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Human Reproduction vol.8 no.ll pp.1807-1812, 1993
The effect of flutamide on pulsatile gonadotrophin
secretion in hyperandrogenaemic women
T.Sir-Petermann1, B.Rabenbauer and L.Wildt
Division of Gynaecological Endocrinology and Reproductive
Medicine, Department of Obstetrics and Gynaecology, University
of Erlangen, Erlangen, Germany
'To whom correspondence should be addressed at: Instituto de
Investigapiones Materno Infantil, Facultad de Medicina, Universidad
de Chile, PO Box 226-3, Santiago, Chile
The pulsatile gonadotrophin secretion in hyperandrogenaemic
women was examined, following short-term androgen
antagonism induced by flutamide, a specific androgen
receptor blocker. Flutamide was administered to seven
hyperandrogenaemic women and five normal cycling women,
at a dose of 250 mg on the evening of day 1, followed by daily
doses of 750 mg for 6 days. Blood samples were collected at
10 min intervals for 8 h before (day 1) and during treatment
(days 2 and 6). Gonadotrophin and prolactin concentrations
were measured in all samples while sex hormone concentrations
were analysed in selected samples. Flutamide administration
to hyperandrogenaemic women was followed by a decrease
in luteinizing hormone (LH) pulse amplitude (P < 0.05),
associated with an apparent decline in mean LH concentrations.
Follicle stimulating hormone (FSH) showed a significant
fall after 6 days of treatment (P < 0.05). Total testosterone,
free testosterone, androstenedione and dihydroepiandrosterone
sulphate were significantly decreased during flutamide
administration, while sex-hormone-binding globulin and
oestradiol were not affected. Normal women showed no
significant changes in the above mentioned parameters. These
results demonstrate that short-term androgen receptor
blockade with flutamide reduces gonadotrophin secretion and
androgen concentration in hyperandrogenaemic women.
Since flutamide is devoid of intrinsic hormonal activity, it is
suggested that the observed hormonal changes are secondary
to the androgen blockade.
Key words: anti-androgens/flutamide/gonadotrophin pulsatility/
hyperandrogenaemia
Introduction
The effects of androgens on gonadotrophin secretion in women
are not completely understood. It has been proposed that
hypersecretion of androgens either directly or as a consequence of
the aromatizauon of oestrogens causes the abnormal gonadotrophin
dynamics which characterize the syndrome of hyperandrogenism
(Rebarer al., 1976; Yen, 1980). Most studies, however, support
the concept uiat testosterone inhibits the hypothalamic-pituitary
axis without its prior conversion to oestradiol (Santen, 1975;
Marynick et al., 1979). It has been demonstrated that luteinizing
hormone (LH) pulse frequency is reduced by testosterone
(Veldhuis et al., 1984; Urban et al., 1988). Since LH pulse
frequency is a good indicator of secretion of gonadotrophinreleasing
hormone (GnRH) from the hypothalamus (Knobil,
1980; Leyendecker et al., 1983), it has been assumed that the
effect of testosterone is exerted on the GnRH pulse generator
(Veldhuis et al., 1984). More recendy, this assumption has been
challenged by the suggestion that testosterone inhibits secretion
of LH and follicle stimulating hormone (FSH) via a GnRHindependent
mechanism acting directly on the pituitary gland
(Sheckter etal., 1989).
Investigation of the effect of androgen on gonadotrophin release
in women is of interest because it has been proposed that
androgens play an important role in uie control of gonadotrophin
secretion, either directly or following their aromatization to
oestrogens, particularly in hyperandrogenaemic women (Dunaif
etal., 1984; Fleming etal., 1985; Vermesh etal., 1987). In
normal women, injection of testosterone is followed by a decrease
of the LH pulse frequency (Serafini etal., 1986), a similar
effect to that observed in normal men (Marynick et al., 1979).
However, since the administration of testosterone to normal
women for a prolonged period of time is not feasible, an
alternative strategy might involve the administration of nonsteroidal
compounds that block the negative feedback actions of
endogenous androgens by means of their binding to androgen
receptors, without acting on gonadotrophin secretion (Urban
et al., 1988). We dierefore set out to analyse the effect of a
specific anti-androgen (flutamide) on the pulsatile gonadotrophin
secretion of hyperandrogenaemic women, in order to further
elucidate the cause—effect relationship between abnormal
gonadotrophin secretion and hyperandrogenaemia.
Materials and methods
Subjects
Seven hyperandrogenaemic women (aged 18-28 years) were
selected for study from the patients attending the Unit of
Endocrinology, Department of Obstetrics and Gynaecology,
University of Erlangen, Germany. Inclusion criteria were:
chronic oligo- or amenorrhoea, hirsutism, and plasma testosterone
concentration >0.6 ng/ml or LH/FSH ratio >3.
Hirsutism was assessed by a standardized procedure and
graded according to the severity from 0 to 3 (0, no hirsutism;
1, mild; 2, moderate; 3, severe). Hyperprolactinaemia, androgensecreting
neoplasms, Cushing's syndrome and attenuated
© Oxford University Press 1807
T.Sir-Petermann, B.Rabenbauer and L.Wildt
21-hydroxylase deficiency as well as thyroid disease were
excluded by appropriate tests.
In addition, five non-hirsute regularly ovulating women (age
22—27 years) acted as the control group. None of these women
had taken oral contraceptives or other medications for at least
6 months before starting the study and serum concentrations of
androgens and gonadotrophins were within normal limits. Prior
to the study, informed consent was obtained from all subjects.
This study was approved by the local ethical committee.
Experimental design
Flutamide, kindly provided by Dr A.Griinschneder (Essex
Pharma GmbH), was orally administered to all women at a dose
of 250 mg on the evening of day 1 and 750 mg per day, divided
in three doses, from day 2 to 6. In control women as well as
in oligomenorrhoeic patients, this treatment was initiated on the
Table I
Subject
no.
Patients
1
2
3
4
5
6b
7b
Mean
SEM
. Clinical parameters in
Age Weight BMP
(years) (kg)
26
18
27
18
19
25
28
23
1.7
Controls
1
2
3
4
5
Mean
SEM
27
24
27
23
22
25
1.0
95
51
69
59
72
51
65
66
5.7
75
54
50
60
64
61
4.3
(kg/m2)
35
23
25
20
25
22
22
25
1.9
25
20
19
23
21
22
1.1
patients and control subjects
Hirsutismd
degree
2 +
3 +
2 +
1 +
3 +
2 +
1 +
-
-
-
-
-
Menstrual
status
Ameno
Ameno
Oligo
Oligo
Ameno
Ameno
Eumeno
Eumeno
Eumeno
Eumeno
Eumeno
Eumeno
c LH/FSH
ratio
5.3
3.7
4.6
3.2
4.2
1.9
0.8
3.8
0.6
0.8
1.5
0.9
0.9
0.8
1.0
0.1
Ultrasound
finding
PCO
PCO
PCO
PCO
PCO
PCO
normal
normal
normal
normal
normal
normal
aBMI = body mass index [weight (kgyheight2 (m)].
bPatients 6 and 7 had plasma testosterone concentrations >0.6 ng/ml.
cAmeno = amenorrhoeic; oligo = oligomenorrhoeic; eumeno =
eumenorrhoeic.
dScale of increasing severity 0—3.
PCO = polycystic ovaries; LH = luteinizing hormone; FSH = follicle
stimulating hormone.
fifth day of the menstrual cycle. In the amenorrhoeic women,
the treatment began whenever feasible.
For the study of pulsatile gonadotrophin secretion, blood
samples were collected over 10 min intervals for 8 h, beginning
at 0900 h on day 1 (before the initiation of flutamide treatment),
on day 2 and on day 6 of treatment, using a sampling device
that allowed the continuous withdrawal of blood through a
heparinized catheter (Bittl et al., 1988).
LH, FSH and prolactin were determined in all samples; total
testosterone, free testosterone, androstenedione, dihydroepiandrosterone
sulphate (DHEAS), 17-hydroxyprogesterone,
oestradiol and sex hormone binding globulin (SHBG) were
measured in samples 1, 24 and 48 on days 1, 2 and 6. The free
androgen index [FAI = testosterone x 100/SHBG (nmol/1)] was
calculated, as the quotient of the molar concentrations of
testosterone and SHBG.
Hormone assays
All hormone determinations were performed in duplicate by
radioimmunoassays, using commercially available kits. All samples
from an individual subject were assessed in one single assay.
Serum LH, FSH and prolactin concentrations were determined
using commercial kits (Amersham International pic, Buckinghamshire,
UK). The intra- and interassay coefficients of variation
respectively were 4.8 and 5.5% for LH; 4.3 and 7.0% for FSH;
and 4.8 and 7.4% for prolactin.
Ultrasound examination
Ovarian morphology was assessed by ultrasound examination,
performed by the full bladder technique using a 3 MHz real time
sector scanner (Sonoline SL-2), with an electronic caliper.
Polycystic ovaries were defined according to the following
criteria: several follicles lined by the ovarian capsule, dense
ovarian stroma and enlargement of the ovaries. These criteria
were similar to those described by Adams et al. (1986).
LH pulse analysis and statistical evaluation
Discrete LH pulses were identified by the computerized version
of the cluster pulse algorithm, developed by Veldhuis and Johnson
(1986). We selected a cluster configuration of 1 x 2 (one sample
for the test peak and two for the test nadir), and a t-value of
2.1/2.1 to constrain the likelihood of false positive pulse
determinations to < 5 %. For the assessment of the LH pulse
frequency, the interpulse interval was measured.
Table II. Plasma gonadotrophin concentrations,
hyperandrogenaemic women before (day 1) and
luteinizing hormone (LH) pulse
during flutamide administration
Control women
day 1 day 2 day
characteristics
(days 2 and 6)
6
and plasma prolactin (PRL)
; values are mean ± SEM
Hyperandrogenaemic
day 1
concentration
women
day 2
in control and
day 6
LH (mlU/ml)
Pulse amplitude (mlU/ml)
Pulse interval (min)
FSH (mlU/ml)
PRL (ng/ml)
5.1 ± 0.6
1.3 ± 0.2
66 ±5
5.1 ± 0.3
6.9 ± 0.9
5.5
1.5
73
4.8
7.2
± 0.8
± 0.4
± 15
± 0.6
± 1.1
5.1
1.3
72
3.8
8.3
± 1.2
± 0.3
± 19
± 0.1
± 1.6
13.5
4.7
70
4.2
7.2
± 3.2
± 0.8a
± 8
± 0.7
± 1.2
11.4 ± 2.5
4.1 ± 1.1
76 ± 11
4.4 ± 0.7
6.3 ± 0.9
10.1
3.5
67
3.1
7.6
± 2.5
± 0.6b
± 3
± 0.6b
± 1.2
aP < 0.05 for difference between hyperandrogenaemic and control women on corresponding day.
bP < 0.05 for difference between day 6 and day 1 in hyperandrogenaemic women.
FSH = follicle stimulating hormone.
1808
Flutamide and gonadotrophin pulsatility
The LH pulse amplitude and interpulse interval, determined
by the cluster analysis, were evaluated by analysis of variance
(ANOVA) followed by Newman—Keul's multiple range tests.
Differences between day 1 and day 6 were sought by paired twotailed
Student's r-test. Results are presented as mean ± SEM.
Results
Table I shows the clinical characteristics and ultrasound findings
for the hyperandrogenaemic women compared to the controls.
The mean age of the two groups was not significantly different.
The body mass index (BMI) was similar in both groups. As
expected, the mean LH/FSH ratio was significantly higher
(P < 0.05) in the hyperandrogenaemic women compared to
the control group.
Pattern of gonadotrophin release
Prior to flutamide administration, LH pulse amplitude was
significantly higher in the hyperandrogenaemic women compared
to controls (P < 0.05), whereas LH pulse frequency was
not significantly different (Table II).
Treatment with flutamide in hyperandrogenaemic patients
resulted in a decrease in LH pulse amplitude (P < 0.05). This
became apparent within 24 h of flutamide administration,
and it was associated with a decline of mean plasma LH
concentration (not significant).
The change in the LH pulse frequency did not show a uniform
pattern (Figure 1): in two patients LH pulse frequency tended
to increase (e.g. patient 7), in two it tended to decrease (e.g.
patient 5) and in three it remained unchanged (e.g. patient 1)
under flutamide treatment. Figure 1 displays the LH pulsatile
pattern of three typical examples.
PAT.1 PAT. 5 PAT. 7
0 1 2 3 k 5 t 7
0 1 J 3 K i t 7 I 0 1 2 3 t S * 7 l 0 1 I 3 k 5 6 7 S
Fig. 1. Luteinizing hormone (LH) pulsatile pattern in three hyperandrogenaemic patients (pat), before (day 1) and during (day 6) flutamide
treatment.
Table m. Steroid levels in plasma before (day 1) and during flutamide administration (day 6); values are mean ± SEM
Control women Hyperandrogenaemic women
Testosterone (ng/ml)
Free testosterone (pg/ml)
Androstenedione (ng/ml)
DHEAS (ng/ml)
Oestradiol (pg/ml)
SHBG 0*g DHT/dl)
day 1
0.42
3.5
2.4
2108
32
1.21
± 0.05a
± 0.4"
± 0.5
± 273b
± 8
± 0.3a
day 6
0.33
3.2
2.2
1277
66
1.06
± 0.06
± 0.5
± 0.6
± 270b
± 22
± 0.2
day 1
1.46
9.0
4.5
3107
81
0.57
± 0.39bc
± 1.4b'c
± 0.9°
± 369*
± 32
± 0.1b
day 6
1.07
6.2
3.3
2158
70
0.56
± 0.26"
± 1.1"
± 0.5d
± 36 ld
± 13
± 0.1
a'bValues significantly different (P < 0.05).
c-dValues significantly different (P < 0.05).
DHEAS = dihydroepiandrosterone sulphate; SHBG = sex hormone binding globulin.
1809
T.Sir-Petermann, B.Rabenbauer and L.Wildt
PAT. 1 PAT. 5 PAT. 7
c
cr
E
5
B
I
i/)
32
2L
16
8
0
(IP/JE
.3-
SHBG
/ml)
c—
3.2
2,4
1,6
0.8
0
32
• 24
—E
• "5)16
Q.
- 1 8
ti_
0
•
• 1 1-
LH FSH - k f t PRL
r SH
• X
i11
ri FrT FrAI SHBG
LH FSH FSH
PRL LH FSH
FSH
PRL
Y-^~\ 1i 11 T FrT FrAI SHBG FrT FrAI SHBG
8
6 2
Q:
to
LL
80
60
UO
20
Fig. 2. Plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), LH/FSH ratio, prolactin (PRL), total
testosterone (T), free testosterone (FrT), free androgen index (FrAI) and sex hormone binding globulin (SHBG) in three
hyperandrogenaemic patients (PAT), before (day 1) and during (day 6) flutamide treatment.
In hyperandrogenaemic women, both FSH and LH concentration
decreased with flutamide treatment (day 1-6, Table II).
However, only the decrease in serum FSH was statistically
significant. No significant changes in pulse frequency or pulse
amplitude were noted in the control group.
Neither the controls nor the hyperandrogenaemic women
showed changes in serum prolactin concentration.
Sex hormone concentrations
Basal plasma concentration of testosterone and free testosterone,
were significantly higher in hyperandrogenaemic women, as
compared to those of control subjects (P < 0.05), while total
plasma, androstenedione, DHEAS and oestradiol concentrations
were not significantly different in the two groups. SBHG
concentrations were lower in hyperandrogenaemic women,
compared to the values in the normal control group (P < 0.05)
(Table HI). Flutamide administration decreased the plasma
concentration of testosterone in five of seven patients and decreased
the plasma concentration of free testosterone, androstenedione
and DHEAS in all patients (P < 0.05). The free androgen index
(FAI) was also significantly decreased in five of seven patients
after 6 days of flutamide administration (Figure 2, lower panel).
Conversely, plasma concentrations of oestradiol and SHBG were
not uniformly or significandy modified (Table HI). Under
flutamide treatment normal women showed a slight but not
significant decrease in testosterone, free testosterone and
androstenedione concentrations. In this group, flutamide
administration induced a significant decrease in the plasma concentration
of DHEAS in two women (P < 0.05).
1810
Discussion
To our knowledge this is the first report dealing with the effect
of flutamide on pulsatile gonadotrophin secretion in hyperandrogenaemic
and normal cycling women. Flutamide blocks
androgen receptors in the central nervous system as well as in
peripheral target organs but has no measurable effects on
oestrogen, progesterone and glucocorticoid receptors (Neri et al.,
1972; Poyet and Labrie, 1985). Its administration for 6 days to
hyperandrogenaemic women produced a significant decrease in
LH pulse amplitude. This was particularly apparent in those
patients who achieved a normalization of testosterone concentration
under flutamide administration. Although it has been postulated
that the increased amplitude of LH pulses in hyperandrogenaemic
women is secondary to androgen aromatization to oestrogen, since
flutamide decreases LH pulse amplitude by directly blocking
androgen receptors, it is possible that LH pulse generation is
restricted by androgens in some hyperandrogenaemic women;
also that LH pulse amplitude is decreased when androgen
receptors are blocked by flutamide. The consequences of blocking
the androgen receptor are difficult to interpret. In some women
LH pulse frequency increased. Since LH pulse frequency reflects
closely the GnRH pulse frequency (Clarke and Cummins, 1982),
it is likely that the effect of testosterone on pulsatile LH secretion
in hyperandrogenaemic women is similar to that observed in
males, namely an inhibition of LH release by its effect on GnRH
release (Veldhuis etal., 1984). Urban et al. (1988) have demonstrated
that LH pulse frequency was increased in normal men
after flutamide administration. FSH and LH concentrations
Flutamide and gonadotrophin pulsatility
followed the same decrease pattern, which probably reflects the
changes of the pulse generator under androgen blockade, as there
is no evidence that flutamide affects oestrogen metabolism
directly.
Another possible explanation for the decrease in the LH pulse
amplitude is that testosterone exerts a direct effect over the release
of LH and FSH at the pituitary level.
In humans, testosterone has been suggested to have a direct
inhibitory effect on the pituitary gland, independently of the effect
of GnRH (Sheckter et al., 1989). It may be speculated that the
reason why oestrogens did not change under flutamide therapy
was that androgens in the range observed in normal and hyperandrogenic
women, which may have a stimulatory effect at the
pituitary level, are inhibited under flutamide therapy. This could,
in addition, explain the decrease in LH amplitude observed under
flutamide treatment. To further clarify if androgen blockade has
a direct action on the pituitary, the effect of flutamide on LH
response to exogenous GnRH should be tested.
These observations disagree with those found by Couzinet et al.
(1989), who studied another pure anti-androgen (anandron) in
normal women and a group of poly cystic ovary patients. They
did not observe any modification of the LH pulse profile and
they concluded that there was no direct androgen effect on
gonadotrophin secretion. However, although flutamide and
anandron are both anti-androgens, they differ in their chemical
composition and therefore they may have different effects.
In the present study, plasma concentration of oestradiol was
not modified during the course of flutamide administration,
suggesting that oestrogens are probably not related to the observed
changes in gonadotrophin secretion under flutamide administration.
Significant decreases in testosterone, androstenedione and
DHEAS under flutamide treatment were observed. In normal
men, the anti-androgenic property of flutamide induces an
increase in serum testosterone and gonadotrophin concentrations
(Knuth et al., 1984). This is in agreement with the view that,
in men, testosterone is the main determinant of the negative
feedback-loop (Gooren et al., 1987), while in women the antiandrogenic
property of flutamide leads to decreased testosterone
and gonadotrophin concentrations.
There are no previous studies dealing with the short-term effect
of flutamide on androgen concentrations in women. However,
flutamide significantly decreased androgen concentrations in
superovulated rats (Yun et al., 1988). Secreto et al. (1988)
reported a sharp decrease in circulating concentrations of DHT
and DHEAS after 1 month of flutamide administration to
postmenopausal patients with breast cancer. These results are
similar to the observations made in the present study.
As there is no conclusive proof of a direct flutamide action
on the ovary, we conclude that the decrease in testosterone
concentration is the consequence of a decreased stimulation of
the ovary by LH.
DHEAS was significantly decreased during the course of
flutamide administration. A similar effect has been described by
Labrie et al. (1985) in men and by Secreto et al. (1988) in
women. This suggests that flutamide is effective in inhibiting
androgen precursor biosynthesis, at the adrenal level. The
mechanism of flutamide action on adrenal androgen biosynthesis
is not completely understood. Previous reports have attributed
this effect to inhibition of adrenal 17—20 lyase (Balzano et al.,
1988). Therefore, the decrease in plasma DHEAS concentrations
reported by Labrie et al. (1985) would be the consequence of
hormone synthesis blockade rather than corticotrophic inhibition.
The effect of flutamide on the biosynthesis of adrenal androgens
may be viewed as a favourable therapeutic effect in the treatment
of adrenal-ovarian hyperandrogenaemia.
Changes in SHBG concentrations were not observed in the
present study, despite the decrease observed in the serum
concentrations of androgens. On the other hand it has been
demonstrated that SHBG is regulated by insulin (Kiddy et al.,
1992) and that flutamide does not modify insulin concentrations
(Rabenbauer etal, 1990). The lack of variation of SHBG
concentration under flutamide administration is probably a result
of the fact that insulin levels were also unchanged by flutamide.
The fact that flutamide is devoid of intrinsic hormonal activity
allowed us to conclude that the observed changes in the LH
pulsatility in women under flutamide administration are secondary
to the androgen blockade.
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Received on March 2, 1993; accepted on July 15, 1993
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