Infertility

AUTHOR: Emelia Argyropoulos Bachman, MD, FACOG

Definition

Infertility in a reproductive-age couple is defined as the inability to conceive after unprotected intercourse for ≥1 yr. When a female is greater than 35 yr of age, an evaluation is recommended after 6 mo without successful pregnancy. Earlier evaluation at any age is warranted with preexisting symptoms or medical conditions.

Synonym

Sterility

ICD-10CM CODES
N46		Male infertility
N46.8		Other male infertility
N46.9		Male infertility, unspecified
N97.0		Female infertility associated with anovulation
N97.1		Female infertility of tubal origin
N97.2		Female infertility of uterine origin
N97.8		Female infertility of other origin
N97.9		Female infertility, unspecified
O09.00		Supervision of pregnancy with history of infertility, unspecified trimester
O09.01		Supervision of pregnancy with history of infertility, first trimester
O09.02		Supervision of pregnancy with history of infertility, second trimester
O09.03		Supervision of pregnancy with history of infertility, third trimester
Z31.81		Encounter for male factor infertility in female patient

Epidemiology & Demographics

Prevalence

One in eight reproductive age couples experience infertility. This prevalence is consistent in all developed countries, and there is evidence that it is historically stable. Infertility affects 8.8% of U.S. women aged 15 to 49 years and approximately 12.7% of reproductive age women seek treatment for infertility each year.¹^,²

Predominant Sex & Age

By definition this is a diagnosis of reproductive age couples. Infertility increases with aging in both males and females, but more dramatically in women (Table 1). Male factor is responsible in nearly 40% of couples, and the female factor is responsible in approximately 50% of couples. The remainder of the cases are either combined male and female, or unexplained infertility, meaning a clear cause is not identified.

TABLE 1 Types of Infertility

Type		Prevalence
Female factor infertility		40%-55%
Male factor infertility		25%-40%
Both male and female factor infertility		10%-30%
Unexplained infertility		25%

From Talley NJ et al: Essentials of internal medicine, ed 4, Chatswood, NSW, 2021, Elsevier Australia.

Peak Incidence

The incidence of infertility increases with age. Subtle decreases in female fertility start as early as age 30. The rate of infertility increases dramatically after age 37, and unassisted pregnancies become extremely uncommon as women reach the mid-40s. There is also a subtle, but still detectable, decrease in male fertility that may start as early as age 30.

Risk Factors

Aging is among the most common risk factors, predominantly among females, although there is evidence that aging affects male fertility as well. Women are increasingly deferring pregnancy due to the lack of a partner or career. Tubal factor infertility can be a result of endometriosis, prior tubal surgery, prior ruptured appendix, or sexually transmitted diseases such as chlamydia and gonorrhea. Ovulatory dysfunction is most commonly caused by polycystic ovarian syndrome (PCOS). Other causes of ovulatory dysfunction include hypothalamic dysfunction, thyroid disorders, hyperprolactinemia, and extremes of weight, particularly obesity. Male factor infertility may be idiopathic or due to trauma, infection, varicocele, obstruction, hypothalamic dysfunction, or exposure to environmental toxins. Smoking is the most common lifestyle choice that impairs fertility.

Physical Findings & Clinical Presentation

Age
Previous fertility, particularly if no pregnancy has occurred in another relationship despite absence of contraception
Absence of secondary sexual characteristics
Abnormal uterine bleeding or absent or irregular menstruation
Clinical signs of androgen excess: Hirsutism, acne, alopecia
Abnormal pelvic exam: Enlarged uterus, adnexal masses, pelvic/abdominal tenderness
History of urologic surgery in male or trauma to testes

Etiology

Female factor:
1. Advanced age
2. Tubal factor: Pelvic inflammatory disease, endometriosis, prior pelvic surgery, history of ruptured appendicitis, prior elective sterilization
3. Anatomic: Uterine fibroids, polyps, intrauterine adhesions, congenital uterine anomalies
4. Oligo-/anovulation: Most frequently due to polycystic ovarian syndrome (PCOS), but also due to thyroid abnormalities, hyperprolactinemia, nonclassic congenital adrenal hyperplasia, or hypothalamic dysfunction
Male factor (Table 2):
1. Abnormal semen analysis
2. Elective sterilization
Idiopathic: Both male and female

TABLE 2 Causes of Male Infertility

Cause		Examples
Hypogonadism
Isolated impairment of sperm production or function
Androgen deficiency and impaired sperm production
Androgen resistance
Disorders of Sperm Transport
Genital tract obstruction		Congenital bilateral absence of the vas deferens, cystic fibrosis, other congenital defects, vasectomy, postinfectious fibrosis, Young syndrome
Accessory gland dysfunction		Androgen deficiency or resistance, infection or inflammation, antisperm antibodies (immunologic)
SNS dysfunction		Autonomic neuropathy, sympatholytic drugs, sympathectomy, retroperitoneal or abdominopelvic surgery, spinal cord injury or disease, vasovasostomy
Ejaculatory Dysfunction
Premature or retarded ejaculation
Retrograde ejaculation		Prostatectomy, bladder neck surgery, autonomic neuropathy, SNS dysfunction
Reduced ejaculation		Androgen deficiency or resistance, SNS dysfunction, ureteral abnormalities
Coital Disorders
Erectile dysfunction
Defects in coital technique		Infrequent intercourse (<once weekly), poor timing in relation to ovulation, premature withdrawal of penis

SNS, Sympathetic nervous system.

From Melmed S et al: Williams textbook of endocrinology, ed 14, Philadelphia, 2019, Elsevier.

TABLE E3 Fertility Preservation Options Among Females

Option	Embryo Freezing	Egg Freezing	Ovarian Tissue Freezing	Radiation Shielding of Gonads	Ovarian Transposition	Radical Trachelectomy	Ovarian Suppression
Medical status	Standard	Standard	Standard	Standard	Standard	Standard	Experimental
Definition	Harvesting eggs, in vitro fertilization, and freezing of embryos for later implantation	Harvesting and freezing of unfertilized eggs	Freezing of ovarian tissue and reimplantation after cancer treatment	Use of shielding to reduce scatter radiation to the reproductive organs	Surgical repositioning of ovaries away from the radiation field	Surgical removal of the cervix with preservation of the uterus	Gonadotropin-releasing hormone analogs or antagonists used to suppress ovaries
Pubertal status	After puberty	After puberty	Before or after puberty	Before or after puberty	Before or after puberty	After puberty	After puberty
Time requirement	10-14 days; outpatient surgical procedure	10-14 days; outpatient surgical procedure	Outpatient surgical procedure	In conjunction with radiation treatments	Outpatient procedure	Inpatient surgical procedure	In conjunction with chemotherapy
Success rates	Approximately 40% per embryo transfer; varies by age and center	Approximately 4%-6% live birth per oocyte; over 5000 live births worldwide	Varies by age. Over 200 live births worldwide	Only possible with selected radiation fields and anatomy	Approximately 50% because of altered blood flow and scattered radiation	No evidence of higher cancer recurrence rates in appropriate candidates	Unknown; conflicting results reported; larger randomized trials in progress
Cost	Approx. $10,000-$12,000/cycle; storage fees additional	Approx. $5500/cycle; storage fees additional	Approx. $10,000 for procedure; storage fees and reimplantation costs additional	Generally included in cost of radiation	May be covered by insurance if performed at the time of another procedure	Generally included in the cost of cancer treatment	Approx. $500/mo, but may be covered in the cost of chemotherapy
Timing	Ideally before treatment, but may perform after depending on ovarian reserve	Ideally before treatment, but may perform after depending on ovarian reserve	Ideally before treatment, but may perform after depending on ovarian reserve	During treatment	Before treatment	During treatment	Start before and continue through treatment
Special considerations	Need partner or donor sperm	Beneficial for single women or those with ethical concerns regarding embryo creation	Not suitable if high risk of ovarian metastases; only preservation option for prepubescent girls	Expertise required; does not protect against effects of chemotherapy	Expertise required	Limited to early-stage cervical cancer; offered at a limited number of centers	Does not protect from radiation effects

Modified from https://www.livestrong.org/fertility. In Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

TREATMENT ³

Once the patient presents for evaluation, testing should be completed as quickly as possible, ideally within one menstrual cycle. The couple should follow up with the evaluating provider once all testing is completed, and treatment should be initiated as abnormalities are found.

Diagnosis ⬆ ⬇

Workup

Confirmation of ovulation: History of regular menstrual cycles, mid-luteal serumprogesterone, basal body temperature testing, urinary luteinizing hormone predictor kits
Complete transvaginal pelvic ultrasound
Ovarian reserve testing: Anti-Müllerian hormone, follicle-stimulating hormone (FSH), and estradiol obtained on cycle day 2, 3, or 4 and antral follicle count
Fallopian tube evaluation: Hysterosalpingogram (HSG) (Fig. E1) or sonohysterosalpingogram
Uterine cavity evaluation: HSG, saline infusion sonohysterography, hysteroscopy, or 3D ultrasound of uterus
Male factor: Semen analysis

Figure E1 Hysterosalpingogram Spot Radiographs Early (A) and Late (B) Demonstrate a Rounded Collection of Contrast Material (Arrowhead) Adjacent to the Dilated Ampullary Portion of the Right Fallopian Tube (Arrow), Caused by Peritubal Pelvic Adhesions Related to Previous Pelvic Inflammatory Disease

Normal Patient Left Fallopian Tube. U, Uterus.

From Fielding JR et al: Gynecologic imaging, Philadelphia, 2011, Saunders.

Laboratory Tests

Semen analysis, using Kruger strict morphology. Abstain 2 to 5 days prior to test.
FSH and estradiol collected cycle day 2, 3, or 4 and anti-Müllerian hormone as a measure of ovarian reserve.
Mid-luteal progesterone (ideally 7 days prior to expected menses). Given variability of serum progesterone measurements throughout the day and absence of a reliable threshold, most practitioners use clinical criteria to diagnose ovulatory dysfunction.
Thyroid-stimulating hormone (TSH).
In patients with oligo- or anovulation: Prolactin, testosterone, 17-hydroxyprogesterone.

Imaging Studies

Day 2 or 3 transvaginal pelvic ultrasound to assess uterine or adnexal abnormalities and to count the number of small antral follicles (2 to 9 mm) as a measure of ovarian reserve. If oligo- or anovulatory, to assess for polycystic-appearing ovary
Hysterosalpingogram (early follicular phase after menses complete but before ovulation, typically between days 5 and 12 of the menstrual cycle)
Also used for imaging of uterine cavity: Saline infusion sonohysterography, 3D ultrasound of uterus, hysteroscopy

Pearls & Considerations ⬆ ⬇

Comments

The incidence of heterotopic pregnancy in patients who have undergone ART is more common compared with an unassisted conception. Identification of a patient with ultrasound-proved intrauterine pregnancy who used ART to conceive should NOT necessarily exclude the possibility of an ectopic gestation.
Single-embryo transfer is recommended in the vast majority of IVF cycles to reduce the rate of multiple gestation and subsequent risks to fetus and mother.
Preimplantation genetic testing for monogenic/single-gene defects (PGT-M) or preimplantation genetic testing for chromosomal structural rearrangement (PGT-SR) is used in selected IVF cycles when one or both parents has one or more known genetic abnormalities or chromosomal rearrangements to test embryos for these specific genetic abnormalities prior to implantation.
Preimplantation genetic testing for aneuploidy (PGT-A) is used in IVF cycles to screen embryos for aneuploidy prior to implantation.

Prevention

Techniques that reduce the incidence of pelvic inflammatory disease, such as condom use, can reduce pelvic adhesions that are associated with tubal factor infertility.
Women should be made aware of the fact that delaying pregnancy into the later reproductive years reduces the likelihood for successful pregnancy. Many women are cryopreserving oocytes or embryos for future use.
Oocyte, embryo, or sperm cryopreservation is recommended for patients undergoing gonadotoxic chemotherapy or radiation treatment as a means of fertility preservation. Ovarian tissue cryopreservation can be used for patients who do not have time to undergo ovarian stimulation. Prepubertal testicular tissue cryopreservation may also be performed under a research protocol. All patients should be referred to a reproductive endocrinologist before planned treatment to discuss fertility preservation options.

Patient & Family Education

Patient support groups such as Resolve (https://www.resolve.org) are available to help couples during evaluation and treatment of infertility, which can be extraordinarily stressful.

Related Content

Infertility (Patient Information)

Amenorrhea (Related Key Topic)

Pelvic Inflammatory Disease (Related Key Topic)

Polycystic Ovary Syndrome (Related Key Topic)

ACUTE GENERAL Rx

Fertility preservation options among females are summarized in Table E3.
Oligo- or anovulation should be treated with ovulation induction agents, such as aromatase inhibitors or clomiphene citrate. A recent multicenter trial found that aromatase inhibitors achieved higher live birth rates than clomiphene citrate.⁴ Historically, clomiphene citrate has been used, but a very well done randomized controlled trial convincingly demonstrated that letrozole is superior in patients with PCOS.⁵ Far less commonly, ovulatory dysfunction is the result of hypothalamic dysfunction. In these patients, once hypothalamic or pituitary abnormalities are excluded with MRI, ovulation can be achieved using injectable gonadotropins.
Tubal factor infertility may be treated surgically if mild, and if the female patient is young and can afford the time to attempt pregnancy over multiple menstrual cycles. If the patient is older or if the tubal pathology is moderate to severe, in vitro fertilization (IVF) is recommended. Indications for IVF are summarized in Box 1.
Uterine anatomic abnormalities such as submucosal fibroids, polyps, intrauterine adhesions, or septate uterus should be corrected if they are identified. Fibroids that do not impact the uterine cavity probably do not interfere with fertility. Removal of intramural or subserosal fibroids is reserved for situations in which these cause distortion of the uterine cavity or bothersome symptoms such as excessive vaginal bleeding, pain, or pressure.
Male infertility: Referral to urologist for complete evaluation. Fertility preservation options for males are summarized in Table E4. If semen analysis is severely abnormal, the following laboratory testing is recommended: Testosterone, FSH, estradiol, luteinizing hormone, TSH and prolactin, karyotype and Y-chromosome microdeletion.
1. Mild male factor infertility may be treated with intrauterine insemination (IUI), but severe male factor will usually require assisted reproductive technologies (ART) with intracytoplasmic sperm injection (ICSI) in the laboratory, where sperm is injected directly into the oocyte.⁶ Some men may require epididymal aspiration or testicular biopsy to obtain sperm for IVF/ICSI. Donor sperm may be necessary in cases of azoospermia due to testicular failure, if male partner has a genetic disorder, or if couple is unable to proceed with IVF/ICSI.
2. Fig. 2 illustrates an algorithm for the evaluation and management of men with oligoasthenoteratospermia.
Unexplained infertility can be treated empirically using superovulation with clomiphene citrate, aromatase inhibitors, or gonadotropins combined with intrauterine insemination with partner’s or donor sperm. Most providers recommend using an oral ovulation induction agent with insemination as a first-line superovulatory agent because it is inexpensive. After three cycles, approximately 30% of couples will conceive. After 3 to 4 cycles, few couples will be successful, and it is recommended to move forward with IVF. There is evidence suggesting that moving to IVF after 3 mo of clomiphene citrate and intrauterine insemination shortens the time interval to achieving pregnancy.⁷ A randomized trial in women with unexplained infertility revealed ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene.
Donor egg or embryo may be required in cases of premature ovarian insufficiency or due to age factor. Some couples may elect to pursue adoption.
For LGBTQ couples, many family building options are available, including IUI or IVF utilizing donor sperm, donor oocytes, donor embryo, and/or gestational carrier, depending on the needs of the couple.

Figure 2 Algorithm for the Evaluation and Management of Men with Oligoasthenoteratospermia

Abx, Antibiotics; ART, assisted reproductive technology; NEG, negative; POS, positive; R/O, rule out; TRUS, transrectal ultrasound; TURED, transurethral resection of the ejaculatory ducts.

From Bach PV, Schlegel PN: Male infertility. In Yen and Jaffe’s reproductive endocrinology, ed 8, Philadelphia, 2019, Elsevier, p 586.

BOX 1 Indications for In Vitro Fertilization

IUI, Intrauterine insemination; TESE, testicular sperm extraction.

Blocked or absent fallopian tubes
Low sperm counts or absent sperm (azoospermia requiring TESE)
Advanced reproductive age
Endometriosis
Unexplained infertility unresponsive to IUI therapy
Screening for aneuploid embryos and/or genetic disease
Fertility preservation

From Gershenson DM et al: Comprehensive gynecology, ed 8, Philadelphia, 2022, Elsevier.

TABLE E4 Fertility Preservation Options for Males

Option	Sperm Banking (Masturbation)	Sperm Banking (Alternative Collection Methods)	Radiation Shielding of Gonads	Testicular Tissue Freezing	Testicular Sperm Extraction
Medical status	Standard	Standard	Standard	Experimental (prepubertal only, postpubertal standard)	Standard
Definition	Sperm is obtained through masturbation, then frozen	Sperm obtained through testicular extraction or electroejaculation under sedation	Use of shielding to reduce the dose of radiation delivered to the testes	Tissue obtained through biopsy and frozen for future use	Use of biopsy to obtain individual sperm from testicular tissue
Pubertal status	After puberty	After puberty	Before and after puberty	Before and after puberty	After puberty
Time requirement	Outpatient procedure	Outpatient procedures	In conjunction with radiation treatments	Outpatient procedure	Outpatient procedure
Success rates	Generally high; the most established technique for men	If sperm is obtained, similar to standard sperm banking	Possible with select radiation fields and anatomy	No available human success rates in prepubertal patients	30%-70% in postpubescent patients
Cost	Approximately $250 per sample. Storage fees average $500/yr	Varies greatly based on collection method	Generally included in the cost of radiation treatments	$500-$2500 for surgery; $300-$1000 for freezing; $500/yr for storage	$4000-$16,000 (in addition to costs for in vitro fertilization)
Timing	Ideally before treatment, but may perform after depending on effect of treatment on spermatogenesis	Ideally before treatment, but may perform after depending on effect of treatment on spermatogenesis	During treatment	Ideally before treatment, but may perform after depending on effect of treatment on spermatogenesis	Ideally before treatment, but may perform after depending on effect of treatment on spermatogenesis
Special considerations	Deposits can be made every 24 hours	Can be considered if male cannot ejaculate	Expertise required; does not protect against effects of chemotherapy	May be only option for prepubescent boys	Center should be able to freeze sperm found at time of biopsy

Modified from https://www.livestrong.org/fertility. In Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

DISPOSITION

Most couples will achieve a pregnancy, provided that they are willing to proceed with treatment including ovulation induction, superovulation, IUI, IVF, or gamete donation.
Adoption is also a worthwhile and viable possibility for couples unable to conceive.

COMPLEMENTARY & ALTERNATIVE MEDICINE

Acupuncture is widely used by women being treated for infertility. Limited data suggest some benefit, with possible mechanisms of action including increasing blood flow to the uterus and/or ovaries. Despite these studies, it is unproven whether acupuncture definitely improves IVF outcomes. Patients may additionally benefit from the stress relief that acupuncture provides.

REFERRAL

Couples should be referred to a reproductive endocrinologist once the complexity of treatment exceeds the comfort level of the provider, whether a family physician, internist, or general gynecologist. Complex ovulation and superovulation induction and ART are best managed by a board-certified reproductive endocrinologist.

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Basic Information ⬇

Diagnosis ⬆ ⬇

Pearls & Considerations ⬆ ⬇

Related Content ⬆