Amanda Kallen, MD

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Many couples choose to be childless; no one chooses to be infertile. In a classic 1956 study by Alan Guttmacher examining conception rates among 5,574 women attempting pregnancy, 85% conceived within 12 months.

However, it has also become increasingly clear that time to conception is strongly influenced by age-related factors, including declining oocyte quantity and quality over time. Indeed, Guttmacher also reported a doubling of median conception time from age 24 to 44.

Thus, while infertility is more the lack of a “normal” physiological outcome than a disease per se, a thorough workup for infertility is essential to identify underlying disease. In addition, lifestyle issues and environmental factors can adversely affect infertility. 

Importantly, infertility may be a marker of non-reproductive disease and often portends serious health issues. 

how each of these factors affect normal physiology, their diagnosis, and the treatment designed to achieve the delivery of a healthy term baby.

The breathtaking physiology of reproduction may go astray in any facet and result in infertility. Evaluation for that aberration, followed by diagnosis-specific treatment, is perhaps the most cost-effective way to help a couple conceive. This is an opportune time to add antenatal screening to the basic diagnostic evaluation of the infertile couple (

Tubal disease is a common cause of infertility, with reported rates between 25-35% of infertility diagnoses

 depending on the population being tested. Tubal obstruction is suspected in women with a history of sexually transmitted infection, cervical dysplasia, abdominal surgery or previous intra-abdominal infection (e.g., ruptured appendix). 

While laparoscopy with chromotubation is often considered the “gold standard” for evaluation of tubal disease, hysterosalpingography (HSG), with a sensitivity and specificity of 65% and 83%, respectively

 is considered the first-line diagnostic tool. 

Radiopaque dye is injected into the uterus and followed through the Fallopian tubes under fluoroscopy. A similar procedure utilizing ultrasound instead of fluoroscopy, sonohysterography (SHG), is less reliable in determining tubal patency although more accurate for uterine evaluation6 with a sensitivity and specificity of 76% and 67%.

Treatment options for tubal infertility include tubal cannulation (for proximal tubal obstruction)

, surgery for tubal reanastomosis, or in vitro fertilization (IVF), which bypasses tubal blockage, with IVF being frequently employed due to success rates and comparable costs with surgery.

Endometriosis is a complex condition characterized by the presence of endometrial tissue in sites outside the uterine cavity. Endometriosis frequently presents with pain and affects 25-40% of women with infertility.

 Posited mechanisms for the relationship between endometriosis and infertility include distortion of pelvic anatomy, tubal obstruction, impaired oocyte quality, release and pickup, and altered endometrial receptivity, although a definite cause-effect relationship between any of these pathologies and endometriosis-related infertility is controversial. 

While excisional surgery has been shown to improve spontaneous pregnancy rates in women with endometriosis

, surgery is not recommended for the routine evaluation of infertility in women without other symptoms of endometriosis.

Endometrial polyps, intracavity leiomyomas, intrauterine synechiae and Mullerian anomalies with associated distortion of the endometrial cavity may be associated with infertility. 

Superior to the HSG in detecting uterine anomalies, sonohysterography detects intrauterine polyps or leiomyomas with a sensitivity and specificity of 91% and 84%, respectively.

 Direct visualization via hysteroscopy may be used to confirm the diagnosis (Figure 1). Treatment to remove the distorting mass is surgical.

The cervix is the entry to the upper reproductive tract. Its alkaline mucus protects sperm from the acidity of the vagina and guides sperm into the upper reproductive tract. 

Structural alterations of the cervix, either congenital or post-surgical (for example, after loop electrosurgical excision procedure (LEEP) or large cervical cone biopsy) can cause cervical stenosis and prevent sperm entry.

Post-operative stenosis is diagnosed by the failure to pass a 1 mm probe into the uterine cavity. The post-coital test, performed after intercourse to assess the viability of sperm in mucus, has been used to evaluate cervical function; however, the limited predictive value of this test has relegated it to history (Table 2). 

In the absence of mucus and in the presence of cervical stenosis, intrauterine insemination is a successful therapy, assuming all other factors are normal.

Failure to ovulate results from a variety of non-reproductive influences including thyroid disease, pituitary disease, elevated androgens from adrenal hyperplasia, obesity, and stress. Anovulation is diagnosed by a mid-luteal serum progesterone concentration <3 ng/ml, although mid-luteal serum progesterone levels are usually higher than 7 ng/mL,

 and should be suspected when cycles are irregular and occur more often than every 21 days and less often than every 36 days. 

The most common cause of anovulation is a metabolic disease, polycystic ovarian syndrome (PCOS) in which multiple follicles exist in various stages of development and are simultaneously a result of and caused by an altered hormonal milieu including insulin resistance, elevated LH, and elevated androgens.

Women who do not ovulate do not produce progesterone and thus are at risk for the consequences of unopposed estrogen:endometrial hyperplasia and cancer. 

Similarly, women with PCOS may experience non-reproductive disorders, particularly, acne, hirsutism and hyperinsulinemia. The metabolic consequences of PCOS increase a woman’s risk of diabetes mellitus, hyperlipidemia, gestational hypertension and gestational diabetes. 

Correcting thyroid deficiency, lowering elevated prolactin, blocking elevated adrenal androgen production often stimulates ovulation. Weight loss of 15% of body weight often prompts ovulation to resume.

Infertility associated with anovulation is best treated with ovulation induction unless other factors such as diminished ovarian reserve and male factors are present.

OVARIAN AGING (DIMINISHED OVARIAN RESERVE)

Female fecundity (the ability to conceive and carry a pregnancy to term) declines with increasing age, decreasing more rapidly after age 35,

 reflecting, in part, the progressive loss of oocytes (the “ovarian reserve”) that occurs with age. Aging oocytes also accumulate meiotic defects and DNA damage, causing deterioration of gamete quality and increasing the risk of aneuploid embryos and miscarriage.

Therefore, women over 35 who have failed to conceive for six months should be offered expedited evaluation and treatment; for women over 40, immediate evaluation is warranted.

Ovarian reserve refers to the number of oocytes available for stimulation and ovulation. It can be evaluated using serum FSH and estradiol concentrations on days 3-5 of a menstrual cycle, serum anti-Müllerian hormone (AMH), and/or ultrasound imaging of the ovaries for antral follicle count and ovarian volume determination (Table 3).

Notably, these tests may be predictive of response to exogenous ovarian stimulation and are not predictive of live birth or even natural fertility. Accelerated oocyte loss can result in loss of fertility and early menopause (prior to age 40). 

While the majority of these cases are idiopathic,

 ovarian reserve should be monitored in women with a history of prior ovarian surgery, chemotherapy, radiation therapy, or with a family history of premature menopause. These women may be at risk for carrying the fragile X (FMR1) pre-mutation and also the consequences of estrogen deprivation.

Disorders of male physiology occur in 35% of infertile couples and are the sole factor in 17% of couples.

Similar to the female, in the male, FSH and LH stimulate the testes to produce testosterone and develop the immature gametes. Unlike the oocytes, sperm mature for three months in the male reproductive tract before being ejaculated.

 of the male may arise from all areas of male reproductive physiology. When testosterone is low but not absent, erectile dysfunction and decreased libido commonly accompany alter semen parameters

 also results in azoospermia. In addition, the concomitant lack of testosterone results in decreased libido and erectile dysfunction. As testosterone concentrations drop in the male, risk for heart disease, hyperlipidemia, osteopenia, and muscular mass loss increases. 

Testosterone failure is diagnosed by a low serum testosterone and elevated LH and FSH. Of course, correcting any hormonal abnormality and screening for related disorders should precede treatment.

Diagnosis of male factor infertility begins with a well collected, comprehensive semen analysis performed in a certified andrology laboratory (Table 4). The semen sample is best collected at the laboratory, but when it must be collected at home, it should be delivered to the laboratory at body temperature within 30 to 60 minutes after ejaculation.

A diagnosis of an “abnormal” semen analysis should only be made after a confirmatory semen analysis has been performed, and must be interpreted in the context of the couple’s overall fertility evaluation. Other tests of sperm function are available, but their practical diagnostic value is subject to interpretation and are clinically not as useful.

 is the absence of sperm in the ejaculate, not necessarily indicating an absence of sperm in the upper reproductive tract or the testes. 

When the vas is patent, retrograde ejaculation may be diagnosed by retrieving sperm from the urine after orgasm and may be washed and used for intrauterine insemination. If the vas is blocked, sperm may be aspirated from the epididymis (MESA) or surgically extracted from the testes (TESA) and used for intracytoplasmic sperm injection (ICSI) at IVF. 

In cases of azoospermia in which the sperm must be retrieved from the testes, testing for a mutation in the DAZ (Deleted in Azoospermia) gene can be a useful predictor of testicular sperm presence, as presence of the DAZ-c mutation predicts an almost 0% likelihood of finding sperm in the testes.

These genes may also be passed on to offspring; affected male patients may opt to use a donor sperm to prevent this outcome. 

Similarly, men with an absent vas deferens may have a mutated allele for cystic fibrosis or a 5-T variant and if sperm is aspirated from the epididymis or testes for use in IVF, the resultant child may inherit cystic fibrosis.

 Thus, screening for the mutations is recommended when an absent vas deferens is detected.

, or less than 15 million sperm/ml, and may signal partial retrograde ejaculation, hormonal disturbance or genetic conditions. If the testosterone levels are normal or low and the LH and FSH are normal, an empirical treatment with clomiphene citrate for 6 to 12 months may increase the sperm count.

Monitoring testosterone and the semen analysis after three months is recommended. 

 is diagnosed when motility is < 40%, while 

Male factor infertility may be treated by intrauterine insemination, possibly combined with ovulation induction of the female (COH-IUI) as discussed below. However, success rates with ICSI at IVF far exceed those with COH-IUI, especially when the normal morphology is <4% or the count is < 2million sperm/cc.

is an assistant professor of Obstetrics, Gynecology, and Reproductive Sciences in the Division of Reproductive Endocrinology and Infertility within the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, Yale University.

is a professor of Obstetrics, Gynecology, and Reproductive Sciences in the Division Chief, Division of Reproductive Endocrinology and Infertility within the Department of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, Yale University.

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Articles

This peer-reviewed article discusses the main causes of infertility, including tubal disease, uterine factor, cervical factor, and ovulatory dysfunction and anovulation. 

Author | Amanda Kallen, MD

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