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Open access

Parijot Kumar, Kevin Marron, and Conor Harrity

Controversy exists regarding the benefits of intravenous intralipid therapy in patients with a poor reproductive history. It is frequently reported that there is no evidence to support the effectiveness, utility or safety for this treatment. While individual studies may be perceived as weak, a systematic review and meta-analysis were performed to determine if there is any advantage to patients. PubMed, Embase and Scopus searches were performed with the target populations being either recurrent pregnancy loss (RPL), or recurrent implantation failure (RIF) undergoing assisted reproductive technology (ART) and receiving intralipid infusions. These cohorts were compared with either placebo, no intervention or alternative treatments. The most relevant outcome measures were considered to be clinical pregnancy rate (CPR), live birth rate (LBR), implantation rate (IR) and miscarriage rate (MR). Twelve studies encompassing 2676 participants met the criteria for selection and were included and reviewed. Treatment of the target population with intralipid led to an improvement in IR (Odds Ratio (OR): 2.97, 2.05–4.29), pregnancy rate (OR: 1.64, 1.31–2.04), and LBR (OR: 2.36, 1.75–3.17), with a reduction in MR (OR: 0.2, 0.14–0.30). Although intravenous intralipid is not recommended as a routine treatment for recurrent miscarriage or implantation failure, there is enough data to suggest consideration in selected patients where routine testing is unremarkable, standard treatments have failed and immunological risk factors are present. The presence of abnormal uterine natural killer (uNK) cells needs more study as a target marker to determine those who could benefit.

Lay summary

There is controversy regarding the benefits and efficacy of intravenous intralipid therapy in patients with a poor reproductive history. It is frequently reported that there is no credible evidence to support their use. A situation we frequently face as medical professionals is patients asking us to consider immune therapy (such as intralipid) for reproductive failure where good quality embryos have been used. Intralipid infusions have been reported to improve pregnancy rates with IVF, and reduce the miscarriage risk in selected patient groups, but study results are not universally accepted. We have performed a detailed review and analysis of the literature to determine if there is any benefit to this immune treatment in specific patient groups. Our paper identified and analyzed 12 studies, finding that treatment with intravenous intralipid leads to an improvement in implantation, pregnancy and live birth rates, with a decrease in miscarriage rate. This study shows that there is evidence to suggest consideration of intralipid in certain patients where standard treatments have failed.

Open access

Synneva Hagen-Lillevik, John S Rushing, Leslie Appiah, Nicola Longo, Ashley Andrews, Kent Lai, and Joshua Johnson

Classic galactosemia is an inborn error of carbohydrate metabolism associated with early-onset primary ovarian insufficiency (POI) in young women. Our understanding of the consequences of galactosemia upon fertility and fecundity of affected women is expanding, but there are important remaining gaps in our knowledge and tools for its management, and a need for continued dialog so that the special features of the condition can be better managed. Here, we review galactosemic POI and its reproductive endocrinological clinical sequelae and summarize current best clinical practices for its management. Special consideration is given to the very early-onset nature of the condition in the pediatric/adolescent patient. Afterward, we summarize our current understanding of the reproductive pathophysiology of galactosemia, including the potential action of toxic galactose metabolites upon the ovary. Our work establishing that ovarian cellular stress reminiscent of endoplasmic reticulum (ER) stress is present in a mouse model of galactosemia, as well as work by other groups, are summarized.

Lay summary

Patients with the condition of classic galactosemia need to maintain a strict lifelong diet that excludes the sugar galactose. This is due to having mutations in enzymes that process galactose, resulting in the buildup of toxic metabolic by-products of the sugar. Young women with classic galactosemia often lose the function of their ovaries very early in life (termed 'primary ovarian insufficiency'), despite adherence to a galactose-restricted diet. This means that in addition to the consequences of the disease, these women also face infertility and the potential need for hormone replacement therapy. This article summarizes current strategies for managing the care of galactosemic girls and women and also what is known of how the condition leads to early primary ovarian insufficiency.

Open access

Michael P Rimmer, Christopher D Gregory, and Rod T Mitchell

Objective

To review the role of extracellular vesicles (EVs) released from the male reproductive tract and their impact on developing sperm. We discuss how sperm exiting the seminiferous tubules, although developmentally mature, require further modification. Acquisition of various functions including increased motility, transfer of cargoes and ability to undertake the acrosome reaction is mediated through the interaction between sperm and EVs.

Methods

A review of the literature identified that EVs are released from different portions of the male reproductive tract, notably the epididymis and prostate. These EVs interact with sperm as they pass from the seminiferous tubules to the epididymis and vas deferens prior to ejaculation.

Results

EVs are small lipid-bound particles carrying bespoke RNA, protein and lipid cargoes. These cargoes are loaded based on the state of the parent cell and are used to communicate with recipient cells. In sperm, these cargoes are essential for post-testicular modification.

Conclusions

Interactions between developing sperm and EVs are important for the subsequent function of sperm. Prior to ejaculation, these interactions confer important changes for the post-testicular modification and development of sperm. Little is known about the interaction between EVs from the testes and the spermatogonial stem cell niche or developing sperm within the seminiferous tubules. However, the numerous roles of EVs in the post-testicular modification of sperm have led many to suspect that they may also play important roles in developing sperm within the testes.

Lay summary

Sperm are crucial for successful fertility. In order to do this, they must be able to swim a large distance to meet the egg in the female reproductive tract and fertilise it. Once released from the testes, sperm may appear to be fully developed, but this is not the case. Several important modifications are required in order for them to swim and fertilise an egg. These modifications are carried out by sending sperm small packages from other cells which contain messages and cargo. We discuss the release of these small packages along with different parts of the male reproductive tract and how they change the way sperm behave and function. This article reviews the literature and known functions of these packages called extracellular vesicles, which are released by the male reproductive tract and modify sperm, transforming their function, before they are ejaculated.

Open access

Chinwe U Nwachukwu, Kathryn J Woad, Nicole Barnes, David S Gardner, and Robert S Robinson

Maternal malnutrition has important developmental consequences for the foetus. Indeed, adverse fetal ovarian development could have lifelong impact, with potentially reduced ovarian reserve and fertility of the offspring. This study investigated the effect of maternal protein restriction on germ cell and blood vessel development in the fetal sheep ovary. Ewes were fed control (n = 7) or low protein (n = 8) diets (17.0 g vs 8.7 g crude protein/MJ metabolizable energy) from conception to day 65 of gestation (gd65). On gd65, fetal ovaries were subjected to histological and immunohistochemical analysis to quantify germ cells (OCT4, VASA, DAZL), proliferation (Ki67), apoptosis (caspase 3) and vascularisation (CD31). Protein restriction reduced the fetal ovary weight (P < 0.05) but had no effect on fetal weight (P > 0.05). The density of germ cells was unaffected by maternal diet (P > 0.05). In the ovarian cortex, OCT4+ve cells were more abundant than DAZL+ve (P < 0.001) and VASA+ve cells (P < 0.001). The numbers, density and estimated total weight of OCT4, DAZL, and VASA+ve cells within the ovigerous cords were similar in both dietary groups (P > 0.05). Similarly, maternal protein restriction had no effect on germ cell proliferation or apoptotic indices (P > 0.05) and the number, area and perimeter of medullary blood vessels and degree of microvascularisation in the cortex (P > 0.05). In conclusion, maternal protein restriction decreased ovarian weight despite not affecting germ cell developmental progress, proliferation, apoptosis, or ovarian vascularity. This suggests that reduced maternal protein has the potential to regulate ovarian development in the offspring.

Lay summary

Variations in a mother’s diet during pregnancy can influence her offspring’s growth and might cause fertility problems in the offspring in later life. We investigated whether reducing the protein fed to sheep during early pregnancy affects their daughters’ ovaries. We then compared our findings to the offspring of sheep on a complete diet. We measured ovary size and estimated the number of germ cells (cells that become eggs) they contained. We used cell markers to assess potential changes in the pattern of germ cell growth, division, and death, and how the ovarian blood supply had developed. We found that protein restriction reduced ovary size. However, the pattern of germ cell development, growth, or death was not altered by poor diet and blood vessels were also unaffected. This suggests that maternal diet can change ovarian development by an unknown mechanism and might reduce future fertility in their offspring.

Open access

Jack Wilkinson and Katie Stocking

Health interventions should be tested before being introduced into clinical practice, to find out whether they work and whether they are harmful. However, research studies will only provide reliable answers to these questions if they are appropriately designed and analysed. But these are not trivial tasks. We review some methodological challenges that arise when evaluating fertility interventions and explain the implications for a non-statistical audience. These include flexibility in outcomes and analyses; use of surrogate outcomes instead of live birth; use of inappropriate denominators; evaluating cumulative outcomes and time to live birth; allowing each patient or couple to contribute to a research study more than once. We highlight recurring errors and present solutions. We conclude by highlighting the importance of collaboration between clinical and methodological experts, as well as people with experience of subfertility, for realising high-quality research.

Lay summary

We do research to find out whether fertility treatments are beneficial and to make sure they don’t cause harm. However, research will only provide reliable answers if it is done properly. It is not unusual for researchers to make mistakes when they are designing research studies and analysing the data that we get from them. In this review, we describe some of the mistakes people make when they do research about fertility treatments and explain how to avoid them. These include challenges which arise due to the large number of things that can be measured and reported when looking to see if fertility treatments work; failure to check whether the treatment increases the number of live births; failing to include all study participants in calculations;challenges in studies where participants may have more than one treatment attempt. We conclude by highlighting the importance of collaboration between clinical and methodological experts, as well as people with experience of fertility problems.

Open access

Peter H Vogt, Jutta Zimmer, Ulrike Bender, and Thomas Strowitzki

The Ubiquitous Transcribed Y (UTY a.k.a. KDM6C) AZFa candidate gene on the human Y chromosome and its paralog on the X chromosome, UTX (a.k.a. KDM6A), encode a histone lysine demethylase removing chromatin H3K27 methylation marks at genes transcriptional start sites for activation. Both proteins harbour the conserved Jumonji C (JmjC) domain, functional in chromatin metabolism, and an extended N-terminal tetratricopeptide repeat (TPR) block involved in specific protein interactions. Specific antisera for human UTY and UTX proteins were developed to distinguish the expression of both proteins in human germ cells by immunohistochemical experiments on appropriate tissue sections. In the male germ line, UTY was expressed in the fraction of A spermatogonia located at the basal membrane, probably including spermatogonia stem cells. UTX expression was more spread in all spermatogonia and in early spermatids. In female germ line, UTX expression was found in the primordial germ cells of the ovary. UTY was also expressed during fetal male germ cell development, whereas UTX expression was visible only at distinct gestation weeks. Based on these results and the conserved neighboured location of UTY and DDX3Y in Yq11 found in mammals of distinct lineages, we conclude that UTY, such as DDX3Y, is part of the Azoospermia factor a (AZFa) locus functioning in human spermatogonia to support the balance of their proliferation-differentiation rate before meiosis. Comparable UTY and DDX3Y expression was also found in gonadoblastoma and dysgerminoma cells found in germ cell nests of the dysgenetic gonads of individuals with disorders of sexual development and a Y chromosome in karyotype (DSD-XY). This confirms that AZFa overlaps with GBY, the Gonadoblastoma susceptibility Y locus, and includes the UTY gene.

Lay Summary

AZFa Y genes are involved in human male germ cells development and support gonadoblastoma (germ cell tumour precursor cells) in the aberrant germ cells of the gonads of females with genetic disorders of sexual development. The AZFa UTY gene on the male Y chromosome is equivalent to UTX on the female X chromosome. These genes are involved in removing gene regulators to enable activation of other genes (i.e. removal of histone methylation known as epigenetic modifications). We wanted to learn the function of UTY and UTX in developing sperm and eggs in human tissues and developed specific antibodies to detect both proteins made by these genes. Both UTY and UTX proteins were detected in adult and fetal sperm precursor cells (spermatogonia). UTX was detected in egg precursor cells (primordial germ cells). UTY was detected in gonadoblastoma and dysgerminoma tumour cells (germ cell tumours originating from genetic disorders of sexual development due to having a Y chromosome). Based on our study, we conclude that UTY is not only part of AZFa, but also of GBY the overlapping gonadoblastoma susceptibility Y region.

Open access

Amy Miller, Elainna Jentz, Cassandra Duncan, and Dana Merriman

Graphical abstract

13-lined ground squirrels (TLGS; Ictidomys tridecemlineatus) are small, omnivorous, fossorial, hibernating sciurids. TLGS are seasonal induced ovulators, with a ~28-day gestation period. The main goal of this study was to ascertain whether enzyme-linked immunosorbent assay (ELISA) of TLGS fecal samples can be used to non-invasively detect pregnancy. Competitive ELISAs for progestogen metabolites were conducted on feces collected from a group of (n =13) females. Feces were collected thrice weekly during the breeding season and frozen for subsequent analysis. Competitive ELISAs were run using progesterone kits ), setting data against seven different time-points between hibernation, emergence, and litter birthdate. Eleven females produced litters. ELISA data from the (n = 2) non-pregnant females demonstrated no rise in progestogen metabolites at any point over 28 days. In contrast, data from the (n = 11) pregnant females all demonstrated a pronounced rise in progestogen metabolites, with most animals displaying progesterone withdrawal in the final week of gestation. A >20-fold rise in progestogen metabolite was observed halfway through gestation (P < 005). Analysis on litter size and progestogen metabolite concentration showed no significant correlation (r2 = −0.615). Initial correlation analysis done on sex ratio of litters vs progestogen metabolites showed no significant effect of progesterone on sex ratios (males: r2 = −0.772, females: r2 = 0.375). This work demonstrated that TLGS also undergo progesterone withdrawal about a week before parturition. We have ascertained that a commercially available progesterone assay kit can detect a significant elevation in progestogen metabolites in this species about halfway through gestation.

Lay summary

This research was conducted to discover whether pregnancy prediction is possible in female 13-lined ground squirrels (TLGS; a small hibernating ground squirrel named for their number of stripes). Pregnancy status in this species, we postulated, could be anticipated by generating profiles for individuals via a non-invasive technique known as fecal endocrine hormone profiling. Fecal samples were collected from 13 females thrice weekly for 4 weeks post-hibernation in the breeding season of 2016. Fecal samples were then processed and run through an assay known as an ELISA giving concentrations of hormone metabolites excreted through feces. We then set these samples against time points to develop a profile for each female. We have ascertained that elevated progesterone (potential pregnancy) can be detected by a commercially available assay kit. Understanding hormone patterns in animals gives researchers a better idea of best husbandry practices, including breeding in managed care.

Open access

Daniella Gilboa, Liron Seidman, Polina Kimiagarov, Avia Noni, Ravid Doron, and Daniel S Seidman

Objective

Oocyte pick-up (OPU) is a painful but essential part of in-vitro fertilization (IVF) that is usually performed under sedation and analgesia (SaA). Our aim was to study that why some women decide to undergo OPU without SaA?

Methods

This was a prospective study using patient questionnaires and the standardized 7-item generalized anxiety disorder (GAD-7) score. The patients were asked to assess the pain experienced during OPU using a visual analog scale (VAS). The study sample was a convenience sample of 100 healthy women undergoing OPU at our unit with or without SaA.

Results

Women who chose to undergo OPU without SaA were significantly more likely to express the fear of anesthesia. A high pain score (VAS ≥ 6) was reported by significantly more patients who underwent OPU without SaA than with SaA. Yet, 98% of the patients who underwent OPU without SaA stated that in future IVF cycles, they would still choose to undergo OPU without SaA. More patients had high anxiety scores among those who underwent OPU with than without SaA.

Conclusions

Women who chose to undergo OPU without SaA reported more often fear of anesthesia. Although these women experienced significantly more pain during OPU, almost all of them suggested that they would still choose to undergo OPU without SaA. Increased anxiety, as expressed by higher GAD-7 scores, was not associated with a tendency to choose SaA during OPU. The option of OPU without SaA seems to be an acceptable option for selected women.

Lay summary

Egg retrieval from the ovaries is a painful part of in vitro fertilization (IVF). It is, therefore, usually performed under sedation and pain relief (analgesia). The aim of this study was to investigate: Why some women decide to undergo egg retrieval without sedation? We prospectively studied 100 women using patient questionnaires and standardized scores in order to measure patient's pain and anxiety levels. We found that women who chose to undergo egg retrieval without sedation were significantly more likely to express fear of anesthesia. As expected, women who decided to forgo sedation experienced more pain during egg retrieval, yet, 98% of them decided that in future IVF cycles, they would still choose to undergo egg retrieval without sedation. Surprisingly, women who had high anxiety scores were not more likely to ask for sedation during egg retrieval. The option to undergo egg retrieval without sedation during IVF seems to be acceptable for some women.

Open access

Valéria Barradas, Mariana Pereira Antoniassi, Paula Intasqui, Marcilio Nichi, Ricardo Pimenta Bertolla, and Deborah Montagnini Spaine

Varicocele, defined by a dilation of efferent testicular veins, is the most commonly identifiable, surgically correctable lesion associated with male-factor infertility, starts at puberty and causes a progressive decline in fertility potential. The pathophysiology of infertility caused by this disease is still poorly understood, but it is suggested that the main mechanism is oxidative stress. Therefore, the aim of this study was to verify if the varicocele is associated with changes in enzymatic antioxidant mechanisms and seminal plasma lipid peroxidation levels in adolescents. We recruited 90 adolescents that were divided into control (C; n  = 27); varicocele and normal semen (VNS; n  =46); varicocele and altered semen (VAS; n  =17). Seminal and serum levels of lipid peroxidation were quantified by thiobarbituric acid reactive substances (TBARS). Seminal plasma antioxidant profile was evaluated by the activities of catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). The VAS group had increased lipid peroxidation levels when compared to the other groups. The levels of serum lipid peroxidation and activities of the enzymes SOD and GPx did not differ between groups. CAT was undetectable by the method used. In conclusion, in adolescents with varicocele and altered semen analysis, there is an increase in seminal lipid peroxidation levels compared to adolescents with varicocele and without seminal change and adolescents without evident varicocele. However, the observed oxidative stress is not caused by a decrease in superoxide dismutase and glutathione peroxidase activities, which did not differ between adolescents with and without evident varicocele.

Lay Summary

Varicocele, defined by a dilation of efferent testicular veins, is the most commonly identifiable, surgically correctable lesion associated with male-factor infertility, starts at puberty and causes a progressive decline in fertile potential. There is still much that is not understood regarding how exactly it affects semen quality, but most studies agree that oxidative stress, which is defined as excessive amounts of free radicals in relation to antioxidant defense, is an important mechanism. In this study, we aimed to verify if the varicocele is associated with changes in antioxidant defense and semen oxidation in 90 adolescents with and without varicocele. In adolescents with varicocele and abnormal semen, there is an increase in semen oxidation compared to controls or to the group with varicocele and normal semen quality. Our results can help to understand how varicocele leads to infertility in adolescents, identifying changes in oxidative activity in semen, since the onset of varicocele and before damage to sperm production can be detected.

Open access

Iman Al-Saleh, Serdar Coskun, Reem Al-Rouqi, Tahreer Al-Rajudi, Chafica Eltabache, Mai Abduljabbar, and Saad Al-Hassan

This study examined the status of oxidative stress in 599 couples undertaking in vitro fertilization (IVF) treatment and its association with reproductive hormones, smoking, and outcomes. Oxidative stress biomarkers such as malondialdehyde, 8-hydroxy-2-deoxyguanosine, hydrogen peroxide (H2O2), catalase (CAT), and total antioxidant capacity (TAC) were determined in follicular fluid and seminal plasma. Tail moment (TM) was used to evaluate DNA damage in the sperm and granulosa cells. Reproductive hormones in serum and cotinine (COT) in urine, follicular fluid, and seminal plasma samples were determined. Separate multivariate linear regression was used to assess associations between levels of each oxidative stress biomarker and each hormone and smoking parameter (modeled as natural log-transformed). The findings indicate that some oxidative stress and DNA damage biomarkers played a role in disrupting certain reproductive hormones in women and their male partners either by overproducing reactive oxygen species or reducing antioxidant defense capacity. Although women were nonsmokers, COT levels > 50 and 10 µg/L in urine and follicular were observed in 5.7 and 1.7%, respectively. Levels of follicular fluid COT were positively associated with H2O2 and TM. We used log-binomial multivariate regression to estimate relative risks for the association between oxidative stress/DNA damage and IVF binary outcomes (fertilization rate > 50%, biochemical pregnancy, clinical pregnancy, and live birth). An increase in the CAT levels of follicular fluid was associated with a 48 and 41% decrease in the risk of poor fertilization rate (≤50%) and unsuccessful live birth, respectively. After the models were adjusted for hormonal factors, the associations remained the same, except that the elevated TAC in follicular fluid became significantly associated with a decrease of 42% in the risk of poor fertilization rate (≤50%). The higher antioxidant activity (CAT and TAC) in follicular fluid might positively impact specific IVF outcomes.

Lay summary

Oxidative stress occurs when antioxidant molecules are insufficient in the body to destroy free radicals that can damage the cells, proteins and DNA, causing different health conditions, including infertility. The role of oxidative stress in female infertility has not received as much attention as male infertility, and research is still limited. This study explored whether the overproduction of free radicals can impact the success of in vitro fertilization (IVF) treatment using several biological markers such as hydrogen peroxide, catalase, and total antioxidant capacity. Our findings revealed that the high antioxidant levels in the fluid surrounding the egg were linked with a high fertilization rate. Additionally, oxidative stress status in couples was associated negatively with several reproductive hormones and smoking status. Biomarkers of oxidative stress and DNA damage might have potential applications in evaluating IVF patients’ clinical characteristics such as causes of infertility, hormonal profile, fertilization rate, implantation and live birth.