Understanding the Causes of Infertility, Risk Factors, and Diagnosis
Understanding the underlying causes of infertility, the potential risk factors, and how to diagnose them may help up to 15% of couples in the United States manage and address infertility.
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- Infertility is a highly stigmatized medical condition that affects nearly 15% of couples in the United States. Despite common misconceptions, infertility can affect both males and females. Understanding the risk factors and underlying causes of infertility may help patients and providers plan a treatment regimen to address these issues and restore fertility.
The Mayo Clinic defines infertility as “not being able to get pregnant despite having frequent, unprotected sex for at least a year for most couples.” This definition only applies to cis-gendered heterosexual couples who can conceive through intercourse; however, people of all sexualities may experience infertility.
An article published by the ethics committee of the American Society for Reproductive Medicine (ASRM) notes that nearly 7.4 million people of reproductive age with female reproductive organs, 12.1%, are infertile. In addition, almost 10% of people with male reproductive anatomy are sub-fertile or sterile despite not having sterility procedures.
In a review and meta-analysis in Human Reproductive Update, researchers note that, between 1973 and 2018, the average sperm count dropped by over 50%. While remaining in the fertile range, data from this study suggest an increased probability of male infertility.
Many patients are unaware they are infertile until they start planning to have children. However, some people may have symptoms indicative of infertility, such as irregular menstrual cycles, changes in hair growth, or sexual function changes.
General Risk Factors
Infertility risk factors include age, tobacco use, alcohol use, weight, and exercise. While risk factors do not mean that a patient is infertile, they are an indicator many providers consider when counseling patients on conception and fertility.
Age
The Mayo Clinic notes that female fertility levels decrease dramatically in their mid-30s. While people can get pregnant and have a child at this age, the probability is significantly lower. The infertility rate for people between 15 and 34 with female reproductive organs is 7.3–9.1%. By 35 years old, that rate jumps to 25%. The risk is even higher for those in their 40s with an infertility rate of 30%.
A clinical trial based at Nanjing University in China is currently analyzing the impacts of maternal age on embryo implantation rates to understand better how maternal age can impact fertility. The study has concluded; however, the research has yet to be published.
Furthermore, many assume that only female fertility declines with age; however, research shows that males over 40 are often less fertile than younger males. An article published in Forbes Health states that fertility in males declines up to 23% each year after 39 years old.
Substance Use
Beyond age, substance use, such as excessive alcohol or tobacco use, can also increase the risk of infertility. Although the pathophysiology connecting excessive alcohol consumption to infertility is not fully understood, it is well documented that, compared to abstaining, increased alcohol consumption reduces the chance of pregnancy in those with female reproductive anatomy.
Data from a study in Fertility Research and Practice estimates that consuming more than ten standard drinks per week decreases the chance of pregnancy by 66% in individuals with female reproductive organs.
In those with male reproductive organs, moderate or low alcohol consumption does not seem to impact fertility significantly; however, some studies suggest that high alcohol consumption reduces normal sperm morphology, which can cause infertility.
Fertility Research and Practice notes, “men who drink heavily should be advised to decrease their alcohol intake. However, those who drink moderately should be counseled regarding alcohol consumption based on their overall health status, and not necessarily on reproductive health.”
In addition to alcohol consumption, the FDA notes that tobacco consumption can reduce fertility by altering hormone production, changing the reproductive system, and damaging the DNA in sperm.
According to ClinicalTrials.gov, researchers in France are studying smoking cessation and its impacts on infertility. Since spermatogenesis cycles are 74 days long, the researchers hope to determine if one cycle or more after smoking cessation yields sperm without damaged DNA.
Other Lifestyle Factors
A patient’s weight may also increase the risk of infertility. The habits of both underweight and obese individuals can contribute to low fertility levels. Excessive exercise and extreme caloric restriction may alter hormone production and fertility; excessive caloric consumption may do the same.
An active study out of the Imperial College in London is analyzing the weight loss in obese males on male infertility and seminal quality. Researchers note that the effects of weight loss on male fertility have yet to be adequately explored.
Causes of Male Infertility
Statistics on infertility suggest that 37% of infertile couples had infertility due to a female reproductive issue. Additionally, 35% had infertility due to male and female reproductive problems. Finally, 8% had infertility due to a male reproductive issue. While the WHO supports these statistics, many believe the data may be skewed due to the stigma around male infertility, leading to underreporting.
While some males may experience idiopathic infertility, 10–20%, many cases of male infertility can be attributed to endocrine disorders, sperm transport disorders, and primary testicular defects.
According to the Cleveland Clinic, some risk factors for infertility are specific to those with male reproductive organs. These factors include enlarged scrotal veins, injury to the scrotum or testicles, hypogonadism, premature ejaculation, testicular cancer, and undescended testes.
StatPearls classifies male infertility into three categories: pre-testicular, testicular, and post-testicular. Pretesticular causes of male infertility refer to most endocrine disorders. This class of reasons may include erectile dysfunction, anejaculation, chromosomal abnormalities, and hypogonadism.
Testicular male infertility includes primitive testicular disruption, varicoceles, testicular tumors, and cryptorchidism. Inflammatory diseases, erectile dysfunction, premature ejaculation, and seminal tract lesions are post-testicular causes of male infertility.
The Mayo Clinic is conducting a clinical trial examining the effect of testicular torsion on male infertility by looking at paternity rates in men treated for testicular torsion between 1970 and 1990.
Causes of Female Infertility
StatPearls notes that ovulatory disorders are the leading cause of female infertility, accounting for a quarter of female infertility cases. Endometriosis, pelvic adhesions, and tubal blockage account for 15%, 12%, and 11% of female infertility cases, respectively. Other tubal abnormalities account for 11% of cases, and hyperprolactinemia accounts for 7%.
Ovulatory Disorders
Ovulatory disorders, sometimes called anovulation, are the leading cause of infertility in those with a uterus. A lack of or irregular ovulation can mean that no egg is being released and fertilized for a viable pregnancy. According to the Mayo Clinic, ovulation disorders can be caused by hormonal imbalances, including hyperprolactinemia, hyperthyroidism, and hypothyroidism.
Four types of ovulatory disorders exist, including hypothalamic amenorrhea, normogonadotropic normoestrogenic anovulation, premature ovarian failure, and pituitary adenoma.
Hypothalamic amenorrhea is caused by elevated cortisol levels, which suppress GnRH secretion and decrease levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Often this condition is associated with eating disorders, excessive exercise, and other restrictive habits.
Polycystic ovary syndrome (PCOS) is the most common type of normogonadotropic normoestrogenic anovulation. This condition is a significant ovulatory disorder implicated in female infertility, accounting for up to 85% of cases. StatPearls notes, “the pathophysiology behind PCOS and infertility is not well understood; classically, abnormal pulsatility of GnRH is described as a possible underlying cause.”
Endometriosis
Endometriosis is also a significant cause of female infertility. Approximately half of all individuals with endometriosis will experience infertility. In healthy patients, endometrial cells grow inside the uterus; however, in patients with endometriosis, the endometrial cells grow outside of the uterus.
Concerning fertility, the early stages of endometriosis are thought to be inflammatory and cause increased production of prostaglandins and cytokines, leading to infertility. Conversely, advanced or severe stages of endometriosis impact tubal motility due to pelvic adhesion, reducing fertility.
Pelvic and Tubal Abnormalities
Another significant contributor to female infertility is pelvic and tubal abnormalities or adhesions. Underlying conditions can cause these factors. Often, these adhesions result from pelvic inflammatory disease, which can result from a history of sexually transmitted infection.
Researchers from the University of Luebeck are recruiting females 18–22 for a longitudinal study on the impacts of sexually transmitted infections on female infertility. The study is expected to conclude in 2028.
Diagnosing Infertility
The diagnostic process for infertility can be lengthy and expensive; however, for many couples attempting to get pregnant, knowing the cause of infertility may guide them to infertility solutions.
Infertility testing for males may include a semen analysis, hormone testing, genetic testing, testicular biopsy, or imaging. For women, infertility testing may consist of ovulation testing, hysterosalpingography, ovarian reserve testing, hormone testing, imaging, hysteroscopy, and laparoscopy.
An article published by Arc Fertility divides the diagnostic tools for infertility into four categories, including the following:
- female endocrine investigation
- pelvic factor investigation
- male factor investigation
- cervical factor investigation
Female Endocrine investigation
This class of diagnostic tools is often used when ovulatory disorders or endocrine disorders are the suspected cause of infertility in those with female reproductive organs. These diagnostic tools may include basal body temperature charting, endometrial biopsy, urine testing to detect luteinizing hormone levels, ultrasounds, blood tests for follicle stimulating hormones, estradiol, anti-mullerian hormone, and antral follicle count, laparoscopy, and genetic testing.
Pelvic Factor Investigation
Ultrasonography, hysterosalpingogram, hysteroscopy, magnetic resonance imaging, laparoscopy, and hydrotubation can all be components of pelvic factor investigation. These tools detect physical or anatomical problems in female reproductive anatomy that can cause infertility.
Male Factor Investigation
The most common type of male factor investigation is a semen analysis; however, other testing may include a sperm fragmentation assay. Providers may also do genetic or hormone testing to assess whether that impacts male fertility.
Cervical Factor Investigation
Cervical factor investigation may include getting a female cervical culture to test for the presence of gonorrhea, chlamydia, and other infectious diseases that may impact fertility in females. Providers may recommend a male urethral culture to test for infectious diseases like a cervical culture.
These tools are less commonly used as they don’t always provide a comprehensive understanding of infertility.
