Frequency, morbidity and equity - the case for increased research on male fertility.

Currently, most men with infertility cannot be given an aetiology, which reflects a lack of knowledge around gamete production and how it is affected by genetics and the environment. A failure to recognize the burden of male infertility and its potential as a biomarker for systemic illness exists. The absence of such knowledge results in patients generally being treated as a uniform group, for whom the strategy is to bypass the causality using medically assisted reproduction (MAR) techniques. In doing so, opportunities to prevent co-morbidity are missed and the burden of MAR is shifted to the woman. To advance understanding of men's reproductive health, longitudinal and multi-national centres for data and sample collection are essential. Such programmes must enable an integrated view of the consequences of genetics, epigenetics and environmental factors on fertility and offspring health. Definition and possible amelioration of the consequences of MAR for conceived children are needed. Inherent in this statement is the necessity to promote fertility restoration and/or use the least invasive MAR strategy available. To achieve this aim, protocols must be rigorously tested and the move towards personalized medicine encouraged. Equally, education of the public, governments and clinicians on the frequency and consequences of infertility is needed. Health options, including male contraceptives, must be expanded, and the opportunities encompassed in such investment understood. The pressing questions related to male reproductive health, spanning the spectrum of andrology are identified in the Expert Recommendation.

Global, regional and national burden of male infertility in 204 countries and territories between 1990 and 2019: an analysis of global burden of disease study.

BACKGROUND: Many countries and regions have experienced male fertility problems due to various influencing factors, especially in less developed countries. Unlike female infertility, male infertility receives insufficient attention. Understanding the changing patterns of male infertility in the world, different regions and different countries is crucial for assessing the global male fertility and reproductive health. METHODS: We obtained data on prevalence, years of life lived with disability (YLD), age-standardized rates of prevalence (ASPR) and age-standardized YLD rate (ASYR) from the Global Burden of Disease Study 2019. We analyzed the burden of male infertility at all levels, including global, regional, national, age stratification and Socio-demographic Index (SDI). RESULTS: In 2019, the global prevalence of male infertility was estimated to be 56,530.4 thousand (95% UI: 31,861.5-90,211.7), reflecting a substantial 76.9% increase since 1990. Furthermore, the global ASPR stood at 1,402.98 (95% UI: 792.24-2,242.45) per 100,000 population in 2019, representing a 19% increase compared to 1990. The regions with the highest ASPR and ASYR for male infertility in 2019 were Western Sub-Saharan Africa, Eastern Europe, and East Asia. Notably, the prevalence and YLD related to male infertility peaked in the 30-34 year age group worldwide. Additionally, the burden of male infertility in the High-middle SDI and Middle SDI regions exceeded the global average in terms of both ASPR and ASYR. CONCLUSION: The global burden of male infertility has exhibited a steady increase from 1990 to 2019, as evidenced by the rising trends in ASPR and ASYR, particularly in the High-middle and Middle SDI regions. Notably, the burden of male infertility in these regions far exceeds the global average. Additionally, since 2010, there has been a notable upward trend in the burden of male infertility in Low and Middle-low SDI regions. Given these findings, it is imperative to prioritize efforts aimed at improving male fertility and reproductive health.

Characterizing the Epidemiology and Provider Landscape of Male Infertility Care in the United States.

OBJECTIVE: To characterize the epidemiology of male factor infertility and identify which types of providers are treating infertile men in the United States. MATERIALS AND METHODS: The National Ambulatory Medical Care Survey was queried between 2006 and 2016 for all ambulatory care visits. Men with a diagnosis of infertility were identified by international classification of disease coding. Comorbidities, demographic and visit information were abstracted from the patients' medical record by a combination of trained surveyors and physicians. The survey data was weighted to create nationally representative estimates, and a combination of Chi-squared and Student's t-tests were utilized to determine significance. RESULT(S): Among the 8.7 billion patient visits between 2006 and 2016, there were 3,422,000 male encounters with a diagnosis of male factor infertility. The most common provider type for male factor infertility encounters was urology (42.12%) followed by primary care (39.79%), gynecology (7.05%) and all other provider types (11.01%). A significant number of men seen for infertility had comorbidities such as cancer (115,000 men, 3.36%) diabetes (267,000 men, 7.81%), depression (301,000 men, 8.8%), and active tobacco use (857,000 men, 30.3%). CONCLUSION: In a nationally representative sample, more than 50% of ambulatory care visits for male factor infertility were not seen by urologists. These men also had a significant number of comorbidities for a relatively young cohort, emphasizing the importance of multidisciplinary care for men with a diagnosis of infertility.

Access to infertility services: characterizing potentially infertile men in the United States with the use of the National Survey for Family Growth.

OBJECTIVE: To characterize the population of subfertile and infertile men in the United States who lack access to infertility services. DESIGN: Analysis of the 2011-2013, 2013-2015, and 2015-2017 waves of the National Survey for Family Growth (NSFG) dataset. SETTING: Not applicable. PATIENT(S): Noninstitutionalized civilian men, ages 15-45 years, who were married or lived with a woman and had not undergone a vasectomy. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE(S): Access to infertility services. RESULT(S): Compared with people who had used infertility services, unevaluated men who self-reported as infertile or subfertile were younger, had lower household incomes, were less educated, and were less likely to be married. Unevaluated infertile men were less likely to have a regular place where they received health care, were more likely to be uninsured, and had a poorer perception of their personal health. On multivariable logistic regression analysis, average household income, marital status, education level, and current insurance status remained significant. CONCLUSION(S): Infertile men who had not used infertility services were less educated, were less likely to have been married, and had a lower household income and private insurance rate compared with men who had used infertility services. These demographic and health care utilization differences can help inform public policy related to fertility.

Care Delivery for Male Infertility: The Present and Future.

Although infertility is now recognized as a disease by multiple organizations including the World Health Organization and the American Medical Association, private insurance companies rarely include coverage for infertility treatments. In this review, the authors assess the current state of care delivery for male infertility care in the United States. They discuss the scope of male infertility as well as the unique burdens it places on patients and review emerging market forces that could affect the future of care delivery for male infertility.

Evaluation, Treatment, and Insurance Coverage for Couples With Male Factor Infertility in the US: A Cross-Sectional Analysis of Survey Data.

OBJECTIVE: To characterize the evaluation, treatment, and insurance coverage among couples with male factor infertility in the United States. MATERIALS AND METHODS: A cohort of 969 couples undergoing fertility treatment with a diagnosis of male factor infertility were identified from an online survey. The proportion of men that were seen/not seen by a male were compared. Insurance coverage related to male factor was also assessed. RESULTS: Overall, 98.0% of the men reported at least one abnormal semen parameter. Of these, 72.0% were referred to a male fertility specialist with the majority being referred by the gynecologist of their female partner. As part of the male evaluation, 72.2% had blood hormone testing. Of the 248 men who were not recommended to see a male fertility specialist, 96.0% had an abnormal semen analysis including 7.6% who had azoospermia. Referral to a male fertility specialist was largely driven by severity of male factor infertility rather than socioeconomic status. Insurance coverage related to male factor infertility was poor with low coverage for sperm extractions (72.9% reported 0-25% coverage) and sperm freezing (83.7% reported 0-25% coverage). CONCLUSION: Although this cohort includes couples with abnormal semen parameters, 28% of the men were not evaluated by a male fertility specialist. In addition, insurance coverage for services related to male factor was low. These findings may be of concern as insufficient evaluation and coverage of the infertile man could lead to missed opportunities for identifying reversible causes of infertility/medical comorbidities and places an unfair burden on the female partner.

Genetic investigations on causes of male infertility in Western Saudi Arabia.

In recent years, genetic studies have yielded great progress in elucidating causes of male infertility. This investigation aims to identify frequent genetic abnormalities, that is, sex chromosome aneuploidies and Y-chromosome microdeletions among infertile men in Western Saudi Arabia. From a population of infertile patients, 88 male patients with either azoospermia or severe oligozoospermia (sperm concentration <5 million/ml) were selected. In addition to a thorough clinical workup, karyotypes and Y-chromosomal microdeletions were investigated. Among those 88 infertile patients, we detected six patients with Klinefelter syndrome, two with 47 XYY syndrome and two with Y-chromosome microdeletions AZFb,c. While the prevalence of sex chromosome aneuploidies was in the range of globally investigated populations, the microdeletions appeared to be less frequent in Western Saudi Arabia compared to other regions of the world. All genetically abnormal cases showed sperm concentration <1 million/ml, and hence, this appears to be the threshold for warranting genetic investigations in Western Saudi Arabia. Since Klinefelter and 47 XYY syndromes were only discovered late in life, upon an infertility investigation, sex chromosome aneuploidies due to their many-fold comorbidities require earlier medical attention. A neonatal screening programme is suggested for detection of these aneuploidies in Saudi Arabia for the general health benefit of these patients.

Routine assessment of occupational exposure and its relation to semen quality in infertile men: a cross-sectional study.

BACKGROUND/AIM: Concerns about the detrimental effects of occupational and environmental exposure on male reproductive function have been raised by reports of declining sperm quality over the last decades. The aim of this study was to investigate the association between altered semen parameters and exposure to occupational risk factors as assessed by questionnaire. MATERIALS AND METHODS: We conducted a cross-sectional questionnaire-based study among a population of 2122 men who underwent andrological investigation for couple infertility. All participants were interviewed and their semen samples were analyzed. Information about medical history and occupational exposure was used to classify participants into exposed and unexposed groups. RESULTS: Exposure to pesticides was associated with a significantly higher risk of asthenozoospermia (adjusted odds ratio [OR] = 1.6; 95% CI, 1.0-2.4) and necrozoospermia (OR = 2.6; 95% CI, 1.4-4.7). Exposure to cement was found to be correlated with a higher risk of oligozoospermia (OR = 1.1; 95% CI, 0.9-1.4). There was no association between semen impairment and exposure to solvents, excess heat, or mechanical vibrations. CONCLUSION: We found an association between self-reported occupational exposure and altered semen parameters. These results support the usefulness of questionnaires for routine assessment and management of occupational exposures in infertile men.

Obstetrics and Gynecology Residency and Fertility Needs.

Infertility is a common reproductive disease, with a prevalence of 9% to 18% of the general population. To date, no studies have attempted to examine the prevalence and experience of infertility among resident physicians in the United States. In female obstetrics and gynecology (Ob/Gyn) residents of age where infertility becomes more prevalent, ability to seek fertility may be influenced by rigorous professional demands and low remuneration. We seek to understand the prevalence of infertility, as well as experience and utilization of infertility services among Ob/Gyn residents. Cross-sectional descriptive survey was distributed among US Accreditation Council for Graduate Medical Education-accredited Ob/Gyn programs. Demographics, intentions to conceive during residency, fertility problems, fertility treatment, affordability of care, and perceptions of support were surveyed. A total of 241 responses were received in an equal distribution between junior (n = 120) and senior (n = 121) residents. The majority of respondents were female (91%), 25 to 35 years old (94%), and married (54%). Eighty-five percent (195 of 230) did not actively pursue fertility during residency. Twenty-nine percent (68 of 235) considered fertility preservation, but only 2% sought consultation. Twenty-nine percent of those interested in fertility (22 of 75) experienced infertility of some degree. Sixty-three percent felt low or no support from the program. Thirty-five percent reported stigma associated with their infertility. In conclusion, infertility is a prevalent reproductive health impairment among Ob/Gyn residents. The majority of residents defer childbearing during residency despite advancing reproductive age. A majority felt little or no support from training programs in addressing their fertility care. Further studies are indicated to understand the barriers and impact among resident trainees.

Inequity between male and female coverage in state infertility laws.

OBJECTIVE: To analyze state insurance laws mandating coverage for male factor infertility and identify possible inequities between male and female coverage in state insurance laws. DESIGN: We identified states with laws or codes related to infertility insurance coverage using the National Conference of States Legislatures' and the National Infertility Association's websites. We performed a primary, systematic analysis of the laws or codes to specifically identify coverage for male factor infertility services. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The presence or absence of language in state insurance laws mandating coverage for male factor infertility care. RESULT(S): There are 15 states with laws mandating insurance coverage for female factor infertility. Only eight of those states (California, Connecticut, Massachusetts, Montana, New Jersey, New York, Ohio, and West Virginia) have mandates for male factor infertility evaluation or treatment. Insurance coverage for male factor infertility is most specific in Massachusetts, New Jersey, and New York, yet significant differences exist in the male factor policies in all eight states. Three states (Massachusetts, New Jersey, and New York) exempt coverage for vasectomy reversal. CONCLUSION(S): Despite national recommendations that male and female partners begin infertility evaluations together, only 8 of 15 states with laws mandating infertility coverage include coverage for the male partner. Excluding men from infertility coverage places an undue burden on female partners and risks missing opportunities to diagnose serious male health conditions, correct reversible causes of infertility, and provide cost-effective treatments that can downgrade the intensity of intervention required to achieve a pregnancy.

Increased risk of incident chronic medical conditions in infertile men: analysis of United States claims data.

OBJECTIVE: To determine the incidence of chronic medical conditions of men with infertility. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Subjects contained within the Truven Health MarketScan claims database from 2001 to 2009. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The development of chronic medical conditions including hypertension, diabetes, hyperlipidemia, renal disease, pulmonary disease, liver disease, depression, peripheral vascular disease, cerebrovascular disease, heart disease, injury, alcohol abuse, drug abuse, anxiety disorders, and bipolar disorder. RESULT(S): In all, 13,027 men diagnosed with male factor infertility were identified with an additional 23,860 receiving only fertility testing. The average age was 33.1 years for men diagnosed with infertility and 32.8 years for men receiving testing alone. After adjusting for confounding factors, men diagnosed with male factor infertility had a higher risk of developing diabetes (hazard ratio [HR] 1.30, 95% confidence interval [CI] 1.10-1.53), ischemic heart disease (HR 1.48, 95% CI 1.19-1.84), alcohol abuse (HR 1.48, 95% CI 1.07-2.05), and drug abuse (1.67, 95% CI 1.06-2.63) compared with men who only received infertility testing. Similar patterns were identified when comparing those with male factor infertility to vasectomized men. The association between male factor infertility and later health outcomes were strongest for men with longer follow-up. CONCLUSION(S): In this cohort of patients in a national insurance database, men diagnosed with male factor infertility had a significantly higher risk of adverse health outcomes in the years after an infertility evaluation. These findings suggest the overall importance of men's reproductive health and warrant additional investigation to understand the association and identify interventions to improve outcomes for these patients.

Male reproductive disorders, diseases, and costs of exposure to endocrine-disrupting chemicals in the European Union.

INTRODUCTION: Increasing evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to male reproductive diseases and disorders. PURPOSE: To estimate the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific EDC exposures in the European Union (EU). METHODS: An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. The cost-of-illness estimation utilized multiple peer-reviewed sources. RESULTS: The expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618,000 additional assisted reproductive technology procedures, costing €4.71 billion annually. Low epidemiological and strong toxicological evidence was also identified for cryptorchidism due to prenatal polybrominated diphenyl ether exposure, resulting in a 40-69% probability that 4615 cases result, at a cost of €130 million (sensitivity analysis, €117-130 million). A much more modest (0-19%) probability of causation in testicular cancer by polybrominated diphenyl ethers was identified due to very low epidemiological and weak toxicological evidence, with 6830 potential cases annually and costs of €848 million annually (sensitivity analysis, €313-848 million). The panel assigned 40-69% probability of lower T concentrations in 55- to 64-year-old men due to phthalate exposure, with 24 800 associated deaths annually and lost economic productivity of €7.96 billion. CONCLUSIONS: EDCs may contribute substantially to male reproductive disorders and diseases, with nearly €15 billion annual associated costs in the EU. These estimates represent only a few EDCs for which there were sufficient epidemiological studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs.

Demographic and socio-economic differences between men seeking infertility evaluation and those seeking surgical sterilization: from the National Survey of Family Growth.

OBJECTIVE: To identify differences in demographic and socio-economic factors between men seeking infertility evaluation and those undergoing vasectomy, to address disparities in access to these services. PATIENTS AND METHODS: Data from Cycle 6 and Cycle 7 (2002 and 2006-2008) of the National Survey of Family Growth (NSFG) were reviewed. The NSFG is a multistage probability survey designed to capture a nationally representative sample of households with men and women aged 15-45 years in the USA. The variables analysed included age, body mass index, self-reported health, alcohol use, race, religious affiliation, marital status, number of offspring, educational attainment, income level, insurance status and metropolitan home designation. Our primary outcome was the correlation of these demographic and socio-economic factors with evaluation for male infertility or vasectomy. RESULTS: Of the 11 067 men identified through the NSFG, 466 men (4.2%) sought infertility evaluation, representing 2 187 455 men nationally, and 326 (2.9%) underwent a vasectomy, representing 1 510 386 men nationally. Those seeking infertility evaluation were more likely to be younger and have fewer children (P = 0.001, 0.001) and less likely to be currently married (78 vs 74%; P = 0.010) or ever married (89 vs 97%; P = 0.002). Men undergoing a vasectomy were more likely to be white (86 vs 70%; P = 0.001). Men seeking infertility evaluation were more likely to have a college or graduate degree compared with men undergoing a vasectomy (68 vs 64%; P = 0.015). There was no difference between the two groups for all other variables. CONCLUSION: While differences in demographic characteristics such as age, offspring number and marital status were identified, measures of health, socio-economic status, religion and insurance were similar between men undergoing vasectomy and those seeking infertility services. These factors help characterize the utilization of male reproductive health services in the USA and may help address disparities in access to these services and improve public health strategies.

Status of sperm morphology assessment: an evaluation of methodology and clinical value.

OBJECTIVE: To characterize methodological changes in sperm morphology assessment and to correlate sperm morphology with clinical outcome. DESIGN: In this observational study, sperm morphology profiles of patients were analyzed. The percentages of morphologically normal spermatozoa were evaluated with respect to changes in morphology assessment criteria; male aging; and prognostic value for outcomes after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). SETTING: Diagnostic and clinical laboratories. PATIENT(S): A total of 8,846 men who visited the diagnostic laboratory; 133 samples from a sperm bank; and 3,676 IVF/ICSI couples. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The percentage of morphologically normal spermatozoa in semen samples. The regression of the individual morphologically normal cell profiles. The relation between the percentage of normal forms with pregnancy outcome after IVF/ICSI. RESULT(S): The percentage of morphologically normal spermatozoa showed a decrease from roughly 30%-80% in 1984 to 0%-10% since 2004. With added evidence from sperm bank samples, this decrease was found to be attributable mainly to changes in morphology assessment criteria. Furthermore, an intraindividual aging effect of 0.51% per year was observed. A statistically significant relationship was found between decreases in percentage of normal forms and a lower probability of ongoing pregnancies after IVF, although the area under the curve was only 54%. CONCLUSION(S): Methodological changes had a strong effect on the percentage of morphologically normal spermatozoa over the past few decades. In addition, male aging results in decreasing sperm morphology. The percentage of morphologically normal spermatozoa has no prognostic value for individual IVF/ICSI patients.

Analysis of semen parameters in male referrals: impact of reference limits, stratification by fertility categories, predictors of change, and comparison of normal semen parameters in subfertile couples.

OBJECTIVE: To [1] determine the impact of semen reference limits on referrals for male fertility evaluations, [2] analyze the stratification of subjects based on published "normal" thresholds, [3] analyze the odds of changing fertility categories during serial tests and thereby the potential impact of inherent variability of semen parameters on referrals, and [4] determine variable(s) predictive of change. DESIGN: Retrospective chart review. SETTING: Academic referral center for male fertility. PATIENT(S): New encounters in a male fertility clinic over a 5-year period that straddles the publication of World Health Organization (WHO) 2010 reference values. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Demographic and clinical variables, semen values, and fertility categories as follows: BE (below WHO 2010 criteria), BTWN (above WHO 2010 but below WHO 1999 criteria), and N (above WHO 1999 criteria). RESULT(S): A total of 82.3% of initial semen tests were categorized as BE, and the predominance of this category was unchanged by publication of the WHO 2010 criteria. Men with initial semen analysis categorized as BTWN or N represented 16.2% and 1.5% of the referral population, respectively. Subjects initially categorized as BTWN were more likely to change fertility categories, and overwhelmingly this migration was downward. Analysis of normal individual semen parameters revealed statistically worse mean concentration and motility when at least one other parameter fell below the WHO 2010 criteria. CONCLUSION(S): Men with semen results above reference criteria are underrepresented, indicating that reference limits influence referral patterns for male fertility evaluations. Normal mean concentration and motility were lower in men with at least one other individual semen parameter below the 2010 criteria, suggesting global dysfunction in spermatogenesis.

Evaluation of exposure to trihalomethanes in tap water and semen quality: a prospective study in Wuhan, China.

Trihalomethanes (THMs) have been demonstrated to adversely affect male reproductive health in animals, but the evidence in humans is limited. The study aimed to examine the association between THM exposure and semen quality in a Chinese population. We recruited 324 men from the same water supply district in Wuhan, China between April 2011 and May 2012. Exposure to THMs was evaluated based on their concentrations in tap water measured within 90 days preceding semen collection, the uptake factors of THMs and personal information on ingestion and showering/bathing. We found that TTHM [sum of chloroform (TCM) and brominated THMs (Br-THMs)], TCM and Br-THM uptakes via ingestion were associated with significant or suggestive decreasing trends in sperm concentration (P for trend=0.01, 0.03 and 0.05, respectively) and sperm count (P for trend=0.02, 0.05 and 0.09, respectively). Our results suggest that THM exposure via ingestion may adversely affect semen quality.

Variability in the morphologic assessment of human sperm: use of the strict criteria recommended by the World Health Organization in 2010.

OBJECTIVE: To determine the variability in the recognition of normal sperm and various sperm defects using the strict criteria recommended by the World Health Organization (5th edition, 2010). DESIGN: Sperm morphologic assessment by three experienced evaluators. SETTING: Image processing laboratory and reproduction research institute. PATIENT(S): Semen donors from a sperm bank. INTERVENTION(S): The morphology of 5,296 sperm was evaluated using statistical analyses of variability. MAIN OUTCOME MEASURE(S): The proportion and coefficients of variation (CVs) of normal sperm, defects of specific parts, and the categories of defects were measured. The degree of agreement between any two of the three evaluators was calculated. The multiple anomalies index, teratozoospermia index, sperm deformity index, and the CVs were also measured. RESULT(S): The CVs of normal sperm, multiple anomalies index, teratozoospermia index, and sperm deformity index were 4.80%, 4.14%, 5.75%, and 6.81%, respectively. A broader range (4.80%-132.97%) of CVs was observed for the recognition of various defects. The coefficients of the degree of agreement concerning specific morphologic parts of sperm varied (0.387-0.607), with lower relative values for the head and mid-piece than for the tail and cytoplasm. CONCLUSION(S): The sperm head is more difficult to evaluate than the other parts using the criteria recommended by the World Health Organization in 2010. The degree of agreement concerning specific parts and various defects varied in broad ranges. A stricter definition for each defect is needed.