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three groups, premenopausal, perimenopausal, and postmenopausal, and compared
them with 354 postmenopausal women receiving different forms of HRT.The total
body fat tissue mass and distribution were analyzed using DXA.Body weight and
BMI were signicantly higher in perimenopausal and postmenopausal than in pre-
menopausal women. 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. Instead, in age-matched HRT- treated postmeno-
pausal women, the fat tissue was similar to that in the premenopausal group.
Perimenopausal and postmenopausal women show a shift to a central, android fat
distribution that can be counteracted by HRT.
14.2 The Menopausal Transition andCardiovascular Risk
Early after themenopause women begin to gain weight, and their body fat is redis-
tributed from a gynecoid to an android pattern. The increase in BMI and thepropor-
tion of visceral fat are strongly correlated with the development of hypertension,
insulin resistance, and a number of metabolic risk factors for CVD.It is otherwise
known that themenopause is associated with an increaseof TG, LDL-C, and lipo-
protein- a (Lp(a)). Levels of HDL-C gradually fall after themenopause, although
concentrations alwaysremain signicantly higher in womenas compared to men.
This nding could beconsidered a protective factor for female subjects.
CVD is the number one cause of death globally, both for men and women. It is
well documented that morbidity and mortality rates from CVD are higher in men
than in women; however, this gender gap narrows after the menopause suggesting
a role of female sex hormones and aging. In fact, the incidence of CVD in women
increases substantially with aging, probably because the menopause diminishes
the gender protection hencecontributing to an adverse impact overcardiovascular
risk variables. Nevertheless, whether this higher cardiovascular risk is a function of
aging or a consequence of the loss of endogenous estrogen due to the menopause or
both has been debated in the literature for many years [10].
Several studies in recent years haveanalyzed the differences of hormonal modi-
cations observed during the menopausal transition between obese and normal-
weight women. For instance, the results of the study of Women’s Health Across the
Nation (SWAN) are worth mentioning; SWAN is a multicenter, multiethnic longitu-
dinal study designed to characterize the physiological and psychosocial changes that
occur during the menopausal transition and to observe their effects on subsequent
health and risk factors for age-related diseases. A total of 3302 women were enrolled
at seven clinical sites between 1996 and 1997. At the time of enrollment, women
were premenopausal, nonhormoneusers, and agedfrom42 to52.The participants
were self-identied as African-American (28%), Caucasian (47%), Chinese (8%),
Hispanic (8%), or Japanese (9%). SWAN has a multidisciplinary focus and thus has
repeated measures of bone health, cardiovascular risk factors, psychosocial factors,
and ovarian hormones [11]. In this set, Matthews etal. evaluated the change in coro-
nary heart disease (CHD) risk factors in relation to a very particular and critical
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period of women’s life that is the nal menstrual period (FMP). Women who experi-
enced a natural menopause (1054 out of the total) were analyzed independent of age
and other confounders. The results showed signicant increases in total cholesterol,
LDL-C, and apolipoprotein B(Apo B) within a year of the FMP; importantly, the
rate of change relative to FMP did not vary by ethnicity, suggesting that menopause
had a uniform inuence on lipids. The other risk factors changed in a linear pattern
consistent with chronologic aging: TG, Lp(a), insulin, factor VIIc, and systolic blood
pressure increased; diastolic blood pressure, tissue plasminogen activator antigen,
brinogen, and high-sensitivity C-reactive protein did not change [10].
Similar to theSWAN study, in thePenn Ovarian Aging Study (POAS), obese
women had lower estradiol (E2) and follicular stimulating hormone (FSH) levels
than nonobese women. However, more rigorous analysis of hormonal changes
between obese and nonobese women before and after the FMP found that the pat-
terns of change in FSH and estradiol (E2) in relation to the FMP were not sta-
tistically different. The E2 change was less pronounced in obese women when
compared with nonobese women. The rate of E2-blunted decline observed among
obese women is physiologically corroborated by a similarly blunted FSH rise sur-
rounding the FMP in obese versus nonobese women. Ultrasound data have shown
no difference in antral follicle count between obese and nonobese women in their
late reproductive years(40–52years). This lack of difference does not support low
ovarian reserve as the mechanism underlying lower E2 levels in obese women pre-
menopausally, mechanismwhich is currently unclear.
In the POAS, theanti-Müllerian hormone (AMH) was found to be lower in obese
women compared to nonobese onesin the late reproductive years, demonstrating
the complex relationship between obesity and reproductive hormones in women
approaching the menopause. Follicular dysfunction and alterations in the central
nervous system regulation of hormonal levels among obese women may be factors,
but additional research in this area is required. The blunted magnitude of change
in reproductive hormones in obese women during menopausal transition may be
related to the modication in the primary source of circulating E2 as the menopausal
transition progresses; the primary source of circulating E2in premenopausal period
is the ovary, whereas in postmenopause, the primary source of circulating E2 is the
aromatization of androgens within the adipose tissue. This change in E2 source pro-
vides postmenopausal obese women with a non-ovarian reservoir of estrogen that
normal-weight women do not have, which may blunt gonadotropin rises and miti-
gate ovarian estrogen loss relatedwiththe menopause. These hormonal alterations
may also blunt menopause-associated adverse health effects [
12, 13]. Data from
the Women’s Healthy Lifestyle Project provide clear evidence that weight gain and
increased waist circumference, along with elevations in lipid levels and other CVD
risk factors, are preventable through lifestyle intervention in healthy menopausal-
aged women. In fact, although these changes are inevitable with age and meno-
pause, physical activity may attenuate the impact of both events. Thus, weight gain
prevention should be recognized as an important health goal for women before they
approach themenopause and women should make regular physical activity [14].
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14.3 Other Menopausal Changes Related toExcessive Body
Weight
Genitourinary syndrome (GSM) is a relatively new terminology describing vulvo-
vaginal changes at menopause, as well as urinary symptoms of frequency, urgency,
nocturia, dysuria, and recurrent urinary tract infections. Vaginal dryness is com-
mon after themenopause and unlike vasomotor symptoms (VMS) itusually persists
and may worsen with time. Urogenital symptoms are effectively treated with either
local (vaginal) or systemic estrogen therapy. Pelvic oor dysfunction is more com-
mon in the overweight and obese women. Risk factors for developing pelvic organ
prolapse (POP) can be divided into obstetric, lifestyle, comorbidity, aging, social,
pelvic oor, and surgical factors. The most important lifestyle factor is a higher
BMI.Obesity may impair pelvic oor function increasing intra-abdominal pressure
that damages pelvic musculature and nerve; this is linked to conduction abnormali-
ties and obesity-related comorbidities including diabetic neuropathy and interverte-
bral disc herniation [15, 16].
14.4 Management ofWomen withtheMetS andObesity
Across theMenopause
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 quit smoking. Some women nd that avoidance of spicy food, hot drinks,
and alcohol lessens their VMS.Obesity is associated with a greater likelihood
of VMS,although women who are overweight (BMI from 25 to <30kg/m
2
), as
opposed to obese (BMI≥ 30 kg/m
2
), are more likely to have severe symptoms.
For obese women, weight loss may lessen VMS, as well as reduce the risks of
CVD;diabetes; urinary incontinence; breast, pancreatic, and endometrial cancer;
and dementia.
Estrogens seem to inuence glucose homeostasis through increased glucose
transport into cells, whereas thelack of estrogens has been associated with a
progressive decrease in glucose-stimulated insulin secretion and insulin sensi-
tivity as well as with insulin resistance. These may explain why HRT adminis-
tration to postmenopausal women is associated with a signicant decrease in the
incidence of type II diabetes. Estrogen deciency is the principal pathophysi-
ological mechanism that underlies menopausal symptoms, and various estrogen
formulations are prescribed as menopausal hormone therapy, which remains
the most effective available therapeutic option. The addition of progesterone
aimsat protectingagainst the consequences of systemic therapy with estrogen
only in women with intact uteri [17], namely, endometrial pathologies, includ-
ing hyperplasia and cancer. The risk- benet ratios of all treatment options must
be considered, taking into acountthe nature and severity of symptoms and indi-
vidual treatment-related risks.
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In the systemic circulation, E2 and estrone, as well as testosterone, are partly
bound to sex hormone-binding globulin (SHBG), as well as to albumin. Increasing
or decreasing SHBG levels will affect the amount of unbound circulatingestrogen
and testosterone [18].
Obesity is a biologically plausible risk factor for venous thromboembolism
(VTE), but the mechanisms underlying the relation of obesity with VTE are not
totally understood. A strong positive correlation between plasminogen activator
inhibitor-1 (PAI-1) levels and BMI has been reported. PAI-1 is the main brinolytic
inhibitor, and reduced plasma brinolytic potential may be a risk factor for venous
thrombosis. Decreased brinolysisdue to a high level of PAI-1 could explain in part
the association of VTE with overweight and obesity. Moreover, other studies sug-
gested that an increased BMI was associated with higher levels of prothrombotic
factors such as brinogen and factor VII(F-VII). Thus, both oral estrogen and obe-
sity may have synergistic effects on the unbalance between procoagulant factors and
antithrombotic mechanisms. By contrast, transdermal estrogen appears to have little
or no effect on hemostasis. Alternatively, increased C-reactive protein levels have
been reported in obese individuals with a history of VTE, and low-grade inam-
mation could explain in part thesendings. In addition to the effects on hemostasis
and inammation, obesity may also have direct mechanical effects on the venous
system. An increased BMI may result in a higher VTE risk through an increased
intra-abdominal pressure and a decreased venous return. These effects may result in
venous hypertension, varicose veins, and venous stasis which promote the develop-
ment of VTE [19].
For those who require pharmacological therapies, average dose HRT is the most
effective treatment for VMS [20] with reductions in both frequency and severity in
the order of 75%, and the improvement ofquality of life in symptomatic women
[21]. HRT should be avoided in those with unexplained vaginal bleeding, active
liver disease, previous breast cancer, coronary heart disease, stroke, personal his-
tory of thromboembolic disease, or aknown high inherited risk. CVD risk factors
do not automatically preclude HRT but should be taken into account. Upregulation
of the hepatic synthesis of procoagulants is another known effect of oral estrogens.
Transdermal estradiol does not seem to increase the risk of venous thromboembolic
events. Evidence shows that transdermal estrogen (≤50μg) 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. In addition, unlike
oral estrogen, transdermal estradiol does not increase the risk of gallbladder disease
[
22, 23].
Estrogen therapy restores thenormal vaginal ora, lowers the pH, and thickens
and revascularizes the vaginal lining. The number of supercial epithelial cells is
increased and symptoms of atrophy are alleviated. Importantly, low-dose vaginal
estrogen improves vaginal atrophy without causing proliferation of the endome-
trium. Given the documented efcacy and proven safety, vaginal estrogen is the
rst-line approach to treat symptoms of vaginal atrophy in the majority of women:
vaginal estrogen is effective, and while systemic absorption does occur, it does
not induce endometrial hyperplasia. Concerns regardingsystemic absorption has
lead to the tendency that vaginal estrogens be avoided in breast cancer patients
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taking aromatase inhibitors. The relationship between HRT and urinary inconti-
nence depends on the delivery route. Systemic HRT worsens urinary incontinence,
but vaginal treatment may improve urge incontinence and prevent recurrent urinary
tract infections. Using very low doses for the rst few weeks is helpful if irritation
occurs, and indeed lower doses of vaginal estrogens, with less frequent administra-
tion, often yields satisfactory results [16, 24].
In conclusion, initiation of hormone therapy is usually contraindicated in
women with a personal history of breast cancer or VTEor those with a high risk
for breast cancer, thrombosis, or stroke. Transdermal estrogen therapy may be
considered and preferred when highly symptomatic women with type 2 diabetes
mellitus or obesity, or those at high risk of CVD,do not respond to non-hormonal
therapies. In general, initiation ofof HRTis not recommended for women who are
aged >60[25].
In order to avoid undue chronic stimulatory effects on the endometrium, con-
trol menstrual bleeding, avoid abnormal bleeding, and avoid cancer development,
the combination of the estrogen with a progestogen is needed. Endometrial cancer
is the most common gynecologic cancer: it is estimated that risk of endometrial
cancer increases about 59% for every 5units ofincrease in BMI(kg/m
2
) and over-
weight and obesity are responsible for 57% of all cases of endometrial cancer in
the USA. Obesity increases exposure to estrogen 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 hyper-
plasia and cancer risk [26].
Progesterone is naturally produced in women in the ovaries (particularly the cor-
pus luteum), in the placenta, and to a certain extent in the adrenalglands. There are
a variety of synthetic progestogens. One of these progestogens, dydrogesterone, is
a retro-progesterone, and another, drospirenone (DRSP), is spironolactone deriva-
tive. The “newer” progestogens belong to different classes based on their struc-
ture. For each of them, progestogenic, as well as antiestrogenic action, is common.
The antiandrogenic effect is relevant for dienogest (DNG) and DRSP and lesserfor
nomegestrol acetate (NOMAC). None of them have a glucocorticoid effect. DRSP
is different due to its strong antimineralocorticoid action and has a favorable effect
on blood pressure. In addition, these progestogens do not interfere with the posi-
tive effect of estrogens on lipid and carbohydrate metabolism, theydo not augment
hemostasis processes as monotherapy, and they avoid theinduction of abnormal
proliferation of the endometrium in doses clinically tested. Therefore, all three pro-
gestogens appear to be suitable for thetreatment of menopausal women [27].
Nonetheless, considering that HRT could create important health risks, it is highly
desirable the discovery of new alternatives for the management of menopause-
related symptoms,with minor side effects. Over the past 15years, hormone prepa-
rations of dehydroepiandrosterone (DHEA) have been available over the counter
and have been sold as the “fountain of youth.” DHEA serves as a precursor for
estrogens and androgens from fetal life to the postmenopause, and many people
believe that DHEA is merely an inactive precursor pool for the formation of bioac-
tive steroid hormones. DHEAs represent the most abundant sex steroid in plasma
in humans (more than 1000 times higher than estradiol and testosterone levels), but
its serum concentration goes down to 10–20% of its maximum level by around the
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age of 70.The large difference between low and high serum DHEA levels has a
major clinical impact. Among postmenopausal women with coronary risk factors,
lower DHEA levels were linkedto higher CVDand all-cause mortality [25]. Several
studies had previously demonstrated that 1-year treatment, using administration of
10mg DHEA daily in symptomatic postmenopausal women with lower (fth per-
centile) baseline DHEAsulphate levels, improved climacteric and sexual symptoms
and directly reversed some age-related changes in adrenal enzymatic pathways,
including adrenal DHEA and progesterone synthesis [28–30].
14.5 Non-hormonal Treatments
In the past 2years, two new pharmaceutical preparations were approved in the
USA and Europe for the treatment of menopausal symptoms: an oral selective
estrogen receptor modulator (SERM), ospemifene, for the treatment of moderate
to severe pain during intercourse associated with vulvovaginal atrophy [31] and
a tissue- selective estrogen complex (TSEC), a combination of oral conjugated
equine estrogen(CEE) and bazedoxifene (BZA,a SERM), for the management
of moderate to severe VMS in women with an intact uterus. Tissue selectivity is
achieved through the concurrent use of estrogen and a SERM, which replaces
a progestogen and selectively blocks the undesirable actions of estrogen. In the
case of CEE-BZAthe proliferative effects of estrogen are blocked in the uterus
and possibly also the breast, whereas the bone-sparing actions of estrogen are
preserved. The role of testosterone for the treatment of postmenopausal desire
or arousal disorders and the long-term implications of such a therapy in post-
menopausal women are unclear. The motivation for combining CEE-BZA is to
retain the benecial effects of estrogens over VMS, vulvovaginal atrophy,and
bone while incorporating the antiestrogenic effects of the SERM on the breast
and endometrium to improve the overall safety prole [32]. The combination of
20mg BZA and 0.45mg CEE is the only approved drug to date for the manage-
ment of moderate to severe VMS in the USA and Europe [33].
Tibolone is a synthetic steroid that is rapidly converted into two metabolites
with estrogenic activity and to a third metabolite characterized by a mixed pro-
gestogenic/androgenic activity. Tibolone controls hot ushes, sweating, and mood
symptoms and is effective at improving libido, due to its androgenic component.
Randomized, controlled studies show that tibolone increases bone mineral density
and reduces fracture risk. These benecial effects are seen over long-term treat-
ments [34] (over 10years) and in both early and late postmenopausal women, as
well as in women with established osteoporosis. The combined analysis of ran-
domized clinical studies oftibolone indicates no increase in risk of breast cancer
development compared with theplacebo group. Tibolone treatment is associated
with a reduction of proliferation and a stimulation of apoptosis in normal breast
cells that is possibly attributable to the impact of this compound on the activity of
estrogen-metabolizing breast enzymes [35]. The metabolization of tibolone is tissue
selective, and the conversion to the progestogenic metabolite is particularly active
in the endometrium. Investigation of endometrial histology in women treated with
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tibolone shows no hyperplasia and a high level of atrophic endometrium, indicating
no proliferative effect of this molecule.
Some non-hormonal therapies are effectiveagainst menopausal VMSand should
be considered for women who do not wish to take estrogens or those with con-
traindications. For VMS,many drugs have demonstrated efcacy in several stud-
ies: paroxetine, uoxetine, and citalopram (which are selective serotonin reuptake
inhibitors); venlafaxine and desvenlafaxine (selective noradrenaline reuptake
inhibitors); clonidine (α
2
-adrenergic receptor agonist); and anticonvulsants (gaba-
pentin and pregabalin). Paroxetine and uoxetine are potent cytochrome P450 2D6
(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 amongtamoxifen users. However, consistency of
treatment response and efcacy of the various alternative options remain question-
able [33, 36–38].
14.6 Conclusions
MetS refers to a clustering within the same individual of hyperinsulinemia, mild to
severe glucose intolerance, dyslipidemia, hypertension, an increased risk for CVD
and diabetes. Parallelto this, adipose tissue could be an “insulator” and interfere
with normal thermoregulatory mechanisms of heat dissipation. Women with higher
abdominal adiposity, particularly subcutaneous adiposity, report an increase of VMS
during the menopausal transition and in theearly postmenopause. Healthy weight
amongmid-agedwomen who areearly in the menopausal transition may help pre-
vent VMS.Overweight women may suffer psychosocial consequences, with a signif-
icant impact on self-esteem and general well-being: obese postmenopausal women
have lower health-related quality of life, physical functioning, energy, and vitality
compared with normal-weight women. Obesity is also a major risk factor for pelvic
oor dysfunction, some cancers (endometrial, breast and colon) and musculoskeletal
disorders, especially osteoarthritis (a highly disabling degenerative disease of the
joints). It could be necessary to encourage lifestyle measures in addition to thera-
peutic interventions throughout the menopausal transition in order to control meno-
pausal obesity and to manage menopause-related symptoms, with mildside effects
(Tables14.1 and 14.2).
Table 14.1 Mechanisms by which estrogen may exert benecial cardiovascular effects
Direct effects Indirect effects
Nitric oxide production and release ↑ Total cholesterol ↓, LDL ↓, HDL ↑
Prostacyclin production and release ↑ Antioxidant effects: oxidation of LDL ↓
Endothelin-1 production and release ↓ Blood pressure ↓
Cytokine release ↓ Insulin sensitivity ↑
Inammation ↓ Homocysteine ↓
Smooth-muscle cell growth ↓ Ischemia/reperfusion injury ↓, cardiac hypertrophy ↓
Atherosclerotic plaque progression ↓
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Fasting glucose Diabetes mellitus,
impaired glucose
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>110mg/dL >100mg/dL or
previously type-II
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Blood pressure ≥140/90mmHg or
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>130/85mmHg or
use of medication
>130/85mmHg or
use of medication
Dyslipidemia (TG) ≥150mg/dL ≥150mg/dL ≥150mg/dL
Dyslipidemia
(HDL-CH)
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<39mg/dL for
females
<50mg/dL for
females
<50mg/dL for
females
Central obesity WHR >0.9in males Waist circumference Waist circumference
>0.85 for females
and/or BMI >30
≥102cm for males >94cm for males
≥88cm for females >80cm for females
for Caucasian race
Microalbuminuria Urinary albumin
excretion ratio
≥20μg/min or
albumin:creatinine
ratio ≥30mg/g
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