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Infertility Afp-2023
Infertility Afp-2023
Infertility Afp-2023
Infertility is the inability to achieve a pregnancy after 12 months of regular, unprotected sexual intercourse. Evaluation and
treatment are recommended earlier than 12 months when risk factors for infertility exist, if the female partner is 35 years
or older, and in the setting of nonheterosexual partnerships. A comprehensive medical history and physical examination
emphasizing the thyroid, breast, and pelvic areas should be performed to help direct diagnosis and treatment. Causes of
infertility in females include uterine and tubal factors, ovarian reserve, ovulatory dysfunction, obesity, and hormone-related
disorders. Common male factor infertility issues include abnormal semen, hormonal disorders, and genetic abnormalities.
Semen analysis is recommended for the initial assessment of the male partner. Evaluation of the female should include
assessment of the uterus and fallopian tubes with ultrasonography or hysterosalpingography when indicated. Laparoscopy,
hysteroscopy, or magnetic resonance imaging may be needed to evaluate for endometriosis, leiomyomas, or evidence of a
previous pelvic infection. Treatment with ovulation induction agents, intrauterine insemination, in vitro fertilization, donor
sperm or eggs, or surgery may be necessary. Unexplained male and female infertility can be treated with intrauterine insem-
ination or in vitro fertilization. Limiting alcohol intake, avoiding tobacco and illicit drug use, consuming a profertility diet,
and losing weight (if obese) may improve pregnancy success rates. (Am Fam Physician. 2023;107(6):623-630. Copyright ©
2023 American Academy of Family Physicians.)
Infertility is the inability to achieve a pregnancy require evaluation and management of fertility
after 12 months of regular, unprotected sexual issues. For this review, female and male refer to
intercourse;more broadly, infertility describes the sex assigned at birth.
the impairment of a person’s capacity to repro-
duce as an individual or with their partner.1 Epidemiology
Infertility affects between 8% and 12% of couples Globally, 48 million couples and 186 million indi-
of reproductive age worldwide, with some varia- viduals are affected by infertility.4 The National
tion based on geographic location.2 In the United Survey of Family Growth shows that 19.4% of
States, 12.2% of females 15 to 49 years of age have currently married women in the United States
received infertility services.3 who are 15 to 49 years of age have had zero births
Primary infertility is having never achieved a and are considered infertile, and 26% of women
pregnancy. Secondary infertility is the inabil- 15 to 49 years of age have impaired fecundity.3-5
ity to achieve a pregnancy after a previous The percentage of women with infertility is lower
pregnancy. Both contribute significantly to infer- among those 15 to 29 years of age and increases
tility worldwide.2 with age. Infertility was formally designated a dis-
This article focuses on infertility in oppo- ease in 2009 by the World Health Organization
site-sex partners; however, same-sex couples and the American Medical Association6; how-
and others in nonheterosexual partnerships also ever, access and cost can be substantial barriers to
receiving infertility care.7
See related editorial on page 573.
Etiology
This clinical content conforms to AAFP criteria for
CME
CME. See CME Quiz on page 575. Causes of infertility are female factor, male fac-
Author disclosure:No relevant financial relationships. tor, and unknown or unexplained. Female factor
Patient information:A handout on this topic is available
accounts for 35% to 50% of infertility causes, male
with the online version of this article. factor accounts for 40% to 50%, and unexplained
infertility may account for up to 30%.8,9
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INFERTILITY
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INFERTILITY
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INFERTILITY
FIGURE 1
Male Female
History and physical exam- History and physical examination: assess for clinical signs of
ination: identify modifiable ovulation, hyperandrogenism, risk factors for infertility
risk factors for infertility,
subfertility (Table 5)
Evidence of ovulation?
Abnormal: Normal:
referral to pursue other
specialist in etiologies Counsel on Optimize Preconception
menstrual cycle, chronic medical counseling No/uncertain Yes
male fertility
ovulation, timed conditions
intercourse Obtain serum A Evaluate ovarian reserve
progesterone Pelvic ultrasonography,
level on day 21 hysterosalpingography
(if abnormal, refer to
gynecologist)
Evaluate for male
infertility
≥ 3 ng per mL < 3 ng per mL
(9.54 nmol per L)
Obtain thyroid-stimulating
Go to A hormone, prolactin, follicle-
stimulating hormone
Evaluate for polycystic
ovary syndrome
A midluteal phase (day 21) serum progesterone level can testosterone and estradiol, which alters the hypothalamic-
be measured to determine ovulatory status. Progester- pituitary-ovarian axis by affecting the pulsatile release of
one levels less than 3 ng per mL (9.54 nmol per L) indicate gonadotropin-releasing hormone needed for normal follic-
anovulation. ular development and ovulation. Hyperthyroidism may lead
to menstrual disturbances.25 Hyperprolactinemia causes
OTHER CONDITIONS anovulation by inhibiting gonadotropin-releasing hor-
Obesity affects fertility in females and males. In males, obe- mone secretion.2
sity is associated with reduced semen quality and impaired
erectile function.23 In females, obesity affects menstrual Male Factor Infertility
function, ovulatory function, and oocyte morphology, The evaluation of the male partner should include a history,
which may impair fertilization and increase rates of miscar- physical examination, and semen analysis.26 The history
riage and obstetric complications.23,24 should focus on reproductive history, presence of sexual
Thyroid disease and hyperprolactinemia are other factors dysfunction (e.g., impaired libido, erectile dysfunction),
that affect ovulation. Hypothyroidism causes a decrease environmental or toxin exposure (heavy metals, pesticides),
in sex hormone–binding globulin and increased unbound tobacco and cannabis use, childhood illness (e.g., mumps,
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INFERTILITY
Treatment of Infertility
TABLE 4 NONGYNECOLOGIC
Optimal treatment of hyperprolactinemia and hypothy-
Indicators of Diminished Ovarian Reserve roidism, which can manifest as amenorrhea in reproduc-
Indicator Value tive-aged women, should result in the resumption of normal
Antimüllerian hormone < 1.0 ng per mL
menstrual cycles and ovulation. Other concurrent etiologies
of infertility can be considered if pregnancy does not occur.
Antral follicle count < 5 to 7
OVARIAN
Follicle-stimulating > 10 mIU per mL (10 IU per L)
hormone Methods for ovulation induction include oral medications,
clomiphene and letrozole, and exogenous gonadotropins.
Information from reference 21.
Clomiphene is a selective estrogen receptor modulator that
mimics a hypoestrogenic state, leading to increased FSH and
the development of multiple dominant follicles.27 The initial
TABLE 5 dosage for clomiphene is 50 mg per day for five days, starting
on days 2 to 5 of the menstrual cycle, and is increased to
Modifiable Risk Factors for Male Infertility 100 mg per day. Letrozole, an aromatase inhibitor, should
be used for five days (days 3 to 7 of the menstrual cycle). The
Alcohol use Obesity
typical dosage is 2.5 to 7.5 mg per day. If pregnancy is not
Environmental or occupational Smoking
exposure to toxic chemicals
achieved after six cycles, the patient should be referred to an
Varicocele
infertility specialist.
Illicit drug use
All ovulation induction medications confer a risk of ovar-
Information from reference 27. ian hyperstimulation syndrome and multifetal gestation.
Ovarian hyperstimulation syndrome manifests as abdom-
inal pain and distention, ascites, gastrointestinal problems,
cryptorchidism), developmental history, medication use respiratory compromise, oliguria, hemoconcentration,
(including exogenous testosterone use), and sexually trans- and thromboembolism and is most common with the use
mitted infections14 (Table 527). The physical examination of gonadotropins and high-dose oral ovulation induction
should include body mass index and penile and testicular medications. Ovarian hyperstimulation syndrome is treated
assessment. The absence of the vas deferens on physical with supportive care, including antiemetics, volume replace-
examination should prompt cystic fibrosis testing. A semen ment, and, in severe cases, paracentesis. Patients should be
analysis should be obtained after two to five days of absti- counseled on these risks before treatment.29
nence and is recommended as the first step in the evalua- For women with polycystic ovary syndrome, multiple
tion of infertility in males. Semen should be collected and randomized controlled trials have found that time to preg-
submitted within one hour of production. If the semen is nancy with letrozole was shorter compared with clomiphene
abnormal, the timing for repeat analysis should be individ- citrate.30,31
ualized, and referral to a urologist is recommended.15 The
World Health Organization laboratory manual provides FALLOPIAN TUBES
parameters for normal semen analysis (https://w ww.ncbi. Occlusion of the fallopian tubes is a major cause of female
nlm.nih.gov/pmc/articles/PMC8706130/pdf/life-11-01368. infertility (25% to 35%). 32 Treatment includes tubal can-
pdf). If azoospermia (i.e., no sperm in the ejaculate) is nulation, tubal anastomosis, or in vitro fertilization (IVF).
noted on semen analysis, genetic testing for Y chromosome The decision to pursue surgical management vs. assisted
microdeletion should be performed.14 reproductive technology (ART) is based on factors related to
pregnancy success such asage, ovarian reserve, and location
Unexplained Infertility of tubal disease or blockage. Referral to a specialist is war-
The diagnosis of unknown or unexplained infertility is ranted for patients with tubal factor infertility.33
made when there is an absence of an identifiable cause for
infertility. The evaluation finds normal ovulatory function, UTERUS
a normal semen analysis, and at least one patent fallopian Referral to gynecologic surgery is highly recommended
tube. Unexplained infertility may account for 30% of infer- when any intrauterine abnormalities are diagnosed. Limited
tility cases.28 studies suggest that removing submucosal fibroids improves
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INFERTILITY
fertility and IVF outcomes. Data are lacking about the mech- rates. Marijuana use has been shown to decrease sperm
anisms through which other intrauterine abnormalities count and delay or inhibit ovulation.36
affect fertility.34
COST AND HEALTH EQUITY ISSUES
MALE INFERTILITY Most private insurers pay for the initial infertility evalua-
Male factor infertility with an abnormal semen analysis tion but not the cost of the laboratory tests, imaging, and
warrants referral to a specialist in
male fertility or a urologist for patients
with obstruction. Pregnancy can be TABLE 6
achieved for most of these patients
with intrauterine insemination, ART, Management of Infertility
or donor sperm (Table 6).14-17 Factors causing
Azoospermia is commonly caused infertility Diagnosis Treatment
by obstruction and requires surgical Male infertility Abnormal semen Intrauterine insemination
evaluation and correction. The main- volume
stay of treatment for unexplained male Abnormal sperm Intracytoplasmic sperm injection
factor infertility is ART.17 count Surgery*
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INFERTILITY
SORT:KEY RECOMMENDATIONS FOR PRACTICE
Evidence
Clinical recommendation rating Comments
Infertility evaluation should begin after 12 months of regular, C Expert opinion and consensus guidelines
unprotected intercourse in a female younger than 35 years, after
six months between 35 and 40 years of age, or immediately if older
than 40 years or if the patient has risk factors for infertility.1,9,10,12
Evaluation of infertility should include semen analysis, history and C Expert opinion and consensus guidelines
physical examination focusing on menstrual history, past infection,
sexual dysfunction, surgical history, and medication use.9
Clomiphene or letrozole with intrauterine insemination should be A Guidelines with grading based on consistent
used as first-line therapy for unexplained infertility.17,28 evidence from randomized controlled trials
showing improved live birth rates compared
with expectant management
All women who are obese should be counseled on lifestyle mod- C Expert opinion
ifications and weight loss to improve spontaneous ovulation and
response to ovulation induction. 23
A = consistent, good-quality patient-oriented evidence;B = inconsistent or limited-quality patient-oriented evidence;C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://w ww.aafp.
org/afpsort.
additional treatment. The median cost of IVF in the United Address correspondence to Kiwita Phillips, MD, Morehouse
States with medications is $19,200. A total of 70% of women School of Medicine, 720 Westview Dr., Atlanta, GA 30310
who undergo IVF go into debt.37 Women without insurance (email:kphillips@msm.edu). Reprints are not available from
coverage for IVF were three times more likely to discontinue the authors.
treatment after one cycle.38 Mandated IVF insurance is vari-
able and is part of only 17 state-funded programs. New York References
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INFERTILITY
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630 American Family Physician www.aafp.org/afp Volume 107, Number 6 ◆ June 2023
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