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Therapeutic Aspects
of Antiandrogens in Women

Androgens and

Evanthia Diamanti-Kandarakis, MD, George Tolis, MD, and
Antoni J. Duleba, MD
OBJECTIVES: We reviewed the mechanisms of androgen actions and the established and experimental uses of antiandrogens in women.
METHODS: Relevant studies were identified through a computerized bibliographic search
(MEDLINE) and through manual review of bibliographies in relevant publications.
RESULTS: Androgens exert major effects on the functions of gonads, sex organs, and various
"nonreproductive" organs and systems, including muscles, liver, skin, nervous system, and the
immune system. Most, but not all, of the actions of androgens may be explained by their binding
with specific androgen receptors. Antiandrogens prevent androgens from expressing their activity
at target cells. They act primarily by binding to androgen receptors and thus preventing activation
of receptors by androgens. Steroidal antiandrogens may also exert a wide range of other hormonal
and antihormonal effects by interacting with receptors for progesterone, glucocorticoids, and mineralocorticoids. Furthermore, some antiandrogens may decrease the production of androgens by
acting at the hypothalamic-pituitary unit and modifying the release of LH, or by directly inhibiting
individual enzymes involved in steroidogenesis. Antiandrogens are widely used in the treatment of
women with various hyperandrogenic conditions, including polycystic ovary syndrome, idiopathic
hirsutism, acne, seborrhea, and hair loss.
CONCLUSIONS: Antiandrogens provide a logical and clinically effective pharmacotherapy of
hyperandrogenic disorders. However, both steroidal and nonsteroidal antiandrogens may cause
significant side effects, largely because of their interactions not only with androgen receptors, but
also with other receptors and various enzymatic activities. Difficulties in designing the optimal
antiandrogen largely result from the complexities of androgen metabolism and action in various
tissues. (J Soc Gynecol Invest 1995;2:577-92)

KEY WORDS: Androgens, antiandrogens, spironolactone.
A ntiandrogens, or androgen antagonists, may be
defined as compounds that interact with the androgen receptor (AR) and thus prevent the biologic actions of androgens on their target tissues. The
ideal antiandrogen should possess high specificity and affinity for the AR but be devoid of any androgenic activity.' Furthermore, the ideal antiandrogen should not have
any other hormonal or antihormonal activity. This strict
definition differentiates true antiandrogens from other
substances that reduce the effects of androgens by interfering with their biosynthesis or metabolism.
In this review, we briefly outline the mechanisms of
androgen action and describe how various antiandrogens
may interfere with these mechanisms. We also discuss
non-AR-mediated actions of individual antiandrogens.
Finally, we review the current clinical experience with
From the 1st Department of Internal Medicine, University of Athens, Laiko
Hospital, Athens, Greece; the Department of Endocrinology, Hippokration Hospital, University of Athens, Athens, Greece; and the Department of Obstetrics
and Gynecology, Yale University School of Medicine, New Haven, Connecticut.
Address reprint requests to Evanthia Diamanti-Kandarakis, MD, 1st Department of Internal Medicine, University of Athens, Laiko Hospital, 34 Areos Street,
P. Faliro, Athens, 17542, Greece.
Copyright © 1995 by the Society for Gynecologic Investigation.

antiandrogens in the treatment of hyperandrogenic disorders in women.

Tissue Sources, Biochemical Pathways,
Transport, and Clinical Markers

Androgens are steroids produced in the testis, ovary, and
adrenal gland; they are further metabolized by various
organs including the placenta, liver, and skin. Their synthesis is stimulated by LH in the testes and ovaries, by
adrenocorticotropic hormone (ACTH) in the adrenal cortex, and by human chonionic gonadotropin (hCG) in the
placenta. Furthermore, androgen steroidogenesis is modulated by a wide range of other substances, including
steroids, growth factors/hormones, cytokines, prostaglandins, and a host of other agents acting in an endocrine, paracrine, and autocrine fashion. In the ovary, both
the theca and strorna have the biosynthetic enzyme machinery to convert cholesterol to androgens. This pathway involves enzymes catalyzing cholesterol side-chain
cleavage and subsequent hydroxylations, dehydrogenations, and isomerizations (Figure 1). A family of cy1071-5576/95/19.50

SSDI 1071-SS76(910O0002-V

Gynecol Invest Vol. 2, No. 4, July/August
July/August 1995
578 JJ Soc Gynecol






Figure 1. Delta-5 (left) and delta-4 (right) biosynthetic pathside chain cleavage; Pc17
ways. P
cytochrome P450; Pscc
= 17-hydroxylase; Pc17,20 = 17-20 lyase; 17-keto r
17ketoreductase; 3B-HSD 3-beta-hydroxysteroid dehydrogenase and delta-5-delta-4 isomerase; Scx-r
5-a reductase; st =




tochrome P-450 enzymes plays a central role in this process. They catalyze the addition of hydroxyl groups to
various substrates by the reduction of 02 with electrons
from nicotinamide adenine dinucleotide phosphate.2
Androgens may act locally at the site of their synthesis
or may be released into the circulation and transported to
distant target tissues. Androgens may be transported in
three forms: free, bound to albumin, and bound to sex
hormone-binding globulin (SHBG). Free, unbound androgens are biologically active; they may enter cells and
interact with specific ARs. Only approximately 2% of
testosterone circulates in its free form; 18% is bound to
albumin and up to 80% is bound to SHBG. The ability of
individual androgens to bind to SHBG depends on the
presence of the C-17 hydroxyl group; consequently, testosterone and Sa-dihydrotestosterone (5a-DHT) bind
tightly to SHBG, whereas androstenedione and dehydroepiandrosterone sulfate (DHEAS) do not.3
Both albumin and SHBG may act as buffers limiting
the fluctuations in the level of free androgen. Furthermore, the protein-bound fraction of androgens is protected from hepatic metabolism and renal clearance. Traditionally, it has been thought that protein-bound androgens are biologically inactive. However, because albumin
binds loosely to androgens, albumin-bound androgens
may be readily available to target tissues. In addition,
even though SHBG binds to androgens with high affinity, SHBG-bound androgens may interact with some tissues, as suggested by observations of SHBG binding to
the prostate and endometrium." 5 Regardless of the activ-


et al
Diamanti-Kandw-Ws et

ity of the SHBG-bound androgens, there is a strong correlation between low SHBG and clinical evidence of hyperandrogenism, even when the total levels of androgens
are within normal limits. Thus, the regulation of SHBG
concentration is of utmost importance. Sex hormonebinding globulin is a beta globulin produced by the liver
under the control of various hormones. In particular, the
production of SHBG is increased by estrogens and thyroxin but is decreased by androgens, acromegaly, obesity, and hyperinsulinemia.
Significant elevation of serum testosterone may be an
important indicator of the presence of an androgenproducing neoplasm. However, in other clinical conditions, androgens such as testosterone, androstenedione,
and DHEAS are relatively nonspecific and insensitive
markers of overproduction of androgens in hirsute
women. Because the active androgen in hair follicles is
5a-DHT (produced in situ by Sa-reduction of testosterone) rather than testosterone, it was suggested that the
best biochemical markers of peripheral/cutaneous androgen action could be stable metabolites of 5a-DHT. Indeed, an elevation of 3a> 1 71-androstanediol glucuronide
and of other conjugated and unconjugated metabolites of
5a-DHT has been demonstrated in hirsute patients.6-8
Recently, however, the role of 3a,17f3-androstanediol
glucuronide as a marker of cutaneous androgen metabolism has been questioned, and at present, the clinical significance of androgen conjugates is uncertain.9-11 This
criticism stems from a greater appreciation of the role
played by the adrenal gland and liver in androgen metabolism. Several studies have demonstrated that the adrenal
gland is the major source of precursors for androstanediol
glucuronide and that the liver may be the major source of

glucuronide conjugation. 12-15 Furthermore, androstanediol glucuronide is not a reliable parameter of androgenicity; changes of its serum level often do not correspond
with the clinical response to treatments of hirsutism


The search for the "ideal" biochemical test of hirsutism
so far has been unsuccessful. The difficulties in correlating the levels of androgens with clinical conditions are
due to the involvement of several organs in androgen
metabolism and the complexity of steroid interconversions.

Mechanism of Androgen Action
Androgens may interact with tissues either by binding
directly to specific ARs or, in some tissues such as the
brain, they may be aromatized to estradiol, which in turn
may bind to estrogen receptors. Limited evidence suggests that androgens may also act by steroid receptorindependent mechanisms; in particular, androgenic modulation of SHBG production appears not to be mediated
by ARs.18'19 Most of the actions of androgens leading to
masculinization are thought to be mediated by ARs.
The most potent natural androgens are testosterone
and 5ca-DHT. The most widely accepted model of an-

4, July/August 1995 579

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Antiandrogens in Women

J Soc Gynecol
Gynecol Invest

drogenic actions relies on the concept of a single intracellular AR.20 According to this model, lipophilic free testosterone diffuses passively into the target cell and binds
to the specific AR. In some tissues, the actions of androgens require 5ax-reduction to 5a-DHT, which binds to
AR with the highest affinity of all natural androgens.21-23
In a classic example, wolffian duct structures (epididymis, vas deferens, seminal vesicles, and ejaculatory ducts)
develop in response to testosterone, whereas organs such
as the prostate and external genitalia require 5oDHT.24'25 These selective responses to testosterone and
5a-DHT may be caused by tissue-specific patterns of intracellular androgen metabolism, high concentrations of
testosterone in some but not other androgen-responsive
tissues, and variable sensitivity of target tissues to the AR
occupancy rate.25'26 The discovery and characterization
of an AR gene provides the major argument for a singlereceptor model.20'27
Alternative, less convincing hypotheses of the mechanisms of androgen action invoke the existence of two
ARs, each selectively or preferentially responding to either testosterone or 5oa-DHT, and/or the presence of
membrane ARs resulting in additional rapid nongenomic
actions of androgens. Evidence supporting these controversial models has been reviewed recently.28
Two isoenzymes of 5cx-reductase have been described
and characterized.2932 The clinical relevance of these observations in the female is not yet certain. In men, type II
5a-reductase is the major isoenzyme.
The structure of the AR and its gene has been elucidated.26'33'34 The single gene encoding the AR encompasses nearly 100 kilobases and is located in the qI1-12
region of the X chromosome. The AR gene consists of
eight exons preceded by a typical promoter region. The
organization of the AR gene is similar to that of the other
steroid receptor genes (Figure 2). Cloning of the AR gene
has permitted detailed molecular analysis of clinical syndromes of androgen resistance associated with AR defects.
The AR is a protein consisting of 917-919 amino acids
and has a molecular weight of approximately 98,000. Androgens bind to the region near the carboxyl terminal end
of the AR. The midportion of the AR contains two "zinc
fingers" and is responsible for a specific DNA-binding
domain. The so-called hinge region between the midportion of the receptor and the androgen-binding domain is

thought to be involved in nuclear transport of the receptor. The NH2-terminal domain of the receptor is thought
to be involved in gene-specific responses.
In the absence of androgens, ARs were detected in the
perinuclear region of the cytoplasm.23 Nuclear transport
(translocation) of the receptors has been detected within
minutes of androgen treatment. After translocation, the
hormone-receptor complex binds to a specific DNAbinding site and induces mRNA transcription, protein
synthesis, and regulation of cell function.2'35
The androgen-binding region of the AR is nearly 5055% homologous to the hormone-binding domain of the
glucocorticoid, mineralocorticoid, and progesterone receptors. The greatest affinity to AR has been demonstrated for 5ot-DHT. Testosterone also binds well to AR
but with lower affinity than 5a-DHT. Dexamethasone,
hydrocortisone, progesterone, and 17f-estradiol do not
compete well with androgens for binding with AR.36

Figure 2. Schematic representation of the androgen receptor.
Numbers indicate the specific
amino acid positions. The amino
and carboxy termini are denoted
as NH2 and COOH, respectively.
DHT = dihydrotestosterone; T
- testosterone.





Factor Binding?


Target Tissues



ANDROGENS AND THE REPRODUCTIVE TISSUES. Androgens exert major effects on the development and function of reproductive tissues. These effects
are particularly profound during embryonic and fetal life.
At 7 weeks of gestation, the fetus of either sex possesses
both male and female genital ducts. At 8 weeks of gestation, the fetal gonads (testis and ovary) develop the
capacity to produce androgens.37 In the presence of sufficient androgenic stimulation, male (wolffian) ducts develop further and ultimately form the epididymis, vas
deferens, and seminal vesicles.'38J9 The wolffian ducts
lack 5a-reductase activity; the formation of the epididymis, vas deferens, and seminal vesicles is mediated by
testosterone and not 5a-DHT. "0 The development of female (mifllenian) ducts may continue in the absence of sex
steroids and results in the formation of the uterus, fallopian tubes, and upper vagina. In the male, the regression
of mrillerian ducts is mediated by the testis-derived antimiullerian hormone, but not by androgens. By 12
weeks, the development of male genital ducts (in the
male) and female genital ducts (in the female) is completed, while the genital ducts of the opposite sex regress.
Androgens play a crucial role in the induction of male
differentiation of the external genitalia and urogenital sinus. Complete male differentiation of these structures
may take place only in the presence of androgenic stim559







58 JJ So

Gyeo Ines

Vol. 2, No.
No. 4, Juy/uus


4, July/August 19

ulus between 8 and 12 weeks of gestation. The urogenital
sinus and genital tubercle possess 5a-reductase activity;
under normal conditions, these structures masculinize in
response to androgens after local conversion of testosterone to 5a-DHT.41 Thereafter, 5a-DHT stimulates development of the prostate, enlargement of the genital tubercle leading to the formation of the penis, and fusion of the
urethral folds and labioscrotal folds. In the female, the
absence of androgenic stimulation results in development
of the external genitalia and urogenital sinus structures in
a female configuration. This may occur in the genotypic
male in pathologic conditions such as gonadal dysgenesis,
5a-reductase deficiency, and androgen insensitivity. After 12 weeks, when the separation of the vagina from the
urogenital sinus is complete, even high levels of androgens cannot cause fusion of the urethral or labioscrotal
folds.42 However, at any point in life, androgens may
stimulate enlargement of structures derived from the genital tubercle and cause clitoromegaly in the female and
penile enlargement in the male.
In adult females, hyperandrogenic conditions exert
profound effects on reproductive function and are associated with ovulatory dysfunction, infertility, and a wide
range of menstrual disorders ranging from amenorrhea to
dysfunctional uterine bleeding. The causes of hyperandrogenism include androgen-producing neoplasms, congenital adrenal hyperplasia, and polycystic ovary syndrome (PCO). Polycystic ovary syndrome is the most
common, and yet the least understood, condition of hyperandrogenism. It is typically characterized by excessive
ovarian production of androgens, elevation of LH, and
hyperinsulinemia secondary to insulin resistance.43-45
Hyperandrogenemia, however, is not likely to be a significant cause of insulin resistance. Several studies have
demonstrated the persistence of insulin resistance despite
suppression of androgen production (by GnRH analogs)
and suppression of androgen action (by androgen antagonists).4"4 Recent evidence suggests that hyperinsulinemia may be the underlying cause of hyperandrogenism
and that treatments that improve insulin sensitivity and
decrease the levels of insulin can alleviate hyperandrogenism. 48-50

ANDROGENS AND THE MUSCLE. Androgen receptors have been identified in the myocardium, vascular
smooth muscle, and striated muscle.51-53 In contrast to
the accessory sex organs, which contain large amounts of
5ct-reductase and which respond primarily to 5a-DHT,
the activity of 5ax-reductase is low in striated muscles and
the heart; it is therefore believed that these tissues respond
directly to testosterone.5254 Androgens stimulate RNA
polymerase activity, increase RNA and protein content,
increase the muscle glycogen content, and initiate a variety of other biochemical and morphologic changes in
skeletal and myocardial muscles. 55-58 Various muscles


Diamanti-Kandarakis et al

respond differently


androgens, especially

in terms of

quantitative and qualitative effects on protein synthesis,
glucose metabolism, and the presence or absence of synergism with growth hormone.5859
Growth hormone-induced cardiac growth is augmented by androgens.59 Castration decreases cardiac
growth and is associated with a reduction of the cardiac
contractile function. Steroidal antiandrogens exert a negcardiac activity, possibly through
an alpha-2-adrenergic effect.50 It is thought that androgens affect cardiac contractility by interfering with the Na
pump in a nondigitalis site and/or with intracellular mediators in the left atrium.61 Androgens may stimulate mitotic activity (demonstrated in myoblast cultures) or produce muscle hypertrophy (observed in vivo).
ative inotropic effect on

ANDROGENS AND LIPID METABOLISM. The effects of androgens on lipid metabolism are complex and
of particular interest, as they may explain the higher
prevalence of atherosclerosis in men than in women. Hyperandrogenemia in women is associated with an increase
of plasma low-density lipoprotein (LDL) cholesterol,
likely due to increasing hepatic lipase activity, which enhances very low-density lipoprotein (VLDL) cholesterol
catabolism by the liver.62'63 Androgens may also cause
increased degradation and decreased serum levels of highdensity lipoprotein (HDL) cholesterol, leading to an unfavorable LDL/HDL ratio. Hyperandrogenic women are
at considerably increased risk of developing myocardial
infarction compared with the age-matched control pop-

Sexual dimorphism has been documented with two
enzymes responsible for HDL metabolism: Lipoprotein
lipase is greater in women than in men, whereas hormone-sensitive lipase is greater in men than in women,
being stimulated by androgens and suppressed by estrogens. These effects of androgens are believed to be receptor mediated, as has been shown in rats.65 A recent preliminary study in humans suggested that blockage of AR
with a pure androgen antagonist, flutamide, leads to a
reduction of total cholesterol and LDL in young women
with PCO syndrome.66 However, the actions of antiandrogens on serum lipids are still poorly understood; studies of the effects of antiandrogen cyproterone acetate in
combination with ethinyl estradiol (in the contraceptive
preparation Diane-35) yielded conflicting results.67'68
The association between hyperandrogenemia and dyslipidemia is complicated by insulin resistance, which is
frequently observed in women with PCO. Hyperinsulinemia resulting from insulin resistance may play a major
direct role in the development of dyslipidemia. At
present, it is unclear whether elevation of androgens
causes or is caused by insulin resistance.46 56'69 77Resolution of this controversy will greatly aid in developing
optimal therapies for hyperandrogenic, dyslipidemic, and
insulin-resistant women.

Antiandrogens in Women

Antiandrogens in WomenI S G
. 2 No 4J/g
J Soc Gynecol, Invest Vol. 2, No. 4, July/August 1995 581

SYSTEM. Androgens play a significant role in the control of development and function of the central nervous
system (CNS). Actions of androgens on the CNS may be
exerted either directly by their interaction with specific
ARs, or indirectly by local aromatization of androgens to
estrogens, which then may interact with estrogen receptors.78


have been detected in many areas
pituitary, hypothalamus, preoptic
amygdala, thalamus, and brain stem.79'80


including the
area, septum,


These receptors appear to be identical to other ARs and
may be activated by both testosterone and Sa-DHT. In
the cortex and pituitary, androgens do not undergo significant aromatization, and it appears that the effects of
androgens on these tissues are mediated by ARs. In contrast, most of the effects of androgens on the hypothalamus and limbic system are thought to be mediated by
estrogen receptors rather than AR.78 This concept, the
aromatization hypothesis, has been validated in studies of
the brain of the female subhuman primate."
Most of the significant effects of androgens on the
CNS have been documented duning the fetal and neonatal
periods. Exposure to androgens during this critical period
affects brain structure and sexual behavior in rodents.
Several sexually dimorphic hypothalamic nuclei have
been identified.S>3-4 It appears that the embryonic mammalian brain is fundamentally female and that the characteristics of its function typical of the male sex are imposed by androgens via conversion to estrogens. Thus,
paradoxically, masculine differentiation of the brain is the
result of actions of estradiol, produced intraneuronally by
the aromatization of testosterone.85'86
The actions of androgens at the pituitary level are
thought to be exerted via AR rather than via aromatization to estradiol.87 It appears that testosterone exerts its
negative feedback effects on LH secretion directly, although Sc-reductase is present in this gland and 5cx-DHT
has also been shown to inhibit LH secretion.88'89 Inhibition of FSH release by testosterone and 5a-DHT has been
observed in some but not in all experimental models.88'89
Experiments in male rats treated with 5ae-reductase inhibitors or with methyl-19-nortestosterone, a synthetic
androgen that cannot undergo 5a-reduction, have suggested that 5a-reduction of testosterone may not be essential in the control of LH secretion in this species.90
However, in castrated mice, treatment with the 5axreductase inhibitor finasteride reversed the testosteroneinduced suppression of LH.91 The clinical importance of
these observations is uncertain, as treatment of PCO patients with finasteride had no demonstrable effect on serum


Modulation of LH and FSH release by androgens may
be mediated by actions at the level of the pituitary and/or
hypothalamus. Experiments in men demonstrated that
infusion of testosterone and estradiol, but not 5ot-DHT,


caused suppression of FSH and LH.93 Studies by Naftolin
et a194 suggested that suppression of gonadotropins by
testosterone may be due, at least in part, to aromatization
of testosterone to estrogens. A recent report described a
patient with estrogen resistance due to a mutation in the
estrogen receptor gene.95 The patient had elevated serum
estrogens, normal testosterone, and high concentrations
of FSH and LH. These observations provide further evidence for a role of estrogen in the feedback inhibition of
gonadotropin secretion.
In women, the role of androgens in the regulation of
LH release is still incompletely understood. Administration of testosterone to ovulatory women has been shown
to result in a decrease of responses of LH to GnRH and a
decrease of LH pulse frequency.96 The inhibition of the
hypothalamic-pituitary axis in these women was not affected by an aromatase inhibitor, testolactone, and therefore may be independent of aromatization of testosterone
to estrogen. In contrast to these findings, evaluation of
hyperandrogenic women failed to demonstrate any significant effects of testosterone on the amount or pattern
of LH release or on LH sensitivity to GnRH.97
Androgens clearly play a significant role in modulat-

ing the behavior of males and females. Although most of
the knowledge on the psychotropic effects of androgens
has been derived from animal research, and the relevance
of these studies to human beings may be limited, there is
also a growing body of literature directly evaluating the
role of androgens in human learning, behavior, and sexuality. Androgens are thought to be responsible for the
sex differences in visual-spatial skills and language fluency.98 Excessive levels of androgens are blamed for sexually provocative and violent behavior; however, there
are few studies on the relation between androgens and
aggression in females. Some investigators found no significant correlation between androgen levels and selfrated or observed aggression, whereas others observed a
clear positive correlation between aggression and blood
levels of testosterone in various female populations.99 Exposure to excessive levels of androgens early in life may
have particularly profound effects on behavior; females
with congenital adrenal hyperplasia may display malelike behavior and sexual preferences. "'0 Undesirable effects of androgens on behavior may be ameliorated by use
of antiandrogens, which are thought to act by blocking
both central and peripheral ARs. Antiandrogens have
been used successfully in men suffering from pathologic
sexual hyperactivity. I'O To date, there are few data on the
psychotropic effects of antiandrogens in women.
Just as excessive levels of androgens may have adverse
effects on behavior, inadequate levels of androgens also
may be detrimental. Several studies have shown an association between the serum levels of testosterone and various aspects of sexuality in women. Testosterone levels

AliJ-J Soc


4, JuyAuut 1995
Vol. 2,
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July/August 95

correlated positively with masturbation frequency, intercourse frequency, sexual arousal, and sexual satisfaction. 1
Furthermore, treatment of oophorectomized
women with pharmacologic doses of androgens has been
reported to increase the level of sexual desire, sexual fantasies, and sexual arousal.'05 However, the effect of androgens on sexuality is still not entirely clear; for example, testosterone levels did not correlate wvith such an
important aspect ofsexual function as sexuality involving
the partner.102
102- 104

ANDROGENS AND THE LIVER. The liver is a major
site of androgens' action and metabolism. The effects of
androgens on the liver are complex and involve both
stimulation and inhibition ofvarious enzymatic activities.
Thus, castration of males results in a reduction of a wide
range of enzymatic activities, including fumarase and aspartate and alanine aminotransferases, and an increase of
5a-reductase. Administration of testosterone to castrated
animals has the opposite effect. Androgens also appear to
play a significant role in the regulation of fatty acid oxidation and the modulation of insulin binding in the
liver."06 "07 Some of the effects of androgens may involve
inhibition of the activity of the catalytic unit of the adenylate cyclase system in hepatic membranes.'08
The actions of androgens on hepatocytes may be exerted at two levels: via specific ARs and via non-receptordependent mechanisms.'` High-affinity liver ARs have
been identified and characterized.'09-1 Receptordependent actions of androgens control, in part, the cytochrome P450-dependent system. The response of this
system to androgens is attenuated by the use of the nonsteroidal antiandrogen flutamide. Non-receptormediated actions on the liver include a nonspecific increase of microsomal protein content and an increase in
liver weight.'8
In addition to the direct action on hepatocytes, androgens may act indirectly by modulating the release of other
hormones that regulate hepatic function. Indirect effects
of androgens may be due in part to their actions in the
anterior hypothalamus or in extrahypothalamic areas.
Regulation of hepatic production of SHBG is of pivotal
importance in controlling the concentration of the active
fraction of androgens. In particular, low levels of SHBG
are associated with hyperandrogenic disorders in females.
Some evidence supports the view that androgens directly
inhibit hepatic production of SHBG.77 This action of androgens is probably not mediated by AR-dependent
mechanisms, as administration of flutamide (pure antiandrogen) did not increase the level of SHBG after it was
reduced by androgen treatment.19 However, there is
growing evidence supporting the hypothesis that low
levels of SHBG in women with PCO may be largely due
to hyperinsulinemia, rather than hyperandrogenism. 2"13 In cultures of human hepatoma cells, an-




Diamanti-Kandarakis et al

drogens stimulated and insulin inhibited SHBG produc-

tion. 114'115 Furthermore, in patients with PCO, suppression of androgen production is not associated with any

appreciable change in SHBG levels, whereas inhibition of
insulin release by diazoxide results in a significant increase
of SHBG. 13
UNIT. Human hair follicles and their associated sebaceous and apocrine glands are the major targets of androgens. Androgens influence hair growth by promoting the
development of terminal hair and prolonging the duration of anagen (growth phase of hair). Androgens also
exert direct effects on sebaceous gland growth and on the
quality of sebum secretion; excessive androgenization of
sebaceous glands results in oily skin and acne.116
Some, but not all actions of androgens on the pilosebaceous unit require the formation of 5a-DHT. It appears
that hair growth is dependent on 5at-reductase activity,
but sebum production is not.92'117 Androgen receptor has
been detected in the cells of dermal papillae, in epidermal
and pilosebaceous duct epidermal keratinocytes, in luminal epithelial cells of apocrine glands, in cells of the secretory coils of sweat glands, and in dermal fibroblasts."18
The sensitivity of the pilosebaceous unit to androgens
varies greatly depending on the site on the body and the
phase of hair growth."19'12'0 Ultimately, the response to
androgens may be controlled by the amount of available
AR and the activity of 5a-reductase (and consequently
the amount of bioactive receptor ligand 5ex-DHT). Regional variations in the amount of AR have been demonstrated; for example, the binding capacity of the AR is
higher in the skin of the external genitalia than in the skin
over the pubis. 121"122 The activity of5ot-reductase is modulated by androgens in some areas such as skin over the
pubis, but appears to be androgen independent in other
areas such the external genitalia. 123
In pathologic conditions, the excessive stimulation of
pilosebaceous units may be due to several abnormalities:
1) an excessive amount of free androgen, 2) increased AR,
and/or 3) excessive 5a-reductase activity. The contribution of each of these mechanisms to the ultimate development of hirsutism has not yet been elucidated. It is
thought, however, that the elevation of free androgens
plays a major role in the pathophysiology of conditions
such as PCO or congenital adrenal hyperplasia. Idiopathic hirsutism, on the other hand, is characterized by
normal levels of circulating androgens. Excessive stimulation of hair follicles in this condition is thought to be
due to increased 5cx-reductase activity.'22"124 Yet even if
elevation of 5cx-reductase is the direct cause of excessive
androgen sensitivity in women with idiopathic hirsutism,
it is unclear what mechanisms lead to abnormal activity
of 5ox-reductase. Increased androgen-binding capacity
cannot explain this condition because total cytosolic plus

Antiandrogens in Women

Gynecol Invest
Soc Gynecol
JJ Soc

nuclear androgen-binding capacity appears to be similar
in men and women, regardless of hirsutism. 122 Thus, the
etiology of idiopathic hirsutism is unclear. 125

cyproterone acetate, inhibits the lymphoid system. 1
This unexpected effect may be due to the immunosuppressive, glucocorticoid activity of this compound, rather
than its antiandrogenic properties.

There is significant sexual dimorphism in the function of
the immune system, whereby females mount a greater
overall immune response than males. It appears that androgens may have multiple effects upon various components of the immune system, including synthesis of immunoglobins, T-cell substrates, and cytokines. Low levels of androgens appear to be associated with an increased
risk of autoimmune disorders. Plasma levels of free androgens were significantly lower in women with rheumatoid arthritis than in age-matched healthy women.126
In addition, oxidation of testosterone to weak androgens
has been demonstrated in women with systemic lupus
erythematosus (SLE).'27
In contrast, increased levels of androgens seem to retard the progress of immune disorders. In animal models
of autoimmune diabetes (nonobese diabetic mouse), androgens had a protective effect against destruction of pancreatic islets and the development of diabetes.'28 An antiinflammatory effect of androgens has been invoked to
explain the attenuation of symptoms after smallpox vaccination and the delay in the evolution of SLE in females
treated with androgens. A therapeutic effect of androgens
has also been described in patients with Klinefelter syndrome associated with SLE. After treatment with testosterone, the numbers of CD3 and CD8 cells increased, the
CD4/CD8 ratio normalized, and the antinuclear antibody
titers declined.'29
In view of these observations, one would predict that
antiandrogens may have stimulatory effects on the immune system. However, a widely used antiandrogen,



Vol. 2, No. 4, July/August 1995 583

Vol. 2, No. 4, July/August



The involvement of androgens in the etiology of many
human disorders has prompted an intensive search for
substances that block the effects of androgens. By strict
definition, antiandrogens are substances that selectively
interact with ARs and thus prevent the binding and subsequent action of androgens. True antiandrogens may be
regarded as competitive inhibitors of testosterone and
DHT at the level of the AR (Figure 3).
Antiandrogens are a diverse group of substances with
widely differing chemical structures and multiple actions;
a single principle describing their structure and their interactions with the AR is therefore not possible. Broadly,
antiandrogens are classified into steroidal and nonsteroidal compounds. '31 To date, the most important and common clinical use of antiandrogens is in the treatment of
prostate cancer. In women, antiandrogens are increasingly used to manage of a broad range of hyperandrogenic disorders, including manifestations of PCO, congenital adrenal hyperplasia, idiopathic hirsutism, acne,
seborrhea, and hair loss. Treatment with antiandrogens is
long term, and discontinuation is associated with recurrence of symptoms and signs of hyperandrogenism.
Some of the effects of antiandrogens, such as changes in
the hair growth pattern, may not be obvious for several
months. Women with the most severe symptoms are
most likely to notice the greatest improvement. Because
all antiandrogens may pose an inherent risk to the fetus,
reliable contraception and appropriate counseling are essential.


Figure 3. Schematic representation of androgen action. Antiandrogens can interfere with androgen action at any point from a to
d. a = receptor-hormone binding; b = translocation of the androgen-receptor complex; c = dimerization; d = binding to DNA.
ARE - androgen response element; HSP 90 = 90 K heat shock protein (cytoplasmic receptor inactivator).

584 J Soc Gynecol Invest Vol. 2, No. 4, July/August
July/August 1995

Steroidal Antiandrogens
CYPROTERONE ACETATE. One of the best-known
steroidal antiandrogens, cyproterone acetate (CPA) is derived from 17-hydroxyprogesterone. Cyproterone acetate blocks androgen action by competitive binding to the
AR; it also has significant progestogenic activity and mild
glucocorticoid activity.'32 Antiandrogenic activity of
CPA is surprising because its 17a-acetyl group would not
be expected to bind well to AR; typically, good receptor
affinity is associated with a free 17x-hydroxyl
group. '31.133,134 Cyproterone acetate binds to the AR
with about 210% of the affinity of testosterone.13' Oral
absorption of CPA is almost complete. Peak plasma concentration after a single oral dose (2 mg) is reached after
3.7 0.8 hours; the post-maximum disposition is biphasic, with half-lives of 3.0 + 1.3 hours and 2.0 + 0.4
days.136 Cyproterone acetate is very lipophilic, and its
long biologic half-life may be explained by its accumulation at high concentrations in fat. The achievement of
equilibrium between its administration and elimination
may require up to 8 days. The half-time of elimination is
prolonged in obese patients. This may explain clinical
observations of delayed withdrawal bleeding after discontinuation of treatment in obese women. In hirsute
women, CPA attenuates androgen action by blocking
AR, as well as by reducing serum testosterone levels (by
inhibiting gonadotropin release) and decreasing 5areductase activity.137
In women, the main indication for the use of CPA is
control of excessive androgenic effects on the pilosebaceous unit. Cyproterone acetate is usually given in combination with an estrogen (usually ethinyl estradiol) as a
contraceptive preparation, primarily to avoid the risks of
feminization of a male fetus. Furthermore, estrogen has
additional inhibitory activity on the pilosebaceous
unit. 138The combination of CPA and estrogen significantly reduces plasma testosterone and androstenedione,
suppresses gonadotropins, and increases SHBG. 139-141
A commonly prescribed schedule involves administration of CPA (50-100 mg/day) on days 5-14 of the cycle
and ethinyl estradiol (35 mg/day) on cycle days 5-25.
This cyclic schedule (reverse sequential regimen), used
since 1969, allows regular uterine bleeding, provides excellent contraception, and is effective in the treatment of
severe hirsutism and acne.142,143 Excellent control of hirsutism, seborrhea, and acne has been obtained with other
protocols using a wide range of doses of CPA (2-100
mg/day) in combination with ethinyl estradiol (20-50
pug/day); these preparations were used either continuously or in a cyclic fashion. 138,140,144-147 Many physicians
prescribe CPA by simply adding a 50-mg tablet to the
first 10 days of a birth control cycle. With the above
therapeutic regimens, 4-9 months are usually required to
improve hirsutism.' 39.142 The beneficial effects of CPA
on hirsutism are dose dependent, as demonstrated in a


et al

Diamanti-Kandarakis et al

prospective double-blind study companing a combination
of CPA (2 mg/day) and ethinyl estradiol (35 ,ug/day)
given on days 5-25 of each month with the same preparation supplemented with additional CPA (100 mg/day
on days 5_15).148
Cyproterone acetate is also gaining popularity for the
treatment of acne, largely because of the significantly better results with a CPA-estrogen combination than with
traditional oral contraceptive preparations or tetracycline. 144'149
Side effects of CPA include fatigue, weight gain, decreased libido (10%), nausea (18%), irregular uterine
bleeding (10%), breast tenderness (30%), and headaches
(20/0).143 Some of these side effects are improved by
combining CPA with estrogen. The effects of such a
combination on the lipid profile are slight and consist of
a small increase in total cholesterol; increases in HDL
cholesterol, HDL2 cholesterol, and Apo-Al lipoproteins;
an increase in the HDL/LDL-cholesterol ratio; and an
increase in triglycerides. 150 Because of the potential hepatotoxicity of CPA, monitoring of serum transaminases
every 3-6 months is recommended. However, to our
knowledge, significant hepatotoxicity has not been reported in women using CPA in a cyclic fashion. Rarely,
administration of CPA may be associated with adrenal
suppression.'1 At present, CPA is widely used in Europe
and Canada but is not available in the United States.

SPIRONOLACTONE. The well-known aldosterone
antagonist, spironolactone (SP), is also a potent antiandrogen. 152.153 The bulky D-ring in combination with a
7-thioacetyl group is thought to modify the binding characteristics of SP and be responsible for its competitive
receptor antagonism. Antiandrogenic properties of SP
have been demonstrated in various experimental systems,.
Spironolactone antagonizes the binding of androgen to
the rat ventral prostate AR in vitro and decreases prostate
weight in vivo. However, SP does not antagonize all
actions of androgens; for example, when administered to
castrated rats, SP did not inhibit the synthesis or accumulation of certain androgen-dependent prostate pro-

teins.15' Such incomplete antagonistic properties again
underline the complexities of the interactions of hormones and antihormones with receptors in vivo.
Spironolactone also interacts with other steroid receptors and with steroidogenic enzymatic systems. In particular, SP has some progestational and possibly partial
antiestrogenic activities. 155.156 It also diminishes androgen biosynthesis in the gonads and in adrenal steroidproducing cells by decreasing the microsomal cytochrome P-450 content.l57 l58 Furthermore, SP has a direct inhibitory effect on 5a-reductase.'59
Orally administered SP is rapidly absorbed and reaches
maximal plasma levels within 30-60 minutes. The
steady-state elimination half-life is 1.4 ± 0.5 hours.160
Although most of the administered dose is excreted in the

in Women

j Soc Gynecol Invest


unne and feces, the enterohepatic route plays a considerable role in the delay of the elimination of this compound.
Intake of food promotes absorption of SP and possibly
decreases its first-pass metabolism. 16' Canrenone, a weak
antiandrogen, has been identified as a major metabolite of
spironolactone. 162-164
The value of SP in the treatment of hyperandrogenic and idiopathic hirsutism has been well documented. 165-169 Furthermore, SP improves acne and seborrhea.157'170 Beneficial effects of SP on hirsutism have
been documented at doses as low as 50 mg/day (administered between days 4 and 22 of each menstrual cycle). 170
This regimen results in an improvement of hirsutism in
3-8 months. For patients with moderate to severe hirsutism, administration of higher doses of SP (200 mg/
day) resulted in decreases in the density, diameter, and
the rate of hair growth within 2 months.17'
Therapy with SP results in a decrease in serum concentrations of total and free testosterone without significant alterations in the levels of LH, FSH, estradiol, progesterone, DHEAS, and cortisol._67"70"7' Use of SP
may lead to a mild increase in serum triglycerides without
affecting the cholesterol level.172 Spironolactone increases
aldosterone levels but has no significant effect on serum
potassium and sodium concentrations.167 However, in
view of potentially dangerous hyperkalemia, SP should
not be used in women with renal insufficiency.
Initially, SP administration may cause polyuria, polydipsia, weakness, and fatigue. Diuretic effects are usually
limited to the first few days of treatment.'7' Long-term
side effects of SP are usually minor but may occur often.
In one series, side effects were reported in 91% of the
patients.'73 Most frequently, patients experenced menstrual disturbances (22%), breast enlargement and tenderness (26%), and dizziness (26% ) 173,174 Menstrual disturbances were usually well controlled by concomitant use
of oral contraceptives. Weak progestogenic activity of SP
may be responsible for the irregular, anovulatory pattern
of menstrual cycles; however, this issue has not been
evaluated adequately. Occasionally, use of SP may be
associated with headaches, increased appetite, and increased body weight. In most patients, the above side
effects are mild and have no clinical significance.
The experience gained with the use of SP suggests that
its dosage should be adjusted according to the severity of
symptoms. 175.176 In mild to moderate hirsutism, oral SP
is often recommended either on a cyclic basis (for example, between days 4 and 22) or daily at the lowest effective
dose (50-75 mg) to minimize side effects. In more severe
cases, higher doses of oral SP (150-200 mg) are recommended. Isolated acne may be treated effectively with
topical cream containing 5% SP. 157,177
OTHER STEROIDAL ANTIANDROGENS. In addition to CPA and SP, antiandrogenic properties are common to other synthetic steroids, including medroxypro-

Vol. 2, No. 4, July/August 1995 58S

gesterone acetate and testolactone. However, these compounds are of little or no use in the treatment of
hyperandrogenic disorders in women because of their
significant interactions with other steroid receptors and!
or steroidogenic pathways. Medroxyprogesterone acetate

is a potent progesterone agonist that also binds to glucocorticoid and mineralocorticoid receptors, whereas testolactone blocks aromatase activity. 131.176.178

Nonsteroidal Antiandrogens
This broad group of drugs includes "pure" nonsteroidal
antiandrogens such as flutamide and nilutamide, as well
as other nonsteroidal agents with antiandrogenic properties, such as cimetidine. "Pure" nonsteroidal androgen
antagonists were developed in the hope of producing
drugs with maximized antiandrogenic potency while
eliminating the side effects common to steroidal antiandrogens. Pure nonsteroidal androgen antagonists bind to
AR with high affinity and have virtually no progestational, glucocorticoid, or any other hormonal or antihormonal activity.

FLUTAMIDE. Flutamide (Sch 13521; 3'-trifluoromethyl-4'-nitro-2-methyl-propinoylanilide) is the bestknown nonsteroidal antiandrogen. Originally, it was
synthesized as a bacteriostatic agent; only subsequently
was it found to possess antiandrogenic properties. After
oral administration, flutamide achieves a maximum serum concentration at approximately 2 hours.'79 Flutamide itself is a relatively weak antiandrogen; however,
upon ingestion it undergoes significant first-pass metabolism to a potent antiandrogen, 2-hydroxyflutamide.
2-Hydroxyflutamide accounts for approximately 23% of
the plasma level of flutamide 1 hour after oral intake.
Steady-state concentrations of 2-hydroxyflutamide were
found after 2-4 days of administration of flutamide (250
mg every 8 hours). Its elimination is monoexponential
with a half-time of 4.3-21.9 hours. 179 Flutamide and
2-hydroxyflutamide are excreted mainly in urine; after 72
hours only 4.2% of the drug is excreted in feces.
Both flutamide and 2-hydroxyflutamide inhibit the
binding of 5oc-DHT to AR and reduce nuclear translocation of the AR. 180-183 Flutamide and 2-hydroxyflutamide have no discernible binding affinity to progesterone, glucocorticoid, mineralocorticoid, or estrogen receptors. 178 The mechanisms of action of flutamide are
still incompletely understood. Although flutamide is considered a pure antiandrogen, it decreases circulating concentrations of DHEAS in postmenopausal women, as
well as androstenedione, 3ot-androstanediol glucuronide,
and DHEAS in young women with PCo.184-186 These
effects may be due to inhibition of adrenal 17-20 lyase.'87
The effects of flutamide on the hypothalamo-pituitarygonadal axis are also poorly understood. Administration
of flutamide to male rats and men increases LH and tes-

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