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Infertility and Contraception

Chapter 408 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Infertility is defined by WHO as the inability to achieve pregnancy over 12 months of unprotected intercourse.
  2. Fecundability declines significantly with age: reduced by 14% in women aged 34–35, 53% in women aged 40–41, and 59% in women aged 42–44.
  3. Etiology distribution: Female factors (30–40%), Male factors (40–50%), and Unexplained infertility (15–30%).
  4. First-line treatment for anovulatory infertility (e.g., PCOS) is letrozole, followed by clomiphene citrate.
  5. LARC methods (IUDs and implants) are the most effective reversible contraceptives with failure rates of 0.1–0.5 pregnancies per 100 women per year.
  6. USMEC Category 4 conditions (e.g., smoking in women ≥35 years, DVT, stroke) represent unacceptable health risks for hormonal contraceptive use.
  7. Levonorgestrel emergency contraception is associated with fewer side effects compared to combined hormonal pills.
  8. IVF is the treatment of choice for tubal factor infertility, bypassing the fallopian tubes.
  9. Submucosal fibroids and intramural fibroids that distort the endometrial cavity may lower pregnancy rates and increase risk of pregnancy loss.
  10. In men with obstructive azoospermia, sperm can be procured by direct aspiration from the epididymis or testis.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Causes of infertility

1. DEFINITION & OVERVIEW

  • The World Health Organization (WHO) categorizes infertility as a disease of the reproductive system.
  • Infertility is defined as the inability to achieve a pregnancy over 12 months of unprotected intercourse.
  • Primary infertility occurs in couples who have never achieved a pregnancy.
  • Secondary infertility refers to infertility after achieving at least one pregnancy.
  • During the first year of attempting pregnancy, the fecundability rate is highest in the first 3 months and declines over the next 9 months.
  • Approximately 85% of couples will achieve pregnancy after 12 months, and 95% will achieve pregnancy after 24 months.
  • Increasing trends toward later childbearing have significant implications due to age-related decrease in fecundability rate.
  • Harrison's defines this as: 'Infertility is the third most common disease worldwide, affecting ~48–72 million couples.'
  • Unintended pregnancies primarily occur due to lack of use or inconsistent use of contraceptives rather than failure of the contraceptive method used.
  • The prevalence of infertility, ~17.5% globally, has remained relatively stable over the past few decades.
  • Compared to women aged 30–31 years of age, fecundability is reduced by 14% in women aged 34–35 years, 19% in women aged 36–37 years, 53% in women aged 40–41 years, and 59% in women aged 42–44 years.
  • The probability of achieving a pregnancy decreases after the age of 35 in women, primarily due to chromosomal abnormalities in the oocyte during meiosis.
  • A similar decline has not been observed in men <50 years of age.
  • The desired ideal number of children per family varies around the globe and is approximately 2.6 in the United States.
  • Couples not using any form of contraception have an 85% chance of achieving a pregnancy over 1 year.

2. ETIOLOGY & PATHOPHYSIOLOGY

  • The causes for infertility are generally classified as female factors, male factors, and unexplained infertility.
  • The distribution of these causes varies significantly across the world.
  • Overall, female factors are present in 30–40% of couples with infertility.
  • Male factors are present in 40–50% of couples with infertility.
  • Both male and female factors are identified in 20–30% of couples.
  • Unexplained infertility refers to the absence of any identified abnormality after completing the fertility workup and occurs in up to 30% of couples.
  • As a result, a complete workup of both partners is recommended in all couples presenting with infertility.

2.1 Female Factors

  • Tubal factors: pelvic inflammatory disease, endometriosis, prior surgery, salpingitis isthmica nodosum.
  • Uterine etiology: fibroids, congenital malformations, uterine scarring.
  • Ovulatory dysfunction: polycystic ovary syndrome [PCOS], diminished ovarian reserve, premature ovarian insufficiency.
  • Endocrine dysfunction: hypothyroidism, hyperprolactinemia.

2.2 Male Factors

  • Anatomic factors in the reproductive system: vasectomy, infection, absence of the vas.
  • Endocrine factors: hypogonadotropic hypogonadism, hypothyroidism, hyperprolactinemia, morbid obesity, use of certain medications.
  • Sexual dysfunction: erectile or ejaculatory dysfunction, decreased libido.
  • Genetic factors contributing to primary testicular dysfunction, including defects in spermatogenesis (Klinefelter's syndrome, Y chromosome microdeletions).
  • Obstructive azoospermia: 40% prevalence.
  • Nonobstructive azoospermia: associated with defects in spermatogenesis.

2.3 Unexplained Infertility

  • Occurs in 15–30% of couples.
  • No clear causes are identified after completing the fertility workup.

3. CLINICAL FEATURES

  • Infertility is associated with psychological stress related not only to the diagnostic and therapeutic procedures themselves but also to repeated cycles of hope and loss associated with each new procedure or cycle of treatment that does not result in the birth of a child.
  • These feelings are often combined with a sense of isolation from friends and family.
  • Counseling and stress-management techniques should be offered early in the evaluation of infertility as many patients do not pursue treatments after the initial consultation.
  • Infertility and its treatment do not appear to be associated with long-term psychological sequelae.

3.1 Female Symptoms & Signs

  • Gynecologic history: menstrual frequency, menorrhagia, dysmenorrhea, history of sexually transmitted infections, endometriosis.
  • Medical and endocrine history: exposure to pelvic radiation, abdominal or pelvic surgeries, tobacco and alcohol use, medication use including cytotoxic drugs, family history of early menopause, and prior history of pregnancy.
  • Physical exam: assessment of weight and blood pressure (BP), thyroid and breast exam, assessment for signs of hyperandrogenism, and pelvic exam to assess uterine size, adnexal masses, and factors that might impact intercourse.
  • Signs of endometriosis: pelvic pain and dysmenorrhea.
  • Signs of fibroids: may lower pregnancy rates and increase risk of pregnancy loss if submucosal or intramural and distorting the endometrial cavity.

3.2 Male Symptoms & Signs

  • History: injuries and surgery in the reproductive tract; mumps orchitis; exposure to pelvic radiation; use of androgens, cytotoxic drugs, and other medications; and fertility with any prior partner.
  • Physical exam: body mass index (BMI), BP, and complete physical exam including testicular exam.
  • Varicocele: repair recommended when associated with abnormal semen parameters or symptomatic from the varicocele.

4. INVESTIGATIONS & DIAGNOSIS

  • Diagnostic evaluation for infertility is typically initiated after 1 year of unprotected intercourse because 80–85% of couples will achieve a pregnancy over this time period.
  • Evaluation can be initiated even prior to meeting the definition of infertility, especially if one of the partners has risk factors for infertility.
  • If the female partner's age is >35 years, it is recommended to initiate evaluation after 6 months of attempting pregnancy.
  • If the age of the female partner is >40 years, it is recommended to start evaluating the couple immediately.
  • The initial evaluation should include detailed medical history, laboratory testing, radiologic evaluation, and preconception counseling for both partners.
  • As multiple causes for infertility may be identified, it is best to perform the complete diagnostic evaluation prior to initiating treatment.

4.1 History & Physical Exam

  • Female partner: gynecologic history, medical and endocrine history, exposure to pelvic radiation, abdominal or pelvic surgeries, tobacco and alcohol use, medication use including cytotoxic drugs, family history of early menopause, and prior history of pregnancy.
  • Male partner: specific questions regarding injuries and surgery in the reproductive tract; mumps orchitis; exposure to pelvic radiation; use of androgens, cytotoxic drugs, and other medications; and fertility with any prior partner.
  • Physical exam: frequency of intercourse, timing of intercourse, use of methods to detect ovulation, and concerns regarding sexual dysfunction over the past several months should be ascertained.

4.2 Ultrasound

  • Abdominal and transvaginal pelvic ultrasound can assess uterine (myomas, adenomyosis, müllerian anomalies) and adnexal abnormalities (endometriosis, polycystic-appearing ovaries).
  • Evaluates ovarian reserve (number of antral follicles in both ovaries).
  • Saline infusion sonogram is more accurate in assessing intrauterine pathology such as polyps and intrauterine scarring compared to HSG and can be combined with ultrasound assessment of the pelvis.

4.3 Ovarian Reserve Evaluation

  • Assessment of ovarian reserve includes measurement of serum FSH and estradiol on day 2 or 3 of the menstrual cycle and serum anti-müllerian hormone (AMH).
  • These screening tests combined with age of the female partner and antral follicle counts measured by ultrasound can identify diminished ovarian reserve and provide information on the urgency to initiate treatment.
  • AMH and antral follicle counts are also used to determine starting doses of gonadotropins for fertility treatments.
  • These markers of ovarian reserve, however, do not predict the likelihood of pregnancy and live birth.

4.4 Endocrine Tests

  • In women with irregular menses, serum TSH, prolactin, and androgens (total and free testosterone) should be measured to identify other causes for anovulation.
  • In women with diminished ovarian reserve and women with premature ovarian insufficiency, the option of using donor oocytes can be offered.

4.5 Hysterosalpingogram (HSG)

  • Performed during the follicular phase to assess the patency of fallopian tubes by injecting radiopaque contrast through the cervix into the uterus and imaging the flow of contrast through one or both tubes.
  • In addition to identifying tubal pathology, an HSG may identify intrauterine abnormalities such as polyps, submucosal myomas, and adhesions.
  • Of note, diagnostic laparoscopy, postcoital test, endometrial biopsy, thrombophilia, and immunologic testing and karyotype are not indicated as part of the initial workup of infertility.
  • Although the negative predictive value of HSG for assessing tubal patency is high, the positive predictive value is relatively low.
  • Interestingly, pregnancy rates have been shown to be higher after an HSG test compared to no testing and higher when oil-based contrast was used compared to water-based contrast, likely related to tubal flushing of mucus plugs.
  • Alternate options that are increasingly used include injection of agitated saline contrast through the cervix into the uterus.

4.6 Semen Analysis

  • The semen sample is collected after 2–7 days of abstinence and provides an assessment of sperm count, motility, morphology, volume, and pH.
  • None of the individual sperm parameters are predictive of fertility, but the likelihood of infertility increases with multiple abnormalities.
  • Those with abnormal sperm parameters based on the WHO criteria (oligoasthenozoospermia is defined as sperm counts <15 million/mL, motility <40%, and normal morphology <4%) should have a physical exam and endocrine evaluation (serum follicle-stimulating hormone [FSH], LH, prolactin, and thyroid-stimulating hormone [TSH]).
  • Those with azoospermia or severe oligospermia (<5 million/mL) should have genetic evaluation (karyotype and Y chromosome microdeletion).
  • Although a DNA sperm fragmentation assay is not part of the initial evaluation, it may be indicated in patients with recurrent pregnancy loss.
  • Sperm antibody testing and scrotal ultrasound should not be routinely performed in infertile men.

4.7 Genetic Screening

  • All couples can be offered preconception genetic screening based on ethnicity, family history, or common autosomal recessive conditions.
  • In men with congenital bilateral absence of the vas deferens (CBAVD), testing for CFTR mutations and genetic counseling are indicated before offering IVF with ICSI.

5. MANAGEMENT & TREATMENT

  • Treatment recommendations depend on the results of the fertility evaluation described above.
  • The success of different treatments depends on several factors including age of the female partner, assessment of ovarian reserve, history of smoking, BMI, and race.
  • Tubal Factor Infertility: Tubal factor infertility constitutes 30–35% of cases of female infertility, and a large majority are secondary to tubal obstruction resulting from sexually transmitted infections.
  • In vitro fertilization (IVF) was first developed as a treatment for tubal factor infertility as it bypasses the fallopian tubes and allows fertilization of oocytes in the laboratory prior to transcervical transfer into the uterus.
  • IVF offers the highest success rates for couples with tubal factor infertility.
  • Tubal repair or reconstruction is typically not recommended in cases associated with tubal infections or hydrosalpinx, due to the low success rate in achieving tubal patency and increased risk of ectopic pregnancy.
  • In fact, removal of hydrosalpinges by salpingectomy will improve pregnancy rates in subsequent IVF treatments as it prevents efflux of tubal fluid into the uterine cavity.
  • If a proximal tubal blockage is observed on HSG, radiographically guided cannulation of fallopian tubes can be attempted.
  • In women with bilateral tubal ligation, the decision between microsurgical reanastomosis versus IVF will depend on a number of factors including patient's age, ovarian reserve, number of children desired, partner's semen parameters, experience of the surgeon, and cost of procedure.
  • Ovulatory Dysfunction: Endocrine conditions such as hypothyroidism and hyperprolactinemia should be treated prior to use of ovulation induction medications.
  • Lifestyle modifications should be recommended in patients with low BMI or obesity.
  • Weight loss in obese women has been shown to increase the likelihood of spontaneous or drug-induced ovulation.
  • First-line treatment for anovulatory infertility (most common etiology is PCOS) includes use of letrozole followed by clomiphene citrate to induce ovulation.
  • A large majority of women with PCOS (60–80%) respond to these oral medications.
  • The addition of metformin, combined with the above medications as a second-line agent, may further increase the chance of ovulation, particularly in obese women.
  • In women with hypothalamic amenorrhea, behavioral modifications such as weight gain and decreased exercise may resume ovulation.
  • If there is no response, judicious use of low-dose injectable gonadotropins can induce monofollicular growth.
  • In women with diminished ovarian reserve, treatment can be escalated from ovulation induction with oral medications and intrauterine insemination (IUI) to IVF, as the overall live birth rates are lower.
  • In both women with diminished ovarian reserve and women with premature ovarian insufficiency, the option of using donor oocytes can be offered.
  • In that case, the egg donor will undergo the IVF procedure, the harvested eggs are fertilized with the male partner's sperm, and the fertilized embryos will be transferred to the patient's uterus.
  • In women with advanced maternal age (>35 years) is associated with a higher risk of aneuploidy and advanced paternal age (>40 years) is associated with adverse health outcomes in the offspring.
  • Male Infertility: Given the high prevalence of male factor infertility (40–50%), timely evaluation and treatment are recommended.
  • Men with abnormal semen parameters have associated health risks and should have a detailed evaluation by specialists in male reproduction.
  • In men with no sperm (azoospermia) in the ejaculate, further evaluation including a repeat semen analysis followed by physical examination, endocrine tests, and genetics studies should be performed to identify obstructive (40% prevalence) versus nonobstructive etiology.
  • First-line treatment for mild to moderate male factor infertility includes IUI alone or IUI combined with ovulation induction, depending on the female partner's age and other causes of infertility.
  • In men with severe male factor infertility (sperm count <5 million/mL or motility <20%), both IVF with intracytoplasmic sperm injection (ICSI) is recommended.
  • In men with obstructive azoospermia, sperm can be procured by direct aspiration from the epididymis or testis.
  • In men with congenital bilateral absence of the vas deferens (CBAVD), testing for CFTR mutations and genetic counseling are indicated before offering IVF with ICSI.
  • In men with nonobstructive azoospermia, microsurgical sperm retrieval from the testes may result in successful pregnancies after IVF-ICSI; however, the use of donor sperm for IUI is an alternate option.
  • Men with hypogonadotropic hypogonadism (e.g., Kallmann's syndrome) can be treated with gonadotropins to initiate spermatogenesis followed by IUI or IVF.
  • Treatment of male sexual dysfunction and avoidance of exogenous androgens are effective strategies for addressing male factor infertility.
  • Repair of a moderate to large varicocele is recommended when associated with abnormal semen parameters or symptomatic from the varicocele; however, it may take several months to detect an improvement in semen parameters.
  • Unexplained Infertility: In 15–30% of couples, no clear causes of infertility are identified.
  • In such cases, it is appropriate to initiate ovarian stimulation with oral medications to increase the number of oocytes combined with IUI timed to ovulation in order to increase the number of motile sperm in the reproductive tract.
  • Depending on the age of the female partner, this approach offers modest success rates limiting its use to 3–6 months before recommending IVF.
  • Overall, IVF is associated with a low risk of complications; the risk of ovarian hyperstimulation syndrome is significantly decreased by judiciously monitoring stimulation and using gonadotropin-releasing hormone (GnRH) to trigger ovulation instead of human chorionic gonadotropin (hCG).
  • Multiple pregnancy remains the highest risk associated with IVF despite improvements in cryopreservation of embryos and age-based guidelines for limiting the number of embryos to transfer.
  • In some couples, the IVF treatment may reveal an underlying cause of infertility such as lower fertilization, embryo cleavage, or blastocyst formation rates.

Table 1 — TABLE 408-1 Assisted Reproductive Technologies

Ovulation induction Oral agents Injectable hormones
Clomiphene citrate (selective estrogen response modulator) Letrozole (aromatase inhibitor) FSH, LH (gonadotropins)

5.1 Ovulatory Dysfunction Treatment

  • First-line treatment for anovulatory infertility (most common etiology is PCOS) includes use of letrozole followed by clomiphene citrate to induce ovulation.
  • A large majority of women with PCOS (60–80%) respond to these oral medications.
  • The addition of metformin, combined with the above medications as a second-line agent, may further increase the chance of ovulation, particularly in obese women.
  • In women with hypothalamic amenorrhea, behavioral modifications such as weight gain and decreased exercise may resume ovulation.
  • If there is no response, judicious use of low-dose injectable gonadotropins can induce monofollicular growth.
  • In women with diminished ovarian reserve, treatment can be escalated from ovulation induction with oral medications and intrauterine insemination (IUI) to IVF, as the overall live birth rates are lower.
  • In both women with diminished ovarian reserve and women with premature ovarian insufficiency, the option of using donor oocytes can be offered.
  • In that case, the egg donor will undergo the IVF procedure, the harvested eggs are fertilized with the male partner's sperm, and the fertilized embryos will be transferred to the patient's uterus.
  • In women with advanced maternal age (>35 years) is associated with a higher risk of aneuploidy and advanced paternal age (>40 years) is associated with adverse health outcomes in the offspring.

5.2 Tubal Factor Infertility Treatment

  • Tubal factor infertility constitutes 30–35% of cases of female infertility, and a large majority are secondary to tubal obstruction resulting from sexually transmitted infections.
  • In vitro fertilization (IVF) was first developed as a treatment for tubal factor infertility as it bypasses the fallopian tubes and allows fertilization of oocytes in the laboratory prior to transcervical transfer into the uterus.
  • IVF offers the highest success rates for couples with tubal factor infertility.
  • Tubal repair or reconstruction is typically not recommended in cases associated with tubal infections or hydrosalpinx, due to the low success rate in achieving tubal patency and increased risk of ectopic pregnancy.
  • In fact, removal of hydrosalpinges by salpingectomy will improve pregnancy rates in subsequent IVF treatments as it prevents efflux of tubal fluid into the uterine cavity.
  • If a proximal tubal blockage is observed on HSG, radiographically guided cannulation of fallopian tubes can be attempted.
  • In women with bilateral tubal ligation, the decision between microsurgical reanastomosis versus IVF will depend on a number of factors including patient's age, ovarian reserve, number of children desired, partner's semen parameters, experience of the surgeon, and cost of procedure.

5.3 Male Infertility Treatment

  • Given the high prevalence of male factor infertility (40–50%), timely evaluation and treatment are recommended.
  • Men with abnormal semen parameters have associated health risks and should have a detailed evaluation by specialists in male reproduction.
  • In men with no sperm (azoospermia) in the ejaculate, further evaluation including a repeat semen analysis followed by physical examination, endocrine tests, and genetics studies should be performed to identify obstructive (40% prevalence) versus nonobstructive etiology.
  • First-line treatment for mild to moderate male factor infertility includes IUI alone or IUI combined with ovulation induction, depending on the female partner's age and other causes of infertility.
  • In men with severe male factor infertility (sperm count <5 million/mL or motility <20%), both IVF with intracytoplasmic sperm injection (ICSI) is recommended.
  • In men with obstructive azoospermia, sperm can be procured by direct aspiration from the epididymis or testis.
  • In men with congenital bilateral absence of the vas deferens (CBAVD), testing for CFTR mutations and genetic counseling are indicated before offering IVF with ICSI.
  • In men with nonobstructive azoospermia, microsurgical sperm retrieval from the testes may result in successful pregnancies after IVF-ICSI; however, the use of donor sperm for IUI is an alternate option.
  • Men with hypogonadotropic hypogonadism (e.g., Kallmann's syndrome) can be treated with gonadotropins to initiate spermatogenesis followed by IUI or IVF.
  • Treatment of male sexual dysfunction and avoidance of exogenous androgens are effective strategies for addressing male factor infertility.
  • Repair of a moderate to large varicocele is recommended when associated with abnormal semen parameters or symptomatic from the varicocele; however, it may take several months to detect an improvement in semen parameters.

5.4 Unexplained Infertility Treatment

  • In 15–30% of couples, no clear causes of infertility are identified.
  • In such cases, it is appropriate to initiate ovarian stimulation with oral medications to increase the number of oocytes combined with IUI timed to ovulation in order to increase the number of motile sperm in the reproductive tract.
  • Depending on the age of the female partner, this approach offers modest success rates limiting its use to 3–6 months before recommending IVF.
  • Overall, IVF is associated with a low risk of complications; the risk of ovarian hyperstimulation syndrome is significantly decreased by judiciously monitoring stimulation and using gonadotropin-releasing hormone (GnRH) to trigger ovulation instead of human chorionic gonadotropin (hCG).
  • Multiple pregnancy remains the highest risk associated with IVF despite improvements in cryopreservation of embryos and age-based guidelines for limiting the number of embryos to transfer.
  • In some couples, the IVF treatment may reveal an underlying cause of infertility such as lower fertilization, embryo cleavage, or blastocyst formation rates.

5.5 Uterine Factors Treatment

  • Fibroids are the most common benign tumors of the reproductive tract and occur in 50–70% of reproductive-age women.
  • It is not clear whether fibroids decrease the likelihood of pregnancy; submucosal fibroids and intramural fibroids that distort the endometrial cavity may lower pregnancy rates and increase the risk of pregnancy loss.
  • Removal of submucosal fibroids, uterine polyps, and intrauterine adhesions hysteroscopically may improve subsequent pregnancy rates.
  • Endometriosis is a common gynecologic condition associated with pelvic pain and dysmenorrhea, and in severe cases, it is associated with tubo-ovarian infertility.
  • Approximately 25–50% of infertile women have endometriosis, and 30–50% of women with endometriosis have infertility.
  • Prolonged medical management to suppress endometriotic lesions and surgical treatment of stage 1 and 2 endometriosis have not been shown to improve subsequent fertility rates.
  • Surgical removal of endometriotic lesions or endometriomas in women with stage 3 or 4 endometriosis may improve subsequent pregnancy rates.
  • First-line treatment of infertility associated with endometriosis alone includes use of oral ovulation induction medications and IUI.

6. CONTRACEPTION

  • The desired ideal number of children per family varies around the globe and is approximately 2.6 in the United States.
  • Couples not using any form of contraception have an 85% chance of achieving a pregnancy over 1 year.
  • Based on these data, couples spend most of their reproductive life preventing a pregnancy and a much smaller proportion attempting to become or being pregnant.
  • It is therefore not surprising that a majority of women who have been sexually active will have used some form of contraception to prevent a pregnancy.
  • Unintended pregnancies primarily occur due to lack of use or inconsistent use of contraceptives rather than failure of the contraceptive method used.
  • Of the different forms of contraception used worldwide in 2022, tubal sterilization was the most common (~219 million) followed by use of male condom (208 million), intrauterine device (IUD) (161 million), and the (birth control) pill (150 million).
  • Contraceptive methods used by married women differ from those used by single women, and the most widely used contraceptive methods differ by world regions.
  • The rates of female sterilization increased steadily in the last century and now show a slight decrease, likely due to the increasing use of long-acting reversible contraceptive (LARC) agents, such as IUDs and implants, which are as effective as sterilization.
  • The convenience of use of contraceptives determines their compliance and efficacy; contraceptives requiring daily and coitus-related use have higher failure rates compared to long-acting reversible and permanent methods.
  • The U.S. Medical Eligibility Criteria (USMEC) for contraceptive use are evidence-based guidelines to help health care providers recommend appropriate contraceptives to women with chronic medical conditions.
  • This excellent resource is adapted from the WHO guidance and is kept up to date through continual review of published literature.

Table 2 — TABLE 408-2 U.S. Medical Eligibility Criteria (USMEC) for Contraceptive Use

USMEC Category 4 (a condition that represents an unacceptable health risk if the contraceptive method is used) USMEC Category 3 (a condition for which the theoretical or proven risks outweigh the advantages for using the method)
Smoking: women age ≥35 years who smoke ≥15 cigarettes per day Smoking: women ≥35 years who smoke <15 cigarettes/day
Known ischemic heart disease or multiple risk factors for cardiovascular disease (older age, smoking, diabetes, low HDL, high LDL, high triglycerides, and hypertension) Hypertension (adequately controlled or systolic 140–159 mmHg or diastolic 90–99 mmHg)
Acute DVT Previous thromboembolic event; lower risk of recurrent DVT
Previous thromboembolic event; high risk of recurrent DVT Superficial thrombosis (acute or history of)
Stroke or known thrombogenic mutations Past history of breast cancer and no evidence for 5 years
Complicated valvular heart disease Anticonvulsant drug therapy (certain anticonvulsants (phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine))
Peripartum cardiomyopathy (<6 months, moderately to severely impaired cardiac function) Antimicrobial therapy: rifampin or rifabutin
Complicated solid organ transplantation Antiretroviral therapy for prevention (preexposure prophylaxis) or treatment of HIV
Hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg, vascular disease) Bariatric surgery (Roux-en-Y gastric bypass or biliopancreatic diversion)
Systemic lupus erythematous (positive or unknown antiphospholipid antibodies) Breast-feeding 21–42 days postpartum with or without risk factors for VTE
Cirrhosis, hepatocellular adenoma or hepatoma (malignant) Breast-feeding <21days postpartum
Viral hepatitis, acute flare Breast cancer
Pregnancy and early postpartum (<21 days) Diabetes: neuropathy/retinopathy/nephropathy
Breast-feeding <21days postpartum Migraines with aura

Table 3 — TABLE 408-3 Effectiveness of Different Forms of Contraception

METHOD OF CONTRACEPTION THEORETICAL EFFECTIVENESS (%) ACTUAL EFFECTIVENESS (%) CONTINUED USE AT 1 YEAR (%) USE OF CONTRACEPTIVE METHOD BY U.S. WOMEN AGE 15–49 (%)
No method 15 15 34.7
Fertility awareness 96 76 47 1.2
Withdrawal 96 78 46 4.4
Barrier methods
Condoms 98 82 43 8.4
Diaphragm 94 82 57 2
Spermicides 82 72 43 1
Sterilization
Female 99.5 99.5 100 18.1
Male 99.5 99.9 100 5.6
Intrauterine device 10.4
Copper T 99.4 99.8 85
Progestin-containing 99.8 99.8 88
Hormonal contraceptives
Combined and progestin only 99.7 91 67 14
Transdermal patch 99.7 91 67 0.5
Vaginal ring 99.7 91 67 1.8
Implant 3.1
Depo-Provera 99.8 94 56
Subdermal implant 99.5 99.5 84
Emergency contraception 95 - - 11

6.1 Permanent Contraception

  • The permanent forms of contraception include tubal sterilization and vasectomy.
  • Male sterilization has declined globally with a rate of <2% in 2022.
  • Vasectomy is a low-risk procedure typically performed in an outpatient setting with a very low failure rate of 0.1 pregnancies per 100 women per year.
  • It is not immediately effective, and patients should be told to use other forms of contraception for a minimum of 3 months after the procedure.
  • Globally, tubal sterilization rates have also declined steadily and represent 23% of all methods.
  • Tubal sterilization can be performed in the postpartum period or as an interval procedure and has a failure rate of 0.5 pregnancies per 100 women per year.
  • Postpartum sterilization can be performed during a cesarean section or after a vaginal delivery via minilaparotomy.
  • Interval procedures can be performed laparoscopically or via mini-laparotomy and include partial or complete salpingectomy or occlusion of the fallopian tubes using electrocoagulation or mechanical devices such as clips.
  • These permanent methods of contraception are highly effective as they avoid the need for user-dependent contraception.
  • All patients should undergo preprocedure counseling regarding risk of failure, permanence of the procedure, regret, and alternatives.

6.2 Hormonal Contraceptives

  • Combined Estrogen- and Progestin-Containing Contraceptives: The mechanism of action of the hormonal contraceptives involves negative feedback from continuous estrogen administration, thereby decreasing FSH secretion, follicular development, and formation of a dominant follicle.
  • The continuous progestin suppresses LH secretion and inhibits ovulation, alters endometrial receptivity, thickens the cervical mucus, and impairs tubal motility.
  • These hormones can be delivered via oral pills to be taken daily, as a transdermal patch that is changed weekly, or a vaginal ring that is replaced monthly or annually.
  • There are numerous pills available containing different doses of estrogen (90 kg.
  • The transdermal mode of delivery is associated with a higher steady state comparable to that of a 40-μg ethinyl estradiol oral contraceptive.
  • Hormonal contraceptives offer additional benefits such as regulation of menstrual cycles; suppression of ovarian cysts; and decrease in menorrhagia, dysmenorrhea, and hyperandrogenism.
  • Common side effects include nausea, breast tenderness, bloating, and intermenstrual bleeding.
  • There may be a mild increase in BP in some patients, and it is recommended to check BP at follow-up visits.
  • In large studies and meta-analyses, hormonal contraceptives are not associated with significant weight gain, mood changes, or effect on libido.
  • Prior to administering hormonal contraceptives, a detailed patient history should be obtained to determine any absolute or relative contraindications to their use.
  • Due to the low but slightly increased risk of deep-vein thrombosis (DVT) associated with estrogen-containing hormonal contraceptives (3–15 per 10,000 women-years), they are contraindicated in the immediate postpartum period, in smokers over the age of 35 years, and in women with a history of hereditary thrombophilias or DVT.
  • The association between risk of DVT and different doses of estrogen (ethinyl estradiol <35 μg) or different routes of administration (transdermal patch) is weak.
  • There is, however, some association between third- and fourth-generation progestins and increased risk of DVT.
  • Routine screening for familial thrombotic disorders is not recommended prior to prescribing hormonal contraceptives.
  • Although obesity is associated with decreased fertility, the vast majority of women with obesity do not experience infertility.
  • The USMEC classifies obesity alone as risk category 2, where the benefits of taking hormonal contraceptives outweigh any theoretical risk.
  • Progestin-Only Hormonal Contraception: Different types of progestins are used for contraception in oral pills, injectable forms, subdermal implants, and IUDs and may be an option for women who have contraindications to the use of estrogen-containing contraceptives (e.g., migraine with aura, DVT, stroke, breast-feeding).
  • The failure rate with progestin-only pills is 9 pregnancies per 100 women per year, whereas the failure rate of progestin IUDs is 0.1 pregnancies per 100 women per year.
  • In addition to acting as a spermicidal, the levonorgestrel IUD also thickens the cervical mucus and thins the endometrium, thereby decreasing its receptivity.
  • The common side effects include irregular bleeding, acne, breast tenderness, and pain with higher rates of expulsion when IUDs are inserted in the immediate postpartum period.
  • Breakthrough bleeding or unscheduled bleeding is commonly reported, as estrogen usually serves to stabilize the endometrial lining and prolonged exposure to progestin alone results in a thinner decidualized lining.
  • Depending on the device used, the progestin IUD is effective for 3–7 years.
  • The injectable form of progestone (medroxyprogesterone acetate) is administered intramuscularly or subcutaneously every 3 months with a failure rate of 3 pregnancies per 100 women per year.
  • Its side effects include weight gain, irregular menses, amenorrhea, and mood changes, and there is a slow return to ovulation and fertility after discontinuation (6–9 months).
  • The subdermal implant contains etonogestrel and is placed easily over the triceps muscle in the inner arm using local anesthesia.
  • It lasts up to 5 years and has a failure rate of 0.05 pregnancies per 100 women per year.
  • Findings from the Contraceptive Choice research project showed that continuation rates were higher for LARC (IUDs and implants) compared to short-acting methods.
  • LARCs are the most effective reversible form of contraception with high continuation and satisfaction rates; hence, they are a good choice in adolescents and nulliparous women.

6.3 Nonhormonal IUD

  • IUDs are a commonly used form of contraception worldwide and are available as hormonal and nonhormonal devices.
  • The nonhormonal copper IUD works as a spermicidal and is effective for up to 12 years with a failure rate of <1 pregnancy per 100 women per year.
  • Patients should be counseled regarding the increased risk of heavy vaginal bleeding and dysmenorrhea resulting in higher discontinuation rates compared to the levonorgestrel-containing IUDs.
  • IUDs can be used in adolescents and adult women and are typically inserted and removed as an office procedure with use of mild analgesics.
  • They can be inserted anytime during a menstrual cycle, referred to as interval insertion, and in the immediate postpartum and postabortion period.

6.4 Barrier Contraception

  • The barrier forms of contraception include condoms (male, female) and diaphragm and cervical cap and have lower effectiveness secondary to inconsistent and incorrect use.
  • They offer several advantages including minimal side effects, lower cost, no requirement for a prescription, and protection from sexually transmitted infections.
  • The failure rate for male and female condoms is 17–21 pregnancies per 100 women per year.
  • Spermicidals can be used in conjunction with barrier methods to improve effectiveness.

6.5 Lactational Contraception

  • Lactation may serve as an effective form of contraception during the first 6 postpartum months if there is exclusive breast-feeding and menstrual cycles have not resumed.

6.6 Emergency Contraception

  • Levonorgestrel administered as a single dose will prevent or delay ovulation and is associated with fewer side effects compared to combined hormonal pills.
  • It is administered as a 30-mg single dose up to 5 days after unprotected intercourse.
  • Overall, the failure rate for all hormonal emergency contraception is 1–3%, with ulipristal acetate being the most effective.
  • Side effects are mild and may include nausea, irregular vaginal bleeding, and fatigue.
  • Emergency contraception should be offered to all women who ask for it up to 5 days after unprotected intercourse and not delayed in order to obtain a pregnancy test or perform a clinical examination.
  • Although body weight can affect the efficacy of emergency hormonal contraception, treatment should not be withheld from overweight and obese women.

7. PROGNOSIS & COMPLICATIONS

  • IVF is associated with a low risk of complications.
  • The risk of ovarian hyperstimulation syndrome is significantly decreased by judiciously monitoring stimulation and using gonadotropin-releasing hormone (GnRH) to trigger ovulation instead of human chorionic gonadotropin (hCG).
  • Multiple pregnancy remains the highest risk associated with IVF despite improvements in cryopreservation of embryos and age-based guidelines for limiting the number of embryos to transfer.
  • In some couples, the IVF treatment may reveal an underlying cause of infertility such as lower fertilization, embryo cleavage, or blastocyst formation rates.
  • In women with advanced maternal age (>35 years) is associated with a higher risk of aneuploidy and advanced paternal age (>40 years) is associated with adverse health outcomes in the offspring.
  • Infertility and its treatment do not appear to be associated with long-term psychological sequelae.

7.1 IVF Complications

  • Overall, IVF is associated with a low risk of complications.
  • The risk of ovarian hyperstimulation syndrome is significantly decreased by judiciously monitoring stimulation and using gonadotropin-releasing hormone (GnRH) to trigger ovulation instead of human chorionic gonadotropin (hCG).
  • Multiple pregnancy remains the highest risk associated with IVF despite improvements in cryopreservation of embryos and age-based guidelines for limiting the number of embryos to transfer.
  • In some couples, the IVF treatment may reveal an underlying cause of infertility such as lower fertilization, embryo cleavage, or blastocyst formation rates.

8. SPECIAL CONSIDERATIONS

  • Preconception counseling regarding smoking cessation is important as evidence suggests that smoking cessation can reverse the detrimental impact of smoking on fecundity.
  • Smoking decreases fertility rates by a direct impact on oocyte DNA and also increases the risk of miscarriage and ectopic pregnancy.
  • In addition, smoking during pregnancy is associated with an increased risk of placental abruption and intrauterine growth restriction (IUGR).
  • Moreover, the impact of smoking on ovarian reserve has been shown to accelerate the time to menopause by 1–4 years.
  • As high levels of caffeine consumption increase the risk of infertility and miscarriage, women should be counseled to restrict caffeine consumption to ≤2 cups while attempting pregnancy and during pregnancy.
  • Use of testosterone products, which are widely used for the treatment of hypoandrogenism and sexual dysfunction in men, should be stopped.
  • Inquiries should be made about possible misuse of androgens for physical appearance or performance enhancement.
  • As part of the preconception counseling, patients should be informed that the fertile window is typically 5–6 days prior to ovulation, and therefore, intercourse every 1–2 days during this time period will increase the chance of pregnancy.
  • Various methods are used by women to detect ovulation, including basal body temperature measurements, assessment of changes in cervical mucus, and urinary LH kits.
  • A rise in basal body temperatures indicates that ovulation has occurred and therefore cannot be used to time intercourse.
  • LH kits can be used to detect the start of ovulation and subsequently time intercourse on the day of the LH surge and the following day.
  • Physicians should counsel patients that advanced maternal age (>35 years) is associated with a higher risk of aneuploidy and advanced paternal age (>40 years) is associated with adverse health outcomes in the offspring.
  • Obesity in women is associated with an increase in anovulatory cycles, miscarriage rates, and maternal and fetal complications in pregnancy.
  • Obesity in men is associated with abnormal sperm parameters.
  • Lifestyle choices such as smoking abstention, adequate physical activity, and a healthy diet can play a role in controlling symptoms and preventing chronic disease.
  • An expanding array of pharmacologic options (e.g., bisphosphonates, SERMs, and other agents for osteoporosis; cholesterol-lowering or antihypertensive agents for cardiovascular disease) should also reduce the widespread reliance on hormone use.
  • However, short-term HT may still benefit some women.
  • For genitourinary symptoms such as vaginal dryness or pain with intercourse/sexual activity, intravaginal estrogen creams, tablets, or rings; prasterone (vaginal dehydroepiandrosterone); and ospemifene are options.
  • Contraindications to low-dose vaginal estrogen include unexplained vaginal bleeding or breast cancer, endometrial cancer, or other estrogen-dependent cancer.
  • Contraindications to ospemifene and prasterone are the same as those for low-dose vaginal estrogen, and contraindications for ospemifene additionally include venous or arterial thromboembolic disease, severe liver disease, and use of estrogens or estrogen agonists-antagonists.
  • In addition to HT, lifestyle choices such as smoking abstention, adequate physical activity, and a healthy diet can play a role in controlling symptoms and preventing chronic disease.
  • An expanding array of pharmacologic options (e.g., bisphosphonates, SERMs, and other agents for osteoporosis; cholesterol-lowering or antihypertensive agents for cardiovascular disease) should also reduce the widespread reliance on hormone use.
  • However, short-term HT may still benefit some women.
  • For genitourinary symptoms such as vaginal dryness or pain with intercourse/sexual activity, intravaginal estrogen creams, tablets, or rings; prasterone (vaginal dehydroepiandrosterone); and ospemifene are options.
  • Contraindications to low-dose vaginal estrogen include unexplained vaginal bleeding or breast cancer, endometrial cancer, or other estrogen-dependent cancer.
  • Contraindications to ospemifene and prasterone are the same as those for low-dose vaginal estrogen, and contraindications for ospemifene additionally include venous or arterial thromboembolic disease, severe liver disease, and use of estrogens or estrogen agonists-antagonists.
  • Research on alternative progestogens and androgen-containing preparations has been limited, particularly with respect to long-term safety.
  • Additional research on the effects of these agents on cardiovascular disease, glucose tolerance, and breast cancer will be of particular interest.
  • For prevention of osteoporosis, alternative therapies such as bisphosphonates or SERMs should be considered.
  • Even for reasonable candidates, strategies to minimize dose and duration of use should be employed.
  • For example, women using HT to relieve intense vasomotor symptoms in early postmenopause should consider discontinuing therapy within 5 years, resuming it only if such symptoms persist.
  • Because of the role of progestogens in increasing breast cancer risk, regimens that employ cyclic rather than continuous progestogen exposure as well as formulations other than MPA should be considered if treatment is extended.
  • Poor candidates are women with elevated cardiovascular risk, those at increased risk of breast cancer, and those at low risk of osteoporosis.

8.1 Lifestyle Modifications

  • Preconception counseling regarding smoking cessation is important as evidence suggests that smoking cessation can reverse the detrimental impact of smoking on fecundity.
  • Smoking decreases fertility rates by a direct impact on oocyte DNA and also increases the risk of miscarriage and ectopic pregnancy.
  • In addition, smoking during pregnancy is associated with an increased risk of placental abruption and intrauterine growth restriction (IUGR).
  • Moreover, the impact of smoking on ovarian reserve has been shown to accelerate the time to menopause by 1–4 years.
  • As high levels of caffeine consumption increase the risk of infertility and miscarriage, women should be counseled to restrict caffeine consumption to ≤2 cups while attempting pregnancy and during pregnancy.
  • Use of testosterone products, which are widely used for the treatment of hypoandrogenism and sexual dysfunction in men, should be stopped.
  • Inquiries should be made about possible misuse of androgens for physical appearance or performance enhancement.
  • As part of the preconception counseling, patients should be informed that the fertile window is typically 5–6 days prior to ovulation, and therefore, intercourse every 1–2 days during this time period will increase the chance of pregnancy.
  • Various methods are used by women to detect ovulation, including basal body temperature measurements, assessment of changes in cervical mucus, and urinary LH kits.
  • A rise in basal body temperatures indicates that ovulation has occurred and therefore cannot be used to time intercourse.
  • LH kits can be used to detect the start of ovulation and subsequently time intercourse on the day of the LH surge and the following day.
  • Physicians should counsel patients that advanced maternal age (>35 years) is associated with a higher risk of aneuploidy and advanced paternal age (>40 years) is associated with adverse health outcomes in the offspring.
  • Obesity in women is associated with an increase in anovulatory cycles, miscarriage rates, and maternal and fetal complications in pregnancy.
  • Obesity in men is associated with abnormal sperm parameters.
  • Lifestyle choices such as smoking abstention, adequate physical activity, and a healthy diet can play a role in controlling symptoms and preventing chronic disease.
  • An expanding array of pharmacologic options (e.g., bisphosphonates, SERMs, and other agents for osteoporosis; cholesterol-lowering or antihypertensive agents for cardiovascular disease) should also reduce the widespread reliance on hormone use.
  • However, short-term HT may still benefit some women.
  • For genitourinary symptoms such as vaginal dryness or pain with intercourse/sexual activity, intravaginal estrogen creams, tablets, or rings; prasterone (vaginal dehydroepiandrosterone); and ospemifene are options.
  • Contraindications to low-dose vaginal estrogen include unexplained vaginal bleeding or breast cancer, endometrial cancer, or other estrogen-dependent cancer.
  • Contraindications to ospemifene and prasterone are the same as those for low-dose vaginal estrogen, and contraindications for ospemifene additionally include venous or arterial thromboembolic disease, severe liver disease, and use of estrogens or estrogen agonists-antagonists.
  • Research on alternative progestogens and androgen-containing preparations has been limited, particularly with respect to long-term safety.
  • Additional research on the effects of these agents on cardiovascular disease, glucose tolerance, and breast cancer will be of particular interest.
  • For prevention of osteoporosis, alternative therapies such as bisphosphonates or SERMs should be considered.
  • Even for reasonable candidates, strategies to minimize dose and duration of use should be employed.
  • For example, women using HT to relieve intense vasomotor symptoms in early postmenopause should consider discontinuing therapy within 5 years, resuming it only if such symptoms persist.
  • Because of the role of progestogens in increasing breast cancer risk, regimens that employ cyclic rather than continuous progestogen exposure as well as formulations other than MPA should be considered if treatment is extended.
  • Poor candidates are women with elevated cardiovascular risk, those at increased risk of breast cancer, and those at low risk of osteoporosis.

9. KEY PEARLS & CLINICAL TRAPS

  • Infertility is the third most common disease worldwide, affecting ~48–72 million couples.
  • Approximately 85% of couples will achieve pregnancy after 12 months, and 95% will achieve pregnancy after 24 months.
  • Fecundability is reduced by 14% in women aged 34–35 years, 19% in women aged 36–37 years, 53% in women aged 40–41 years, and 59% in women aged 42–44 years.
  • First-line treatment for anovulatory infertility (most common etiology is PCOS) includes use of letrozole followed by clomiphene citrate to induce ovulation.
  • A large majority of women with PCOS (60–80%) respond to these oral medications.
  • The addition of metformin, combined with the above medications as a second-line agent, may further increase the chance of ovulation, particularly in obese women.
  • IVF offers the highest success rates for couples with tubal factor infertility.
  • Tubal repair or reconstruction is typically not recommended in cases associated with tubal infections or hydrosalpinx, due to the low success rate in achieving tubal patency and increased risk of ectopic pregnancy.
  • In fact, removal of hydrosalpinges by salpingectomy will improve pregnancy rates in subsequent IVF treatments as it prevents efflux of tubal fluid into the uterine cavity.
  • In men with severe male factor infertility (sperm count <5 million/mL or motility <20%), both IVF with intracytoplasmic sperm injection (ICSI) is recommended.
  • In men with obstructive azoospermia, sperm can be procured by direct aspiration from the epididymis or testis.
  • In men with congenital bilateral absence of the vas deferens (CBAVD), testing for CFTR mutations and genetic counseling are indicated before offering IVF with ICSI.
  • In men with nonobstructive azoospermia, microsurgical sperm retrieval from the testes may result in successful pregnancies after IVF-ICSI; however, the use of donor sperm for IUI is an alternate option.
  • Men with hypogonadotropic hypogonadism (e.g., Kallmann's syndrome) can be treated with gonadotropins to initiate spermatogenesis followed by IUI or IVF.
  • Treatment of male sexual dysfunction and avoidance of exogenous androgens are effective strategies for addressing male factor infertility.
  • Repair of a moderate to large varicocele is recommended when associated with abnormal semen parameters or symptomatic from the varicocele; however, it may take several months to detect an improvement in semen parameters.
  • LARC (IUDs and implants) are the most effective reversible form of contraception with high continuation and satisfaction rates; hence, they are a good choice in adolescents and nulliparous women.
  • The failure rate for male and female condoms is 17–21 pregnancies per 100 women per year.
  • USMEC Category 4 conditions (e.g., smoking in women ≥35 years, DVT, stroke) represent unacceptable health risks for hormonal contraceptive use.
  • Levonorgestrel emergency contraception is associated with fewer side effects compared to combined hormonal pills.
  • Overall, the failure rate for all hormonal emergency contraception is 1–3%, with ulipristal acetate being the most effective.
  • Emergency contraception should be offered to all women who ask for it up to 5 days after unprotected intercourse and not delayed in order to obtain a pregnancy test or perform a clinical examination.
  • Although body weight can affect the efficacy of emergency hormonal contraception, treatment should not be withheld from overweight and obese women.
  • Infertility and its treatment do not appear to be associated with long-term psychological sequelae.
  • Counseling and stress-management techniques should be offered early in the evaluation of infertility as many patients do not pursue treatments after the initial consultation.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Causes of infertility

Caption: FIGURE 408-1 Causes of infertility. History and Physical Exam A detailed history obtained from both partners is essential to identify risk factors for infertility. In the female partner, gynecologic history (menstrual frequency, menorrhagia, dys- in menorrhea, history of sexually transmitted infections, endometriosis), medical and endocrine history, exposure to pelvic radiation, abdominal or pelvic surgeries, tobacco and alcohol use, medication use including cytotoxic drugs, family history of early menopause, and prior history — Figure 408-1: Causes of infertility. The figure illustrates the distribution of infertility causes among couples, categorized into Female causes (30–40%), Male causes (40–50%), and Unexplained infertility (15–30%). Female causes are further subdivided into Tubal, Uterine, Ovulatory dysfunction, and Endocrine dysfunction. Male causes are subdivided into Testicular defects/genetic, Endocrine, Anatomic, and Other. Unexplained infertility is listed separately.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.