Infertility: Causes, Common Presentations, and Treatments

Infertility is a common condition that has a wide range of causes and treatments. This presentation reviews recommended approaches to the diagnosis and evaluation of infertility, discusses some of the common and uncommon causative conditions, and describes available therapies.

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According to the American Society for Reproductive Medicine, infertility is defined as the inability to conceive after 12 months or more of appropriate, timed unprotected intercourse or therapeutic donor insemination (TDI); for women aged 35 years or older, evaluation and treatment are warranted after 6 months of unprotected intercourse or TDI.^[1] Average fecundity (ie, the monthly probability of conceiving a pregnancy that results in a live birth) is 15-18% per cycle. Observational studies suggest that about 85-90% of couples conceive after 1 year of intercourse; thus, as many as one in six couples will experience infertility.^[2]

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Infertility can be caused by problems specific to either males (35%) or females (35%).^[3] Additionally, there are causes of infertility that affect both sexes equally, such as drugs, environmental exposure, diet, and exercise (10%). Furthermore, it is also possible for the male and female partners to be affected by distinct causes concomitantly (<10%). Finally, 10% of cases of infertility remain unexplained after all known causes have been ruled out. This is a diagnosis of exclusion.

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The causes of infertility are commonly referred to as factors. For example, when a patient has a partner with abnormal sperm production or function, the problem is male factor infertility. Male factor infertility derives from three types of causes: pretesticular, testicular, and posttesticular.^[4] Pretesticular causes include problems with the hypothalamus, pituitary, or gonadal axis; an example is Kallmann syndrome (gonadotropin-releasing hormone [GnRH] neuron deficiency). Testicular causes include genetic problems (eg, Klinefelter syndrome) and nongenetic problems (eg, chemotherapy, infection, and varicocele). Posttesticular causes are obstructive to sperm (eg, hypospadias, cryptorchidism, absence of the vas deferens, infections, surgery, and trauma).

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Like male infertility, female infertility is classified into various factors on the basis of the anatomic location of the problem. The location can be anywhere in the female reproductive tract,^[5] which includes the cervix, the uterus, the fallopian tubes, the ovaries, and the peritoneum. Thus, women may have cervical factor, uterine factor, tubal factor, ovarian factor, or peritoneal factor infertility.

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Women with cervical factor infertility typically have a diagnosis of cervical stenosis, which prevents the sperm from entering the uterus and reaching the egg. Cervical stenosis can be a consequence of surgery (eg, a loop electrosurgical excision procedure [LEEP]), cervical infection with resultant scarring, hypoestrogenism, or radiation-induced changes; in rare cases, it can be congenital. Cervical factor infertility can also involve having dysfunctional or inadequate cervical mucus. Fertile cervical mucus (often descriptively referred to as egg-white cervical mucus) is necessary for transport of the sperm upward from the vagina into the uterus and is produced in response to the midcycle estrogen surge.

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Uterine factor infertility may result from a wide array of conditions. Congenital causes (eg, müllerian anomalies) can range from minor conditions to very severe ones.^[6] For example, in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, patients have normal ovaries but no upper vagina or uterus. Another congenital cause of uterine factor infertility is exposure to diethylstilbestrol (DES) in utero. Later in life, these so-called DES daughters are found to have T-shaped uteri that result in infertility, recurrent miscarriage, and preterm deliveries. Acquired causes of uterine factor infertility include endometritis, Asherman syndrome (scarring of the uterine lining [shown]), fibroids, and polyps, as well as iatrogenic causes such as hysterectomy.

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Tubal factor infertility derives from blockage or absence of one or both fallopian tubes. If both fallopian tubes are blocked, the embryo cannot travel into the uterus for implantation. Causes of tubal infertility include prior infection, previous tubal surgery, other tubal injury, or (rarely) fallopian tube torsion and necrosis.^[7] One common cause is a dilated and fluid-filled fallopian tube on one or both sides, a condition known as hydrosalpinx. Even if one tube is normal, a hydrosalpinx on the opposite side will leak inflammatory fluid into the endometrium, thereby decreasing pregnancy rates. Treatment of hydrosalpinx consists of removal or proximal occlusion of the affected fallopian tube.

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Ovarian factor infertility accounts for 40% of cases of female infertility. Ovarian reserve decreases with age, and the decline becomes steeper starting at approximately the age of 30 years.^[8] One of the most common causes of infertility is ovulatory dysfunction, including polycystic ovarian syndrome (PCOS). Patients with PCOS may have various other conditions as well, such as obesity and metabolic syndrome, and should be carefully followed long after their infertility has been diagnosed and treated. Finally, medical disorders (eg, malnutrition, excessive exercise, eating disorders, hypothyroidism, and hyperprolactinemia) can also contribute to anovulation by causing alterations in the hypothalamic-pituitary-ovarian (HPO) axis.

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Peritoneal factor infertility is caused by diseases in the pelvis and peritoneum, such as pelvic inflammatory disease (PID), pelvic adhesions, and endometriosis. Endometriosis is a condition in which endometrial tissue is found outside of the uterus. Endometriosis-associated infertility has been hypothesized to be due to (1) distorted adnexal anatomy, (2) dysfunctional oocyte development, and (3) reduced endometrial receptivity.^[9] Endometriosis is characterized by dysmenorrhea, dyspareunia, and dyschezia, among other symptoms. Patients with suspected endometriosis should be referred to providers who can perform surgery both to diagnose and to treat the disease.

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The basic workup of a patient with infertility begins with a thorough history, which should include pregnancy history, medical and surgical history, infection history, sexual history, menstrual history, and paternal history.^[10] A thorough physical examination is essential. Pelvic ultrasonography may be performed to evaluate antral follicle count, ovarian cysts, fibroids, polyps, and hydrosalpinx. Most patients need assessment of tubal patency by means of hysterosalpingography (HSG). Some patients need saline-infusion sonography (SIS) to characterize intracavitary abnormalities. Initial laboratory work should include determination of levels of follicle-stimulating hormone (FSH), estradiol, and possibly antimüllerian hormone (AMH) for ovarian reserve (this is optional).

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Patients who have ovulatory dysfunction should also be assessed for abnormal thyroid-stimulating hormone (TSH) and prolactin levels, which are easily correctable causes of irregular ovulation. In patients whose ovulation status is unclear, it may be helpful to obtain a midluteal progesterone value (typically on cycle day 21) to determine whether a patient is ovulatory. Patients who demonstrate signs or symptoms of hyperandrogenism (eg, hirsutism or virilization) should be referred to a specialist for assessment of androgen levels and targeted assessment of a possible neoplasm. Finally, a semen analysis is imperative (see slide 13).

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One of the most important tests in a standard infertility workup is the semen analysis. This test is useful in identifying abnormalities in sperm form and function that may be amenable to treatment aimed at improving a couple's fertility. Terms used to describe abnormal sperm include azoospermia (absence of sperm), oligospermia (decreased sperm concentration, <15 million/mL), asthenospermia (<40% with normal motility), and teratospermia (<4% with normal morphology). Patients can also have a combination of abnormalities, such as oligoasthenoteratozoospermia (concomitant abnormalities of concentration, motility, and morphology).

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Treatment of infertility depends on the specific diagnosis. If the diagnosis is male factor infertility with mild oligospermia or asthenospermia, patients may benefit from sperm washing and intrauterine insemination (IUI). Severe male factor infertility often necessitates the use of in-vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) or TDI. Women with uterine factor infertility due to fibroids or polyps may require surgery. Women with ovarian factor infertility (anovulation) generally require ovulation induction with medications such as clomiphene citrate, letrozole, or injectable gonadotropins. Women with tubal or peritoneal factor infertility generally require surgical correction or IVF.

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Assisted reproductive technology (ART) is a collective term for various technologies in which eggs and sperm are handled outside the body. It includes IVF and variations such as gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT). Briefly, a single IVF cycle consists of the following steps: ovarian stimulation, follicular aspiration, oocyte classification, sperm preparation, oocyte insemination and fertilization, embryo culture, and embryo transfer. The cycle generally takes about 2 weeks. Success rates are largely dependent on patient age, starting at 35-50% in women younger than 35 years and gradually falling to 5-10% or lower in women older than 40 years.^[3]

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A 25-year-old woman and her partner come to your office to discuss their trouble with conceiving. They have been having unprotected intercourse for the past 2 years, but no pregnancy has resulted. The patient is obese and says that she has "always been on the heavy side." She describes having a period every 2-5 months and states that when she does menstruate, the bleeding is very heavy. She has visible hair on her chin and upper lip, as well as moderate acne on her forehead.

What is the most likely cause of this couple's infertility?

1. Androgen-secreting ovarian tumor
2. Male factor infertility
3. PCOS
4. Hydrosalpinx

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Answer: C. PCOS.

PCOS is a condition of abnormal ovulation that, according to the Rotterdam criteria, is defined by the presence of at least two of the following: (1) oligoovulation or anovulation, (2) clinical or laboratory signs of hyperandrogenism, and (3) polycystic appearance of ovaries on ultrasonography. Assessment should include a morning 17-hydroxyprogesterone level to exclude congenital adrenal hyperplasia (CAH), along with TSH and prolactin levels. PCOS is associated with several long-term risks, such as insulin resistance, hyperlipidemia, and coronary vascular disease. Treatment of infertility in patients with PCOS usually involves ovulation induction with oral medications, followed by injectable gonadotropins in the event of inadequate response.

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A 30-year-old nulliparous woman and her partner come to your office with a complaint of inability to conceive after 2 years of unprotected intercourse. The patient's partner has two children from a previous marriage. The patient's history is significant for a remote history of chlamydial infection as a teenager, but she cannot remember if this was treated. Her menses are regular and occur every 28 days. The remaining findings from her history and physical examination are unremarkable.

What is the most likely diagnosis?

1. Cervical stenosis
2. Tubal factor infertility
3. PCOS
4. Endometriosis

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Answer: B. Tubal factor infertility.

Tubal occlusion should always be ruled out, but it is a particular concern in this patient because of her history of (possibly untreated) chlamydial infection. The rates of infertility after one, two, and three or more episodes of PID are about 12%, 23%, and 53%, respectively.^[11] Treatment generally consists of laparoscopic salpingectomy (shown) followed by IVF (if both tubes were removed). In some cases, there also is a role for tubal occlusion performed with tubal clips in order to prevent the spillage of inflammatory fluid into the uterine cavity before the start of IVF treatment.

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A 28-year-old woman and her 30-year-old fiancé come to your office to discuss their infertility. They have been attempting to conceive for 15 months, without success. The patient has had two previous uncomplicated vaginal deliveries after pregnancies with a different partner, and her fiancé has never fathered children. The patient describes regular menstrual cycles, with mild cramps during her period. She denies having any major medical problems, as does her partner.

What is the most likely diagnosis?

1. Male factor infertility
2. Uterine scarring (Asherman syndrome)
3. Thyroid disease
4. PCOS

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Answer: A. Male factor infertility.

The patient's history of previous uncomplicated pregnancies and normal menstrual cycles, in conjunction with the partner's lack of children, suggests that the problem may be male factor infertility. This form of infertility accounts for as many as 40% of cases where couples are unable to conceive. A semen analysis should always be performed as part of the initial infertility workup. It may show abnormalities in sperm concentration, motility, morphology (shown), or volume. The usual treatment for severe male factor infertility is TDI or IVF with ICSI. In the process of ICSI, a single isolated sperm is directly injected into the cytoplasm of the oocyte to increase the odds of fertilization.

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A 26-year-old woman and her 25-year-old husband come to your office for a second opinion. They have been attempting to conceive for 2 years, without success. They have recently been to a reproductive endocrinologist in a neighboring town, and they bring their laboratory results and imaging studies. The husband's semen analysis yielded normal findings, with good sperm parameters. The patient underwent ultrasonography and HSG, with normal findings in both cases, and she had normal results on AMH, FSH, TSH, prolactin, and ovulatory day 21 progesterone studies. Her menstrual history is unremarkable.

What is the diagnosis?

1. Hypothyroidism
2. Unexplained infertility
3. Anovulation (ovarian factor infertility)
4. Male factor infertility

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Answer: B. Unexplained infertility.

In approximately 10% of infertile couples, unfortunately, the infertility has no identifiable cause. Possible subtle causes include autoimmune conditions resulting in early pregnancy loss, as well as still-unidentified problems with implantation or fertilization. In unexplained infertility, the average fecundity per cycle is 3%. The initial treatment of choice is often ovulation induction with IUI. The combination of these two therapies can increase fecundity to about 10-15% per cycle. If this combined approach is unsuccessful after 3-6 cycles, IVF may be indicated. Newer data show that IVF is probably more cost-effective than diagnostic laparoscopy for possible peritoneal factor infertility.^[12]

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A 23-year-old woman and her 24-year-old husband come to the office with a complaint of inability to conceive after 14 months of unprotected intercourse. Both partners' past medical histories are unremarkable. The patient reports that she has very regular cycles every 28 days, but she experiences severe cramping that starts several days before her menses and continues through about day 3. This cramping has gotten worse over time. She also reports experiencing rectal pain when she has a bowel movement while menstruating. She is very concerned about these symptoms and asks what they can indicate.

What is the most likely diagnosis?

1. Ovarian factor infertility (anovulation)
2. Cervical factor infertility
3. Tubal factor infertility
4. Peritoneal factor infertility

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Answer: D. Peritoneal factor infertility.

This patient has some classic signs of endometriosis. Her menses are regular, but she has pelvic pain leading up to menstruation. She has pain with bowel movements during menses, which can be due to endometrial implants in the pouch of Douglas. She may also report pain with certain sexual positions, sometimes described as deep dyspareunia. Management of endometriosis has changed substantially over the past few decades. Studies show higher pregnancy rates with IVF as compared with laparoscopic ablation of endometriosis. Currently, laparoscopy is reserved for patients with other symptoms (eg, pelvic pain or undiagnosed ovarian masses) and those in whom IVF is not an option.

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