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Infertility: A primer for primary care providers

Cunningham, Jill MHS, PA-C

Journal of the American Academy of PAs: September 2017 - Volume 30 - Issue 9 - p 19–25
doi: 10.1097/01.JAA.0000522130.01619.b7
CME: Primary Care
Free
CME

ABSTRACT Infertility is a potentially life-changing diagnosis for couples who are trying to conceive. A diagnosis of infertility and the associated management plan can lead to psychological stress, anxiety, and depression for one or both partners. Infertility affects 6% of married women of reproductive age in the United States. Once a couple is determined to be infertile, prompt referral to a specialist is indicated. Treatment varies according to the cause and may include medication, surgical intervention, or assisted reproductive technology.

Jill Cunningham is an assistant professor in the PA program at Philadelphia (Pa.) College of Osteopathic Medicine. The author has disclosed no potential conflicts of interest, financial or otherwise.

Earn Category I CME Credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa.org. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of September 2017.

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Box 1

Box 1

Infertility is a unique condition since it most often affects a couple rather than an individual. Infertility is generally defined as a couple's inability to conceive after one year of frequent, unprotected intercourse. A report from the CDC's National Survey of Family Growth (NSFG) of married women ages 15 to 44 years from 2006 to 2010 revealed that 1.5 million women in the United States were affected by infertility, and 6.7 million reported an impaired ability to become pregnant or carry a baby to term (impaired fecundity).1 Although the prevalence of infertility has remained relatively stable in the past several decades, the demand for infertility services has increased substantially. This is partially due to delayed childbearing trends in the United States combined with advances in assisted reproductive technology.2 The percentage of births in women age 30 years and older has increased significantly from 1975 to 2010 and women over age 40 years now represent the proportionally fastest growing age group having children.3,4 A diagnosis of infertility, its associated management plan, and potential complications can lead to significant emotional, physical, and financial hardships for all involved. For this reason, infertility has become a growing public health concern.3 About 12% of women of reproductive age have reported having an infertility workup and each year, about 7 million American couples seek infertility care.5 The desire to have one's own biologic children can be quite compelling for those trying to conceive and the effects of infertility for individuals and couples who are unable to conceive can be devastating.3 In an effort to help prevent infertility and the adverse consequences associated with its treatment, the CDC has initiated the National Public Health Action Plan for the Detection, Prevention, and Management of Infertility.3

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CAUSES

Fertility rates are affected by multiple factors: age, acute or chronic conditions, environmental toxins, occupational exposures, general lifestyle issues, infectious diseases, genetic conditions, and specific reproductive disorders that can affect either the man or woman attempting to conceive.3 According to a World Health Organization (WHO) study of 8,500 infertile couples in developed countries, the following causes were found: female factor infertility, 37%; male factor infertility, 8%; and both female and male factor infertility, 35% (Figure 1).6 The remaining couples were considered to have unexplained infertility or became pregnant during the study. Another study reported combined factors, 40%; male factor infertility, 26% to 30%; ovulatory dysfunction, 21% to 25%; and tubal factors, 14% to 20%.1 These findings may be interpreted as incongruent but they actually are a reflection of the uncertain causal relationship between abnormalities on infertility testing and the actual cause of infertility.

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FIGURE 1

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Age is one of the most significant factors associated with infertility. Fecundability, the ability to achieve pregnancy per cycle, has been demonstrated to decrease as women get older. Not only does the number of oocytes decrease throughout reproductive years, the remaining oocytes are of poorer quality, which leads to an increased incidence of chromosomal abnormalities and spontaneous abortions.2 Women also face an increased risk for disorders contributing to infertility as they age, such as endometriosis, leiomyomata, or tubal disease.3 For this reason, women age 35 years or older are determined to be infertile after only 6 months or less of frequent, unprotected sexual intercourse, and should be evaluated for infertility issues earlier than healthy women under age 35 years.7

Age also affects a man's ability to reproduce: Increasing age is associated with a decrease in the quality, quantity, motility, and morphology of sperm.8 Clinicians must investigate other possible causes of oligozoospermia (decreased sperm production), azoospermia (absence of sperm), decreased sperm motility, or abnormal morphology. Varicocele is a common cause for decreased sperm count and impaired sperm motility.9 Men with either unilateral or bilateral cryptorchidism also suffer from oligozoospermia and decreased fertility when compared with men with descended testes.10 Hypogonadism will result in testosterone deficiency, which affects spermatogenesis.10 Chronic conditions such as chronic renal disease, cirrhosis, or malnutrition can lead to primary or secondary hypogonadism. Clinicians should also investigate conditions affecting the successful delivery of sperm such as sexual dysfunction issues, spinal cord disease/trauma, autonomic disease, retrograde ejaculation, hypospadias or congenital anatomic abnormalities.11

The most common cause of female factor infertility is ovulatory dysfunction.6 Women affected by oligoovulation or anovulation have difficulty becoming pregnant because an oocyte is not available every month for fertilization. The most frequent cause of anovulation is polycystic ovarian syndrome (PCOS).12 Ovulatory dysfunction can also occur as a result of any disturbance in the hypothalamic-pituitary axis. Triggers of hypothalamic-pituitary axis dysfunction include intense exercise, eating disorders, extreme stress, hyperprolactinemia, pituitary adenomas, or autoimmune disease.13 Certain medications are associated with ovulatory dysfunction, including antidepressants, antipsychotics, corticosteroids, and chemotherapeutic agents. Clinicians should consider primary ovarian insufficiency in patients under age 40 years presenting with amenorrhea or irregular menses.14

Clinicians also should investigate tubal or uterine pathology. Fallopian tube obstruction and pelvic adhesions will prevent the necessary transport of the oocyte and sperm for fertilization and implantation. Pelvic inflammatory disease (PID) is a prime cause of tubal obstruction. Gonorrhea and chlamydia are preventable and treatable causes for PID.15 Other conditions that can affect the tubal/pelvic anatomy are endometriosis, Asherman syndrome, previous ectopic pregnancy, inflammatory bowel disease, pelvic tuberculosis, and appendicitis. Patients with uterine leiomyoma or uterine anomalies may have difficulty with normal implantation.16 Müllerian anomalies such as bicornuate uterus or septate uterus are commonly associated with recurrent pregnancy loss.17

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HISTORY AND PHYSICAL EXAMINATION

The optimal timing for an infertility evaluation by a specialist is after 1 year of frequent, unprotected sex for young couples with no obvious risk factors. An evaluation should be performed at 6 months in couples where the woman is between age 35 and 40 years, or earlier when significant risk factors are present (Table 1).7 Same-sex couples, single patients looking to parent or couples without reproductive organs should be referred for counseling about fertility options early in the process of family planning. Although the detailed infertility workup should be done by a reproductive endocrinologist, the initial history and physical evaluation may be performed by a primary care provider. Once risk factors are identified, referral to a practitioner with technical expertise in the field of infertility is more cost-effective. According to observational studies, specialists also were more able to fulfill the emotional, informational, and diagnostic needs of their patients.18

TABLE 1

TABLE 1

In heterosexual couples, both partners should be present at initial evaluation. Ask women about any past pregnancies, spontaneous or therapeutic abortions, and any abdominal or pelvic surgeries. Obtain a thorough menstrual history. Ask the patient about a past medical history of sexually transmitted infections, endometriosis, chronic illnesses, or history of malignancy. Obtain a family history of fertility problems, recurrent miscarriages, chromosomal or genetic diseases, or endometriosis. The onset of menopause for family members is of particular interest as is any history of primary ovarian insufficiency. Document the patient's medications, vitamin supplementation, smoking, illicit drug use, alcohol use, exercise, diet, stress relief methods, occupational exposures, and hobbies.

The physical examination should focus on the patient's weight, BP, heart, lungs, thyroid, neck, abdomen, and skin. Notable findings include acanthosis nigricans, hirsutism, thyromegaly or goiter, rashes, abdominal striae, or alopecia. Perform a breast and pelvic examination, noting any masses, galactorrhea, pelvic lesions, or discharge.

Obtain an extensive history from the male partner as well. Ask about his sexual development as a child, acute and chronic medical conditions, history of sexually transmitted infections, pelvic surgeries, previous pelvic irradiation, and previous children or infertility issues. Document his medications, vitamin supplementation, smoking, illicit drug use, alcohol use, exercise, diet, stress relief methods, occupational exposures, and hobbies. The physical examination should focus on the heart, lungs, abdomen, thyroid, neck, skin, and genitals.

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DIAGNOSTIC STUDIES

For him

The cornerstone of the male infertility workup is the semen analysis.19 Unfortunately, according to the data from the NSFG, 18% to 27% of the men from infertile couples lacked any evaluation. This indicates that up to 860,000 men in that cohort may have had undiagnosed male factor infertility.20 Semen analysis examines volume and pH; microscopic debris or agglutination; sperm concentration, motility, and morphology; sperm leukocyte count; and immature germ cells. The WHO developed new standardized methods for evaluation and updated the semen analysis reference limits in 2010 (Table 2).21 Collect a sample in the office after the patient has been abstinent for 2 to 7 days. Ideally, collect at least two samples 1 to 2 weeks apart to control for variability of semen analyses. Any abnormalities in the initial sample should be confirmed with a repeat analysis. If repeat analysis is abnormal, refer the patient to a urologist or male reproductive specialist, who will order serum levels of testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin. Patients with oligozoospermia or azoospermia and normal hormone levels will be evaluated for retrograde ejaculation, obstructive azoospermia, impaired spermatogenesis, or sperm antibodies. A scrotal ultrasound can be useful in confirming the presence of a varicocele and can be used to identify obstructions or testicular pathology.22 In patients with oligozoospermia or azoospermia with low testosterone levels, causes include primary or secondary hypogonadism.

TABLE 2

TABLE 2

FIGURE 1

FIGURE 1

Genetic testing is suggested for men with oligozoospermia or azoospermia, to evaluate for chromosomal conditions. For instance, men with the cystic fibrosis conductance regulator (CFTR) gene mutation may present with obstructive azoospermia; normal testicular volume; and normal testosterone, FSH, and LH levels.23 Patients with microdeletions of the Y chromosome also typically present with azoospermia.24 In men with a normal semen analysis confirmed by repeat test, the investigational focus should be directed toward the female partner. If no abnormalities are found in the woman, more specialized semen studies may be performed by an endocrinologist specializing in male reproduction.25

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For her

Start with the most common cause: ovulatory dysfunction. Generally, women who report regular menstrual cycles with associated symptoms of bloating, dysmenorrhea, and breast tenderness are considered most likely to be ovulating (Figure 1). However, confirm ovulation early in the investigation by checking a Day 21 serum progesterone level. If a woman's cycle tends to be longer than 28 or 30 days, progesterone levels can be checked 7 days before expected menses. A progesterone level greater than 5 ng/mL is considered evidence of ovulation.1 Any one abnormal progesterone level should be confirmed with a second level because hormone release is pulsatile. Urinary LH excretion kits also are useful to establish ovulation. In patients with amenorrhea, a progesterone challenge may be administered. Oral progestin is given to the patient for 5 to 10 days. If bleeding occurs within 2 weeks of stopping the progestin, this suggests that the patient is not ovulating. If no bleeding occurs, the patient most likely is ovulating but estrogen levels may be low or she may have a problem with outflow obstruction.26

If the patient is found to be anovulatory, obtain HCG, serum testosterone, prolactin, LH, FSH, estradiol, and thyroid-stimulating hormone (TSH) levels to help differentiate the cause. According to the Rotterdam criteria, any two of the following suggest a diagnosis of PCOS: oligo- or anovulation, clinical or chemical evidence of hyperandrogenism, and polycystic ovaries on ultrasound.27 A patient under age 40 years with low estradiol levels and an elevated Day 3 FSH is diagnosed with primary ovarian insufficiency.14 A review of the patient's current medications, in addition to thyroid studies or an MRI of the head, will help elucidate a cause for hyperprolactinemia.

Thorough evaluation of uterine and tubal anatomy also is vital to the infertility workup. A transvaginal or pelvic ultrasound is a useful, minimally invasive, and cost-effective place to start. Various abnormalities may be identified with ultrasound, such as uterine leiomyomata or other uterine or ovarian tumors. Ultrasound also can be used to determine the number of antral follicles available in order to help assess a patient's ovarian reserve. With the infusion of 0.9% sodium chloride solution into the uterus, one also can visualize any intrauterine adhesions, polyps, or congenital uterine anomalies. A hysterosalpingogram also will identify uterine anatomic abnormalities such as bicornuate uterus or a septate uterus, as well as any issues with tubal patency.

Women with a history of dysmenorrhea and abnormal menstrual bleeding may benefit from more invasive testing. A laparoscopy will identify any endometrial tissue growth, adhesions, or scarring in the fallopian tubes or adnexal anatomy associated with endometriosis, previous ectopic pregnancy, or abdominal surgery. Hysteroscopy also lets clinicians search for intrauterine adhesions associated with Asherman syndrome from prior curettage or pelvic infections or surgeries.

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PREVENTION

Primary care providers can play a significant role in preventing infertility by educating patients about risk factors, managing chronic conditions that affect fertility, and screening for and treating preventable causes. Chlamydia or gonorrhea, for instance, were estimated to affect up to 18% of women using assisted reproductive technologies.3 These same conditions have been found to affect sperm counts in men.

The CDC's National Public Health Action Plan discusses the need for new methods to measure infertility and for early identification of medical conditions that are precursors to infertility. Integrating fertility services into primary care would expand screening, testing, identifying risk factors, and counseling services. By educating primary care providers about the causes of infertility, patients can be told about preventive measures and therapeutic options that may reduce the need for invasive methods to treat infertility later.3

Preventive care also involves counseling patients about modifiable risk factors. This can be reinforced and monitored on a regular basis by clinicians working in primary care. Both partners should avoid smoking or illicit drug use and limit alcohol consumption. Patients should eat a diet rich in nutrients and essential vitamins and aim for a body mass index (BMI) between 19 and 30. Obesity has been found to impair fertility as well as patients' response to fertility treatment.1,28 Encourage exercise as part of a healthful lifestyle.

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TREATMENT

For her

Once a reproductive endocrinologist establishes the cause of infertility, the patient will be started on a management plan. For women suffering from PCOS, the initial management is a low glycemic index diet and exercise. Even a modest weight loss of 5% to 10% may restore fertility alone or with the assistance of medications, such as metformin.29 Clomiphene citrate, letrozole, or injectable gonadotropins also may be administered if needed in an attempt to induce ovulation.12,30 In women who have hyperprolactinemia, therapy should address the source of the condition, whether it is the result of a particular medication, thyroid condition, or pituitary adenoma. Patients suffering from primary ovarian insufficiency may be referred for assisted reproductive technology to obtain oocytes from a donor. For patients with endometriosis or Asherman syndrome, laparoscopic removal of adhesions and scar tissue may increase fertility. These patients also may benefit from the use of assisted reproductive technologies.

Uterine anomalies causing problems with implantation or recurrent spontaneous abortions may be corrected by hysteroscopic resection. Although the surgical treatment of uterine leiomyoma is controversial, women with a submucosal fibroid or intramural fibroid may benefit with myomectomy.31

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For him

Male infertility management options also depend on the underlying cause. In cases where variations in anatomy, a varicocele, or an obstruction is found, referral for surgical correction is indicated. Treatment with gonadotropin therapy or antiestrogens has been associated with increased live birth rates in small randomized controlled trials in couples undergoing assisted reproductive technology.1 The mainstay of therapy for male factor infertility, however, is in vitro fertilization (IVF) with or without the assistance of intracytoplasmic sperm injection.

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ASSISTED REPRODUCTIVE TECHNOLOGY

Despite an exhaustive evaluation of tubal and uterine patency, ovulatory dysfunction, and semen analysis, 10% to 30% of couples seeking treatment for infertility are left with the diagnosis of unexplained infertility.32 The term subfertility may be more appropriate because a small percentage of these couples will conceive without intervention. Treatment for couples with unexplained infertility is empiric and options include expectant management, or assisted reproductive technology (ovulation stimulation, intrauterine insemination, and IVF). Empiric treatment can be particularly distressing for patients because both the cause and management of their infertility are uncertain and limited evidence exists to support the efficacy of current treatments.32 Nevertheless, assisted reproductive technology contributes to about 1.6% of all live births in the United States yearly and 18.7% of all multiple births.33

In ovulation stimulation, also called superovulation, a patient is given medication to induce the development of more than one follicle per cycle, combined with timed intercourse or intrauterine insemination.34 Clomiphene citrate, letrozole, or injectable gonadotropins are used to increase the number of dominant follicles available for fertilization.35 This method can be helpful for patients with subclinical ovulatory dysfunction. Combined with intrauterine insemination or IVF, superovulation also can help patients with cervical mucus problems, low sperm counts, or patients using a sperm donor.

Before using clomiphene, letrozole, or injectable gonadotropins, patients typically are tested for ovarian reserve, which may include a Day 3 FSH plus estradiol level, antral follicle count, or antimüllerian hormone levels. When the results reveal a diminished ovarian reserve, patients may have a limited response to injectable medications and lower fertility rates with IVF or intrauterine insemination.36,37

IVF is the most common method of assisted reproductive technology, accounting for more than 99% of all fertility procedures in the United States.33 IVF involves the retrieval of oocytes after ovarian stimulation; the oocytes are combined with sperm in the laboratory to achieve fertilization. One or more embryos are then transferred to the uterine cavity for implantation.15 Indications for IVF include unexplained infertility, tubal obstruction, severe male factor infertility, diminished ovarian reserve, ovarian failure (with donor eggs), uterine adhesions, or any other causes of infertility after failing treatment with less-invasive therapies. Generally, before proceeding to IVF, intrauterine insemination will be offered for three to six cycles in patients who lack severe factors for infertility, such as blocked fallopian tubes. However, women over age 40 years commonly are offered IVF at initial consultation. One of the major disadvantages of IVF is its high cost, which averages more than $12,000 per cycle in the United States. Access and use of IVF varies because it is not covered by insurance in many states.3 Additionally, the medications and procedures may be associated with significant risks for the woman, including ovarian hyperstimulation syndrome or increased risk of gynecological or breast cancer. There is also an increased risk of multiple gestation, preterm birth, low birth weight, or congenital anomalies.3

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COUNSELING

A diagnosis of infertility can be one of the most devastating life crises that a couple can face, leading to feelings of isolation, social stigma, and loss of control.38 For these reasons, counseling is an essential component of the treatment process for both partners. In a small study of 32 couples in Montreal, Quebec, couples were interviewed about their experiences with infertility and assisted reproductive technology and their psychosocial needs during treatment. Results of this study revealed the need for patients to be educated about the expectations of treatment, focusing on the physical and emotional demands. Participants also stressed the importance of having access to couples counseling and the availability of mentors.38

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CONCLUSION

Infertility is a relatively common condition that poses significant psychological, economic, and medical demands on those who are affected. Although the incidence of infertility has remained stable, the demand for fertility services has grown substantially. Educating primary care providers about the causes and risk factors associated with infertility can lead to better prevention, early identification, timely referral, and more cost-effective care of patients who may need specialized care for conception issues.

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REFERENCES

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34. Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril. 2013;100(2):341–348.
35. Diamond MP, Legro RS, Coutifaris C, et al Letrozole, gonadotropin, or clomiphene for unexplained infertility. N Engl J Med. 2015;373(13):1230–1240.
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Keywords:

infertility; assisted reproductive technology; intrauterine insemination; ovulatory dysfunction; varicocele; polycystic ovarian syndrome

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