Sexual reproduction crucially depends on the production of sperm in males and oocytes in females. Both types of gamete arise from the same precursor, the germ cells. We review the events that ...characterize the development of germ cells during fetal life as they commit to, and prepare for, oogenesis or spermatogenesis. In females, fetal germ cells enter meiosis, whereas in males they delay meiosis and instead lose pluripotency, activate an irreversible program of prospermatogonial differentiation, and temporarily cease dividing. Both pathways involve sex-specific molecular signals from the somatic cells of the developing gonads and a suite of intrinsic receptors, signal transducers, transcription factors, RNA stability factors, and epigenetic modulators that act in complex, interconnected positive and negative regulatory networks. Understanding these networks is important in the contexts of the etiology, diagnosis, and treatment of infertility and gonadal cancers, and in efforts to augment human and animal fertility using stem cell approaches.
We aim to provide a review of the literature to summarize the potential causes that lead to a disparity in infertility evaluation and the implications of male factor infertility.
Owing to current ...social constructs, women are more likely to seek medical attention and establish reproductive health evaluation at an earlier age. The male factor evaluation in infertility usually gets delayed and can contribute to a couple's inability to conceive. Furthermore, the cost of assisted reproductive technology is not inconsequential and identifying reversible causes of male infertility could lead to substantial cost-savings to the couple. Additionally, male infertility has been identified as a potential early surrogate for adverse health outcomes and an early identification could serve to counsel these patients on lifestyle modification.
Infertility is defined as the inability to conceive after 12 months of unprotected intercourse with 15% of couples reporting difficulties in conception. Traditionally, female factor evaluation has been the driver for the infertility workup. It is estimated that male factor is likely to play a role in 50% of infertile couples with sole contribution in 20% of cases. It is therefore crucial to ensure appropriate investigations of both partners to rule out potentially reversible causes of infertility to improve their chances of natural fecundity.
Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several ...MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF. These three CFAP47 variants were absent in human control population genome databases and were predicted to be deleterious by multiple bioinformatic tools. CFAP47 encodes a cilia- and flagella-associated protein that is highly expressed in testis. Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47. Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene. All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes. We also generated a Cfap47-mutated mouse model, the adult males of which were sterile and presented with reduced sperm motility and abnormal flagellar morphology and movement. However, fertility could be rescued by the use of intra-cytoplasmic sperm injections (ICSIs). Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested. These findings will provide important guidance for genetic counseling and assisted reproduction treatments.
Our study examined the psychological outcomes associated with failed ART treatment outcomes in men and women.
A systematic search for studies published between January 1980 and August 2015 was ...performed across seven electronic databases.
Studies were included if they contained data on psychosocial outcomes taken pre and post ART treatment.
A standardised form was used to extract data and was verified by two independent reviewers. Studies were meta-analysed to determine the association of depression and anxiety with ART treatment outcomes. Narrative synthesis identified factors to explain variations in the size and directions of effects and relationships explored within and between the studies.
Both depression and anxiety increased after a ART treatment failure with an overall pooled standardised mean difference (SMD) of 0.41 (95% CI: 0.27, 0.55) for depression and 0.21 (95% CI: 0.13, 0.29) for anxiety. In contrast, depression decreased after a successful treatment, SMD of -0.24 (95% CI: -0.37,-0.11). Both depression and anxiety decreased as time passed from ART procedure. Nonetheless, these remained higher than baseline measures in the group with the failed outcome even six months after the procedure. Studies included in the narrative synthesis also confirmed an association with negative psychological outcomes in relation to marital satisfaction and general well-being following treatment failure.
Linking ART failure and psychosocial outcomes may elucidate the experience of treatment subgroups, influence deliberations around recommendations for resource allocation and health policy and guide patient and clinician decision making.
Observational studies have linked cytokines to the occurrence of female and male infertility. However, it is not clear how biomarkers of inflammation are causally related to infertility. To explore ...whether genetic variants in circulating cytokines are associated with the pathogenesis of infertility, we performed two-sample Mendelian randomization (MR) analysis.
A total of 31,112 individuals of European ancestry were included in a genome-wide association study (GWAS) of 47 circulating cytokines as instrumental variables (IVs). Outcome data were female infertility, including four different subtypes, and male infertility, from the FinnGen consortium. Five MR methods, including inverse-variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode were employed to examine the genetic association between cytokines and the risk of female infertility and male infertility. The false discovery rate (FDR) was controlled using the Benjamini–Hochberg method.
After FDR correction, cis-protein quantitative trait locus (cis-pQTL) instruments showed that the cytokines GROa and MCSF were positively associated with female infertility. In analyses of subtypes of female infertility, eotaxin and sICAM were inversely associated with ovulation-related infertility; MCP3 alone was positively associated with uterus-related infertility; GROa and MCSF were positively correlated with infertility of cervical, vaginal, and other or unspecified origin; and MIP1a was negatively correlated with tubal origin infertility. The cytokines HGF, IL-2ra, and RANTES were positively correlated with male infertility. Similar findings were obtained in sensitivity analyses. There was no evidence of pleiotropy or heterogeneity in the results.
These findings contribute to current understanding of the role of cytokine biomarkers in the etiology of female and male infertility. Furthermore clinical experimental validation is required to evaluate the potential of these cytokines as biomarkers.
•Based on cis-pQTL instrument selection criteria and after FDR correction, we found that GROa and MCSF were positively associated with overall female infertility risk.•In the female infertility subtype analyses, eotaxin and sICAM were inversely associated with ovulation-related infertility risk. MCP3 was the only cytokine that was positively associated with uterus-related infertility. GROa and MCSF were positively correlated with infertility of cervical, vaginal, and other or unspecified origin; and MIP1a was negatively correlated with tubal origin infertility.•The cytokines HGF, IL-2ra, and RANTES were positively correlated with male infertility.•Based on the cis-eQTL criteria, only IL-2ra and RANTES were positively correlated with male infertility, but there was no significance after FDR correction.
To determine the optimal infertility therapy for women at the end of their reproductive potential.
Randomized clinical trial.
Academic medical centers and private infertility center in a state with ...mandated insurance coverage.
Couples with ≥ 6 months of unexplained infertility; female partner aged 38-42 years.
Randomized to treatment with two cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant.
Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after two treatment cycles and at the end of treatment.
We randomized 154 couples to receive CC/IUI (N = 51), FSH/IUI (N = 52), or immediate IVF (N = 51); 140 (90.9%) couples initiated treatment. The cumulative clinical pregnancy rates per couple after the first two cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. After all treatments, 110 (71.4%) of 154 couples had conceived a clinically recognized pregnancy, and 46.1% had delivered at least one live-born baby; 84.2% of all live-born infants resulting from treatment were achieved via IVF. There were 36% fewer treatment cycles in the IVF arm compared with either COH/IUI arm, and the couples conceived a pregnancy leading to a live birth after fewer treatment cycles.
A randomized controlled trial in older women with unexplained infertility to compare treatment initiated with two cycles of controlled ovarian hyperstimulation/IUI versus immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group.
NCT00246506.
A couple may be considered to have fertility problems if they have been trying to conceive for over 1 year with no success. Worldwide, the inability to have children affects 10% to 15% of all ...couples. Subfertility can be divided into either male or female factor, or both partners can be affected. However, for some couples the cause for subfertility cannot be identified, and this is called unexplained subfertility. It is thought that oxidative stress is involved in the pathophysiology of subfertility, and antioxidants are thought to reduce the damage caused by oxidative stress. Antioxidants are widely available and inexpensive. However, there is currently little high-quality evidence to show that taking antioxidants will provide any benefit or harm for infertile couples.
Infertility is the inability to achieve a pregnancy after 12 months of regular, unprotected sexual intercourse. Evaluation and treatment are recommended earlier than 12 months when risk factors for ...infertility exist, if the female partner is 35 years or older, and in the setting of nonheterosexual partnerships. A comprehensive medical history and physical examination emphasizing the thyroid, breast, and pelvic areas should be performed to help direct diagnosis and treatment. Causes of infertility in females include uterine and tubal factors, ovarian reserve, ovulatory dysfunction, obesity, and hormone-related disorders. Common male factor infertility issues include abnormal semen, hormonal disorders, and genetic abnormalities. Semen analysis is recommended for the initial assessment of the male partner. Evaluation of the female should include assessment of the uterus and fallopian tubes with ultrasonography or hysterosalpingography when indicated. Laparoscopy, hysteroscopy, or magnetic resonance imaging may be needed to evaluate for endometriosis, leiomyomas, or evidence of a previous pelvic infection. Treatment with ovulation induction agents, intrauterine insemination, in vitro fertilization, donor sperm or eggs, or surgery may be necessary. Unexplained male and female infertility can be treated with intrauterine insemination or in vitro fertilization. Limiting alcohol intake, avoiding tobacco and illicit drug use, consuming a profertility diet, and losing weight (if obese) may improve pregnancy success rates.
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