Open Journal Systems

CLINICAL AND SURGICAL PRACTICE

Received: March 15^th 2013

Accepted: May 20^th 2013

Clinical practice guideline. Diagnosis and treatment of postmenopausal and perinemopausia

Alberto Alvarado-García,^a Tomás Hernández-Quijano,^b Marcelino Hernández-Valencia,^c Miriam Concepción Negrín-Pérez,^d Brendha Ríos-Castillo,^e Gregorio Urbano Valencia-Pérez,^f Víctor Saúl Vital-Reyes,^g Ma. Antonia Basavilvazo-Rodríguez,^h Laura del Pilar Torres-Arreola,ⁱ Guillermo Federico Ortiz-Luna,^j Fernando Sánchez-Aguirre,^k Armando Montaño-Uscanga^k

^aAsociación Mexicana para el Estudio del Climaterio, Distrito Federal

^bHospital de Oncología, Centro Médico Nacional Siglo XXI

^cUnidad de Investigación de Enfermedades Endócrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI

^dServicio de Ginecología y Obstetricia, Hospital Angeles del Pedregal, Distrito Federal

^eHospital Ginecología y Obstetricia 3 “Dr. Víctor Manuel Espinosa de los Reyes Sánchez”

^fHospital General de Zona 2 “Francisco del Paso y Troncoso”

^gServicio de Biología de la Reproducción Humana, Hospital de Ginecología y Obstetricia 3

^hCoordinaciónde Programas Médicos, División de Excelencia Clínica, Coordinación de Unidades Médicas de Alta Especialidad,

ⁱÁrea de Guías de Práctica, División de Excelencia Clínica, Coordinación de Unidades Médicas de Alta Especialidad

^jClínica de Climaterio, Instituto Nacional de Perinatología, Secretaría de Salud

^kAsociación Mexicana para el Estudio del Climaterio, Distrito Federal

^{b,c,e,f,g,h,i}Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Ma. Antonia Basavilvazo-Rodríguez

Telephone: (01) 5726 1700, extensions: 14027, 14533

Email: dra.basa06@gmail.com

Post-menopause is the period of life where a deep decline occurs in circulating estrogen levels, inducing the appearance of psycho and somatic symptoms. The classification to understand the chronology of reproductive aging in women (known as STRAW) determines the clinical and endocrine changes contemplating menstrual cycles, symptoms, measurements of FSH, LH, inhibin B, anti-Mullerian hormone , and follicular account. The diagnosis of menopause is established by the absence of menstruation for 12 months or more. The most frequent clinical manifestations of the climacteric syndrome transition to menopause are: menstrual disorders, vasomotor symptoms (flushes and/or sweats) and genitourinary manifestations. The assessment of women in the peri- or postmenopause aims to develop: cervicovaginal cytology, lipid profile , serum glucose, basal Mammography at least a year before, pelvic ultrasound, urinalysis, serum TSH, Densitometry in patients older than 60 years if there is no recourse can be applied and FRAX. Drug therapy for the treatment of disorders of the transition to menopause or menopause is divided into: Hormone Therapy (HT) based estrogens and progestin hormone not being the most recommended the serotonin reuptake inhibitors and norepinephrine , clonidine, gabapentin or veralipride.

Keywords: Menopause; Postmenopausal; Aging

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The purpose of this guide is to provide staff of the three levels of care with recommendations based on the best available evidence in an attempt to standardize national actions on:

• Updating the available scientific information on the comprehensive care of peri- or postmenopause.

• The promotion of good practice in safety for hormone therapy.

• The increase in diagnosis and timely treatment.

• The promotion of risk screening in peri- and postmenopause.

Definition

Menopause

Event or stage in the life of a woman that marks the end of reproductive life. With menopause, women arrive more objectively at the absence of menstruation after 12 months. It is considered natural or physiological when occurring after 40 years of age.¹

Climacteric syndrome

The set of signs and symptoms that occur in perimenopause and postmenopause, including vasomotor symptoms, sleep disorders, psychological disorders, and genital atrophy.³

Transition to menopause

Starts with variations in menstrual cycle length and with an increase in follicle stimulating hormone (FSH), without increase in luteinizing hormone (LH); it ends with the absence of menstruation at 12 months.

Perimenopause

This means on or around menopause. It begins with the transition to menopause and ends one year after the last menstrual period.^3-6

Postmenopausal

The period beginning from the year of the absence of menstruation until the end of life.^3-6

Early postmenopause

The time within five years after the last menstrual period, whether natural or induced.^5,6

Users

General practitioners, ob-gyn physicians, internists, endocrinologists, psychiatrists, and psychologists; healthcare personnel.

Target population

Women in perimenopause or postmenopause.

Methods

A standardized search sequence was established. The first step was to look for clinical practice guidelines (CPG) and additional bibliography that was related to the topic of menopause or perimenopause. The search was limited to humans, publications from the last five years, in English or Spanish, the document type being clinical practice guidelines, and validated MeSH terms were used: Menopausal (s) and Postmenopause, Hormone therapy. The databases Tripdatabase, PubMed, Guideline Clearinghouse, Cochrane Library, and Ovid were used.
Only five clinical practice guidelines with their respective scales of evidence and recommendations (Table I) were found. These guidelines were useful to complement the rest of the information obtained from systematic reviews, meta-analyses, clinical trials, and observational studies. They were classified based on the modified Shekelle scale (Table II). Evidence is listed as E and recommendations as R.

When points were issued from undocumented experts, in the bibliography this was classified as Good Practice Point.

Background

With the increase in life expectancy (from 49 to 77.6 years) and the reduction of perinatal mortality, the over-50 population has increased; out of 112,336,538 of national residents, females predominate with 57,481,307 (51.3%), so women manage to live almost a third of their lives after menopause, which occurs in Mexico between 49 and 50 years of age.^8,9

Women in perimenopause or postmenopause may have a variable clinical profile in each patient and may be asymptomatic or mildly to severely symptomatic. Symptomatic cases may have a high severity that affects their quality of life, a circumstance that will affect their role in society, the economy, and in the health of the population. Another important aspect to consider in this population is comorbidity involving physical and metabolic changes, which have a high incidence of cardiovascular disease, metabolic syndrome, and deterioration of bone mass.

Individualization is of key importance in the decision to use hormone therapy (HT) and one should consider the health of woman and her lifestyle, as well as risk factors for thrombosis, cardiovascular or cerebrovascular diseases, or breast cancer.⁶

Evidence and recommendations

Prevention

Several observational studies have shown an association between certain risk factors and the frequency or intensity of vasomotor symptoms; they are classified as non-modifiable and modifiable.

Non-modifiable factors:

• African-American population. Induced menopause or abrupt onset of menopause.
• Chronic conditions.

Modifiable factors:

• Obesity or overweight.
• Smoking.
• Sedentary lifestyle.
• Schooling or low socioeconomic status.
• History of anxiety and depression. (E: Ia-IIb)⁴

R: Health personnel should encouraged change to healthy lifestyles, such as regular exercise, weight control, smoking or alcohol reduction (R: A, D)⁴ and a diet rich in calcium. (R: A)⁹

We recommend the consumption of calcium-rich foods low in saturated fats; when there is intolerance to dairy, calcium and vitamin D supplements are to be given. (Table III) (R: A)⁹

Clinical manifestations

The classification to understand the chronology of reproductive aging in women (known as STRAW) is useful to determine the clinical, endocrine, and reproductive changes. This classification includes menstrual cycles, symptoms, and measurements of FSH, LH, inhibin B, anti-mullerian hormone (AMH), and follicular account, which varies by the stage that the woman is at: reproductive, transition to menopause, and postmenopause. The STRAW classification is useful for detecting the diagnosis in these stages (Figure 1). (E: IV.)³

R: To assess the woman and classify her by STRAW classification, identifying what stage she is in, and classifying according to each case by:

• Reproductive stage.
• Transition to menopause or perimenopause.
• Postmenopause. (R: D)³
• The diagnosis of menopause is established by the absence of menstruation for 12 months or more in a woman with a uterus. (R: D)³

The diagnosis of climacteric syndrome is clinical, and is based on a clinical history oriented and based on menstrual disorders, vasomotor symptoms (hot flashes or sweats), urogenital manifestations, psychological disorders (changes of mood, anxiety, depression, disturbed sleep pattern). (R: B, D)³

Diagnostic tests

FSH levels above 25 IU/L are seen in transition to menopause and postmenopause, and it is amenorrhea for more than 12 months that marks menopause. (E: III)⁵

The measurement of FSH or AMH is in cases of diagnostic uncertainty or in women with hysterectomy for the diagnosis of menopause or transition to menopause. (R: D)³

Lipid and glucose metabolism and fat distribution in the center of the body are altered in the transition to menopause or menopause with increased cardiovascular risk, and increased metabolic syndrome. (E: IV)³

R: A comprehensive evaluation of women in the menopausal phase must include the following studies:

• Pap smear.
• Lipid profile.
• Serum glucose.
• Basal mammography at least a year earlier.
• Pelvic ultrasound.
• General tests of urine.
• Serum TSH. (R: D)
• Densitometry in patients over 60 years; lacking this resource one can apply FRAX. (R: D)²

Treatment

The treatment of clinical disorders is divided into pharmacological and non-pharmacological. Pharmacological contains two subgroups:

• Hormone therapy, which is based on estrogen or progestin.
• The non-hormonal therapy, which is based on serotonin reuptake inhibitors and norepinephrine, such as clonidine, gabapentin or veralipride. (E: IV)¹⁰

First-line hormonal treatment (estrogen or estrogen-progestin) or non-hormonal in case of contraindication (desvenlafaxine, venlafaxine or clonidine) should be offered for the treatment of disorders of the transition to menopause or menopause. (R: A, 1, IA, D)^{1,3,5,6,10-22}

Hormonal treatment

Hormone therapy (HT) has proven to be the most effective for the control of vasomotor symptoms and urogenital atrophy in menopause. (E: IA, IV, 1)^{1,3,5,6,10-22}

The main indications for the use of HT to control the disorders of menopause are:

• Vasomotor symptoms (hot flashes, sweating, or tachycardia).
• Vulvovaginal atrophy (painful sexual intercourse or dyspareunia, burning, dryness).
• Prevention of osteoporosis in postmenopause (in patients with osteoporosis risk factors) as long as there is no contraindication. (R: A)¹⁰

Hormonal schemes

According to the method of administration of estrogen, progesterone, or progestins, there are different schemes of combined HT:

• Cyclical therapy.
• Cyclical-combined.
• Continuous cyclical (sequential).
• Continuous cyclical (sequential) long cycle.
• Continuous combined.
• Intermittent combined. (E: IV)¹¹

Combined HT (estrogen-progestin) is indicated in women with an intact uterus to reduce the risk of endometrial hyperplasia or cancer. (R: Ia, D)¹⁰

HT scheme will be selected according to the menopausal stage; in the transition and perimenopause stage, sequential combined regimens are recommended; after menopause, a continuous combined scheme. (R: D)¹²

The choice of the management scheme of combined HT depends on the patient’s choice as to whether or not to continue with cyclical bleeding. (R: D)¹²

Cyclical HT is indicated in women with a uterus in perimenopause who want to continue having menstrual cycles. (Good practice)

In our country the most recommended schemes are continuous cyclic therapy (also called sequential): estrogen used every day with the addition of progestogen 10-14 days each month. (R: A)

Continuous combined therapy: uses fixed daily doses of estrogen-progestin. (Good practice)

For the choice of progestin, one must additionally consider endometrial protection, its tolerance, its impact on metabolism, and its mineralocorticoid, glucocorticoid, and androgenic effects (R: D).¹³

Safety of hormone therapy

HT should not be considered as a single system offered a standard woman; the benefits and risks vary according to the characteristics of each patient, in which the risks can be minimized and benefits maximized, so therapy must be individualized. (R: D)¹⁰

HT use is well justified in healthy women under 60 years or within 10 years of menopause. (R: A, D)^1,10

Women with premature menopause or primary ovarian failure (before age 40) are at increased risk of cardiovascular, metabolic, and bone diseases. (E: IV)¹⁴

HT should be offered to women with premature menopause for the time until they reach the average age at which menopause occurs spontaneously in this population (age 50). (R: A, D)^1,14

Low doses of HT should be considered to control the clinical manifestations of peri- and postmenopause; the time needed for control should be considered. (R: A, D)^1,14

There is no reason to impose mandatory limitations of HT duration. This should be individualized according to the clinical profile of the patient, if it should be with estrogen therapy only, low doses, or orally, the risk-benefit basis should always be assessed. (E: IV)⁶

It is advisable that combined oral HT (estrogen-progestin) is used for a period less than three years; simple estrogen therapy can be used more safely (up to seven). (R: A)¹

It is necessary to assess and identify the duration and dose; the approach must be based on the detection of the risk profile (thrombosis, breast cancer, cardiovascular disease, and cerebrovascular disease), as long as the benefit outweighs the risks. (R: A, D)^1,5

The use for periods longer than five years is justified if:

• Symptomatic recurrence is presented which interferes in the patient’s quality of life.
• It is in women under 60 years with indications and in low doses.
• Low risk profile for thrombotic events, strokes, and breast cancer). (R: A)^1,6,14

The use of local estrogen therapy is indicated when the symptoms are located exclusively in the urogenital area. (R: A)^1,14
One should consider transdermal delivery in patients with climacteric syndrome who also have hypertension, hypertriglyceridemia, or chronic liver disease. (R: D)^5,14

Risks of hormone therapy

There are multiple pieces of evidence on the adverse effects of HT; the most important are:

• Breast cancer.
• Cardiovascular events.
• Strokes.
• Thrombotic events.

HT should be considered only for a precise indication, based on the contraindications and potential individual benefit. (E: 1, IV)^1,10,14

Candidates for HT should be informed about the increased risk of breast cancer, stroke, and cerebral and thrombotic events. (R: A)¹⁰

Premature menopause or premature ovarian failure patients have a low risk of breast cancer. In women over 60, HT should not be used without a precise indication and only after appropriate consent and attention to cardiovascular risk factors. (E: IV)⁶

HT should not be used with estrogen without progestational opposition in women with a uterus, as this increases the risk of endometrial hyperplasia, which is increased if high doses are used. (R: A)^1,10

The risk of breast cancer is higher in patients with combined hormone therapy (use of progestins, especially oral medroxyprogesterone acetate) with 3-5 years of use. Simple estrogen HT showed increased risk of breast cancer starting in the seventh year of use. (E: IV)¹⁰

HT candidates should be informed about the increased risk of breast cancer, especially with combination therapy of conjugated equine estrogen plus oral medroxyprogesterone acetate. These patients should undergo annual or biannual mammography according to their risk profile. (Good practice)

The available scientific literature dealing with the risk of ovarian cancer in patients with hormonal therapy is controversial; it is accepted that HT with estrogen may be associated with a slightly increased risk of ovarian cancer of 0.7 per 1000 women over 5 years of use, but not with combined hormone therapy. (E: IV)¹⁰

In women receiving hormone therapy after 10 years of menopause the risk of cardiovascular disease increases significantly. In patients over 60, hormone therapy increases the risk of cerebrovascular disease. (E: IV)¹⁰

It is advisable not to use combined HT with medroxyprogesterone acetate in patients 60 years or older with comorbidity, as this increases the risk of stroke and thrombotic events. (R: A)¹

The risk of venous thromboembolism increases with any hormonal therapy, especially in the first year of use with oral administration. (E: IV)¹⁰

Contraindications

Hormone therapy should not be indicated in patients with:

• Breast cancer.
• Estrogen-dependent malignant conditions.
• Abnormal uterine bleeding of unknown cause.
• Untreated endometrial hyperplasia.
• Previous idiopathic or venous thromboembolism.
• Arterial thromboembolic disease.
• Ischemic heart disease.
• Acute liver disease.
• Uncontrolled hypertension.
• Hypersensitivity to drugs or excipients.
• Cutaneous porphyria (absolute contraindication). (R: A)¹

Non-serious side effects

Side effects of HT that have been reported and are infrequent are:

• Uterine bleeding (which begins or returns).
• Breast tenderness.
• Nausea.
• Abdominal distention.
• Fluid retention in the extremities.
• Changes in the shape of the cornea.
• Headache or migraine.
• Dizziness.
• Changes in mood (with combination therapy (E: Ia)^15,16

HT with tibolone in patients with dysfunctional uterine bleeding disorders in perimenopause can be considered, as it shows reduced bleeding. (R: A)¹⁶

Trimegestone is recommended as progestational therapy in patients showing bleeding profile with other hormonal therapies. (R: C)¹⁷

Bioidentical hormones

These are hormones such as estradiol, estrone or estriol, progesterone, testosterone, and growth hormone, considered "natural”; they are synthesized from the Mexican yam plant (sweet potato) and are identical to ovarian estrogens; they are considered non-tested products. (E: IV)¹⁴

The use of bioidentical hormones is not recommended as hormone treatment. (R: D)¹⁴

Non-hormonal treatment

Non-hormonal drugs that have shown efficacy to reduce vasomotor symptoms are divided into:

• Drugs

• Serotonin and norepinephrine reuptake inhibitors (desvenlafaxine or venlafaxine).
• Clonidine, gabapentin.
• Veralipride.

• Phytotherapy

• Ginseng.
• Mexican Yam.
• Valerian.
• Derivatives of soy (isoflavones, genistein, daitsein), lignans (cereals, fruits, vegetables) and seeds.
• Coumestans (alfalfa) (E: Ia, Ib)^18,19

Non-hormonal therapy is indicated when there is contraindication for it for the control of vasomotor syndrome or in patients who do not accept HT. It is shown most useful in patients with mild vasomotor symptoms. (R: A, 1B)^18,22

The serotonin and norepinephrine reuptake inhibitor drug that has been most effective in controlling vasomotor symptoms is desvenlafaxine. (E: III)¹⁹

In Mexico, COFEPRIS, through the Centro Nacional de Farmacovigilancia, issued safety recommendations in May 2009 regarding the use of veralipride. These are still valid and are as follows:

• It is indicated only for the control of hot flashes and psychofunctional manifestations of menopause.
• It is important to respect the therapeutic regimen of daily use at a dose of 100 mg for 20 days with 10 days off.
• It should be monitored and closely watched to detect effects of dyskinesia.
• Close monitoring should be done and reporting of any suspected adverse reactions. (R: D)²⁰

The use of veralipride as non-hormonal treatment to control vasomotor symptoms in menopause should be done by prescription only, in doses recommended by COFEPRIS, and with close medical supervision in patients with minimal chances of neurological effects; this should avoid the most serious side effects that are cause for discontinuation. (Good practice point)

Non-hormonal medications to control vasomotor symptoms should be second-line therapy in patients who do not want to use HT or who have contraindication; they should also be informed that it has not shown greater reliable efficacy than single or combined HT. (E: A)²¹

The patients taking alternative treatments should be warned of the adverse effects, since they are not regulated products for health control. (E: IB)²²

Reference criteria

Reference for patients in first to second level perimenopause and postmenopause is in the following cases:

• Patients who need HT and in whom there is suspicion of uterine fibroids, endometrial hyperplasia or polyps, cervical or ovarian cancer, or coagulopathy.
• Patients who have no response to established hormonal treatment.
• Patients with HT contraindication. (R: D)³

Patients evaluated or treated by medical specialist will be referred back to primary care when:

• There is control with established treatment.
• They do not accept HT. (Good practice point).

Monitoring and follow-up

The group that developed this guide accepts the recommendation that the peri- or postmenopausal patient should be closely monitored and any suspected adverse reactions reported based on adverse events from HT or the more frequent non-hormonal medicines in the first months of use. (E: T)²⁰

Comprehensive assessment should be annual and should include: complete medical history, laboratory tests (glucose, lipid profile), Pap smear, mammogram, and pelvic ultrasound in patients with uterine bleeding or patients at high risk for endometrial cancer. Bone densitometry should be considered in each case. (R: D)¹⁴

It is important to monitor the patient in the first three to six months of beginning hormone therapy, in order to evaluate efficacy and tolerance and to provide greater safety. (Good practice point)

Acknowledgements

We thank the library scientist Francisco Garcia Gomez, at the Centro Nacional de Investigación Documental en Salud (CENAIDS) of the Centro Médico Nacional Siglo XXI (Instituto Mexicano del Seguro Social) for the facilities for the development of this clinical practice guideline.

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