Management of Menopause

By Dr. Amir M HanafiUnder supervision of Dr. Abeer

Case scenario

• A 51-year-old woman has a complaint that her menses are becoming less frequent than they used to be, every 45 days compared to every 32 days before, she also complains of frequent and distressing hot flashes that interfere with her work and sleep, and vaginal dryness that makes sexual intercourse with her husband uncomfortable. She is otherwise healthy.

• How do you diagnose menopause?• What’s the differential diagnosis?• What are the most common problems?• What’s the proposed management of those

problems?

Introduction

• Natural menopause is the permanent cessation of menses, after a woman has 12 months of amenorrhea without any other cause.

• It occurs at a median age of 51.4 years in normal women, and is a reflection of ovarian follicular depletion, with hypoestrogenemia and high FSH.

Introduction

• Menopause before age 40 years is considered to be abnormal and is referred to as primary ovarian insufficiency (premature ovarian failure).

• The menopausal transition, or perimenopause, occurs after the reproductive years, but before menopause, and is characterized by irregular menstrual cycles, endocrine changes, and symptoms such as hot flashes.

Diagnosis – S/O

• Hot flashes — The most common symptom during the menopausal transition and menopause– occur in up to 80 percent of women in some cultures.– only about 20 to 30 percent of women seek medical

attention for treatment.– Some women first develop hot flashes that cluster

around menses during their late reproductive years, but symptoms are typically mild and do not require treatment.

• Sleep disturbance — women experience sleep disturbances even in the absence of hot flashes.

• The estimated prevalence of difficulty sleeping based upon two longitudinal cohort studies was 32 to 46%.

• Anxiety and depression symptoms may also contribute to sleep disturbances; in one study, they were predictive of subjective sleep disturbances.

• In addition, perimenopausal women with hot flashes are more likely to be depressed. Primary sleep disorders are also common in this population.

• Depression — A number of reports indicate that there is a significant increased risk of new onset depression in women during the menopausal transition compared with their premenopausal years. The risk then decreases in the early postmenopause.

• In a study to determine risk factors for depressive disorders, a diagnosis of depression was 2.5 times more likely to occur in the menopausal transition compared with when the woman was premenopausal (odds ratio [OR] 2.50; 95% CI 1.25-5.02).

• Vaginal dryness — The epithelial lining of the vagina and urethra are estrogen-dependent tissues, and estrogen deficiency leads to thinning of the vaginal epithelium. This results in vaginal atrophy (atrophic vaginitis), causing symptoms of vaginal dryness, itching, and often dyspareunia.

• The prevalence of vaginal dryness in one longitudinal study was 3, 4, 21, and 47 percent of women in the reproductive, early menopausal transition, late menopausal transition, and three years postmenopausal stages, respectively.

• Early in the menopause transition, women may notice a slight decrease in vaginal lubrication upon sexual arousal, which is often one of the first signs of estrogen insufficiency.

• Sexual function — The cervix also can atrophy and become flush the vaginal vault. The elasticity of the vaginal wall may decrease and the entire vagina can become shorter or narrower.

• Continuing sexual activity may prevent these changes in size and shape of the vagina, even in the absence of estrogen therapy .

• Symptoms related to genitourinary atrophy are exquisitely responsive to estrogen therapy, in particular, vaginal estrogen therapy.

• Cognitive changes — Women often describe problems with memory loss and difficulty concentrating during the menopausal transition and menopause, and substantial biologic evidence supports the importance of estrogen to cognitive function.

• A decline in cognitive function was not observed in the SWAN study, but increases in anxiety and depression had independent, unfavorable effects on cognitive performance .

• Joint pain — While women who are obese or depressed are more likely to experience joint pain, there also appears to be an association with menopausal status, with peri- and postmenopausal women experiencing more joint pain than premenopausal women.

• It is unclear if the pain is related to estrogen deficiency or a rheumatologic disorder, but in the Women's Health Initiative, women with joint pain or stiffness at baseline were more likely to get relief with either combined estrogen-progestin therapy or unopposed estrogen than with placebo.

• Other– Breast pain – Breast pain and tenderness are common

in the early menopausal transition, but begin to diminish in the late menopausal transition. This is probably due to the fluctuations in serum estradiol concentrations.

– Menstrual migraines – Menstrual migraines are migraine headaches that cluster around the onset of each menstrual period. In many women, these headaches worsen in frequency and intensity during the menopausal transition.

Diagnosis summary

• In normal, healthy women over age 45 years:– We make the diagnosis of the menopausal

transition or “perimenopause” based upon a change in intermenstrual interval with or without menopausal symptoms.

– A high serum follicle-stimulating hormone (FSH) concentration is not required to make the diagnosis.

– We diagnose menopause as 12 months of amenorrhea in the absence of other biological or physiological causes.

• In women between the ages of 40 and 45 years:– same as that for women over 45 years, except that

other causes of menstrual cycle dysfunction must first be ruled out (eg, endocrine evaluation for non-menopausal causes of oligo/amenorrheamust be normal including serum human chorionic gonadotropin [hCG], prolactin, and thyroid stimulating hormone [TSH]).

• For women under age 40 years:– Women in this age group should not be diagnosed

with either the menopausal transition or menopause. They have primary ovarian insufficiency (premature ovarian failure).

• Special situations– Women with underlying menstrual cycle

disorders — the STRAW staging system does not apply to women with underlying menstrual disorders such as polycystic ovary syndrome (PCOS) or hypothalamic amenorrhea. we suggest measuring FSH concentration for diagnostic purposes.

• Women taking oral contraceptives — We suggest stopping the pill and measuring serum FSH two to four weeks later. A level ≥25 IU/L indicates that the patient has likely entered the menopausal transition. However, there is no FSH value that would provide absolute reassurance that she is postmenopausal.

• Post-hysterectomy or endometrial ablation —In this setting, we suggest measurement of FSH concentration. A serum FSH >25 IU/L, particularly in the setting of hot flashes, is suggestive of the late menopausal transition. For a postmenopausal woman, FSH would be considerably higher (in the 70 to 100 IU/L range).

DIFFERENTIAL DIAGNOSIS

• Hyper/hypothyroidism• Pregnancy• hyperprolactinemia, • Medications• Carcinoid• Pheochromocytoma• underlying malignancy.

Treatment – Risk factors for VMS•Obesity•Smoking•Reduced physical activity•Socioeconomic factors•Hormonal concentrations – Annual serum follicle-stimulating hormone (FSH) levels is associated with both the prevalence and frequency of VMS.•Ethnic factors – African-American women report more frequent hot flashes than Caucasian women, and Japanese and Chinese women less so.

TREATMENT – NON HORMONAL

• simple behavioral measures, such as:• lowering room temperature• using fans• dressing in layers of clothing that can be easily shed• avoiding triggers (such as spicy foods and stressful

situations)• Some clinicians recommend vitamin E to women

with mild hot flashes because, at low doses, it is well tolerated and not associated with toxicity.

TREATMENT- INCONSISTENT EVIDENCE

• Isoflavones present in soy containing foods.• Black cohosh األسود الثعبان جذور• Acupuncture • Paced respiration • Mind-body based therapies • Weight loss • Exercise

TREATMENT - INEFFECTIVE

• Evening primrose oil (EPO) • Flaxseed الكتان بذور• Other: ginseng or dong quai, Wild yam and

progesterone creams ,Traditional medicinal Chinese herbs, reflexology, and magnetic devices have all been studied and appear to have no beneficial effect.

TREATMENT - HORMONAL

• The goal of MHT is to relieve menopausal symptoms, most importantly hot flashes (vasomotor symptoms).

• In the past, hormone therapy (HT) was also used long-term for prevention of chronic disease (coronary heart disease [CHD] and osteoporosis). However, we do not recommend HT for prevention of disease, given the results of the Women’s Health Initiative (WHI), a set of two large randomized trials that demonstrated an unfavorable risk-benefit profile of HT.

TREATMENT - HORMONAL

• Candidates/indications for most women in their late 40s or 50s with moderate to severe vasomotor symptoms with the exception of those with a history of:– breast cancer– CHD– a previous venous thromboembolic event or stroke– active liver disease– those at high risk for these complications.

TREATMENT - HORMONAL

• Inconsistent benefit:– Vaginal atrophy– Depression– Joint aches and pains– Cognitive function and dementia – Prevention dementia. – Prevention of CHD. – Osteoporosis: we now recommend

bisphosphonates.

TREATMENT - HORMONAL

• Estrogen therapy remains the gold standard for relief of menopausal symptoms, in particular, hot flashes.

• All routes of administration appear to be equally effective for symptom relief (and bone density), but their metabolic effects differ.

• Oral estrogen has more favorable effects on lipid profiles, but there is no evidence that this results in long-term clinical benefit.

• On the other hand, oral estrogens are associated with:– negative impact on libido and sexual function, but this has

not been proven. – Similar effects on thyroid-binding globulin (TBG): increased

TBG and lower bioavailable T4. – Lastly, the risks of venous thromboembolism (VTE) and

stroke appear to be higher with oral when compared with transdermal estrogen.

• We suggest transdermal 17-beta estradiol for most women because of the potential advantages outlined above, However, the baseline risk of both VTE and stroke is very low in otherwise healthy, young postmenopausal women. Therefore, if a patient prefers an oral preparation over a transdermal one (cost or personal preference), we consider oral estrogen to be safe.

• In addition to oral and transdermal estrogen preparations, estrogen is available as a vaginal ring and as a topical spray, cream, or gel. The topical spray has been linked to adverse effects in children and pets exposed to the drug via skin contact.

TREATMENT - HORMONAL

• Dose — We typically begin with a transdermal estradiol 0.025 mg patch (or if using oral estradiol, 0.5 mg/day).

• If hot flashes are still present after one month, we increase transdermal estradiol to 0.0375 mg and reassess one month later.

• If symptoms are still not relieved, we increase further to 0.05 mg.

• An exception to this approach is the patient with severe symptoms; we start with a transdermal dose of 0.05 mg to achieve more rapid relief of symptoms.

• “Standard” doses of estrogen given daily (Conjugated Estrogen 0.625 mg or its equivalent) are sufficient to reduce hot flash frequency and severity by approximately 75 percent relative to placebo.

• In a systematic review and meta-analysis, CE and 17-beta estradiol (oral or transdermal) were equally effective.

• Estrogen should be administered continuously; past regimens where estrogen was administered days 1 to 25 of the calendar month are considered to be obsolete.

• Women will often get hot flashes during the days off, and there is no known advantage to stopping for several days each month.

• These doses of estrogen are adequate for symptom relief in the majority of women. An exception is younger women after bilateral oophorectomy.

• They often require higher doses (eg, up to 0.1 mg transdermal estradiol) for the first two to three years after surgery; the dose can subsequently be tapered down.

• Factors affecting oral estrogen metabolism :• The above dosing suggestions may need to be increased in:

– women taking anticonvulsant drugs (phenytoin, carbamazepine), which increase the hepatic clearance of estrogens. However, there is no way to predict how much more estrogen is needed so a transdermal estrogen may be better since it avoids the first pass hepatic metabolism.

– In women receiving T4 replacement therapy, the addition of oral estrogen therapy may increase T4 requirements.

• The above dosing suggestions may need to be decreased in:– Concurrent acute alcohol ingestion.– Women with end-stage renal disease.

Adding a progestin

• All women with an intact uterus need a progestin in addition to estrogen to prevent endometrial hyperplasia, which can occur after as little as six months of unopposed estrogen therapy (ET).

• While MPA is endometrial protective, it was associated with an excess risk of coronary heart disease (CHD) and breast cancer.

• In addition, regimens using continuous versus cyclic MPA may be associated with a higher risk of breast cancer.

• An alternative progestin, natural micronized progesterone, is also considered to be endometrial protective (200 mg/day for 12 days/month or 100 mg daily

• In practice, we prescribe oral micronized progesterone as our first-line progestin.

• For women who are perimenopausal or newly menopausal, we start with cyclic administration. Continuous administration in this population is associated with irregular, unscheduled bleeding due to the exogenous hormones and the continued endogenous ovarian function.

• For women who are ≥2 to 3 years postmenopause, we use a continuous regimen. While there is often early breakthrough bleeding even after menopause, most women do eventually develop amenorrhea, a desired goal of continuous administration

• Mood symptoms and/or withdrawal bleeding — Some women are unable to tolerate cyclic progestin administration because of mood side effects, bloating and monthly bleeding.

• For any of these concerns, we suggest switching to a continuous regimen. However, for women who are newly menopausal, breakthrough bleeding can be anticipated.

• Women who cannot tolerate oral progestins — Some women are unable to tolerate any oral progestin, whether given in a cyclic or continuous regimen. In this case, we often suggest off-label use of the lower dose levonorgestrel-releasing intrauterine device (IUD).

• Duration — Short-term therapy is considered to be two to three years, and generally not more than five years.

• Only the minority of women who are unable to successfully discontinue estrogen (because of persistent symptoms) should consider extended use of estrogen therapy.

• Side effects — Common side effects of estrogen include breast soreness, which can often be minimized by using lower doses.

• As noted above, some women experience mood symptoms and bloating with progestin therapy.

• Vaginal bleeding occurs in almost all women receiving cyclic estrogen-progestin regimens and is common in the early months of continuous estrogen-progestin regimen.

STOPPING HORMONE THERAPY

• Abrupt withdrawal of exogenous estrogen at any age may result in (55%) the return of hot flashes and other menopausal symptoms.

• When tapering, one suggested approach is to decrease the estrogen by one pill per week (ie, six pills per week, then five pills per week, etc) until the taper is completed. The progestin is tapered on the same schedule.

• In our experience, women who are unable to tolerate a six-week taper temporarily resume their estrogen, and we then try a much slower taper, sometimes over one year (six pills per week for two months, five pills per week for one month, etc).

• Managing recurrent symptoms — In women who have recurrent vasomotor symptoms after stopping therapy, there is currently no way to determine whether the symptoms will resolve quickly or persist for a prolonged time.

• In women who develop recurrent hot flashes, we first encourage them to monitor their symptoms over the subsequent few months to see if they resolve or improve.

• If there is no improvement, or if the recurrent flushes during or immediately after the taper are difficult to tolerate, we try a non-estrogen alternative, such as a selective serotonin reuptake inhibitor (SSRI) or gabapentin.

Special Issues

• Migraines — not considered to be a contraindication to menopausal hormone therapy (MHT).

• For women with hot flashes and estrogen-associated migraines (which typically worsen during perimenopause), estrogen therapy often improves both symptoms.

• In this setting we suggest continuous transdermal hormone regimens (as opposed to cyclic regimens) to avoid triggering estrogen-withdrawal headaches.

• Depression — The risk of depression during perimenopause is higher than during the pre- or postmenopausal years.

• Selective serotonin reuptake inhibitors (SSRIs) are effective for perimenopausal depression, and some provide modest benefit for hot flashes as well.

• Our approach is to choose initial therapy based upon the woman’s predominant symptom. If her main concern is depression, and hot flashes are not severe, we start with an SSRI.

• On the other hand, if vasomotor symptoms are the major symptom and depression or mood symptoms are mild, we start with HT.

• For women in whom depression and vasomotor symptoms are both severe, we start both estrogen and an SSRI and refer to a psychopharmacologist for further consultation and monitoring.

• Primary ovarian insufficiency — HT is started at a younger age in these women, and current guidelines suggest that therapy should be continued until the average age of menopause (age 50 to 51 years) to prevent premature bone loss, coronary heart disease (CHD), and stroke.

• Breast cancer patients experience early menopause due to adjuvant chemotherapy and may have vasomotor symptoms due to tamoxifen therapy.

• We therefore do not recommend estrogen for women with a personal history of breast cancer.

• Known thrombophilia — MHT increases the risk of venous thrombosis by approximately twofold.

• This appears to be true for oral preparations, but perhaps not for transdermal preparations.

• Data suggest that women who have factor V Leiden and use oral HT have a 15-fold increased risk of venous thromboembolism (VTE).

• Therefore, HT should be avoided in postmenopausal women with prothrombotic mutations.