Open Journal of Obstetrics and Gynecology, 2011, 1, 228-233
doi:10.4236/ojog.2011.14045 Published Online December 2011 (http://www.SciRP.org/journal/ojog/
OJOG
).
Published Online December 2011 in SciRes. http://www.scirp.org/journal/OJOG
Increased free androgen index is associated with hypertension
in premenopausal women
Liselott Andersson1, Mats Eliasson2,3, Inger Sundström Poromaa4
1Department of Obstetrics and Gynecology, Sunderby Hospital, Luleå, Sweden;
2Department of Internal Medicine, Sunderby Hospital, Luleå, Sweden;
3Department of Public Health and Clinical Medicine, Umeå University, Luleå, Sweden;
4Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
Received 15 August 2011; revised 20 September 2011; accepted 4 October 2011.
ABSTRACT
Objective: Increased testosterone and decreased sex
hormone-binding globulin (SHBG) are associated
with a number of adverse cardiovascular risk factors
in postmenopausal women. The aim of this popula-
tion-based study of women aged 25 to 50 was to as-
sess the relationship between free androgen index
(FAI) and cardiovascular risk factors in premeno-
pausal women. Methods: A population-based survey
of 396 premenopausal women with no hormonal trea-
tment was undertaken as part of the Northern Swe-
den MONICA study. The study involved question-
naires, anthropometry and assays of testoste rone and
SHBG. Results: Increased FAI was associated with a
number of cardiovascular risk factors in premeno-
pausal women but this relationship was strongly af-
fected by body mass index (BMI). After adjustment
for age and BMI, FAI was significantly associated
with increased systolic and diastolic blood pressures.
Conclusion: Hyperandrogenism is associated with
increased blood pressure and these findings empha-
size the need to assess cardiovascular risk factors in
women with hyperandrogenism of all ages.
Keywords: Free Androgen Index; Blood Pressure
1. INTRODUCTION
Testosterone is carried in peripheral blood bound to sex
hormone binding globulin, with approximately 1% - 2%
of testosterone free and the remaining testosterone loo-
sely bound to albumin [1]. The free androgen index (FAI),
i.e. the ratio between testosterone and sex hormone bin-
ding globulin (SHBG), may be used as an approximation
of biologically available androgens in women, and lon-
gitudinal studies in aging women indicate that SHBG
levels decrease with increasing age, thus resulting in su-
ccessively increasing amounts of biologically available
androgen in healthy women [2].
Increased testosterone and decreased sex hormone-
binding globulin (SHBG) have been strongly associated
with a number of adverse cardiovascular disease (CVD)
risk factors in postmenopausal women, such as central
adiposity, decreased high-density lipoprotein (HDL)
cholesterol levels and increased systolic and diastolic
blood pressures [3-6]. A nested case-control study of po-
stmenopausal women also suggested that higher free
androgen index was associated with CVD events such as
first occurrence of nonfatal myocardial infarction, coro-
nary revascularization, nonfatal stroke, coronary disease,
or stroke death, although this association was not inde-
pendent of body mass index and other cardiovascular
risk factors [7]. Besides a possible role of androgen hor-
mones and SHBG in cardiovascular disease, low levels
of SHBG have consistently been linked to higher rates of
diabetes [8-9] and might contribute to a more adverse car-
diovascular risk profile in women with diabetes [10-11].
Sex hormone levels may also be associated with CVD
risk factors in pre- and perimenopausal women, although
fewer studies have been conducted in this age-group
[12-14]. In younger women most interest has instead
been devoted to patients with polycystic ovary syndrome
(PCOS), which is a hyperandrogenic population with nu-
merous risk factors for later development of CVD [15].
However, in contrast to healthy women, we have previ-
ously shown that testosterone levels gradually decrease
with increasing age in PCOS women [16], although le-
vels remain elevated in comparison with age-matched
controls [17].
Outside the PCOS patient population, no population-
based studies have been conducted in premenopausal
women concerning the association between free andro-
gen index and cardiovascular risk factors. Thus, the pur-
pose of this population-based study of premenopausal

L. Andersson et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 228-233 229
women aged 25 to 50 was to assess whether free andro-
gen index is associated with risk factors for cardiovas-
cular disease, even in younger women.
2. MATERIALS AND METHODS
2.1. Patients
This study used data from the Northern Sweden compo-
nent of the WHO MONICA study, originally designed to
evaluate risk factors for cardiovascular disease and type
2 diabetes. Briefly, information was collected during a
population-based survey during January to April 2004
[18]. Subjects were randomly selected from population
registers, stratified for age (25 years - 74 years) and gen-
der, in the two most northern counties of Sweden (target
population 312,000). For the entire MONICA study
1250 men and 1250 women were invited, but for the
purpose of this study, only women below age 50 years
were considered. Details of sampling and selection ap-
pear elsewhere and participation rate was 78% [18]. A
total of 500 women 50 years or younger were eligible for
this study. Exclusion criteria were postmenopausal
status (more than 12 months since last menses), ongoing
pregnancy, and use of hormone replacement therapy or
combined oral contraceptives during the last year.
The Research Ethics Committee of Umeå University
and the National Computer Data Inspection Board ap-
proved the Northern Sweden MONICA study. A specific
approval for this sub-study was also obtained from The
Research Ethics Committee of Umeå University. Parti-
cipants gave written consent.
2.2. Study Procedures
Subjects were weighed on an electronic scale. The sub-
jects wore light clothes and no shoes and weight was
measured to the nearest 0.2 kg. Height without shoes
was measured to the nearest centimeter. Body mass in-
dex (BMI) was calculated as weight (kg) divided by
height (m2). To record waist circumference, measure-
ment was performed midway between the lower rib mar-
gin and iliac crest to the nearest 0.0 cm or 0.5 cm. The
blood pressure was measured twice in every person after
a five-minute rest in a sitting position with Hawksley’s
random zero sphygmomanometer. The mean value of the
two measurements was used.
Blood samples were drawn after at least a 4-h fast (in
approximately 65% of subjects blood samples were dra-
wn after an overnight fast).
The participants were asked to complete question-
naires including items about smoking habits, sociodemo-
graphic data and previously known cardiovascular dis-
ease. The questionnaire also included a number of ques-
tions for assessment of reproductive status including
menstrual pattern, last menstrual period, use of oral con-
traceptives and hormone replacement therapy during the
past year.
The highest attained educational level was classified
as primary school (up to 9 years of school), secondary
school (10 years - 12 years of school) and university stu-
dies. Regular smokers smoked at least one cigarette a
day; all other subjects were considered as nonsmokers.
Participants were classified as physically active if re-
porting physical activity more than two hours per week;
all other subjects were considered not physically active.
A positive family history of diabetes, stroke and cardio-
vascular disease was only reported when occurring in
first-degree relatives. A history of gestational diabetes
was only assessed in parous subjects. Hypertension and
elevated serum cholesterol were considered prevalent in
women on medication for these reasons.
2.3. Assays
Total cholesterol was determined by a dry chemistry
method (Vitros 950; Kodak Echtachem, Rochester, NY,
USA). The measurement of total cholesterol is accredi-
ted by the national accreditation body, SWEDAC, with
coefficients of variation of 3.6% at 3.91 mmol·L–1 and
3.1% at 6.66 mmol·L–1.
An oral glucose tolerance test (OGTT; 75 g glucose)
was performed in a random sub-sample (approximately
65%) of the non-diabetic participants after an overnight
fast. A venous blood sample was taken immediately be-
fore the glucose load and after two hours. Glucose levels
were analyzed without delay on a HemoCue Glucose
201 device (HemoCue AB, Angelholm, Sweden) and
converted to plasma glucose levels by a correction factor
of 1.11. According to previous validation of this proce-
dure, the adjusted data for glucose showed a high corre-
lation to plasma glucose simultaneously measured by the
hexokinase method in a sub-sample [18]. SHBG and
testosterone were analyzed on a Modular E170 (Roche
Diagnostics, Mannheim, Germany). The total coefficients
of variation of the instrument for the analytes were 1.5%
at 43 nmol/L for SHBG and 6.8% at 3.9 nmol/L for tes-
tosterone. Free androgen index was calculated as testos-
terone (nmol/L)/SHBG (nmol/L) × 100.
Physical and biochemical parameters were analyzed
using partial correlation test with adjustment for age and
BMI and with logarithmic FAI. The women were grou-
ped into quartiles depending on level of FAI. Dichoto-
mized and continuous variables were compared between
groups using linear or logistic regression analysis and
adjusted for age and BMI. The software package SPSS
(version 12.0) was used for statistical analyses.
3. RESULTS
Fifteen postmenopausal women, 53 women on combined
oral contraceptives, 16 women on hormone replacement
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L. Andersson et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 228-233 230
OJOG
therapy, 10 pregnant women and 20 women lacking a blood
sample were excluded. Hence, 396 women 50 years or
younger were included in the study.
Sociodemographic, anthropometric and reproductive
data are presented in Table 1 and given according to
quartiles of FAI. Women in the highest quartile, i.e. with
the highest level of free testosterone (or the lowest level
of SHBG), were significantly older and had higher BMI
than those in the lower three quartiles. BMI was 4.5
kg/m2 higher in the fourth FAI quartile compared to the
lowest. Compared to the lowest FAI quartile, women
with the highest FAI had lower educational level and
were more often smokers. Otherwise, women in the dif-
ferent FAI quartiles did not differ regarding use of snuff
or physical activity.
Hypertension was significantly more common among
women in the highest FAI quartile (Table 2). In the low-
est FAI quartile was hypertension prevalent in 19.2% of
the subjects while 35.4% of women in the highest quar-
tile had hypertension.
Table 1. Physical characteristics, sociodemographic and reproductive data in women according to free androgen index quartiles.
FAI lowest
0.13 - 1.10 (n = 99)
FAI
1.11 - 1.84 (n = 99)
FAI
1.85 - 3.07 (n = 99)
FAI highest
3.08 - 68.9 (n = 99)
Age (years ± SD) 39.3 ± 7.2 38.5 ± 6.7 37.3 ± 7.3 41.0 ± 5.5a
Parity (mean ± SD) 2.2 ± 1.0 2.4 ± 1.2 2.0 ± 0.9 2.4 ± 0.8
BMI 24.2 ± 3.6 24.6 ± 4.6 26.1 ± 4.6c 28.4 ± 6.2b
Waist, cm 80.2 ± 10.0 80.3 ± 11.3 84.7 ± 12.6 90.9 ± 14.3a
Marital status Living single OR (95% CI) 1 1.40 (0.72 - 2.72) 0.70 (0.33 - 1.46) 0.88 (0.42 - 1.85)
Cases, n 20 (20.2%) 24 (24.5 %) 13 (13.1%) 18 (18.2%)
Educational level < university level OR (95% CI) 1 1.10 (0.62 - 1.93) 0.87 (0.49 - 1.53) 1.98 (1.05 - 3.75)d
Cases, n 59 (59.6%) 63 (63.6%) 57 (57.6%) 73 (74.5%)
Smoking Smokers OR (95% CI) 1 1.62 (0.77 - 3.41) 3.50 (1.74 - 7.04) d 2.38 (1.13 - 5.02) d
Cases, n 13 (13.1%) 21 (21.4%) 35 (35.4%) 26 (26.5%)
Snuff Snuff users OR (95% CI) 1 1.43 (0.62 - 3.31) 1.66 (0.72 - 3.83) 1.51 (0.62 - 3.70)
Cases, n 10 (10.2%) 16 (16.3%) 14 (14.3%) 14 (14.1%)
Physically Not active OR (95% CI) 1 0.63 (0.29 - 1.38) 1.20 (0.59 - 2.43) 1.04 (0.50 - 2.18)
active Cases, n 18 (18.2%) 12 (12.1%) 23 (23.2%) 23 (23.2%)
ap < 0.05 - 0.01 compared to the two intermediate FAI quartiles, one-way ANOVA with post hoc Tukey Honestly Significance test. bp < 0.05 - 0.001 compared
to all other FAI quartiles, one-way ANOVA with post hoc Tukey Honestly Significance test. cp < 0.05 compared to the lowest FAI quartile, one-way ANOVA
with post hoc Tukey Honestly Significance test. dp < 0.05 - 0.01 compared to the lowest FAI quartile, multivariate logistic regression adjusted for age and body
mass index.
Table 2. Data on diabetes, cardiovascular disease and family history in women according to free androgen index quartiles.
FAI lowest
0.13 - 1.10 (n = 99)
FAI
1.11 - 1.84 (n = 99)
FAI
1.85 - 3.07 (n = 99)
FAI highest
3.08 - 68.9 (n = 99)
Diabetes OR (95 % CI) 1 1.12 (0.07 - 18.70) n.c. 4.62 (0.49 - 43.22)
cases, n (%) 1 (1.0%) 1 (1.0%) 0 5 (5.1%)
Hypertension OR (95 % CI) 1 0.55 (0.24 - 1.22) 0.98 (0.47 - 2.03) 2.00 (1.01 - 4.00) a
cases, n (%) 19 (19.2%) 11 (11.1%) 19 (19.2%) 35 (35.4%)
Elevated serum cholesterol OR (95 % CI) 1 1.50 (0.40 - 5.66) 1.26 (0.32 - 5.00) 2.14 (0.63 - 7.28)
cases, n (%) 4 (4.0%) 6 (6.1%) 5 (5.1%) 12 (12.1%)
Previous gestational diabetes OR (95 % CI) 1 1.65 (0.57 - 4.74) 0.68 (0.20 - 2.35) 2.30 (0.81 - 6.56)
cases, n (%) 6 (6.1%) 10 (10.1%) 5 (5.1%) 15 (15.2%)
Family history of diabetes OR (95 % CI) 1 1.12 (0.58 - 2.40) 1.00 (0.46 - 2.21) 1.86 (0.90 - 3.83)
cases, n (%) 16 (16.2%) 17 (17.2%) 15 (15.2%) 29 (29.3%)
Family history of hypertension OR (95 % CI) 1 1.04 (0.58 - 1.86) 1.55 (0.85 - 2.81) 1.11 (0.61 - 2.04)
cases, n (%) 48 (48.5%) 47 (47.5%) 55 (55.6%) 56 (56.6%)
Family history of myocardial OR (95 % CI) 1 0.68 (0.23 - 2.01) 1.00 (0.36 - 2.76) 0.51 (0.16 - 1.64)
infarction cases, n (%) 9 (9.1%) 6 (6.1%) 8 (8.1%) 5 (5.1%)
Family history of stroke OR (95 % CI) 1 0.84 (0.25 - 2.89) 0.16 (0.02 - 1.42) 0.41 (0.09 - 1.80)
cases, n (%) 6 (6.1%) 5 (5.1%) 1 (1.0%) 3 (3.0%)
ap < 0.01 compared to all other FAI quartiles, multivariate logistic regression adjusted for age and body mass index.

L. Andersson et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 228-233 231
Among women within the highest FAI quartile cho-
lesterol, waist circumference, and blood pressure were
significantly higher than in the three groups with lower
FAI. However, after adjustment for age and BMI, only
systolic and diastolic blood pressures were significantly
higher (Table 3). Blood pressure was 9/7 mm Hg higher
in the highest FAI quartiles than in the lowest quartile.
Similarly, free androgen index was significantly and
positively correlated with systolic and diastolic blood
pressures (Table 4).
4. DISCUSSION
The main finding of the present study was that young
and premenopausal women within the highest quartile of
free androgen levels had several risk factors for cardio-
vascular disease. However, when adjusted for age and
BMI the only associations that remained were the ones
between high FAI and high systolic and diastolic blood
pressures, respectively. This finding is in line with pre-
vious studies in pre- and perimenopausal [14,19] as well
as postmenopausal women [3-6]. In perimenopausal wo-
men free androgen index was positively and independ-
ently associated with a number of cardiovascular risk
factors such as total cholesterol, low-density lipoprotein
cholesterol, lipoprotein (a), insulin, plasminogen activator
Table 3. Physical and biochemical measures in women ac-
cording to free androgen index quartiles.
FAI lowest
0.13 - 1.10
(n = 99)
FAI
1.11 - 1.84
(n = 99)
FAI
1.85 - 3.07
(n = 99)
FAI highest
3.08 - 68.9
(n = 99)
Fasting glucose,
mmol/l 5.1 ± 0.5 5.2 ± 0.5 5.1 ± 0.6 5.5 ± 1.6
2-hour glucose,
OGTT, mmol/l 5.3 ± 1.3 5.5 ±1 .0 5.5 ± 1.6 5.9 ± 2.2
Total chole-sterol,
mmol/l 5.1 ± 1.1 4.9 ± 0.9 5.2 ± 1.0 5.5 ± 1.1
SBP, mmHg 115 ± 15 112 ± 11 114 ± 11 124 ± 19 a
DBP, mmHg 72 ± 9 71 ± 8 71 ± 8 79 ± 13b
ap < 0.01, bp < 0.001 compared to all other FAI quartiles, ANCOVA ad-
justed for age and body mass index. For the glucose variable and for the 2
hour glucose variable, data was missing in 161 (40.7%) women and in 212
(53.5%) women, respectively. For all other variables, data was missing in
0.3% - 1.0% of women. OGTT, oral glucose tolerance test, SBP systolic
blood pressure, DBP diastolic blood pressure.
Ta b l e 4 . Partial correlations between free androgen index and
physical or biochemical parameters, adjusted for age and body
mass index.
Fasting
glucose
2 hour
glucose Cholesterol WC SBPDBP
Free androgen
index –0.018 0.119 0.052 –0.08 0.213a0.262b
ap < 0.01, bp < 0.001. For the glucose variable, data was missing in 161
(40.7%) women. For all other variables, data was missing in 0.3% - 1.0% of
women. SBP systolic blood pressure, DBP diastolic blood pressure, WC
waist circumference.
inhibitor-1, tissue plasminogen activator and high sensi-
tive c-reactive protein, systolic and diastolic blood pres-
sures [14].
In our cohort of women across different age groups,
women with the highest free androgen index were found
to be significantly older than the remaining women. This
finding is in line with previous longitudinal studies indi-
cating that increased BMI over time is closely related to
lowering of SHBG levels [20]. However, a recent longi-
tudinal study in healthy women suggested that, not only
did SHBG levels decline with increasing age, testoster-
one levels also displayed a gradual increase from the age
of 40 and onwards [2].
We were also able to confirm prior findings of an as-
sociation between free androgen levels and increased
systolic and diastolic blood pressures, although the ma-
jority of these studies were conducted in older, postme-
nopausal women [3-6,12-14,19]. In addition, the preva-
lence of manifest hypertension was approximately 35%
among women with the highest FAI. Notably, in our pre-
vious longitudinal study of 40-year old PCOS women,
systolic and diastolic did not differ from controls fol-
lowing adjustment for BMI, and manifest hypertension
was only prevalent in approximately 16% of PCOS wo-
men [21].
The free androgen index is mainly driven by the SHBG
levels and the best known function of SHBG is to regu-
late the availability of biologically active free testoster-
one and estradiol and their metabolic clearance rate [22].
SHBG production is stimulated by estradiol and inhib-
ited by androgens indicating that a high level of SHBG
would temper the unfavorable effects of free androgens
on blood pressure. Besides its contribution to free an-
drogen levels, low levels of SHBG have consistently
been linked to insulin resistance [23], higher rates of
diabetes [8-9,23] and might contribute to a more adverse
cardiovascular risk profile in women with diabetes
[10-11]. Testosterone on its own may also contribute to
the increased blood pressure found in our women within
the highest FAI quartile. Previous animal studies have
indicated a prohypertensive effect of androgens which
may be mediated through increased vascular tone via
upregulation of thromboxane A2 expression, norepine-
phrine, angiotensin II and endothelin-1 synthesis [24].
Other means by which androgens may influence blood
pressure also include effects on the renin-angiotensin-al-
dosterone system [24].
Our findings also indicate a clear association between
obesity and increased waist circumference, as a measure
of central adiposity, and elevated free androgen levels.
This finding is in line with a number of studies [3-6,
12-14,19,25] and is further evidenced by studies sug-
gesting that weight loss, whether induced by bariatric su-
rgery, anti-obesity agents, or life-style interventions, will
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L. Andersson et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 228-233 232
reduce androgen levels [25-26].
The major limitation of this study is the relatively
small sample size, which might raise questions whether
this study was adequately powered for some of the ana-
lyses. However, the study has pointed out that increased
FAI is associated with a number of cardiovascular risk
factors but these relationships seem to be strongly af-
fected by BMI. Free androgen index was significantly
and independently associated with increased systolic and
diastolic blood pressures, emphasizing the need to assess
cardiovascular risk factors in women with hyperandro-
genism across all ages.
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