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
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.
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.
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
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.
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
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
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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Keywords:Copyright © 2017 American Academy of Physician Assistants
infertility; assisted reproductive technology; intrauterine insemination; ovulatory dysfunction; varicocele; polycystic ovarian syndrome