© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 162 (2): ITC2-1. * For Best Viewing:...

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in the clinic

Perimenopause


What is perimenopause?

Transitional time late in a woman’s reproductive life

Time of hormonal flux

Also called “menopause transition”

Duration = 5 years

Symptoms may begin 8 yrs before final menstrual period

Average age at onset: 47.5 yrs


How is it diagnosed?

Early perimenopause: variable cycle length (>7 days different from normal cycle)

Late perimenopause: >2 missed cycles or >60 days amenorrhea

During both phases

Ovarian function progressively decreases

Follicle-stimulating hormone, luteinizing hormone increase

No diagnosis required unless symptoms are present

Irregular menstrual bleeding, hot flashes, night sweats

Mood changes, sleep disturbances, sexual dysfunction

Lab tests not usually needed to make treatment decisions


CLINICAL BOTTOM LINE: Diagnosis... Diagnosis is based on characteristic symptoms

Abnormal uterine bleeding

Hot flashes

Night sweats

Symptoms occur up to 8 years before final menstrual period

Laboratory testing not helpful for establishing diagnosis

Including FSH and estradiol levels


What types of menstrual changes occur during perimenopause?

Abnormal uterine bleeding associated with anovulatory cycles

Light and infrequent bleeding

Unpredictable and heavy menstrual bleeding

Prolonged menses

Spotting


What is the differential diagnosis of AUB in perimenopausal women?

PALM-COEIN Classification for Causes of AUB

Structural

Polyp

Adenomyosis

Leiomyoma

Malignancy and hyperplasia

Nonstructural

Coagulopathy

Ovulatory dysfunction

Endometrial

Iatrogenic

Not yet classified


What type of evaluation should be performed in perimenopausal women experiencing AUB?

History

Bleeding severity, associated pain, family history bleeding

Possible underlying coagulopathy

HMB since menarche

Significant bleeding with dental work, surgery, parturition

Easy bruising, gum bleeding, or epistaxis

Medications

Associated with AUB: anticoagulants; HT; herbal products

Physical exam

Assess for structural lesions involving the vagina or cervix

Assess for palpable abnormalities of the uterus


Suggested Tests for Evaluation of AUB All women should have the following tests:

Pregnancy test (urine or serum)

Complete blood count, Thyroid stimulating hormone

Cervical cancer screening with pap test

Endometrial biopsy if age > 45 years

Selected tests to consider during the initial evaluation: Chlamydia

Prolactin level

Prothrombin time and partial thromboplastin time

Transvaginal ultrasonography

Saline infusion sonohysterography

If symptoms persist or structural abnormalities are present: Saline-infused sonohysterography

Hysteroscopy


What therapies should be offered to perimenopausal women with AUB?

Contraceptive-dose hormones often preferred

Suppress ovulation + control menstrual patterns + protect against pregnancy more than postmenopausal-dose HT

Levonorgestrel intrauterine system

More effective than low-dose combined oral contraceptives for reducing menstrual blood loss

Surgical options (endometrial ablation, hysterectomy)

Option when medical therapy failed or is contraindicated + childbearing is completed

Therapy should be dictated by patient’s goals


What are the prevalence and associated risk factors for VMS?

Prevalence

60%–80% in late perimenopause, early postmenopause

Some women may experience VMS even earlier

Risk factors

Obesity

African American race

Lower education

Anxiety


What effective hormonal and nonhormonal therapies are available to treat moderate to severe VMS?

Mild and infrequent VMS

Use conservative measures

Dress in layers, avoid hot and spicy foods, lower room temp

Moderate to severe VMS in frequency and intensity

Negatively affects sleep, mood, and QOL

Hormonal and nonhormonal therapies can restore thermoregulatory dysfunction

Low-dose combination contraceptive methods relieve hot flashes, control menstrual cycles, prevent pregnancy


Effective Nonhormonal Therapies for VMS

SSRIs

Reduce hot flashes by about 1/d

Escitalopram may be more efficacious than other SSRIs

Avoid tamoxifen + paroxetine in breast cancer survivors

AEs: Nausea, fatigue, palpitations, dry mouth, rash, sleep disturbance, sweating, dizziness, headache, low libido

Venlafaxine (SNRI)

Reduces hot flashes by about 1/d

AEs: Possible small increases in systolic and diastolic BP

Gabapentin

Less reduction in hot flashes than with SSRIs, venlafaxine

Optimal dosing unclear; likely between 900–2400 mg/d

AEs: Dizziness, unsteadiness, fatigue, and somnolence


Which complementary and alternative therapies are effective for treating VMS? Ineffective

Yoga, paced respiration

Cognitive behavioral therapy

Ginseng root, Dong quai

Phytoestrogens

Data insufficient

Black cohosh

Vitamin E

Acupuncture

Exercise

Possibly beneficial

Red clover for hot flashes


What are the prevalence and risk factors for sleep and mood disorders?

Sleep problems

Affect at least one-third

Sleep difficulties highest risk in late perimenopause

Risk factors: lower inhibin B levels, stress, depression, nocturia, hx sleep disorders, number of physical conditions, use of prescription sleep medications

Depression

Risk is higher during perimenopause

Risk factors: history of depression, higher BMI, use of psychotropic medications, major life stressors


What treatments are available for management of sleep disorders?

Nonpharmacologic therapies

Consistent recreational physical activity

Pharmacologic therapies

Antidepressants and hypnotics

May reduce insomnia for those with both sleep disturbances and VMS


What are the concerns regarding sexual dysfunction?

Sexual interest/arousal disorder

β-blockers, SSRIs, SNRIs, HT: may contribute to sexual dysfunction

Oral combination hormonal contraceptives decrease free testosterone but have unclear effect on libido

Nonoral contraceptives may be associated with better sexual function

Painful sexual intercourse

Due to vaginal atrophy or inadequate lubrication

Exam showing pale vaginal mucosa, petechiae, and loss of ruggae helps confirm Dx and direct appropriate treatment


How is sexual dysfunction managed?

Direct treatment to the underlying diagnosis

For low desire

Flibanserin

Transdermal testosterone therapy (off-label; use adequate contraception)

For discomfort due to vaginal atrophy or inadequate lubrication

Vaginal moisturizers and lubricants

Vaginal estrogen treatment usually reserved for postmenopausal women


CLINICAL BOTTOM LINE: Evaluation and Treatment...

AUB caused by structural and nonstructural abnormalities PALM-COEIN classification system guides evaluation

Endometrial biopsy to r/o hyperplasia or cancer For all women older than 45 years with AUB

Multiple medical therapies can improve bleeding patterns Once AUB classified as anovulatory Hormonal contraceptives reduce AUB, control VMS,

prevent pregnancy


What types of hormonal contraceptive options are available for perimenopausal women?

CHCs

Contain both estrogen and progestin

Available in pill, patch, and ring formulations

Oral CHCs with low doses of ethinyl estradiol often sufficient to control hormonal fluctuations

Progestins only

Later generations created to decrease androgenic activity

Can be safely used in many of women with contraindications to CHCs


Contraindications to CHC Migraine headache with aura at any age

Cigarette smokers > 35 y

History of VTE/pulmonary embolism, stroke, MI

Uncontrolled hypertension: >160mmHg systolic or >100mgHg diastolic

Systemic lupus erythematosus with positive antiphospholipids

Postpartum <21 d

History of bariatric surgery (malabsorptive type)

Diabetes (retinopathy, nephropathy, or neuropathy or >20 y duration)

Current breast cancer

Hepatocellular adenoma, malignant hepatoma, severe decompensated cirrhosis, acute or flare of viral hepatitis

Undiagnosed abnormal uterine bleeding

Complicated valvular heart disease, known thrombotic mutations

Organ transplantation only if complicated


What are the cardiovascular risks of CHCs in perimenopausal women?

Perimenopausal women have a higher baseline risk for MI and stroke than younger women

Consider risks for these events in association with CHC use

Absolute rates of stroke and MI with oral CHCs are low

Nonoral CHCs (vaginal ring, patch) may carry increased stroke risk compared with oral CHCs


What are the risks for VTE associated with CHC use among perimenopausal women?

VTE events in perimenopausal women are more common

Baseline risk for VTE increases with age

Type of progestin may affect this risk

If concern for VTE risk is high (family history, obesity), then first- or second-generation progestins may be preferred

Third-generation progestin norgestimate not associated with increased risk for VTE —may be a good option for women with refractory hirsutism

Unclear whether nonoral CHCs have an increased risk for VTE as compared with oral CHCs

Fourth generation progestin drospirenone has not been clearly associated with increased risk for VTE —may improve premenstrual dysphoric disorder.


What are special considerations in perimenopausal women at risk for bone loss?

Increased risk for osteopenia and osteoporosis

Due to increasing age and declining estrogen levels

DMPA use increases bone loss

Provides contraception and regulates menstrual cycles

But suppresses endogenous estrogen levels

Bone loss may not be completely reversible

Consider use of CHCs or the levonorgestrel IUS instead


What other medical conditions affect decisions when prescribing CHCs?

Obesity, hypertension, diabetes, hyperlipidemia

CV and VTE risk increased when combined with CHCs

DMPA not favored due to metabolic effects

If CVD risk factors: progestin-only method often prescribed

Cancer

Even in those at highest risk for breast cancer, risk-benefit ratio seems to favor benefit of CHC use, when appropriate

Menstrual migraines

CDC: don’t use estrogen-containing products in women >35 years who have migraine (and at any age if aura present)

Progestin-only methods may relieve symptoms


When and how should women transition from CHCs to HT?

Women can continue on CHCs until age 55

With yearly evaluation of safety and symptoms

FSH levels help guide decisions to transition off CHCs

No hormonal contraception for 14 days before FSH test

Suggested transitions off hormonal contraception

Depo-Provera: Continue until age 50-51, if signs of hypoestrogen, offer estrogen therapy until age 55; in women >50, 2 consecutive FSH levels >35 IU/L drawn at injection visit at least 90 days apart suggest menopause

Mirena IUD: 12 months amenorrhea + 2 FSH levels > 35 IU/L

Copper IUD: 12 months amenorrhea + 2 FSH levels >35 IU/L


CHCs and HT differ in formulation and potency

Oral and nonoral CHCs: ethinyl estradiol typically used

Systemic HT: 17 β-estradiol or conjugated equine estrogen most commonly used

Standard-dose oral CHCs: 20-35 mcg ethinyl estradiol (ultra-low-dose: 10 mcg)

Standard oral HT: ≤5 mcg ethinyl estradiol, 17 β-estradiol ≤1 mg, or 0.625 mg conjugated equine estrogen

No indication to start HT after discontinuation of CHCs unless bothersome symptoms occur / persist


CLINICAL BOTTOM LINE: Treatment...

Hormonal contraception preferred for managing AUB & VMS Symptom relief Improved cycle control Protection against unintended pregnancy

Both CHC and progestin-only hormonal contraceptives can be used safely in most women

HT is used once menopause occurs

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