Current Topics in Menopause

We describe how a woman’s age at menopause and whether she experiences natural or surgical menopause depends on her social and biological experiences from prenatal through adult life. We contrast evidence from Western industrialized nations and developing countries. Menopause occurs because of the depletion of the follicular reserve or as a result of surgery. Among the most robust risk factors for age at natural menopause are those that influence follicular pool development and decline, including birth outcomes, early life development and socioeconomic status, smoking, and parity. Relationships with indicators of reproductive health from earlier in life, adult weight, and adult socioeconomic status have less robust relationships with age at and type of menopause. Hysterectomy is related to socioeconomic status across the life course, parity, and weight in mid to later adulthood. While studies from Western industrialized countries are more numerous, studies from developing countries suggest differences in socioeconomic status and early life development for both age at menopause and type of menopause. We close by providing suggestions for how future research may further the understanding of the interaction of social and biological contributors to age at and type of menopause

Menopause marks an upper limit of a female’s reproductive period. It is one of the key physiological events in female life and has a pronounced effect on postmenopausal health. Age at natural menopause (ANM) has been associated with many health problems and therefore attracted much attention in the last two decades. As a complex trait, ANM is determined by many genetic and environmental factors and their interactions. During last two decades, large efforts have been made to determine a genetic basis of natural menopause and its timing, which allowed for identifying a number of candidate genes and genomic regions. However, the problem is still far from its solution. The systems approach, which incorporates candidate gene association studies, genome-wide association studies, linkage analysis, gene expression microarrays and proteomics in a single pipeline, may open new venues and greatly advance progress in this area.

Women experience two lifetime reproductive transitions (puberty and perimenopause). The purposes of this chapter are to propose an update in terminology for the transition to menopause, to describe the hormonal changes during this important life phase and to show that perimenopause is a time of major bone loss. This new terminology means that any woman over the age of 35 (and sometimes younger) who, despite regular flow, experiences typical midlife changes (such as night sweats, heavy flow, increased cramps) is considered to have entered early perimenopause. Late perimenopause is the 12 months after the last menstruation. Menopause (sometimes called “postmenopause”) then commences and continues for the remainder of women’s lives. Hormonal changes in perimenopause are extremely complex and reflect dys-regulation and eventual cessation of the highly coordinated interplay of ovarian, pituitary and hypothalamic hormones within the menstrual cycle. Among other changes, perimenopausal estradiol levels are variable and often higher, ovulation becomes disturbed and luteal phase progesterone levels become lower. A second, higher estradiol peak (luteal-out-of-phase event, LOOP) may also occur. Bone changes are primarily related to variable estradiol, insufficient progesterone and perhaps to increasing gonadotropin levels. Usual weight gain decreases midlife bone loss. Increased cancellous bone loss in the spine (by quantitative computed tomography) and total hip (dual energy X ray absorptiometry) are primarily related to higher bone resorption, and become maximal in the late menopausal transition and late perimenopause. In summary, the perimenopause involves major changes in experiences, menstrual cycles, hormone levels and bone physiology.

Bone is a metabolically active tissue that undergoes continuous regeneration, which provides the skeleton its regenerative and functional adaptation capacity. Although there have been significant advances in the understanding of the mechanism remodelling process in recent years, there is still much to learn on many aspects. The regulation of bone remodelling is a complex process that it integrates different stimuli such as mechanical factors, hormones, cytokines and growth factors. In younger individuals, the bone mass remains practically unchanged, while menopause, aging and some diseases alter bone balance. The main effect of menopause on the skeleton is increased bone resorption resulting in bone loss, which also influences the decrease in intestinal and renal absorption of calcium. The estrogen deficiency plays an important role in the changes of bone mass and calcium metabolism. The bone loss begins in the perimenopausal period but persist until the end of life and it is the main cause of osteoporotic fractures in older women.

In this chapter we address the controversies found in studies investigating the effect of estrogen treatment on cognitive function. There is ample biological evidence to suggest that estrogens can protect the aging brain. Observational studies have often shown that women taking hormones are protected against dementia. However, these studies are contaminated by report bias and healthy user bias. Women who have dementia are more likely to forget that they have used hormones in the past and use of hormones for menopausal complaints was part of a healthy life style pattern for many women. This makes it difficult to disentangle positive effects of hormones per se. In addition, several large treatment studies suggested that older women who use hormone treatment for a prolonged period of time have an increased risk of dementia. Our metaanalyses suggest that estrogen treatment only has positive effects on cognition for a number of months regardless of age of women. In older women long term effects can even be negative. Whether the outcome may be different using different hormone regimens or for subgroups of women remains to be investigated.

Cardiovascular disease is the major cause of mortality in women and in men. The incidence of cardiac events in women is lower than in men during the fertile age but increases after menopause. Sex hormones exert significant effects on the cardiovascular system and ovarian hormone deficiency associated with menopause may play an important role in the development of cardiovascular diseases. The reduced risk of cardiovascular diseases associated with hormone replacement therapy, reported in the observational studies, has not been subsequently confirmed in the randomized clinical trials. Thus, hormone replacement therapy is not recommended for cardiovascular prevention. It is extremely important to carefully assess the risk of cardiovascular diseases in women in the peri- and postmenopausal period, in order to develop appropriate prevention strategies. Risk assessment should be extended to older age groups in order to account for the delayed onset of cardiovascular diseases in women. Some therapeutic options may not be equally effective and safe in men and women. However, under-representation of women in cardiovascular research has been demonstrated. The EuroHeart project showed that the 62 randomized clinical trials published between 2006 and 2009 enrolled 33.5% of women and only 50% of the trials reported the analysis of the results by gender. Cardiovascular clinical trials enrolling a significant proportion of women to allow for pre-specified gender analysis should be conducted. Enrolment criteria and follow-up duration should allow the inclusion of women at risk of developing cardiac events.

Postmenopausal women are at a higher risk to develop obesity. Forty four percent of postmenopausal women are overweight while twenty three percent of whom are considered obese with a body mass index (BMI) above 30 kg/m². Large increases in weight have been shown to amplify the risk of: coronary artery disease, cerebrovascular disease, hypertension, hyperlipidemia, type II diabetes, cholelithiasis, pulmonary embolism, sleep apnea, gynecological problems, osteoarthritis, and psychiatric illness. Obesity leads to a higher risk for gynecologic cancer, cardiovascular disease, venous thromboembolism, osteoarthritis, and chronic back pain. Decline in estrogen levels associated with depression and physical inactivity are the major causes of the postmenopausal obesity. Thus, lifestyle modification including weight loss and physical activity is necessary to prevent these diseases by reducing the use of medications and by prolonging survival. In the present study we review current information about postmenopausal obesity, its origin and consequences and try to provide strategies for its treatment. Weight gain during the menopausal transition may be inevitable and unpreventable, but lifestyle alterations may help to minimize it. It must also be noted that these treatments may or may not be effective for every person; obesity may now need "personalized treatment".

Industrialization across the 20th and 21st century has led to a greater than ever longevity and a smaller than ever birth rate. Because of female’s advantage in survival, a predominance of females achieving old age is observed globally. For first time in the human history, industrialized societies bear mounting burdens of chronic lifestyle-related diseases, such as obesity and type 2 diabetes (t2DM). In the contrary, ovarian follicle depletion leading to menopause has not be influenced by environmental factors and has been constant for centuries. The evolutionary origin of human menopause remains an enigma. The fact is that the human female reproductive system ages to the point of failure at a relatively young age, and thus it is not surprising to see a postmenopausal increase in the incidence of so many disorders above that expected by age alone. Metabolic syndrome (MS) could be characterized as the ''Pandora’s box'', due to its content and the surrounding debate concerning its clinical utility, keeps ultimately the importance of a cluster of cardiometabolic risk factors which identify individuals at high risk of both t2DM and cardiovascular disease (CVD). The evolutionary origins of the MS are debated. Insulin resistance, chronic inflammation and abdominal fat accumulation are thought to be implicated in its pathophysiology. CVD is the most common cause of mortality in women worldwide, but incidence in women lags behind men by 10 years. Normal aging and alterations of the hormonal milieu related to menopause contribute to changes in risk factors for CVD, such as visceral adiposity. Emerging evidence points to the adipose tissue as a crossroad in the development of the MS, inflammation and atherosclerosis. Underlying mechanisms involve disequilibrium between proinflammatory cytokines (high interleukin- 6/C-reactive protein) and the anti-inflammatory adipokine (low adiponectin).

A number of factors are known to increase the risk of developing breast cancer. The most important of these is age, but race and ethnicity are associated with important differences in risk. Nulliparity and birth events, benign breast disease, and the use of replacement hormonal therapy at menopause also contribute to risk. Family history and the presence of predisposing genetic mutations are important factors as is ethanol consumption. Circulating estrogen levels can stratify risk, but their use in clinical settings is not routine. Risk for breast cancer can be easily and rapidly assessed in the clinic, and validated, quantitative models are available to accomplish this task. Mammographic breast density identifies postmenopausal women who are at increased risk. Multiple, published, randomized studies show that the selective estrogen response modifiers (SERMs) tamoxifen and raloxifene can safely reduce the risk of invasive breast cancer in both preand postmenopausal women. Tamoxifen provides net benefit to all premenopausal women who are at increased risk while raloxifene reduces risk nearly as much in postmenopausal women and offers increased safety. Both tamoxifen and raloxifene reduce both the incidence of in situ cancers and bone fractures. Women with a history of benign breast disease and a family history of invasive breast cancer in first-degree relatives and women with lobular carcinoma in situ derive substantial net benefit when using SERMs for breast cancer risk reduction. Of the 50 million white women in the U.S. aged 35 to 79 years, 2.4 million would have a positive benefit/risk index for chemoprevention.

The risk for endometrial carcinoma is directly related to age, with most cases occurring after the menopause. At this age group, the synthesis of estrogens continues, despite the decline of ovarian function. Androgen metabolism, in particular, is accelerated postmenopausally in all women, with the conversion of androstenedione to estrone. The reaction increases with increasing body weight. Thus, estrone, while a weak estrogen, by acting continuously and over a long period of time in its target tissue, the endometrium, may elicit the same biological response as does a potent estrogen such as estradiol in premenopausal women. This is evidenced by the fact that the postmenopausal endometrium, whilst atrophic, not only is potentially capable of giving genesis to endometrial carcinoma, but it does show a dramatic increase in the incidence of endometrial cancer during these years. Hence, endometrial carcinomas should no longer be regarded as “estrogen dependent” (Typed I carcinomas occurring in premenopausal women) or “estrogen independent” (Typed II carcinomas developing at menopause), but rather as neoplasms of high and low hormone dependency. Despite a general belief to the contrary, 55% of endometrial neoplasms occurring during menopause are G1 endometrioid adenocarcinomas, and almost 20% are G2-G3. A G1 endometrioid adenocarcinoma developing in a postmenopausal woman, however, has the same favorable prognosis as does an adenocarcinoma of similar type and grade originating in young pre-menopausal women. On the other hand, Grade 3 endometrioid adenocarcinomas together with serous papillary and clear cell carcinomas (which by definition are also Grade 3) are of poor prognosis. Hence, is neither the state of the nonneoplastic endometrium (atrophic or hyperplastic) nor the menopausal status that determines the behaviour of an endometrial tumor, but rather is the histological type (whether endometrioid or non endometrioid) and the degree of tumor differentiation (whether low or high grade) that matters. On this basis, it is believed that the malignant potential of endometrial carcinomas can be defined precisely.

The differential diagnosis of the adnexal mass indeed varies with the age. Age is the most important factor in determining the potential for malignancy. In postmenopausal women, an adnexal mass should be considered highly abnormal and must be promptly evaluated. The risk of malignancy in this age group is increased from 13% in premenopausal to 45% in postmenopausal women, however 55% of postmenopausal women with palpable ovaries do have a benign tumor. The most common ovarian tumors in this age group include epithelial ovarian tumors followed by stromal tumors and sex-cord tumors. The standard operative approach to adnexal masses in postmenopausal women has been explorative laparotomy to ensure adequate exposure for the treatment of ovarian cancer. However, laparoscopic evaluation of suspicious adnexal masses is considered a reasonable approach with ability to perform frozen section histologic analysis and confirm to laparotomy if needed.

The chapter includes a brief history of, and the interpretation offered by early Greek and other physicians in ancient times, regarding the changes which occurred in older women, together with a brief list of the many therapies available to early physicians to treat these women, from antiquity till the discovery and introduction of estrogen in the 20th century. Also included is a review of the more recent development of bio-identical and synthetic hormones for use in managing symptoms of hormone deficiency. The reason for using hormone therapy with the benefits identified and the improved health outcomes following use of long-term hormone therapy are listed. A brief comment is also made regarding the exploitation by the media and some health care providers of those adverse results identified in the Women’s Health Initiative study in 2002 and Million Women Study in 2003 and their role in modifying the use of hormone therapy for postmenopausal women. Because of the fear that women using hormone therapy will develop Breast Cancer, Alzheimer’s Dementia or Cardiovascular Disease the role of estrogen/progestin therapy on these outcomes is also briefly mentioned. The necessity for beginning therapy during the ‘window of opportunity’ is explained. The development, and the advantages, of various routes for delivery of hormones in order to reduce the risk of any adverse response to HRT are also discussed. The value of using HRT and other therapies for preventing and treating osteoporosis is presented and finally the most common alternative therapies currently being promoted for treating post-menopausal symptoms are critiqued.

Hot flushes affect approximately 75% of postmenopausal women and are one of the most distressing symptoms that women experience as they enter the menopause. The treatment of hot flushes is a common clinical challenge. A large body of data shows that HRT effectively relieves vasomotor symptoms by 80-90%, however, many patients may be unable or unwilling to undergo hormonal treatment. Publication of the results of the Women’s Health Initiative (WHI) and the Million Women Study (MWS) has led to considerable uncertainties about the role of hormone replacement therapy (HRT) among health professionals and women. All of these concerns have generated interest in nonhormonal treatment and many women seek alternative strategies to relieve climacteric complaints. The use of complementary and alternative medicine (CAM) among menopausal women has increased in the last years. This growth highlights the need for a critical evaluation of the tolerability and effectiveness of these readily available therapies. This chapter provides an overview for the evidence underlying the commonly used non-hormonal therapies for menopausal symptoms in terms of their efficacy and safety when used for relief of menopausal-related symptoms.

Premature Menopause (PM) is defined as menopause occurring prior to the age of 40 years. It may occur spontaneously or as a result of medical intervention including pelvic surgery, chemotherapy or radiotherapy. Spontaneous PM affects approximately 1% of women with a potentially higher incidence of induced PM with increasing rates of cancer survival. In the majority of women, the cause of spontaneous PM is unknown. PM results in both significant short term (menopausal symptoms, psychological distress, sexual dysfunction) and long term sequelae (infertility, an increased risk of osteoporosis, cardiovascular disease, cognitive dysfunction, dementia and overall mortality). Diagnosis can be difficult and is often delayed. Unless contraindicated, hormone replacement therapy is indicated until at least age 51 years for symptom relief and prevention of long term complications. Management should also be directed at lifestyle measures for symptom control and minimizing long term risks, treating sexual dysfunction, infertility treatment where desired, psychological support and education. Multi-disciplinary care is required to manage the complex needs of these patients.