GENERAL GYNECOLOGY

Evaluation of hormonal suppression with two contraceptive

regimens using ethinyl estradiol and desogestrel
Danitza Thomazi Gassen

Liliane Diefenthaeler Herter

Juliana Kliemann Chagas

Helena Schmid
Received: 18 May 2012 / Accepted: 21 August 2012
Springer-Verlag 2012
Abstract
Purpose Because of the lack of data on hormone levels in
the hormone-free interval of the contraceptive regimens with
desogestrel and ethynil estradiol, the objective of this study
was to compare hormonal levels of follicle-stimulating hor-
mone (FSH), luteinizing hormone (LH), estradiol, and inhibin
B using two contraceptive regimens with those steroids.
Methods Prospective and randomized study with 21
patients. Eleven patients received a 21/7 regimen (group 1)
and ten patients received a 21/2 placebo/5 ethinyl estradiol
10 lg regimen (group 2).
Results We found a signicant increase in FSH and LH
levels in both groups. There was a signicant reduction of
inhibin B in the 21/2/5 regimen. No difference in estradiol
levels was found.
Conclusions Steroids withdrawal in the hormone-free
interval causes reduced inhibition of the HPO axis. The
signicant decrease in inhibin B levels of group 2 suggests
better suppression of the HPO axis in the 21/2/5 regimen.
Keywords Oral contraceptives LH FSH Estradiol
Inhibin B
Introduction
Several regimens of oral contraceptives (OCs) have been
used, namely: the traditional 21 days of active pills fol-
lowed by a 7-day hormone-free interval (HFI); continuous
use (without HFI); extended use (HFI after use of active
pills usually for 90 days); and shortened HFI (\7 days of
interval) with or without addition of low-dose ethinyl
estradiol (EE).
Some authors have found that a reduction of the 7-day
HFI of OCs instead of the traditional regimen (21/7) could
increase the suppression of the hypothalamic-pituitary-
ovarian (HPO) axis. In fact, ovarian suppression in regi-
mens with shortened HFI has been demonstrated in eight
studies using different formulations and variable length of
the HFI [17].
This HPO axis suppression in the shortened HFI OCs
could decrease follicular development, reduce premenstrual
symptoms, acne, dysmenorrhea, and excessive bleeding, as
well as provide menstrual cycle control to those women who
do not want to suppress menstruation [812].
Few studies have evaluated hormone levels in the phase
of the regimen consisting of 21 days of desogestrel (DSG)
150 lg/EE 20 lg, 2 days of placebo, and 5 days of EE
D. T. Gassen J. K. Chagas H. Schmid
Post-graduation Program in Medical Science, Universidade
Federal de Ciencias da Saude de Porto Alegre (UFCSPA),
Rua Sarmento Leite, 245, Porto Alegre,
RS CEP 90050-170, Brazil
D. T. Gassen (&)
Al Roberto Grossembacher, 42, Vorstadt, Blumenau,
SC CEP 89015450, Brazil
e-mail: danitza.gassen@gmail.com
L. D. Herter
Department of Gynecology, Universidade Federal de Ciencias da
Saude de Porto Alegre (UFCSPA), Rua Sarmento Leite,
245, Porto Alegre, RS CEP 90050-170, Brazil
H. Schmid
Department of Internal Medicine, Universidade Federal de
Ciencias da Saude de Porto Alegre (UFCSPA), Rua Sarmento
Leite, 245, Porto Alegre, RS CEP 90050-170, Brazil
H. Schmid
Department of Internal Medicine, Universidade Federal do Rio
Grande do Sul (UFRGS), Av. Paulo Gama, 110, Porto Alegre,
RS CEP 90046-900, Brazil
1 3
Arch Gynecol Obstet
DOI 10.1007/s00404-012-2545-6
10 lg (21/2/5), although this preparation has been pro-
posed to minimize premenstrual symptoms.
Therefore, the objective of the present study was to
compare the hormonal status [follicle-stimulating hormone
(FSH), luteinizing hormone (LH), estradiol, and inhibin B]
during the HFI between the 21/7 regimen and the 21/2/5
regimen containing EE 20 lg and DSG 150 lg.
Materials and methods
Twenty-four patients were selected from the gynecology
outpatient clinic of our hospital to participate in a ran-
domized clinical trial. The patients age ranged from 16 to
35 years and they were using or not using of hormonal
contraceptive methods during the period between August
2008 and March 2009.
The exclusion criteria were formal contraindications to
the use of combined hormonal contraceptives; use of
quarterly injectable hormonal contraceptives in the pre-
vious 6 months or monthly injectable or subdermal
implant contraceptives in the previous 2 months; use
of any medications that could affect the effectiveness of
OCs, such as phenytoin, phenobarbital, topiramate, car-
bamazepine, rifampicin, rifabutin, nelnavir, ritonavir,
and nevirapine.
Patients were allocated in two groups according to the
order of arrival at the clinic. Each group received a random
selection of sealed boxes of contraceptives.
Group 1 (21/7 regimen): 21 days of EE 20 lg combined
with DSG 150 lg and a 7-day pill-free interval.
Group 2 (21/2/5 regimen): 21 days of EE 20 lg
combined with DSG 150 lg, followed by 2 days of
placebo, and 5 days of EE 10 lg. This regimen was
called shortened hormone-free interval because it has
2 days of placebo, followed by 5 days of a low-dose of
EE (10 lg).
There was no masking after randomization.
Group 1 patients took the medication for 21 days and
made a 7-day pill-free interval, while Group 2 patients took
the medication continuously. Both groups were followed
for at least three cycles. The rst 2 months using the pill
were considered necessary to reach a steady-state condi-
tion. At least three complete packs should be used before
blood sample collection.
The present study was approved by the ethics committee
of our hospital and all patients signed an informed consent.
At baseline and after each month, for 3 months, data on
body weight, height, blood pressure, gastrointestinal
symptoms, medication in use, delayed pill intake, and
adverse effects were evaluated. At each visit, patients
received new packs of OCs.
Blood samples were collected on the last day of DSG ?
EE pills of the pack; on the second, fourth, and sixth days
HFI (HFI without steroids in the 21/7 regimen and HFI with
placebo ? low-dose EE in the 21/2/5 regimen); and on the
third day of the next pack for determination of FSH, LH,
estradiol, and inhibin B. After centrifugation and separation
of the serum, the samples were stored at -20 C.
After all samples were collected and frozen, hormone
levels were analyzed on the same day and in duplicate.
FSH and LH were measured by electrochemilumines-
cence immunoassay (Roche Diagnostics GmbH, Mann-
heim, Germany). As specied by the LH kit, the levels of
LH in the follicular phase range from 2.4 to 12.6 mIU/ml,
at mid-cycle from 14 to 95.6 mIU/ml, and in the luteal
phase from 1.0 to 11.4 mIU/ml. During the use of OC, LH
values were lower than 5.6 mIU/ml. Intra- and inter-assay
errors were \6 %.
As specied by the FSH kit, the levels of FSH in the
follicular phase range from 3.5 to 12.4 mIU/ml, at mid-
cycle from 4.7 to 21.5 mIU/ml, and in the luteal phase
from 1.7 to 7.7 mIU/ml. During the use of OC, FSH values
were lower than 5.6 mIU/ml. As described by the manu-
facturer of the kit, intra- and inter-assay errors were\6 %.
Estradiol was measured using the 17b-Estradiol Immu-
Chem
TM
I125 radioimmunoassay kit (ICN Pharmaceuticals,
Inc., Diagnostics Division Orangeburg, NY, USA). The
physiological levels of estradiol were described as varying
from 40 to 500 pg/ml and between 40 and 60 pg/ml when
on use of OC. As described by the manufacturer of the kit,
intra- and inter-assay errors were described as 5 %.
Inhibin B was measured using the DSL-10-84100
ACTIVE Inhibin B ELISA kit (Diagnostic Systems Lab-
oratories, Inc. Webster, TX, USA). As described by the
manufacturer of the kit, the intra-assay error was 4.6 % and
the inter-assay error was 6.3 %.
The quantity and days of menstrual bleeding were
recorded by the patients themselves, using a calendar of
menstrual ow, where intense bleeding corresponded to C8
full pads/day, moderate bleeding was considered 37 full
pads/day, and light bleeding was B2 full pads/day. Every
small amount of bleeding occured during the OC use not
included in the HFI was called spotting, and episodes of
moderate or heavy bleeding that occured outside of the HFI
were called inter-menstrual bleeding.
Statistical analysis was performed using the IBM SPSS
version 19.0 (IBM Corporation, Somers, NY, USA). Con-
tinuous variables were tested for normality using the Shap-
iroWilk test. Those variables that did not show normal
distribution (LH, 17-b estradiol) were subjected to loga-
rithmic transformation prior to analysis. Whenever appro-
priate, the comparisons were performed using the paired
t test, McNemars test and two-way repeated measures
ANOVA. The level of signicance was set at a = 0.05.
Arch Gynecol Obstet
1 3
Results
Of the 24 patients selected, two dropped out of the study
while using the second pack of pills. One participant had to
withdraw from the study because of occurrence of chlo-
asma in the 21/7 regimen and the other one because she did
not tolerate spotting in the 21/2/5 regimen. Another patient
withdrew from the 21/2/5 regimen in the third month
before blood collection for personal reasons. In total, 21
patients completed the study. Because of inappropriate
storage, same samples were excluded from hormone
measurement. Two patients in the 21/2/5 regimen forgot to
take one pill in the last pack before blood collection, and
these patients completed more than one pack before blood
collections (Fig. 1).
The groups had homogeneous characteristics. BMI and
the mean systolic and diastolic pressures did not differ at
baseline and after 3 months of OC use for any group. The
values are described in Table 1.
Symptoms evaluation
In the present study, frequency of uterine bleeding was
assessed during 90 days. We found the occurrence of
spotting in two (8 %) patients in the 21/2/5 regimen and in
one (9 %) patient in the 21/7 regimen (p = 0.29). None of
them made prior use of the OC in study. None had spotting
in the third month using the pill.
Only one patient in the 21/7 regimen referred nausea as
a side effect.
Hormone levels
There was no hormonal difference on the last day of
DSG ? EE pills (day 21) between the two groups, which
corresponds to the maximum hormonal suppression of the
cycle for the two groups with the same steroid dosage in
the pill (Table 2).
Estradiol
No signicant differences were found when estradiol was
analyzed in each group or between groups during the
hormone-free interval (HFI) until the beginning of a new
pack (Fig. 2).
There was a trend of higher estradiol levels on the
second and fourth day HFI in the 21/2/5 regimen with
subsequent decrease in their levels on the sixth day HFI
and on the third day of a new pack. A trend of lower levels
were maintained compared with the 21/7 regimen, but
there was no signicant difference between them (Fig. 2).
Inhibin B
Regarding inhibin B, there was a decrease from 82.34 pg/
ml on the fourth day HFI to 61.50 pg/ml on the third day of
use of a new pack, when the two groups were evaluated
together (p = 0.043).
When each group was analyzed individually, the 21/2/5
regimen showed increased levels of inhibin B from
Fig. 1 Flow chart of patients
during the study
Arch Gynecol Obstet
1 3
61.43 pg/ml on the last day of DSG ? EE pills to
81.20 pg/ml on the second day HFI (p = 0.15) and then,
there was a progressive decrease to 51.10 pg/ml at the start
of a new pack (p = 0.009) (Fig. 3).
There was a trend of higher inhibin B levels in the 21/7
regimen from the last day of DSG ? EE pills (74.3 pg/ml)
until the fourth day (90.0 pg/ml) of the HFI than in the
21/2/5 regimen, but there was no signicant difference
between the groups (Fig. 3).
FSH
The analysis of the two groups revealed a signicant
increase in FSH levels from 2.27 mUI/ml on the last day
of DSG ? EE pills to 2.94, 5.55 and 6.31 mUI/ml on
the second, fourth and sixth days HFI, respectively
(p \0.001).
There was an increase in FSH levels in the 21/7 regimen
from 2.33 mIU/ml on the last day of DSG ? EE pills to
6.09, and 6.87 mUI/ml on the fourth and sixth days HFI
(p \0.001). There was also a signicant increase of
2.98 mUI/ml on the second day HFI to 6.09 and 6.87 mUI/
ml on the fourth and sixth days HFI (p \0.001) (Fig. 4).
Despite a decline from 6.87 mUI/ml on the sixth day
HFI to 4.43 mUI/ml 3 days after the start of new pack
Fig. 2 Estradiol levels in each group (mean SEM)
74,3 9,5
79,89,5
90,09,5
84,39,5
71,99,5
61,410,1
81,210,1
a
74,710,1
56,310,1
51,110,1
a
0
20
40
60
80
100
D
S
G
+
E
E
2
0
00*****D
S
G
+
E
E
2
0
D
S
G
+
E
E
2
0
D
S
G
+
E
E
2
0
p
g
/
m
l
Inhibin B
21/7 regimen 21/2/5 regimen
collections
Fig. 3 Inhibin B levels in each group (mean SEM) (a) statistical
signicance (p \0.05)
Table 1 Baseline and after 3 months patients characteristics reported as least square means (SEM)
Characteristics Baseline After 3 months p
21/7 regimen 21/2/5 regimen 21/7 regimen 21/2/5/regimen
Age (years) 24.7 (3.71) 24.8 (3.16) 0.939
BMI (kg/m
2
) 23.14 (4.28) 21.99 (1.88) 23.49 (4.00) 21.88 (1.55) 0.334
Systolic blood pressure (mmHg) 107.2 (2.59) 106.0 (2.72) 108.18 (2.59) 102.0 (2.72) 0.70
Diastolic blood pressure (mmHg) 62.9 (1.69) 63.5 (1.78) 61.8 (1.69) 63.0 (1.78) 0.35
SEM standard error of the mean
Table 2 Hormonal evaluation on the last day of DSG ? EE pills
21/7 Regimen 21/2/5 Regimen p
Estradiol (pg/ml) 50.06 6.10 44.11 6.47 0.22
Inhibin (pg/ml) 74.33 9.49 61.43 10.06 0.35
FSH (mUI/ml) 2.33 0.70 2.22 0.74 0.91
LH (mUI/ml) 1.54 1.30 2.51 1.38 0.61
SEM standard error of the mean
Values are given in mean SEM
2,30,7
a,b,c
3,00,7
d,e
6,10,7
a,d
6,90,7
b,e,f
5,10,7
i,m
2,20,7
g,h,i
2,90,7
j,l,m
5,00,7
g,j
5,80,7
h,l
4,40,7
c,f
0
2
4
6
8
D
S
G
+
E
E
2
0
00*****D
S
G
+
E
E
2
0
D
S
G
+
E
E
2
0
D
S
G
+
E
E
2
0
m
U
I
/
m
l
FSH
21/7 regimen 21/2/5 regimen
collections
Fig. 4 FSH levels in each group (mean SEM) (aj, l, m) mean
statistical signicance (p \0.05)
Arch Gynecol Obstet
1 3
(p = 0.007), the FSH levels in the 21/7 regimen remained
higher on the third day of a new pack (4.43 mUI/ml)
compared to the last day of DSG ? EE pills (2.33 mUI/
ml), p = 0.023 (Fig. 4).
In the 21/2/5 regimen, FSH levels showed signicant
increase from 2.22 mUI/ml on the last day of DSG ? EE
pills to 5.03 and 5.76 mUI/ml on the fourth and sixth days
HFI, respectively (p = 0.003 and p \0.001). The levels
remained high on the third day of a new pack (5.08 mUI/
ml) compared to the last day of DSG ? EE pills
(2.22 mUI/ml) and the second day HFI (2.92 mUI/ml),
p = 0.003 and p = 0.029 (Fig. 4).
There was no difference between the groups in the HFI
or at beginning of a new pack.
LH
When each group was analyzed individually, the 21/7
regimen showed increased LH levels from 1.54 mUI/ml on
the last day of DSG ? EE pills to 2.52, 3.72, 6.58 and
4.99 mUI/ml on the second, fourth, and sixth days HFI
and on the third day of a new pack, respectively (p = 0.006
and p \0.001) (Fig. 5).
The 21/2/5 regimen also had increased values from
2.86 mUI/ml on the last day of DSG ? EE pills to 4.41
and 5.21 mUI/ml on the fourth and sixth days HFI and
6.61 mUI/ml on the third day of a new pack (p \0.001).
This increase was also observed from 3.17 mUI/ml on the
second day HFI to 4.41 and 5.21 mUI/ml on the fourth and
sixth days HFI, respectively (p = 0.012) (Fig. 5).
There was no signicant difference between the groups
at different times.
Discussion
In the present study, the two OC regimens used looked
clinically similar, since the frequency of uterine bleeding
did not differ between them. The number of spotting days
when the patients were using their rst two packs was
in agreement with other studies of shortened HFI of OCs
[1, 3, 13].
Inhibin B is described as higher in the early follicular
phase of a normal cycle, being a sensitive marker of
granulosa cell activity. One reason for the signicant
inhibin B decrease in the present study, with the 21/2/5
regimen may be the addition of EE at lower doses, perhaps
sufcient to suppress the HPO axis.
FSH levels also increased in both groups until the sixth
day HFI and on the third day after starting a new pack, it
decreased.
LH levels increased equally in both groups until the sixth
day HFI. There was a tendency for the hormone levels to
decrease in the 21/7 regimen, but this was not true for the
21/2/5 regimen. Probably, the suppression of FSHand LHto
basal levels occurred later after the beginning of a new pack
in both groups, when no measurements were done.
On looking at the results of the present study, we see
that there is individual variations of the return of pituitary
and ovarian activity during the HFI. Similar ndings were
reported by Van der Vange et al. [14], when the follicular
development in the HFI was evaluated and the nding was
that at least 30 % of women in use of low-dose OC had a
mean of 18 mm diameter follicles. These follicles may
alter serum levels of estradiol and inhibin B, and indirectly
change FSH and LH levels by the feedback system.
Besides the different follicular development, the
metabolism of EE varies from one individual to another
individual and from one population to another. Also, an
important variation in different samples collected from the
same individual has been demonstrated [15, 16].
Forgetting to take the pills is another reason for indi-
vidual variation, especially if it occurs more than once and
early in the pack. In the present study, to decrease this
possibility, two patients who forgot to take the pills prior to
blood collection only had their blood collected following
the fourth cycle.
There was no difference between the two regimes
regarding any of the hormones measured, which is not in
accordance with some of the ndings from studies evalu-
ating hormonal suppression with shortened HFI of OCs.
Willis et al. [7] assessed the same hormones in 12 patients
with 0.03 mg of EE and 3 mg of drospirenone (DRSP) in
21/7 and 23/3 or 23/4 regimens, and found greater pituitary
and ovarian suppression with shortened HFI for all four
hormones. The difference was statistically signicant. In
this study, the curves increased in the 21/7 regimen for all
hormones until the end of blood collection, which coin-
cided with the rst day of use from the next pack, whereas
our data showed that a slight decline started on the third
day of the beginning of a new pack. Such comparisons
1,50,4
a,b,c,d
2,50,4
a,e,f,g
3,70,4
b,e
6,60,4
c,f
4,90,4
d,g
2,90,4
h,i,j
3,20,4
l,m,n
4,40,4
h,l
5,20,4
i,m
6,60,4
j,n
0
2
4
6
8
D
S
G
+
E
E
2
0
00*****D
S
G
+
E
E
2
0
D
S
G
+
E
E
2
0
D
S
G
+
E
E
2
0
m
U
I
/
m
l
LH
21/7 regimen 21/2/5 regimen
collections
Fig. 5 LH levels in each group (mean SEM) (aj, ln) mean
statistical signicance (p \0.05)
Arch Gynecol Obstet
1 3
should consider that the dose of EE was higher in the study
by Willis et al. and that DRSP has a longer half-life than
desogestrel (DSG), the progesterone used in the present
study.
Klipping et al. [5] also found less hormonal uctuation
of estradiol, FSH, and LH in the 24/4 regimen with DRSP
3 mg/EE 20 lg compared with the 21/7 regimen using the
same OCs even after excluding the rst three pills of the
next cycle.
Spona et al. [1] found no difference in FSH levels
between the groups in the 21/7 regimen and 23/4 regimen
with 20 lg EE ? 75 lg gestodene in three treatment
cycles. These authors found higher levels of 17 b-estradiol
and LH in the 21/7 regimen than in the 23/4 regimen.
In a study evaluating continuous and 21/2/5 regimens of
DSG 150 lg/EE 20 lg and a 21/7 regimen of levonorge-
strel (LNG) 100 lg/EE 20 lg, a greater suppression of LH
and FSH in the 21/2/5 regimen was found compared with
the 21/7 regimen, although the types of progesterone varied
[2]. The suppression in the continuous regimen of DSG
150/EE 20 was higher than in the 21/2/5 regimen.
One of the few studies that evaluated hormone levels
using DSG 150 lg/EE 20 lg in the 21/2/5 regimen ana-
lyzed EE, estradiol, FSH, and LH levels in only four
patients and found no statistical difference [3]. The authors
argued that this variation could be correlated with the
perceived individual variability in the study, because of the
variation in the size of the follicles.
In conclusion, the elevation of gonadotropins observed
in our study was expected: there was decreased inhibition
of the HPO axis caused by estrogen and progestin with-
drawal (negative feedback). Inhibin B, which reects the
activity of granulosa cells, showed a faster decreased in the
21/2/5 regimen. Further studies are needed to determine
whether the 21/2/5 regimen reduces premenstrual symp-
toms and/or increases contraception efcacy when com-
pared with the 21/7 regimen.
Conict of interest This study was partially funded by Merck
Sharp and Dohme Corporation.
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