Sterility, an Overlooked Health Condition

: Clinically, infertility is deﬁned as the inability to conceive after a certain period. In contrast, sterility is deﬁned as the inability to produce a biological child; however, this is not a practical deﬁnition that can be applied in a clinical setting to a patient’s diagnosis. Unlike infertility, sterility is rarely discussed in biomedical and clinical literature and is often used synonymously with infertility. Infertility a ﬀ ects about 10% of couples globally, but the prevalence of sterility remains unknown. We divide sterility into three subtypes natural, clinical, and hardship. To estimate sterility prevalence, we analyzed primary literature and meta-analysis papers on the rates of live births and pregnancies throughout several treatments of infertile couples (e.g., untreated patients, in vitro fertilization-treated, and patients administered other treatments). This analysis indicates that all treatments fail in delivering a biological child to most couples, suggesting that most infertile couples may fail to conceive. More comprehensive primary studies are needed to provide a precise estimate of sterility. Furthermore, research is needed to study the causes of sterility, as well as develop methods for diagnosis and treatment that are ﬁnancially a ﬀ ordable and emotionally tolerable. Altogether, sterility is an under-discussed condition that is more common than expected, as many infertile couples are unable to conceive and are, in e ﬀ ect, sterile.

The field of reproductive medicine has established protocols that clinicians follow to diagnose, manage, and treat infertile couples that are published by various well-respected societies and organizations [17][18][19][20][21][22][23][24][25][26]. For the couples that seek treatment, the male and female should be seen together by the clinician to make an accurate evaluation. They should be counseled on the definition of infertility, factors that contribute to infertility, as well as principles of infertility care. The clinician can also offer an option to investigate further why the couple is experiencing infertility. This investigation would include male and female workup. Based on the diagnosis, three main types of fertility assistance can be offered, such as medical treatment, surgical treatment, or assisted reproductive technology Women 2020, 1 30 (i.e., in vitro fertilization (IVF) or Intracytoplasmic sperm injection (ICSI)). In general, these documents do not name sterility as a diagnosis. Sterility is only discussed in the context of oocyte donation in ovulation disorders and donor insemination in non-obstructive azoospermia and severe deficits in semen quality.
In this review, we aim to shed light on the gaps in knowledge and the future directions of sterility research. We point out that "sterility" lacks a practical definition, and we define it as the inability to conceive due to natural, clinical, or hardship reasons, which can be applied to both prospective and retrospective determinations of the condition (Section 1). We also emphasize that there is currently no available test to diagnose patients with clinical sterility (i.e., no prospective determination) (Section 2). A reliable analysis of sterility prevalence is unavailable. We estimate it by reviewing papers on live births without treatment (since most couples do not seek treatment), as well as failed live birth rates in patients treated with varicocele repair, intrauterine insemination (IUI), or IVF (i.e., via retrospective determination). When estimating sterility prevalence, we provide a general statement because the estimation is based on small studies, and further investigation is needed to give a specific number (Section 3). We highlight the importance of understanding sterility for patients, physicians, and researchers (Section 4). Finally, we then address other factors such as economic, physical, and psychological burdens that cause patients to discontinue treatment, thereby increasing sterility prevalence (Section 5). We focus on the failure rate of treatment through this discussion, aiming to bring more awareness to sterility and its surprisingly high prevalence. This paper focuses on involuntary sterility and does not include surgical sterility (information about the latter is available [27,28]).

There Is a Need to Diagnose Sterility Prospectively
Sterility and infertility are used interchangeably in many papers, leading to confusion on their distinct meaning [29][30][31][32][33][34][35]. However, few articles have proposed a distinction between the two terms [36][37][38][39][40][41][42]. Most articles define sterility as "the inability to conceive a child." In contrast, infertility is defined as "the inability to produce a live child after one year of attempting to do so" [36][37][38][39]41]. Other sources discuss sterility by using the term "involuntarily childless" [43][44][45][46][47][48][49]. Few definitions further specify that sterility is the inability to have biological children through natural means [40,42]. This specification is a crucial supplement that considers the measurable ability of medical intervention to overcome sterility conditions. As the differences in definitions need better clarity, we propose that there is a need to universally differentiate natural sterility from clinical sterility to highlight the chances of treatment success. Natural sterility is the couple's physiological inability to conceive a child without medical intervention (i.e., "natural means"). Clinical sterility is the couple's physiological inability to conceive a child even after medical intervention, including surgical intervention. Clinical sterility is a subtype of natural sterility, in that clinical sterility is natural sterility for which treatment of the patient will not result in conception. It also appears that a fraction of clinically sterile couples is unable to take advantage of available treatments due to extraneous factors such as economic, psychological, or physical factors. We propose to call this Hardship sterility, a term we coined for this type of sterility ( Figure 1). Both clinical sterility and hardship sterility can be reduced dramatically by developing new and improved reproductive treatments.

Figure 1.
Categories of Sterility include Natural Sterility, Clinical Sterility, and Hardship Sterility. Natural sterility is the couple's physiological inability to conceive a child without medical intervention, an example being someone with no sperm (right), a characteristic is an innate or acquired reproductive defect (bottom), and medical assistance (left) can be used to correct this abnormality. Clinical sterility is the couple's physiological inability to conceive a child even after a medical intervention. An example characteristic of prospective clinical sterility is unable to be determined (blue right), due to the lack of a diagnostic test (bottom), which calls for the creation of diagnostic tests (blue left). An example characteristic of retrospective clinical sterility is a couple that failed nine cycles of in vitro fertilization / Intracytoplasmic sperm injection (IVF/ICSI) (red right). Therapeutic strategies to correct clinical sterility are needed (red left). Hardship sterility, identifies couples who cannot take advantage of available treatments due to economic, psychological, or physical reasons, caused by economic, physical, and psychological factors (right), and its characteristic is unequal access to treatment (bottom). Hardship sterility can be alleviated by devising affordable and tolerable fertility treatments (left). Future research has two challenges associated with diagnosing natural sterility and clinical sterility that need to be addressed. (i) The term sterility is used qualitatively, and a patient is either sterile or fertile. This qualitative usage hinders sterility determination, as a couple could have a low or meager chance of conceiving rather than no chance at all, as the term "sterility" is defined. A much better approach would be to define sterility quantitatively and as part of a hierarchy ranging from fertility to sterility. Indeed, the Ethics Committee of the American Society of Reproductive Medicine (ASRM) coined the term "futility" to describe fertility treatments that have 1% or less chance of achieving a live birth [50]. (ii) Prospectively diagnosing clinical sterility is challenging, while natural sterility can be determined prospectively by routine diagnostic tests and includes a lack of sperm cells or oocytes. This is due to current technology that allows most natural sterility conditions to be treated, facilitating conception in some patients. These conditions include but are not limited to impotence, structural abnormalities in the male or female reproductive tract, endometriosis [51,52], lack of sperm in the ejaculate (azoospermia) [53,54], ovarian failure [55,56], and varicoceles [57,58].
As a first step towards overcoming the challenges associated with handling sterility in the clinic, we propose to extend the fertility hierarchy proposed by the World Health Organization [59]. The extended hierarchy ranges from fertile, infertile, prospectively clinically sterile, and retrospectively clinically sterile, which is derived from the concept of reproductive futility ( Figure 2). According to the World Health Organization, a fertile couple conceives naturally within one year of trying, and an infertile couple fails to conceive naturally within one year of trying. The two extensions are Natural sterility is the couple's physiological inability to conceive a child without medical intervention, an example being someone with no sperm (right), a characteristic is an innate or acquired reproductive defect (bottom), and medical assistance (left) can be used to correct this abnormality. Clinical sterility is the couple's physiological inability to conceive a child even after a medical intervention. An example characteristic of prospective clinical sterility is unable to be determined (blue right), due to the lack of a diagnostic test (bottom), which calls for the creation of diagnostic tests (blue left). An example characteristic of retrospective clinical sterility is a couple that failed nine cycles of in vitro fertilization / Intracytoplasmic sperm injection (IVF/ICSI) (red right). Therapeutic strategies to correct clinical sterility are needed (red left). Hardship sterility, identifies couples who cannot take advantage of available treatments due to economic, psychological, or physical reasons, caused by economic, physical, and psychological factors (right), and its characteristic is unequal access to treatment (bottom). Hardship sterility can be alleviated by devising affordable and tolerable fertility treatments (left). Future research has two challenges associated with diagnosing natural sterility and clinical sterility that need to be addressed. (i) The term sterility is used qualitatively, and a patient is either sterile or fertile. This qualitative usage hinders sterility determination, as a couple could have a low or meager chance of conceiving rather than no chance at all, as the term "sterility" is defined. A much better approach would be to define sterility quantitatively and as part of a hierarchy ranging from fertility to sterility. Indeed, the Ethics Committee of the American Society of Reproductive Medicine (ASRM) coined the term "futility" to describe fertility treatments that have 1% or less chance of achieving a live birth [50]. (ii) Prospectively diagnosing clinical sterility is challenging, while natural sterility can be determined prospectively by routine diagnostic tests and includes a lack of sperm cells or oocytes. This is due to current technology that allows most natural sterility conditions to be treated, facilitating conception in some patients. These conditions include but are not limited to impotence, structural abnormalities in the male or female reproductive tract, endometriosis [51,52], lack of sperm in the ejaculate (azoospermia) [53,54], ovarian failure [55,56], and varicoceles [57,58].
As a first step towards overcoming the challenges associated with handling sterility in the clinic, we propose to extend the fertility hierarchy proposed by the World Health Organization [59]. The extended hierarchy ranges from fertile, infertile, prospectively clinically sterile, and retrospectively clinically sterile, which is derived from the concept of reproductive futility ( Figure 2). According to the World Health Organization, a fertile couple conceives naturally within one year of trying, and an infertile couple fails to conceive naturally within one year of trying. The two extensions are elaborations of the "futility" concept proposed by the Ethics Committee of the American Society of Reproductive Medicine (ASRM) [50]. The first extension adds the definition of a prospectively clinically sterile couple, who has 1% or less chance of achieving a live birth with reproductive medicine assistance. The second extension introduces a retrospectively clinically sterile couple, who have 1% or less chance of achieving a live birth after failing multiple levels (tiers) of reproductive medical assistance. For these definitions to be employed, researchers need to develop diagnostic tests that provide sufficient quantitative information regarding conception chances. It would be essential to have cutoff values that distinguish infertility (a condition that can be treated) from sterility (a condition that most likely will not be treated).
Women 2020, 1, FOR PEER REVIEW 4 elaborations of the "futility" concept proposed by the Ethics Committee of the American Society of Reproductive Medicine (ASRM) [50]. The first extension adds the definition of a prospectively clinically sterile couple, who has 1% or less chance of achieving a live birth with reproductive medicine assistance. The second extension introduces a retrospectively clinically sterile couple, who have 1% or less chance of achieving a live birth after failing multiple levels (tiers) of reproductive medical assistance. For these definitions to be employed, researchers need to develop diagnostic tests that provide sufficient quantitative information regarding conception chances. It would be essential to have cutoff values that distinguish infertility (a condition that can be treated) from sterility (a condition that most likely will not be treated).

Figure 2.
A Fertility Hierarchy ranges from Fertile, Infertile, Prospectively Clinically Sterile, to Retrospectively Clinically Sterile. The fertility hierarchy starts with a fertile couple. If natural conception does not occur within one year of trying, the couple will be identified as an infertile couple. The infertile couple consults with a physician and undergoes a diagnostic test, such as a semen analysis to test for natural sterility. A naturally sterile couple then has the choice of undergoing treatment or not. If they are unable or unwilling to undergo treatment, they are considered to have hardship sterility. A naturally sterile couple that chooses to receive treatment may be identified as prospectively clinically sterile or retrospectively clinically sterile. See more detail in the text.
A second step for overcoming the challenges associated with handling sterility is the development of cutoff values for existing tests and new diagnostic tests for determining sterility prospectively. An example is having cutoff-values for DNA quality that have no realistic chance of producing an offspring [60]. New diagnostic tests may include examining essential sperm structures that currently do not have diagnostic tests, such as the centrioles [61]. Ultimately, it would be useful to develop a comprehensive functional test for sperm that is ethical (not involved in destroying human embryos) and economical. Another approach would be the development of a multiparametric analysis of the sperm [62]. Developing such diagnostic tools would potentially spare many couples the cost and hardship associated with treatment as well as provide couples with more accurate information regarding their chances of conception, which may assist in their decision to undergo treatment [63].
An attempt to determine futility conditions was made by the Ethics Committee of the ASRM. Their suggestions for treatment of futility highlighted challenges associated with determining futility and sterility prospectively [50]. For example, they suggested that it is futile to treat couples with IVF Figure 2. A Fertility Hierarchy ranges from Fertile, Infertile, Prospectively Clinically Sterile, to Retrospectively Clinically Sterile. The fertility hierarchy starts with a fertile couple. If natural conception does not occur within one year of trying, the couple will be identified as an infertile couple. The infertile couple consults with a physician and undergoes a diagnostic test, such as a semen analysis to test for natural sterility. A naturally sterile couple then has the choice of undergoing treatment or not. If they are unable or unwilling to undergo treatment, they are considered to have hardship sterility. A naturally sterile couple that chooses to receive treatment may be identified as prospectively clinically sterile or retrospectively clinically sterile. See more detail in the text.
A second step for overcoming the challenges associated with handling sterility is the development of cutoff values for existing tests and new diagnostic tests for determining sterility prospectively. An example is having cutoff-values for DNA quality that have no realistic chance of producing an offspring [60]. New diagnostic tests may include examining essential sperm structures that currently do not have diagnostic tests, such as the centrioles [61]. Ultimately, it would be useful to develop a comprehensive functional test for sperm that is ethical (not involved in destroying human embryos) and economical. Another approach would be the development of a multi-parametric analysis of the sperm [62]. Developing such diagnostic tools would potentially spare many couples the cost and hardship associated with treatment as well as provide couples with more accurate information regarding their chances of conception, which may assist in their decision to undergo treatment [63]. An attempt to determine futility conditions was made by the Ethics Committee of the ASRM. Their suggestions for treatment of futility highlighted challenges associated with determining futility and sterility prospectively [50]. For example, they suggested that it is futile to treat couples with IVF if a female has an ovarian failure. However, a futility diagnosis seems inappropriate in this case, as multiple studies indicate the success of treatment is as high as 21% under these conditions [55,64,65]. Another example in which futility was determined involved a male partner who lacked viable spermatozoa. A determination of futility is also inappropriate because multiple studies indicate that treatment chances can be as high as 25% and 36% [66][67][68]. Another example involved a couple who underwent numerous IVF cycles without adequate egg production, fertilization, or embryo development. This example represents a retrospective determination of futility, as prospectively, the chances of success appear to be more than 1% and are around 4-5% [69]. As shown, none of these scenarios included a 1% or less chance of achieving a live birth, and therefore cannot be considered to determine futility.

Most Treatments of Infertile Couples Fail to Deliver a Live Birth
One of the main challenges in studying sterility is a lack of reliable sources for the prevalence of sterility among infertile couples. One small cross-sectional study which consisted of 116 people found that~4% of all couples remain involuntarily childless [70]. Multiple studies examine women who are involuntarily childless and suggest that, on average, 3.9% of females are sterile [37,[43][44][45][46][47][48][49] (Table 1). In contrast, the prevalence of male sterility is rarely provided, although the general prevalence of male childlessness is high (12-40%) [71,72]. From these prevalence rates, it is impossible to estimate involuntarily childlessness in infertile couples accurately, but it appears to be higher than 4%. We assessed sterility by combining information on live birth rates and pregnancies in infertile couples. Infertile couples can be divided into two main groups based on the treatment they receive: (i) Not treated; this is the largest group, comprising 64-78% of infertile couples [73] and (ii) Treated by IUI, varicocele repair, or IVF/ICSI.

Untreated Infertile Couples
The proportion of infertile couples that do not receive clinical treatments is surprisingly high. A meta-analysis of four studies that included a total of 1846 patients in developed countries (e.g., the United Kingdom, France, and the United States) determined that only 22.4% of infertile couples received treatment for infertility [73]. According to a more recent study of the National Survey of Family Growth in the United States, only 36% of infertile couples ages 25-44 used infertility services during 2006 to 2010 [74]. These data suggest that most infertile couples (64%) are untreated for infertility.

Treated Infertile Couples
Here, we discuss several fertility treatments: varicocele surgery, IUI, and ICSI. Varicocele surgery is a common treatment provided to one-third of male infertility cases [86]. An older meta-analysis paper that included seven studies totaling 281 couples between 1979 and 2001 estimated that 78% of infertile couples treated with varicocele repair were unable to produce a live birth [87]. Seven other papers analyzed 594 couples between the years 1998 and 2019 [88][89][90][91][92][93][94] (Table 2). In all studies, most infertile couples failed to deliver a biological child (78%, 67%, 81%, 50%, 90%, 79%, and 75%) with a weighted average of 69%. All of these studies reported pregnancies, and therefore, the actual prevalence of sterility in this group is likely to be higher. Some factors contributing to unsuccessful pregnancies after varicocele repair included lower sperm count and longer infertility duration before surgery and immotile sperm after surgery.
IUI is a well-known infertility treatment that should be administered before IVF in most protocols [95,96]. The National Survey of Family Growth reported that 7.4% of infertile couples aged 25-44 underwent IUI in 2006-2010 [74]. Between the years 1993 and 2016, eight papers estimated the rate of live births among 15,172 couples who underwent IUI treatment [82,83,[97][98][99][100][101] (Table 3). In all these studies, most infertile couples failed to deliver a biological child (66%, 79%, 79%, 62%, 81%, 78%, 90%, and 69%) with a weighted average of 69%. Similar factors that prevented untreated infertile couples from spontaneously conceiving contributed to unsuccessful live births in IUI treated couples. These factors also included unexplained infertility, endometriosis, and cervical, tubal, ovulatory, or seminal defects. These studies from different locations summarize how many live births and pregnancies were achieved through these treatments. 1  The National Survey of Family Growth reported that 3.1% of women aged 25-44 utilized ART, making it the lowest used infertility service [74]. The Society for Assisted Reproductive Technology report for 2017 states that a total of 72,253 new and 45,472 continuing female patients underwent IVF with their own oocytes. This is equal to 0.07% and 0.12% of 60,800,000 married couples in the USA in 2017. Assuming an infertility rate of 12-15.5% in the USA, this is calculated to 0.84-1.09% and 1.44-1.86% of infertile patients utilizing IVF in 2017 [74,102]. In total, 3.1% or less of infertile women undergo IVF.
Five high-quality studies traced the cumulative live birth rate success over many IVF cycles with large cohorts of patients [69,[103][104][105][106]. These studies were conducted in the United States, the United Kingdom, Australia, and New Zealand over two decades  and each study involved 56,652 to 178,898 females. Two of these studies (Smith et al., 2015 andStern et al., 2008) included women who used donor oocytes. The use of donor oocytes increases the chance of success in some cases but does not always result in a biological child [107]. Therefore, we have excluded pregnancies resulting from donor oocytes from our analysis. In four of these studies [103][104][105][106], the statistics used to calculate the cumulative live birth rate were split into optimistic or conservative estimations. The conservative calculation assumed that women who stopped receiving treatment would not have any live births, which aligns with the clinic's results. The optimistic calculation assumed that women who stopped receiving treatment would have the same chance of conceiving as those who continued. While the optimistic calculation demonstrates the potential of ICSI to produce live births in an ideal scenario, it is not realistic when considering real-life conditions (see discussion below on hardship sterility); therefore, we used the conservative estimates here. Based on all conservative estimates and excluding donor oocyte treatment, sterility prevalence percentages are 67%, 56%, 49%, 49%, 46%, and 47% in the ICSI group (Figure 3). Women 2020, 1, FOR PEER REVIEW 8 Figure 3. ICSI failed to result in a live birth in more than 47% treated infertile couples. The information found in the literature on sterility did not allow us to determine a precise prevalence rate. However, based on the literature reviewed above and assuming that the infertile couples in these studies did not receive additional treatments, we estimate that many, if not most, infertile couples are sterile (Figure 4).
We considered the following five points: (1) 10% of couples are infertile couples, and more than 4% are involuntarily childless or sterile; (2) At the least, 64% of infertile couples are not treated, and 70% of them fail to have a live birth; (3) 7.4% of infertile couples undergo IUI, and 69% of them fail to have a live birth; (4) ~33% of infertile men undergo varicocele treatment, and 69% of them fail to have a live birth; (5) ~3.1% of infertile women undergo ICSI, and 47% of them fail to have a live birth. The information found in the literature on sterility did not allow us to determine a precise prevalence rate. However, based on the literature reviewed above and assuming that the infertile couples in these studies did not receive additional treatments, we estimate that many, if not most, infertile couples are sterile (Figure 4).
We considered the following five points: (1) 10% of couples are infertile couples, and more than 4% are involuntarily childless or sterile; (2) At the least, 64% of infertile couples are not treated, and 70% of them fail to have a live birth; (3) 7.4% of infertile couples undergo IUI, and 69% of them fail to have a live birth; (4)~33% of infertile men undergo varicocele treatment, and 69% of them fail to have a live birth; (5)~3.1% of infertile women undergo ICSI, and 47% of them fail to have a live birth.
Based on this information, we consider the sterility rate to be within a range. The lowest sterility prevalence rate limit is 40% of infertile couples (Point 1 above). The highest limit was calculated by a weighted average of points 2-5 above and results in 76% of infertile couples being sterile. More research is needed for a precise estimate.
(1) 10% of couples are infertile couples, and more than 4% are involuntarily childless or sterile; (2) At the least, 64% of infertile couples are not treated, and 70% of them fail to have a live birth; (3) 7.4% of infertile couples undergo IUI, and 69% of them fail to have a live birth; (4) ~33% of infertile men undergo varicocele treatment, and 69% of them fail to have a live birth; (5) ~3.1% of infertile women undergo ICSI, and 47% of them fail to have a live birth.

Understanding Sterility Will Benefit the Patient, Physician, and Researchers
An understanding of sterility will benefit the patient, physician, and researchers. Patients will benefit from knowing their condition regarding sterility in two main ways. Firstly, understanding the prevalence of sterility will enable couples to make better-informed decisions when seeking treatment after being diagnosed with infertility. Secondly, a full understanding of a sterility diagnosis can save couples time and money and spare them from invasive treatments and unnecessary frustration. They may also be encouraged to seek non-biological children using donor oocytes, donor sperm, surrogacy, or adoption.
Physicians treating patients will benefit from understanding sterility and its prevalence in two main ways. Firstly, it will help the physician to remain ethical. According to the Ethics Committee of the American Society of Reproductive Medicine, it is unethical to continue treatments if patients are not fully educated about the probability of a successful birth [50]. With proper education, however, it remains the choice of the patient to continue treatment or not. Secondly, this understanding will contribute to physician credibility, as it will enable them to make the most accurate treatment recommendation aimed at achieving the most successful fertility outcome.
Researchers will benefit from a greater understanding of sterility and its prevalence. Firstly, the surprisingly high prevalence of sterility will encourage more in-depth research on the cause of clinical sterility where treatment is unavailable. Secondly, this research could lead to the determination of official cut of values for clinical sterility to existing diagnostic tests (which currently only few specific sperm properties) and the development of comprehensive functional and multiparametric diagnostic tools, as well as the eventual development of therapeutics.
Ultimately, these positive outcomes will benefit treatment-seeking patients, as they will lead to personalized treatment plans specifically tailored to their situation.

Economic, Physical, and Psychological Burdens Contribute to Hardship Sterility
Economic, physical, and psychological burdens contribute to reduced fertility. It was estimated that 2.5% of women in the USA were childless because of poverty and 8.1% because of high cost of childrearing [108]. Consequentially, not all infertile patients seek fertility treatments due to the associated high costs and the physical and psychological burdens, resulting in hardship sterility. In the United States, the average cost for IVF treatment in 2001 was $9226 per IVF cycle and $56,419 for a live birth [109]. In 2006, the average cost of one IVF cycle was $12,513, while the cost of live birth was $41,132 [110]. In 2011, the average cost of IVF resulting in a live birth was $61,377 [111]. It is reasonable, then, that the cost of IVF treatment plays a major role in couples' decisions to discontinue treatment [112].
A systematic analysis that reviewed 22 studies with 21,453 patients from 8 different countries found that 15.32% of patients decided not to continue treatment during the diagnostic phase because of the cost, while 9.19% overall discontinued due to financial reasons [112]. Additional major reasons reported by patients for discontinuing fertility treatments included treatment postponement (39.18%), relational and personal problems (16.67%), and the psychological (14%) and physical (6.32%) health of the female partner or couple [112].
Another study surveyed patients who possessed insurance coverage for three IVF cycles but still discontinued treatment. Of the 47 patients that responded, 39% blamed stress as the reason for dropping out of treatment [113]. This indicates that the psychological turmoil associated with fertility treatments caused some couples to choose to discontinue treatment, thereby contributing to sterility prevalence. This also suggests that improving the efficiency of treatments may encourage more couples to continue treatments, thereby reducing the rate of hardship sterility.
The most optimistic scenario in the ICSI cumulative live birth rate studies showed that only 10.6% of couples were left without a child after undergoing nine fertility treatments ( Figure 5). This indicates that if couples can endure nine treatments, their chances of having a child increase significantly, demonstrating the potential of ICSI. It is possible to significantly decrease the sterility rate if the efficiency of fertility treatments is improved [104]. For example, the use of a surrogate improves the chance of having a live birth, but surrogacy is a costly option that is not widely used [114]. Since onlỹ 3.1% of infertile people undergo ICSI, and 78% do not seek treatment, the real potential of having a child with ICSI is unclear.
Women 2020, 1, FOR PEER REVIEW 10 prevalence. This also suggests that improving the efficiency of treatments may encourage more couples to continue treatments, thereby reducing the rate of hardship sterility. The most optimistic scenario in the ICSI cumulative live birth rate studies showed that only 10.6% of couples were left without a child after undergoing nine fertility treatments ( Figure 5). This indicates that if couples can endure nine treatments, their chances of having a child increase significantly, demonstrating the potential of ICSI. It is possible to significantly decrease the sterility rate if the efficiency of fertility treatments is improved [104]. For example, the use of a surrogate improves the chance of having a live birth, but surrogacy is a costly option that is not widely used [114]. Since only ~3.1% of infertile people undergo ICSI, and 78% do not seek treatment, the real potential of having a child with ICSI is unclear. used a calculation that excluded women who used donor oocytes, but was split by age category, so the results for women below the age of 40 were used. Stern et al. (2008) did not calculate an optimal estimate, so it was not included. Our calculation included women of all ages, with a mean age of 33-35 years old. Using the optimal estimate's best-case scenario, 10.6% of women will be left without a child after treatment. References: [103][104][105][106].

Discussion
Based on the above information, it is likely that the prevalence of sterility is significantly high, and about 40-76% of infertile couples are sterile. In this study, we highlight the need to investigate this thoroughly and conclusively in the future. Although there is a major difference between sterility and infertility, much remains unknown about sterility due to a lack of clinical literature on the topic. used a calculation that excluded women who used donor oocytes, but was split by age category, so the results for women below the age of 40 were used. Stern et al. (2008) did not calculate an optimal estimate, so it was not included. Our calculation included women of all ages, with a mean age of 33-35 years old. Using the optimal estimate's best-case scenario, 10.6% of women will be left without a child after treatment. References: [103][104][105][106].

Discussion
Based on the above information, it is likely that the prevalence of sterility is significantly high, and about 40-76% of infertile couples are sterile. In this study, we highlight the need to investigate this thoroughly and conclusively in the future. Although there is a major difference between sterility and infertility, much remains unknown about sterility due to a lack of clinical literature on the topic. The reason for this lack of literature on female and male sterility is unclear; perhaps the topic is not commonly discussed due to the stigma associated with the term. For example, patients, whether female or male, might be more distressed with a diagnosis of sterility than with one of infertility. On the same note, it may be that a diagnosis of sterility may exacerbate psychological problems and lead to other social issues for some patients.
Due to the lack of information available on sterility, no prospectively functional definition exists. Although many fertility experts intuitively differentiate between natural sterility and clinical sterility, there is currently no official recognition of the differences between them. Another important deficiency is the absence of official cutoff values to diagnose sterility and a more comprehensive test to predict sterility confidently. Possible routes to accomplish this are to develop multi-quantitative parametric tests that use many aspects of reproductive biology and provide an estimate the chance to conceive with current treatment or to develop a comprehensive functional test.
Additionally, the invasive and expensive nature of IVF/ICSI treatment causes many patients to discontinue treatment, which further contributes to sterility prevalence. It is important to include in the discussion that reproductive treatment is affected by extraneous factors such as finance. Therefore, it is important to intensify discussions on sterility and sterility prevalence as well as to direct research toward the development of clinical sterility diagnostic tools.

Acknowledgments:
We would like to thank Nahshon Puente for his assistance in preparing the manuscript and to the University of Toledo Medical Student Research Program for granting the supporting R.R. to conduct this research.

Conflicts of Interest:
The authors declare no conflict of interest.

Clinical Sterility
The physiological inability of a couple to conceive a child even after medical intervention, including surgical intervention.

Clinically Sterile Couple
A couple with 1% or less chance of achieving a live birth with reproductive medicine assistance.

Cumulative Live Birth Rate
A couple's chance to have a live birth after cumulative cycles of fertility treatment.

Fertile Couple
A couple that conceives naturally within one year of trying.

Hardship Sterility
The physiological inability of a couple to conceive a child even after medical intervention because of economic, psychological, or physical reasons.

ICSI
Intracytoplasmic sperm injection; a fertility procedure in which sperm is injected into an egg.

Infertility
A difficulty to conceive that is defined in most cases as the inability to conceive a biological child after one year of attempting.

IUI
Intrauterine insemination; a fertility procedure in which sperm is placed inside a female's uterus.

IVF
In-vitro fertilization; a fertility treatment that combines the egg and sperm outside the body, and then the embryo is transferred into the uterus.

Natural Sterility
The physiological inability of a couple to conceive a child without medical intervention (i.e., "natural means").

Prospective Determination
The ability to diagnose a patient with clinical sterility before beginning treatment.

Reproductively Futile Couple
A couple with 1% or less chance of achieving a live birth with reproductive medicine assistance.

Retrospective Determination
The ability to diagnose a patient with clinical sterility after treatments have failed.

Retrospectively Clinically Sterile Couple
A couple with 1% or less chance of achieving a live birth after failing multiple treatments of reproductive medical assistance.
Prospectively Clinically Sterile Couple A couple with 1% or less chance of achieving a live birth with reproductive medicine assistance.

Sterility
The inability to conceive due to natural, clinical, or hardship factors, determined either prospectively or retrospectively.

Varicocele Repair
Repair of the enlarged veins within the scrotum