INTRODUCTION

Infertility is defined as the inability to conceive after 1 year of unprotected

intercourse.

1 The definition is based upon the observation that roughly 85% of

couples with normal fertility will achieve pregnancy within 1 year.

2 Data from the

2006 to 2010 National Survey of Family Growth revealed that 6% of married women

15 to 44 years old, or 1.53 million, were infertile and approximately 12% of women

in this age group had used infertility services.

3,4 Many factors affect infertility rates,

but advancing maternal age appears to be a prominent influence. The incidence of

infertility in women 15 to 24 years old was 7%, whereas in women 35 to 44 years

old, it was 27%.

3 This is accompanied by an age-related increase in chromosomal

abnormalities and spontaneous abortion rates.

5 The physiologic factors of

reproductive aging are amplified by a trend toward delayed childbearing in the

United States. In 1970, 1 out of 100 women had their first child at age 35 or older. In

2006, this increased to 1 out of 12 women.

6 Male fertility is impacted by age as well,

with higher infertility rates after age 39.

3 However, determining the exact

contribution of male age to infertility is complicated by the influence of female age.

The complex physical, psychological, and social implications have led to a

national focus on infertility as a public health priority.

7 Treatment plans vary widely

depending on the contributions of both female and male factors. An individualized

approach is necessary to balance the risks and benefits of the various therapeutic

options and maximize clinical outcomes.

PATHOPHYSIOLOGY AND DIAGNOSIS

CASE 48-1

QUESTION 1: T.R. is a 32-year-old woman who presents to her gynecologist with concerns that she and her

husband, age 37, have not conceived despite having unprotected intercourse on average 2 to 3 times/week for

the past 14 months. Her prior contraceptive method was a combined oral contraceptive which she used for 12

years and discontinued 2 years ago. At that time, the couple used male condoms until 14 months ago when they

stopped using contraception altogether. What is the recommended initial approach to this couple’s concern?

Evaluation of infertility generally begins after a couple has attempted to conceive

for at least 12 months without success. Evaluation after just 6 months of unsuccessful

conception is recommended in women older than age 35 or in those with a history of

conditions associated with infertility, such as amenorrhea, endometriosis, or pelvic

inflammatory disease.

2

This couple has failed to conceive after 14 months of regular, unprotected

intercourse, which supports an evaluation of both partners at this time. The diagnostic

process first involves a thorough assessment of medical conditions, lifestyle

parameters, and medication exposures. This is followed by complete physical

examinations and laboratory assessments with other diagnostic procedures as

warranted.

General Risk Factors

CASE 48-1, QUESTION 2: Additional information is obtained about the couple’s social history. T.R. works

as a bank teller and her husband is a financial planner. Neither T.R. nor her husband smoke tobacco or use

illicit substances. Both drink one to two cups of caffeinated coffee each day and drink alcohol socially, an

average of one to three drinks each on weekends. What lifestyle factors may contribute to infertility in this

couple?

Lifestyle factors such as tobacco or illicit drug use and caffeine intake are known

contributors to infertility. Tobacco use can be linked to 13% of female infertility

cases.

8

In addition to the negative effects on fetal development during pregnancy,

tobacco use can worsen ovulatory function. It also induces chromosomal changes that

alter sperm production and function.

8 Caffeine is associated with decreased fertility

with higher levels of intake, but moderate use of one to two cups of coffee or

equivalent appears to have minimal impact. Although a link between alcohol use and

infertility is not definitive, it is recommended that women limit their use to no more

than one drink per day. Complete abstinence from alcohol is recommended once

pregnancy is confirmed.

9 Use of illicit substances such as marijuana impairs fertility

and decreases the success of fertility treatments.

9,10 Occupational and environmental

exposures to pesticides, heavy metals, and toxins such as organic solvents used in dry

cleaning and printing are additional contributors.

9

The couple’s lack of tobacco or illicit drug use eliminates these as potential

contributors and their occupations do not fit known high-risk exposure profiles. Their

pattern of caffeine and alcohol use is not greater than the amount currently

documented to affect fertility. Assessment of other causes of infertility is warranted.

Female Factor Infertility

OVULATORY DYSFUNCTION

CASE 48-1, QUESTION 3: T.R.’s medical history is significant for exercise-induced asthma diagnosed at

age 10. Her medications include an albuterol inhaler used as needed for shortness of breath. She is 5 feet 5

inches tall and weighs 140 lb. Her reproductive history reveals menarche at age 13, no prior pregnancies, and

regular menstrual cycles approximately 25 to 26 days in length since discontinuing the oral contraceptive. She

reports the menstrual bleeding phase to be 4 to 5 days in length and does not complain of excessive bleeding. A

physical examination is performed along with a pelvic examination with no notable abnormalities. What

information does this provide about possible female factors associated with infertility?

An important focus when evaluating causes of infertility is ovulatory function,

which is associated with up to 40% of female factor infertility.

2 A thorough

reproductive history should document age of menarche, menstrual cycle patterns,

premenstrual symptoms, and previous pregnancies. A history of regular menstrual

cycles of 21 to 35 days with premenstrual symptoms or dysmenorrhea is considered

consistent with ovulatory cycles.

2

Ovarian function is regulated through complex feedback mechanisms within the

hypothalamic–pituitary–ovarian axis (see Chapter 50, Disorders Related to the

Menstrual Cycle, Fig. 50-1). This involves release of gonadotropin-releasing

hormone (GnRH) from the hypothalamus, follicle-stimulating hormone (FSH) and

luteinizing hormone (LH) from the pituitary gland, and estrogen and progesterone

from the ovaries. Table 48-1 provides an overview of abbreviations commonly

associated with diagnosis and management of infertility for use throughout the

chapter.

Conditions such as thyroid dysfunction, hyperprolactinemia, and polycystic ovary

syndrome (PCOS) can disrupt these feedback mechanisms and induce anovulation.

Signs may be evident upon physical examination, including an enlarged thyroid

(thyroid dysfunction), abnormal discharge from the breast (hyperprolactinemia), or

signs of hyperandrogenism (PCOS). Obesity is another feature associated with

PCOS. Conversely, extremely low body weight and excessive exercise may

negatively impact ovulatory function at the hypothalamic level. Weight gain improves

menstrual regulation in women with anovulation associated with low body fat.

Primary ovarian failure can result from exposure to chemotherapy agents or radiation

treatments as well as ovarian surgery. As previously discussed, the aging process

itself is characterized by diminished ovarian follicular reserve.

2

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Table 48-1

Common Abbreviations Associated with Infertility Diagnosis and Treatment

ART Assisted reproductive technology

CC Clomiphene citrate

COS Controlled ovarian stimulation

FSH Follicle-stimulating hormone

GnRH Gonadotropin-releasing hormone

hCG Human chorionic gonadotropin

HSG Hysterosalpingogram

hMG Human menopausal gonadotropin

IUI Intrauterine insemination

ICSI Intracytoplasmic sperm injection

IVF In vitro fertilization

LH Luteinizing hormone

OHSS Ovarian hyperstimulation syndrome

OI Ovulation induction

SO Superovulation

T.R.’s reproductive history is consistent with regular menstrual cycles which are

likely ovulatory. It would be helpful to identify whether she reports any symptoms of

premenstrual syndrome or dysmenorrhea which are associated with ovulatory cycles.

Her physical examination is unremarkable and her medical history does not reveal

any conditions associated with anovulation. Her weight is not likely a factor because

her body mass index of approximately 23 kg/m2

is in the normal range. She has no

known history of exposure to chemotherapy or ovarian surgery which could directly

impact ovarian function. The only parameter consistent with female factor infertility

is T.R.’s age. At 32 years old, she may be experiencing an initial age-related decline

in ovarian function consistent with infertility.

CASE 48-1, QUESTION 4: T.R. reports using a home ovulation test kit for the last two menstrual cycles

which both yielded positive results. She is referred for a series of laboratory tests with the following findings:

Thyroid-stimulating hormone, 3.2 mIU/L

Prolactin, 8.4 ng/mL

Cycle day 3 FSH, 4 mIU/mL

Cycle day 3 estradiol, 38 pg/mL

What additional information about her ovulatory function can be determined from these results?

Several methods are available to further define ovulatory function. Basal body

temperature monitoring is accomplished through the measurement of body

temperature every morning upon waking with a basal or digital thermometer.

Temperature fluctuations typically follow a biphasic pattern during the menstrual

cycle, with a sustained rise in basal body temperature of approximately 0.5°F to

1.0°F after ovulation. If this pattern is apparent through daily documentation in a

temperature diary, it can be assumed that ovulation occurred during that cycle. The

accuracy of this method is complicated by daily temperature fluctuations, inconsistent

measurement technique, and illness. It has largely been replaced by the use of home

ovulation test kits that detect urinary LH. The patient initiates daily urine tests during

the follicular phase, with the initial testing day determined by the length and

regularity of her menstrual cycle (Fig. 48-1). A positive test documents the LH surge,

signaling that ovulation will occur in an average of 24 hours.

2,11 Home ovulation test

kits that detect changes in cervical mucus or saliva samples are not typically used for

diagnostic purposes. They are useful, however, for patients who are timing

intercourse during their most fertile period around ovulation.

9,11

Indirect measurements of ovulation are available, but not widely performed. A

serum progesterone concentration measured in the mid-luteal phase greater than 3

ng/mL is considered consistent with an ovulatory cycle. Alternatively, an endometrial

biopsy performed just prior to menses measures the degree of progesteronestimulated growth, signifying whether ovulation likely occurred. The invasive nature

of this test limits its feasibility in most diagnostic evaluations.

2

In patients who are anovulatory, additional laboratory assessments of thyroid

function and prolactin levels document potential secondary causes. Anovulation

associated with hyperprolactinemia is treated with oral dopamine agonists such as

cabergoline.

12 Elevated testosterone levels may correspond with physical signs of

hyperandrogenism and PCOS. The treatment of PCOS is discussed elsewhere (see

Chapter 50, Disorders Related to the Menstrual Cycle).

Assessment of ovarian reserve may be performed in women older than age 35 to

help guide fertility treatment choices. There are multiple methods that can be used.

One involves the measurement of basal levels of serum FSH with or without

estradiol on day 2, 3, or 4 of the menstrual cycle, with day 1 being the first day of

menses. Because the number of ovarian follicles declines with age, pituitary release

of FSH increases. Therefore, elevated levels of basal FSH (>10–20 IU/L) suggest

diminished ovarian function. Unfortunately, the interpretation is complicated by

individual variability in FSH levels from cycle to cycle as well as varying

laboratory-specific reference ranges. A serum estradiol level of >60 to 80 pg/mL

with normal FSH levels is also associated with a poor prognosis for success with

infertility treatments.

2,13 Measurement of inhibin B, which is secreted from the

ovarian granulosa cells during the follicular phase of the menstrual cycle, is an

additional marker. Low levels of inhibin B correlate with elevated FSH levels and a

possible decline in ovarian function. However, due to the variability with this

measurement, it is not recommended as a routine evaluation of ovarian reserve.

13

The clomiphene citrate challenge test provides another option for assessing

ovarian reserve. This involves the administration of clomiphene citrate (CC), a

selective estrogen receptor modulator, at a dose of 100 mg once daily on days 5

through 9 of the menstrual cycle. In addition to the estradiol and FSH measurements

on day 3 as described previously, FSH is also measured on day 10. The expected

response is suppression of FSH by the developing ovarian follicles. Elevated levels

at either day 3 or 10 suggest diminished ovarian reserve. The value of this test as a

predictor of response to ovarian stimulation is not clearly supported in the

literature.

2,13

Direct visualization of the ovaries through a transvaginal ultrasound may be used

in conjunction with the hormone testing described previously. An assessment of

ovarian volume and the antral follicle count can be made. The antral follicles, or

those 2 to 10 mm in diameter, are responsive to FSH in the early follicular phase and

decline in number with age. An antral follicle count of 3 to 6 is considered low and

predicts poor ovarian response to various infertility treatments.

2,13

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Figure 48-1 The menstrual cycle.

The laboratory assessment of T.R. provides additional data regarding her ovarian

function. Ovulatory cycles are supported by the positive urinary LH surge with the

home test kit as well as the normal (nonelevated) day 3 FSH and estradiol levels.

Her normal thyroid-stimulating hormone and prolactin levels indicate a low

probability of secondary causes of anovulation. Because T.R. is younger than 35 and

there are no other indicators of ovulatory dysfunction, additional testing of ovarian

reserve may not be necessary. The initial findings of T.R.’s infertility assessment

show that ovulatory dysfunction is not likely to be a contributor.

STRUCTURAL FACTORS

CASE 48-1, QUESTION 5: Because T.R. has normal ovulatory function, further causes of female factor

infertility will be investigated. What testing is recommended to rule out structural causes of infertility?

Structural abnormalities in the uterine cavity or fallopian tubes are additional

causes of female factor infertility. These may develop in utero or result from scar

tissue or lesions secondary to conditions such as endometriosis. In some cases of

endometriosis, surgical interventions improve fertility outcomes, but this is highly

dependent on the severity and location of the lesions.

14 Further discussion of the

diagnosis and treatment of endometriosis is provided elsewhere (see Chapter 50,

Disorders Related to the Menstrual Cycle). Pelvic inflammatory disease from

sexually transmitted infections such as chlamydia or gonorrhea is a risk factor for

tubal infertility.

2

The use of invasive procedures to explore structural causes of female infertility is

dictated by the reproductive history and findings of the physical examination and

laboratory tests. Abnormalities of the ovaries, uterus, and fallopian tubes are

evaluated through various procedures. Transvaginal ultrasonography utilizes vaginal

insertion of an ultrasound probe to visualize ovarian structure and developing

follicles. A hysterosalpingogram (HSG) is performed to confirm normal fallopian

tube structure. During this process, dye is injected into the uterus through a catheter

and visualized on X-ray to determine any blockages or malformations. Hysteroscopy

and laparoscopy are more invasive procedures that allow for direct visualization of

the uterus or pelvic anatomy. These are typically reserved for further examination of

abnormalities detected by initial testing.

2

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Impaired cervical mucus production and quality are additional structural factors

that can impact sperm motility and the fertilization process. Cervical mucus increases

in volume and becomes thinner as the follicular phase progresses to facilitate sperm

transport at ovulation. The “postcoital test” or microscopic examination of cervical

mucus within hours of intercourse can be performed to confirm the presence of motile

sperm, but is no longer recommended for routine use.

2

In the evaluation of this couple, it is important to verify T.R.’s sexual history and

any possible exposures to sexually transmitted infections, such as chlamydia. An

HSG should be ordered to determine whether she has patent fallopian tubes and to

provide basic information about the shape of her uterine cavity. If there are abnormal

findings from this test, further hysteroscopic or laparoscopic procedures can be

performed. A laparoscopy would be necessary to fully evaluate any peritoneal

adhesions from undetected endometriosis, but her medical history does not warrant

this invasive procedure at this time.

Male Factor Infertility

CASE 48-1, QUESTION 6: The results of the HSG are normal, so the infertility assessment turns now to the

evaluation of T.R.’s husband. He is healthy with no chronic medical conditions or medication use. He denies

symptoms of low libido or signs of erectile or ejaculatory dysfunction during intercourse. A complete physical

examination, including the genitalia, reveals normal findings. His semen analysis yields the following results:

Semen volume, 5 mL

Sperm number, 400 × 10

6

Sperm concentration, 112 × 10

6

/mL

Sperm total motility, 65%

Sperm progressive motility, 61%

Sperm vitality, 80%

Sperm morphology, 30%

A second semen analysis confirms these results. What conclusions about the cause of infertility can be made

from these findings?

Infertility is associated with male factors in approximately 20% of cases. Male

and female factors contribute to infertility in 30% to 40% of couples.

15 Male factor

infertility is often an outcome of impaired sperm production or function, which can

originate from a variety of causes. Impaired sperm production may be associated

with hypogonadism resulting from testicular trauma, cryptorchidism, radiation, or

antiandrogen medications.

15,16 Varicoceles, or dilated scrotal veins, affect testicular

function in up to 40% of men with infertility. It appears that the resulting abnormal

venous perfusion and elevated testicular temperature impair spermatogenesis.

17

Genetic conditions may disrupt androgen synthesis or cause defects in the LH or FSH

receptor. Azoospermia, or no presence of sperm in the ejaculate, is also apparent in

certain genetic disorders, such as Klinefelter syndrome. Pituitary tumors can reduce

FSH and LH secretion and impair sperm production. Sperm transport defects result

from erectile dysfunction, retrograde ejaculation, or obstruction of the vas deferens

or epididymis. Medications such as antidepressants or antihypertensives can worsen

libido and ejaculatory function.

16

A complete physical examination of the man is performed to identify signs of

androgen deficiency such as small testicular size or an abnormal pattern of male hair

growth. In some cases, anatomic defects such as varicoceles can be identified and

repaired surgically.

17 However, the primary evaluation tool for male infertility is the

semen analysis. Although there are home test kits for male infertility that utilize a

semen sample, they are not recommended for diagnostic purposes because a positive

result merely confirms that the sperm count is above a predetermined level. There is

no quantification of the number of sperm or evaluation of sperm quality, so it does

not rule out sperm abnormalities. A detailed semen analysis is required to fully

evaluate male factor infertility. The evaluation of two semen analyses on different

occasions is recommended.

15 The World Health Organization publishes reference

values for semen characteristics (Table 48-2).

18 Results lower than these cut-off

values are not definitive for male factor infertility, but do suggest the need to confirm

the findings with a second semen analysis.

15

Table 48-2

Semen Analysis: Lower Reference Limits for Selected Parameters

Parameter Lower Reference Limit

Semen volume (mL) 1.5

Totalsperm number (10

6

/ejaculate) 39

Sperm concentration (10

6

/mL) 15

Total motility (progressive + nonprogressive, %) 40

Progressive motility (%) 32

Vitality (live spermatozoa, %) 58

Sperm morphology (normal forms, %) 4

Source: World Health Organization, Department of Reproductive Health and Research. WHO Laboratory Manual

for the Examination and Processing of Human Semen. 5th ed. Geneva, Switzerland: World Health Organization

Press; 2010:224.

Abnormal findings on the semen analysis may be suggestive of the underlying

cause of infertility. Low semen volume suggests structural causes of ejaculatory

dysfunction. Additional hormone testing, including FSH, testosterone, and prolactin

levels, may be necessary to distinguish factors associated with a low sperm count or

motility. Low FSH and testosterone are consistent with hypogonadotropic

hypogonadism.

16