the android woman – a risky condition

Journal of Internal Medicine 1996; 239 : 105–110

R E V I E W

The android woman – a risky condition

PER BJO> RNTORPFrom the Department of Heart and Lung Diseases, Sahlgren’s Hospital, University of GoX teborg, GoX teborg, Sweden

Abstract. Bjo$ rntorp P (Department of Heart and

Lung Diseases, Sahlgren’s Hospital, University of

Go$ teborg, Go$ teborg, Sweden). The android woman –

a risky condition (Review). J Intern Med 1996; 239:

105–110.

Normal women produce small amounts of active

androgens. When androgen levels are elevated, such

as for example in the polycystic ovary syndrome, this

is followed by the development of male physical

characteristics ofmuscle mass, structure and function

as well as android adipose tissue distribution and

function. Psychological features and stress reactions

also seem similar to those of men. Such women have

an increased risk of developing hypertension, non-

insulin-dependent diabetes mellitus and cardio-

vascular disease. Recent data have shown that these

physical, and psychological characteristics, as well as

risk of ill health, are also found in the population of

Introduction

Normal women produce small amounts of testos-

terone, as well as other, less active androgens of

mainly adrenal origin. With production above a

certain level a number of android, male charac-

teristics appear. There is now evidence that this is

followed not only by several psychological and

physical android characteristics, but also by the risk

of developing cardiovascular disease (CVD), and non-

insulin-dependent diabetes mellitus (NIDDM). This

occurs not only in severe hyperandrogenicity (HA),

women selected at random. Women in the lowest

quintiles of levels of sex-hormone-binding globulin –

an indicator inversely related to active androgens –

are at risk of developing hypertension, non-insulin-

dependent diabetes mellitus and cardiovascular mor-

tality. The mechanism probably includes muscular

insulin resistance, following a relative androgen

excess.

It is thus apparent that androgens, even within

the highest levels of the nonselected population of

women, are powerful predictors of serious disease

development. The population at risk might be as

large as about 20% of middle-aged women. This is an

area of female disease risk which requires more

attention in screening and intervention procedures.

Keywords : androgens, cardiovascular disease,

diabetes, hypertension, women.

such as in the polycystic ovarian syndrome (PCO), or

adrenal tumours producing excess androgens, but

also in the upper range of testosterone concentrations

in nonselected populations of women. This neglected

cause of morbidity in women will be briefly reviewed

in the following article.

Physical characteristics

Women with severe HA tend to have problems with

increased hairgrowth in areas in which this would

typically occur in men, including the face, and often

# 1996 Blackwell Science Ltd 105

106 P. BJO> RNTORP

need depilation procedures. This disappears after

amelioration of HA by oestrogen treatment, for

example [1]. Whether this is a problem in the upper

normal range of testosterone values amongst women

does not seem to have been directly studied, but

epidemiological studies and anecdotal evidence

suggest a gradient of free testosterone values and

increased hair growth from north to south in

European countries [2]. This hair growth and

increased free testosterone is clearly a male charac-

teristic, and administration of testosterone to trans-

sexual women is known to be rapidly followed by a

male type of distribution of hair growth, including

the beard.

Women with HA also have a distribution of adipose

tissue to central, visceral parts of the body – a male

characteristic [3]. This has been described not only

in the PCO [4], but also amongst both pre- and post

menopausal women in nonselected population

studies [5]. In addition, women with visceral obesity

are hyperandrogenic [3, 6], and this is seen both

with and without accompanying NIDDM [7]. The

mechanism for the association between visceral fat

accumulation and hyperandrogenicity is poorly

understood, but may involve regulation of adipose

tissue metabolism by sex steroid hormones, which

varies in different adipose tissue regions and is

determined by the density of specific steroid hormone

receptors [8]. Normal, premenopausal women have

enlarged fat cells in the gluteofemoral region, consti-

tuting a basis for the development of the charac-

teristic gluteofemoral adipose tissue in women, which

is usually small or absent in men. This is paralleled

by a high lipoprotein lipase activity, the main

enzymic regulator of adipocyte triglyceride accumu-

lation, as well as a low lipid mobilization activity, and

has been suggested to be an energy depot reserved

for lactation [9]. These characteristics are lacking

in hyperandrogenic women, in women after meno-

pause, and in men, but reappear upon oestrogen

treatment of menopausal women [10].

Hyperandrogenic women then, in essence, do not

have the characteristic female subcutaneous gluteo-

femoral adipose tissue depot. It might be considered,

therefore, that storage of excess triglycerides has

instead to take place proportionally more in central

regions of adipose tissue. Other more direct mech-

anisms might also be involved for this redistribution

of fat masses, but these are currently not known.

Lean body mass has been reported to be elevated in

hyperandrogenic women with visceral obesity, and

is parallel to testosterone concentrations in women

with NIDDM [7, 11]. Again this is a male charac-

teristic, because men have a larger lean body mass

than women, the excess being mainly skeletal

muscles.

There are also qualitative male characteristics of

muscle in hyperandrogenic women. The genders

have different muscle-fibre composition, men having

more ‘athletic ’, type II, white, glycolytic fibres, and

less ‘endurance’, type I, red, oxidative fibres than

women [12]. Such a male-type fibre composition of

muscles is found in obese women with HA and

android type, visceral fat distribution with or without

NIDDM, whilst women without HA, with their excess

body fat distributed in a normal, female way, do not

have this male type of muscle [11–14]. In addition,

the density of muscle capillaries is lower in such

women with HA [11, 13–14]. These are apparently

the effects of testosterone [15]. The muscle charac-

teristics mentioned may be of importance for the

regulation of muscular and systemic insulin sen-

sitivity, as will be discussed in a later section.

Psychological characteristics

Male and female psychological characteristics are

clearly different. For example, aggressiveness is

considered to be more prevalent amongst men than

amongst women. Women with hirsutism and HA, or

an elevated waist}hip circumference ratio, closely

associated with a relative hyperandrogenicity, have

been found to have different scores in personality

measurements than normal women, but the findings

are not consistent [16, 17]. Men and women seem to

respond differently both psychologically and endo-

crinologically to standardized stress [18]. In women

with HA, an increased level of anxiety and cortisol

secretion after stress have been reported [19, 20] –

reactions described as typical for men [16].

In summary, women with HA seem to exhibit a

number of physiological and psychological charac-

teristics which are typically found in men. They are

thus android in both bodily and psychological

variables. This is associated with several risk factors

and prevalent diseases, again more prevalent in men

than in women, which will be reviewed below.

# 1996 Blackwell Science Ltd Journal of Internal Medicine 239 : 105–110

REVIEW: THE ANDROID WOMAN 107

CVD, NIDDM, and premature mortality inhyperandrogenic women

A prominent abnormality in women with HA is

insulin resistance. This has been observed not only in

the PCO syndrome but also in population studies,

and in visceral obesity with or without NIDDM [4–7].

There is an ongoing discussion of which of these

(androgen production or insulin resistance) is the

primary factor. Insulin resistance is associated with

hyperinsulinaemia, which might be followed by

increased androgen production. It might also be that

androgens produce insulin resistance. This field has

recently been reviewed [21]. The arguments for the

first alternative seem mainly to be based on in-vitro

data with isolated ovarian cells, producing androgens

when exposed to insulin. On the other hand, women

exposed to prolonged hyperinsulinaemia from ex-

ogenous sources in clamp studies, or women with

insulinoma, do not develop hyperandrogenism [21].

Normal, transsexual women, as well as female rats,

receiving testosterone, become severely insulin re-

sistant [15, 22], showing that testosterone adminis-

tration is followed by insulin resistance. Therefore it

seems likely that spontaneously occurring HA is

followed by insulin resistance.

In population studies, women with a low con-

centration of sex-hormone-binding globulin (SHBG),

a sign of HA, have been found to have an increased

risk of developing NIDDM [5, 23]. Insulin was also

found to be a powerful precursor to the development

of NIDDM, and these two risk factors correlated

strongly, suggesting the possibility that HA is causing

insulin resistance in analogy with the effects of

testosterone administration to women and female

rats, which is followed by insulin resistance [15, 22].

The risk was confined exclusively to the lowest

quintile of SHBG distribution. The risk ratio between

this quintile and the four higher quintiles was about

5:1, increasing steeply towards the lower end of the

SHBG distribution, reaching about 20:1 in the lowest

5%. The risk was independent of menopausal state

[5]. These findings indicate that about 20% of the

population of women is at risk of developing NIDDM,

due to HA, and that this risk increases up to a point

where one out of five women develop NIDDM within

a period of about 12 years when HA is most

pronounced [5]. There were no obvious physical

signs of HA or signs of PCO in these women. The

study referred to was performed in Swedish women,

but similar findings have subsequently also been

reported in other populations [23]. It is thus apparent

that a relatively mild HA in the general population

of women is predisposing for the development of

NIDDM.

A recent follow-up of the cohort of women from

Go$ teborg has now shown that a low SHBG is also a

risk factor for CVD mortality [24]. Again there was a

steep increase of the risk gradient towards the lowest

SHBG values. A low SHBG was closely associated

statistically with other established risk factors for

CVD, such as insulin [5], triglycerides, hypertension

and the waist}hip circumference ratio [25], and the

HA may well exert its effects via these factors [24].

A low SHBG also seems to predict the development

of hypertension [26].

It is thus apparent that a low SHBG, indicating HA

in women, is associated with insulin resistance,

elevated triglycerides and blood pressure, centralized

obesity and increased risk of developing NIDDM and

CVD. This cluster of risk factors and diseases [27] is

now often called the ‘ insulin resistance syndrome’ or

the ‘metabolic syndrome’. The evidence summarized

above strongly suggests that HA is an integral part of

this syndrome in women; in fact, HA may trigger the

supposed main driving power of the syndrome: the

insulin resistance.

The distribution of SHBG values, particularly in

relation to the risk for NIDDM, shows a clear

threshold phenomenon, and is found only in the

lowest quintile [5]. It would therefore be reasonably

easy to use SHBG values for screening purposes to

find women with an increased risk of developing

NIDDM and}or CVD, and to recommend preventive

measures in such women. Obviously, if the origin of

the HA was known, the preventive or therapeutic

possibilities would be much improved.

Men

Men have about 10 times higher testosterone values

than women, and one may therefore wonder why

men are not particularly prone to develop, for

example, insulin resistance. Men [28] or male rats

[29] receiving androgens to bring them above their

physiological range of testosterone values become

insulin resistant, in analogy with women with HA.

Interestingly, men with subnormal testosterone

values are also insulin resistant [30], a phenomenon

which is reproducible in castrated male rats [29].


108 P. BJO> RNTORP

Testosterone substitution to normal circulating

values improves insulin resistance markedly in men

[31] and totally ameliorates insulin resistance in rats

[29], strongly suggesting that testosterone deficiency

at least partly causes the insulin resistance. It thus

appears that testosterone values in a ‘window’ of the

normal range in men is followed by optimal insulin

sensitivity. An analogous situation might be con-

sidered in women, where the ‘window’ is set at

much lower testosterone concentrations, without a

certain, definable lower limit. It is thus apparent that

women are much more sensitive to testosterone than

are men. The explanation of this is not clear, but it

may involve differences in sensitivity and metabolism

of testosterone in both sexes [32].

Mechanisms

Insulin resistance is thus apparently a key feature

in the early consequences of HA in women. The

mechanism for this has been studied in a hyper-

androgenized, female rat model. The insulin re-

sistance is localized to muscle tissue, and affects both

glucose transport and glycogen synthesis, the latter

mediated via the insulin-sensitive part of the glycogen

synthase system. Furthermore, muscle fibre com-

position changes towards a lower type I}type II ratio,

and capillarization is diminished [33]. All these

characteristics of muscle have been found in women

with spontaneous or induced HA, suggesting that

the findings in the rat model are pertinent to human

conditions [11, 13, 32].

In an intermediary step, insulin binds to capillary

endothelial cells before transcapillary transport to its

site of action on the insulin receptor at the muscle

cell [34]. This transport has recently been suggested

to be rate-limiting for insulin action in muscle [35].

A consistent finding in the studied conditions with

spontaneous or induced HA in women or female rats

is a low capillary density in muscles [11, 13–15]. In

kinetic studies of insulin uptake and translocation in

different muscles in normal rats, insulin binding to

capillaries is parallel to capillary density and blood

flow, whilst the transcapillary transport rate of

insulin is not different [36]. After testosterone

administration, capillary density, blood flow, insulin

binding and insulin sensitivity decrease in parallel,

whilst transcapillary transport rate does not change

in comparison with controls (Holma$ ng, Jennische,

Rippe, Bjo$ rntorp, unpublished observations). Taken

together, these findings suggest that the delivery of

insulin for transport through the capillary barrier is

insufficient in testosterone-treated female rats due to

too low a capillary density and blood flow. This, then,

is causing an apparent insulin resistance, which

might be characterized as a diminished availability to

circulating insulin of responsive metabolic pathways

in muscle. Direct effects by testosterone on post-

receptor events may not be excluded, however. This

is presumably also the case in spontaneous HA states

in women, where capillary density is low and closely

associated with the degree of insulin resistance [11,

13, 14].

Origin of hyperandrogenicity in women

Testosterone in normal women is produced mainly

from the ovaries. In women with android fat dis-

tribution and HA, the rate of production of tes-

tosterone has been shown to be elevated [37]. The

site of production of excess androgens in HA has

been suggested to be the ovaries [38], but corre-

sponding information for the relatively small tes-

tosterone elevation in the upper range of the general

population of women is not available. Neither is it

known why some women produce more androgens

than others. It has been suggested, however, that a

stressful environment might be involved in hypo-

thalamic mechanisms with neuroendocrine conse-

quences [19], suggesting that androgens might have

adrenal origin. Clearly, the regulation of androgen

production in women requires more attention in

attempts to understand why androgen production is

elevated in some women, because such overpro-

duction seems to destroy the natural protection of

women in comparison with men from prevalent

disease, notably CVD.

Summary and conclusions

Hyperandrogenism in women is associated with male

physical characteristics in terms of adipose tissue

distribution and function, as well as muscle mass,

structure and function. Furthermore, there are

several male psychological traits in such women,

such as stress reactions.

Women with HA have a high prevalence of

metabolic risk factors for NIDDM and CVD as well as

hypertension, and low SHBG concentrations, an

indicator of HA in women, is a predictor for NIDDM,


REVIEW: THE ANDROID WOMAN 109

CVD and premature death. This cluster of metabolic

derangements and diseases are characteristic of the

metabolic syndrome, and HA in women thus seems

to be an integral part of this syndrome.

The mechanism behind this cluster of phenomena

in women with HA is probably an effect of tes-

tosterone in inducing muscular and systemic insulin

resistance. This might partly be due to a diminished

insulin binding to a contracted bed of capillary

endothelium, and subsequent diminished blood flow

and insufficient delivery of insulin to its site of action

on the muscle cell. Post-receptor perturbations may

also be involved.

It should be noted that the male psychological,

somatic and metabolic characteristics of women with

HA are found not only in severe, fairly rare, clinical

HA states, but also in the upper part of the

distribution of androgenicity of nonselected popu-

lations of women. This might constitute as many as

20% of women, and the disease risk is thus a problem

of considerable quantitative importance. Such

women are threatened by an increased risk of

prevalent, serious disease and mortality, and seem to

have lost their natural, female protection against, for

example, CVD. The distribution of androgenicity of

clinical importance amongst women is apparently

such that the group at risk can be relatively easily

identified. It seems highly desirable to introduce

preventive and therapeutic regimens for such

women. Adequate interventions would clearly be

easier to define if the origin and cause of the HA in

women were known. Today we could recommend

HA women to avoid developing obesity, which is

known to amplify insulin resistance.

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S-413 45 Go$ teborg, Sweden.


the android woman – a risky condition

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