3050 PART 12 Endocrinology and Metabolism

along with an increased risk of osteoporosis (e.g., those with osteopenia, a personal or family history of nontraumatic fracture, or a weight

<125 lb), who also have no personal or family history of breast cancer

in a first-degree relative or other contraindications, and who have a

strong personal preference for therapy. Poor candidates are women

with elevated cardiovascular risk, those at increased risk of breast

cancer, and those at low risk of osteoporosis. 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. For prevention of osteoporosis,

alternative therapies such as bisphosphonates or SERMs should be

considered. Research on alternative progestogens and androgencontaining 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 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.

■ FURTHER READING

Bassuk SS, Manson JE: Menopausal hormone therapy and cardiovascular disease risk: Utility of biomarkers and clinical factors for risk

stratification. Clin Chem 60:68, 2014.

Canonico M et al: Hormone replacement therapy and risk of venous

thromboembolism in postmenopausal women: Systematic review

and meta-analysis. BMJ 336:1227, 2008.

Kaunitz AM, Manson JE: Management of menopausal symptoms.

Obstet Gynecol 126:859, 2015.

Manson JE, Bassuk SS: Hot Flashes, Hormones and Your Health.

New York, McGraw-Hill, 2007.

Manson JE et al: Menopausal hormone therapy and health outcomes

during the intervention and extended poststopping phases of the

Women’s Health Initiative randomized trials. JAMA 310:1353, 2013.

Manson JE et al: The Women’s Health Initiative trials of menopausal

hormone therapy: Lessons learned. Menopause 27:918, 2020.

North American Menopause Society: The 2017 hormone therapy position statement of the North American Menopause Society.

Menopause 24:728, 2017.

North American Menopause Society: The 2020 genitourinary

syndrome of menopause position statement of the North American

Menopause Society. Menopause 27:976, 2020.

Pinkerton JV: Hormone therapy for postmenopausal women. N Engl

J Med 382:446, 2020.

Shifren JL et al: Menopausal hormone therapy. JAMA 321:2458,

2019.

INFERTILITY

The World Health Organization (WHO) categorizes infertility as a

disease of the reproductive system. Infertility is the third most common disease worldwide, affecting ~48 million couples. It is defined

as the inability to achieve a pregnancy over 12 months of unprotected

intercourse. The prevalence of infertility, ~15% globally, has remained

relatively stable over the past few decades. Primary infertility occurs

in couples who have never achieved a pregnancy, whereas secondary

infertility refers to infertility after achieving at least one pregnancy.

During the first year of attempting pregnancy, the fecundability rate,

defined as the ability to achieve a pregnancy within one menstrual

cycle, 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 can have significant implications

due to age-related decrease in the fecundability rate. 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.

■ ETIOLOGY

The causes for infertility are generally classified as female, male, and

unexplained (Fig. 396-1). The female causes include tubal factors (pelvic inflammatory disease, salpingitis isthmica nodosum, endometriosis, prior surgery), uterine etiology (congenital malformations, fibroids,

uterine scarring), ovulatory dysfunction (polycystic ovary syndrome

[PCOS], diminished ovarian reserve, premature ovarian insufficiency),

and endocrine dysfunction (hypothyroidism, hyperprolactinemia).

Although 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 aged <50 years. The male causes of infertility include anatomic

factors in the reproductive system (vasectomy, infection, absence of

the vas), endocrine factors (hypogonadotropic hypogonadism, hypothyroidism, hyperprolactinemia, morbid obesity, medications), sexual

dysfunction (erectile or ejaculatory dysfunction, decreased libido), and

genetic factors contributing to primary testicular dysfunction, including defects in spermatogenesis (Klinefelter’s syndrome, Y chromosome

microdeletions). The distribution of these causes varies significantly in

couples across the world. Overall, female factors are present in 30–40%

of couples with infertility, male factors are present in 40–50%, and both

male and female factors are identified in 20–30%. Unexplained infertility refers to the absence of any identified abnormality after completing

the fertility workup and occurs in 10–15% of couples. As a result, a

complete workup of both partners is recommended in all couples presenting with infertility.

■ FERTILITY EVALUATION

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 of the couple can be

initiated even prior to meeting the definition of infertility, especially

if they have 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,

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.

396 Infertility and

Contraception

Anuja Dokras, Janet E. Hall

3051 Infertility and Contraception CHAPTER 396

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, 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 should be assessed. In addition,

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. Physical exam in the female

partner should include 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. Similarly, a detailed history should be

obtained in the male partner with specific questions regarding injuries

and surgery in the male reproductive tract; mumps orchitis; exposure

to pelvic radiation; use of androgens, cytotoxic drugs, and other medications; and fertility with any prior partner. The exam in the male partner should include body mass index (BMI), BP, and complete physical

exam including testicular exam.

Ultrasound An abdominal and transvaginal pelvic ultrasound

can assess uterine (myomas, adenomyosis, müllerian anomalies) and

adnexal abnormalities (endometriosis, polycystic-appearing ovaries)

and evaluate ovarian reserve (number of antral follicles in both

ovaries).

Ovulation Assessment Women who have regular menstrual

cycles between 25 and 35 days will typically have ovulatory cycles.

Ovulation can be assessed by using ovulation detection strips at home

to detect urinary luteinizing hormone (LH) or by measuring a serum

progesterone level 7 days after ovulation. Basal body temperatures can

also be used to confirm ovulation when a rise in temperature is noted

in the luteal phase. However, basal body temperature measurements

are less reliable than the above methods.

Hysterosalpingogram An hysterosalpingogram (HSG) is 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.

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 in women after an HSG

test compared to those who did not have the test, likely related to tubal

flushing. Alternate options that are increasingly used include injection of

Endocrine

Endocrine Anatomic Testicular

defects/

genetic

Unknown

Tubal Uterine Other Ovulatory

dysfunction

Causes of infertility

12–15% of reproductive

aged women

Unexplained

15–30%

Male causes

40–50%

Female causes

30–40%

FIGURE 396-1 Causes of infertility. FSH, follicle-stimulating hormone; LH, luteinizing hormone.

agitated saline contrast through the cervix into the uterus. Tubal patency

is assessed by demonstrating passage of agitated saline contrast through

the tubes or accumulation in the cul de sac as visualized by ultrasonography. A 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.

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.

Endocrine Tests In women with irregular menses, serum TSH,

prolactin, and androgens should be measured to identify other causes

for anovulation.

Semen Analysis (see Chap. 391) The semen sample is collected

after 2–7 days of abstinence and provides an assessment of sperm

count, motility, morphology, volume, and pH. Although there is significant overlap between semen parameters of fertile and infertile men,

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 further endocrine (serum follicle-stimulating hormone

[FSH], LH, prolactin, and thyroid-stimulating hormone [TSH]) and

genetic evaluation (karyotype and Y chromosome microdeletion).

Genetic Screening All couples can be offered preconception

genetic screening based on ethnicity, family history, or common autosomal recessive conditions.

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.

■ COUNSELING AND TREATMENT

Preconception Counseling All patients seeking fertility care

should be provided with preconception counseling. This includes

counseling about eating disorders or lifestyle modifications for weight

management as 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. Preconception counseling regarding smoking cessation is

3052 PART 12 Endocrinology and Metabolism

important as there is evidence to suggest 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

rates, 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 (Chap. 399). 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.

Treatment Treatment recommendations depend on the results of

the fertility evaluation described above (Table 396-1). 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 STIs. 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 transfer into the uterus. IVF offers the highest success rates

for couples with tubal factor infertility. Tubal repair or reconstruction

is not recommended in most cases associated with underlying tubal

infections or hydrosalpinx due to both 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. 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, and experience of the surgeon.

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 women with

anovulatory infertility (most common etiology is PCOS) includes

use of medications such as letrozole and clomiphene citrate to induce

ovulation. A large majority of women with PCOS (60–80%) respond to

these oral medications, and the addition of metformin, 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 pregnancy 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.

Male Infertility Given the high prevalence of male factor infertility (40–50%), timely evaluation and treatment are recommended. In

men with no sperm (azoospermia) in the ejaculate, further evaluation

including a physical examination, endocrine tests, and genetics studies

should be performed to identify obstructive (40% prevalence among

men with azoospermia) 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, IVF with intracytoplasmic sperm injection 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. In men

with nonobstructive azoospermia, sperm retrieval from the testes may

be less successful, and 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 if

the patient is symptomatic from the varicocele.

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

developing oocytes and combine this 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 and can be used for 3–6 months before recommending

IVF. Overall, IVF is associated with a low risk of complications; the risk

of ovarian hyperstimulation syndrome has been significantly decreased

by judiciously monitoring stimulation and using alternate protocols.

Multiple pregnancy remains the highest risk associated with IVF

despite improvements in cryopreservation of embryos and age-based

guidelines for the number of embryos to transfer. In some couples, the

IVF treatment may reveal an underlying cause of infertility such as

lower fertilization or embryo cleavage rates. Of note, guidelines from

different medical societies around the world vary in the rapidity of

offering IVF for unexplained infertility.

Uterine Factors Fibroids are the most common benign tumors

of the reproductive tract and occur in 50–70% of reproductive-age

TABLE 396-1 Assisted Reproductive Technologies

Ovulation induction

Oral agents

Injectable hormones

Clomiphene citrate (selective estrogen

response modulator)

Letrozole (aromatase inhibitor)

FSH, LH (gonadotropins)

Intrauterine insemination (IUI) Office-based procedure by which washed and

concentrated ejaculated sperm is deposited

in the uterine cavity via a soft catheter passed

through the cervix

In vitro fertilization (IVF) Oocytes are harvested transvaginally under

local anesthesia or intravenous sedation and

incubated with sperm to facilitate fertilization.

The fertilized embryos are cultured for 3 days

(cleavage stage) or 5 days (blastocyst stage)

prior to transcervical placement of one or more

embryos, depending on the age of the female

patient, into the uterine cavity under ultrasound

guidance.

Intracytoplasmic sperm

injection (ICSI)

In cases of severe male factor infertility, a

single motile sperm is injected into the oocyte

in order to facilitate fertilization.

Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone.

3053 Infertility and Contraception CHAPTER 396

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

adhesions hysteroscopically may improve subsequent pregnancy rates.

Endometriosis 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 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.

■ PSYCHOLOGICAL ASPECTS OF INFERTILITY

It is well recognized that 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.

Importantly, infertility and its treatment do not appear to be associated

with long-term psychological sequelae.

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 2019,

tubal sterilization was the most common (~219 million) followed by

use of male condom (189 million), intrauterine device (IUD) (159

million), and the (birth control) pill (151 million). 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 (Table 396-2).

This excellent resource is adapted from the WHO guidance and is kept

up to date through continual review of published literature.

■ TYPES OF CONTRACEPTION

These can be classified in a number of ways, such as permanent versus

reversible, hormonal versus nonhormonal, or barrier versus nonbarrier

(Table 396-3).

Permanent Contraception The permanent forms of contraception include tubal sterilization and vasectomy, with twice as many

women choosing permanent sterilization compared to men. 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. 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 mini-laparotomy. 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 userdependent contraception. All patients should undergo preprocedure

counseling regarding risk of failure, permanence of the procedure,

regret, and alternatives.

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 (<50 μg) and types of

progestins and varying doses within a pack (monophasic vs multiphasic); the pills can be taken in a cyclic or extended cycle schedule. The

contraceptive efficacy is similar with varying doses of estrogen and

progestin. Decreasing the duration of hormone-free days may decrease

some side effects associated with menses, such as menstrual migraines

and dysmenorrhea. The overall failure rate for combined hormonal

contraceptives is 8 pregnancies per 100 women per year, although

compliance with daily use of pills may be lower, affecting efficacy. The

contraceptive patch and vaginal ring have higher compliance compared

to daily pills. Use of the contraceptive patch is associated with a low risk

TABLE 396-2 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)

Women age >35 years who smoke ≥15 cigarettes per day

Known ischemic heart disease or multiple risk factors for cardiovascular disease

(older age, smoking, diabetes, and hypertension)

Acute DVT

Previous thromboembolic event; high risk of recurrent DVT

Stroke or known thrombogenic mutations

Complicated valvular heart disease

Peripartum cardiomyopathy

Complicated solid organ transplantation

Hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg, vascular disease)

Systemic lupus erythematous (positive or unknown antiphospholipid antibodies)

Cirrhosis, hepatic adenoma or hepatoma

Viral hepatitis, acute flare

Pregnancy and early postpartum (<21 days)

Breast-feeding <21days postpartum

Breast cancer

USMEC Category 3 (a condition for which the theoretical or proven

risks outweigh the advantages for using the method)

Previous thromboembolic event; lower risk of recurrent DVT

Past history of breast cancer and no evidence for 5 years

Hypertension (adequately controlled or systolic 140–159 mmHg or diastolic

90–99 mmHg)

Women receiving anticonvulsant drug therapy

Women receiving antiretroviral therapy for prevention or treatment of HIV

Women following bariatric surgery (Roux-en-Y gastric bypass or biliopancreatic

diversion)

Breast-feeding 21–42 days postpartum

Abbreviation: DVT, deep-vein thrombosis.

3054 PART 12 Endocrinology and Metabolism

of skin reactions and a lower efficacy in women weighing >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 symptoms; in addition,

they reduce the risk of both endometrial (50% reduction) and ovarian

cancer (40% reduction). 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 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 effect is irregular bleeding, pain, and rarely expulsion. 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 progesterone (medroxyprogesterone acetate) is administered 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.

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.

Barrier Contraception The barrier forms of contraception

include condoms (male, female) and diaphragm and cervical cap and

TABLE 396-3 Effectiveness of Different Forms of Contraception

METHOD OF CONTRACEPTION

THEORETICAL

EFFECTIVENESS (%) ACTUAL EFFECTIVENESS (%)

CONTINUED USE AT

1 YEAR (%)

USE OF METHOD BY U.S. WOMEN AT RISK

OF UNINTENDED PREGNANCY (%)

No method 15 15 10

Fertility awareness 96 76 47 1.2

Withdrawal 96 78 46 4.4

Barrier methods

Condoms 98 82 43 13.7

Diaphragm 94 82 57 2

Spermicides 82 72 43 1

Sterilization

Female 99.5 99.5 100 22.6

Male 99.5 99.9 100 7.4

Intrauterine device 9.3

Copper T 99.4 99.8 85

Progestin-containing 99.8 99.8 88

Hormonal contraceptives

Combined and progestin only 99.7 91 67 23.3

Transdermal patch 99.7 91 67 0.5

Vaginal ring 99.7 91 67 1.8

Implant 1.2

Depo-Provera 99.8 94 56

Subdermal implant 99.5 99.5 84

Emergency contraception 95 - - 11

Sources: Data from J Trussell et al: Contraceptive Efficacy, in Contraceptive Technology, 20th revised ed, RA Hatcher et al (eds). New York, Ardent Media, 2011; CDC.

NCHS National Survey of Family Growth, 2011-2013; J Jones et al: Current contraceptive use in the United States, 2006-2010, and changes in patterns of use since 1995.

Natl Health Stat Report 60:1, 2012, and NE Birgisson et al: Preventing unintended pregnancy: The contraceptive CHOICE project in review. J Womens Health (Larchmt)

24:349, 2015.

3055 Sexual Dysfunction CHAPTER 397

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.

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. The contraceptive

effect occurs due to suppression of gonadotropin-releasing hormone pulsatility associated with suckling. The failure rate under these circumstances

can be as low as 0.5–1.5 pregnancies per 100 women per year.

Fertility Awareness The standard days method is typically used

by women with regular menstrual cycles whereby they track their

cycles to avoid intercourse from cycle days 8–19.

Emergency Contraception Also known as postcoital contraception, this method is used after an unprotected or inadequately protected act of intercourse. The probability of pregnancy independent

of the time of the month is 8%, but the probability varies significantly

in relation to proximity to ovulation and may be as high has 30%.

Many women are not aware of the availability of emergency contraception and its appropriate use. As the probability of pregnancy is

highest if there has been unprotected intercourse during the 3 days

prior to ovulation, the timing of administration and type of emergency contraceptive used determine the efficacy. The emergency

contraception options include the copper IUD and oral medications

such as ulipristal acetate, levonorgestrel, and combined hormonal

pills. The copper IUD prevents fertilization and implantation and

is the most effective choice if inserted within 5 days of unprotected

intercourse. It can also be offered to obese women in whom other

hormonal forms of emergency contraceptive may be less effective.

Ulipristal acetate, a progesterone receptor antagonist, blocks the

ability of endogenous progesterone to act on its receptors and inhibits the LH surge, delaying or inhibiting ovulation, and may directly

inhibit follicular rupture. It is administered as a 30-mg single dose up

to 5 days after unprotected intercourse. Levonorgestrel administered

as a single dose will prevent or delay ovulation and 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,

it should not be withheld from overweight and obese women.

■ CONTRACEPTION COUNSELING

Patients should be provided information regarding the different methods of contraception, side effects, noncontraceptive benefits, efficacy,

need for strict compliance, and impact on future fertility. In order to

facilitate patient-centric care, the provider should discuss plans for

future pregnancy and whether childbearing is complete. A detailed

patient history should be reviewed to identify potential contraindications such as migraines with aura, smoking, and hypertension.

Providers should refer to the most updated USMEC or WHO Medical

Eligibility Criteria for Contraceptive Use guidelines when counseling

patients with associated comorbidities. As part of the shared decisionmaking approach, the patient’s choice should be the guiding factor,

and the discussion should be nonjudgmental. Adolescents should be

offered access to the full range of contraceptive options. In a low-risk

patient, hormonal contraceptives can be prescribed from menarche

to menopause; regular evaluation of side effects and assessment of

changes in the patient’s medical history, however, are required.

■ FURTHER READING

Centers for Disease Control and Prevention: Reproductive

health. Available at https://www.cdc.gov/reproductivehealth/Infertility

/#e. Accessed December 23, 2020.

Cooper TG et al: World Health Organization reference values for

human semen characteristics. Hum Reprod Update 16:231, 2010.

Curtis KM, Peipert JF: Long-acting reversible contraception. N Engl

J Med 376:461, 2017

Curtis KM et al: U.S. medical eligibility criteria for contraceptive use,

2016. MMWR Recomm Rep 65(3):1, 2016.

Infertility Workup for the Women’s Health Specialist: ACOG

Committee Opinion, Number 781. Obstet Gynecol 133:e377, 2019.

Kulkarni AD et al: Fertility treatments and multiple births in the

United States. N Engl J Med 369:2218, 2013.

Mascarenhas MN et al. National, regional, and global trends in

infertility prevalence since 1990: A systematic analysis of 277 health

surveys. PLoS Med 9:e1001356, 2012.

Slama R et al: Estimation of the frequency of involuntary infertility on

a nation-wide basis. Hum Reprod 27:1489, 2012.

Steiner AZ et al: Association between biomarkers of ovarian reserve

and infertility among older women of reproductive age. JAMA

318:1367, 2017.

World Health Organization: Infertility. https://www.who.int/

news-room/fact-sheets/detail/infertility. Accessed December 23, 2020.

Male sexual dysfunction affects up to 31% of middle-aged and

elderly men, whereas female sexual dysfunction, although studied less

intensely, has a higher prevalence (43%) than male sexual dysfunction.

Demographic changes, the popularity of newer treatments, and greater

awareness of sexual dysfunction by patients and society have led to

increased diagnosis and associated health care expenditures for the

management of this common disorder. Sexual health and satisfaction

with sex life are important aspects of quality of life for many, including

those in poor health. Because many patients are reluctant to initiate

discussion of their sex lives, physicians should address this topic

directly to elicit a history of sexual dysfunction. Specifically addressing

sexual health should be a routine part of the clinical encounter.

MALE SEXUAL DYSFUNCTION

■ PHYSIOLOGY OF MALE SEXUAL RESPONSE

Normal male sexual function includes (1) sufficient libido, (2) the

ability to achieve and maintain penile erection, (3) ejaculation, and

(4) detumescence. Libido refers to sexual desire and is influenced by a

variety of visual, olfactory, tactile, auditory, imaginative, and hormonal

stimuli. Sex steroids, particularly testosterone, act to increase libido.

Libido can be diminished by emotional context, systemic illness, hormonal disturbances, psychiatric disorders, and medications.

Penile tumescence leading to erection depends on an increased flow

of blood into the lacunar network accompanied by complete relaxation

of the arteries and corporal smooth muscle. The microarchitecture of

the corpora is composed of a mass of smooth muscle (trabecula) that

contains a network of endothelial-lined vessels (lacunar spaces). Subsequent compression of the trabecular smooth muscle against the fibroelastic tunica albuginea causes a passive closure of the emissary veins

and accumulation of blood in the corpora. In the presence of a full

erection and a competent valve mechanism, the corpora become noncompressible cylinders from which blood does not escape. This cascade of relaxation and venous occlusion culminates in a rigid erection.

The central nervous system (CNS) exerts an important influence

by either stimulating or antagonizing spinal pathways that mediate

erectile function and ejaculation. The erectile response is mediated

397 Sexual Dysfunction

Kevin T. McVary

3056 PART 12 Endocrinology and Metabolism

by a combination of central (psychogenic) innervation and peripheral

(reflexogenic) innervation. Sensory nerves that originate from receptors in the penile skin and glans converge to form the dorsal nerve of

the penis, which travels to the S2-S4 dorsal root ganglia via the pudendal nerve. Parasympathetic nerve fibers to the penis arise from neurons

in the intermediolateral columns of the S2-S4 sacral spinal segments.

Sympathetic innervation originates from the T-11 to the L-2 spinal

segments and descends through the hypogastric plexus.

Neural input to smooth-muscle tone is crucial to the initiation

and maintenance of an erection. There is also an intricate interaction

between the corporal smooth-muscle cell and its overlying endothelial

cell lining (Fig. 397-1). Nitric oxide, which induces vascular relaxation,

promotes erection and is opposed by endothelin 1 (ET-1) and Rho

kinase, which mediate vascular contraction. Nitric oxide is synthesized

from L-arginine by nitric oxide synthase (NOS) and is released from

the nonadrenergic, noncholinergic (NANC) autonomic nerve supply

to act postjunctionally on smooth-muscle cells. Nitric oxide increases

the production of cyclic 3′,5′-guanosine monophosphate (cyclic GMP),

which induces relaxation of smooth muscle (Fig. 397-2). Cyclic GMP

is metabolized by phosphodiesterase type 5 (PDE-5). Inhibitors of

PDE-5 such as the oral medications sildenafil, tadalafil, vardenafil,

and avanafil maintain erections by reducing the breakdown of cyclic

FIGURE 397-1 Pathways that control erection and detumescence. Outflow from the parasympathetic nervous system leads to relaxation of the cavernous sinusoids in

two ways, both of which increase the concentration of nitric oxide (NO) in smooth-muscle cells. First, NO is the neurotransmitter in nonadrenergic, noncholinergic (NANC)

fibers; second, stimulation of endothelial nitric oxide synthase (eNOS) through cholinergic output causes increased production of NO. The NO produced in the endothelium

then diffuses into the smooth-muscle cells and decreases its intracellular calcium concentration through a pathway mediated by cyclic guanosine monophosphate

(cGMP), leading to relaxation. A separate mechanism that decreases the intracellular calcium level is mediated by cyclic adenosine monophosphate (cAMP). With

increased cavernosal blood flow, as well as increased levels of vascular endothelial growth factor (VEGF), the endothelial release of NO is further sustained through the

phosphatidylinositol 3 (PI3) kinase pathway. Active treatments (red boxes) include drugs that affect the cGMP pathway (phosphodiesterase type 5 [PDE-5] inhibitors and

guanylyl cyclase agonists), the cAMP pathway (alprostadil), or both pathways (papaverine), along with neural-tone mediators (phentolamine and Rho kinase inhibitors).

Agents that are being developed include guanylyl cyclase agonists (to bypass the need for endogenous NO) and Rho kinase inhibitors (to inhibit tonic contraction of

smooth-muscle cells mediated through endothelin). α1, α-adrenergic receptor; GPCR, G protein–coupled receptor; GTP, guanosine triphosphate; iCa2+, intracellular calcium;

NOS, nitric oxide synthase; PGE, prostaglandin E; PGF, prostaglandin F. (Reproduced with permission from KT McVary: Clinical practice. Erectile dysfunction. N Engl J Med

357:2472, 2007.)

Increased blood flow Increases

sheer stress

Alprostadil

Detumescence

ATP

Adenylyl

cyclase cAMP

kinase

cGMP

kinase

Guanylyl

cyclase

NO

NO

NO

NANC

α1

cAMP

5′ AMP

5′ AMP

PDE2, 3, 4

PDE5

Decreased Ca2+ Decreased Ca2+

Relaxation

PGE

GPCR

Pl3-kinase

L-Arginine

eNOS

cGMP

GTP

Smooth-muscle cell

Tonic

inhibition

Endothelial cell Parasympathetic nervous system

Angiotensin II

PGF2α

Endothelin-1

Sympathetic nervous system

Phentolamine

Papaverine

Rho kinase

inhibitors

Guanylyl

cyclase agonists

PDE5 inhibitors

GMP. However, if nitric oxide is not produced at some level, PDE-5

inhibitors are ineffective, as these drugs facilitate, but do not initiate,

the initial enzyme cascade. In addition to nitric oxide, vasoactive prostaglandins (PGE1

, PGF2α) are synthesized within the cavernosal tissue

and increase cyclic AMP levels, also leading to relaxation of cavernosal

smooth-muscle cells.

Ejaculation is stimulated by the sympathetic nervous system; this

results in contraction of the epididymis, vas deferens, seminal vesicles,

and prostate, causing seminal fluid to enter the urethra. Seminal fluid

emission is followed by rhythmic contractions of the bulbocavernosus

and ischiocavernosus muscles, leading to ejaculation. This is followed

by expulsion, characterized by stereotypic rhythmic contractions of

the striated perineal muscles, leading to forceful expulsion of semen

with the bladder neck closed. This emission and expulsion are controlled by the autonomic (parasympathetic and sympathetic) and

somatic spinal centers, respectively. The synchronization between

autonomic and somatic spinal centers is orchestrated by interneurons

that form a spinal ejaculation generator that is present in mammals

including man.

Premature ejaculation usually is related to anxiety or a learned

behavior and is amenable to behavioral therapy or treatment with

medications such as selective serotonin reuptake inhibitors (SSRIs).

3057 Sexual Dysfunction CHAPTER 397

Retrograde ejaculation (RE) results when the internal urethral sphincter does not close; it may occur in men with diabetes or after surgery

involving the bladder neck. Anejaculation, the failure of a portion or

the whole of the emission process often confused with RE, is commonly the result of selective alpha blockers used in male voiding dysfunction (e.g., tamsulosin, silodosin).

Detumescence is mediated by norepinephrine from the sympathetic

nerves, endothelin from the vascular surface, and smooth-muscle contraction induced by postsynaptic α-adrenergic receptors and activation

of Rho kinase. These events increase venous outflow and restore the

flaccid state. Venous leak can cause premature detumescence and is

caused by insufficient relaxation of the corporal smooth muscle rather

than a specific anatomic defect. Priapism refers to a persistent and

painful erection and may be associated with sickle cell anemia, hypercoagulable states, spinal cord injury, or injection of vasodilator agents

into the penis.

■ ERECTILE DYSFUNCTION

Epidemiology Erectile dysfunction (ED) is not considered a

normal part of the aging process. Nonetheless, it is associated with

certain physiologic and psychological changes related to age. In the

Massachusetts Male Aging Study (MMAS), a community-based survey

of men aged 40–70, 52% of responders reported some degree of ED.

Complete ED occurred in 10% of respondents, moderate ED in 25%,

and minimal ED in 17%. The incidence of moderate or severe ED more

than doubled between the ages of 40 and 70. In the National Health

and Social Life Survey (NHSLS), which included a sample of men and

women aged 18–59, 10% of men reported being unable to maintain

an erection (corresponding to the proportion of men in the MMAS

reporting severe ED). Incidence was highest among men in the age

group 50–59 (21%) and men who were poor (14%), divorced (14%),

and less educated (13%).

The incidence of ED is also higher among men with certain medical

disorders, such as diabetes mellitus, obesity, lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH), heart

disease, hypertension, decreased high-density lipoprotein (HDL) levels, and diseases associated with general systemic inflammation (e.g.,

rheumatoid arthritis). Cardiovascular disease and ED share etiologies

as well as pathophysiology (e.g., endothelial dysfunction), and the

degree of ED appears to correlate with the severity of cardiovascular

disease. Consequently, ED represents a “sentinel symptom” in patients

with occult cardiovascular and peripheral vascular disease.

Smoking is also a significant risk factor in the development of ED.

Medications used in treating diabetes or cardiovascular disease are

additional risk factors (see below). There is a higher incidence of ED

among men who have undergone radiation or surgery for prostate cancer and in those with a lower spinal cord injury. Psychological causes of

ED include depression, anger, stress from employment or relationships,

anxiety, and other stress-related causes.

Pathophysiology ED may result from three basic mechanisms:

(1) failure to initiate (psychogenic, endocrinologic, or neurogenic), (2)

failure to fill (arteriogenic), and (3) failure to store adequate blood volume within the lacunar network (veno-occlusive dysfunction). These

categories are not mutually exclusive, and multiple factors contribute to

ED in many patients. For example, diminished filling pressure can lead

secondarily to venous leak. Psychogenic factors frequently coexist with

other etiologic factors and should be considered in all cases. Diabetic,

atherosclerotic, and drug-related causes account for >80% of cases of

ED in older men.

Vasculogenic The most common organic cause of ED is a disturbance of blood flow to and from the penis. Atherosclerotic or

traumatic arterial disease can decrease flow to the lacunar spaces,

resulting in decreased rigidity and an increased time to full erection.

Excessive outflow through the veins despite adequate inflow also

may contribute to ED. Structural alterations to the fibroelastic components of the corpora may cause a loss of compliance and inability

to compress the tunical veins. This condition may result from aging,

increased cross-linking of collagen fibers induced by nonenzymatic

glycosylation, hypoxemia, or altered synthesis of collagen associated

with hypercholesterolemia.

Neurogenic Disorders that affect the sacral spinal cord or the

autonomic fibers to the penis preclude nervous system relaxation of

penile smooth muscle, thus leading to ED. In patients with spinal cord

injury, the degree of ED depends on the completeness and level of the

lesion. Patients with incomplete lesions or injuries to the upper part

of the spinal cord are more likely to retain erectile capabilities than

are those with complete lesions or injuries to the lower part. Although

75% of patients with spinal cord injuries have some erectile capability,

only 25% have erections sufficient for penetration. Other neurologic

disorders commonly associated with ED include multiple sclerosis

and peripheral neuropathy. The latter is often due to either diabetes

or alcoholism. Pelvic surgery may cause ED through disruption of the

autonomic nerve supply.

Endocrinologic Androgens increase libido, but their exact role

in erectile function is unclear. Individuals with castrate levels of

testosterone can achieve erections from visual or sexual stimuli.

Nonetheless, normal levels of testosterone appear to be important for

erectile function, in which the upregulation of nitric oxide synthase

and the nitric oxide cascade is optimized (Fig. 397-1A). Androgen

replacement therapy can improve depressed erectile function when

it is secondary to hypogonadism; however, it is not useful for ED

when endogenous testosterone levels are normal. Increased prolactin

may decrease libido by suppressing gonadotropin-releasing hormone

(GnRH) resulting in decreased testosterone levels. Treatment of

hyperprolactinemia with dopamine agonists can restore libido and

eugonadism.

Diabetic ED occurs in 35–75% of men with diabetes mellitus.

Pathologic mechanisms are related primarily to diabetes-associated

vascular and neurologic complications. Diabetic macrovascular

complications are related mainly to age, whereas microvascular

complications correlate with the duration of diabetes and the degree

of glycemic control (Chap. 403). Individuals with diabetes also have

reduced amounts of nitric oxide synthase in both endothelial and

neural tissues.

–

L-Arginine

Cyclic GMP 5’-GMP

PDE-5

Erection

Smooth-muscle

relaxation

NO

iCa2+

NOS

Sildenafil

Vardenafil

Tadalafil

Avanafil

FIGURE 397-2 Biochemical pathways modified by phosphodiesterase type 5 (PDE-5)

inhibitors. Sildenafil, vardenafil, tadalafil, and avanafil enhance erectile function

by inhibiting PDE-5, thereby maintaining high levels of cyclic 3′,5′-guanosine

monophosphate (cyclic GMP). iCa2+, intracellular calcium; NO, nitric oxide; NOS,

nitric oxide synthase.

3058 PART 12 Endocrinology and Metabolism

TABLE 397-1 Drugs Associated with Erectile Dysfunction

CLASSIFICATION DRUGS POSSIBLE SUBSTITUTES

Diuretics Thiazides

Spironolactone

Antihypertensives Calcium channel

blockers

α-Adrenergic blockers

Prazosin

Terazosin

Doxazosin

ACE inhibitors

Methyldopa

Clonidine

Reserpine

Beta blockers

Guanethidine

Cardiac/

antihyperlipidemics

Digoxin

Gemfibrozil

Clofibrate

Antidepressants Selective serotonin

reuptake inhibitors

Bupropion

Nefazodone

Mirtazapine

Tricyclic antidepressants

Lithium

Monoamine oxidase

inhibitors

Tranquilizers Butyrophenones

Phenothiazines

H2

 antagonists Ranitidine Proton pump inhibitors

(PPI)

Omeprazole

Esomeprazole

Pantoprazole

Rabeprazole

Cimetidine

Hormones Progesterone

Estrogens

Corticosteroids

GnRH agonists

5α-Reductase inhibitors

Cyproterone acetate

Cytotoxic agents Cyclophosphamide

Methotrexate

Roferon-A

Anticholinergics Disopyramide

Anticonvulsants

Recreational Ethanol

Cocaine

Marijuana

Abbreviations: ACE, angiotensin-converting enzyme; GnRH, gonadotropin-releasing

hormone.

Psychogenic Two mechanisms contribute to the inhibition of

erections in psychogenic ED. First, psychogenic stimuli to the sacral

cord may inhibit reflexogenic responses, thereby blocking activation

of vasodilator outflow to the penis. Second, excess sympathetic stimulation in an anxious man may increase penile smooth-muscle tone.

The most common causes of psychogenic ED are performance anxiety,

depression, relationship conflict, loss of attraction, sexual inhibition,

conflicts over sexual preference, sexual abuse in childhood, and fear

of pregnancy or sexually transmitted disease. Almost all patients with

ED, even when it has a defined organic basis, develop a psychogenic

component as a reaction to ED.

Medication-Related Medication-induced ED (Table 397-1) is

estimated to occur in 25% of men seen in general medical clinics.

The adverse effects related to drug therapy are additive, especially

in older men. In addition to the drug itself, the underlying disease

being treated is likely to contribute to sexual dysfunction (e.g., hypertension). Among the antihypertensive agents, the thiazide diuretics

and beta blockers have been implicated most frequently. Calcium

channel blockers and angiotensin-converting enzyme inhibitors are

cited less frequently. These drugs may act directly at the corporal

level (e.g., calcium channel blockers) or indirectly by reducing pelvic blood pressure, which is important in the development of penile

rigidity. α-Adrenergic blockers are less likely to cause ED. Estrogens,

GnRH agonists, H2

 antagonists, and spironolactone cause ED by suppressing gonadotropin production or by blocking androgen action.

Antidepressant and antipsychotic agents—particularly neuroleptics,

tricyclics, and SSRIs—are associated with erectile, ejaculatory, orgasmic, and sexual desire difficulties. Among the SSRIs, paroxetine and

escitalopram have been associated with the highest risk of sexual

dysfunction. Bupropion, nefazodone, and mirtazapine appear less

likely to cause sexual dysfunction. A number of molecular pathways

have been implicated in antidepressant-induced sexual adverse events.

Serotonin has been hypothesized to inhibit normal sexual response by

decreasing dopamine-enhanced libido, arousal, and erection and by

increasing prolactin release. SSRIs have also been shown to be potent

inhibitors of nitric oxide synthase.

If there is a strong association between the institution of a drug and

the onset of ED, alternative medications should be considered. Otherwise, it is often practical to treat the ED without attempting multiple

changes in medications as it may be difficult to establish a causal role

for a drug.

APPROACH TO THE PATIENT

Erectile Dysfunction

A good physician–patient relationship helps unravel the possible

causes of ED, many of which require discussion of personal and

sensitive topics. For this reason, a primary care provider is often

ideally suited to initiate the evaluation. However, a significant

percentage of men experience ED and remain undiagnosed unless

specifically questioned about this issue. By far the two most common reasons for underreporting of ED are patient embarrassment

and perceptions of physicians’ inattention to the disorder. Once

the topic is initiated by the physician, patients are more willing to

discuss their potency issues. A complete medical and sexual history

should be taken in an effort to assess whether the cause of ED is

organic, psychogenic, or multifactorial (Fig. 397-3).

Both the patient and his sexual partner should be interviewed

regarding sexual history. ED should be distinguished from other

sexual problems, such as premature ejaculation. Lifestyle factors

such as sexual orientation, the patient’s distress from ED, performance anxiety, and details of sexual techniques should be addressed.

Validated questionnaires are available to assess ED, including the

International Index of Erectile Function (IIEF) and the more easily

administered Sexual Health Inventory for Men (SHIM), a validated

abridged version of the IIEF. These can assess the severity of ED,

measure treatment effectiveness, and guide future management.

The initial evaluation of ED begins with a review of the patient’s

medical, surgical, sexual, and psychosocial histories. The history

should note whether the patient has experienced pelvic trauma,

surgery, or radiation. In light of the increasing recognition of the

relationship between lower urinary tract symptoms (LUTS/BPH)

and ED, it is advisable to evaluate for the presence of associated urinary symptoms. Questions should focus on the onset of symptoms,

the presence and duration of partial erections, and the progression