3059 Sexual Dysfunction CHAPTER 397

Patient/partner education

Goal-directed therapy planning

Sex therapy

Special testing

Treatment

 success

Treatment

 success

Oral PDE-5 inhibitors

Vacuum device Implantation/

 vascular surgery

Intraurethral or injection therapy

Problem resolved

Problem persists

History: Medical, sexual, and psychosocial

Physical examination

Serum: Testosterone and prolactin levels

Lifestyle risk management

Medication review

FIGURE 397-3 Algorithm for the evaluation and management of patients with

erectile dysfunction. PDE, phosphodiesterase.

of ED. A history of nocturnal or early morning erections may be

useful for distinguishing physiologic ED from psychogenic ED.

Nocturnal erections occur during rapid eye movement (REM) sleep

and require intact neurologic and circulatory systems. Organic

causes of ED generally are characterized by a gradual and persistent change in rigidity or the inability to sustain nocturnal, coital,

or self-stimulated erections. The patient should be questioned

about the presence of penile curvature or pain with coitus. It is

also important to address libido, as decreased sexual drive and ED

are sometimes the earliest signs of endocrine abnormalities (e.g.,

increased prolactin, decreased testosterone levels). It is useful to

ask whether the problem is confined to coitus with one partner or

also involves other partners; ED not uncommonly arises with new

or extramarital sexual relationships. Situational ED, as opposed to

consistent ED, suggests psychogenic causes. For men being treated

for ED, referral to a mental health professional should be considered

to promote treatment adherence, reduce performance anxiety, and

integrate treatments into a sexual relationship. Ejaculation is much

less commonly affected than erection, but questions should be

asked about whether ejaculation is normal, premature, delayed, or

absent. Relevant risk factors should be identified, such as diabetes

mellitus, coronary artery disease (CAD), and neurologic disorders.

The patient’s surgical history should be explored with an emphasis

on bowel, bladder, prostate, and vascular procedures. A complete

drug history, including tobacco, alcohol, marijuana, and illicit drug

inquiries, is also important. Social changes that may precipitate ED

are also crucial to the evaluation, including health worries, spousal

death, divorce, relationship difficulties, and financial concerns.

Because ED commonly involves a host of endothelial cell risk

factors, men with ED report higher rates of overt and silent myocardial infarction. Therefore, ED in an otherwise asymptomatic male

warrants consideration of other vascular disorders, including CAD.

Men who suffer from ED are at high risk for concomitant LUTS

from BPH and vice versa. Given that some treatments of one disorder will impact the other, the clinician should consider an assessment of LUTS in any man with ED.

The physical examination is an essential element in the assessment of ED. Signs of hypertension as well as evidence of thyroid,

hepatic, hematologic, cardiovascular, or renal diseases should be

sought. An assessment should be made of the endocrine and vascular systems, the external genitalia, and the prostate gland. The

penis should be palpated carefully along the corpora to detect

fibrotic plaques. Reduced testicular size and loss of secondary

sexual characteristics are suggestive of hypogonadism. Neurologic

examination should include assessment of anal sphincter tone,

investigation of the bulbocavernosus reflex, and testing for peripheral neuropathy.

Although hyperprolactinemia is uncommon, a serum prolactin

level should be measured in hypogonadal men, as decreased libido

and/or ED may be the presenting symptoms of a prolactinoma or

another mass lesion of the sella (Chap. 380). The serum testosterone level should be measured, and if it is low, gonadotropins

should be measured to determine whether hypogonadism is primary (testicular) or secondary (hypothalamic-pituitary) in origin

(Chap. 391). If not performed recently, serum chemistries, complete blood count (CBC), hemoglobin A1c, and lipid profiles may be

of value, as they can yield evidence of anemia, diabetes, hyperlipidemia, or other systemic diseases associated with ED.

Additional diagnostic testing is rarely necessary in the evaluation

of ED. However, in selected patients, specialized testing may provide

insight into pathologic mechanisms of ED and aid in the selection

of treatment options. Optional specialized testing includes (1) studies of nocturnal penile tumescence and rigidity, (2) vascular testing

(in-office injection of vasoactive substances, penile Doppler ultrasound, penile angiography, dynamic infusion cavernosography/

cavernosometry), (3) neurologic testing (biothesiometry-graded

vibratory perception, somatosensory-evoked potentials), and (4)

psychological diagnostic tests. The information potentially gained

from these procedures must be balanced against their invasiveness,

cost, and impact on ultimate treatment outcome.

Clinicians should counsel men with ED who have comorbidities

known to negatively affect erectile function that lifestyle modifications, including changes in diet and increased physical activity,

improve overall health and may improve erectile function.

TREATMENT

Male Sexual Dysfunction

PATIENT EDUCATION

Patient and partner education is essential in the treatment of ED.

In goal-directed therapy, education facilitates understanding of

the disease, the results of the tests, and the selection of treatment.

Discussion of treatment options helps clarify how treatment is best

offered and stratify first- and second-line therapies. Patients with

high-risk lifestyle issues such as obesity, smoking, alcohol abuse,

and recreational drug use should be counseled on the role those

factors play in the development of ED.

Therapies currently employed for the treatment of ED include

oral phosphodiesterase type 5 inhibitor (PDE-5i) therapy (most

commonly used), injection therapies, testosterone therapy, penile

devices, and psychological therapy. In addition, limited data suggest

that treatments for underlying risk factors and comorbidities—

for example, weight loss, exercise, stress reduction, and smoking

cessation—may improve erectile function. Decisions regarding

therapy should take into account the preferences and expectations

of patients and their partners.

ORAL AGENTS

Sildenafil, tadalafil, vardenafil, and avanafil are the only approved

and effective oral agents for the treatment of ED. These four medications have markedly improved the management of ED because

they are effective for the treatment of a broad range of causes,

including psychogenic, diabetic, vasculogenic, post radical prostatectomy (nerve-sparing procedures), and post spinal cord injury.

They belong to a class of medications that are selective and potent

inhibitors of PDE-5, the predominant phosphodiesterase isoform

found in the penis. They are administered in graduated doses

and enhance erections after sexual stimulation (Fig. 397-2). The

onset of action is ~30–120 min, depending on the medication

used and other factors, such as recent food intake. Reduced initial

3060 PART 12 Endocrinology and Metabolism

TABLE 397-2 PDE-5 Inhibitorsa

DRUG ONSET OF ACTION T1/2 DOSE ADVERSE EFFECTS CONTRAINDICATIONS

Sildenafil Tmax 30–120 min

Duration 4 h

High-fat meal decreases absorption

Alcohol use may affect efficacy

2–5 h 25–100 mg

Starting dose 50 mg

Headache, flushing,

dyspepsia, nasal

congestion, altered vision

Nitrates

Hypotension

Cardiovascular risk factors

Retinitis pigmentosa

Change dose with some antiretrovirals

Should be on stable dose of alpha

blockers

Vardenafil Tmax 30–120 min

Duration 4–5 h

High-fat meal decreases absorption

ETOH may affect efficacy

4.5 h 5–10 mg Headache, flushing,

rhinitis, dyspepsia

Same as sildenafil

May have minor prolongation

of QT interval

Concomitant use of class I

anti-arrhythmic

Tadalafil Tmax 30–60 min

Duration 12–36 h

Plasma concentration not affected by food

or ETOH

17.5 h 10 or 20 mg; 2.5 or 5 mg

for daily dose

Headache, dyspepsia,

backpain, nasal

congestion, myalgia

Same as sildenafil

Avanafil Tmax 30 min

Duration 2 h

Plasma concentration not affected by food

3–5 h 50, 100, and 200 mg dose Headache, flushing,

nasal congestion

nasopharyngitis back pain

Same as sildenafil

a

Sildenafil, vardenafil, tadalafil, and the newest option, avanafil, appear to be equally effective, but tadalafil has a longer duration of action and avanafil has a more rapid

onset.

Abbreviation: ETOH, ethanol; PDE-5, phosphodiesterase type 5.

doses should be considered for patients who are elderly, are taking

concomitant alpha blockers, have renal insufficiency, or are taking

medications that inhibit the CYP3A4 metabolic pathway in the

liver (e.g., erythromycin, cimetidine, ketoconazole, clarithromycin,

diltiazem, itraconazole, ritonavir, verapamil, grapefruit, and possibly itraconazole and mibefradil), as they may increase the serum

concentration of the PDE-5i or promote hypotension.

Initially, there were concerns about the cardiovascular safety

of these drugs. It is known that these agents can act as mild vasodilators, and warnings exist about orthostatic hypotension with

concomitant use of alpha blockers. The use of PDE-5is is not

contraindicated in men who are also receiving alpha blockers, but

they must be stabilized on the medication prior to initiating PDE-5i

therapy. Earlier concerns that the use of PDE-5is would increase

cardiovascular events have been mitigated by the results of several

controlled trials showing no increase in myocardial ischemic events

or overall mortality compared to the general population.

Several randomized trials have demonstrated the efficacy of this

class of medications. There are no compelling data to support the

superiority of one PDE-5i over another. Subtle differences between

agents have variable clinical relevance (Table 397-2).

Patients may fail to respond to a PDE-5i for several reasons

(Table 397-3). Some patients may not tolerate PDE-5i secondary

to adverse events from vasodilation in nonpenile tissues expressing

PDE-5 or from the inhibition of homologous nonpenile isozymes

(i.e., PDE-6 found in the retina). Abnormal vision attributed to the

effects of PDE-5i on retinal PDE-6 is of short duration, reported

only with sildenafil, and not thought to be clinically significant. A

more serious concern is the possibility that PDE-5is may cause nonarteritic anterior ischemic optic neuropathy (NAION); although

data to support that association are limited, it is prudent to avoid

the use of these agents in men with a prior history of NAION.

Testosterone supplementation combined with a PDE-5i may be

beneficial in improving erectile function in hypogonadal men with

ED who are unresponsive to PDE-5i alone. These drugs do not

affect ejaculation, orgasm, or sexual drive. Side effects associated

with PDE-5is include headaches (19%), facial flushing (9%), dyspepsia (6%), and nasal congestion (4%). Approximately 7% of men

using sildenafil may experience transient altered color vision (blue

halo effect), and 6% of men taking tadalafil may experience loin

pain. PDE-5i is contraindicated in men receiving nitrate therapy for

cardiovascular disease, including agents delivered by the oral, sublingual, transnasal, and topical routes. These agents can potentiate

its hypotensive effect and may result in profound shock. Likewise,

amyl/butyl nitrate “poppers” may have a fatal synergistic effect on

blood pressure. PDE-5is also should be avoided in patients with

congestive heart failure and cardiomyopathy because of the risk

of vascular collapse. Because sexual activity leads to an increase in

physiologic expenditure (5–6 metabolic equivalent tasks [METs]),

physicians have been advised to exercise caution in prescribing any

drug for sexual activity to those with active coronary disease, heart

failure, borderline hypotension, or hypovolemia and to those on

complex antihypertensive regimens.

Although the various forms of PDE-5is have a common mechanism of action, there are a few differences among the four agents

(Table 397-2). Tadalafil is unique in its longer half-life, and avanafil appears to have the fastest onset of action. All four drugs are

effective for patients with ED of all ages, severities, and etiologies.

Although there are pharmacokinetic and pharmacodynamic differences among these agents, clinically relevant differences are not

clear.

ANDROGEN THERAPY

Testosterone replacement is used to treat both primary and secondary

causes of hypogonadism (Chap. 391). Men with ED and testosterone

deficiency (TD) who are considering ED treatment with a PDE-5i

should be informed that PDE-5is may be more effective if combined

TABLE 397-3 Issues to Consider if Patients Report Failure of

Phosphodiesterase Type 5 Inhibitor (PDE-5i) to Improve Erectile

Dysfunction

1. A trial of medication on at least 6 different days at the maximal dose should

be performed before declaring patient nonresponsive to PDE-5i use.

2. Confirm that the patient did not partake in a high-fat meal prior to taking

medication; pertains to sildenafil.

3. Failure to include physical and psychic stimulation at the time of foreplay to

induce endogenous NO.

4. Took medications at an appropriate time frame prior to step 3: half-hour prior

for avanafil, 1 h for sildenafil/vardenafil, or 2.5 h for tadalafil.

5. Unrecognized hypogonadism.

Abbreviation: NO, nitric oxide.

3061 Sexual Dysfunction CHAPTER 397

with testosterone therapy. Androgen supplementation in the setting

of normal testosterone is not efficacious in the treatment of ED and is

discouraged secondary to additional risk for toxicity without benefit.

Methods of androgen replacement include transdermal patches and

gels, including cutaneous nasal and axillary gels. Parenteral long-acting testosterone esters (enanthate and cypionate), long-acting subcutaneous pellets, and oral preparations (17 α-alkylated derivatives)

are also available (Chap. 391). With the possible exception a newer

oral testosterone undecanoate, oral androgen preparations have the

potential for hepatotoxicity and should be avoided.

The increased scrutiny of testosterone caused the U.S. Food

and Drug Administration (FDA) to issue a warning that there is a

“weak signal” that testosterone replacement therapy increases the

risk of thromboembolic events and may have addictive properties.

Although testosterone therapy has known risks, such as water

retention in heart failure patients and worsening sleep apnea,

increasing evidence suggests that, when monitored appropriately,

this therapy decreases the risk for metabolic syndrome, changes

body composition by increasing lean muscle mass, and improves

insulin sensitivity and average hemoglobin A1c. This evidence,

combined with the fact that hypogonadism is a known risk factor

for metabolic syndrome and cardiovascular disease, has led to the

conclusion that testosterone therapy for age-related hypogonadism

in fact improves overall health and decreases the risk of cardiovascular events. It is important to note that men with secondary

hypogonadism who desire fertility should not be treated directly

with testosterone, but with an alternative such as the selective

estrogen receptor modulator (SERM) clomiphene citrate, which

increases gonadotropin levels, stimulating testicular testosterone

production.

Testosterone circulates in the body in two forms: free and unbound

or that bound to proteins such as albumin or sex hormone–binding

globulin (SHBG). SHBG has a very high affinity for testosterone, and

thus, testosterone bound to SHBG does not bind to the androgen

receptor and is not bioavailable. Bioavailable testosterone is any testosterone that is not bound to SHBG. Unfortunately, reliable assays

to directly measure bioavailable testosterone or free testosterone are

expensive, difficult to perform, and thus not offered by most laboratories. However, direct measurement of SHBG is inexpensive and

reliable, allowing free and bioavailable testosterone to be calculated.

Men who receive testosterone should be reevaluated after

3–6 months and at least annually thereafter for testosterone levels,

erectile function, and adverse effects, which may include gynecomastia, sleep apnea, development or exacerbation of LUTS or BPH,

prostate cancer, lowering of HDL, erythrocytosis, elevations of liver

function tests, and reduced fertility. Periodic reevaluation should

include measurement of hemoglobin and prostate-specific antigen

and digital rectal examination. Therapy should be discontinued in

patients who do not respond within 6 months without an alternate

explanation (e.g., elevated estradiol).

VACUUM CONSTRICTION DEVICES

Vacuum constriction devices (VCDs) are a well-established noninvasive therapy. They are a reasonable treatment alternative for

select patients who cannot take PDE-5is or do not desire other

interventions. VCDs draw venous blood into the penis and use a

constriction ring to restrict venous return and maintain tumescence. Adverse events with VCD include pain, numbness, bruising,

and altered ejaculation. Additionally, many patients complain that

the devices are cumbersome and that the induced erections have a

nonphysiologic appearance and feel.

INTRAURETHRAL ALPROSTADIL

If a patient fails to respond to oral agents, a reasonable next choice is

intraurethral or self-injection of vasoactive substances. Intraurethral

prostaglandin E1

 (alprostadil), in the form of a semisolid pellet (doses

of 125–1000 μg), is delivered with an applicator. Approximately 65%

of men receiving intraurethral alprostadil respond with an erection

when tested in the office, but <50% achieve successful coitus at

home. Intraurethral insertion is associated with a markedly reduced

incidence of priapism in comparison to intracavernosal injection.

INTRACAVERNOSAL SELF-INJECTION

Injection of synthetic formulations of alprostadil is effective in

70–80% of patients with ED, but discontinuation rates are high

because of the invasive nature of administration. Doses range

between 1 and 40 μg. Injection therapy is contraindicated in men

with a history of hypersensitivity to the drug and men at risk for

priapism (hypercoagulable states, sickle cell disease). Side effects

include local adverse events, prolonged erections, pain, and fibrosis

with chronic use. Various combinations of alprostadil, phentolamine, and/or papaverine sometimes are used.

SURGERY

An important but less frequently used form of therapy for ED

involves the surgical implantation of a semirigid or inflatable

penile prosthesis. Because of the permanence of prosthetic devices,

patients should first consider less invasive options for treatment.

These surgical treatments are associated with a low rate of complications and are used for those who do not want the less spontaneous medical treatments, in PDE-5i–refractory ED, or in men

who cannot tolerate such medications. Despite the requirement

for surgery, penile prostheses are associated with very high rates of

patient and partner satisfaction.

SEX THERAPY

A course of sex therapy may be useful for addressing specific

interpersonal factors that may affect sexual functioning. These

approaches may be useful in patients who have psychogenic or

social components to their ED, although data from randomized trials are scanty and inconsistent. It is preferable to include

both partners in therapy if the patient is involved in an ongoing

relationship.

FEMALE SEXUAL DYSFUNCTION

Female sexual dysfunction (FSD) has traditionally included disorders of

desire, arousal, pain, and muted orgasm. The associated risk factors for

FSD are similar to those in males: cardiovascular disease, endocrine disorders, hypertension, neurologic disorders, and smoking (Table 397-4).

Women with hypertension report significantly lower sexual satisfaction (especially younger women).

■ EPIDEMIOLOGY

Epidemiologic data are limited, but the available estimates suggest that

as many as 43% of women complain of at least one sexual problem.

Despite the recent interest in organic causes of FSD, desire and arousal

phase disorders (including lubrication complaints) remain the most

TABLE 397-4 Risk Factors for Female Sexual Dysfunction

Neurologic disease: stroke, spinal cord injury, parkinsonism

Trauma, genital surgery, radiation

Endocrinopathies: diabetes, hyperprolactinemia

Liver and/or renal failure

Cardiovascular disease, especially hypertension

Psychological factors and interpersonal relationship disorders: sexual abuse,

life stressors

Medications

Antiandrogens: cimetidine, spironolactone

Antidepressants, alcohol, hypnotics, sedatives

Antiestrogens or GnRH antagonists

Antihistamines, sympathomimetic amines

Antihypertensives: diuretics, calcium channel blockers

Alkylating agents

Anticholinergics

Abbreviation: GnRH, gonadotropin-releasing hormone.

3062 PART 12 Endocrinology and Metabolism

common presenting problems when surveyed in a community-based

population.

■ PHYSIOLOGY OF THE FEMALE SEXUAL RESPONSE

The normal female sexual response requires the presence of estrogens.

A role for androgens is also likely but less well established. In the

CNS, estrogens and androgens work synergistically to enhance sexual

arousal and response. A number of studies report enhanced libido in

women during preovulatory phases of the menstrual cycle, suggesting

that hormones involved in the ovulatory surge (e.g., estrogens) increase

desire.

Sexual motivation is heavily influenced by context, including the

environment and partner factors. Once sufficient sexual desire is

reached, sexual arousal is mediated by the central and autonomic

nervous systems. Cerebral sympathetic outflow is thought to increase

desire, and peripheral parasympathetic activity results in clitoral vasocongestion and vaginal secretion (lubrication).

The neurotransmitters for clitoral corporal engorgement are similar

to those in the male penile tissues, with a prominent role for neural,

smooth-muscle, and endothelial released nitric oxide (NO). A fine

network of vaginal nerves and arterioles promotes a vaginal transudate.

The major transmitters of this complex vaginal response are not certain, but roles for NO and vasoactive intestinal polypeptide (VIP) are

suspected. Investigators studying the normal female sexual response

have challenged the long-held construct of a linear and unmitigated

relationship between initial desire, arousal, vasocongestion, lubrication, and eventual orgasm. Caregivers should consider a paradigm

of a positive emotional and physical outcome with one, many, or no

orgasmic peak and release.

Although there are anatomic differences as well as variation in

the density of vascular and neural beds in males and females, the

primary effectors of sexual response are strikingly similar. Intact

sensation is important for arousal. Thus, reduced levels of sexual

functioning are more common in women with peripheral neuropathies (e.g., diabetes). Vaginal lubrication is a transudate of serum

that results from the increased pelvic blood flow associated with

arousal. Vascular insufficiency from a variety of causes may compromise adequate lubrication and result in dyspareunia. Cavernosal and

arteriole smooth-muscle relaxation occurs via increased NO synthase (NOS) activity and produces engorgement in the clitoris and

the surrounding vestibule. Orgasm requires an intact sympathetic

outflow tract; hence, orgasmic disorders are common in female

patients with spinal cord injuries.

APPROACH TO THE PATIENT

Female Sexual Dysfunction

Many women do not volunteer information about their sexual

response. Open-ended questions in a supportive atmosphere are

helpful in initiating a discussion of sexual integrity in women who

are reluctant to discuss such issues. Once a complaint has been

voiced, a comprehensive evaluation should be performed, including

a medical history, a psychosocial history, a physical examination,

and limited laboratory testing.

The history should include the usual medical, surgical, obstetric,

psychological, gynecologic, sexual, and social information. Past

experiences, intimacy, knowledge, and partner availability should

also be ascertained. Medical disorders that may affect sexual health

should be delineated. They include diabetes, cardiovascular disease, gynecologic conditions, obstetric history, depression, anxiety

disorders, and neurologic disease. Medications should be reviewed

as they may affect arousal, libido, and orgasm. The need for counseling and recognizing life stresses should be identified. The physical examination should assess the genitalia, including the clitoris.

Pelvic floor examination may identify prolapse or other disorders.

Laboratory studies are needed, especially if menopausal status

is uncertain. Estradiol, follicle-stimulating hormone (FSH), and

luteinizing hormone (LH) are usually obtained, and dehydroepiandrosterone (DHEA) should be considered as it reflects adrenal

androgen secretion. A CBC, liver function assessment, and lipid

studies may be useful, if not otherwise obtained. Complicated

diagnostic evaluation such as clitoral Doppler ultrasonography and

biothesiometry require expensive equipment and are of uncertain

utility. It is important for the patient to identify which symptoms

are most distressing.

The evaluation of FSD previously occurred exclusively in a psychosocial context. However, inconsistencies between diagnostic categories based only on psychosocial considerations and the emerging

recognition of organic etiologies have led to a new classification of

FSD. This diagnostic scheme is based on four components that

are not mutually exclusive: (1) hypoactive sexual desire—the persistent or recurrent lack of sexual thoughts and/or receptivity to

sexual activity, which causes personal distress; hypoactive sexual

desire may result from endocrine failure or may be associated with

psychological or emotional disorders, (2) sexual interest arousal

disorder—the persistent or recurrent inability to attain or maintain

sexual excitement, which causes personal distress, (3) orgasmic

disorder—the persistent or recurrent loss of orgasmic potential after

sufficient sexual stimulation and arousal, which causes personal

distress, and (4) sexual pain disorder—persistent or recurrent genital pain associated with noncoital sexual stimulation, which causes

personal distress. This newer classification emphasizes “personal

distress” as a requirement for dysfunction and provides clinicians

with an organized framework for evaluation before or in conjunction with more traditional counseling methods.

TREATMENT

Female Sexual Dysfunction

GENERAL

An open discussion with the patient is important as couples

may need to be educated about normal anatomy and physiologic

responses, including the role of orgasm, in sexual encounters.

Physiologic changes associated with aging and/or disease should be

explained. Couples may need to be reminded that clitoral stimulation rather than coital intromission may be more beneficial.

Behavioral modification and nonpharmacologic therapies should

be a first step. Patient and partner counseling may improve communication and relationship strains. Lifestyle changes involving known

risk factors can be an important part of the treatment process.

Emphasis on maximizing physical health and avoiding lifestyles

(e.g., smoking, alcohol abuse) and medications likely to produce

FSD is important (Table 397-3). The use of topical lubricants may

address complaints of dyspareunia and dryness. Contributing medications such as antidepressants may need to be altered, including

the use of medications with less impact on sexual function, dose

reduction, medication switching, or drug holidays.

HORMONAL THERAPY

In postmenopausal women, estrogen replacement therapy may

be helpful in treating vaginal atrophy, decreasing coital pain, and

improving clitoral sensitivity (Chap. 395). Menopause and its

transition represent significant risk factors for the development of

vulvovaginal atrophy–related sexual dysfunction. Available vaginal

estrogen preparations include conjugated equine estrogens, estradiol vaginal cream, a sustained-release intravaginal estradiol ring,

or a low-dose estradiol tablet. Vaginal estrogen preparations with

the lowest systemic absorption rate may be preferred in women

with history of breast cancer and severe vaginal atrophy. Vaginal

lubricants and moisturizers applied on a regular basis have an

efficacy comparable to that of local estrogen therapy and should

be offered to women wishing to avoid the use of vaginal estrogens.

If a hormonal supplement is chosen, then estrogen replacement in

3063Women’s Health CHAPTER 398

the form of local cream is the preferred method as it avoids systemic side effects. Androgen levels in women decline substantially

before menopause. However, low levels of testosterone or DHEA

are not effective predictors of a positive therapeutic outcome with

androgen therapy. The widespread use of exogenous androgens

is not supported by the literature except in select circumstances

(premature ovarian failure or menopausal states) and in secondary

arousal disorders.

Atrophic vaginitis is very common in postmenopausal women

and is most commonly treated with estrogen-based treatments.

However, many women are hesitant to use estrogen-based treatments due to health concerns or are unable to use them due to a history of breast cancer or endometrial cancer. Hyaluronic acid vaginal

gel has been found to be efficacious in treating atrophic vaginitis.

ORAL AGENTS

Flibanserin, originally developed as an antidepressant, has been

approved by the FDA as a treatment for low sexual desire in

premenopausal women. Flibanserin, a postsynaptic agonist of

serotonin receptor 1A and antagonist of serotonin receptor 2A,

increases sexual desire and reduces resultant stress in women

with hyposexual desire disorder (HSDD) with few adverse effects.

Flibanserin has two principal pharmacologic actions in neural

microcircuits: it acts as a full agonist at postsynaptic 5-HT1A

receptors and an antagonist at postsynaptic 5-HT2A receptors.

Exclusive binding at these receptors differentiates flibanserin

from buspirone and bupropion. This action in the prefrontal

cortex causes the downstream release of dopamine and norepinephrine and reduction of serotonin. Flibanserin acts selectively

on pyramidal neurons that excite brainstem 5-HT neurons yet

also selectively on pyramidal neurons that inhibit brainstem norepinephrine and dopamine neurons.

Flibanserin may boost sex drive in women who experience low

sexual desire and who find the experience distressing. The drug

should be discontinued if there is no improvement in sex drive after

8 weeks. Potentially serious side effects include low blood pressure,

dizziness, and fainting, particularly if it is mixed with alcohol.

Other common adverse events include dizziness, nausea, fatigue,

sleepiness, and insomnia. Health care professionals and pharmacies

dealing with flibanserin have to undergo a certification (risk evaluation and mitigation strategy [REMS]) process, and patients need to

submit a written agreement to abstain from alcohol. The goal of the

flibanserin REMS is to inform patients about the increased risk of

hypotension and syncope due to an interaction with alcohol.

Bremelanotide, a melanocortin 4 receptor agonist, has recently

been approved for HSDD. It demonstrates significant improvement

in desire and a significant decrease in distress related to lack of

desire. The most common adverse effects include nausea (39.9%),

facial flushing (20.4%), and headache (11%). Bremelanotide’s place

in therapy is unknown, as the trials met statistical significance

for change in sexual desire elements and distress related to sexual

desire, yet the clinical benefit may only be modest. It is a subcutaneous injection given 45 min prior to sexual activity. Bremelanotide

has no clinically significant interactions with ethanol. Prescribing

guidelines recommend no more than one dose in 24 h and no more

than eight doses per month. Individuals should discontinue use

after 8 weeks without benefit.

The efficacy of PDE-5is in FDS has been a marked disappointment in light of the proposed role of NO-dependent physiology in

the normal female sexual response. The use of PDE-5is for FSD

should be discouraged pending proof that they are effective.

CLITORAL VACUUM DEVICE

In patients with arousal and orgasmic difficulties, the option of

using a clitoral vacuum device may be explored. This handheld

battery-operated device has a small soft plastic cup that applies

a vacuum over the stimulated clitoris. This causes increased cavernosal blood flow, engorgement, and vaginal lubrication.

■ FURTHER READING

Bhasin S: A perspective on the evolving landscape in male reproductive medicine. J Clin Endocrinol Metab 101:827, 2016.

Burnett AL et al: Erectile dysfunction: AUA Guideline. J Urol

200:633, 2018.

Cappelleri JC, Rosen RC: The Sexual Health Inventory for Men

(SHIM): A 5-year review of research and clinical experience. Int J

Impot Res 17:307, 2005.

Geerkens MJM et al: Sexual dysfunction and bother due to erectile

dysfunction in the healthy elderly male population: Prevalence from

a systematic review. Eur Urol Focus 6:776, 2020.

McVary KT: Clinical practice. Erectile dysfunction. N Engl J Med

357:2472, 2007.

Wheeler LJ, Guntupalli SR: Female sexual dysfunction: Pharmacologic and therapeutic interventions. Obstet Gynecol 136:174, 2020.

The clinical discipline of women’s health is well established. Indeed,

its emphasis on greater attention to patient education and medical

decision-making is a paradigm for what has become known as patientcentered health care. Moreover, the recognition of sex differences in

gene expression, disease processes, and health outcomes is an important example of precision medicine. Sex difference refers to the biologic

differences conferred by sex chromosomes and hormones. In contrast,

gender differences are related to psychosocial roles and cultural expectations. The study of sex differences continues to grow as a scientific

discipline. In 2016, the National Institutes of Health recognized its

importance by implementing the expectation that sex should be considered as a biologic variable in study designs, analyses, and reporting

in not only human but also vertebrate animal research. Strong scientific

justification must be provided to limit research to only one sex.

DISEASE RISK: REALITY AND PERCEPTION

The leading causes of death are the same in women and men: (1) heart

disease and (2) cancer (Fig. 398-1). The leading cause of cancer death,

lung cancer, is the same in both sexes. Breast cancer is the second

leading cause of cancer death in women, but it causes ~70% fewer total

deaths than does lung cancer. Men are more likely than women to die

from suicide and accidents.

Maternal mortality continues to be higher in the United States than

in other industrialized nations and is associated with substantial health

disparities in maternal deaths. U.S. maternal mortality rates declined for

the majority of the twentieth century given improvements in maternity

care and safer surgical techniques; however, the rates began to rise again

in 2000. The most current national data for maternal mortality were

reported in 2018, over 10 years since the prior updated statistics. Over the

past decade, the mortality rate has remained relatively stable. In 2018, the

mortality rate was 17.4 deaths per 100,000 live births. The mortality rates

for non-Hispanic black women were highest at 37.3 deaths per 100,000

live births (2.5 times the rate for non-Hispanic white women [14.9 deaths

per 100,00 live births], 3.2 times the rate for Hispanic women [11.8

deaths], and 2.8 times the rate for Asian women [13.3 deaths]).

Women’s risk for many diseases increases at menopause. The

median age of menopause in Caucasian women from industrialized

countries is between 50 and 52 years, where women spend one-third of

their lives in the postmenopausal period. Menopause occurs at earlier

ages in Hispanic and African-American women as well as in women of

lower socioeconomic status. Estrogen levels fall abruptly at menopause,

inducing a variety of physiologic and metabolic responses. Rates of

398 Women’s Health

Emily Nosova, Andrea Dunaif

3064 PART 12 Endocrinology and Metabolism

cardiovascular disease (CVD) increase and bone density decreases

rapidly after menopause.

In the United States, women live on average 5.0 years longer than

men, with a life expectancy at birth in 2018 of 81.2 years in women

compared with 76.2 years in men of all races. Life expectancy was lower

in African Americans of both sexes and higher in Hispanics of both

sexes than their Caucasian counterparts. Accordingly, elderly women

outnumber elderly men, so that age-related conditions, such as hypertension, have a female preponderance.

SEX DIFFERENCES IN HEALTH

AND DISEASE

■ ALZHEIMER’S DISEASE

(See also Chap. 431.) Alzheimer’s disease (AD) affects approximately

twice as many women as men. Because the risk for AD increases with

age, part of this sex difference is accounted for by the fact that women

live longer than men. However, even in relatively younger groups

(60–70 years of age), there is still a higher incidence of AD among

women. Additional factors may contribute to the increased risk for AD

in women, including sex differences in brain size, structure, and functional organization. Multimodal neuroimaging has demonstrated that

certain biomarkers of the preclinical phase of AD, including a decline

in neuronal mitochondrial function and impaired cerebral glucose

metabolism, are evident earlier in women and are even distinguishable

during the perimenopausal endocrine transition. There is emerging

evidence for sex-specific differences in gene expression, not only for

genes on the X and Y chromosomes but also for some autosomal genes.

These genetic differences may translate into variable severity of AD,

with women experiencing greater deficits in cognition. The ε4 allele

of the apolipoprotein E gene (APOε4), a cholesterol carrier integral for

lipid transport in the brain, is a major risk factor for AD. Recent studies show that the APOε4 genotype is strongly linked to development

of sporadic AD in women (Fig. 398-2). Women who carry either the

APOε4 homo- or heterozygous isoform have an increased risk of progressing from healthy aging patterns to cognitive impairment or AD,

whereas men who carry either isoform experience marginal impact on

their memory or cognition.

Estrogens have pleiotropic genomic and nongenomic effects on

the central nervous system, including neurotrophic actions in key

areas involved in cognition and memory. Women with AD have

lower endogenous estrogen levels than do women without AD. These

Cancer 21%

Heart Disease

22%

All Other

26%

Women

Septicemia 2%

Kidney

disease 2%

Influenza &

Pneumonia 2%

Diabetes 3%

Accidents 4%

AD

5% Stroke

6%

CLRD

6%

Heart Disease

24%

Cancer 22%

All Other

25%

Men

Suicide 3%

Liver Disease

Cirrhosis 2%

Influenza &

Pneumonia 2%

Diabetes 3%

Accidents 7%

AD 3%

Stroke 4%

CLRD 5%

FIGURE 398-1 Percent distribution of 10 leading causes of death in (A) women compared to (B) men in the United States in 2018. In both women and men, the first and

second leading causes of death are the same, heart disease and cancer, respectively. Causes of death then diverge by sex. For example, accidents are the third leading

cause of death in men but the sixth leading cause of death in women. Chronic lower respiratory disease (CLRD), stroke, and Alzheimer’s disease (AD) cause a larger

percentage of deaths in women than in men. Suicide is among the 10 leading causes of death in men but not in women. (Data from SL Murphy, J Xu, KD Kochanek, E Arias,

B Tejada-Vera: Deaths: Final Data for 2018. Natl Vital Stat Rep 69:1, 2021.)

observations have led to the hypothesis that estrogen is neuroprotective.

The Women’s Health Initiative Memory Study (WHIMS), an ancillary

study in the Women’s Health Initiative (WHI) in women aged ≥65 years,

found significantly increased risk for both dementia and mild cognitive impairment in women receiving estrogen alone or estrogen with

progestin compared to placebo. However, the Kronos Early Estrogen

Prevention Study (KEEPS), a randomized clinical trial of early hormone therapy (HT) initiation after menopause that compared conjugated equine estrogen (CEE), transdermal estradiol (both estrogen

arms included cyclic oral micronized progesterone), and placebo,

found no adverse effect of HT on cognitive function. In summary,

there is no evidence from placebo-controlled trials that HT improves

cognitive function.

While studies have shown a link between female sex and AD, other

neurodegenerative disorders, including Parkinson’s disease (PD) and

amyotrophic lateral sclerosis (ALS), exhibit a stronger association with

male sex. Men are 1.5 times more likely to develop PD than women

across all age groups. A possible explanation for the male predilection

may be the effect of Y-chromosome exclusive gene sex-determining

region Y (SRY) on nigrostriatal dopaminergic (NSDA) neurons:

the SRY upregulates neuronal numbers, synthesis of dopamine, and

metabolism of neurons.

ALS is a highly variable disease in symptomatology and age at onset.

Men are diagnosed with ALS earlier in life and exhibit a more severe

disease course, even though survival patterns are similar between the

two sexes. Despite this variability, epidemiologic data have demonstrated that, in females, ALS starts in the bulbar tract, whereas in males,

ALS tends to begin in the motor neurons of the lumbar tract. Reasons

for the sex differences observed in ALS remain unclear. However, there

is some evidence to suggest that a more prolonged reproductive condition, defined as a longer duration exposure to estrogen via oral contraceptive use versus natural menopause, may exert a neuroprotective role

on motor neurons among women diagnosed with ALS.

■ CVD AND STROKE

(See also Chap. 273.) There are major sex differences in CVD, the leading cause of death in developed countries. However, there are also major

gender differences because of perceptions by both women and their

health care providers that women are at lower risk for CVD. As a result of

these misconceptions, women are less likely to seek medical help when

they experience symptoms of CVD. Health care providers are less likely

to suspect CVD, so women receive fewer interventions for modifiable

3065Women’s Health CHAPTER 398

risk factors as well as fewer acute interventions than do men. Women

and their health care providers are also less aware that prodromal symptoms of cardiac disease differ in women compared to men. Women are

less likely than men to present with chest pain and more likely to present

with fatigue, shortness of breath, indigestion/nausea, and anxiety.

Sex steroids have major effects on the cardiovascular system and

lipid metabolism. Estrogen increases high-density lipoprotein (HDL)

and lowers low-density lipoprotein (LDL), whereas androgens have the

opposite effect. Estrogen has direct vasodilatory effects on the vascular

endothelium, enhances insulin sensitivity, and has antioxidant and

anti-inflammatory properties. There is a striking increase in CVD

after both natural and surgical menopause, suggesting that endogenous

estrogens are cardioprotective. Women also have longer QT intervals

on electrocardiograms, and this increases their susceptibility to certain

arrhythmias.

CVD presents differently in women, who are usually 10–15 years

older than their male counterparts and are more likely to have comorbidities such as hypertension, congestive heart failure, and diabetes

mellitus (DM). In the Framingham study, angina was the most common initial symptom of CVD in women, whereas myocardial infarction (MI) was the most common initial presentation in men. Women

more often have atypical symptoms such as fatigue, anxiety, nausea,

indigestion, and upper back pain. Although awareness that heart disease is the leading cause of death in women has nearly doubled over

the past 15 years, women remain less aware that its symptoms are often

atypical and are less likely to contact 9-1-1 when they experience such

symptoms.

Deaths from CVD had decreased markedly in men since 1980,

whereas CVD deaths only started to decrease substantially in women

beginning in 2000. After 2010, death rates from CVD among both

sexes stabilized and even began to increase slightly in men. Women

with MI are more likely to present with cardiac arrest or cardiogenic

shock, whereas men are more likely to present with ventricular tachycardia. Further, younger women with MI are more likely to die than are

men of similar age. However, this mortality gap has decreased in recent

years because younger women have experienced greater improvements

in survival after MI than men. The improvement in survival is due

largely to a reduction in comorbidities, suggesting a greater attention

to modifiable risk factors in women.

Sex differences account for more variable short-term outcomes

observed among women with CVD who receive therapeutic intervention, as compared to men. Women undergoing CABG surgery have

more advanced disease, a higher perioperative mortality rate, less relief

of angina, and less graft patency; however, 5- and 10-year survival rates

are similar. Women undergoing percutaneous transluminal coronary

angioplasty have lower rates of initial angiographic and clinical success

than men, but they also have a lower rate of restenosis and a better

long-term outcome. Women may benefit less and have more frequent

serious bleeding complications from thrombolytic therapy compared

with men. Factors such as older age, more comorbid conditions,

ADAM/ORX

Testosterone

Spine

density

AR

ROS ROS

Microglia

activation

Microglia

activation

Estrogens

Circulating

lipids

Polymorphisms

Menopause/OVX

ERα

Polymorphisms

Apoε4

ERα

ERβ

Amyloid plaque

DHT

Neuroprotection

FIGURE 398-2 Sex differences and actions of sex steroid hormones on amyloid plaque deposition, neuroinflammation, and neuroprotection. The ε4 allele of the

apolipoprotein E gene (APOε4), a cholesterol carrier integral for lipid transport in the brain, has been identified as a major genetic risk factor for the sporadic development

of Alzheimer’s disease (AD). Woman who carry either the homo- or heterozygous APOε4 isoform have higher rates of amyloid plaque deposition. The APOε4 variant

has relatively limited effects in men with either the homo- or the heterozygous isoforms. AR, androgen receptor; DHT, dihydrotestosterone; ER, estrogen receptor;

ROS, reactive oxygen species. (Reproduced with permission from E Vegeto et al: The role of sex and sex hormones in neurodegenerative diseases. Endocr Rev

41:273, 2020.)

3066 PART 12 Endocrinology and Metabolism

smaller body size, and more severe CVD in women at the time of

events or procedures account in part for the observed sex differences.

Elevated cholesterol levels, hypertension, smoking, obesity, low

HDL cholesterol levels, DM, and lack of physical activity are important

risk factors for CVD in both men and women. Total triglyceride levels

are an independent risk factor for CVD in women but not in men. Low

HDL cholesterol and DM are more important risk factors for CVD in

women than in men. Several disorders affect women exclusively, such

as pregnancy-associated hypertension, preeclampsia, gestational DM,

and polycystic ovary syndrome, or predominantly, such as rheumatoid

arthritis (RA) and systemic lupus erythematosus (SLE). Cholesterol-lowering drugs are equally effective in men and women for primary

and secondary prevention of CVD. In contrast to men, randomized

trials showed that aspirin was not effective in the primary prevention of

CVD in women; it did significantly reduce the risk of ischemic stroke.

Recent studies demonstrate strong associations between certain

adverse pregnancy outcomes (APO) and the development of CVD in

postmenopausal women, a risk that has been previously underappreciated. In an analysis of WHI data, nearly 29% of women surveyed

reported at least one APO, defined as a hypertensive disorder during

pregnancy, low or high neonatal birth weight, gestational diabetes, or

preterm delivery of 3 weeks or greater. Each outcome, when analyzed

independently, was significantly associated with the development of

CVD after menopause. When multivariate modeling incorporated

all of the APO variables and accounted for body mass index (BMI),

socioeconomic status, and parity, low birth weight and hypertensive

disorders remained significantly associated with later-onset CVD. A

recent meta-analysis examined the association of female reproductive

factors and the development of future CVD. The greatest risk for CVD

(at least 2-fold) was conferred by a history of stillbirth, preterm birth,

or preeclampsia, followed by a 1.5- to 1.9-fold risk with gestational

diabetes and hypertension, premature ovarian insufficiency, and placental abruption; the lowest risk (<1.5-fold) was associated with early

menarche, early menopause, parity, and polycystic ovary syndrome.

Given these strong associations, targeted counseling and increased

surveillance of CVD risk factors is warranted for women in high-risk

groups.

The sex differences in CVD prevalence, beneficial biologic effects

of estrogen on the cardiovascular system, and reduced risk for CVD in

observational studies led to the hypothesis that HT was cardioprotective. However, the WHI, which studied >16,000 women on CEE plus

medroxyprogesterone acetate (MPA) or placebo and >10,000 women

with hysterectomy on CEE alone or placebo, did not demonstrate a

benefit of HT for the primary or secondary prevention of CVD. In

addition, CEE plus MPA was associated with an increased risk for

CVD, particularly in the first year of therapy, whereas CEE alone neither increased nor decreased CVD risk. Both HT groups were associated with an increased risk for ischemic stroke. In a subgroup analysis

of the WHI estrogen-alone trial, a relatively younger age (50–59 years)

combined with a history of bilateral salpingo-oophorectomy (BSO)

was associated with a >30% CEE treatment–associated reduction in

all-cause mortality, whereas CEE-treated older women with prior BSO

did not see a significant reduction in any other outcomes, including

incidence of coronary artery disease, invasive breast cancer, all-cause

mortality, and a composite index of the aforementioned outcomes

plus stroke, hip fracture, pulmonary embolism, and colorectal cancer.

These results suggest that postmenopausal women younger than 60

with prior BSO may have mortality benefit from HT, while women

older than 60 with BSO may suffer consequences associated with HT.

More recent data from KEEPS indicate that even if estrogen therapy

is initiated shortly after the menopausal transition, it does not reduce

atherosclerotic progression or impact CVD outcomes. Additionally,

HT and placebo groups have similar outcomes with respect to venous

thromboembolism and breast cancer. Although HT does not slow

CVD development as previously thought, findings from KEEPS suggest that treated women experience significant improvements in vasomotor symptoms, mood, sexual function, and bone density, especially

when therapy is started sooner after menopause onset.

HT is discussed further in Chap. 395.

■ DIABETES MELLITUS

(See also Chap. 403.) Women are more sensitive to insulin than men.

Despite this, the prevalence of type 2 DM is similar in men and women.

There is a sex difference in the relationship between endogenous

androgen levels and DM risk. Higher bioavailable testosterone levels

are associated with increased risk in women, whereas lower bioavailable testosterone levels are associated with increased risk in men. This

observation has been confirmed in a recent Mendelian randomization

that found that genetically determined higher testosterone increases

risk for DM in women but reduces risk in men. Polycystic ovary

syndrome, preeclampsia, pregnancy-associated hypertension, and gestational DM—common conditions in premenopausal women—are

associated with a significantly increased risk for type 2 DM. Among

individuals with DM, women have a greater risk for MI than do men.

Women with DM have a sixfold greater risk of dying of CVD compared

to women without DM.

Premenopausal women with DM lose the cardioprotective effect of

female sex and have rates of CVD identical to those in males. These

women have impaired endothelial function and reduced coronary

vasodilatory responses, which may predispose to cardiovascular complications. Women with DM are more likely to have left ventricular

hypertrophy. Women with DM receive less aggressive treatment for

modifiable CVD risk factors than men with DM.

■ HYPERTENSION

(See also Chap. 277.) After age 60, hypertension is more common in

U.S. women than in men, largely because of the high prevalence of

hypertension in older age groups and the longer survival of women.

Isolated systolic hypertension is present in 30% of women >60 years

old. Sex hormones affect blood pressure. Both normotensive and

hypertensive women have higher blood pressure levels during the

follicular phase than during the luteal phase. In the Nurses’ Health

Study, the relative risk of hypertension was 1.8 in current users of oral

contraceptives, but this risk is lower with the newer low-dose contraceptive preparations. HT is not associated with hypertension. Among

secondary causes of hypertension, there is a female preponderance of

renal artery fibromuscular dysplasia.

The benefits of treatment for hypertension have been dramatic in

both women and men. A meta-analysis of the effects of hypertension

treatment, the Individual Data Analysis of Antihypertensive Intervention Trial, found a reduction of risk for stroke and major cardiovascular

events in women. The effectiveness of various antihypertensive drugs

appears to be comparable in women and men; however, women may

experience more side effects, such as cough with angiotensin-converting

enzyme inhibitors.

■ AUTOIMMUNE DISORDERS

(See also Chap. 355.) Most autoimmune disorders occur more commonly in women than in men; they include autoimmune thyroid and

liver diseases, SLE, RA, scleroderma, multiple sclerosis (MS), and idiopathic thrombocytopenic purpura. However, there is no sex difference

in the incidence of type 1 DM, and ankylosing spondylitis occurs more

commonly in men. Sex differences in both immune responses and

adverse reactions to vaccines have been reported. For example, there is

a female preponderance of postvaccination arthritis.

Adaptive immune responses are more robust in women than in

men; this may be explained by the stimulatory actions of estrogens

and the inhibitory actions of androgens on the cellular mediators

of immunity. Consistent with an important role for sex hormones,

there is variation in immune responses during the menstrual cycle,

and the activity of certain autoimmune disorders is altered by castration or pregnancy (e.g., RA and MS may remit during pregnancy).

Nevertheless, the majority of studies show that exogenous estrogens

and progestins in the form of HT or oral contraceptives do not alter

autoimmune disease incidence or activity. Exposure to fetal antigens,

including circulating fetal cells that persist in certain tissues, has been

speculated to increase the risk of autoimmune responses. There is

clearly an important genetic component to autoimmunity, as indicated

by the familial clustering and HLA association of many such disorders.

3067Women’s Health CHAPTER 398

X chromosome genes also contribute to sex differences in immunity.

Indeed, nonrandom X chromosome inactivation may be a risk factor

for autoimmune diseases.

■ HIV INFECTION

(See also Chap. 202.) Women accounted for almost 18% of the

~36,400 new HIV diagnoses in the United States in 2018. Annual HIV

diagnoses remained stable among women from 2014 to 2018. In 2018,

the infectivity rate for black/African-American females was 13 times

the rate for white females and 4 times higher than Hispanic/Latino

females. Nevertheless, AIDS remains an important cause of death in

younger women, particularly African-American women aged 25–44 years.

Heterosexual contact with an at-risk partner is the fastest-growing transmission category, and women are more susceptible to HIV infection

during vaginal sex than men. This increased susceptibility is accounted

for in part by an increased prevalence of sexually transmitted diseases,

i.e., gonorrhea and syphilis, in women.

Some studies have suggested that hormonal contraceptives may

increase the risk of HIV transmission. Progesterone has been shown

to increase susceptibility to infection in nonhuman primate models of

HIV. Women are also more likely to be infected by multiple variants of

the virus than men. Women with HIV have more rapid decreases in

their CD4 cell counts than do men. Compared with men, HIV-infected

women more frequently develop candidiasis, but Kaposi’s sarcoma is

less common than it is in men. Women have more adverse reactions,

such as lipodystrophy, dyslipidemia, and rash, with antiretroviral therapy than do men. This observation is explained in part by sex differences in the pharmacokinetics of certain antiretroviral drugs, resulting

in higher plasma concentrations in women.

■ OBESITY

(See also Chap. 402.) The prevalence of both obesity (BMI ≥30 kg/m2

)

and abdominal obesity (waist circumference ≥88 cm in women) are similar in U.S. women and men. In 2018, the age-adjusted prevalence of obesity in U.S. adults was 42.4%, and there were no significant differences

between women and men, even across different age groups. In 2018, the

prevalence of obesity was 41.9% for women and 43.0% for men. The

prevalence of obesity was highest among non-Hispanic black women

(56.9%) as compared with non-Hispanic white (39.8%), Hispanic

(43.7%), and non-Hispanic Asian women (17.2%). Non-Hispanic black

women had a higher prevalence of obesity compared to non-Hispanic

black men. There were no significant differences in prevalence between

men and women among non-Hispanic white, non-Hispanic Asian, or

Hispanic adults. More than 80% of patients who undergo bariatric surgery are women. Pregnancy and menopause are risk factors for obesity.

There are major sex differences in body fat distribution. Women

characteristically have a gluteal and femoral or gynoid pattern of fat

distribution, whereas men typically have a central or android pattern.

Women have more subcutaneous fat than men. In women, endogenous androgen levels are positively associated with abdominal obesity,

and androgen administration increases visceral fat. In contrast, there

is an inverse relationship between endogenous androgen levels and

abdominal obesity in men. Further, androgen administration decreases

visceral fat in these obese men. The reasons for these sex differences

in the relationship between visceral fat and androgens are unknown;

however, emerging evidence suggests that there is a contribution of

genetic variation. Studies in humans also suggest that sex steroids play

a role in modulating food intake and energy expenditure.

In men and women, abdominal obesity characterized by increased

visceral fat is associated with an increased risk for CVD and DM.

Obesity increases a woman’s risk for certain cancers, in particular postmenopausal breast and endometrial cancer, in part because adipose tissue provides an extragonadal source of estrogen through aromatization

of circulating adrenal and ovarian androgens, especially the conversion

of androstenedione to estrone. Obesity increases the risk of infertility,

miscarriage, and complications of pregnancy.

■ OSTEOPOROSIS

(See also Chap. 411.) Osteoporosis is about five times more common

in postmenopausal women than in age-matched men, and osteoporotic

hip fractures are a major cause of morbidity in elderly women. Men

accumulate more bone mass and lose bone more slowly than do

women. Sex differences in bone mass are found as early as infancy.

Calcium intake, vitamin D, and estrogen all play important roles in

bone formation and bone loss. Particularly during adolescence, calcium intake is an important determinant of peak bone mass. Vitamin

D deficiency is surprisingly common in elderly women, occurring in

>40% of women living in northern latitudes. Receptors for estrogens

and androgens have been identified in bone. Estrogen deficiency is

associated with increased osteoclast activity and a decreased number of

bone-forming units, leading to net bone loss. The aromatase enzyme,

which converts androgens to estrogens, is also present in bone. Estrogen is an important determinant of bone mass in men (derived from

the aromatization of androgens) as well as in women.

■ PHARMACOLOGY

On average, women have lower body weights, smaller organs, a higher

percentage of body fat, and lower total-body water than men. There are

also important sex differences in drug action and metabolism that are

not accounted for by these differences in body size and composition.

Sex steroids alter the binding and metabolism of a number of drugs.

Further, menstrual cycle phase and pregnancy can alter drug action.

Women also take more medications than men, including over-thecounter formulations and supplements. The greater use of medications

combined with these biologic differences may account for the reported

higher frequency of adverse drug reactions in women than in men.

Two-thirds of cases of drug-induced torsades des pointes, a rare,

life-threatening ventricular arrhythmia, occur in women because they

have a longer, more vulnerable QT interval. These drugs, which include

certain antihistamines, antibiotics, antiarrhythmics, and antipsychotics, can prolong cardiac repolarization by blocking cardiac voltagegated potassium channels.

■ PSYCHOLOGICAL DISORDERS

(See also Chap. 452.) Depression, anxiety, and affective and eating

disorders (bulimia and anorexia nervosa) are more common in women

than in men. Epidemiologic studies from both developed and developing nations consistently find major depression to be twice as common

in women as in men, with the sex difference becoming evident in early

adolescence. Depression occurs in 10% of women during pregnancy

and in 10–15% of women during the postpartum period. There is a high

likelihood of recurrence of postpartum depression with subsequent

pregnancies. The incidence of major depression diminishes after the age

of 45 years and does not increase with the onset of menopause. Depression in women appears to have a worse prognosis than does depression

in men; episodes last longer, and there is a lower rate of spontaneous

remission. Schizophrenia and bipolar disorders occur at equal rates in

men and women, although there may be sex differences in symptoms.

Both biologic and social factors account for the greater prevalence of

depressive disorders in women. Men have higher levels of the neurotransmitter serotonin. Sex steroids also affect mood, and fluctuations during

the menstrual cycle have been linked to symptoms of premenstrual

syndrome. Sex hormones differentially affect the hypothalamic-pituitary-adrenal responses to stress. Testosterone appears to blunt cortisol

responses to corticotropin-releasing hormone. Both low and high levels

of estrogen can activate the hypothalamic-pituitary-adrenal axis.

■ COVID-19 INFECTION

(See also Chap. 199.) Soon after the discovery of COVID-19, which

was identified in November 2019 in Wuhan, China, as being caused

by the novel coronavirus SARS-CoV-2, it was evident that there were

appreciable sex differences in severity and outcomes. Indeed, initial

observational data from the winter of 2019 and spring of 2020 demonstrated a higher overall incidence of infectious cases, hospitalizations,

intensive care unit admissions, and case-fatality rates among men as

compared to women. More pronounced sex differences were observed

with advanced age, with a higher overall incidence in older male age

groups. These sex differences have persisted among different racial,

ethnic, and socioeconomic groups and across all continents, as SARSCoV-2 became a global pandemic.

3068 PART 12 Endocrinology and Metabolism

SARS-CoV2

ACE2

Virus entry Virus

entry

Cytosol

HSP

Activated

Translocation

AR AR HSP

Nucleus

TMPRSS2 mRNA

ARE

TMPRSS2 mRNA

TMPRSS2 ARE TMPRSS2

?

TMPRSS2

Attachment

Activation

SARS-CoV2

TMPRSS2 ACE2

Attachment

Activation

Testosterone

SARS-CoV2

FIGURE 398-3 Proposed sex hormone differences in TMPRSS2-mediated SARS-CoV-2 host cell entry. The virus

entry point into cells is the membrane-bound angiotensin-converting enzyme 2 (ACE2) receptor. The cell-membrane

protease, TMPRSS2, is also vital for host cell entry. Circulating levels of ACE2, expressed abundantly in the lung, heart,

and kidney tissues, have been reported to be relatively higher in men. Upregulation of the ACE2 receptor in men may

provide greater opportunity for cellular entry, viral replication, symptom development, and multiorgan involvement.

(Reproduced with permission from C Gebhard et al: Impact of sex and gender on COVID-19 outcomes in Europe. Biol

Sex Differ 11:29, 2020.)

There are several potential mechanisms for these sex-specific effects of

SARS-CoV-2 infection. The virus’s entry

point into cells is the membrane-bound

angiotensin-converting enzyme 2 (ACE2)

receptor, and it also harnesses the primer

TMPRSS2, a cellular serine protease

(Fig. 398-3). Circulating levels of ACE2,

which is expressed in a variety of tissues

including the lung, heart, and kidneys,

have been reported to be relatively higher

in men who have diabetes and/or kidney disease, as well as in healthy men;

however, not all studies have reported

similar sex differences. One hypothesis

is that upregulation of the ACE2 receptor

in men may provide greater opportunity

for cellular entry, viral replication, and

development of symptoms and deleterious sequelae.

ACE2 plays a critical role in bronchial

transient secretory cells/type II alveolar

cells as well as the renin-angiotensin-aldosterone system (RAAS). In the RAAS,

ACE2 opposes angiotensin II’s vasoconstrictive actions by converting angiotensin II to the vasodilatory angiotensin 1-7

in critical tissues, including cardiac myocytes, cardiac fibroblasts, and coronary

endothelial cells. Importantly, recent evidence has shown the impact of sex and

sex hormones on the RAAS and ACE2:

estrogen downregulates angiotensin II

receptor type 1 and regulates renin activity, as well as modulates local RAAS in

the atrial myocardium. Furthermore, it has been shown that ovariectomized females have increased ACE2 activity and expression in their

kidney and adipose tissue and that estradiol replacement reduces ACE2

expression. On the contrary, orchiectomized males have decreased

ACE2 activity. Estrogen appears to reduce ACE2 expression in the

heart and kidney in both rodent and human studies.

TMPRSS2, a vital contributor to SARS-CoV-2 cellular invasion, is a

protein that is most abundantly expressed in prostate epithelial tissue,

including high-grade prostate cancers and metastases. Accordingly, the

protein’s involvement in viral priming is thought to be an important

reason for the higher case-fatality rate observed in men; however, the

association has not yet been proven. TMPRSS2 is also expressed in

airway epithelia, where its physiologic function is not entirely clear.

Transcription of the cellular protein is regulated by androgenic ligands and androgen receptor binding element; it is unknown whether

estrogen plays a role in its regulation. Emerging in vitro studies have

demonstrated that a TMPRSS2 inhibitor blocks viral entry into cells.

These data may serve as an important foundation for sex-specific and

personalized therapeutic approaches in the future.

■ SUBSTANCE ABUSE AND TOBACCO

(See also Chaps. 453 and 454.) Substance abuse is more common in

men than in women. However, one-third of Americans who suffer

from alcoholism are women. Women are less likely to be diagnosed

with alcoholism than men. A greater proportion of men than women

seek help for alcohol and drug abuse. Men are more likely to go to an

alcohol or drug treatment facility, whereas women tend to approach a

primary care physician or mental health professional for help under

the guise of a psychosocial problem. Blood alcohol levels are higher

in women than in men after drinking equivalent amounts of alcohol, adjusted for body weight. This greater bioavailability of alcohol

in women is due to both the smaller volume of distribution and the

slower gastric metabolism of alcohol secondary to lower activity of

gastric alcohol dehydrogenase than is the case in men. Women with

alcoholism have a higher mortality rate than do women and men without alcoholism. Women also appear to develop alcoholic liver disease

and other alcohol-related diseases with shorter drinking histories and

lower levels of alcohol consumption. Alcohol abuse also poses special

risks to a woman, adversely affecting fertility and the health of the baby

(fetal alcohol syndrome). Even moderate alcohol use increases the risk

of breast cancer, hypertension, and stroke in women.

More men than women smoke tobacco, but this sex difference continues to decrease. Women have a much larger burden of smoking-related

disease. Smoking markedly increases the risk of CVD in premenopausal

women and is also associated with a decrease in the age of menopause.

Women who smoke are more likely to develop chronic obstructive pulmonary disease and lung cancer than men and at lower levels of tobacco

exposure. Postmenopausal women who smoke have lower bone density

than women who never smoked. Smoking during pregnancy increases

the risk of preterm deliveries and low birth weight infants.

■ VIOLENCE AGAINST WOMEN

More than one in four women in the United States have experienced

rape, physical violence, and/or stalking by an intimate partner. Adult

women are much more likely to be raped by a spouse, ex-spouse, or

acquaintance than by a stranger. Intimate partner violence (IPV) is a

leading cause of death among young women. Rates of reported IPV

in the United States increased dramatically amid stay-at-home orders

during the COVID-19 pandemic. IPV is an important risk factor

for depression, substance abuse, and suicide in women. Screening

instruments can accurately identify women experiencing IPV and

should be administered in settings that ensure adequate privacy and

safety.

SUMMARY

Women’s health is now a mature discipline, and the importance of

sex differences in biologic processes is well recognized. Nevertheless,

ongoing misperceptions about disease risk, not only among women but

3069 Men’s Health CHAPTER 399

also among their health care providers, result in inadequate attention to

modifiable risk factors. Research into the fundamental mechanisms of

sex differences will provide important biologic insights. Furthermore,

those insights will have an impact on both women’s and men’s health.

■ FURTHER READING

Bunders MJ, Altfeld M: Implications of sex differences in immunity

for SARS-CoV-2 pathogenesis and design of therapeutic interventions. Immunity 53:3, 2020.

Manson JE et al: Menopausal estrogen-alone therapy and health

outcomes in women with and without bilateral oophorectomy: A

randomized trial. Ann Intern Med 171:6, 2019.

National Institutes of Health: Sex/gender influences

in health and disease. https://orwh.od.nih.gov/sex-gender/

sexgender-influences-health-and-disease.

Vegeto E et al: The role of sex and sex hormones in neurodegenerative

diseases. Endocr Rev 41:273, 2020.

Zhao D et al: Endogenous sex hormones and incident cardiovascular

disease in post-menopausal women. J Am Coll Cardiol 71:22, 2018.

The emergence of men’s health as a distinct discipline within internal

medicine is founded on the wide consensus that men and women differ

across their life span in their susceptibility to disease, in the clinical

manifestations of the disease, and in their response to treatment. Furthermore, men and women weigh the health consequences of illness

differently and have different motivation for seeking care. Men and

women experience different types of disparities in access to health care

services and in the manner in which health care is delivered to them

because of a complex array of socioeconomic and cultural factors. Attitudinal and institutional barriers to accessing care, fear and embarrassment due to the perception that it is not manly to seek medical help,

and reticence on the part of patients and physicians in discussing issues

related to sexuality, drug use, and aging have heightened the need for

programs tailored to address the specific health needs of men.

The sex differences in disease prevalence, susceptibility, and clinical

manifestations of the disease were discussed in Chap. 398 (Women’s

Health) and will not be discussed here. It is notable that the two leading

causes of death in both men and women—heart disease and cancer—are

the same. However, men have higher prevalence of neurodevelopmental

and degenerative disorders, substance use disorders, including the use

of performance-enhancing drugs and alcohol dependence, diabetes,

and cardiovascular disease, and women have a higher prevalence

of autoimmune disorders, depression, rheumatologic disorders, and

osteoporosis. Men are substantially more likely to die from accidents,

suicides, and homicides than women. Among men 15–34 years of age,

unintentional injuries, homicides, and suicides account for over threefourths of all deaths. Among men 35–64 years of age, heart disease,

cancer, and unintentional injuries are the leading causes of death.

Among men ≥65 years of age, heart disease, cancer, lower respiratory

tract infections, and stroke are the major causes of death.

From 1999 to 2010, the mortality rates in the United States

decreased for men and women of all age groups, largely due to reduced

death rates from heart attacks, cancer, motor vehicle injuries, and HIV

infection. However, during the past decade, troubling disparities in

sex-specific mortality rates have emerged among middle-aged men in

the United States. From 2010 to 2017, the death rates have risen and

life expectancy has decreased for young and middle-aged men. The

399 Men’s Health

Shalender Bhasin

increase in mortality rates among people aged 25–64 was the highest

in the Ohio Valley and Appalachia, and in the New England states of

New Hampshire, Maine, and Vermont. The rising mortality rates in

young and middle-aged men have been attributed to an increase in

deaths due to drug overdose, alcohol-related liver disease, and suicide.

The rising rates of “deaths of despair” among young and middle-aged

men, especially white non-Hispanics, have been associated with deterioration in economic and social well-being, reduced rates of marriage

and labor force participation, and poor physical and mental health.

The biologic bases of sex differences in disease susceptibility, progression, and manifestation remain incompletely understood and

are likely multifactorial. Undoubtedly, sex-specific differences in the

genetic architecture and circulating sex hormones influence disease

phenotype; additionally, epigenetic effects of sex hormones during

fetal life, early childhood, and pubertal development may epigenetically imprint sexual and nonsexual behaviors, body composition, and

disease susceptibility. The circulating and tissue concentrations of sex

hormones differ substantially in men and women, and these hormonal

differences may affect gene expression in cells of males and females in

all parts of the body. The presence of only one X chromosome in men

renders them more susceptible to X-linked disorders than women. Due

to the X inactivation of one randomly chosen X chromosome, women’s

bodies contain two epigenetically different cell populations. The genes

that do not undergo X inactivation exhibit dosage differences between

male and female cells. Expression of the Y chromosome genes in men

may affect the function of somatic cells containing the Y chromosome.

The differences in the imprinting of maternally and paternally derived

genes may also contribute to sex differences in the expression of disease. Reproductive load and physiologic changes during pregnancy,

including profound hormonal and metabolic shifts and microchimerism (transfer of cells from the mother to the fetus and from the fetus

to the mother), may affect disease susceptibility and disease severity in

women. Sociocultural norms of child-rearing practices, societal expectations of gender roles, and the long-term economic impact of these

practices and gender roles influence health behaviors and disease risk.

Furthermore, the trajectories of age-related changes in sex hormones

during the reproductive and postreproductive years vary substantially

between men and women and influence the sex-specific patterns of

the temporal evolution of age-related conditions such as osteoporosis,

breast cancer, and autoimmune disease.

In a reflection of the growing attention on issues related to men’s

health, men’s health clinics have mushroomed all over the country.

Although the major threats to men’s health have not changed—heart

disease, cancer, and unintentional injury continue to dominate the list

of major medical causes of morbidity and mortality in men—the men

who attend men’s health clinics do so largely for sexual, reproductive,

and urologic health concerns involving common conditions, such as

androgen deficiency syndromes, age-related decline in testosterone levels, sexual dysfunction, muscle dysmorphia and anabolic-androgenic

steroid (AAS) use, lower urinary tract symptoms (LUTS), and medical

complications of prostate cancer therapy, which are the subjects of

this chapter. Additionally, we are witnessing the emergence of new

categories of body image disorders in men that had not been recognized until the 1980s, such as the body dysmorphia syndrome and

the use of performance-enhancing drugs to increase muscularity and

lean appearance. Although menopause has been the subject of intense

investigation for more than five decades, these issues that are specific to

men’s health are just beginning to gain the attention that they deserve

because of their high prevalence and impact on overall health, wellbeing, and quality of life.

AGING-RELATED CHANGES IN MALE

REPRODUCTIVE FUNCTION

A number of cross-sectional and longitudinal studies (e.g., the

Baltimore Longitudinal Study of Aging, the Framingham Heart Study

[FHS], the Massachusetts Male Aging Study, and the European Male

Aging Study [EMAS]) have established that testosterone concentrations decrease with advancing age. This age-related decline starts in

the third decade of life and progresses slowly (Fig. 399-1); the rate

3070 PART 12 Endocrinology and Metabolism

Among the small number of randomized trials that have evaluated

the efficacy of testosterone treatment in older men, the Testosterone

Trials (TTrials)—a set of seven coordinated placebo-controlled trials of

testosterone replacement conducted in 788 community-dwelling older

men aged 65 years or older, who had an average of two morning,

fasting total testosterone levels, measured using liquid chromatography–

tandem mass spectrometry (LC-MS/MS), <275 ng/dL—have provided the

most comprehensive data on the efficacy of testosterone treatment.

The eligible men in the TTrials were required to have one or more of

the following: low sexual desire, mobility limitation, and/or fatigue,

and they were allocated using minimization to receive either placebo

gel or testosterone gel for 1 year. Testosterone treatment was associated with greater improvement in overall sexual activity, sexual desire,

erectile function, and satisfaction with sexual experience than placebo

(Table 399-2). Testosterone treatment improved volumetric as well as

areal bone density and estimated bone strength more than placebo; the

improvements in volumetric bone density in the spine were greater

than in the hip and greater in the trabecular than the peripheral bone.

Testosterone treatment also corrected anemia in a greater proportion

of older men with unexplained anemia of aging than placebo. No trials

have been large enough or long enough to determine the long-term

benefits of testosterone treatment in older men on clinically important

outcomes such as disability, fractures, progression from prediabetes

to diabetes, remission of dysthymia, and progression to Alzheimer’s

disease (AD) in men at risk of AD.

Testosterone therapy of healthy older men with low or low-normal

testosterone levels is associated with greater increments in lean body

mass, grip strength, and some measures of physical function than

those associated with placebo (Fig. 399-2). In the TTrials, testosterone

therapy of older hypogonadal men with self-reported mobility limitation consistently improved self-reported walking ability and modestly

improved 6-min walking distance across all TTtrials participants

but did not affect falls. Testosterone treatment of hypogonadal men

without a depressive disorder has been associated with a small but significantly greater improvement in depressive symptoms compared to

placebo; however, testosterone treatment alone or as an adjunct to antidepressant pharmacologic therapy has not been found to be efficacious

in major depressive disorder. Two small, randomized trials in men with

late-onset, low-grade persistent depressive disorder (dysthymia) have

reported improvements in depressive symptoms in dysthymic men

with low testosterone levels. In a large randomized trial (T4DM Trial)

in men aged 50–74 years without hypogonadism, who had a waist

circumference of ≥95 cm and impaired glucose tolerance or newly

diagnosed type 2 diabetes, testosterone treatment in conjunction with

20–29

200

Testosterone level (ng/dL)

400

600

800

1000

30–39 40–49

Total testosterone (ng/dL) vs. age (y)

50–59

Age (y)

60–69 70–79 80+

FHS EMAS MrOS

FIGURE 399-1 Age-related decline in total testosterone levels. Total testosterone

levels measured using liquid chromatography–tandem mass spectrometry in men

of the Framingham Heart Study (FHS), the European Male Aging Study (EMAS), and

the Osteoporotic Fractures in Men Study (MrOS). (Reproduced with permission

from S Bhasin et al: Reference ranges for testosterone in men generated using

liquid chromatography tandem mass spectrometry in a community-based sample of

healthy nonobese young men in the Framingham Heart Study and applied to three

geographically distinct cohorts. J Clin Endocrinol Metab 96:2430, 2011.)

TABLE 399-1 Association of Testosterone Levels with Outcomes

in Older Men

1. Positively associated with:

• Muscle mass and muscle strength

• Self-reported and performance-based measures of physical function

• Sexual desire

• Bone mineral density, bone geometry and quality, and volumetric bone

mineral density

2. Negatively associated with risk of:

• Coronary artery disease

• Type 2 diabetes mellitus

• Metabolic syndrome

• All-cause mortality

• Falls and fracture risk

• Dementia and Alzheimer’s disease

• Frailty

• Late-onset low-grade persistent depressive disorder (dysthymia)

3. Not associated with:

• Lower urinary tract symptoms

• Erectile dysfunction

• Major depressive disorder

of decline in testosterone concentrations is greater in obese men, in

men with chronic illness, and in those taking medications than in

healthy older men. Because sex hormone–binding globulin (SHBG)

concentrations are higher in older men than in younger men, free or

bioavailable testosterone concentrations decline with aging to a greater

extent than total testosterone concentrations. The age-related decline

in testosterone is due to defects at all levels of the hypothalamic-pituitary-testicular (HPT) axis: pulsatile gonadotropin-releasing hormone

(GnRH) secretion is attenuated, luteinizing hormone (LH) response to

GnRH is reduced, and testicular response to LH is impaired. However,

the gradual rise of LH with aging suggests that testis dysfunction is the

main cause of declining androgen levels. The magnitude and trajectory

of age-related decline in testosterone levels are affected by adiposity

and weight change, comorbid conditions, and genetic factors. In the

EMAS, 2.1% of community-dwelling men aged 40–70 years had total

testosterone levels <317 ng/dL and a free testosterone level of <64 pg/

mL, as well as sexual symptoms.

In epidemiologic surveys, low total and bioavailable testosterone

concentrations in middle-aged and older men have been associated

with decreased sexual desire, poor erections, and diminished early

morning erections; lower appendicular skeletal muscle mass, muscle

strength, and self-reported physical function; increased risk of mobility limitation and falls; higher visceral fat mass, insulin resistance,

and type 2 diabetes; reduced telomere length and increased all-cause

and cardiovascular mortality; lower areal and volumetric bone mineral density and bone quality; and higher rates of bone fractures

(Table 399-1). Hypogonadal men often report low mood. However,

testosterone levels have not been consistently associated with major

depressive disorder; rather, low testosterone levels are more robustly

associated with late-onset, low-grade, persistent depressive disorder

previously referred to as dysthymia. An analysis of signs and symptoms

in older men in the EMAS revealed a syndromic association of sexual

symptoms with total testosterone levels <320 ng/dL and free testosterone levels <64 pg/mL in community-dwelling older men. Neither

testosterone nor dihydrotesterone levels are associated with the risk of

prostate cancer or LUTS.

Mendelian randomization studies using data from the United Kingdom

Biobank Study found a sexual dimorphic relation between genetically

determined testosterone levels and the risk of type 2 diabetes; in men,

lower genetically determined testosterone levels were associated with

higher risk of type 2 diabetes, but in women, higher genetically determined testosterone levels were associated with higher risk of type 2

diabetes. Higher genetically determined testosterone levels were also

associated with increased risk of prostate cancer in men in this study.