Introduction

An infertility diagnosis can feel isolating, due to the social stigma and the lack of open discussion about fertility issues. But in reality, as many as 15% of couples will require an infertility evaluation [1]. With the increasing trend of postponing family building to allow time for career development, many women may experience subfertility for months, leaving little time for evaluation and successful treatment. An infertility diagnosis may be straightforward for some, while yielding no explanations for others; and treatment options, even when available, may be too costly.

Diagnosing infertility early, evaluating and eliminating potential causes, and creating a plan for supportive treatments are key in effectively helping these patients towards their goal of having a baby.

What Are Infertility and Subfertility?

Infertility is defined as the inability for a couple to conceive via unprotected sexual intercourse or therapeutic donor insemination within 12 months if less than 35 years of age or within 6 months if greater than 35 years of age [2, 3]. Women older than 40 years old may need more immediate evaluation and treatment depending on the clinical scenario [4].

Subfertility is the term used to describe the failure to conceive within 6–12 months, based on age, without any evidence of sterility (e.g., vasectomy, bilateral tubal ligation, etc.). Fecundability is another common description used in studies evaluating infertility, and it describes the probability for a couple to conceive within one menstrual cycle.

These terms, however, are not all-inclusive and do not capture the full spectrum of patients who may need or seek fertility treatments. For example, a same-sex couple would have a 0% fecundability, and a single unmarried woman could not be diagnosed with infertility because she is not part of a “couple.” Though most healthcare providers may not subscribe to such literal interpretations, such patients often have difficulty obtaining clearance from insurance providers for infertility coverage due to these narrow definitions [5••]. Perhaps partly for this reason, same-sex couples are four times more likely than heterosexual couples to adopt [6].

Thus, healthcare providers should be aware that an overly simplistic or heteronormative definition of infertility can lead to injustices and lost opportunities for individuals and families of all descriptions to achieve their family-building goals.

Causes and Prevalence of Infertility

There are different subcategories of infertility: uterine factor, tubal factor, ovarian factor (ovarian dysfunction), male factor, and unexplained. To present the appropriate treatment options, each patient must be evaluated individually to accurately diagnose the factor(s) affecting their fertility.

Uterine factor infertility is the term used when a woman is infertile due to uterine pathology such as leiomyoma, adenomyosis, uterine polyps, mullerian anomalies, uterine synechiae, and endometritis. The overall prevalence is approximately 10–13% [7, 8]. Correction of the underlying etiology, usually via surgical management, may allow for conception without use of assisted reproduction technology (ART).

Tubal factor infertility is found in approximately 30–35% of infertile women [9]. The main cause of tubal factor infertility is pelvic inflammatory disease (PID) or acute salpingitis [10]. The second most likely cause (approximately 7–14%) of tubal factor infertility is endometriosis [11]. Other causes include prior surgeries, history of bilateral tubal ligation, history of pelvic infection (e.g., chlamydia or gonorrhea), salpingitis isthmica nodosa, ruptured appendix, or abdominal trauma.

Ovarian factor infertility (or ovarian dysfunction) is one of the most common causes of infertility. It occurs in approximately 15% of all infertile couples and is seen in 40% of all infertile women [12]. The potential etiologies of ovarian factor infertility include diminished ovarian reserve and ovulatory dysfunction (Table 1). Patients with ovulatory dysfunction have inconsistent or absent ovulation resulting from one of several different factors such as thyroid dysfunction, hyperprolactinemia, obesity, and polycystic ovarian syndrome (PCOS), which is the most common endocrine disorder in reproductive-aged women.

Table 1 Factors that may lead to ovarian factor infertility
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Male factor infertility occurs in approximately 30–40% of all couples with infertility and is the sole diagnosis in 20% of infertile couples [7]. Identification of male factor infertility occurs when there are two abnormal semen analyses found on evaluation of infertility. Normal semen parameters based on the World Health Organization (WHO) 2010 criteria can be seen in Table 2. Semen parameters outside the normal range deem the sample abnormal and require a repeat analysis. There is significant intrapatient variability between semen analyses and the subjective nature of assessment by andrology technicians that patients yielding two abnormal samples are most likely to have male factor infertility [13]. Timing of repeat analysis is controversial and dependent on the results of the initial analysis [14]; however, most clinics suggest obtaining a repeat semen analysis within 1–2 months. Common causes of male factor infertility include exogenous testosterone use, trauma, varicoceles, prior testicular surgery, genetic anomalies, congenital bilateral absence of vas deferens, and drug use. The identification of the etiology of male factor infertility is key to proper treatment and counseling regarding ability for future fertility.

Table 2 2010 WHO criteria for semen analysis
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Unexplained infertility occurs in 30% of couples [15]. The diagnosis is made when the basic evaluation for infertility in both partners is normal, with no abnormal findings: tubal patency, evidence of regular ovulation and normal ovarian reserve, and a normal semen analysis.

Evaluation of Female Infertility

A detailed history and physical exam are essential in identifying potential etiologies of infertility in the female patient. The history should focus on obtaining information on menstrual history, pregnancy history, prior use of contraception, prior history of sexually transmitted infection, duration of infertility, coital frequency and timing, prior fertility treatments, past surgical procedures, sexual history, family history, occupational hazards, and use of substances (including nicotine) [16••]. A review of organ systems that may contribute to infertility should also be obtained (e.g., thyroid disease, galactorrhea, hirsutism, etc.).

Physical examination of the female patient should include vital signs, weight, thyroid and breast examination, signs of androgen excess (acne and hirsutism), and pelvic exam. The pelvic examination should include characterization of uterine size, shape, and mobility, as well as palpation of the adnexa for possible masses or tenderness.

There are several findings that may be noticed on physical exam that could alter or delay fertility management. Patients who are underweight or obese may have delayed fertility management until a normal weight or approved weight is achieved. Most fertility clinics have body mass index (BMI) cutoff that has been agreed upon by that institution’s anesthesia and maternal fetal medicine specialists on safety and ethical reasons before proceeding with fertility treatment. Prior studies have shown that obesity is related to increased frequency of euploid miscarriages, decreased live birth rate, poor oocyte quality, and increased cycle cancellation [17, 18]. Underweight patients are at risk of ovarian hyperstimulation syndrome and should be counseled appropriately regarding this risk prior to starting treatment. The presence of acne or hirsutism should trigger physicians to investigate for potential signs of polycystic ovarian syndrome (PCOS). Women with PCOS suspected to undergo infertility treatment require special attention given history of anovulation, risk of ovarian hyperstimulation, and common association with obesity [19]. Other pertinent findings that may be elicited from a physical exam include the presence of a uterine fibroid or adnexal mass (e.g., endometrioma or dysgerminoma). Depending on the size and location of these masses, surgical removal may be required prior to starting infertility treatment.

Following a detailed history and physical (H&P), laboratory and radiologic evaluation helps to narrow the potential diagnoses. Common laboratory values obtained include antimullerian hormone (AMH) and day 2–5 follicle stimulating hormone (FSH) and estradiol (E2), mid-luteal progesterone level, thyroid stimulating hormone (TSH), and prolactin.

AMH, or anti-Mullerian hormone, is produced by the granulosa cells of antral follicles. Serum AMH is now a widely used and convenient measure of ovarian reserve; because its production is independent of gonadotropins, it can be obtained at any time during the menstrual cycle with relative consistency in results [20,21,22,23]. AMH levels less than 1 ng/mL have been associated with poor response to ovarian stimulation, poor embryo quality, and poor in vitro fertilization (IVF) outcomes [24,25,26,27]. In women with PCOS, who typically have an abundance of antral follicles, serum AMH levels are significantly higher, approximately 2–3 times that of age-matched controls, reflecting the larger pool of follicles present in the polycystic ovary [28, 29].

Day 3 FSH and E2 have been traditional measures of ovarian reserve. High levels of FSH (> 10–20 IU/L) have been associated with poor ovarian stimulation and failure to conceive [30]. The sensitivity and specificity of serum FSH vary widely. The specificity of an elevated FSH is approximately 83–100% for predicting poor response to stimulation; however, the sensitivity is 10–80% [30]. This wide range is primarily due to the cycle-to-cycle variation of FSH values. Estradiol (E2) is used in addition to FSH to help interpret a normal FSH value. An elevated day 3 serum E2 level (> 60–80 pg/mL) in the setting of a normal FSH value has had limited evidence for an association with poor response to gonadotropin stimulation, lower pregnancy rate, and higher IVF cancellations [31,32,33].

Mid-luteal progesterone level is an objective test used to assess if ovulation has occurred. A single value of serum progesterone > 3 ng/mL in the luteal phase should confidently confirm ovulation [34]. This measurement can also be used as a marker to begin long luteal stimulation cycles in women who are poor responders to prior conventional agonist cycles; and as a marker for probability of live birth in ovarian stimulation cycles using clomiphene, letrozole, or gonadotropins with intrauterine insemination [35].

Other hormones such as TSH and prolactin can influence ovulatory function and fertility outcomes. A serum TSH should be obtained to rule out potential thyroid dysfunction as the cause of infertility and/or menstrual irregularity. Serum prolactin should be checked only in those patients who present with galactorrhea or irregular menstrual cycles [13]. TSH levels ≥ 2.5 mIU/L have been inversely related to clinical pregnancy outcomes. Women with TSH levels ≥ 2.5 mIU/L should be started on replacement therapy (e.g. levothyroxine) and not begin infertility treatment until the TSH has improved. In addition, hyperprolactinemia is associated with amenorrhea and infertility due to inhibition of gonadotropin secretion and gonadotropin releasing hormone (GnRH) pulsatility. Treatment with a dopamine agonist (e.g., cabergoline or bromocriptine) should be used and may ultimately restore menstrual regularity and ovulation in most women [36].

Common imaging studies used in the evaluation of infertility include transvaginal ultrasound to evaluate pelvic anatomy and to obtain an antral follicle count (an additional test of ovarian reserve). Traditional 2D ultrasonography is useful for the identification of uterine pathology such as fibroids but has limited utility in the evaluation of intracavitary pathology, which is better visualized with saline infusion sonography (SIS) or hysterosalpingography, the latter of which has the additional advantage of testing for tubal patency. Diagnostic hysteroscopy remains the gold standard for evaluation of the uterine cavity and can be performed either in office or in the operating room.

Evaluation of Male Infertility

Similar to the evaluation of the female patient, evaluation of the male patient should begin with a thorough history. With a basic reproductive history and semen analysis for initial workup, the obstetrician-gynecologist can expedite evaluation and referral to a urologist and male infertility specialist for further evaluation if indicated.

Relevant components of the history include past medical and surgical history, medication use (including past use of testosterone or prior gonadotoxic chemotherapy), and substance use including tobacco, marijuana, or excessive alcohol intake. The history should also address any past infections (specifically sexually transmitted infections and any childhood infections such as mumps), problems with sexual function including erectile and/or ejaculatory dysfunction, potential occupational exposures to excessive heat, radiation, or toxic chemicals, and any specific genital trauma or history of hernia. Information about prior paternity or history of infertility with a previous partner are also important to elicit.

The 2010 World Health Organization (WHO) criteria is the most commonly used diagnostic tool to evaluate semen parameters (Table 2). However, healthcare providers should counsel Black and Asian men appropriately when reviewing semen analysis results evaluated using the WHO criteria, as the normative values used therein were based upon a cohort lacking in racial diversity [37, 38•]. Male patients with abnormal semen analyses on two separate occasions should be referred to a urologist, preferably a male fertility specialist, for further evaluation [39]. Additional testing beyond a routine semen analysis, including advanced sperm function testing such as DNA fragmentation testing, should not be routinely ordered in the evaluation of male infertility [13].

Management of Infertility

The management of infertility is based on several components: maternal age, type of female infertility, presence or absence of male factor infertility, insurance coverage, history of genetic diseases, and planned family size. Briefly, most patients seeking infertility do not have insurance coverage and usually start with using oral ovarian hyperstimulation medications (e.g., clomiphene or letrozole) for three to six cycles. Gonadotropins are rarely used due to the high prevalence of multiples and increased risk of ovarian hyperstimulation compared to clomiphene and letrozole. Patients with a history of mild to moderate male factor infertility may have intrauterine insemination (IUI) with partner or donor sperm in addition to oral ovarian hyperstimulation. If couples fail to conceive after three to six cycles of ovarian hyperstimulation, or have severe male factor infertility not conducive to IUI, then they may be recommended to undergo IVF, with or without intracytoplasmic sperm insemination (ICSI), to improve their chances of becoming pregnant. Couples with a history of genetic conditions or carriers for lethal anomalies may desire to undergo IVF to allow for preimplantion genetic testing (PGT) and select for embryos that do carry the risk of having those conditions.

Conclusion

Patients concerned about fertility will often seek the advice of their obstetrician/gynecologist first. Understanding the essential components of an initial workup, including medical history, physical examination, and other testing, can help providers identify potential fertility issues sooner and refer patients to a specialist for further evaluation and treatment if needed. Providing appropriate counseling and testing can also equip patients with valuable information about their reproductive health and treatment options while offering compassion as they face a potentially emotional diagnosis.