto PI, Viganò P
Hum Reprod Update · 2023 May · PMID 36655536 · Full text
BACKGROUND: Preimplantation genetic testing (PGT) of embryos developed in vitro requires a biopsy for obtaining cellular samples for the analysis. Signs of cell injury have been described in association with this procedu...
BACKGROUND: Preimplantation genetic testing (PGT) of embryos developed in vitro requires a biopsy for obtaining cellular samples for the analysis. Signs of cell injury have been described in association with this procedure. Thus, the consequences of the biopsy on obstetric and neonatal outcomes have been the subject of some quantitative analyses, although the reliability of data pooling may be limited by important issues in the various reports. OBJECTIVE AND RATIONALE: The present review identifies evidence for whether pregnancies conceived after embryo biopsy are associated with a higher risk of adverse obstetric, neonatal, and long-term outcomes. Available evidence has been summarized considering manipulation at various stages of embryo development. SEARCH METHODS: We used the scoping review methodology. Searches of article databases were performed with keywords pertaining to the embryo biopsy technique and obstetric, neonatal, and postnatal outcomes. Studies in which embryos were biopsied at different stages (i.e. both at the cleavage and blastocyst stages) were excluded. We included data on fresh and frozen embryo transfers. The final sample of 31 documents was subjected to qualitative thematic analysis. OUTCOMES: Sound evidence is lacking to fully address the issues on the potential obstetric, neonatal or long-term consequences of embryo biopsy. For polar body biopsy, the literature is too scant to draw any conclusion. Some data, although limited and controversial, suggest a possible association of embryo biopsy at the cleavage stage with an increased risk of low birthweight and small for gestational age neonates compared to babies derived from non-biopsied embryos. An increase in preterm deliveries and birth defects in cases of trophectoderm biopsy was suggested. For both biopsy methods (at the cleavage and blastocyst stages), an increased risk for hypertensive disorders of pregnancy was found. However, these findings may be explained by confounders such as other embryo manipulation procedures or by intrinsic patient or population characteristics. WIDER IMPLICATIONS: Since there is inadequate evidence to assess obstetric, neonatal, and long-term health outcomes following embryo biopsy, an invasive PGT strategy should be developed with a cautious approach. A non-invasive approach, based on the analysis of embryo cell-free DNA, needs to be pursued to overcome the potential limitations of embryo biopsy.
Anti-Müllerian hormone for the diagnosis and prediction of menopause: a systematic review.
Nelson SM, Davis SR, Kalantaridou S … +3 more , Lumsden MA, Panay N, Anderson RA
Hum Reprod Update · 2023 May · PMID 36651193 · Full text
BACKGROUND: The early onset of menopause is associated with increased risks of cardiovascular disease and osteoporosis. As a woman's circulating anti-Müllerian hormone (AMH) concentration reflects the number of follicles...
BACKGROUND: The early onset of menopause is associated with increased risks of cardiovascular disease and osteoporosis. As a woman's circulating anti-Müllerian hormone (AMH) concentration reflects the number of follicles remaining in the ovary and declines towards the menopause, serum AMH may be of value in the early diagnosis and prediction of age at menopause. OBJECTIVE AND RATIONALE: This systematic review was undertaken to determine whether there is evidence to support the use of AMH alone, or in conjunction with other markers, to diagnose menopause, to predict menopause, or to predict and/or diagnose premature ovarian insufficiency (POI). SEARCH METHODS: A systematic literature search for publications reporting on AMH in relation to menopause or POI was conducted in PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials up to 31 May 2022. Data were extracted and synthesized using the Synthesis Without Meta-analysis for diagnosis of menopause, prediction of menopause, prediction of menopause with a single/repeat measurement of AMH, validation of prediction models, short-term prediction in perimenopausal women, and diagnosis and prediction of POI. Risk-of-bias was evaluated using the Tool to Assess Risk of Bias in Cohort Studies protocol and studies at high risk of bias were excluded. OUTCOMES: A total of 3207 studies were identified, and 41, including 28 858 women, were deemed relevant and included. Of the three studies that assessed AMH for the diagnosis of menopause, one showed that undetectable AMH had equivalent diagnostic accuracy to elevated FSH (>22.3 mIU/ml). No study assessed whether AMH could be used to shorten the 12 months of amenorrhoea required for a formal diagnosis of menopause. Studies assessing AMH with the onset of menopause (27 publications [n = 23 835 women]) generally indicated that lower age-specific AMH concentrations are associated with an earlier age at menopause. However, AMH alone could not be used to predict age at menopause with precision (with estimates and CIs ranging from 2 to 12 years for women aged <40 years). The predictive value of AMH increased with age, as the interval of prediction (time to menopause) shortened. There was evidence that undetectable, or extremely low AMH, may aid early diagnosis of POI in young women with a family history of POI, and women presenting with primary or secondary amenorrhoea (11 studies [n = 4537]). WIDER IMPLICATIONS: The findings of this systematic review support the use of serum AMH to study the age of menopause in population studies. The increased sensitivity of current AMH assays provides improved accuracy for the prediction of imminent menopause, but diagnostic use for individual patients has not been rigorously examined. Prediction of age at menopause remains imprecise when it is not imminent, although the finding of very low AMH values in young women is both of clinical value in indicating an increased risk of developing POI and may facilitate timely diagnosis.
Offspring physiology following the use of IVM, IVF and ICSI: a systematic review and meta-analysis of animal studies.
Beilby KH, Kneebone E, Roseboom TJ … +6 more , van Marrewijk IM, Thompson JG, Norman RJ, Robker RL, Mol BWJ, Wang R
Hum Reprod Update · 2023 May · PMID 36611003 · Full text
BACKGROUND: Since the birth of the first baby using IVF technology in 1978, over 10 million children have been conceived via ART. Although most aspects of ARTs were developed in animal models, the introduction of these t...
BACKGROUND: Since the birth of the first baby using IVF technology in 1978, over 10 million children have been conceived via ART. Although most aspects of ARTs were developed in animal models, the introduction of these technologies into clinical practice was performed without comprehensive assessment of their long-term safety. The monitoring of these technologies over time has revealed differences in the physiology of babies produced using ARTs, yet due to the pathology of those presenting for treatment, it is challenging to separate the cause of infertility from the effect of treatments offered. The use of systematic review and meta-analysis to investigate the impacts of the predominant ART interventions used clinically in human populations on animals produced in healthy fertile populations offers an alternative approach to understanding the long-term safety of reproductive technologies. OBJECTIVE AND RATIONALE: This systematic review and meta-analysis aimed to examine the evidence available from animal studies on physiological outcomes in the offspring conceived after IVF, IVM or ICSI, compared to in vivo fertilization, and to provide an overview on the landscape of research in this area. SEARCH METHODS: PubMed, Embase and Commonwealth Agricultural Bureaux (CAB) Abstracts were searched for relevant studies published until 27 August 2021. Search terms relating to assisted reproductive technology, postnatal outcomes and mammalian animal models were used. Studies that compared postnatal outcomes between in vitro-conceived (IVF, ICSI or IVM) and in vivo-conceived mammalian animal models were included. In vivo conception included mating, artificial insemination, or either of these followed by embryo transfer to a recipient animal with or without in vitro culture. Outcomes included birth weight, gestation length, cardiovascular, metabolic and behavioural characteristics and lifespan. OUTCOMES: A total of 61 studies in five different species (bovine, equine, murine, ovine and non-human primate) met the inclusion criteria. The bovine model was the most frequently used in IVM studies (32/40), while the murine model was mostly used in IVF (17/20) and ICSI (6/8) investigations. Despite considerable heterogeneity, these studies suggest that the use of IVF or maturation results in offspring with higher birthweights and a longer length of gestation, with most of this evidence coming from studies in cattle. These techniques may also impair glucose and lipid metabolism in male mice. The findings on cardiovascular outcomes and behaviour outcomes were inconsistent across studies. WIDER IMPLICATIONS: Conception via in vitro or in vivo means appears to have an influence on measurable outcomes of offspring physiology, manifesting differently across the species studied. Importantly, it can be noted that these measurable differences are noticeable in healthy, fertile animal populations. Thus, common ART interventions may have long-term consequences for those conceived through these techniques, regardless of the pathology underpinning diagnosed infertility. However, due to heterogeneous methods, results and measured outcomes, highlighted in this review, it is difficult to draw firm conclusions. Optimizing animal and human studies that investigate the safety of new reproductive technologies will provide insight into safeguarding the introduction of novel interventions into the clinical setting. Cautiously prescribing the use of ARTs clinically may also be considered to reduce the chance of promoting adverse outcomes in children conceived before long-term safety is confidently documented.
What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis.
Venetis CA, Storr A, Chua SJ … +4 more , Mol BW, Longobardi S, Yin X, D'Hooghe T
Hum Reprod Update · 2023 May · PMID 36594696 · Full text
BACKGROUND: Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety. OB...
BACKGROUND: Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety. OBJECTIVE AND RATIONALE: A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates. SEARCH METHODS: The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included. OUTCOMES: The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates. WIDER IMPLICATIONS: Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.
A systematic review and evidence assessment of monogenic gene-disease relationships in human female infertility and differences in sex development.
Van Der Kelen A, Okutman Ö, Javey E … +13 more , Serdarogullari M, Janssens C, Ghosh MS, Dequeker BJH, Perold F, Kastner C, Kieffer E, Segers I, Gheldof A, Hes FJ, Sermon K, Verpoest W, Viville S
Hum Reprod Update · 2023 Mar · PMID 36571510 · Publisher ↗
BACKGROUND: As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasi...
BACKGROUND: As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified genes allows an accurate diagnosis for previously idiopathic cases of female infertility and more appropriate patient care. However, robust evidence of the gene-disease relationships (GDR) allowing the proper translation to clinical application is still missing in many cases. OBJECTIVE AND RATIONALE: An evidence-based curation of currently identified genes involved in female infertility and differences in sex development (DSD) would significantly improve both diagnostic performance and genetic research. We therefore performed a systematic review to summarize current knowledge and assess the available GDR. SEARCH METHODS: PRISMA guidelines were applied to curate all available information from PubMed and Web of Science on genetics of human female infertility and DSD leading to infertility, from 1 January 1988 to 1 November 2021. The reviewed pathologies include non-syndromic as well as syndromic female infertility, and endocrine and reproductive system disorders. The evidence that an identified phenotype is caused by pathogenic variants in a specific gene was assessed according to a standardized scoring system. A final score (no evidence, limited, moderate, strong, or definitive) was assigned to every GDR. OUTCOMES: A total of 45 271 publications were identified and screened for inclusion of which 1078 were selected for gene and variant extraction. We have identified 395 genes and validated 466 GDRs covering all reported monogenic causes of female infertility and DSD. Furthermore, we present a genetic diagnostic flowchart including 105 genes with at least moderate evidence for female infertility and suggest recommendations for future research. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of female infertility. WIDER IMPLICATIONS: We have comprehensively reviewed the existing research on the genetics of female infertility and DSD, which will enable the development of diagnostic panels using validated genes. Whole genome analysis is shifting from predominantly research to clinical application, increasing its diagnostic potential. These new diagnostic possibilities will not only decrease the number of idiopathic cases but will also render genetic counselling more effective for infertile patients and their families.
Epigenetic clocks provide clues to the mystery of uterine ageing.
Deryabin PI, Borodkina AV
Hum Reprod Update · 2023 May · PMID 36515535 · Publisher ↗
BACKGROUND: Rising maternal ages and age-related fertility decline are a global challenge for modern reproductive medicine. Clinicians and researchers pay specific attention to ovarian ageing and hormonal insufficiency i...
BACKGROUND: Rising maternal ages and age-related fertility decline are a global challenge for modern reproductive medicine. Clinicians and researchers pay specific attention to ovarian ageing and hormonal insufficiency in this regard. However, uterine ageing is often left out of the picture, with the majority of reproductive clinicians being close to unanimous on the absence of age-related functional decline in the uterine tissues. Therefore, most existing techniques to treat an age-related decline in implantation rates are based primarily on hormonal supplementation and oocyte donation. Solving the issue of uterine ageing might lead to an adjustment to these methods. OBJECTIVE AND RATIONALE: A focus on uterine ageing and the possibility of slowing it emerged with the development of the information theory of ageing, which identifies genomic instability and erosion of the epigenetic landscape as important drivers of age-related decline in the functionality of most cells and tissues. Age-related smoothing of this landscape and a decline in tissue function can be assessed by measuring the ticking of epigenetic clocks. Within this review, we explore whether the uterus experiences age-related alterations using this elegant approach. We analyse existing data on epigenetic clocks in the endometrium, highlight approaches to improve the accuracy of the clocks in this cycling tissue, speculate on the endometrial pathologies whose progression might be predicted by the altered speed of epigenetic clocks and discuss the possibilities of slowing down the ticking of these clocks. SEARCH METHODS: Data for this review were identified by searches of Medline, PubMed and Google Scholar. References from relevant articles using the search terms 'ageing', 'maternal age', 'female reproduction', 'uterus', 'endometrium', 'implantation', 'decidualization', 'epigenetic clock', 'biological age', 'DNA methylation', 'fertility' and 'infertility' were selected. A total of 95 articles published in English between 1985 and 2022 were included, six of which describe the use of the epigenetic clock to evaluate uterine/endometrium ageing. OUTCOMES: Application of the Horvath and DNAm PhenoAge epigenetic clocks demonstrated a poor correlation with chronological age in the endometrium. Several approaches were suggested to enhance the predictive power of epigenetic clocks for the endometrium. The first was to increase the number of samples in the training dataset, as for the Zang clock, or to use more sophisticated clock-building algorithms, as for the AltumAge clock. The second method is to adjust the clocks according to the dynamic nature of the endometrium. Using either approach revealed a strong correlation with chronological age in the endometrium, providing solid evidence for age-related functional decline in this tissue. Furthermore, age acceleration/deceleration, as estimated by epigenetic clocks, might be a promising tool to predict or to gain insights into the origin of various endometrial pathologies, including recurrent implantation failure, cancer and endometriosis. Finally, there are several strategies to slow down or even reverse epigenetic clocks that might be applied to reduce the risk of age-related uterine impairments. WIDER IMPLICATIONS: The uterine factor should be considered, along with ovarian issues, to correct for the decline in female fertility with age. Epigenetic clocks can be tested to gain a deeper understanding of various endometrial disorders.
The hypergonadotropic hypogonadism conundrum of classic galactosemia.
Derks B, Rivera-Cruz G, Hagen-Lillevik S … +8 more , Vos EN, Demirbas D, Lai K, Treacy EP, Levy HL, Wilkins-Haug LE, Rubio-Gozalbo ME, Berry GT
Hum Reprod Update · 2023 Mar · PMID 36512573 · Full text
BACKGROUND: Hypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data h...
BACKGROUND: Hypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data have become available regarding the clinical spectrum, and the impact on fertility. Many women have been counseled for infertility and the majority never try to conceive, yet spontaneous pregnancies can occur. Onset and mechanism of damage have not been elucidated, yet new insights at the molecular level are becoming available that might greatly benefit our understanding. Fertility preservation options have expanded, and treatments to mitigate this complication either by directly rescuing the metabolic defect or by influencing the cascade of events are being explored. OBJECTIVE AND RATIONALE: The aims are to review: the clinical picture and the need to revisit the counseling paradigm; insights into the onset and mechanism of damage at the molecular level; and current treatments to mitigate ovarian damage. SEARCH METHODS: In addition to the work on this topic by the authors, the PubMed database has been used to search for peer-reviewed articles and reviews using the following terms: 'classic galactosemia', 'gonadal damage', 'primary ovarian insufficiency', 'fertility', 'animal models' and 'fertility preservation' in combination with other keywords related to the subject area. All relevant publications until August 2022 have been critically evaluated and reviewed. OUTCOMES: A diagnosis of premature ovarian insufficiency (POI) results in a significant psychological burden with a high incidence of depression and anxiety that urges adequate counseling at an early stage, appropriate treatment and timely discussion of fertility preservation options. The cause of POI in CG is unknown, but evidence exists of dysregulation in pathways crucial for folliculogenesis such as phosphatidylinositol 3-kinase/protein kinase B, inositol pathway, mitogen-activated protein kinase, insulin-like growth factor-1 and transforming growth factor-beta signaling. Recent findings from the GalT gene-trapped (GalTKO) mouse model suggest that early molecular changes in 1-month-old ovaries elicit an accelerated growth activation and burnout of primordial follicles, resembling the progressive ovarian failure seen in patients. Although data on safety and efficacy outcomes are still limited, ovarian tissue cryopreservation can be a fertility preservation option. Treatments to overcome the genetic defect, for example nucleic acid therapy such as mRNA or gene therapy, or that influence the cascade of events are being explored at the (pre-)clinical level. WIDER IMPLICATIONS: Elucidation of the molecular pathways underlying POI of any origin can greatly advance our insight into the pathogenesis and open new treatment avenues. Alterations in these molecular pathways might serve as markers of disease progression and efficiency of new treatment options.
The impact of vincristine on testicular development and function in childhood cancer.
Clark I, Brougham MFH, Spears N … +1 more , Mitchell RT
Hum Reprod Update · 2023 Mar · PMID 36495566 · Full text
BACKGROUND: Increasing childhood cancer survival rates in recent decades have led to an increased focus on fertility as a long-term complication of cancer treatment. Male childhood cancer survivors often face compromised...
BACKGROUND: Increasing childhood cancer survival rates in recent decades have led to an increased focus on fertility as a long-term complication of cancer treatment. Male childhood cancer survivors often face compromised testicular function as a late effect of chemotherapy exposure, with no well-established options to prevent such damage and subsequent infertility. Despite vincristine being considered to be associated with low-gonadotoxic potential, in prepubertal rodents, it was recently shown to result in morphological alterations of the testis and in severely impaired fertility. OBJECTIVE AND RATIONALE: This systematic review aimed to evaluate the effects of vincristine-containing regimens on human prepubertal testis with reference to testicular function and fertility in adulthood. SEARCH METHODS: The systematic search of the literature was conducted according to PRISMA guidelines, and the study was registered with PROSPERO. PubMed and Scopus were searched for articles published in English between 01 January 1900 and 05 March 2021, with the search including 'chemotherapy', 'vincristine', 'prepubertal', 'testis', 'spermatogenesis' and related terms. Abstracts and full-text articles were screened and selected for, providing they met the inclusion criteria (≤12 years at treatment, exposure to vincristine-containing regimens and long-term fertility outcomes). Additional studies were identified via bibliography screening. Bias evaluation across included studies was conducted using the ROBINS-I tool, subdivided into assessment for confounding, participant selection, intervention classification, missing data, outcome measurements and selection of reported results. OUTCOMES: Our initial search identified 288 articles of which 24 (8%; n = 7134 males) met all inclusion criteria. Control groups were included for 9/24 (38%) studies and 4/24 (17%) studies provided sub-analysis of the relative gonadotoxicity of vincristine-based agents. Primary outcome measures were: fertility and parenthood; semen analysis (World Health Organization criteria); and hormonal function and testicular volume. For the studies that performed vincristine sub-analysis, none reported negative associations with vincristine for the potential of siring a pregnancy, including the largest (n = 6224; hazard ratio = 0.56) controlled study. For semen analysis, no significant difference versus healthy controls was illustrated for mitotic inhibitors (including vincristine) following sub-analysis in one study (n = 143). For hormone analysis, a single study did not find significant impacts on spermatogenesis attributed to vincristine based on levels of FSH and semen analysis, which meant that its administration was unlikely to be responsible for the diminished testicular reserve; however, most of the studies were based on low numbers of patients receiving vincristine-containing chemotherapy. Analysis of bias demonstrated that studies which included vincristine exposure sub-analysis had a lower risk of bias when compared with cohorts which did not. WIDER IMPLICATIONS: In contrast to recent findings in rodent studies, the limited number of clinical studies do not indicate gonadotoxic effects of vincristine following prepubertal exposure. However, given the relative lack of data from studies with vincristine sub-analysis, experimental studies involving vincristine exposure using human testicular tissues are warranted. Results from such studies could better inform paediatric cancer patients about their future fertility and eligibility for fertility preservation before initiation of treatment.
Contraceptives and cancer risks in BRCA1/2 pathogenic variant carriers: a systematic review and meta-analysis.
van Bommel MHD, IntHout J, Veldmate G … +4 more , Kets CM, de Hullu JA, van Altena AM, Harmsen MG
Hum Reprod Update · 2023 Mar · PMID 36383189 · Full text
BACKGROUND: Increasing numbers of BReast CAncer (BRCA) 1 or 2 pathogenic variant (PV) carriers, who have an inherited predisposition to breast and ovarian cancer, are being identified. Among these women, data regarding t...
BACKGROUND: Increasing numbers of BReast CAncer (BRCA) 1 or 2 pathogenic variant (PV) carriers, who have an inherited predisposition to breast and ovarian cancer, are being identified. Among these women, data regarding the effects of contraception on cancer risks are unclear and various guidelines provide various recommendations. OBJECTIVE AND RATIONALE: We aim to optimize counselling regarding contraception for BRCA1/2-PV carriers. Therefore, we performed a systematic review and meta-analysis. We investigated the risk ratio for developing breast cancer or ovarian cancer in BRCA1/2-PV carriers who have used any form of contraception versus non-users. Second, we analysed breast and ovarian cancer risk among BRCA1/2-PV carriers as influenced by the duration of contraceptive use and by the time since last use. In addition, we provide an overview of all relevant international guidelines regarding contraceptive use for BRCA1/2-PV carriers. SEARCH METHODS: A systematic search in the Medline database and Cochrane library identified studies describing breast and/or ovarian cancer risk in BRCA1/2-PV carriers as modified by contraception until June 2021. The search included medical subject headings, keywords and synonyms related to BRCA and contraceptives (any kind). PRISMA guidance was followed. Risk Of Bias In Non-randomized Studies of Interventions and Grading of Recommendations, Assessment, Development and Evaluations assessments were performed. Random-effects meta-analyses were used to estimate pooled effects for breast and ovarian cancer risk separately. Subgroup analyses were conducted for BRCA1 versus BRCA2 and for the various contraceptive methods. OUTCOMES: Results of the breast cancer risk with oral contraceptive pill (OCP) analysis depended on the outcome measure. Meta-analyses of seven studies with 7525 women revealed a hazard ratio (HR) of 1.55 (95% CI: 1.36-1.76) and of four studies including 9106 women resulted in an odds ratio (OR) of 1.06 (95% CI: 0.90-1.25), heterogeneity (I2) 0% and 52%, respectively. Breast cancer risk was still increased in ever-users compared with never-users >10 years after last OCP use. In contrast, ovarian cancer risk was decreased among OCP users: HR 0.62 (95% CI: 0.52-0.74) based on two studies including 10 981 women (I2: 0%), and OR 0.49 (95% CI: 0.38-0.63) based on eight studies including 10 390 women (I2: 64%). The protective effect vanished after cessation of use. Tubal ligation also protects against ovarian cancer: one study including 3319 women (I2: 0%): HR: 0.44 (95% CI: 0.26-0.74) and three studies with 7691 women (I2: 44%): OR: 0.74 (95% CI: 0.53-1.03). Data regarding other contraceptives were unavailable. No differences were observed between BRCA1 and BRCA2-PV carriers. The quality of evidence was either low or very low. WIDER IMPLICATIONS: The OCP potentially increases breast cancer risk, while ovarian cancer risk decreases with either the OCP and tubal ligation in BRCA1/2-PV carriers. Counselling of BRCA1/2-PV carriers should be personalized; the genetic and non-genetic factors (like prior risk-reducing surgeries, prior breast cancer and age) and patients' preferences (reversibility, ease of use, reliability and effect on menstrual cycle) should be balanced. To further optimize counselling for high-risk women, future research should focus on other (commonly used) contraceptive methods and cancer risks in this specific population, and on the potential impact of changing formulations over time.
Temporal trends in sperm count: a systematic review and meta-regression analysis of samples collected globally in the 20th and 21st centuries.
Levine H, Jørgensen N, Martino-Andrade A … +5 more , Mendiola J, Weksler-Derri D, Jolles M, Pinotti R, Swan SH
Hum Reprod Update · 2023 Mar · PMID 36377604 · Publisher ↗
BACKGROUND: Numerous studies have reported declines in semen quality and other markers of male reproductive health. Our previous meta-analysis reported a significant decrease in sperm concentration (SC) and total sperm c...
BACKGROUND: Numerous studies have reported declines in semen quality and other markers of male reproductive health. Our previous meta-analysis reported a significant decrease in sperm concentration (SC) and total sperm count (TSC) among men from North America-Europe-Australia (NEA) based on studies published during 1981-2013. At that time, there were too few studies with data from South/Central America-Asia-Africa (SAA) to reliably estimate trends among men from these continents. OBJECTIVE AND RATIONALE: The aim of this study was to examine trends in sperm count among men from all continents. The broader implications of a global decline in sperm count, the knowledge gaps left unfilled by our prior analysis and the controversies surrounding this issue warranted an up-to-date meta-analysis. SEARCH METHODS: We searched PubMed/MEDLINE and EMBASE to identify studies of human SC and TSC published during 2014-2019. After review of 2936 abstracts and 868 full articles, 44 estimates of SC and TSC from 38 studies met the protocol criteria. Data were extracted on semen parameters (SC, TSC, semen volume), collection year and covariates. Combining these new data with data from our previous meta-analysis, the current meta-analysis includes results from 223 studies, yielding 288 estimates based on semen samples collected 1973-2018. Slopes of SC and TSC were estimated as functions of sample collection year using simple linear regression as well as weighted meta-regression. The latter models were adjusted for predetermined covariates and examined for modification by fertility status (unselected by fertility versus fertile), and by two groups of continents: NEA and SAA. These analyses were repeated for data collected post-2000. Multiple sensitivity analyses were conducted to examine assumptions, including linearity. OUTCOMES: Overall, SC declined appreciably between 1973 and 2018 (slope in the simple linear model: -0.87 million/ml/year, 95% CI: -0.89 to -0.86; P < 0.001). In an adjusted meta-regression model, which included two interaction terms [time × fertility group (P = 0.012) and time × continents (P = 0.058)], declines were seen among unselected men from NEA (-1.27; -1.78 to -0.77; P < 0.001) and unselected men from SAA (-0.65; -1.29 to -0.01; P = 0.045) and fertile men from NEA (-0.50; -1.00 to -0.01; P = 0.046). Among unselected men from all continents, the mean SC declined by 51.6% between 1973 and 2018 (-1.17: -1.66 to -0.68; P < 0.001). The slope for SC among unselected men was steeper in a model restricted to post-2000 data (-1.73: -3.23 to -0.24; P = 0.024) and the percent decline per year doubled, increasing from 1.16% post-1972 to 2.64% post-2000. Results were similar for TSC, with a 62.3% overall decline among unselected men (-4.70 million/year; -6.56 to -2.83; P < 0.001) in the adjusted meta-regression model. All results changed only minimally in multiple sensitivity analyses. WIDER IMPLICATIONS: This analysis is the first to report a decline in sperm count among unselected men from South/Central America-Asia-Africa, in contrast to our previous meta-analysis that was underpowered to examine those continents. Furthermore, data suggest that this world-wide decline is continuing in the 21st century at an accelerated pace. Research on the causes of this continuing decline and actions to prevent further disruption of male reproductive health are urgently needed.
SARS-CoV-2, fertility and assisted reproduction.
Ata B, Vermeulen N, Mocanu E … +5 more , Gianaroli L, Lundin K, Rautakallio-Hokkanen S, Tapanainen JS, Veiga A
Hum Reprod Update · 2023 Mar · PMID 36374645 · Full text
BACKGROUND: In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge of the virus and its transmission has become available, allowing ART acti...
BACKGROUND: In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge of the virus and its transmission has become available, allowing ART activities to resume. Still, questions on the impact of the virus on human gametes and fertility remain. OBJECTIVE AND RATIONALE: This article summarizes published data, aiming to clarify the impact of SARS-CoV-2 and the COVID-19 disease on human fertility and assisted reproduction, as well as the impact of vaccination, and from this, provide answers to questions that are relevant for people contemplating pregnancy and for health care professionals. SEARCH METHODS: PUBMED/MEDLINE and the WHO COVID-19 database were searched from inception to 5 October 2022 with search terms focusing on 'SARS-CoV-2' and gametes, embryos, reproductive function, fertility and ART. Non-English studies and papers published prior to 2020 were excluded, as well as reviews and non-peer reviewed publications. Full papers were assessed for relevance and quality, where feasible. OUTCOMES: From the 148 papers included, the following observations were made. The SARS-CoV-2-binding proteins, angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2), are expressed in the testis, but co-expression remains to be proven. There is some evidence of SARS-CoV-2 RNA in the ejaculate of COVID-19 patients with severe disease, but not in those with mild/moderate disease. SARS-CoV-2 infection can impair spermatogenesis, but this seems to resolve after one spermatogenic cycle. Testosterone levels seem to be lower during and after COVID-19, but long-term data are lacking; disease severity may be associated with testosterone levels. COVID-19 cannot be considered a sexually transmitted disease. There is no co-expression of ACE2 and TMPRSS2 in the myometrium, uterus, ovaries or fallopian tubes. Oocytes seem to have the receptors and protease machinery to be susceptible to SARS-CoV-2 infection; however, viral RNA in oocytes has not been detected so far. Women contemplating pregnancy following COVID-19 may benefit from screening for thyroid dysfunction. There is a possible (transient) impact of COVID-19 on menstrual patterns. Embryos, and particularly late blastocysts, seem to have the machinery to be susceptible to SARS-CoV-2 infection. Most studies have not reported a significant impact of COVID-19 on ovarian reserve, ovarian function or follicular fluid parameters. Previous asymptomatic or mild SARS-CoV-2 infection in females does not seem to negatively affect laboratory and clinical outcomes of ART. There are no data on the minimum required interval, if any, between COVID-19 recovery and ART. There is no evidence of a negative effect of SARS-CoV-2 vaccination on semen parameters or spermatogenesis, ovarian function, ovarian reserve or folliculogenesis. A transient effect on the menstrual cycle has been documented. Despite concerns, cross reactivity between anti-SARS-CoV-2 spike protein antibodies and Syncytin-1, an essential protein in human implantation, is absent. There is no influence of mRNA SARS-CoV-2 vaccine on patients' performance during their immediate subsequent ART cycle. Pregnancy rates post-vaccination are similar to those in unvaccinated patients. WIDER IMPLICATIONS: This review highlights existing knowledge on the impact of SARS-CoV-2 infection or COVID-19 on fertility and assisted reproduction, but also identifies gaps and offers suggestions for future research. The knowledge presented should help to provide evidence-based advice for practitioners and couples contemplating pregnancy alike, facilitating informed decision-making in an environment of significant emotional turmoil.
Correction to: Comparison of dietary and physical activity behaviors in women with and without polycystic ovary syndrome: a systematic review and meta-analysis of 39 471 women.
Hum Reprod Update · 2023 Jan · PMID 36326693 · Full text
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Efficacy of psychological interventions for mental health and pregnancy rates among individuals with infertility: a systematic review and meta-analysis.
Dube L, Bright K, Hayden KA … +1 more , Gordon JL
Hum Reprod Update · 2023 Jan · PMID 36191078 · Publisher ↗
BACKGROUND: Depression and anxiety are highly prevalent among individuals struggling with infertility. Thus, numerous psychological interventions have been adapted to infertility, with the aim of relieving distress as we...
BACKGROUND: Depression and anxiety are highly prevalent among individuals struggling with infertility. Thus, numerous psychological interventions have been adapted to infertility, with the aim of relieving distress as well as increasing pregnancy rates. OBJECTIVE AND RATIONALE: This systematic review and meta-analysis aimed to identify all randomized controlled trials (RCTs) evaluating the effect of psychological interventions on infertility-related distress and pregnancy rates among individuals and/or couples with infertility and to analyse their overall effect. It also sought to examine potential treatment moderators, including intervention length, format and therapeutic approach. SEARCH METHODS: An electronic search of 11 databases, including MEDLINE, EMBASE, PsycINFO and Cochrane Central Register of Controlled Trials, was performed for studies published until January 2022. The inclusion criteria were RCTs conducted on humans and published in English. Psychological outcomes of interest included anxiety, depression, infertility-related distress, wellbeing and marital satisfaction. The Cochrane Risk of Bias tool was used to assess study quality, and the Grading of Recommendations Assessment, Development and Evaluation was used to assess the overall quality of the research evidence. OUTCOMES: There were 58 RCTs in total, including 54 which included psychological outcomes and 21 which assessed pregnancy rates. Studies originated from all regions of the world, but nearly half of the studies were from the Middle East. Although a beneficial effect on combined psychological outcomes was found (Hedge's g = 0.82, P < 0.0001), it was moderated by region (P < 0.00001) such that studies from the Middle East exhibited large effects (g = 1.40, P < 0.0001), while the effects were small among studies conducted elsewhere (g = 0.23, P < 0.0001). Statistically adjusting for study region in a meta-regression, neither intervention length, therapeutic approach, therapy format, nor participant gender (P > 0.05) moderated the effect of treatment. A beneficial treatment effect on pregnancy (RR (95% CI) = 1.25 (1.07-1.47), P = 0.005) was not moderated by region, treatment length, approach or format (P > 0.05). Largely due to the lack of high quality RCTs, the quality of the available evidence was rated as low to moderate. WIDER IMPLICATIONS: This is the first meta-analysis of RCTs testing the effect of psychological interventions on infertility-related distress and pregnancy rates. These findings suggest that in most regions of the world, psychological interventions are associated with small reductions in distress and modest effects on conception, suggesting the need for more effective interventions. These findings must be considered in light of the fact that the majority of the included RCTs were deemed to be at high risk of bias. Rigorously conducted trials are needed.
Defensins: defenders of human reproductive health.
Zhai YJ, Feng Y, Ma X … +1 more , Ma F
Hum Reprod Update · 2023 Jan · PMID 36130055 · Full text
BACKGROUND: Reproductive tract infection is an important factor leading to male and female infertility. Among female infertility factors, microbial and viral infections are the main factors affecting female reproductive...
BACKGROUND: Reproductive tract infection is an important factor leading to male and female infertility. Among female infertility factors, microbial and viral infections are the main factors affecting female reproductive health and causing tubal infertility, ectopic tubal pregnancy and premature delivery. Among male infertility factors, 13-15% of male infertility is related to infection. Defensins are cationic antibacterial and antiviral peptides, classified into α-defensins, β-defensins and θ-defensins. Humans only have α-defensins and β-defensins. Apart from their direct antimicrobial functions, defensins have an immunomodulatory function and are involved in many physiological processes. Studies have shown that defensins are widely distributed in the female reproductive tract (FRT) and male reproductive tract (MRT), playing a dual role of host defence and fertility protection. However, to our knowledge, the distribution, regulation and function of defensins in the reproductive tract and their relation to reproduction have not been reviewed. OBJECTIVE AND RATIONALE: This review summarizes the expression, distribution and regulation of defensins in the reproductive tracts to reveal the updated research on the dual role of defensins in host defence and the protection of fertility. SEARCH METHODS: A systematic search was conducted in PubMed using the related keywords through April 2022. Related data from original researches and reviews were integrated to comprehensively review the current findings and understanding of defensins in the human reproductive system. Meanwhile, female and male transcriptome data in the GEO database were screened to analyze defensins in the human reproductive tracts. OUTCOMES: Two transcriptome databases from the GEO database (GSE7307 and GSE150852) combined with existing researches reveal the expression levels and role of the defensins in the reproductive tracts. In the FRT, a high expression level of α-defensin is found, and the expression levels of defensins in the vulva and vagina are higher than those in other organs. The expression of defensins in the endometrium varies with menstrual cycle stages and with microbial invasion. Defensins also participate in the local immune response to regulate the risk of spontaneous preterm birth. In the MRT, a high expression level of β-defensins is also found. It is mainly highly expressed in the epididymal caput and corpus, indicating that defensins play an important role in sperm maturation. The expression of defensins in the MRT varies with androgen levels, age and the status of microbial invasion. They protect the male reproductive system from bacterial infections by neutralizing lipopolysaccharide and downregulating pro-inflammatory cytokines. In addition, animal and clinical studies have shown that defensins play an important role in sperm maturation, motility and fertilization. WIDER IMPLICATIONS: As a broad-spectrum antimicrobial peptide without drug resistance, defensin has great potential for developing new natural antimicrobial treatments for reproductive tract infections. However, increasing evidence has shown that defensins can not only inhibit microbial invasion but can also promote the invasion and adhesion of some microorganisms in certain biological environments, such as human immunodeficiency virus. Therefore, the safety of defensins as reproductive tract anti-infective drugs needs more in-depth research. In addition, the modulatory role of defensins in fertility requires more in-depth research since the current conclusions are based on small-size samples. At present, scientists have made many attempts at the clinical transformation of defensins. However, defensins have problems such as poor stability, low bioavailability and difficulties in their synthesis. Therefore, the production of safe, effective and low-cost drugs remains a challenge.
Age-associated epigenetic changes in mammalian sperm: implications for offspring health and development.
Ashapkin V, Suvorov A, Pilsner JR … +2 more , Krawetz SA, Sergeyev O
Hum Reprod Update · 2023 Jan · PMID 36066418 · Full text
BACKGROUND: Modern reproductive behavior in most developed countries is characterized by delayed parenthood. Older gametes are generally less fertile, accumulating and compounding the effects of varied environmental expo...
BACKGROUND: Modern reproductive behavior in most developed countries is characterized by delayed parenthood. Older gametes are generally less fertile, accumulating and compounding the effects of varied environmental exposures that are modified by lifestyle factors. Clinicians are primarily concerned with advanced maternal age, while the influence of paternal age on fertility, early development and offspring health remains underappreciated. There is a growing trend to use assisted reproductive technologies for couples of advanced reproductive age. Thus, the number of children born from older gametes is increasing. OBJECTIVE AND RATIONALE: We review studies reporting age-associated epigenetic changes in mammals and humans in sperm, including DNA methylation, histone modifications and non-coding RNAs. The interplay between environment, fertility, ART and age-related epigenetic signatures is explored. We focus on the association of sperm epigenetics on epigenetic and phenotype events in embryos and offspring. SEARCH METHODS: Peer-reviewed original and review articles over the last two decades were selected using PubMed and the Web of Science for this narrative review. Searches were performed by adopting the two groups of main terms. The first group included 'advanced paternal age', 'paternal age', 'postponed fatherhood', 'late fatherhood', 'old fatherhood' and the second group included 'sperm epigenetics', 'sperm', 'semen', 'epigenetic', 'inheritance', 'DNA methylation', 'chromatin', 'non-coding RNA', 'assisted reproduction', 'epigenetic clock'. OUTCOMES: Age is a powerful factor in humans and rodent models associated with increased de novo mutations and a modified sperm epigenome. Age affects all known epigenetic mechanisms, including DNA methylation, histone modifications and profiles of small non-coding (snc)RNA. While DNA methylation is the most investigated, there is a controversy about the direction of age-dependent changes in differentially hypo- or hypermethylated regions with advanced age. Successful development of the human sperm epigenetic clock based on cross-sectional data and four different methods for DNA methylation analysis indicates that at least some CpG exhibit a linear relationship between methylation levels and age. Rodent studies show a significant overlap between genes regulated through age-dependent differentially methylated regions and genes targeted by age-dependent sncRNA. Both age-dependent epigenetic mechanisms target gene networks enriched for embryo developmental, neurodevelopmental, growth and metabolic pathways. Thus, age-dependent changes in the sperm epigenome cannot be described as a stochastic accumulation of random epimutations and may be linked with autism spectrum disorders. Chemical and lifestyle exposures and ART techniques may affect the epigenetic aging of sperm. Although most epigenetic modifications are erased in the early mammalian embryo, there is growing evidence that an altered offspring epigenome and phenotype is linked with advanced paternal age due to the father's sperm accumulating epigenetic changes with time. It has been hypothesized that age-induced changes in the sperm epigenome are profound, physiological and dynamic over years, yet stable over days and months, and likely irreversible. WIDER IMPLICATIONS: This review raises a concern about delayed fatherhood and age-associated changes in the sperm epigenome that may compromise reproductive health of fathers and transfer altered epigenetic information to subsequent generations. Prospective studies using healthy males that consider confounders are recommended. We suggest a broader discussion focused on regulation of the father's age in natural and ART conceptions is needed. The professional community should be informed and should raise awareness in the population and when counseling older men.
Sexual dysfunction and disorders as a consequence of infertility: a systematic review and meta-analysis.
Leeners B, Tschudin S, Wischmann T … +1 more , Kalaitzopoulos DR
Hum Reprod Update · 2023 Jan · PMID 35900268 · Publisher ↗
BACKGROUND: Sexuality has a key impact on quality of life and on reproductive health. Infertility often results in sexual dysfunction. Despite this close association, addressing sexuality is not a standard component of i...
BACKGROUND: Sexuality has a key impact on quality of life and on reproductive health. Infertility often results in sexual dysfunction. Despite this close association, addressing sexuality is not a standard component of infertility counselling, especially since in most countries sexual medicine is not a core element of specialist training. Even today, many doctors and patients consider discussing sexuality to be more challenging than other aspects of reproductive medicine. The present review addresses the complex consequences of infertility on sexuality. OBJECTIVE AND RATIONALE: Our goals were: (i) to identify the prevalence of sexual problems resulting from infertility, (ii) to evaluate characteristics of sexual difficulties and disorders resulting from infertility and (iii) to analyse factors involved in the complex association between sexual problems and infertility. SEARCH METHODS: A systematic search for publications containing keywords related to sexual disorders and infertility was performed via PubMed, Web of Science and Psyndex. A total of 170 manuscripts published between January 1966 and April 2021 were identified after verification of inclusion and exclusion criteria. The reference lists in these manuscripts were searched for further relevant literature. Studies were reviewed for quality-related methodological details. OUTCOMES: Couples diagnosed with infertility have an increased risk of sexual disorders. Loss of sexual desire and erectile dysfunction are among the most frequent sexual disorders resulting from infertility. Currently available literature reflects only fragmentarily the complexity of the diverse interactions. Sexuality plays out against the backdrop of interactions among personal, cultural, infertility-related and sexuality-related factors. Considering this complexity, it is crucial to evaluate individual profiles as well as partnership interactions to avoid a negative impact of infertility on a couple's sexual life. WIDER IMPLICATIONS: Identifying sexual disorders as relevant considerations in the context of infertility and exploring their impact during the entire course of diagnosis and treatment constitute an important contribution to comprehensively care for the couples concerned. Counselling should focus on preventing the onset and aggravation of sexual disorders. As sexuality represents a major component of quality of life and of partnership, such support may improve not only the current overall wellbeing but also the chances of a satisfactory long-term partnership and family life.
Indoor and outdoor air pollution and couple fecundability: a systematic review.
Siegel EL, Ghassabian A, Hipwell AE … +9 more , Factor-Litvak P, Zhu Y, Steinthal HG, Focella C, Battaglia L, Porucznik CA, Collingwood SC, Klein-Fedyshin M, Kahn LG
Hum Reprod Update · 2023 Jan · PMID 35894871 · Full text
BACKGROUND: Air pollution is both a sensory blight and a threat to human health. Inhaled environmental pollutants can be naturally occurring or human-made, and include traffic-related air pollution (TRAP), ozone, particu...
BACKGROUND: Air pollution is both a sensory blight and a threat to human health. Inhaled environmental pollutants can be naturally occurring or human-made, and include traffic-related air pollution (TRAP), ozone, particulate matter (PM) and volatile organic compounds, among other substances, including those from secondhand smoking. Studies of air pollution on reproductive and endocrine systems have reported associations of TRAP, secondhand smoke (SHS), organic solvents and biomass fueled-cooking with adverse birth outcomes. While some evidence suggests that air pollution contributes to infertility, the extant literature is mixed, and varying effects of pollutants have been reported. OBJECTIVE AND RATIONALE: Although some reviews have studied the association between common outdoor air pollutants and time to pregnancy (TTP), there are no comprehensive reviews that also include exposure to indoor inhaled pollutants, such as airborne occupational toxicants and SHS. The current systematic review summarizes the strength of evidence for associations of outdoor air pollution, SHS and indoor inhaled air pollution with couple fecundability and identifies gaps and limitations in the literature to inform policy decisions and future research. SEARCH METHODS: We performed an electronic search of six databases for original research articles in English published since 1990 on TTP or fecundability and a number of chemicals in the context of air pollution, inhalation and aerosolization. Standardized forms for screening, data extraction and study quality were developed using DistillerSR software and completed in duplicate. We used the Newcastle-Ottawa Scale to assess risk of bias and devised additional quality metrics based on specific methodological features of both air pollution and fecundability studies. OUTCOMES: The search returned 5200 articles, 4994 of which were excluded at the level of title and abstract screening. After full-text screening, 35 papers remained for data extraction and synthesis. An additional 3 papers were identified independently that fit criteria, and 5 papers involving multiple routes of exposure were removed, yielding 33 articles from 28 studies for analysis. There were 8 papers that examined outdoor air quality, while 6 papers examined SHS exposure and 19 papers examined indoor air quality. The results indicated an association between outdoor air pollution and reduced fecundability, including TRAP and specifically nitrogen oxides and PM with a diameter of ≤2.5 µm, as well as exposure to SHS and formaldehyde. However, exposure windows differed greatly between studies as did the method of exposure assessment. There was little evidence that exposure to volatile solvents is associated with reduced fecundability. WIDER IMPLICATIONS: The evidence suggests that exposure to outdoor air pollutants, SHS and some occupational inhaled pollutants may reduce fecundability. Future studies of SHS should use indoor air monitors and biomarkers to improve exposure assessment. Air monitors that capture real-time exposure can provide valuable insight about the role of indoor air pollution and are helpful in assessing the short-term acute effects of pollutants on TTP.
Biomechanical forces and signals operating in the ovary during folliculogenesis and their dysregulation: implications for fertility.
Fiorentino G, Cimadomo D, Innocenti F … +7 more , Soscia D, Vaiarelli A, Ubaldi FM, Gennarelli G, Garagna S, Rienzi L, Zuccotti M
Hum Reprod Update · 2023 Jan · PMID 35856663 · Publisher ↗
BACKGROUND: Folliculogenesis occurs in the highly dynamic environment of the ovary. Follicle cyclic recruitment, neo-angiogenesis, spatial displacement, follicle atresia and ovulation stand out as major events resulting...
BACKGROUND: Folliculogenesis occurs in the highly dynamic environment of the ovary. Follicle cyclic recruitment, neo-angiogenesis, spatial displacement, follicle atresia and ovulation stand out as major events resulting from the interplay between mechanical forces and molecular signals. Morphological and functional changes to the growing follicle and to the surrounding tissue are required to produce oocytes capable of supporting preimplantation development to the blastocyst stage. OBJECTIVE AND RATIONALE: This review will summarize the ovarian morphological and functional context that contributes to follicle recruitment, growth and ovulation, as well as to the acquisition of oocyte developmental competence. We will describe the changes occurring during folliculogenesis to the ovarian extracellular matrix (ECM) and to the vasculature, their influence on the mechanical properties of the ovarian tissue, and, in turn, their influence on the regulation of signal transduction. Also, we will outline how their dysregulation might be associated with pathologies such as polycystic ovary syndrome (PCOS), endometriosis or premature ovarian insufficiency (POI). Finally, for each of these three pathologies, we will highlight therapeutic strategies attempting to correct the altered biomechanical context in order to restore fertility. SEARCH METHODS: For each area discussed, a systematic bibliographical search was performed, without temporal limits, using PubMed Central, Web of Science and Scopus search engines employing the keywords extracellular matrix, mechanobiology, biomechanics, vasculature, angiogenesis or signalling pathway in combination with: ovary, oogenesis, oocyte, folliculogenesis, ovarian follicle, theca, granulosa, cumulus, follicular fluid, corpus luteum, meiosis, oocyte developmental competence, preimplantation, polycystic ovary syndrome, premature ovarian insufficiency or endometriosis. OUTCOMES: Through search engines queries, we yielded a total of 37 368 papers that were further selected based on our focus on mammals and, specifically, on rodents, bovine, equine, ovine, primates and human, and also were trimmed around each specific topic of the review. After the elimination of duplicates, this selection process resulted in 628 papers, of which 287 were cited in the manuscript. Among these, 89.2% were published in the past 22 years, while the remaining 8.0%, 2.4% or 0.3% were published during the 1990s, 1980s or before, respectively. During folliculogenesis, changes occur to the ovarian ECM composition and organization that, together with vasculature modelling around the growing follicle, are aimed to sustain its recruitment and growth, and the maturation of the enclosed oocyte. These events define the scenario in which mechanical forces are key to the regulation of cascades of molecular signals. Alterations to this context determine impaired folliculogenesis and decreased oocyte developmental potential, as observed in pathological conditions which are causes of infertility, such as PCOS, endometriosis or POI. WIDER IMPLICATIONS: The knowledge of these mechanisms and the rules that govern them lay a sound basis to explain how follicles recruitment and growth are modulated, and stimulate insights to develop, in clinical practice, strategies to improve follicular recruitment and oocyte competence, particularly for pathologies like PCOS, endometriosis and POI.
Bioengineering trends in female reproduction: a systematic review.
Francés-Herrero E, Lopez R, Hellström M … +5 more , de Miguel-Gómez L, Herraiz S, Brännström M, Pellicer A, Cervelló I
Hum Reprod Update · 2022 Nov · PMID 35652272 · Full text
BACKGROUND: To provide the optimal milieu for implantation and fetal development, the female reproductive system must orchestrate uterine dynamics with the appropriate hormones produced by the ovaries. Mature oocytes may...
BACKGROUND: To provide the optimal milieu for implantation and fetal development, the female reproductive system must orchestrate uterine dynamics with the appropriate hormones produced by the ovaries. Mature oocytes may be fertilized in the fallopian tubes, and the resulting zygote is transported toward the uterus, where it can implant and continue developing. The cervix acts as a physical barrier to protect the fetus throughout pregnancy, and the vagina acts as a birth canal (involving uterine and cervix mechanisms) and facilitates copulation. Fertility can be compromised by pathologies that affect any of these organs or processes, and therefore, being able to accurately model them or restore their function is of paramount importance in applied and translational research. However, innate differences in human and animal model reproductive tracts, and the static nature of 2D cell/tissue culture techniques, necessitate continued research and development of dynamic and more complex in vitro platforms, ex vivo approaches and in vivo therapies to study and support reproductive biology. To meet this need, bioengineering is propelling the research on female reproduction into a new dimension through a wide range of potential applications and preclinical models, and the burgeoning number and variety of studies makes for a rapidly changing state of the field. OBJECTIVE AND RATIONALE: This review aims to summarize the mounting evidence on bioengineering strategies, platforms and therapies currently available and under development in the context of female reproductive medicine, in order to further understand female reproductive biology and provide new options for fertility restoration. Specifically, techniques used in, or for, the uterus (endometrium and myometrium), ovary, fallopian tubes, cervix and vagina will be discussed. SEARCH METHODS: A systematic search of full-text articles available in PubMed and Embase databases was conducted to identify relevant studies published between January 2000 and September 2021. The search terms included: bioengineering, reproduction, artificial, biomaterial, microfluidic, bioprinting, organoid, hydrogel, scaffold, uterus, endometrium, ovary, fallopian tubes, oviduct, cervix, vagina, endometriosis, adenomyosis, uterine fibroids, chlamydia, Asherman's syndrome, intrauterine adhesions, uterine polyps, polycystic ovary syndrome and primary ovarian insufficiency. Additional studies were identified by manually searching the references of the selected articles and of complementary reviews. Eligibility criteria included original, rigorous and accessible peer-reviewed work, published in English, on female reproductive bioengineering techniques in preclinical (in vitro/in vivo/ex vivo) and/or clinical testing phases. OUTCOMES: Out of the 10 390 records identified, 312 studies were included for systematic review. Owing to inconsistencies in the study measurements and designs, the findings were assessed qualitatively rather than by meta-analysis. Hydrogels and scaffolds were commonly applied in various bioengineering-related studies of the female reproductive tract. Emerging technologies, such as organoids and bioprinting, offered personalized diagnoses and alternative treatment options, respectively. Promising microfluidic systems combining various bioengineering approaches have also shown translational value. WIDER IMPLICATIONS: The complexity of the molecular, endocrine and tissue-level interactions regulating female reproduction present challenges for bioengineering approaches to replace female reproductive organs. However, interdisciplinary work is providing valuable insight into the physicochemical properties necessary for reproductive biological processes to occur. Defining the landscape of reproductive bioengineering technologies currently available and under development for women can provide alternative models for toxicology/drug testing, ex vivo fertility options, clinical therapies and a basis for future organ regeneration studies.
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