Menopause Neerja Goel, Bindiya Gupta
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SECTION I
1Basic Sciences2

Definitions and EpidemiologyCHAPTER 1

Himsweta Srivastava,
Bindiya Gupta
 
INTRODUCTION
Menopause is defined as the time when ovaries cease functioning and menstrual periods stop, marking the end of reproductive years. Diagnosis of menopause is mostly retrospective and a woman is considered to have reached menopause when she has stopped having a monthly period for 12 consecutive months. Menopause can occur naturally (spontaneously)—on average around age 51 (range 40–60 years)—or be induced through a medical intervention (surgery, chemotherapy, or pelvic radiation therapy).1 Aging of the female reproductive system begins at 20 weeks gestation with regard to follicle atresia and proceeds as a continuum. It consists of a steady loss of oocytes from atresia or ovulation, and does not necessarily occur at a constant rate. Due to the relatively wide age range (40–58 years) for natural menopause, chronologic age is a poor indicator of the beginning or the end of menopause transition.2
 
DEMOGRAPHICS
In USA, an estimated 6000 women aged between 40 and 59 years reach menopause every day. Life expectancy at birth in women in developed countries is 81 years.3 With increasing life expectancy, many women will spend up to 40% of their lives or on an average 20 years in the postmenopausal stage. It is estimated that half of all women who reach age 50 will live to be at least age 80.4 Hence with menopause occurring in the early fifties, managing the postreproductive period which extends over several decades is an increasingly important public health issue.
The Indian scenario is no different. India has a large population and has crossed 1 billion. The number of menopausal women between ages 40 and 60 years comes in around 43 million.5 The sheer size of these figures indicates 4the necessity of implementing menopause education within India. The average age of Indian woman is 68 years, expected to increase to 73 years by 2021 and the average age of menopause is 48 ± 2 years, earlier than Caucasians.3,6,7 So Indian women will at least live just over 20 years during the postmenopausal phase.
 
DEFINITIONS
(As recommended by the stages of reproductive aging workshop—STRAW, Council of Affiliated Menopause Societies—CAMS.)
Menopause: It is that point in time when permanent cessation of menstruation occurs following the loss of ovarian activity. The term is derived from the Greek words men (month) and pausis (cessation). As defined by STRAW, sponta-neous or natural menopause is recognized to have occurred after 12 months of amenorrhea alongwith final menstrual period (FMP) with no obvious pathologic cause.
Induced menopause: The cessation of menstruation that follows either surgical removal of both ovaries (bilateral oophorectomy), iatrogenic ablation of ovarian function due to chemotherapy or pelvic radiation therapy.
Premenopause: The term is used ambiguously and the term implies “the whole time before menopause”. It encompasses the entire reproductive period from menarche to the final menstrual period (FMP).
Perimenopause: It includes the period beginning with the first clinical, biological and endocrinal features of the approaching menopause, such as vasomotor symptoms and menstrual irregularity, and ends 12 months after the final menstrual period. It is classified into early and late perimenopause depending on menstrual irregularity.
Menopausal transition: The years prior to menopause that encompass the change from normal ovulatory cycles to cessation of menses. It is marked by irregularity of menstrual cycles caused by rise in levels of follicle stimulating hormone (FSH) and ends with the FMP. Women experiencing induced menopause do not experience this transition. This term is no longer used alone and may be interchangeably used with perimenopause.
Early menopause: It is a vague term often used to describe natural or induced menopause that occurs well before the natural age of menopause. It encompasses premature menopause.
Premature menopause: Menopause that occurs at an age younger than 2 standard deviations below the mean estimated age for the reference population. According to CAMS, it is defined as menopause before 40 years of age.85
Climacteric: It is the phase encompassing the transition from reproductive to nonreproductive state. The menopause is itself a specific event that occurs during climacteric. It is sometimes, but not always, associated with symptoms. If symptoms occur it is termed as climacteric syndrome.
Postmenopause: It refers to the years after the FMP resulting from spontaneous or induced menopause.
 
STAGES OF REPRODUCTIVE AGING
The 2001 Stages of Reproductive Aging Workshop (STRAW) proposed nomen-clature and a staging system for ovarian aging including menstrual and qualitative hormonal criteria to define each stage.1 The STRAW staging system is widely considered gold standard for characterizing reproductive aging through menopause. STRAW divided the adult female life into three broad phases: reproductive, menopausal transition and postmenopause. These three phases included a total of seven stages centered on the final menstrual period or FMP (Stage 0).
In 2011, STRAW + 10 recommended updates in the 2001 STRAW classification (Table 1.1).9 STRAW + 10 recommended modifications to the criteria for the late reproductive stage (Stage −3) as well as the early postmenopause stage (Stage +1) and provided information on the duration of the late transition (Stage −1) and early postmenopause (Stage +1) stages. Evidence now supports the applicability of the STRAW + 10 recommendations for most women. Epidemiologic and clinical studies have documented that the process of reproductive aging, although influenced by demographic factors, lifestyle, and BMI, follows a robust and predictable pattern.10–12 Although smoking and BMI influence hormonal levels and the timing of transition, these factors do not alter the trajectory of change in bleeding patterns or hormonal levels with reproductive aging. Therefore, the STRAW + 10 staging system is applicable to women regardless of age, demographic, body mass index (BMI), or lifestyle characteristics.
 
AGE OF MENOPAUSE
Age at menopause is a marker for aging and health. Early menopause is associated with increased risk of cardiovascular disease (25%), early decline in cognitive function, lower bone mineral density and osteoporosis. Delayed menopause although has been associated with increased risk of breast and endometrial cancer, it is also associated with greater life expectancy and reduced all cause mortality.13 Delayed menopause is associated with reduced risk of cardiovascular disease, stroke, atherosclerosis, reduced risk of osteoporosis and fracture.146
Table 1.1   STRAW +10 classification
Menarche
FMP (0)
Stage
−5
−4
−3b
−3a
−2
−1
+1a
+1b
+1c
+2
Terminology
Reproductive
Menopausal transition
Postmenopause
Early
Peak
Late
Early
Late
Early
Late
Perimenopause
Duration
Variable
Variable
1–3 years
2 years (1 + 1)
3–6 years
Remaining lifespan
Principle criteria
Menstrual cycle
Variable to regular
Regular
Regular
Subtle changes in flow/length
Variable length persistent ≥7-day difference in length of consecutive cycles
Interval of amenorrhea of >= 60 days
Supportive criteria
Endocrine
FSH
AMH
Inhibin B
Low
Low
Variable
Low
Low
↑ Variable
Low
Low
↑> 25 IU/L**
Low
Low
↑ Variable
Low
Low
Stabilizes
Very low
Very low
Antral follicle count
Low
Low
Low
Low
Very low
Very low
Descriptive characteristics
Symptoms
Vasomotor symptoms likely
Vasomotor symptoms most likely
Increasing symptoms of urogenital atrophy
↑: elevated, ** FSH measurement by standard assays
7
 
Trends in Age at Menopause
Researchers have reported trends in the age at menopause at international, national and local levels. The median age of menopause in American women born between 1908 and 1922, with menstruation in 1930's to 1970's was 50.5 years, with 75% reaching menopause by 52.4 years and 95% by 54.7 years.15 A seventeen months increase in the mean age of menopause was observed for those born in 1915 to those in 1939 (49.9 versus 50.5 years).16 The age at natural menopause ranged from 49 to 51 years, with a lower limit of 40 years between 1979 and 1988 and World Health Organization has reported an average age at menopause of 51 years in 1990's in industrialized countries.17,18
 
Factors Affecting Timing of Menopause
A number of demographic (education, employment, race, ethinicity), reproductive (parity, oral contraceptive use), familial, genetic and lifestyle factors are important determinants of the age at which natural menopause occurs as described below and summarized in Table 1.2. Among the various factors affecting age at natural menopause, smoking, lower parity and lower socioeconomic status have been found consistently to be associated with earlier menopause, an indicator of reduced longevity.
 
Factors Affecting Oocyte Survival and Co-relation with Menstrual Cycles
Age at menopause depends on varying rates of atresia of ovarian follicles than to the absolute number of oocytes depleted. The estimated number of oocytes are 1–2 million at birth, 300,000–400,000 by menarche and <1000 at menopause.19 With increasing number of years, decreasing number of follicles coincide with diminished oocyte quality and are associated with changes in menstrual cycle regularity and fecundity. The factors associated with selective survival of oocytes over the years include genetic variations (Bcl-2, Bax), epigenetic alterations (DNA methylation) and exogenous factors like smoking, obesity, parity and age related changes in hypothalamic pituitary adernal (HPA) axis.
It has been observed that women aged 20–35 years, with shorter menstrual cycle length (<26 days) underwent natural menopause 1.4 years earlier than women with cycle lengths between 26 and 32 days.20 The mean duration further increased by 0.8 years, in women with a cycle length of 33 days or longer.20 There is no definite co-relation between age at menopause and age at menarche. The association gets masked by exogenous factors like parity, hormonal contraception, smoking, obesity, environmental endocrine disruptors and complex interactions between genetic, epigenetic and environmental factors.218
 
Genetic Factors and Heritability
Samples from participants of Nurses' Health Study and Women's Genome Health Study identified 13 single nucleotide polymorphisms on 4 chromosomes that were associated with age at menopause. It was seen that pathways of steroid biosynthesis and metabolism were associated with age at menopause.22
A study reported that women's age at natural menopause was positively associated with their mother's age at natural menopause, showing genetic control.23,24 Studies have reported estimates of heritability ranging from 30 to 85%.25,26 Pedigree analysis reveals a dominant pattern of inheritance through maternal or paternal relatives in early menopause or premature ovarian failure.
 
Race and Ethinicity
A multiethnic cohort study of 95,000 women aged 45–74 years in 1993–1996 followed till date has established a strong association between ethinicity with natural age at menopause.27 According to this study, natural menopause occurred earlier in both US and non US born Latinas, later among Japanese-Americans as compared to non hispanic whites (NHW) and non hispanic blacks (NHB). Non hispanic whites have lower estradiol levels than NHB, while latter had an early perimenopause. African American women experience natural menopause 2 years earlier than white women.28 Asian women have a similar age at menopause as their Caucasian counterparts while Thai and Mayan women have a lower median age at menopause despite their high parity. Women living in developing countries experience natural menopause several years earlier than those in developed countries.29 Women living in urban areas have a later natural menopause than women in rural areas.30
 
Hormonal Exposures
Exposure to hormonal factors during the prenatal, postnatal, adolescent and reproductive years have the potential to alter ovarian changes that affect age at menopause. Few cross-sectional studies have found late menopause to be associated with increasing parity.23,31 Many studies have reported that women who have used oral contraceptives have a later age at menopause. It is proposed that oral contraceptives delay depletion of oocytes.32 Women exposed to DES were found to more likely start menopause a year before the unexposed.33
 
Socioeconomic Factor
A lower socioeconomic status (SES) is associated with an earlier age at natural menopause. On comparing specific markers of SES, both higher education and adult occupational status are associated with higher age at menopause.34 It has 9been shown that early life SES resources have a stronger influence as compared to adult resources. It is proposed that SES influence on age of menopause may be through factors such as smoking, BMI, psychological stressors and nutrition. Also, it has been studied that single women experience an earlier menopause.
 
Psychological Factors/Stress
The timing of menopause is sensitive to psychological stress. Childhood stress like parental socioemotional involvement and childhood abuse has been found to accelerate the age of menopause due to increased rate of follicular atresia.35 According to The Study of Women's Health Across the Nation (SWAN), childhood abuse has also be linked to increase in vasomotor symptoms in menopause.32 Stress in adulthood also modulates the rate of cellular aging. In vivo studies have demonstrated a positive corelation between high levels of chronic stress and shortened telomeres (indicating cellular aging), high levels of oxidative stress and low antral follicle count.36,37 Depression not only intensifies menopausal symptoms, but has found to accelerate ovarian aging.
 
Body Mass Index/Obesity
Increased body mass index (BMI) and upper body fat distribution (increased waist to hip ratio) is associated with later age at natural menopause. Malnourished women reached menopause 4 years earlier than well nourished women because of less body fat in thinner women.38
 
Diet
Effect of intake of specific dietary patterns to age at menopause is not consistent. Vegetarians were observed to have an earlier age at menopause, whereas another study in Japan reported that higher green and yellow vegetable intake was significantly associated with later age at menopause.39,40 Dietary fibers may interrupt enterohepatic circulation of sex hormones leading to lower estrogen concentrations amongst vegetarians. Various studies have demonstrated that high total calories, fat, meat and protein intake are associated with late age of menopause while high carbohydrate consumption, fiber, vegetables, cereals and coffee cause menopause at an earlier age.41 Soy has shown to have no effect on natural age at menopause.
 
Smoking and Alcohol
Active smoking results in an earlier menopause, i.e. 1–2 years earlier than comparable nonsmokers and a shorter perimenopause.42 This is because the polycyclic aromatic hydrocarbons in cigarette smoke are known to be toxic to ovarian follicles leading to premature loss of ovarian follicles. Also estrogen is 10more rapidly metabolized in the livers of smokers leading to earlier reduction of estrogen levels. Smokers also have a higher incidence of surgical menopause than nonsmokers. Further smoking has also been observed to have anti-estrogenic effect; interactions have been linked between smoking and methyl tetra hydrofolate reductase (MTHFR) gene. There is a dose-response relationship with the number of cigarettes smoked and the duration of smoking. In the SWAN study, the median age of menopause was 51.4 years with an earlier onset associated with smoking.32 Prenatal exposure to cigarette smoking has been found to be associated with early age at menopause in women who never smoked as adults.
Increased alcohol consumption is significantly associated with later age at menopause as they have higher blood and urinary levels of estrogen and greater bone density.42
 
Others
Few studies have examined the effect of physical activity on age at natural menopause. Results of these studies have not been consistent, although it is associated with decreased concentrations of reproductive hormones and infrequent ovulation. Women living at high altitude undergo natural menopause 1–1.5 years earlier than those living at lower altitudes. Although much data is not available, environmental endocrine disruptors like polychlorinated biphenyls and dichlorophenyl trichloroethane demonstrate estrogenic activity and are associated with early natural menopause.
Increasing knowledge about how these factors affect follicular atresia, hormone levels and thus the timing of the final menstrual period will help in understanding and dealing with the individual presentations of menopause.
Table 1.2   Factors related to age at natural menopause
Factors related to earlier menopause
Factors related to late menopause
Rural areas, high altitude
Urban areas
Developing countries
White women, developed countries
Racial factors—African, Asian
Multiparity
Lower socioeconomic status
Higher socioeconomic status
Polymenorrheic or irregular cycles
Use of oral contraceptive pills
Lower age at menopause in mother
Increased BMI
Low weight at 2 years of age
Increased weight at 2 years of age
Early life stressors (parental divorce)
Increased physical activity
Smoking habits—active and passive
Alcohol intake
Malnourished and undernourished
Meat consumption
Vegetarian diet
Higher total intake of calories, fat fruits and protein
High intake of coffee
11
 
EPIDEMIOLOGY OF MENOPAUSAL SYMPTOMS
Menopausal symptoms include hot flushes and night sweats, depression, tiredness and sexual problems. In terms of attitudes towards menopause; some women dread and fear menopause while other women embrace or at least accept menopause.
 
Vasomotor Symptoms
Approximately 70% of women in western countries will experience vasomotor symptoms, however women from eastern countries experience lesser hot flushes and night sweats.43 Women with higher level of education have fewer symptoms while cigarette smoking and high body mass index predispose a woman to more severe or frequent hot flushes.44 In Indian menopausal women, vasomotor symptoms have been found to be different in the rural and urban areas. The overall prevalence of the vasomotor symptoms among the postmenopausal women (combined hot flushes and night sweats) was reported to be 60.9% in a study conducted in rural south India.45 Another study done in Punjab by Sharda Sidhu et al. observed that the prevalence of vasomotor symptoms was 55.08%.46
 
Psychological Symptoms
This includes depressed mood, anxiety, irritability, mood swings, lethargy and lack of energy. Menopausal transition confers higher risk for development of depression. Previous psychological problems and current life stresses appear to increase risk.47 The prevalence of depressive symptoms in India varies from 14 to 24.7%.45,48 The prevalence of sleep related symptoms in postmenopausal women in India has been observed to be 40–50%.47,48
 
Sexual Dysfunction
The most prevalent sexual problems among women are low desire (43%), difficulty with vaginal lubrication (39%) and inability to climax (34%).49
 
Chronic Conditions Affecting Postmenopausal Health
These include cardiovascular disease, osteoporosis, dementia, cancer and urinary incontinence.
Coronary heart disease and stroke are the major health risks among postmenopausal women. The incidence of CVD among Indian women has significantly risen. The prevalence of metabolic syndrome (MS) and all its individual components are found to be significantly higher among postmenopausal (7.6 times) and perimenopausal women (6.4 times) as 12compared to premenopausal women.50 The projected deaths from cardiovascular diseases by 2020 are estimated to be 42% of the total deaths.
Osteopenia is present in 35–40% of women between 40 and 65 years. This is attributable to low calcium intake in youth and later, lack of exercise in all ages and lack of sun exposure in women in urban areas. The symptom of joint pain in India has been noted in 10–20% of postmenopausal women.45,46
Cancer rates for Indian women between the ages 35–64 are steadily growing. The common cancers in women in India are those of cervix (13.1–35%), breast (12.1–27.5%), ovary (3.5–7.8%) and endometrium (0.7–2.2%).
Urogenital atrophy affects 25% of postmenopausal women resulting in dyspareunia, itching, dryness and incontinence. Prevalence of urinary incontinence in USA has been found to be 45%.51 The prevalence of urinary symptoms in Indian women was found to be in the range of 10–15% among various studies conducted in India.45,46
 
KEY POINTS
  • Menopause is diagnosed retrospectively and is defined as the cessation of menstruation for 12 months after the last menstrual period. It reflects a cessation of ovulation owing to a loss of ovarian follicles resulting in decreased estradiol and inhibin levels, and increase in serum FSH levels.
  • Mean age at menopause in India is in the range of 48 ± 2 years.
  • Early menopause is associated with increased risk of cardiovascular disease and osteoporosis whereas delayed menopause carries risk of breast, ovarian and endometrial cancer.
  • Various factors like demographic, genetic, lifestyle affect the age at which natural menopause occurs.
  • Prevalence of menopausal symptoms also varies between different cultures, geographical areas and level of education of the women.
  • Prevalence of vasomotor symptoms varies between 55 and 60% while psychological symptoms and mood disturbances are seen in 13–25%. Urogenital atrophy is common approximately affecting 25% of women.
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