Introduction
Menopause is the permanent cessation of menses due to oocyte depletion
[
1,
2]. It is characterised by a substantial decrease in endogenous
oestrogen production and represents the end of female reproductive life. Women after
menopause exhibit not only hormonal but also various phenotypical and biochemical
changes, which can predispose them to the development of type 2 diabetes mellitus
(T2DM) [
1,
2]. The transition from pre- to post-reproductive life is
associated with weight gain, especially with central obesity and an increase in
waist circumference [
1,
2]. Beyond central fat accumulation, menopause is
associated with sarcopenia and decreased muscle mass, which further contribute to
the change in body composition [
1‐
3]. Whether these phenomena are not only the result of
chronological aging, but also affected by ovarian aging has been a matter of
scientific discussion [
1‐
5]. A percentage of post-menopausal women present
with climacteric symptoms and have an indication to receive menopausal hormone
therapy (MHT) [
6‐
9]. In the past,
T2DM was considered an equivalent of cardiovascular disease (CVD), which would
suggest that women with the disease should not receive MHT [
8]. This notion may still deter many clinicians
from prescribing MHT to these patients. However, nowadays there is evidence to
support an individualized approach after careful evaluation of their CVD risk
[
2,
7].
The aim of this review is to analyse the risk of T2DM development after
menopause and the potential use of MHT for the management of climacteric symptoms in
these women. This article is based on previously conducted studies and does not
contain any studies with human participants or animals performed by any of the
authors.
T2DM Development after Menopause
The prevalence of T2DM is increasing in western countries, indeed
reaching epidemic proportions. This is broadly associated with aging and obesity,
with diagnosed cases representing 5–10% of the general adult population
[
8,
10]. Initial findings of major studies suggested that impaired
glucose metabolism after menopause was not related to decreased oestrogen
concentration, but was merely the result of chronological aging [
11,
12]. However, later analysis of data from the Study of Women’s
Health Across the Nation (SWAN) concluded that the lower the oestradiol
concentrations, the higher risk for T2DM development [
13]. Other studies have confirmed that T2DM risk is indeed
associated with a decline in ovarian function. The EPIC (European Prospective
Investigation into Cancer)-InterAct study showed that premature ovarian
insufficiency (before 40 years) was associated with a 32% higher risk for T2DM,
after following up women prospectively for 11 years [
14]. Another Chinese observational study including 16,299 women
provided evidence that early menopause (before 45 years) was associated with a 20%
higher risk for T2DM [
15]. Similarly,
studies with women after ovariectomy (surgical menopause), including data from the
National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Follow-up
Study, reported increased risk (up to 57%) for the development of T2DM [
16,
17].
A recent systematic review and meta-analysis [
18] included 13 studies with 191,762 women in
total, 21,664 of whom developed T2DM. Women with early menopause (40–45 years of
age) or premature ovarian insufficiency (< 40 years of age) present increased
risk for T2DM [odds ratio (OR): 1.12, 95% confidence interval (CI) 1.01–1.20,
p = 0.02;
p = 0.001 and OR: 1.53, 95% CI 1.03–2.27,
p = 0.035;
p = 0.001,
respectively] [
18]. Later analysis of
124,379 post-menopausal women from the Women’s Health Initiative (WHI) study showed
that women with short reproductive lifetimes (< 30 years between the age of
menarche and the age of the final period) had a 37% greater risk for the development
of T2DM compared with those 36–40 years between the age of menarche and the age of
the final period. Interestingly, this result was reached after adjustment for
chronological age [
19].
Indeed, menopause is accompanied by various consequences that could
explain the increased T2DM risk [
1,
2,
8]. One of the most prevalent changes is weight gain, associated
with an increase in total body fat mass, especially with central abdominal fat
accumulation and an increase in waist circumference [
2‐
4,
20]. With the use
of dual-energy x-ray absorptiometry (DXA), computed tomography (CT) or other
accurate body composition assessment techniques, it has been shown that the main
parameter affected during menopause is the intra-abdominal fat [
21‐
24]. When
peri-menopausal women were studied for 4 years, it was found that only those
entering menopause exhibited increased visceral fat [
25]. Additionally, menopausal women exhibited a significant
reduction in energy expenditure from fat oxidation without important changes in
energy intake [
25]. Indeed, energy
expenditure seems to be the earliest event, resulting probably from the decrease of
the activation capacity of oestrogen receptor-α (ERα) [
26,
27]. Such a relative loss of activation of the ERα can also
affect the hypothalamic neuron activity as well as the ability of the sympathetic
nervous system to regulate fat distribution through thermogenic activation in
adipose tissue [
28‐
30]. Menopause is
also associated with sarcopenia and decreased muscle mass [
22].
These changes in abdominal obesity and muscle mass may lead to physical
and psychological morbidity [
1,
2,
4]. A vicious cycle of subsequent excessive energy intake,
sedentary lifestyle and stress may then start and further deteriorate the
phenotypical and biochemical alterations of menopausal women [
2,
4].
Abdominal fat deposition and decreased muscle mass due to sarcopenia
after menopause lead to systemic low-grade inflammation [
8]. Visceral adiposity augments the production of
cytokines, contributing to the development of insulin resistance in the peripheral
tissues [
8]. Furthermore, menopause is a
state of relative androgen excess. The post-menopausal ovary continues to secrete
androgens, with higher bioavailability, because of the decrease in sex
hormone-binding globulin (SHBG). These hormonal changes further increase insulin
resistance [
31]. There is also scarce
evidence of the possible direct effect of menopause on insulin resistance,
independently of body composition [
31‐
34]. While relevant differences were not
detected with the use of euglycaemic and hyperinsulinaemic clamps, the gold standard
technique, insulin resistance was found to be increased in post-menopausal women
with the use of intravenous glucose tolerance test (IVGTT) [
32‐
34]. The insulin action may be affected by
related changes in insulin metabolism, such as liver clearance [
32,
33]. Moreover, experimental studies with female rodents and mice
have provided evidence that both decreased oestradiol levels and decreased
oestradiol action through the ERα could cause insulin resistance in skeletal muscle,
liver and adipose tissue [
35‐
43]. Pancreatic β
cells need to compensate insulin resistance to maintain normal glucose levels. There
is scarce data regarding the effect of menopause on insulin secretion, deriving
mainly from animal studies [
33].
Ovariectomy of rodents has been consistently shown to deteriorate β pancreatic cell
function, while the decreased oestradiol action via ERα and ERβ seems to affect the
survival of β cells and insulin secretion [
44‐
47]. Of course, the genetic predisposition of β
pancreatic cell dysfunction represents a crucial parameter for the ultimate
development of T2DM [
33,
44,
47].
MHT in Women with T2DM
Some women after menopause present hot flushes or night sweats, known
also as climacteric or vasomotor symptoms [
1,
2]. MHT is
indicated in such women, after evaluation of other comorbidities [
1,
2,
6,
7]. Recently, such symptoms have been associated with increased
risk of incident T2DM. A total of 150,007 women from the WHI study were
prospectively examined for the potential association of T2DM with climacteric
symptoms [
48]. Interestingly, any
vasomotor symptom was associated with an 18% increase in the risk of T2DM [hazard
ratio (HR): 1.18, 95% CI 1.14–1.22] and this was independent of obesity. The more
severe the symptoms and the longer their duration, the higher the risk for T2DM
development is [
48].
In the past, T2DM was broadly considered CVD equivalent, or at least as
an important CVD risk factor for women [
49], and this may still deter many clinicians from prescribing
MHT to such women. However, there is strong evidence for beneficial effects of MHT
in glucose homeostasis in women with or without T2DM. In women without T2DM, a
meta-analysis of 107 trials provided evidence that MHT can reduce abdominal fat,
HOMA-IR by 13% and incident T2DM by 30% [
50]. In women with T2DM, MHT exerts beneficial effects on fasting
glucose and HOMA-IR. The reduction in insulin resistance, as represented by HOMA-IR,
was 36%, even greater than in women without T2DM. This meta-analysis included very
important studies and large randomised controlled trials (RCTs), such as the
Post-menopausal Estrogen/Progestin Interventions (PEPI) study [
51], the Heart and Estrogen/Progestin
Replacement Study (HERS) [
52] and the
WHI Study [
53]. On top of improved
glucose homeostasis, MHT appears to improve other important CVD risk factors, such
as blood pressure, LDL cholesterol, triglycerides, lipoprotein(a), adhesion and
coagulation molecules [
50,
54].
The favourable effects of MHT on glucose metabolism appear to extend
beyond the correction of metabolic changes caused during menopausal transition. MHT
decreases abdominal fat deposition [
1]
through the increase of lipid oxidation and enhancement of energy expenditure
[
1,
38]. However, reduced central obesity is not necessarily the main
mechanism. Indeed, in HERS [
52] and WHI
trials [
53] as well as NHS
[
55] and E3N [
56] observational studies, the reduction in
incident T2DM incidence was independent of the reduction in body weight and waist
circumference. There is evidence that oestrogens may act directly on ERs in liver,
muscle or adipose tissue, improving insulin sensitivity and contributing to improved
glucose control and homeostasis [
57,
58]. Furthermore, oestrogens may
augment insulin secretion via a direct action on ERs in pancreatic β-cells, shown in
experimental studies with rodents [
44,
45].
Conjugated oestrogens (CEs) combined with medroxyprogesterone acetate
(MPA) represent the type of MHT mostly investigated in large studies. CEs are
available only in tablets, while 17β-oestradiol is available in both tablets and
transdermal regimens. Oral oestrogens harbour stronger beneficial effects on insulin
sensitivity, suppression of hepatic glucose production and cholesterol levels
because of the first-pass metabolism in the liver [
1,
2,
50,
59]. However, they increase hepatic synthesis of triglycerides,
coagulation factors and other inflammatory markers [
60].
Progestogens have been traditionally shown to decrease the beneficial
effects of oestrogens on glucose metabolism. This phenomenon is dose-dependent and
related to the development of insulin resistance [
61,
62]. However, it
appears that there are differences among various regimens. Indeed, MPA is known to
have glucocorticoid activity, while levonorgestrel is a testosterone-derived
product, both increasing insulin resistance. Conversely, natural progesterone,
norethisterone acetate (NETA) and dydrogesterone are more neutral regarding glucose
metabolism [
63‐
66].
Given the beneficial effects of MHT on glycaemic control, an
individualised approach in treating climacteric symptoms in post-menopausal women
with T2DM should be considered, after careful evaluation of their CVD risk
[
1,
2,
7,
67] (Table
1). Women should be stratified according to their CVD risk. In
older women with T2DM (> 60 years or > 10 years in menopause), MHT should not
be initiated, as such a therapy may destabilise mature atherosclerotic plaques,
resulting in thrombotic episodes. In obese women with T2DM or those with moderate
CVD risk, transdermal 17β-oestradiol could be used. Some experts recommend the use
of the coronary artery calcium score to identify women with established but latent
CVD [
1,
2,
7,
67]. This route of delivery presents more
beneficial effects regarding triglyceride concentrations and coagulation factors. In
peri- or recently post-menopausal diabetic women with low risk for CVD, oral
oestrogens can be used as they have the stronger beneficial effects on glucose and
lipid metabolism profiles. In any case, a progestogen with neutral effects on
glucose metabolism should be used, such as natural progesterone, dydrogesterone or
transdermal norethisterone [
1,
2,
7,
67].
Table 1MHT: suggestions for use in women with T2DM
> 60 years old or > 10 years in menopause or High CVD risk | NO |
Obese women or Moderate CVD risk | YES Prefer transdermal 17β-oestradiol Prefer neutral progestogen |
Peri- or recently postmenopausal and Low CVD risk | YES Prefer oral oestrogens Prefer neutral progestogen |