Female infertility: Evaluation

INTRODUCTION — Multiple tests have been proposed for evaluation of female infertility. Some of these tests are supported by good evidence, while others are not. This topic will provide an evidence-based approach to the evaluation of female infertility. The etiology and treatment of female infertility, as well as the etiology, evaluation, and treatment of male infertility, are discussed separately.

●(See "Overview of infertility".)

●(See "Female infertility: Causes".)

●(See "Female infertility: Treatments".)

●(See "Causes of male infertility".)

●(See "Approach to the male with infertility".)

●(See "Treatments for male infertility".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

WHEN TO INITIATE AN INFERTILITY EVALUATION — An infertility evaluation is usually initiated after one year of regular unprotected intercourse in women under age 35 years and after six months of unprotected intercourse in women age 35 years and older (table 1). However, the evaluation may be initiated sooner in women aged 40 years and older and those with irregular menstrual cycles or known risk factors for infertility, such as endometriosis, a history of pelvic inflammatory disease, history of pelvic surgery or reproductive tract malformations, or known male factor.

The basic evaluation can be performed by an interested and experienced primary care physician or an obstetrician-gynecologist. The primary care physician generally should refer the patient to a specialist for treatment of infertility. Many gynecologists initiate treatment prior to referral to a reproductive endocrinologist. This decision depends upon the results of infertility tests and clinician experience.

INITIAL APPROACH — Both partners of an infertile couple should be evaluated for factors that could be impairing fertility. The infertility specialist then uses this information to counsel the couple about the possible etiologies of their infertility and to offer a treatment plan targeted to their specific needs.

It is important to remember that the couple may have multiple factors contributing to their infertility; therefore, a complete initial diagnostic evaluation should be performed to detect the most common causes of infertility, if present. When applicable, evaluation of both partners is performed concurrently [1].

The recognition, evaluation, and treatment of infertility are stressful for most couples [2]. The clinician should not ignore the couple's emotional state, which may include depression, anger, anxiety, and marital discord. Information should be supportive and informative. (See "Psychological stress and infertility".)

History and physical examination — Findings on history and physical examination may suggest the cause of infertility and thus help focus the diagnostic evaluation. Components of the infertility history are listed in the table (table 2).

History — The most important points in the history are:

●Duration of infertility and results of previous evaluation and therapy.

●Menstrual history (cycle length and characteristics), which helps in determining ovulatory status. For example, regular monthly cycles with molimina (breast tenderness, ovulatory pain, bloating) suggest that the patient is ovulatory, and characteristics such as severe dysmenorrhea suggest endometriosis. Menstrual cycle length may also be a general indicator of ovarian reserve. A meta-analysis including over 12,000 females reported that short menstrual cycle length (21 to 27 days) was associated with reduced ovarian reserve, including lower anti-müllerian hormone levels and antral follicle counts, compared with normal (28 to 31 days) and long (32 to 35 days) cycle lengths [3].

●Medical, surgical, and gynecologic history (including sexually transmitted infections, pelvic inflammatory disease, and treatment of abnormal Pap smears) to look for conditions, procedures, or medications potentially associated with infertility. At a minimum, the review of systems should determine whether the patient has symptoms of thyroid disease, galactorrhea, hirsutism, pelvic or abdominal pain, dysmenorrhea, or dyspareunia. Young women who have undergone unilateral oophorectomy generally do not have reduced fertility since young women have many primordial follicles per ovary; however, prior unilateral oophorectomy may impact fertility in older women as they may develop diminished ovarian reserve sooner than women with two ovaries [4].

●Obstetric history to assess for events potentially associated with subsequent infertility or adverse outcome in a future pregnancy.

●Sexual history, including sexual dysfunction and frequency and timing of coitus. Infrequent or ineffective coitus can be an explanation for infertility.

●Family history, including family members with infertility, birth defects, genetic mutations, or intellectual disability. Women with fragile X premutation may develop premature ovarian failure, while males may have learning problems, developmental delay, or autistic features.

●Personal and lifestyle history including age, occupation, exercise, stress, dieting/changes in weight, smoking, and alcohol use, all of which can affect fertility.

Physical examination — The physical examination should assess for signs of potential causes of infertility. The patient's body mass index (BMI) should be calculated and fat distribution noted, as extremes of BMI are associated with reduced fertility and abdominal obesity is associated with insulin resistance.

In the setting of primary amenorrhea, incomplete development of secondary sexual characteristics is a sign of hypogonadotropic hypogonadism. A body habitus that is short and stocky, with a squarely shaped chest, suggests Turner syndrome in patients with absent periods.

Abnormalities of the thyroid gland, galactorrhea, or signs of androgen excess (hirsutism, acne, male pattern baldness, virilization) suggest the presence of an endocrinopathy (eg, hyper- or hypothyroidism, hyperprolactinemia, polycystic ovary syndrome, adrenal disorder).

Tenderness or masses in the adnexae or posterior cul-de-sac (pouch of Douglas) are consistent with chronic pelvic inflammatory disease or endometriosis. Palpable tender nodules in the posterior cul-de-sac, uterosacral ligaments, or rectovaginal septum are additional signs of endometriosis.

Vaginal/cervical structural abnormalities or discharge suggest the presence of a müllerian anomaly, infection, or cervical factor.

Uterine enlargement, irregularity, or lack of mobility are signs of a uterine anomaly, leiomyoma, endometriosis, or pelvic adhesive disease.

These conditions are described in detail separately:

●(See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact".)

●(See "Pelvic inflammatory disease: Clinical manifestations and diagnosis".)

●(See "Congenital uterine anomalies: Clinical manifestations and diagnosis".)

●(See "Clinical manifestations and evaluation of hyperprolactinemia".)

●(See "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)

●(See "Diagnosis of hyperthyroidism".)

●(See "Clinical manifestations of polycystic ovary syndrome in adults".)

●(See "Clinical manifestations and diagnosis of Turner syndrome".)

●(See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history".)

Diagnostic tests — In addition to the history and physical examination, the initial diagnostic evaluation consists of:

●Semen analysis to detect male factor infertility.

●Documentation of normal ovulatory function. Women with regular menses approximately every four weeks with molimina symptoms are almost always ovulatory.

●A test to rule out tubal occlusion and assess the uterine cavity. We usually perform a hysterosalpingogram (HSG), or hysterosalpingo-contrast sonography (HyCoSy), which evaluates both the uterus and tubes, but laparoscopy with chromotubation combined with hysteroscopy may be more appropriate in women suspected of having endometriosis. Dilute methylene blue can be used for the chromotubation dye. (See 'Role of laparoscopy' below.)

●A test or tests of ovarian reserve such as cycle day 3 follicle-stimulating hormone (FSH) or estradiol, clomiphene citrate challenge test, anti-müllerian hormone (AMH), or antral follicle count.

Risk factors noted from the couple's history may indicate the need for additional testing after the initial infertility evaluation.

Preconceptional laboratory screening may also be undertaken at this time so these results can be used for diagnostic and therapeutic counseling. Genetic screening should be offered in accordance with risk as defined by ethnicity. The components of preconception evaluation and counseling are discussed separately. (See "The preconception office visit", section on 'Laboratory assessment'.)

Semen analysis — The semen analysis is the cornerstone of the assessment of the male partner of an infertile couple. In addition to the standard analysis, specialized analyses can be performed in some laboratories. The semen sample should be collected after two to seven days of abstinence and should be submitted to the laboratory within one hour of collection [5].

It is difficult to predict the likelihood of pregnancy based upon the results of semen analysis alone, as there is extensive overlap between the semen parameters of fertile and infertile men. If the semen analysis is abnormal, the clinician should review details of specimen collection and transport with the patient, repeat the test due to the marked inherent variability of semen analyses, and consider referral to a urologist or other specialist in male reproduction.

The techniques for semen analysis and interpretation of results are discussed in detail separately. (See "Approach to the male with infertility", section on 'Semen analysis'.)

Assessment of ovulatory function — Assessment of ovulatory function is a key component of the evaluation of the female partner since ovulatory dysfunction is a common cause of infertility. The treatment of women with ovulatory dysfunction is aimed at improving or inducing ovulatory function; a variety of treatment strategies is available. (See "Female infertility: Treatments".)

Women who have regular menses approximately every 28 days with molimina symptoms prior to menses (breast tenderness, bloating, fatigue, etc.) are most likely ovulatory. In women who do not describe their cycles as such, laboratory assessment of ovulation should be performed. Ovulation is most easily documented by a mid-luteal phase serum progesterone level, which should be obtained approximately one week before the expected menses. For a typical 28-day cycle, the test would be obtained on day 21. A progesterone level >3 ng/mL is evidence of recent ovulation [6].

An alternative is to have the patient use an over-the-counter urinary ovulation prediction kit. These kits detect luteinizing hormone (LH) and are highly effective for predicting the timing of the LH surge that reliably indicates ovulation. Home kits have a 5 to 10 percent false positive and false negative rate. Therefore, serum confirmation can be useful in patients who are unable to detect a urinary LH surge.

Other methods of determining ovulation, such as daily ultrasounds to follow the development and ultimately the disappearance of a follicle (the most accurate method of documenting ovulation [7]) and endometrial biopsy to document secretory changes in the endometrium are too expensive or invasive for routine diagnostic assessment of ovulation.

If the mid-luteal progesterone concentration is <3 ng/mL or the cycles are highly irregular, the patient is evaluated for causes of anovulation. The minimal work-up includes serum prolactin, thyroid-stimulating hormone (TSH), FSH, and assessment for polycystic ovary syndrome (PCOS). The etiology and diagnostic evaluation of anovulation are reviewed separately. (See "Evaluation and management of secondary amenorrhea".)

Assessment of ovarian reserve — Diminished ovarian reserve can refer to diminished oocyte quality, oocyte quantity, or reproductive potential [8]. The identification of diminished ovarian reserve is an important component of the initial infertility evaluation as patients are presenting for diagnostic evaluation later in their reproductive lifespan. Guidelines for testing from national organizations are available [8,9]. However, there is no ideal test for assessing ovarian reserve. A number of screening tests are utilized, but no single test is highly reliable for predicting pregnancy potential. Therefore, coordination of tests provides the best assessment.

We test ovarian reserve with an AMH level and a day 3 FSH and estradiol levels. Other tests such as the clomiphene citrate challenge test (CCCT) and antral follicle count are also utilized in some circumstances. These tests have good specificity for predicting a poor response in in vitro fertilization (IVF) cycles, but have more limited value for predicting IVF outcome.

Day 3 FSH and CCCT — Both the day 3 FSH level (where day 1 is the first day of full menstrual flow) and the CCCT, which is a provocative test for measurement of FSH, are widely used for screening ovarian reserve. The CCCT involves oral administration of 100 mg clomiphene citrate on cycle days 5 through 9 with measurement of day 3 and day 10 FSH levels and day 3 estradiol level.

The premise of these tests is that women with good ovarian reserve have sufficient production of ovarian hormones from small follicles early in the menstrual cycle to maintain FSH at a low level. In contrast, women with a reduced pool of follicles and oocytes have insufficient production of ovarian hormones to provide normal inhibition of pituitary secretion of FSH, so FSH rises early in the cycle [10].

Meta-analyses of nonrandomized studies concluded that basal cycle day 3 FSH and the CCCT perform similarly for predicting ability to achieve a clinical pregnancy in women undergoing infertility treatment [11,12]. With either test, a normal result is not useful in predicting fertility, but a highly abnormal result (we use FSH >15 milli-international units/mL) suggests that pregnancy is unlikely with treatment involving the woman's own oocytes, particularly in women of more advanced reproductive age.

Based on these findings and the cost advantage and simplicity of the day 3 FSH, we obtain a day 3 FSH concentration and consider a value less than 10 milli-international units/mL suggestive of adequate ovarian reserve, and levels of 10 to 15 milli-international units/mL borderline. The upper threshold for a normal FSH concentration is laboratory dependent; cutoff values of 10 to 25 milli-international units/mL have been reported because of use of different FSH assay reference standards and assay methodologies.

We also check a cycle day 3 estradiol level, although there are conflicting data as to whether it is predictive of ovarian reserve and the response to ovarian stimulation (as in IVF) [13,14]. We consider a value <80 pg/mL suggestive of adequate ovarian reserve, but other cutoffs are also utilized. In one prospective study of women undergoing IVF, day 3 estradiol levels >80 pg/mL resulted in higher cycle cancellation rates and lower pregnancy rates, and estradiol levels >100 pg/mL were associated with a 0 percent pregnancy rate [15].

Elevated basal estradiol levels are due to advanced premature follicle recruitment that occurs in women with poor ovarian reserve. High estradiol levels can inhibit pituitary FSH production and thus mask one of the signs of decreased ovarian reserve in perimenopausal women. Thus, measurement of both FSH and estradiol levels helps to avoid false-negative FSH testing.

If CCCT is performed, we consider FSH less than 10 milli-international units/mL on both day 3 and day 10 suggestive of adequate ovarian reserve; a borderline FSH of 10 to 15 milli-international units/mL and an elevated FSH level on either day 3 or day 10 suggests decreased ovarian reserve. Estradiol can be measured on day 3, but a cycle day 10 estradiol is not part of the standard CCCT as it reflects the magnitude of the ovarian follicular response to clomiphene 100 mg daily for five days, not ovarian reserve.

If the day 3 FSH or CCCT is abnormal, the patient should be referred to a reproductive endocrinologist to discuss further diagnostic and treatment options. These options depend on the results of other diagnostic tests, the patient's age [16], and other factors and may include aggressive ovulation induction, IVF, or use of donor oocytes. However, patients with markedly diminished ovarian reserve rarely conceive without the use of donor eggs.

Anti-müllerian hormone — AMH is a member of the TGF-beta family and is expressed by the small (<8 mm) preantral and early antral follicles. The AMH level reflects the size of the primordial follicle pool, and may be the best biochemical marker of ovarian function across an array of clinical situations [17]. Unlike the day 3 FSH, AMH can be measured anytime during the menstrual cycle and typically demonstrates minimal intercycle and intracycle variability since the growth of small preantral follicles that express it is continuous, not cyclical. In adult women, AMH levels gradually decline as the primordial follicle pool declines with age [18]; AMH is undetectable at menopause [19].  

While AMH level is an early indicator of declining ovarian function, interpretation and clinical implication of test results vary with the patient’s underlying fertility status. Because of the nuances in interpreting AMH, we do not advise using direct-to-consumer AMH tests, which may provide false or misleading claims [20].

●For patients planning IVF or with ovarian injury – In patients planning IVF, AMH level correlates with the number of oocytes retrieved after stimulation and is the best biomarker for predicting poor and excessive ovarian response [13,21-23]. However, its diagnostic accuracy for predicting live birth is poor, so it should not be used to exclude couples from IVF or intracytoplasmic sperm injection (ICSI) [24,25]. It may also play a useful role in identifying reduced ovarian follicle pool in certain types of patients, such as women with demonstrated infertility, cancer patients, and patients who have had significant ovarian injury from radiation or surgery [26].

●For patients without infertility or ovarian injury – In contrast to women with infertility, AMH levels in women without infertility do not correlate with future fertility potential or the time to pregnancy and should not be used to predict reproductive status or onset of menopause [25,27].

For women with demonstrated infertility, there is no consensus on the threshold value suggestive of reduced fertility potential [13,19,26,28-32]. Interpretation of AMH levels is laboratory assay-dependent [33-35], and there is no international standard; therefore, clinicians should be guided by their own laboratory's reference ranges. In general, a level well above the laboratory's lower threshold for normal suggests adequate ovarian reserve. As the level falls below the lower limit of normal, the probability of diminished ovarian reserve progressively increases, with very low levels suggesting pregnancy is less likely to occur and the patient will have a poor response to IVF [13,28]. One review suggested the following general guidelines [36]:

●AMH <0.5 ng/mL predicts reduced ovarian reserve with less than three follicles in an IVF cycle.

●AMH <1.0 ng/mL predicts baseline ovarian reserve with a likelihood of limited eggs at retrieval.

●AMH >1.0 ng/mL but <3.5 ng/mL suggests a good response to stimulation.

●AMH >3.5 ng/mL predicts a vigorous response to ovarian stimulation and caution should be exercised in order to avoid ovarian hyperstimulation syndrome.

Assessment of fallopian tube patency — We perform HSG as the first-line test for evaluation of tubal patency because of therapeutic, as well as diagnostic, benefits [37]. HyCoSy is a reasonable alternative; the choice of test is determined by availability.

When the diagnosis is in doubt, more invasive tests can be used to confirm the diagnosis and provide an opportunity for concurrent therapeutic intervention. These tests include laparoscopy with chromotubation and fluoroscopic/hysteroscopic selective tubal cannulation.

Hysterosalpingogram — HSG is the standard of care to look for tubal occlusion in all patients (image 1), unless laparoscopy is planned [38-40]. In HSG, water- or lipid-soluble contrast media is used to fill the uterus and fallopian tubes, which are then imaged using fluoroscopy (ionizing radiation). HyCoSy is a reasonable alternative. HSG also provides information about the uterine cavity. Women with abnormalities on HSG should be referred to a reproductive endocrinologist to discuss treatment options. (See "Hysterosalpingography".)

HSG is not useful for detecting peritubal adhesions or endometriosis [38]. We perform diagnostic laparoscopy and chromotubation in women suspected of having endometriosis or pelvic adhesions related to a previous pelvic infection or surgery. Ablation of implants and lysis of adhesions, when indicated, can be performed at the same procedure. (See 'Role of laparoscopy' below.)

A meta-analysis of 20 studies involving 4179 patients compared HSG and laparoscopy with chromotubation (the gold standard); the calculated sensitivity and specificity for diagnosis of tubal patency were only 65 and 83 percent, respectively [38]. However, when subgroups of women undergoing HSG were analyzed, HSG appeared to have very high specificity and sensitivity for diagnosing distal tubal occlusion or major distal tubal adhesions, but much lower specificity for diagnosing proximal tubal occlusion.

Proximal tubal occlusion on HSG often represents testing artifact due to tubal spasm or poor catheter positioning leading to unilateral tubal perfusion. Given these deficiencies, findings of proximal tubal occlusion on HSG could be confirmed by a secondary test such as a repeat HSG, fluoroscopic or hysteroscopic selective tubal perfusion, or laparoscopic chromotubation if definitive diagnosis will influence further management.

Diagnostic HSG also appears to have therapeutic effects. A systematic review of 12 randomized trials found that pregnancy rates were significantly higher in subfertile women who underwent tubal flushing with oil soluble media than in those who did not undergo HSG (odds ratio [OR] 3.30, 95% CI 2.00-5.43), and that pregnancy rates were similar whether oil or water soluble media were used (OR 1.21, 95%CI 0.95-1.54) [37].

Hysterosalpingo-contrast sonography — Hysterosalpingo-contrast sonography (HyCoSy) uses ultrasound to view the uterus, tubes, and adnexa before and after transcervical injection of echogenic contrast media (either microbubble contrast or agitated saline). It is a safe, well tolerated, quick and easy method for obtaining information on tubal status, the uterine cavity, the ovaries, and the myometrium using conventional ultrasound [40,41]. In a 2014 systematic review of studies that compared HyCoSy with HSG for diagnosis of tubal occlusion in subfertile women, both tests had high diagnostic accuracy compared with laparoscopy (reference standard), with no significant difference between them. For HyCoSy, sensitivity was 0.92 (95% CI 0.82-0.96) and specificity was 0.95 (95% CI 0.90-0.97) per tube for diagnosing tubal occlusion. Tubal spasm and tubal fistula, as well as operator error could account for misdiagnoses. In our experience, patients tolerate HyCoSy better than HSG, and it is increasingly utilized as an alternative method to image the uterus and determine tubal patency if available.

Assessment of the uterine cavity — Modalities to assess the uterine cavity include saline infusion sonohysterography, three-dimensional sonography, hysterosalpingography (HSG), and hysteroscopy. Saline infusion sonohysterography is the preferred imaging modality to assess the uterine cavity because it provides information about the endometrial cavity, myometrium, and adnexa. While routine ultrasonography can be used to detect suspected leiomyomata, saline infusion sonohysterography is much better than routine ultrasonography for diagnosis of intrauterine adhesions, polyps, and congenital uterine anomalies [42] and performs similarly to hysteroscopy at detecting intrauterine pathology [43]. A variant of sonohysterography, HyCoSy, is a simple, time-efficient, and effective method to evaluate tubal patency, the uterine cavity, and the myometrium with one test [41]. (See "Saline infusion sonohysterography" and 'Hysterosalpingo-contrast sonography' above.)

While HSG is typically performed to assess tubal patency, HSG can also identify developmental or acquired abnormalities of the uterine cavity that negatively impact fertility, such as submucous fibroids, a T-shaped cavity (associated with DES exposure), polyps, synechiae, and congenital müllerian anomalies. Women who require tubal evaluation typically undergo HSG to assess both fallopian tube patency and uterine cavity anatomy. For women suspected of having a uterine septum on HSG, three-dimensional ultrasound or magnetic resonance imaging can distinguish between a uterine septum and a bicornuate uterus. Abnormalities found on HSG generally require further evaluation by other imaging modalities (three-dimensional sonography, sonohysterography, or magnetic resonance imaging), hysteroscopy, or laparoscopy and referral to a reproductive endocrinologist. (See "Hysterosalpingography" and "Congenital uterine anomalies: Clinical manifestations and diagnosis", section on 'Diagnostic tools'.)

Hysteroscopy is the definitive method for evaluation of abnormalities of the endometrial cavity and also offers the opportunity for treatment at the time of diagnosis when performed in the operating room. Limitations of hysteroscopy include lack of information about the myometrium, fallopian tubes, and adnexal structures. However, when hysteroscopy is performed with laparoscopy, the endometrial cavity and pelvic structures can be evaluated simultaneously, and thus eliminate the need for a separate study of the fallopian tubes. If the endometrial cavity is assessed by another modality, routine use of hysteroscopy may not be necessary. In a multicenter trial of 750 women with infertility and a normal transvaginal ultrasound of the uterine cavity, there were no differences in the live birth rates among the women assigned to routine hysteroscopy prior to IVF and the women who went directly to IVF without hysteroscopy (53 versus 51 percent) [44].

In our practice, we perform HSG or HyCoSy in infertile patients requiring assessment of tubal patency and uterine cavity evaluation. In women requiring only uterine cavity evaluation and no information on tubal status (eg, patients going directly to IVF for severe male factor), we perform either saline infusion sonohysterography or flexible hysteroscopy in the office to assess the uterine cavity.

Evaluation of uterine anomalies depends on the anomaly.

●(See "Overview of hysteroscopy".)

●(See "Saline infusion sonohysterography".)

●(See "Congenital uterine anomalies: Clinical manifestations and diagnosis".)

●(See "Uterine fibroids (leiomyomas): Hysteroscopic myomectomy".)

●(See "Intrauterine adhesions: Clinical manifestation and diagnosis".)

ROLE OF LAPAROSCOPY — The role of laparoscopy in the evaluation of infertility is controversial. Laparoscopy is invasive and expensive. Findings at laparoscopy usually do not alter the initial treatment of the infertile couple when the initial infertility evaluation is normal or when it shows severe male factor infertility. However, as endometriosis may be present in up to 50 percent of women who present with a complaint of infertility [45,46], the clinician must decide when women who present for the evaluation of infertility undergo surgical exploration for endometriosis and other pathology as part of their workup.

●Laparoscopy may be indicated in women in whom endometriosis or pelvic adhesions/tubal disease is suspected based on physical examination, HSG, or history (eg, current dysmenorrhea, pelvic pain, or deep dyspareunia; previous complicated appendicitis, pelvic infection, pelvic surgery, or ectopic pregnancy) [45,47,48]. When we perform laparoscopy, we also perform chromotubation to assess tubal patency and hysteroscopy to evaluate the uterine cavity. For this reason, if laparoscopy is planned, then HSG can be omitted [49]. (See "Endometriosis: Treatment of infertility in females".)

●Women with infertility but no endometriosis symptoms or prior surgical exploration undergo a complete infertility evaluation, as do their partners. Couples with a normal infertility evaluation (ie, unexplained infertility) typically undergo a trial of ovarian stimulation with or without intrauterine insemination, and many will conceive without further intervention. No randomized trials have assessed the cost-effectiveness and timing of diagnostic laparoscopy prior to ovulation induction in couples with unexplained infertility. Couples with tubal or male factor infertility are typically offered IVF as one of their treatment options and bypass laparoscopy. (See "Unexplained infertility" and "In vitro fertilization: Overview of clinical issues and questions".)

The advantage of performing laparoscopy early in the evaluation of women suspected of having endometriosis or pelvic adhesions is that surgical therapy can be initiated or referred directly to IVF, while avoiding potentially ineffective or unnecessary empiric medical treatment such as ovulation induction. Endometriosis, if identified, can be excised/ablated at the time of the diagnostic procedure, and pelvic adhesions can be lysed. (See "Endometriosis: Treatment of infertility in females".)

The use of laparoscopy to treat infertility is covered in detail separately. (See "Female infertility: Reproductive surgery".)

TESTS OF LIMITED CLINICAL UTILITY

Postcoital test — In agreement with other experts, we do not recommend postcoital testing or the sperm mucus penetration test, as neither test helps guide treatment selection [1,50,51].

The postcoital test has poor diagnostic potential and predictive value [52,53] that is due, in part, to the lack of consensus on a normal versus abnormal test result and to low inter- and intraobserver reproducibility [54]. In addition, interventions designed to improve cervical factor infertility have not been effective, while widely used infertility therapies, such as intrauterine insemination and IVF, bypass the cervix, so improving cervical factors becomes irrelevant. Importantly, a randomized trial that compared the outcome of infertility investigations with and without the postcoital test showed no difference in pregnancy rates at 24 months [55]. Thus, incorporation of the postcoital test in standard infertility evaluations increases the number of tests and treatments but has no effect on the pregnancy rate.

Endometrial biopsy — The American Society of Reproductive Medicine highlights the lack of benefit of the endometrial biopsy in the evaluation of the infertile female and does not recommend use of this test unless endometrial pathology is strongly suspected [1,56]. Historically, endometrial biopsy has been performed for two reasons: (1) to document a secretory endometrium, which is indirect evidence that ovulation has occurred, and (2) to evaluate whether the maturity of the secretory endometrium is in phase (ie, consistent with menstrual cycle date) or out of phase (ie, luteal phase defect). It is not a good test for either indication because it is invasive, expensive, uncomfortable, unnecessary for evaluation of ovulation, and ineffective for assessment of endometrial receptivity (ie, the ability of the endometrium to allow the blastocyst to attach, invade, and implant).

As discussed above, ovulation is optimally assessed using serum progesterone level >3 ng/mL obtained in the late luteal phase. (See 'Assessment of ovulatory function' above.)

Although endometrial receptivity during the implantation window is crucial for achieving pregnancy, histological assessment of endometrial response has a poor correlation with fertility [57-61]. For example, when repeated endometrial biopsies are performed in normal fertile women, half will have a single out-of-phase biopsy (using two-day or greater lag criteria) and over one-quarter will have sequential out-of-phase biopsies [62,63]. Moreover, in one study of 619 women with regular menstrual cycles, a biopsy that was out-of-phase by greater than two days was actually more common in fertile women than in infertile women (at day 21 to 22: 49 versus 43 percent; at day 26 to 27: 35 versus 23 percent). Thus, it appears that histological dating does not discriminate fertile from infertile couples [62,63]. As the treatment of luteal phase defect does not improve pregnancy outcome in infertile women, luteal phase evaluation by histological dating of the endometrium is not recommended [56].

Basal body temperature records — Basal body temperature charts are the least expensive method for detecting ovulation, although interpretation of the charts can be difficult and subject to wide interobserver variation [64,65]. We prefer serum or urine testing for assessment of ovulatory status in women with irregular cycles. (See 'Assessment of ovulatory function' above.)

Progesterone released from the corpus luteum at the time of ovulation has potent effects on the hypothalamus, one of which is to increase body temperature. As a result, daily temperature monitoring can be used to document progesterone production and, therefore, ovulation. The woman takes her temperature by putting the thermometer under her tongue every morning while she is still in the basal state (ie, before she gets out of bed, uses the bathroom, or has anything to eat or drink) and records the temperature on a chart. Although there is an expected amount of daily variability, an approximately 0.5ºF rise in body temperature can be detected in the luteal phase of the menstrual cycle compared with the follicular phase. In a normal cycle, the temperature rise begins one or two days after the LH surge and persists for at least 10 days. Thus, temperature changes are sufficient to retrospectively identify ovulation, but they occur too late to be useful for timing intercourse.

Mycoplasma cultures — We do not suggest obtaining routine Ureaplasma urealyticum and Mycoplasma hominis cultures given that there is minimal evidence for a role of these organisms in female infertility [66]. (See "Mycoplasma hominis and Ureaplasma infections".)

Testing for antibodies — Routine testing for antiphospholipid, antisperm, antinuclear, and antithyroid antibodies is not supported by existing data [67]. Although an association between antiphospholipid antibodies and recurrent pregnancy loss has been established, the other autoimmune factors remain under investigation as markers of fertility treatment failure. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

Karyotype — There is a general consensus to counsel and offer to karyotype the male partner if there is severe oligospermia, as these men are at higher risk of karyotypic abnormalities. Separate testing for Y chromosome microdeletions may also be offered. We suggest karyotyping women with premature ovarian insufficiency or a family history of early ovarian insufficiency (prior to age 40) and both partners if there have been recurrent pregnancy losses. In most other circumstances, karyotyping is not indicated as part of the initial evaluation because of the low incidence of abnormalities in women with unexplained infertility, endometriosis, or tubal factor infertility [68]. Karyotype may be useful in patients with these conditions who have failed initial treatment approaches and plan to undergo IVF, although the cost-effectiveness of universal karyotype screening prior to IVF has not been established [69].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Female infertility (The Basics)" and "Patient education: Infertility in couples (The Basics)")

●Beyond the Basics topics (see "Patient education: Ovulation induction with clomiphene or letrozole (Beyond the Basics)" and "Patient education: Evaluation of infertility in couples (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●When to initiate an infertility evaluation – The timing of an infertility evaluation is impacted mainly by the age of the female partner but also influenced by the underlying health status of both partners (table 1).

•Standard – We offer an infertility evaluation to females under age 35 years who have not been able to conceive after 12 months of unprotected and frequent intercourse. (See 'When to initiate an infertility evaluation' above.)

•Earlier evaluation – Earlier evaluation (eg, after six months) is indicated in some patients, such as when the female partner is over 35 years of age or has a history of oligo/amenorrhea, known or suspected tubal disease or endometriosis, or when the male partners has a known male factor for infertility.

•Immediate evaluation – Immediate evaluation may be undertaken in female patients aged 40 years and older, those with a history of chemotherapy or radiation therapy, and those in whom there is a clear anatomic contributor to infertility (eg, vasectomy or tubal obstruction). (See 'Initial approach' above.)

●Components of initial evaluation – Both partners of an infertile couple should be evaluated for factors that could be impairing fertility; multiple contributing factors may coexist. (See 'Initial approach' above.)

•History and physical examination – The history (table 2) and physical examination are directed at identifying signs and symptoms suggestive of the etiology of the infertility. (See 'History and physical examination' above.)

•Diagnostic tests – The basic infertility evaluation of all couples consists of (see 'Diagnostic tests' above):

-Semen analysis. (See 'Semen analysis' above.)

-Assessment of ovulatory status by history or laboratory testing. (See 'Assessment of ovulatory function' above.)

-Determination of tubal patency and presence or absence of abnormalities of the uterine cavity, usually by hysterosalpingogram. (See 'Assessment of fallopian tube patency' above and 'Assessment of the uterine cavity' above.)

•Assessment of ovarian reserve – For the evaluation of women with infertility, we assess ovarian reserve with an anti-müllerian hormone (AMH) level and day 3 follicle-stimulating hormone (FSH) and estradiol levels. Other tests such as the antral follicle count and/or clomiphene citrate challenge test (CCCT) may be utilized. (See 'Assessment of ovarian reserve' above.)

●Role of laparoscopy – Diagnostic laparoscopy may be indicated for females with suspected high-stage endometriosis or pelvic adhesions or other coexisting factors warranting laparoscopy, such as significant pelvic pain or worrisome ovarian cysts. When we perform laparoscopy, we also perform chromotubation to assess tubal patency and hysteroscopy to evaluate the uterine cavity. (See 'Role of laparoscopy' above.)

●Tests of limited clinical utility – Tests of limited clinical utility include the postcoital test, basal body temperature recording, endometrial biopsy to detect luteal phase defect, genital cultures for mycoplasma, antibody testing (antiphospholipid, antisperm, antinuclear, and antithyroid antibodies), and karyotype. (See 'Tests of limited clinical utility' above.)