Abstract

Genetic defects in sperm are responsible for a great percentage of male infertility. Dysregulation of these genes directly influences sperm morphology, motility, and viability. Therefore, analyzing gene expression aberrancies is a must in male infertility. Microarray analysis is practically used for several aspects of male infertility, including the detection of differentially expressed genes and the identification of potential infertility biomarkers. We conducted a meta-analysis using microarray datasets, including the datasets containing sperm tissues from both healthy and infertile males. Seven datasets qualified for inclusion in this study and were then transformed into a single set of meta-data. For these genes, expression and diagnostic analyses were conducted. Additionally, enrichment analysis revealed the role and function of these genes in cellular processes. Six genes—S100Z, SLC2A2, IMPG1, HOXD12, RAPGEFL1, and DMBX1—were found to be significantly down-regulated in the sperm of infertile men. Notably, the expression of these genes was highly correlated in the sperm of these men. In addition, receiver operating curve analysis indicated that these genes may serve as useful biomarkers for infertility diagnosis. The role of these genes in transporting glucose, vitamins, and fructose as the sperm’s primary fuel source was suggested by pathway analysis.

Introduction

Infertility is a developing concern, affecting between 10 and 15% of couples worldwide (Wasilewski et al., 2020). Male factor infertility accounts for approximately 50 % of all sterility cases, with sperm abnormalities being the most common cause (Kumar and Singh, 2015). The traditional analysis of sperm provides fundamental information regarding sperm count, motility, and morphology but fails to identify the underlying molecular abnormalities (Boitrelle et al., 2021; Vasan, 2011; Auger, 2010).

Microarray analysis is a high-throughput technique that permits the simultaneous identification of numerous gene expression alterations (Mutch et al., 2001). Recently, it has been utilized to investigate the genetic basis of male infertility and sperm dysfunction (Garrido et al., 2013; Garrido et al., 2009). Sperm microarray analysis can provide a comprehensive picture of the sperm’s molecular landscape, including gene expression patterns and DNA copy number variations (CNVs) that may be responsible for infertility (Waclawska and Kurpisz, 2012). The identification of specific genes and pathways involved in sperm function and fertilization can lead to the development of novel therapeutic targets for male infertility (You et al., 2019). So far, over 2000 genes and pathways are recognized to be involved in spermatogenesis; hence, spotting differentially expressed genes (DEGs) may disclose infertility etiology (Babakhanzadeh et al., 2020; Lee and Ramasamy, 2018). Among the genes associated with male infertility and the disorders caused by their defect are CFTR (congenital unilateral/bilateral absence of vas deferens), AR (non-obstructive azoospermia) (Bieniek et al., 2021), LRRC6 (primary ciliary dyskinesia) (Li et al., 2023), APOA1 (testicular amyloidosis) (Houston et al., 2022), and SRY (sexual development disorders) (Jiang et al., 2013). Signaling pathways such as JAKs, MAPKs, etc. are also involved in this disease (Fig. 1). Genetic factors account for approximately 15% of the causes of male infertility, which may manifest as deficiencies in sperm count or sperm quality (Salas-Huetos and Aston, 2021). However, the genetic cause of male infertility remains unknown in about 40% of cases (Krausz and Riera-Escamilla, 2018). Several DEGs and CNVs have been confirmed to play a role in spermatogenesis and fertilization as a result of microarray analysis of sperm from infertile men. For instance, Hashemi et al. used microarray analysis to reveal multiple gene dysregulations such as RAD23B, OBFC2A, CHEK2, TRIP13, and POLD4, which primarily mediate DNA damage detection and repair and regulate cell proliferation (Hashemi Karoii et al., 2022).

Conclusion

Downregulation of six novel genes (S100Z, SLC2A2, IMPG1, HOXD12, RAPGEFL1, and DMBX1) in the sperm of infertile males was identified by this study via meta-analysis of microarray data. Furthermore, the potential use of these dysregulations as diagnostic biomarkers was demonstrated through ROC curve analysis.

5.1. Future prospective
Advantages of using microarrays for infertile sperm include the discovery of underlying genetic pathways and the suggestion of novel diagnostic biomarkers. Our findings may prove useful in the treatment and accurate diagnosis of male infertility.

5.2. Limitations
Although the study of microarrays is a high-throughput method, we recommend verifying the data with a gold-standard method, such as real-time polymerase chain reaction (RT-PCR). Given the scarcity of samples, we would be overjoyed if subsequent research confirmed the molecular level findings reported here. As for the diagnostics, commenting on ideal biomarkers require several studies with a wide sample size, therefore, testing our findings on a cohort will disclose the accurate and real ability of these DEGs in identifying infertility.

Folliculogenesis describes the process of activating an oocyte-containing primordial follicle from the ovarian reserve, and its development to the mature ovulatory stage. This process is highly complex and is controlled by extra- and intra-ovarian signalling events. Oocyte competence and capacity for fertilisation to support a viable pregnancy is acquired during folliculogenesis. Cancer, and cancer-based therapies can negatively affect this process, compromising fertility. Currently, preservation of fertility in these patients remains limited to surrogacy, oocyte freezing, oocyte donation or in vitro maturation (IVM). Recent reports of stem cells being used to produce fully competent oocytes, and subsequently healthy offspring in mice, has opened up a novel avenue for fertility preservation. However, translating these findings into human health first relies on enhancing our understanding of follicle growth, and mimicking its intricacies in vitro. Indeed, the future of oocytes from stem cells in humans comes with many possibilities, but currently faces several technical and ethical obstacles.

Overview of folliculogenesis and building a competent oocyte

The ovarian follicle containing an oocyte surrounded by somatic cells is the niche for the female germline which must be nourished and protected from sustained damage. The germ cells that eventually form follicles are first identified at 4 weeks gestation among stem cells in the embryonic epiblast. After migration to the gonadal ridge and proliferation, they enter meiosis and form nests surrounded by pre-granulosa cells. The nests breakdown between 25 and 40 weeks gestation to form primordial follicles, each of which contains an oocyte arrested in prophase of the meiotic cell cycle, surrounded by a single layer of squamous or flattened pre-granulosa cells. This process called oogenesis occurs over 150 and 250 days in the fetal ovary (Figure 1) (1, 2). At birth, the human female has approximately 300,000 primordial follicles (range 35,000-2.5 million), defined as the ovarian reserve (1, 3).This reserve is not replenished after birth under normal physiological circumstances. The size of the ovarian reserve declines with age until <1000 primordial follicles are present at the time of menopause (3, 4). The length of the fertile period from puberty to menopause is determined by (a) the rate of death of primordial follicles before being selected to activate, (b) their rate of activation, and (c) the size of the ovarian reserve at birth (1, 5). It follows that genetic or environmental factors such as chemotherapeutic agents or radiation that reduce the size of the ovarian reserve will shorten or even eliminate the fertile period.

Infertility is defined as the inability of a couple to conceive a child after one year of regular sexual life without contraceptive techniques (Tekin et al., 2004). Infertility is one of the major health-therapeutic problems in different societies. The high prevalence (8 to 12%) of this problem makes it very important. A significant proportion of infertility is dependent on environmental conditions and acquired risk factors which are preventable. Different environmental conditions show the necessity of studying the different causes of infertility in each region. In today’s modern world there are many reasons for infertility in men and women, one of the most important of which from the viewpoints of experts is the age of the couple. Couples should be aware that the fertility rate of a woman under 25 years of age is more than 80% but for a woman over 35 this rate is under 50% (Tekin et al., 2004).

It is likely that the number of ova is limited after reproductive age; that factor alone can reduce fertility and increase the risk of birth defects in the fetus and newborn. In addition, men over 35 compared with men under 35 have less chances of fertility, and the risk of chromosomal abnormalities is higher in their children. One of the factors with a significant impact on male infertility is environmental, industrial and air pollution, which minimizes the sperm counts, and decreasing fertility (Tekin et al., 2004).

According to studies, obesity and ovarian dysfunction in women are risk factors for infertility. Various studies conducted around the world have shown that women who are overweight or obese require more time to get pregnant, compared with normal or standard weight women, and pregnancy in obese women is more likely to be unsuccessful. According to experts, obesity in men and women increases the level of hormones in their bodies, affecting the reproductive process. In fact, abnormal secretion of hormones can lead to weight gain and negative effects on the male and female germ cell production (Tekin et al., 2004).

The thyroid hormones act on nearly every cell in the body. They act to increase the basal metabolic rate, affect protein synthesis and regulate long bone growth and neural maturation. The thyroid hormones are essential for the proper development and differentiation of all cells of the human body. The thyroid hormones also affect the female reproductive organs. In combination with follicle-stimulating hormone, triiodothyronine (T3) enhances granulosa cell proliferation and inhibits granulosa cell apoptosis by the phosphatidylinositol 3-kinase/Akt (also known as protein kinase B) pathway [1]. Leukemia inhibitory factor (LIF) is involved in the embryo implantation process and expressed in the mid-secretory endometrium [2]. Thyroid-stimulating hormone (TSH) significantly upregulates LIF expression in endometrial cell cultures, suggesting a potential role of TSH in the implantation process [3]. Moreover, T3 increases the expression of matrix metalloproteinases (MMP), MMP-2, MMP-3, fetal fibronectin, and integrin a5b1T3 in cultured early placental extravillous trophoblasts, suggesting that it plays a vital role in regulating the invasive potential of extravillous trophoblasts [4]. The thyroid hormones are involved in almost all phases of reproduction, from folliculogenesis to placentation. This review focuses on the interactions between thyroid dysfunctions and subfertility, as well as the proper work-up and management of thyroid dysfunctions in subfertile women.

Objective: To evaluate the recovery of semen quality in a cohort of infertile men after known hyperthermic exposure to hot tubs, hot baths or whirlpool baths. Materials and Methods: A consecutive cohort of infertile men had a history remarkable for wet heat exposure in the forms of hot tubs, Jacuzzi or hot baths. Clinical characteristics and exposure parameters were assessed before exposure was discontinued, and semen parameters analyzed before and after discontinuation of hyperthermic exposure. A significant seminal response to withdrawal of hyperthermia was defined as ≥ 200% increase in the total motile sperm count (TMC = volume x concentration x motile fraction) during follow-up after cessation of wet heat exposure. Results: Eleven infertile men (mean age 36.5 years, range 31-44) exposed to hyperthermia were evaluated pre and postexposure. Five patients (45%) responded favorably to cessation of heat exposure and had a mean increase in total motile sperm counts of 491%. This increase was largely the result of a statistically significant increase in sperm motility from a mean of 12% at baseline to 34% post-intervention (p = 0.02). Among non-responders, a smoking history revealed a mean of 5.6 pack-years, compared to 0.11 pack-years among responders. The prevalence of varicoceles was similar in both cohorts

INTRODUCTION

Spermatogenesis is sensitive to a variety of chemical and physical stressors. Testicular hyperthermia has been known to have a deleterious effect on male fertility since the time of Hippocrates and is a well-recognized cause of impaired sperm production (1). Its detrimental effect has been demonstrated in both animal models and in humans (2-4). Whether due to endogenous (such as high fevers) or exogenous stimuli, heat decreases sperm concentration, impairs motility, and reduces the number of morphologically normal sperm (5-8). This effect is striking enough that the effect of laptop computers on scrotal hyperther-

Infertility is defined as the failure to conceive, with no contraception, after one year of regular intercourse in women < 35 years and after 6 months in women > 35 years. A review on causes, management and treatment of endocrine causes of female infertility was performed. Epidemiological data suggest that around 10% to 15% of couples are infertile. Anovulatory problems are responsible from 25% to 50% of causes of female infertility. Advanced age, obesity, and drugs, have a negative effect on fertility. Different hypothalamic, pituitary, thyroid, adrenal, and ovarian disorders may affect fertility as well. Infertility is a growing phenomenon in developed societies. We here provide information about how to identify endocrine patients with ovulatory dysfunction. Women must be advised about limiting factors to be avoided, in order to protect their fertility. Arq Bras Endocrinol Metab. 2014;58(2):144-52

NTRODUCTION

I nfertility is defined as the failure to conceive after one year of regular intercourse in women < 35 years not using contraception and after six months in women > 35 years (1). Epidemiological data suggest that about 10% to 15% of all couples will experience difficulties to conceive (primary infertility) or to conceive the number of children they wanted (secondary infertility).

Based on a survey performed in developed countries, the World Health Organization (WHO) estimates that female infertility accounts for 37% of causes in infertile couples, male infertility for 8% and both – male and female infertility – for 35%. Five percent of couples have unexplained infertility and 15% became pregnant during the study. The most common identifiable factors that accounted for female infertility, were ovulatory disorders (25%), endometriosis (15%), pelvic adhesions (11%), tubal blockage (11%), other tubal abnormalities (11 %), and hyperprolactinemia (7%). Other reports describe ovulatory disorders as responsible for more than half of the causes of female infertility (2).

مقاله سال 2016

It is estimated that in 2010 more than 1.5 million people was diagnosed with neoplastic disease, 10% of whom were younger than 45 years. Retaining fertility and having children is an important aspect of life and antineoplastic therapy for these people [1]. It is estimated that 3/4 of people below the age of 35 who were diagnosed with neoplastic disease and treated during childhood will want to have children. Approximately 81% of adolescent girls and 93% of their parents are interested in their children’s fertility preservation during antineoplastic therapy [1]. It is estimated that 45% of physicians do not discuss the issue of fertility preservation and do not suggest appropriate consultations before starting antineoplastic therapy [1, 2].

Therapeutic methods used in antineoplastic treatment cause fertility impairment or sterilization due to permanent damage to reproductive cells [1]. The risk of sterilization depends on patient’s age during therapy, type of neoplasm, radiation dose and treatment area. It is known that systemic treatment and radiotherapy can lead to fertility impairment and the combination of these two gives an additive effect [1, 3]. Radiotherapy can cause pituitary dysfunction, leading indirectly to impairment of ovarian function, or result directly in inability to conceive and carry a pregnancy to full term [4].

The aim of this article is to raise the issue of infertility in these patients. It is of growing importance due to the increase in the number of children and young adults who underwent radiotherapy in the past. Still improving longterm results of these therapies mean that this issue must be addressed. Additionally, there is only a small number of studies concerning fertility impairment and radiotherapy, and their results are usually extrapolated from experimental studies or case reports.

Infertility is a common problem affecting one couple out of every six couples (Brugo-Olmedo, Chillik, & Kopelman, 2001). It is defined as incapacity to become pregnant after mostly 12 months of sexual intercourse, without using any contraception. In this respect, primary infertility was defined as the “Inability to conceive within one year of exposure to pregnancy (i.e.-being sexually active, usingnon-contraception, and non-lactating) among women aged 15-49 years” (Nygren et al., 2011).

The 12-month prevalence rate of infertility ranges from 3.5% to 16.7% in more developed countries and from 6.9% to 9.3% in the less-developed ones, with an estimated overall median prevalence of 9% (Boivin, Bunting, Collins, & Nygren, 2007). Differences between the developed and developing world are emerging due to variations of infertility care and different socio-cultural values surrounding procreation and childlessness (OMbelet, 2011). In recent years, the prevalence of infertility has been significantly increased (Brugo-Olmed et al., 2001). The increasing trend could be due to delayed childbearing of couples, alterations in semen quality due to habits such as cigarette smoking and alcohol, changes in sexual behavior and elimination of most taboos (Brugo-Olmed et al., 2001).

Infertility has been recognized as a potentially serious, costly and burdensome problem for affected families (Mohammad & Ardalan, 2009). It is a medical circumstance that not only has health implications for those involved, but also is a condition linked to individual human rights (OMbelet, 2011; Naab, Brown, & Heidrich, 2013). The social stigma of childlessness still leads to isolation and abandonment in many developing countries (Gannon, Glover, & Abel, 2004).

Couples who have no identified cause of infertility should be counseled on timing of intercourse for the most fertile period (i.e., the six days preceding ovulation).42 Urinary luteinizing hormone kits indicate the midcycle luteinizing hormone surge that precedes ovulation by one to two days. These may be purchased over the counter and allow couples to predict the most fertile days in the cycle.6 Accuracy may be improved by use on midday or evening urine specimens, which correlate better with the peak in serum luteinizing hormone levels.43 Other low-cost methods of monitoring for ovulation, although less effective, include basal body temperature measurements and cervical mucus changes.42 However, none of these methods has been proven to increase pregnancy rates when used to predict timing of intercourse. Additionally, there is concern that the stress of a strict schedule for intercourse may lead to reduced frequency of intercourse.44 Therefore, a simple recommendation is for vaginal intercourse every two to three days to optimize the chance of pregnancy.8

Patients should be counseled that 50% of couples who have not conceived in the first year of trying will conceive in the second year.8 Couples with unexplained infertility may want to consider another year of intercourse before moving to more costly and invasive therapies, such as assisted reproductive technology.8 Intrauterine insemination and ovulation induction do not result in increased pregnancy rates in women with unexplained infertility.8,45

مقاله سال 2017

Background: Chlamydia, caused by the bacterium Chlamydia trachomatis(C. trachomatis), is the most common sexually transmitted disease. The incidence is not clear due to the asymptomatic nature of early stage of infections. The incidence of Chlamydia has not been fully investigated in the Chinese Han population. Since chronic infection with can C. trachomatis can lead to infertility in males and females, it is important to determine the impact of infection on clinical outcomes. The aim of this study is to explore the epidemiology of C. trachomatis in subfertile couples and to determine whether infections will adversely affect clinical outcomes after assisted reproduction technique (ART) treatment.

Plain English summary

One of the most common bacterial sexually transmitted disease is Chlamydia, caused by Chlamydia trachomatis (C. trachomatis), the exact incidence of Chlamydia is unknown because the infection is often asymptomatic in the early stage. The incidence of Chlamydia it has not been fully investigated in the Chinese Han population.

Since chronic infection with C. trachomatis can induce infertility in males and females. The aim of the study is to explore the epidemiology of C. trachomatis in subfertile couples and to determine adverse effects on clinical outcomes after assisted reproduction technique (ART) treatments.

A total of 30760 subfertile patients were tested for C. trachomatis in our center from January 2010 to December 2014. C. trachomatis-specific DNA was detected by Taqman PCR. The prevalence and characteristics of C. trachomatis were identified for subfertile couples and clinical outcomes were collected and analyzed. A retrospective study was performed.