Download Fasting Plasma Glucose Levels and Endogenous

Clinical Science (1991)80,199-203
199
Fasting plasma glucose levels and endogenous androgens in
non-diabetic postmenopausal women
KAY-TEE KHAW
AND
ELIZABETH BARRETT-CONNOR*
Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, U.K., and
*Department of Community and Family Medicine M-007, School of Medicine, University of California San Diego, La Jolla, California,
U.S.A.
(Received 13 July/l7 September 1990; accepted 20 September 1990)
SUMMARY
INTRODUCTION
1. The clinical association between glucose intolerance, hyperinsulinaemia, insulin resistance and
hyperandrogenism is well recognized in premenopausal
women with polycystic ovarian disease. We examined the
hypothesis that fasting plasma glucose levels might be
related to endogenous androgen levels in postmenopausal
women in the absence of overt clinical disease.
2. In a Southern Californian cohort of 848 nondiabetic postmenopausal women aged 50-79 years, fasting plasma glucose levels positively correlated with levels
of the endogenous androgens dehydroepiandrosterone
sulphate and free testosterone and negatively with sexhormone-binding globulin across the whole range of
glucose and hormone levels. Mean dihydroepiandrosterone sulphate and free testosterone levels were 16%
and 46% higher, respectively, and mean sex-hormonebinding globulin levels 27% lower in the top compared
with the bottom quartile of fasting plasma glucose levels.
This relationship was independent of age, body mass
index, cigarette smoking habit and exogenous oestrogen
use.
3. These findings raise questions about the possible
physiological role of androgens in the regulation of
glucose metabolism and insulin resistance and, possibly,
in the mediation of the some of the cardiovascular consequences of diabetes in women.
Achard & Thiers in 1921 [l]described an association
between diabetes mellitus and virilism in women (‘diabkte
des femmes a barbe’) in conjunction with post-mortem
adrenal hyperplasia. More recently, clinical studies have
reported decreased glucose tolerance and increased
insulin levels, correlating with hyperandrogenism, in
patients with polycystic ovarian disease, suggesting a
relationship between hyperandrogenism and insulin
resistance [2-51. We present the first population-based
data which provide evidence that the relationship
between fasting plasma glucose and endogenous
androgen levels is apparent throughout the whole physiological distribution in postmenopausal women.
Key words: androgens, plasma glucose, women.
Abbreviations: DHEAS, dehydroepiandrosterone sulphate; SHBG, sex-hormone-binding globulin.
Correspondence: Professor Kay-Tee Khaw, Clinical Gerontology Unit, University of Cambridge School of Medicine,
Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ,
U.K.
Reprint requests: Professor Elizabeth Barrett-Connor,
Department of Community and Family Medicine M-007,
University of California San Diego, La Jolla, CA 92093, U.S.A.
METHODS
Between 1972 and 1974,82% of a geographically defined
community in Rancho Bernardo, Southern California,
U.S.A. [6], participated in a survey of cardiovascular
disease risk factors. All subjects underwent a standardized medical interview which included questions about
personal history of diabetes, medication use, including
exogenous hormones, and cigarette smoking habit.
Virtually all women taking exogenous sex hormones in
this cohort were on unopposed conjugated oestrogens
(Premarin). Height and weight were measured with participants in light clothing without shoes; plasma was
obtained by venepuncture between 07.30 and 11.00
hours from subjects who had fasted for at least 12 h.
Plasma glucose levels were measured by using the hexokinase method in a standardized reference laboratory.
The plasma samples for sex hormone assays were frozen
at - 70°C. In 1984-1986 samples were first thawed for
sex hormone radioimmunoassays in an endocrinology
research laboratory [7, 81. Previous work has demonstrated no hormone deterioration over 15 years when
sera were frozen and stored in tightly sealed containers.
K.-T. Khaw and E. Barrett-Connor
200
The sensitivity and intra- and inter-assay coefficients of
variation, respectively, were: dehydroepiandrosterone
sulphate (DHEAS), 0.05 pmol/l, 5% and 10%;
androstenedione, 0.10 nmol/l, 4% and 8%; testosterone,
0.09 nmol/l, 4% and 10%; oestrone, 25 pmol/l, 15% and
16%; and oestradiol, 18 pmol/l, 8% and 12%. Sexhormone-binding globulin (SHBG)was determined by the
method of Rosner [9]. After analysing hormones in a
randomly selected sample of women, the study sample
size was expanded to include all eligible women who had
available stored frozen serum. In these later samples,
cortisol and non-SHBG-bound (or free) testosterone and
oestradiol were also estimated using a modification of the
method of Tremblay & Dube [lo]. Data were analysed
using the Statistical Package for the Social Sciences
(SPSSX). Analysis of variance techniques were used for
age adjustment where required.
RESULTS
There were 944 women, aged 50-79 years, with available
hormone results. We excluded the 27 women who had a
personal history of diabetes, and a further 32 women who
had a fasting plasma glucose level of 7.8 mmol/l(l40 mg/
dl) or greater. The oestrone and oestradiol hormone distributions were very skewed due to women who had preor pen-menopausal levels; we did not have follicle-stimulating hormone or luteinizing hormone levels available, so
to derive a postmenopausal group we excluded women
with oestrone > 700 pmol/l or oestradiol 3 350 pmol/l,
as well as women with extreme outlying values (testosterone 3 3.5 nmol/l). A further 37 were thus excluded, leaving a total of 848 women for analysis.
Table 1 shows the distribution of variables in this
cohort of women. Table 2 shows correlations of fasting
plasma glucose and hormone levels with age and with
body mass index after adjusting for age. Fasting plasma
glucose levels did not relate significantly to age in this
older cohort of non-diabetic women; the adrenal
androgens DHEAS and androstenedione, cortisol,
oestrone, total and free oestradiol and SHBG were significantly negatively related to age; total testosterone was
positively related to age. Only androstenedione, cortisol
and SHBG were significantly negatively related to body
mass index after adjusting for age. Fasting plasma glucose
levels were significantly positively related to age-adjusted
body mass index.
Table 3 shows mean age- and body mass indexadjusted (using analysis of variance) hormone levels by
quartile of fasting plasma glucose level. For both DHEAS
and free testosterone levels, there was a signifiant positive
trend, with increasing mean hormone levels with increasing quartile of fasting plasma glucose level. A negative
trend was apparent for SHBG, with mean levels decreasing with increasing quartile of fasting plasma glucose level.
No trends were apparent for androstenedione, total testosterone, oestrone, total and free oestradiol and cortisol.
Table 3 also shows age- and body mass index-adjusted
partial correlation coefficients of fasting plasma glucose
level with hormones and SHBG in all the women. Fasting
plasma glucose level was significantly positively correlated with DHEAS and free testosterone and was significantly negatively correlated with SHBG; there was no
significant correlation of fasting plasma glucose level with
androstenedione, total testosterone, oestrone, total and
free oestradiol or cortisol.
There were 267 women taking exogenous oestrogens
and 197 current cigarette smokers; in this cohort,
oestrogen use and current cigarette smoking were
associated with some differences in both fasting plasma
glucose level and hormone levels. However, the positive
relationship of fasting plasma glucose levels with
androgens was independent of both smoking and
oestrogen use, and were consistent after stratification.
Table 4 shows age- and body mass index-adjusted
hormone levels by oestrogen use and by fasting plasma
glucose level above and below the median. DHEAS,
androstenedione, free testosterone and SHBG were sig-
Table 1. Distribution of variables in non-diabetic [no personal history of diabetes, fasting plasma
glucose level < 7.8 mmol/l (140 mg/dl)] postmenopausal Rancho Bernard0 women aged 50-79
years in 1972-1974
Mean
n
SD
~
Age (years)
Body mass index ( kg/m2)
DHEAS (pmol/l)
Androstenedione (nmol/l)
Testosterone (nmol/l)
Oestrone (pmol/l)
Oestradiol (pmol/l)
lo6X SHBG (mol/l)
Testosterone/SHBG ratio
Free testosterone (nmol/l)
Free/total testosterone ratio
Free oestradiol (pmol/l)
Cortisol (nmol/l)
Current cigarette smokers (no.)
Current oestrogen users (no.)
64.9
24.2
2.07
2.04
0.86
160
65
4.72
0.35
0.35
0.47
41
527
197 (23.2%)
267 (31.5%)
7.0
3.6
1.46
1.01
0.49
11
61
3.62
0.46
0.25
0.24
39
195
848
848
848
848
848
848
848
848
848
371
37 1
37 1
371
848
848
Plasma glucose and androgen levels in women
nificantly related to both oestrogen use and category of
fasting plasma glucose level.
The magnitude of the significant relationship between
plasma glucose levels and hormones was not large; however, that a significant relationship could be demonstrated
at all was surprising given that only one blood sample was
used to characterize the individual with respect both to
plasma glucose level [l11 and to hormones. All samples
were taken in the morning from fasting subjects, thus
reducing diurnal variation. Random measurement errors
would tend to reduce the magnitude of any association.
Additionally, the distribution of fasting plasma glucose
level was a truncated one with high values excluded,
reducing the range, and hence the power of the study.
These factors, together with the consistent and
dose-response nature of the relationships, make it seem
unlikely that the associations between fasting plasma
glucose level and DHEAS, free testosterone and SHBG
are spurious. The associations were independent of age
and body mass index as well as exogenous oestrogen use
[ 121 and cigarette smoking, other possible confounding
variables.
The relationship of free testosterone to fasting plasma
glucose level is consistent with other studies [13],
although the association of DHEAS, the adrenal
androgen, with fasting plasma glucose level is less clear.
Schriock et al. [ 141 have even suggested that DHEAS and
testosterone have divergent effects on insulin. Differences
between studies may reflect case selection in the clinical
studies or differences between pre- and post-menopausal
women.
There are several possible explanations for the
observed association between androgens and fasting
plasma glucose level. First, they could both be markers of
some other underlying physiological process such as
stress. DHEAS and cortisol are secreted by the adrenals
in response to adrenocorticotropic hormone [ 151; high
cortisol levels are well recognized to be associated with
impaired glucose tolerance in Cushing's syndrome.
DHEAS could simply be concomitant with the increased
cortisol; however, cortisol levels did not relate to fasting
plasma glucose levels in this cohort.
DISCUSSION
This study, in postmenopausal women, demonstrates a
relationship between fasting plasma glucose and
endogenous androgen levels. These data demonstrate that
such a relationship exists in a population through the
whole physiological range of fasting plasma glucose level,
DHEAS and free testosterone, well below any clinically
defined abnormal levels; we excluded all diabetic subjects
and any women with fasting plasma glucose levels above
the traditionally accepted criterion for diabetes mellitus.
Table 2. Correlation coefficients of fasting plasma glucose
and hormones with age and body mass index in nondiabetic [no personal history of diabetes, < 7 . 8 mmol/l
fasting plasma glucose level (140 mg/dl)] postmenopausal
Rancho Bernardo women aged 50-79 years in
1972-1974
Statistical significance:*P<0.05, **P< 0.01, ***P< 0.001.
Correlation coefficient (r)
~~~~
Age
Body mass index
Fasting plasma glucose level
DHEAS
Androstenedione
Testosterone
Oestrone
Oestradiol
SHBG
Free testosterone
Free/total testosterone ratio
Free oestradiol
Cortisol
0.1 I**
0.0 1
- 0.20***
-0.10**
0.08*
-0.10**
-0.12**
-OM***
0.05
0.08
- 0.23
-0.11
201
Body mass index
(age-adjusted)
0.17***
-0.01
- 0.08*
- 0.05
0.03
0.06
-0.19***
0.08
0.14**
0.10
-0.13**
Table 3. Age- and body mass index (BMI)-adjusted mean hormone levels by quartile of fasting plasma glucose level using
analysis of variance, and age- and BMI-adjusted partial correlation coefficient (r) of fasting plasma glucose with hormone
levels in non-diabetic [no personal history of diabetes, fasting plasma glucose level <7.8 mmol/l (140 mg/dl)] postmenopausal Rancho Bernardo women aged 50-79 years in 1972-1974
Statistical significance: * P < 0.01, **P< 0.001.
Age- and BMI-adjusted mean hormone level
Quartile of fasting plasma glucose level (mmol/I)... < 5.3
DHEAS (pmol/I)
Androstenedione (nmol/l)
Testosterone (nmol/l)
Oestrone (pmol/l)
Oestradiol (pmol/l)
10' x SHBG (mol/l)
Free testosterone (nmol/l)
Free/total testosterone ratio
Free oestradiol (pmol/l)
Cortisol (nmol/l)
1.95
2.03
0.87
159
60
5.36
0.28
0.40
30
508
5.3-5.7
5.8-6.2
> 6.2
Age- and
BMI-adjusted
partial correlation
coeficient (r)
1.99
2.03
0.88
165
59
5.01
0.34
0.43
39
540
3.30
2.15
0.89
157
57
4.5 1
0.35
0.44
2.32
2.20
0.87
154
57
3.91
0.38
0.52
38
524
0.12*
0.06
0.02
-0.01
-0.03
-0.15**
0.13*
0.14*
0.07
0.0 1
44
538
202
K.-T. Khaw and E. Barrett-Connor
Table 4. Age- and body mass index (BM1)-adjusted hormone levels using analysis of variance
category by fasting plasma glucose level and current oestrogen use in non-diabetic [no personal
history of diabetes, fasting plasma glucose level < 7.8 mmol/l ( < 140 mg/dl)] postmenopausal
Rancho Bernard0 women aged 50-79 years in 1972-1974
Statistical significance: a, fasting plasma glucose category effect, P < 0.05; b, oestrogen effect,
P < 0.05.
Age- and BMI-adjusted mean hormone level
Fasting plasma glucose level category.. .
< 5.7 mmol/l
Oestrogen use.. . Non
DHEAS (pmol/l)
Androstenedione (mmol/l)
Testosterone (nmol/l)
Oestrone (pmol/l)
Oestradiol (pmol/l)
lohx SHBG (mol/l)
Testosterone/SHBG ratio
Free testosterone (nmol/l)
Free testosterone/testosterone ratio
Free oestradiol (pmol/l)
Cortisol (nmol/l)
2.13
2.07
0.86
128
53
4.04
0.38
0.36
0.45
33
49 1
Clinical studies have suggested another, biologically
plausible, explanation. A clear relationship between
hyperandrogenism and insulin resistance in women with
polycystic ovarian disease independent of obesity has
been documented [2-51. Women with polycystic ovarian
disease have been reported to have impaired glucose
tolerance and elevated levels of insulin, DHEAS,
androstenedione and testosterone; in these women,
insulin levels positively correlated with androstenedione
and testosterone levels. Which abnormality may be causal
is not clear; it is possible that high plasma glucose levels of
insulin resistance might affect androgen production but
there is little evidence to support this hypothesis. Chang et
al. [4] suggested that insulin resistance might be a consequence of hyperandrogenism. This is supported by
observations that exogenous androgen therapy is associated with alterations of carbohydrate metabolism, is
reversible with withdrawal [ 161 and that reduction of the
raised androgen levels in patients with acanthosis
nigricans is associated with decreased insulin resistance
[17, 181.
Some other observations also tend to support this
notion. Central adiposity has been associated with
increased risk of diabetes in both men and women. In premenopausal women, an increasing android (upper body
or central) fat distribution is associated with progressively
diminished glucose tolerance, hyperinsulinaemia and
insulin insensitivity in peripheral tissues [ 13, 18-20].
Qualitative differences in metabolism in adipose tissue at
different sites have been reported. Abdominal and
femoral adipocytes exhibit differential insulin sensitivity
[21]. A high basal lipolysis rate found in abdominal
adipocytes [ 18, 191 could impair adipocyte glucose oxidation. Increased free fatty acid release in the circulation
could inhibit glucose utilization by other tissues [22].
Evans et al. [13] suggested, that in premenopausal
=
> 5.7 mmol/l
Current
Non
Current
Statistical
significance
1.50
1.79
0.88
236
71
7.50
0.20
0.27
0.36
58
368
2.43
2.2 1
0.86
124
53
3.13
0.43
0.43
0.54
1.70
1.92
0.88
237
72
6.59
0.25
0.33
0.43
65
585
a, b
a, b
b
b
b
a, b
a
a, b
a, b
b
b
I
40
577
women, a relative increase in tissue exposure to unbound
androgens might be responsible in part for localization of
fat in the upper body, enlargement of abdominal adipocytes and the accompanying imbalance in glucose-insulin
homoeostasis. In the present cohort of postmenopausal
women, we did not have baseline measures of insulin
levels or body fat distribution, but androgen levels were
predictive of subsequent central adiposity 14 years later
(K. T. Khaw & E. Barrett-Connor, unpublished work);
other studies have reported an association between free
testosterone levels and increased waist/hip ratio in
women [13, 231. It could thus be hypothesized that
increased androgens might increase central adiposity,
leading to insulin resistance and an increase in glucose
levels.
Virtually all previous studies have been conducted in
selected small groups of premenopausal women, often
with clinically defined conditions. This finding of a
positive relationship of fasting plasma glucose levels with
adrenal androgens in a population of non-diabetic postmenopausal women may thus be of interest for several
reasons. First, this relationship is independent of premenopausal ovarian function. If the metabolic changes
seen in women with polycystic ovaries are also seen postmenopausally, this could elucidate possible causes of the
syndrome, suggesting that polycystic ovaries are a result,
not a cause, of various metabolic processes. It has been
suggested that polycystic ovaries, a common finding in
normal premenopausal women, are but one end of a
distribution spectrum in a population of which clinically
significant derangements are but an extreme [24]. These
could thus reflect the top end of a range of adrenal
androgenic activity. Secondly, whether clinically overt
diabetes is a distinct disease or is also just one end of a
range of degrees of glucose tolerance is debated. Several
studies have shown a stepwise increasing cardiovascular
Plasma glucose and androgen levels in women
risk associated with increasing glycaemia, as indicated by
a single measurement of fasting plasma glucose level, in
the absence of overt diabetes, analogous to that for blood
pressure [25-281. Thus, the observation that the relationship between fasting glucose levels and endogenous
androgens occurs as a continuum over the physiological
ranges, rather than only in pathological conditions, may
lead to a better understanding of mechanism of glucose
tolerance as well as of impaired glucose tolerance and
hence a better understanding of the mechanisms which
lead to the cardiovascular consequences of diabetes.
These results suggest a possible explanation for why
the recognized fe,male protection from cardiovascular
disease is lost in diabetic women [29, 301. The higher
androgen levels associated with increased fasting glucose
levels raise questions about the role of androgens in
increasing susceptibility to heart disease in women by
making them more male-like. Elucidation of the
mechanism by which they act may give us clues as to why
certain men and women may be more prone to diabetes
or heart disease and may indicate means of intervention
and prevention.
ACKNOWLEDGMENTS
This study was supported by grants from NIDDK DK
3 1801, NHLBI HL 349 1 and the American Heart Association.
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