Infertility: A practical framework

MALE FACTOR INFERTILITY

Although male partners are often highly engaged in and supportive of the fertility evaluation, some are reluctant to undergo testing, and some wish to undergo semen analysis only after female factors have been ruled out. Our practice is to evaluate male factors immediately, due to the high contribution of male factors (up to 40% of cases) either alone or in combination with female factors.³²

Men at particularly increased risk of semen abnormalities include those with a history of chemotherapy or radiation or exposure to toxins (eg, environmental exposures, alcohol, tobacco, illicit substances) and prescribed medications.

At a minimum, for the male partner, a reproductive history should be taken and a semen analysis ordered. Men should be directly queried about testosterone use, as this often-used anabolic steroid hormone can severely impair sperm production.

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Normal semen parameters as designated by the World Health Organization³³ are listed in Table 3. Home collection can be offered at some centers to allay any uneasiness associated with the procedure. Although frequent ejaculation does not appear to affect sperm counts, the ASRM recommends performing formal semen analysis after a window of abstinence of 2 to 5 days.³⁴ The test should be repeated if the result is abnormal, as transient influences such as recent illness may manifest in the sperm parameters for up to 3 months after recovery; this extended effect is related to the duration of normal germ cell maturation. Although there are some differences in sperm parameters of older men, reproductive success does not seem significantly diminished.

Men who have low sperm counts, motility, or morphology scores based on World Health Organization criteria should not be deemed “infertile,” as there is significant variation from one analysis to the next, and normal fertility has been reported in men with notably low sperm counts. Particular caution should be exercised in interpreting low morphology scores in men with normal counts and motility, as this parameter appears to have the least prognostic value in this context. Men with abnormal semen analyses should be referred to a specialist for further urologic evaluation and treatment.

Treatments for male factor infertility include surgery, steroid hormones, and possibly intrauterine insemination or assisted reproductive technology. In even the most challenging cases, male infertility is now largely treatable with intracytoplasmic sperm injection with assisted reproductive technology. While most advances in in vitro fertilization have been evolutionary, intracytoplasmic sperm injection was revolutionary. This breakthrough technology allows a single sperm to be injected directly into the oocyte. Sperm for this procedure can be obtained either from the ejaculate or from microsurgical testicular sperm extraction.

ANOVULATION

Anovulation manifests with oligo- or amenorrhea and may explain up to 40% of female infertility.² There are myriad causes of anovulation (Table 4); however, polycystic ovary syndrome is the most common.

A thorough menstrual history can be informative, as most females of reproductive age have a fairly predictable 25-to-35-day monthly menstrual cycle. Women presenting with menstrual charting with this pattern do not require laboratory confirmation of ovulation. Basal body temperatures are rarely used currently, as they are time-consuming, can induce stress, and are confirmatory rather than predictive of ovulation. Endometrial biopsy for endometrial “dating” is no longer performed in infertile women.

If laboratory confirmation is desired, LH kit testing with a commercially available test or a luteal phase serum progesterone obtained 7 days after suspected ovulation can be obtained. A serum progesterone level higher than 3 ng/mL is indicative of ovulation.¹⁹ Due to the notable fluctuations in ovulatory-appearing progesterone levels over several hours, caution must be taken in interpreting a lower-normal level as indicative of a luteal phase insufficiency.

Polycystic ovary syndrome

Polycystic ovary syndrome is important to understand because it is a metabolic condition that predisposes patients to a variety of health risks. Along with gynecologic consequences such as infertility, abnormal uterine bleeding, and endometrial pathology, it is often accompanied by alterations in glucose and lipid metabolism, obesity, hypertension, and cardiovascular disease.³⁵

Despite its name, the syndrome does not involve the presence of classic ovarian cysts. In fact, the cysts associated with polycystic ovary syndrome are dense accumulations of antral follicles arranged peripherally in the ovarian cortex; they should not be removed surgically as they represent the ovarian reserve.

Although ovaries that appear polycystic on transvaginal ultrasonography are often associated with the syndrome, they are not invariably present and are not absolutely required for the diagnosis of polycystic ovary syndrome based on the most commonly used criteria.³⁵ Several diagnostic criteria have been proposed for polycystic ovary syndrome and its phenotypes. The 2003 revised Rotterdam criteria require 2 out of the following 3 features:

• Oligo-ovulation or anovulation
• Evidence of hyperandrogenism, whether clinical (eg, acne or hirsutism) or based on laboratory testing
• Polycystic-appearing ovaries on ultrasonography.

There is no single test that can diagnose the disease. Although polycystic ovary syndrome is often characterized by elevated LH levels, LH–FSH ratios, and fasting insulin levels, these are not diagnostic criteria. The diagnosis hinges on excluding other causes of anovulation such as thyroid disease, hyperprolactinemia, 21-hydroxylase deficiency, androgen-producing neoplasms, and Cushing syndrome. In addition to checking serum testosterone levels, irregular menstrual cycles and infertility should be assessed at minimum with measurement of TSH, prolactin, and day-3 FSH. Obese women should be screened for metabolic syndrome, which should include an assessment of impaired glucose tolerance with a 2-hour oral glucose tolerance test.³⁶

Women with polycystic ovary syndrome are known to have insulin resistance, which is difficult to assess and is independent of their body mass index.³⁷ They often report a family history of diabetes or a personal history of gestational diabetes or giving birth to infants who are large for gestational age. Although most women diagnosed with insulin resistance and anovulatory infertility will not yet have a diagnosis of diabetes, women with polycystic ovary syndrome are 3 to 7 times more likely to develop type 2 diabetes later in life³⁷ and are at increased risk of lipid abnormalities, cardiovascular disease, and stroke. Therefore, interventions to address the compounding influences of polycystic ovary syndrome and obesity can improve fertility outcomes and help prevent long-term sequelae that accompany the syndrome.

Treatment for women with polycystic ovary syndrome attempting conception includes lifestyle modifications, medications for ovulation induction, and possible use of insulin sensitizers. Metformin alone is not effective as a single agent for achieving pregnancy.³⁸ Diet, weight loss, and exercise can have dramatic effects on ovulation and pregnancy and should be highly encouraged.

Ovulation induction is often required in anovulatory women, either in combination with lifestyle modifications or used subsequently if modifications are not successful. Letrozole is advised as the initial agent in women with obesity and anovulatory infertility rather than clomiphene citrate; a side-by-side comparison demonstrated increased rates of ovulation and live birth with letrozole.³⁹

Once-daily letrozole 2.5 mg or clomiphene 50 mg can be prescribed for 5 days, from cycle days 3 through 7 to cycle days 5 through 9. If this initial dosing fails to result in ovulation, the dose can be increased. Known adverse effects are hot flashes, headaches, ovarian cysts, and increased risk of multiple gestation.

Metformin should be considered as an adjunct to fertility treatments in women with polycystic ovary syndrome, especially those with obesity or impaired glucose tolerance, or if there is no response to standard ovulation induction.

Ovarian hyperstimulation syndrome (cystic enlargement of the ovaries with potentially dangerous fluid and electrolyte imbalances) can occur in women with polycystic ovary syndrome; however, it rarely occurs with oral medications.