19.1

Introduction

Menopause is an inevitable component of ageing and encompasses the loss of ovarian reproductive function, either occurring spontaneously or secondary to other conditions. This has a significant influence in women’s quality of life and the likelihood of healthy ageing:

• 1.
  

  Temporal changes in health and quality of life (vasomotor symptoms (VMS), sleep disturbance, and depression).

  
  
• 2.
  

  Longer term changes in several health outcomes (urogenital symptoms, bone, and lipids).

  
  
• 3.
  

  The loss of sex hormones during ageing contributes to changes in body mass, musculoskeletal integrity, sexual dysfunction, and long-term risks of health and disease.

  
  
• 4.
  

  Metabolic syndrome (insulin resistance syndrome) increases in prevalence after menopause and consists of insulin resistance, abdominal obesity, dyslipidaemia, elevated blood pressure, and proinflammatory and prothrombotic states.

  
  
• 5.
  

  The prevalence of obesity [body mass index (BMI) of >30 kg/m ² ] is higher in postmenopausal women than in premenopausal women.

  
  
• 6.
  

  This is a multifactorial process consequence of reduced energy expenditure due to physical inactivity, compounded by depression, muscle atrophy, and a lower basal metabolic rate.

  
  
• 7.
  

  Increase of total body fat and a redistribution of body fat from the periphery to the trunk, which results in visceral adiposity. Postmenopausal women had 36% more trunk fat, 49% greater intraabdominal fat area, and 22% greater subcutaneous abdominal fat area than premenopausal women in studies where computed tomography and magnetic resonance imaging have been used.

19.2

Oestrogens and menopausal obesity

• 1.
  

  Recent studies with oestrogen receptors (ER) knockout mice have helped to unravel the role of the ERs in brain degeneration, osteoporosis, cardiovascular diseases (CVDs), and obesity.

  
  
• 2.
  

  Sex hormones help integrate metabolic interaction among major organs that are essential for metabolically intensive activities such as reproduction and metabolic function.

  
  
• 3.
  

  Sex steroids are also required to regulate adipocytes’ metabolism and also influence the sex specific remodelling of particular adipose depots.

  
  
• 4.
  

  The function of oestrogens is mediated by nuclear receptors (ER α and ER β) that are transcription factors that belong to the superfamily of nuclear receptors. ER α and ER β are expressed by human subcutaneous and visceral adipose tissue, whereas only ER α mRNA has been identified in brown adipose tissue.

  
  
• 5.
  

  ER α plays a major role in the activity of adipocytes and sexual dimorphism of fat distribution. Polymorphism of ER α in humans is associated with risk factors for cardiovascular disease.

  
  
• 6.
  

  Body weight and BMI were significantly higher in perimenopausal and postmenopausal than in premenopausal women.

  
  
• 7.
  

  SWAN cross-sectional analysis showed no correlation between obesity and age at natural menopause, but obesity was associated with a likelihood of surgical menopause.

  
  
• 8.
  

  Concentrations of sex hormones partially control fat distribution: men have less total body fat but more central/intraabdominal adipose tissue, whereas women tend to have more total fat in gluteal/femoral and subcutaneous depots.

  
  
• 9.
  

  Fat tissue and regional fat tissue as a percentage of total fat tissue were higher in the trunk and arms in perimenopausal and postmenopausal than in premenopausal women. The shift to a central, android fat distribution can be counteracted by HRT.

  
  
• 10.
  

  The mean oestradiol level E2 change in transition from premenopausal to postmenopausal was less pronounced in obese women when compared with nonobese women. Obese women had lower premenopausal mean E2 levels but higher postmenopausal mean E2 levels.

  
  
• 11.
  

  Large observational studies have reported that obesity is a key factor for perimenopausal VMS but not postmenopausal VMS.

  
  
• 12.
  

  Data from WHI have shown that obesity is an important correlate for multiple urogenital symptoms, and obese women were twice as likely to report severe vaginal discharge and almost four times more likely to report severe itching/irritation compared with low, normal-weight women, controlling for diabetes.

  
  
• 13.
  

  It has been hypothesised that adipose tissue functions as an insulator and interferes with normal thermoregulatory mechanisms of heat dissipation.

  
  
• 14.
  

  A study using computed tomography demonstrated an increase in subcutaneous adipose tissue with age with age, independent of menopausal status, whereas visceral and total body fat increased only in women who became postmenopausal during the 4 years of follow-up. The change in visceral obesity was accompanied by a decrease in visceral circulating oestradiol and increase in FSH.

  
  
• 15.
  

  Ultrasound scanning has shown no difference in antral follicle count between obese and nonobese women in late reproductive age.

  
  
• 16.
  

  Follicular dysfunction and alterations in central nervous system regulation of hormonal levels among obese women may be contributory factors.

  
  
• 17.
  

  Change occurs in the primary source of circulating E2 as the menopause transition progresses; the primary source of circulating E2 premenopausally is the ovary, whereas in postmenopause the primary source of circulating E2 is the aromatisation of androgens within the adipose tissue.

19.3

Lifestyle intervention and hormone replacement therapy

Hot flushes and menopausal symptoms, in general, are more frequent in obese women compared to women with normal BMI.

• 1.
  

  Women who gain weight during the menopausal transition are more prone to have menopausal symptoms.

  
  
• 2.
  

  Obesity is associated with a greater likelihood of VMS, although women who are overweight (BMI from 25 to 30 kg/m ² ), as opposed to obese (BMI >30 kg/m ² ), are more likely to have severe symptoms.

Obese postmenopausal women are at increased risk of developing coronary heart disease (CHD).

• 1.
  

  According to the Nurses’ Health Study, a 5 kg/m ² increase in BMI is associated with a 30% increase in the incidence of CHD in women, independently of other CHD risk factors, such as age, smoking, physical activity, alcohol intake, or family history of CHD.

  
  
• 2.
  

  Stroke risk increases linearly with increasing BMI, independently of sex and race.

  
  
• 3.
  

  Women with BMI >32 kg/m ² have a relative risk of 2.37 of developing ischaemic stroke.

  
  
• 4.
  

  Women who gain 10–20 kg during their adult life have a 69% increase in the risk of ischaemic stroke.

Obese postmenopausal women are at increased risk of developing breast cancer with a relative risk of breast cancer ranging between 1.26 and 2.52.

A 5 kg/m ² increase in BMI is associated with a 12% increase in the incidence of breast cancer.

• 1.
  

  Possible explanations are the higher endogenous oestrogens produced by the aromatisation of precursor adrenal and ovarian androgens in adipose tissue and mitogenic IGF-1 activity associated with insulin resistance.

  
  
• 2.
  

  Apart from absolute body weight, the weight gained after 30th–40th year of age and especially perimenopausally appears to constitute an extra risk for breast cancer.

Obesity is associated with the increased risk of venous thromboembolism (VTE).

VTE is rare in premenopausal and young postmenopausal women and its incidence increases with age, BMI, and the presence of prothrombotic mutations (factor V-Leiden and prothrombin G20210A).

• 1.
  

  Obesity is a biologically plausible risk factor for VTE, but the mechanisms underlying the relation of obesity with VTE are not totally understood.

  
  
• 2.
  

  A strong positive correlation between plasminogen activator inhibitor-1 (PAI-1) level and BMI has been reported.

  
  
• 3.
  

  PAI-1 is the main fibrinolytic inhibitor, and reduced plasma fibrinolytic potential may be a risk factor for venous thrombosis.

  
  
• 4.
  

  Decreased fibrinolysis because of a high level of PAI-1 could explain in part the association of VTE with overweight and obesity.

  
  
• 5.
  

  Increased BMI was associated with higher levels of prothrombotic factors such as fibrinogen and factor (F) VII.

  
  
• 6.
  

  Both oral oestrogen and obesity may have synergistic effects on the imbalance between procoagulant factors and antithrombotic mechanisms.

  
  
• 7.
  

  By contrast, transdermal oestrogen appears to have little or no effect on haemostasis. Alternatively, increased C-reactive protein levels have been reported in obese individuals with a history of VTE, and low-grade inflammation could explain in part these findings.

  
  
• 8.
  

  In addition to the effects on haemostasis and inflammation, obesity may also have direct mechanic effects on the venous area.

  
  
• 9.
  

  An increased BMI may result in a higher VTE risk through an increased intra-abdominal pressure and a decreased venous return.

  
  
• 10.
  

  These effects may result in venous hypertension, varicose veins, and venous stasis, which promote the development of VTE.

19.4

Healthy lifestyle

• 1.
  

  All women at midlife should be encouraged to maintain or achieve a normal body weight, be physically active, adopt a healthy diet, limit alcohol consumption, and not smoke.

  
  
• 2.
  

  For obese women, weight loss may lessen VMS as well as reduce the risks of CVD, diabetes, urinary incontinence, breast, pancreatic, and endometrial cancers, and dementia.

  
  
• 1.
  

  HRT administration to postmenopausal women is associated with a significant decrease in the incidence of type 2 diabetes by the following mechanism :

  
  
  
  
  • a.
    

    Oestrogens seem to influence glucose homeostasis through increased glucose transport into the cells.

    
    
  • b.
    

    Lack of oestrogens has been associated with a progressive decrease in glucose-stimulated insulin secretion and insulin sensitivity as well as with insulin resistance.

    
    
  • c.
    

    In the systemic circulation, E2 and oestrone are partly bound to sex hormone binding globulin (SHBG), as well as to albumin, as is testosterone.

    
    
  • d.
    

    Increasing or decreasing SHBG levels will affect the amount of unbound oestrogen and testosterone in the circulation.

    
    
  • e.
    

    The aim of additional progesterone in women with intact uteri is to protect against the development of endometrial pathologies, including hyperplasia and cancer.

  
  

For those who require pharmacological therapies, average-dose HRT is the most effective treatment for VMS with reductions in both frequency and severity in the order of 75%, and HRT may improve quality of life in symptomatic women.

• 1.
  

  Obese postmenopausal women requiring HRT should be thoroughly evaluated at baseline and the severity of symptoms and risk of fracture should be weighed against individual risks of breast cancer, CVD, and VTE.

  
  
• 2.
  

  There is a rationale to use the lowest effective dose—oral conjugated equine oestrogens (CEEs) 0.300–0.400 mg or oestradiol 0.5–1 mg orally or 25–50 μg transdermally, and it may be preferable using the transdermal route.

  
  
• 3.
  

  HRT should be avoided in those with unexplained vaginal bleeding, active liver disease, previous breast cancer, CHD, stroke, personal history of thromboembolic disease, or known high inherited risk.

  
  
• 4.
  

  CVD risk factors do not automatically preclude HRT but should be taken into account.

  
  
• 5.
  

  Upregulation of the hepatic synthesis of procoagulants is another known effect of oral oestrogens.

  
  
• 6.
  

  Transdermal oestradiol does not seem to increase the risk of venous thromboembolic events.

  
  
• 7.
  

  Evidence shows that transdermal oestrogen (<=50 μg) is associated with a lower risk of deep vein thrombosis, stroke, and myocardial infarction compared to oral therapy and may be the preferred mode of treatment in women with an increased thrombosis risk, such as obese women and smokers.

Genitourinary syndrome (GSM) is a relatively new terminology describing vulvovaginal changes at menopause, as well as urinary symptoms of frequency, urgency, nocturia, dysuria, and recurrent urinary tract infections.

• 1.
  

  Vaginal dryness is common after menopause and unlike VMS usually persists and may worsen with time.

  
  
• 2.
  

  Urogenital symptoms are effectively treated with either local (vaginal) or systemic oestrogen therapy.

  
  
• 3.
  

  Oestrogen therapy restores normal vaginal flora, lowers the pH, and thickens and revascularises the vaginal lining.

  
  
• 4.
  

  The number of superficial epithelial cells is increased, and symptoms of atrophy are alleviated. Low-dose vaginal oestrogen improves vaginal atrophy without causing proliferation of the endometrium.

  
  
• 5.
  

  Initiation of HRT is usually contraindicated in women with a personal history of breast cancer or VTE, or those with a high risk for breast cancer, thrombosis, or stroke.

  
  
• 6.
  

  Transdermal oestrogen therapy may be considered and preferred when highly symptomatic women with type 2 DM or obesity, or those at high risk of CVD, do not respond to nonhormonal therapies.

  
  
• 7.
  

  Commencement of systemic hormone therapy is not recommended for women who are aged >60 years.

19.5

Progesterone

The combination of the oestrogen with a progestogen is used to avoid undue chronic stimulatory effects on the endometrium.

Endometrial cancer is the most common gynaecologic cancer, it is estimated that risk of endometrial cancer increases about 59% for every 5 unit increase in BMI (kg/m ² ), and overweight and obesity are responsible for 57% of all cases of endometrial cancer in the United States.

Obesity increases on exposure to oestrogen unopposed by progesterone in pre- and postmenopausal women. The inclusion of progesterone appears to increase breast cancer risk, but progestogens are still indicated to prevent endometrial hyperplasia and cancer risk.

• 1.
  

  Progesterone is naturally produced in the ovaries (particularly the corpus luteum), in the placenta, and, to a certain extent, in the adrenals, and there are a variety of synthetic progestogens.

  
  
• 2.
  

  One of these progestogens, dydrogesterone, is a retroprogesterone and, another, drospirenone (DRSP), is a spironolactone derivative.

  
  
• 3.
  

  The “newer” progestogens belong to different classes based on their structure. For each of them the progestogenic, as well as the antioestrogenic action, is common.

  
  
• 4.
  

  The antiandrogenic effect is relevant for dienogest and DRSP and minor for nomegestrol acetate. None of them have a glucocorticoid effect.

  
  
• 5.
  

  DRSP is different due to its strong antimineralocorticoid action and has a favourable effect on blood pressure. In addition, these progestogens do not interfere with the positive effect of oestrogens on lipid and carbohydrate metabolism, do not augment haemostasis processes as monotherapy, and avoid induction of abnormal proliferation of the endometrium in doses clinically tested.

Therefore all three progestogens appear to be suitable for the treatment of menopausal women.

The most recent Position Statement of the North American Menopause Society on HRT suggests that HRT may help attenuate abdominal adipose accumulation and the weight gains that are often associated with the menopause transition, and it significantly reduces the diagnosis of new-onset type 2 DM.

19.6

Emerging therapies

HRT could create important health risks; it is highly desirable to discover new alternatives in the menopause-related symptoms management, with minor side effects.

• 1.
  

  Dehydroepiandrosterone (DHEA) have been available over the counter. DHEA serves as a precursor for oestrogens and androgens from foetal life to post menopause.

  
  
• 2.
  

  DHEA may be an inactive precursor pool for the formation of bioactive steroid hormones.

  
  
• 3.
  

  DHEA-sulfate (DHEAS) represents the most abundant sex steroid in plasma in humans (more than 1000 times higher than oestradiol and testosterone levels), but its serum concentration goes down to 10%–20% of its maximum level by around the age of 70 years. The large difference between low and high serum DHEA levels has a major clinical impact.

  
  
• 4.
  

  Among postmenopausal women with coronary risk factors, lower DHEA levels were linked with higher mortality from CVD and all-cause mortality.

  
  
• 5.
  

  DHEA 10 mg daily administration in symptomatic postmenopausal women with lower (5th percentile) baseline DHEAS levels, may improve climacteric and sexual symptoms and directly reverse some age-related changes in adrenal enzymatic pathways, including adrenal DHEA and progesterone synthesis.

An oral selective ER modulator (SERM), ospemifene, has been approved for the treatment of moderate-to-severe pain during intercourse associated with vulvovaginal atrophy.

A tissue-specific SERM–oestrogen complex (a combination of oral CEE and bazedoxifene (BZA) (a SERM)) has been approved for the management of moderate-to-severe VMS in women with an intact uterus.

• 1.
  

  Tissue selectivity is achieved through the concurrent use of oestrogen and a SERM, which replaces a progestogen and selectively blocks the undesirable actions of oestrogen.

  
  
• 2.
  

  In the case of CEE-BZA, the proliferative effects of oestrogen are blocked in the uterus and possibly also the breast, whereas the bone-sparing actions of oestrogen are preserved.

  
  
• 3.
  

  The rationale for combining oestrogens with a SERM (T-SEC, combination of CEE and BZA (SERM)) is to retain the beneficial effects of oestrogens on VMS, VVA, and bone while incorporating the antiestrogenic effects of the SERM on the breast and endometrium to improve the overall safety profile.

  
  
• 4.
  

  The tissue-selective oestrogen complex (combination of 0.45 mg of oral CEE and 20 mg BZA (a SERM)) has been approved for the management of moderate-to-severe VMS in the United States and Europe.

Tibolone is a synthetic steroid that is rapidly converted to two metabolites with estrogenic activity and to a third metabolite characterised by a mixed progestogenic/androgenic activity.

• 1.
  

  Tibolone controls hot flushes, sweating, and mood symptoms and is effective in improving libido, due to its androgenic component.

  
  
• 2.
  

  Randomised, controlled studies show that tibolone increases bone mineral density and reduces fracture risk. These beneficial effects are seen over long-term treatments (over 10 years) and both in early and late postmenopausal women as well as in women with established osteoporosis.

  
  
• 3.
  

  The combined analysis of randomised clinical studies on tibolone indicates no increase in risk of breast cancer development compared with placebo.

  
  
• 4.
  

  Tibolone treatment is associated with a reduction of proliferation and a stimulation of apoptosis in normal breast cells that are possibly attributable to the impact of this compound on the activity of oestrogen-metabolising breast enzymes.

  
  
• 5.
  

  The metabolisation of tibolone is tissue selective, and the conversion to the progestogenic metabolite is particularly active in the endometrium.

  
  
• 6.
  

  Investigation of endometrial histology in women treated with tibolone shows no hyperplasia and a high level of atrophic endometrium, indicating no proliferative effect of this molecule.

A number of nonhormonal therapies are efficacious against menopausal VMS and should be considered for women who do not wish to take oestrogen or those with contraindications.

• 1.
  

  For VMS, many drugs have demonstrated efficacy in several studies: paroxetine, fluoxetine, and citalopram (which are selective serotonin reuptake inhibitors); venlafaxine and desvenlafaxine (selective noradrenaline reuptake inhibitors); clonidine (α2-adrenergic receptor agonist); and anticonvulsants (gabapentin and pregabalin).

  
  
• 2.
  

  Paroxetine and fluoxetine are potent cytochrome P4502D6 (CYP2D6) inhibitors and as they decrease the metabolism of Tamoxifen (a SERM used in the treatment of breast cancer)—which may reduce its anticancer effects—these drugs should be avoided in tamoxifen users.

  
  
• 3.
  

  Consistency of treatment response and efficacy of the various alternative options remain questionable.

19.7

Conclusion

• 1.
  

  The decision to start HRT in a women transitioning towards menopause requires a personalised discussion on the unique balance of risks and benefits.

  
  
• 2.
  

  During counselling, the importance of improving lifestyle, dietary habits, and implementing physical activity, especially their preventive role in cardiovascular disease, should be reiterated.

  
  
• 3.
  

  Evidence suggests that the balance of benefits and risks for HRT is more favourable within the first 10 years of menopause.

  
  
• 4.
  

  Based on the WHI data, the greatest risk appears to be associated with combined oestrogen–progestin therapy, therefore newer preparations may have a useful role in future practice.

  
  
• 5.
  

  Menopausal hormone therapy remains the most effective treatment of VMS and is also indicated for GSM and bone protection.

  
  
• 6.
  

  The duration of use for HRT should be individualised to take account of each patient’s requirements and risk-benefit profile.

  
  
• 7.
  

  The ultimate aim is to relieve bothersome menopausal symptoms and reduce the risk of osteoporosis and cardiovascular disease, without increasing the risk of endometrial or breast cancer.