# Infertility: Initial Evaluation and Management

## Definitions

Infertility is defined as the failure to achieve clinical pregnancy after 12 months of regular unprotected intercourse. Evaluation should be initiated earlier, after 6 months, in women aged 35 or older or those with known risk factors such as irregular cycles, endometriosis, prior pelvic surgery, or male factor concerns. Primary infertility refers to patients who have never achieved a pregnancy, while secondary infertility applies to those with infertility after at least one prior pregnancy, regardless of its outcome. Fecundability is the probability of achieving pregnancy in a single menstrual cycle, which is approximately 20 to 25% in healthy couples. Subfertility describes reduced fecundability and encompasses the spectrum between normal fertility and absolute sterility.

## Epidemiology

Infertility affects approximately 15% of couples. The distribution of causes is roughly 40% female factor, 30% male factor, 20% combined, and 10 to 15% unexplained. The prevalence is increasing due to delayed childbearing, rising rates of obesity, and declining semen parameters.

## Etiologic Categories

### Female Factors

Ovulatory dysfunction accounts for 25 to 30% of female factor infertility and includes PCOS, hypothalamic amenorrhea, hyperprolactinemia, thyroid disorders, and premature ovarian insufficiency. Tubal and peritoneal factors, also responsible for 25 to 30% of cases, encompass tubal occlusion from pelvic inflammatory disease or sexually transmitted infections, endometriosis, prior ectopic pregnancy, prior pelvic surgery, and adhesions. Uterine factors account for 5 to 10% and include submucosal fibroids, endometrial polyps, Asherman syndrome, and Mullerian anomalies such as a septate uterus. Diminished ovarian reserve from advanced maternal age, prior ovarian surgery, or genetic factors is an increasingly important cause. Cervical factor accounts for less than 5% and is rarely a primary cause of infertility.

### Male Factors

Male factors include abnormal semen parameters such as oligospermia, asthenospermia, and teratospermia. Varicocele is a common correctable cause. Obstructive azoospermia may result from vasectomy or congenital bilateral absence of the vas deferens. Non-obstructive azoospermia is associated with Klinefelter syndrome and Y chromosome microdeletions. Ejaculatory dysfunction and hypogonadism (primary or secondary) are additional causes. Environmental and lifestyle factors including heat exposure, tobacco, cannabis, and anabolic steroid use can impair spermatogenesis.

## Female Evaluation

### History

A thorough history covers menstrual cycle regularity and length, dysmenorrhea, prior pregnancies and their outcomes, sexual history including frequency, timing, and dyspareunia, prior pelvic infections, surgeries, or ectopic pregnancies, and symptoms of endometriosis. Medical conditions such as thyroid disease, diabetes, and autoimmune disorders are relevant. Medications, supplements, substance use, and family history of infertility, premature menopause, or genetic conditions should be documented.

### Assessment of Ovulation

Regular menstrual cycles occurring every 24 to 35 days are strongly predictive of ovulation. Basal body temperature charting can confirm ovulation retrospectively when a biphasic pattern showing a 0.3 to 0.5 degree Fahrenheit rise during the luteal phase is observed. Urinary LH surge detection kits predict ovulation 24 to 36 hours before it occurs. Mid-luteal serum progesterone drawn 7 days before expected menses confirms ovulation when the level exceeds 3 ng/mL. Endometrial biopsy is no longer recommended for routine ovulation assessment.

### Ovarian Reserve Testing

Day 3 FSH and estradiol provide information about ovarian reserve. An FSH above 10 to 12 mIU/mL suggests diminished reserve. An elevated day 3 estradiol above 60 to 80 pg/mL with a normal FSH may mask diminished reserve, since the estradiol suppresses FSH through negative feedback. Anti-Mullerian hormone can be drawn on any cycle day, reflects the antral follicle pool, and is the most convenient ovarian reserve marker. A level below 1.0 ng/mL indicates diminished ovarian reserve. AMH declines with age but does not predict egg quality. Antral follicle count is obtained by transvaginal ultrasound on cycle day 2 to 5, counting follicles measuring 2 to 9 mm in both ovaries. A total antral follicle count below 5 to 7 suggests diminished reserve. The clomiphene citrate challenge test is rarely used now, having been largely replaced by AMH and AFC.

### Tubal Assessment

Hysterosalpingography is the first-line test for tubal patency. Contrast is injected through the cervix under fluoroscopy, and spill of contrast from the fimbriated ends confirms patency. HSG also evaluates uterine cavity contour. It cannot reliably distinguish between tubal spasm and true occlusion. A noteworthy finding from the H2Oil randomized controlled trial is that oil-soluble contrast may have a small therapeutic effect, improving fertility rates. Saline infusion sonohysterography evaluates the uterine cavity for polyps, fibroids, and adhesions but does not assess tubal patency. Hysterosalpingo-contrast sonography (HyCoSy) is an ultrasound-based tubal assessment using agitated saline or contrast and is gaining use as an alternative to HSG. Diagnostic laparoscopy with chromopertubation remains the gold standard for tubal assessment but is reserved for suspected endometriosis or equivocal results from other tests and is not a routine first-line study.

<image>Hysterosalpingography images showing normal findings with bilateral contrast spill confirming tubal patency and normal uterine cavity, compared with abnormal findings showing proximal tubal occlusion bilaterally, unilateral hydrosalpinx with distal tubal dilation and no spill, and a uterine filling defect suggestive of a polyp or submucous fibroid</image>

### Uterine Evaluation

HSG assesses cavity contour and can reveal filling defects and anomalies. Saline infusion sonohysterography is superior to HSG for detecting intracavitary pathology such as polyps and submucosal fibroids. MRI is used for delineating Mullerian anomalies, particularly for distinguishing a septate from a bicornuate uterus. Hysteroscopy serves as both the diagnostic and therapeutic gold standard for intracavitary lesions.

## Male Evaluation

### Semen Analysis

Semen analysis is the cornerstone of the male evaluation. The specimen should be collected after 2 to 5 days of abstinence. If results are abnormal, the analysis should be repeated 2 to 3 months later, as the spermatogenesis cycle spans approximately 72 days. The WHO 2021 reference values include a volume of at least 1.4 mL, concentration of at least 16 million per mL, total motility of at least 42%, progressive motility of at least 30%, normal morphology of at least 4% by strict Kruger criteria, and total sperm count of at least 39 million per ejaculate.

| Parameter | WHO 2021 Lower Reference Limit |
|---|---|
| Volume | ≥1.4 mL |
| Concentration | ≥16 million/mL |
| Total sperm count | ≥39 million/ejaculate |
| Total motility | ≥42% |
| Progressive motility | ≥30% |
| Normal morphology (strict Kruger) | ≥4% |

### Abnormal Semen Analysis -- Further Workup

An abnormal result should first be confirmed with a repeat analysis. Hormonal evaluation includes FSH, LH, total testosterone, and prolactin. Referral to a reproductive urologist is indicated for azoospermia (to distinguish obstructive from non-obstructive causes), severe oligospermia below 5 million per mL, and varicocele assessment. Genetic testing with karyotype, Y chromosome microdeletion analysis, and CFTR mutation testing (if congenital bilateral absence of the vas deferens is suspected) may be warranted.

## Unexplained Infertility

Unexplained infertility is a diagnosis of exclusion, assigned when ovulation is confirmed, tubes are patent, the uterine cavity is normal, and the semen analysis is normal. It accounts for 10 to 15% of infertile couples. The underlying cause is likely multifactorial, involving subtle ovulatory dysfunction, impaired oocyte quality, peritoneal environment factors, or immunologic issues. Age-related decline in oocyte quality is probably the predominant factor in many cases.

## Treatment

### Lifestyle Optimization

Weight management targeting a BMI between 19 and 30 optimizes fertility. Smoking cessation is important for both partners. Alcohol and caffeine should be limited. Folic acid at 400 to 800 mcg daily should be started preconceptionally. Regular moderate exercise is encouraged, while excessive exercise should be avoided. For men, reducing heat exposure to the testes from tight underwear, hot tubs, and laptop use may improve semen parameters.

### Ovulation Induction

#### Letrozole (Aromatase Inhibitor)

Letrozole is the first-line agent for ovulation induction in PCOS, with the NICHD randomized controlled trial demonstrating superior live birth rates compared to clomiphene. The dose is 2.5 to 7.5 mg daily on cycle days 3 to 7. By inhibiting aromatase, letrozole decreases estrogen levels, which results in increased FSH release. It has advantages over clomiphene including a lower multiple pregnancy rate and less anti-estrogenic effect on the endometrium.

#### Clomiphene Citrate

Clomiphene citrate at 50 to 150 mg daily on cycle days 5 to 9 is a selective estrogen receptor modulator that blocks estrogen feedback at the hypothalamus and pituitary. Its anti-estrogenic effects on the endometrium and cervical mucus are potential disadvantages. The ovulation rate is approximately 80%, with a per-cycle pregnancy rate of about 10 to 15%. A maximum of 6 ovulatory cycles is recommended, as returns diminish after that.

#### Gonadotropins (Injectable FSH)

Gonadotropins are second-line after oral agents fail. They require close monitoring with ultrasound and estradiol levels because of the risk of ovarian hyperstimulation syndrome and multiple pregnancy. A low-dose step-up protocol is used for PCOS patients to minimize hyperstimulation.

### Intrauterine Insemination (IUI)

Intrauterine insemination involves placing washed sperm directly into the uterine cavity around the time of ovulation. It is typically combined with ovulation induction using letrozole or clomiphene with or without a trigger shot. Indications include unexplained infertility, mild male factor, cervical factor, and ovulatory dysfunction. Success rates are 10 to 20% per cycle when combined with ovulation induction. Three to six cycles are generally recommended before proceeding to IVF.

### In Vitro Fertilization (IVF)

IVF involves controlled ovarian hyperstimulation, oocyte retrieval, fertilization in the laboratory, and embryo transfer. Indications include tubal factor, severe male factor, failed ovulation induction or IUI, moderate to severe endometriosis, diminished ovarian reserve, advanced maternal age, and unexplained infertility after failed initial treatments. Success rates are 40 to 50% live birth per transfer for women under 35 and decline with increasing age. Intracytoplasmic sperm injection (ICSI) involves direct injection of a single sperm into the oocyte and is used for severe male factor or prior fertilization failure. Preimplantation genetic testing for aneuploidy (PGT-A) involves trophectoderm biopsy to screen for chromosomal abnormalities.

<image>Stepwise treatment algorithm for infertility: lifestyle optimization for all patients, then ovulation induction with letrozole or clomiphene plus timed intercourse or IUI for 3-6 cycles, followed by gonadotropins with IUI, and finally IVF/ICSI for refractory cases, with accelerated timelines for advanced maternal age or severe male/tubal factor</image>

### When to Refer to REI

Referral to a reproductive endocrinology and infertility specialist is indicated for patients aged 38 or older (to expedite evaluation and treatment), bilateral tubal occlusion, severe male factor (azoospermia or severe oligospermia), diminished ovarian reserve (low AMH or high FSH), failure of 3 to 6 cycles of ovulation induction plus IUI, known stage III to IV endometriosis, need for IVF, ICSI, or fertility preservation, and recurrent pregnancy loss.

## Clinical Pearls

Both partners should be evaluated simultaneously. A semen analysis should not be deferred until after completing the entire female workup.

AMH is the most convenient ovarian reserve marker because it can be drawn on any cycle day and remains stable across the cycle, though it does not predict egg quality.

Letrozole has surpassed clomiphene as the preferred first-line ovulation induction agent for PCOS.

HSG with oil-soluble contrast may have a small therapeutic benefit through flushing of the tubes. The H2Oil trial demonstrated higher ongoing pregnancy rates with oil-based contrast.

Unexplained infertility in a woman aged 38 or older should be treated more aggressively, with early referral for IVF rather than prolonged empiric IUI cycles.

A single abnormal semen analysis should be confirmed with a repeat test 2 to 3 months later before diagnosing male factor infertility.

Folic acid supplementation should begin at least 1 month before conception. Women with a prior neural tube defect-affected pregnancy should take 4 mg daily.

## References

- ACOG Committee Opinion No. 781: Infertility Workup for the Women's Health Specialist (2019)
- ASRM Practice Committee. Diagnostic evaluation of the infertile female. Fertil Steril. 2015;103:e44-e50
- ASRM Practice Committee. Diagnostic evaluation of the infertile male. Fertil Steril. 2015;103:e18-e25
- Legro RS et al. Letrozole versus clomiphene for infertility in PCOS. N Engl J Med. 2014;371:119-129
- Dreyer K et al. (H2Oil trial). Oil-based or water-based contrast for hysterosalpingography. N Engl J Med. 2017;376:2043-2052
- WHO Laboratory Manual for the Examination and Processing of Human Semen, 6th Edition (2021)
- NICE Guideline NG156: Fertility Problems -- Assessment and Treatment (2017, updated 2023)