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Chapter 3: Clinical Issues

DECLINE IN FERTILITY

Key Points

  1. Fertility declines with increasing age, notably after age 35 years, or approximately 15 years before menopause. Age-related declines in fertility have been confirmed in epidemiologic studies as well as by the observation of declining pregnancy rates with advancing age in cycles of donor insemination and in vitro fertilization (IVF).
  2. Advanced maternal age (≥35 years) is associated with increased risks for spontaneous miscarriage (50% by age 45 years), chromosomal abnormalities in the fetus, and other pregnancy complications including premature labor, fetal mortality, and the need for cesarean delivery.
  3. Diminished ovarian reserve is associated with decreased oocyte quality, oocyte quantity, and ability to conceive. There is no single ideal test for assessing ovarian reserve. Options include measurement of FSH and estradiol levels on cycle day 3, clomiphene citrate challenge testing, ovarian antral follicle count by transvaginal ultrasound, and AMH levels.
  4. Age-related anatomic changes such as fibroids, tubal disease, or endometriosis may contribute to decreased fertility with advancing age.
  5. For women with infertility due to advanced reproductive age, controlled ovarian hyperstimulation with intrauterine insemination and IVF may increase the likelihood of pregnancy. For women with significantly decreased ovarian reserve, IVF with oocyte donation and adoption are options for family building. Gestational carriers may be advised for women at high risk for adverse outcomes during pregnancy.
  6. The success of the infertility treatment depends on the woman’s age, ovarian reserve, general health, indications for treatment, and the treatment modality used, with success rates decreasing with increasing age.

Recommendations for Clinical Care

  1. Women should be counseled about the increased risk of infertility and adverse pregnancy outcomes with advancing age. (Level II)
  2. Fertility treatment with a woman’s own oocytes is not advised after age 43 years because of the extremely low likelihood of a successful pregnancy. Any fertility treatment, including donor-oocyte IVF, is not recommended after age 50 years because of increased risks associated with pregnancy. (Level II)
  3. The success of oocyte-donation IVF in women in their 50s and even early 60s confirms that pregnancy is possible in women with a normal uterus, regardless of age or the absence of oocytes. (Level II)
  4. In older women undergoing oocyte-donation IVF, single-embryo transfer should be strongly considered because of the risks associated with multiple births. (Level II)
  5. Women of advancing age considering donor-oocyte IVF should be counseled about parenting issues and health concerns specific to their age and the age and health of their partner. (Level II)

UTERINE BLEEDING

Key Points

  1. Approximately 90% of women experience 4 to 8 years of menstrual cycle changes before natural menopause, which may include heavier flow of longer duration resulting in anemia, avoidance of activities (including sex), and diminished quality of life.
  2. Early perimenopause is characterized by disturbances in the timing and regulation of ovulation, whereas late perimenopause is characterized by decreased ovulation. Prolonged anovulation may lead to unopposed estrogen exposure, increasing the risk of endometrial hyperplasia or cancer.
  3. Approximately 80% of women treated for heavy menstrual bleeding have no anatomic pathology. In addition to perimenopausal anovulation, irregular bleeding can be caused by anovulation associated with thyroid abnormalities, hyperprolactinemia, or polycystic ovarian syndrome. Anatomic causes of abnormal uterine bleeding (AUB) include polyps, fibroids, endometritis, endometrial hyperplasia, and cancer.
  4. Evaluation of AUB may include the following laboratory tests, based on the clinical situation: complete blood count, pregnancy test, coagulation profile, sexually transmitted infection panel, liver function tests, and levels of thyroid-stimulating hormone, prolactin, follicle-stimulating hormone, estradiol, progesterone, testosterone, and dehydroepiandrosterone sulfate. Procedures may include cervical cytology, transvaginal ultrasonography, saline infusion sonohysterography, office hysteroscopy, office endometrial sampling, and dilation and curettage.
  5. Medical management is the least invasive and least expensive means of controlling heavy and/or irregular uterine bleeding, although adverse effects and poor compliance may limit success. Nonhormonal agents used to manage AUB include nonsteroidal anti-inflammatory agents, tranexamic acid, and desmopressin for women with an underlying bleeding disorder.
  6. Hormonal options for managing AUB include low-dose oral contraceptives, cyclic oral progestogens, depot medroxyprogesterone acetate injections, the levonorgestrel-releasing intrauterine system, and gonadotropin-releasing hormone (GnRH) agonists. The use of GnRH agonists is limited by their expense and resulting hot flashes and bone loss. Estrogen-containing contraceptives should not be used in women aged older than 35 years who smoke or in perimenopausal women at increased risk for cardiovascular disease. Management of AUB represents off-label use for most hormonal therapies.
  7. Surgical options for managing AUB include endometrial ablation techniques, polypectomy, myomectomy, and hysterectomy. Although endometrial ablation represents a relatively effective and safe intervention, women must be informed that these procedures may impede the diagnosis of endometrial cancer later in life because of reduced bleeding, an early sign of cancer, and difficulty sampling the endometrium. Minimally invasive surgical approaches, including hysteroscopy and laparoscopy, are often an option.

Recommendations for Clinical Care

  1. Pregnancy must be excluded in any sexually active woman of reproductive age who presents with AUB. (Level I)
  2. Perimenopausal women with AUB and postmenopausal women with any bleeding require a comprehensive evaluation. (Level I)
  3. Once pathology has been excluded, management of AUB may be medical (hormonal and/or nonhormonal) or surgical. Management should be individualized based on personal preferences, the need for contraception, menopause status, underlying medical problems, and the degree of bleeding and its impact on a woman’s health and quality of life. (Level II)

VASOMOTOR SYMPTOMS

Key Points

  1. Hot flashes occur in up to 75% of women, and although most women experience them for 6 months to 2 years, some women may experience bothersome hot flashes for 10 years or longer.
  2. Lifestyle changes, including keeping core body temperature low, maintaining a healthy body weight, refraining from smoking, exercising regularly, and practicing relaxation techniques, may provide some relief.
  3. Nonprescription remedies such as soy, isoflavone supplements, black cohosh, vitamin E, and omega-3 fatty acids are generally low risk but with efficacy generally similar to placebo.
  4. Menopausal hormone therapy is the most effective treatment for vasomotor symptoms. Options include systemic estrogen or estrogen-progestogen (in women with a uterus), progestogen alone, or combined oral contraceptives in women requiring contraception.
  5. The selective estrogen receptor modulator bazedoxifene combined with conjugated estrogen is FDA approved for the treatment of hot flashes.
  6. Custom-compounded bioidentical hormones are not recommended because of lack of regulation, rigorous safety and efficacy testing, batch standardization, and purity measures.
  7. Selective serotonin-reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors that have been shown to be more effective than placebo for hot flashes include paroxetine, escitalopram, venlafaxine, and desvenlafaxine; paroxetine 7.5 mg is the only SSRI approved by FDA for this indication.
  8. Gabapentin and clonidine also have been shown to have some efficacy in the treatment of hot flashes but have not been approved by FDA for this indication.

Recommendations for Clinical Care

  1. Treatment for hot flashes should be considered if symptoms are bothersome, disrupt sleep, or adversely affect quality of life. Therapy should be tailored to the individual woman’s medical history, treatment goals, and personal attitudes toward menopause and medication use. (Level I)
  2. The decision to initiate therapy for hot flashes, the type of therapy elected, and the duration of treatment should be individualized for each woman, with consideration given to comorbid conditions, the severity of symptoms, and the potential risks of treatment. (Level II)
  3. The need for treatment should be periodically evaluated as most women will experience improvement in vasomotor symptoms over time. The need for extended treatment of persistent, bothersome hot flashes requires an individualized assessment of risks and benefits. (Level II)

GENITOURINARY SYNDROME OF MENOPAUSE/SYMPTOMATIC VULVOVAGINAL ATROPHY

Key Points

  1. Genitourinary syndrome of menopause (GSM) is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired sexual function; and urinary symptoms of urgency, dysuria, and recurrent urinary tract infections (UTIs).
  2. Symptoms of GSM/VVA can have a negative effect on quality of life that may extend to activities of daily living, exercise, sexual function, and interpersonal relationships.
  3. Treatment for GSM/VVA includes nonhormonal vaginal lubricants and moisturizers, low-dose vaginal estrogen therapy (ET), systemic ET (when being prescribed for treatment of bothersome vasomotor symptoms), and ospemifene (an oral estrogen agonist/antagonist).
  4. Low-dose vaginal ET results in minimal systemic absorption.
  5. Vaginal ET, but not systemic ET, reduces the risk of recurrent UTIs.

Recommendations for Clinical Care

  1. Healthcare providers should ask all perimenopausal and postmenopausal women about vulvovaginal and urinary symptoms at every comprehensive visit. (Level II)
  2. Women with GSM/VVA should consider nonhormonal vaginal lubricants and moisturizers as initial therapy. (Level II)
  3. Low-dose vaginal ET (available as a cream, tablet, or ring) is a highly effective treatment for persistent symptoms of GSM/VVA. (Level I)
  4. The estrogen agonist/antagonist ospemifene is an oral agent for the treatment of moderate to severe dyspareunia due to GSM/VVA. (Level I)
  5. Progestogen therapy for endometrial protection is not recommended with the use of low-dose vaginal ET, although studies of endometrial safety with vaginal ET do not extend beyond 1 year. (Level I)
  6. In postmenopausal women with recurrent UTIs, consider treatment with low-dose vaginal ET or prophylactic antibiotics. (Level I)
  7. Any bleeding in a postmenopausal woman, including postcoital bleeding, requires a thorough evaluation. (Level I)
  8. All women with GSM/VVA should be counseled about available management strategies and provided with information about the efficacy, risks, and benefits of nonhormonal and hormonal interventions. (Level II)

URINARY INCONTINENCE

Key Points

  1. Approximately 50% of midlife women report urinary incontinence, but embarrassment and lack of awareness about effective treatment options prevent many women from seeking treatment.
  2. Although the prevalence of urinary incontinence increases with age, there is no strong association between urinary incontinence and menopause.
  3. Stress incontinence (leakage with increases in intra-abdominal pressure) is related to poor urethral support, urethral sphincter weakness, and/or dysfunction of the pelvic floor muscles, whereas urgency incontinence (leakage with a sense of urinary urgency) is caused by uninhibited contractions of the detrusor muscle.
  4. Evaluation of urinary incontinence should focus on defining the type(s) of incontinence a woman experiences so that type-specific treatments can be offered.

Recommendations for Clinical Care

  1. Healthcare providers should ask their midlife patients about bothersome urinary incontinence symptoms at every comprehensive visit. (Level II)
  2. Most stress incontinence can be successfully treated with behavioral therapies (eg, weight loss), pelvic floor muscle therapy (Kegel exercises, physical therapy), and pessaries. (Level II)
  3. Surgery for stress incontinence (most commonly midurethral slings) has a success rate of approximately 85%, although long-term (>5 years) effectiveness is not well established. (Level I)
  4. Most urgency incontinence can be successfully managed with behavioral therapies (eg, caffeine and fluid restriction), bladder retraining, and anticholinergic medications. (Level I)
  5. Vaginal estrogen therapy may improve symptoms of irritative voiding and urinary urgency. (Level II)
  6. Botox injections and sacral neuromodulation treatments are generally reserved for urgency incontinence symptoms associated with detrusor overactivity after more conservative treatment options have failed. (Level I)

SEXUAL FUNCTION

Key Points

  1. Sexual problems are highly prevalent in midlife women and often associated with distress.
  2. Hormonal changes at menopause as well as other physiological, psychological, sociocultural, interpersonal, and lifestyle factors contribute to midlife sexual problems.
  3. Dyspareunia due to vaginal atrophy is an important and treatable cause of sexual problems after menopause.
  4. Although testosterone levels decline with age, an association between low testosterone levels and impaired female sexual function has not been demonstrated.

Recommendations for Clinical Care

  1. Healthcare providers should ask their midlife patients about sexual concerns at every comprehensive visit. (Level II)
  2. Counseling and sex therapy, with a focus on modifying sexual technique, increasing sexual novelty, and enhancing the partner relationship and communication, are effective interventions for many individuals and couples with sexual problems. (Level II)
  3. Symptomatic vulvovaginal atrophy (VVA) may be treated with vaginal moisturizers, lubricants, low-dose vaginal estrogen therapy, and ospemifene. Choice of therapy depends on the severity of symptoms and the patient’s medical history and personal preferences. Dyspareunia independent of VVA may improve with pelvic floor physical therapy. (Level II)
  4. Treatment of underlying depression and anxiety and adjustment of antidepressant medication may be helpful for problems of sexual interest and arousal. Bupropion and PDE-5 inhibitors may have a role in the treatment of SSRI-induced sexual dysfunction. (Level II)
  5. There is some evidence to support the use of testosterone therapy in carefully selected postmenopausal women with female sexual interest/arousal disorder (previously known as hypoactive sexual desire disorder) and no other etiology for their sexual problem, although a formulation designed for women and long-term safety data are lacking. (Level I)

SLEEP DISTURBANCE

Key Points

  1. Chronic sleep disturbance can have important consequences for daytime functioning, overall well-being, health, and public safety.
  2. Women undergoing the menopause transition are more likely to report reduced sleep quality, and those with hot flashes are more likely to report disturbed sleep and meet criteria for chronic insomnia
  3. Primary sleep disorders of insomnia, sleep apnea, and restless legs syndrome are common in midlife women.
  4. Sleep disturbance is a common symptom of clinical depression, which occurs more frequently during the menopause transition.
  5. Women with vasomotor symptoms report improved sleep quality when they receive hormonal and nonhormonal medication treatments for hot flashes.
  6. Cognitive-behavior therapy (CBT) is a safe and effective treatment for insomnia.

Recommendations for Clinical Care

  1. Women reporting disturbed sleep during midlife should be evaluated, and the specific causative condition should be identified and treated. (Level II)
  2. Women with bothersome nighttime hot flashes may experience improved sleep quality when their hot flashes are treated with hormonal or nonhormonal medications. (Level I)
  3. Pharmacologic sleep aides are effective treatments for insomnia and sleep disturbance, but their use should be time limited. Behavioral strategies, including sleep hygiene and CBT, also are effective. (Level I)
  4. Women whose sleep disturbance may be attributable to clinical depression, sleep apnea, or restless legs syndrome/periodic limb movement disorder should be referred for diagnosis and treatment. (Level II)

HEADACHE

Key Points

  1. The World Health Organization ranks headache disorders in the top five most disabling conditions for women.
  2. Although most primary headaches are tension type, the majority of women who present to an outpatient clinic with a chief complaint of headache meet the criteria for migraines, and half do not receive appropriate treatment.
  3. Certain headache characteristics should trigger heightened concern and consideration of further investigation. These include “worst ever,” new onset at age older than 50 years, sudden onset during activity, increased frequency or severity, and associated nocturnal awakening. A headache accompanied by stiff neck, high fever, confusion, dizziness, weakness, or focal neurologic signs generally requires further evaluation, as does a headache in the setting of malignancy, immunosuppression, or systemic infection.
  4. Migraines without aura are much more common than migraines with aura. Women with migraine without aura often experience improvement in headache frequency and severity with menopause. Improvement with menopause is less likely in those whose headaches are associated with aura.
  5. Migraine with aura is associated with a significant increased risk of stroke, especially in women who smoke or use oral contraceptives. 

Recommendations for Clinical Care

  1. Nonsteroidal anti-inflammatory drugs are generally the most effective therapy for tension-type headaches, whereas tricyclic antidepressants are most effective for prophylaxis. (Level II)
  2. Migraines should be considered more frequently in the differential of headache when accompanied by nausea, vomiting, photophobia, or phonophobia. (Level I)
  3. Women with migraines should keep a diary of their potential triggers to identify possible avoidance strategies for prevention. (Level I)
  4. Combination oral contraceptives should be avoided in women with migraines with significant comorbidities for stroke, including those with aura at any age, those without aura who are older than 35 years, and those who smoke. (Level I)
  5. Postmenopausal women with migraines and bothersome vasomotor symptoms may use hormone therapy (HT) at doses typically prescribed for midlife women. Hormone therapy may improve or worsen headaches. Continuous rather than cyclic HT is advised because changes in hormone levels may trigger a headache. (Level II)
  6. Women with migraines with aura should be advised to stop smoking. (Level I)

COGNITION

Key Points

  1. Symptoms of poor concentration, poor memory, and trouble multitasking are common during the menopause transition and early postmenopause.
  2. Memory performance and processing speed decline slightly during the menopausal transition but appear to return to premenopausal levels after menopause. Menopausal symptoms may be associated with cognitive complaints
  3. Cognitive symptoms can be influenced by sleep disturbances, depressed mood, hot flashes, fatigue, physical symptoms, medication use, and a variety of midlife stressors.
  4. Hormone therapy (HT) does not substantially affect memory, attention, or higher order cognitive skills.
  5. Early removal of the ovaries is associated with an increased risk of dementia that may be offset by use of estrogen therapy (ET) until the typical age at menopause.
  6. Combined HT begun after age 65 years increases the risk of dementia

Recommendations for Clinical Care

  1. For midlife patients with cognitive symptoms, healthcare providers should explain that such symptoms are common and appear to improve after the menopausal transition. They should review medication use and evaluate and treat, as appropriate, sleep disturbances, depressed mood, hot flashes, fatigue, physical symptoms, and situational stressors. (Level II)
  2. Healthcare providers should consider additional evaluation for midlife patients with cognitive impairment, cognitive symptoms accompanied by functional impairment, or a family history of dementia beginning before age 60 years. (Level II)
  3. Women who undergo oophorectomy before age 48 years may be advised that taking ET until the typical age at menopause appears to lower the risk of dementia later in life. (Level II)
  4. In perimenopausal and postmenopausal women, HT should not be used to improve cognitive skills. (Level III)
  5. In older postmenopausal women, HT should not be used to prevent dementia or treat Alzheimer disease. (Level I)
  6. Interventions that reduce cardiovascular risk, including smoking cessation, weight management, regular aerobic exercise, and control of diabetes, hypertension, and hyperlipidemia, also may reduce the risk of cognitive decline. (Level II)

PSYCHOLOGICAL SYMPTOMS

Key Points

  1. Most women do not become clinically depressed during the menopause transition; however, psychological symptoms, including depressed mood, anxiety, and decreased sense of well-being are common.
  2. Women with a history of a mood or anxiety disorder and early childhood stressful life events are at higher risk of increased psychological symptoms during the menopause transition. A history of premenstrual syndrome or postpartum depression is a strong risk factor for mood symptoms at midlife. 
  3. Life stressors are common at midlife and often coincide with the menopause transition.

 Recommendations for Clinical Care

  1. Healthcare providers should screen for psychological symptoms at midlife and treat psychological problems when indicated or provide appropriate referrals. (Level II)
  2. Mild depressive symptoms respond well to psychotherapy. Moderate or severe depressive symptoms generally require pharmacologic treatment in addition to psychotherapy. (Level I)
  3. Nonpharmacologic methods, including counseling and stress-reduction techniques, should be considered to reduce the adverse effects of stressors that commonly occur at midlife. (Level II)
  4. Education is key in helping women understand and cope with mood symptoms related to the menopause transition. (Level II)

SEXUALLY TRANSMITTED INFECTIONS

Key Points

  1. Although most sexually transmitted infections (STIs) occur in younger women, perimenopausal and postmenopausal women remain susceptible to infections, especially given that sexual activity may cause microabrasions in delicate, atrophic genital tissues, increasing exposure to pathogens.
  2. Human papillomavirus (HPV) is the most common STI in the United States.
  3. Risk factors for midlife women for hepatitis B, hepatitis C, and HIV include sexual activity outside of a long-term mutually monogamous relationship, seeking evaluation and/or treatment for STIs, and injection-drug use, among others.
  4. Baby boomers (those born between 1945 and 1965) are at the highest risk of hepatitis C infection, with infection rates five times that of other birth cohorts.
  5. Gonorrhea and chlamydia are best detected by nucleic acid amplification tests. Detection rates are equivalent using a vaginal swab or endocervical sample. Urine tests are acceptable but may miss up to 10% of infections.
  6. Women with HIV have unique gynecologic problems that can include an earlier and more symptomatic perimenopausal transition.

Recommendations for Clinical Care

  1. Midlife women at high risk for STIs, including those with a new sexual partner or multiple sexual partners or whose partner has multiple sexual partners, should be screened for STIs. (Level I)
  2. Clinicians should utilize the evidence-based guidelines from the Centers for Disease Control and Prevention regarding the management of STIs. (Level I)
  3. All adults should be screened at least once in their lifetime for HIV. (Level I)
  4. Pap screening every 3 years or Pap and HPV co-testing every 5 years is recommended for women aged 30 to 65 years. Women aged older than 65 years may discontinue screening if they 1) have no history of a high-grade dysplasia in the past 20 years, 2) are not immunosuppressed, 3) were not diethylstilbestrol exposed, and 4) have had at least three normal Pap tests (or two Pap/HPV co-tests) since age 55 years. (Level I)
  5. Older women with and without risk factors for hepatitis B who have never received the hepatitis B vaccination should be counseled regarding the benefits of vaccination. (Level I)
  6. All women with diabetes and chronic liver disease should be vaccinated against hepatitis B. (Level I)

 

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