By: J.Y. Gillet, G. Andre, B. Faguer, R. Erny, M. Buvat-Herbaut, M.A. Domin, J.M. Kuhn, B. Hedon, E. Drapier-Faure, J. Barrat, P. Lopes, G. Magnin, J.J. Leng,
M.A. Bruhat, E. Philippe
The effects of oral micronized progesterone on the endometrium and bleeding pattern have
been assessed in a multicenter study of 101 postmenopausal patients. During a minimum of
6 cycles, the participants received either percutaneous 17^-estradiol (1.5 mg/day) associated
with micronized progesterone (100 mg/day), given at bedtime for 21/28 days or 25 days/calendar
month (n = 98) [1], or E2 (3 mg/day) for 25 days associated with progesterone (300
mg/day), from day 16 to day 25 {n = 3) [2], according to their willingness to induce, or not,
cyclic withdrawal bleeding. Each endometrial biopsy performed at 6-month minimum was
assessed by two independent pathologists: results showed 61% quiescent without mitosis, 23%
mildly active with very rare mitoses and 8% partial secretory endometrium. The remaining
biopsies showed inadequate tissue (4%) or a sub-atrophy (4%). No hyperplasia was found by
any pathologist. In the case of inadequate material, the mean thickness of endometrial mucosa
measured by ultrasonography was 3.9 mm. Amenorrhea incidence was 93.3 and 91.6% at the
3rd and 6th month of therapy, respectively. No bleeding occurred in more than 80% of
women. The results show that a low dose of oral progesterone (100 mg/day), given during 25
days, efficiently protects the endometrium by fully inhibiting mitoses and induces amenorrhea
in the majority of postmenopausal women, allowing better compliance to long-term therapy.
1. Introduction
Today, hormone replacement therapy (HRT) compliance remains below expectation
[1-3] even in well motivated women [4], Uterine bleeding appears to be one of
the most frequent factors involved in the patients decision to discontinue HRT. The
current tendency is thus to use a schedule of estrogen-progestin combination, that
minimizes the frequency of irregular or regular bleeding while ensuring an efficient
prevention of endometrial hyperplasia.
The aim of this multicenter study, for which 13 investigation centers have been involved,
was to establish whether a low daily dose of oral micronized progesterone
(100 mg/day), given in a simplified association with an estrogen for 21/28
days/month, efificiently controls the mitotic activity of glands, without inducing the
cyclic bleeding linked to a mimicked stromal cycle and the irregular bleeding mostly
due to severe atrophy associated with continuous HRT and potentially responsible
for premature withdrawal therapy. All endometrial tissue samples obtained by biopsies
were evaluated by at least two independent pathologists. One of them was
chosen from the 13 local pathologists and the other one was the coordinator
pathologist who had a special interest in HRT.
2. Subjects and methods
One hundred and one healthy non-hysterectomized post-menopausal women,
aged 39-66 years (mean 53.9 ± 4.9 years) seeking hormone replacement therapy
(HRT) in 13 gynecology departments in France, between 1990 and 1992, gave their
written informed consent for participating in the study approved by an ethical committee.
All these patients had amenorrhea for at least 12 months. None of them
reported any spotting or breakthrough bleeding while receiving a previous HRT,
leading to the suspicion of a pre-existent endometrial hyperplasia. All patients
underwent Papanicolaou-smears and an X-ray examination of the breast within the
6th and the 12th previous months, respectively, to exclude any neoplasia.
Two different treatment regimens were offered to the patients according to their
willingness or refusal to reinduce regular bleeding. Women who wanted to have
regular monthly bleeding were treated with percutaneous 17;8-estradiol (OESTROGEL
® dispenser') at a daily dose of 3 mg of estradiol administered on the
shoulders and the arms once daily from day 1 to day 25 of each calendar month and
associated with oral micronized progesterone (UTROGESTAN®^), 300 mg/day
(e.g. 100 mg in the morning and 200 mg at bedtime), from day 16 to day 25. No treatment
was administered during the days 26-30 to 31. This 'high dose' treatment
regimen ('High E-P' group) is known to induce a high rate of regular bleeding [5].
The 'low dose' treatment regimen consisted of percutaneous 17;8-estradiol
(OESTROGEL® dispenser') at an initial daily dose of 1.5 mg of estradiol, administered
once daily, from day 1 to day 21 per cycle of 28 days, or to day 25 of
the calendar month and associated with oral micronized progesterone (UTROGESTAN
® ), 100 mg/day, given at bedtime from day 1 to day 21 or 25 ('Low E-P'
group). No treatment was administered between days 22 and 28 for the 28-days
regimen and between days 26 and 30 to 31 for the calendar month regimen Within
the first 3 treated-months the initial dose of OESTROGEL® was eventually adapted,
in order to obtain in each individual the optimal therapeutic plasma estradiol (E2)
level, which is between 60 and 150 pg/ml. Estradiol and progesterone treatment remained
unchanged throughout the study which lasts a minimum of 6 months. All
women underwent a clinical observation at entry and between days 17-25 of the 3rd
and the 6th (to 13th) month of therapy. Assessment of therapy acceptability and
comphance was performed. A precise monthly record of bleeding schedule was obtained
from each patient.
Endometrial biopsies were taken using a Cornier pipelle or a Novak curette after
12 days or more of progesterone exposure, (which is between day 12 and day 25 of
the substituted cycle). All tissues obtained were fixed in Bouin's solution and then
stained, following hemalum-eosin and PAS methods. All tissue samples were assessed
blindly by the local pathologist and later reviewed by the coordinator pathologist
who, in addition to the morphologic analyses, performed a mitoses count by light
microscopic examination through an eyepiece with a grid. The number of mitoses
was expressed as number of mitoses per 1000 epithelial gland cells. In the event of
insufficient samples for morphological assessment, an endovaginal ultrasonography
was undertaken to measure the thickness of the endometrial mucosa. Estradiol plasma
levels were determined between days 15 and 25 of the 3rd and 6th (to 13th)
month of therapy by either immunoenzymoassay or radioimmunoassay (RIA). Plasma
E2 levels were then checked at random by a specific RIA, following column
chromatography (Fondation de Recherche en Hormonologie, Fresnes, France). This
open multicenter study was coordinated by the first author.
3. Results
3.1. Patients
Among the 101 women qualified for the study, only three chose the 'High E-P'
treatment regimen since they preferred to have cyclic bleeding (group I). They were
younger than the other women (mean age: 49.3 years) and had a shorter duration
of menopause (mean duration of 24 months vs. 57.8 months for the 'Low E-P'
group). None of them had previously received an HRT.
The 98 remaining women who preferred the 'Low E-P' treatment regimen (group
II), expected to avoid any bleeding. The majority of the physicians prefered a 25-
day/month regimen (group Ila: 87 patients) rather than a 21-day/28 days regimen
(group lib: 11 patients). The mean age of the patients from group Ila was 53.7
(S.D. = 5) and was not different from the age of the patients from group lib. The
mean duration of the menopause for group II patients was 57.8 months (range
12-216 months). Of these women, 46% had previously received HRT with percutaneous
17|3-E2 and oral micronized progesterone (Pg) in a cyclic sequence. They had
withdrawn from this HRT 1 month before initiating the tested therapy. The mean
(± S.D.) duration of their hormonal therapy at the time of the endometrial biopsy
was 6.6 ±1.4 months (range 5-13).
Ten patients wished to prematurely interrupt therapy at the lst-5th month because
of the following reasons: fed up with treatment (2 patients), weight increase
(2), nausea (1), vertigo and difficulty in following the therapy (1), spottings in relation
to sub-therapeutic (217 pg/ml) levels of E2 (1) and metrorrhagia for three patients:
the first case being linked to a severe atrophy of the endometrial mucosa,
confirmed by biopsy; the second case leading to hysteroscopy revealing a preexisting
polyp, (previous history of metrorrhagia requiring METHERGIN®); and
the third case was due to a submucosa fibromyoma. No patient has been lost to
follow-up. Transient adverse events have only been reported by three patients of
group Ila: in mastodynia form (n = 2) starting on the 1st or 2nd month of therapy
and disappearing after reduction of the gel dose to 0.75 mg/day: and one case of
depressive mood starting on the 2nd month of therapy but concomitantly to a viral
hepatitis.
3.2. Plasma E2 levels
In the 'Low E-P' group, mean plasma E2 levels were within the recommended
range of therapeutic efficacy (109.9 ± 80.6 pg/ml and 83.7 ± 53.4 pg/ml) at the 3rd
and 6th-13th month of therapy. Checking of these levels by a unique specific RIA
had only been possible for 13 patients at the 3rd month and 34 patients at the 6th
(to 13th) month because of technical reasons. We could not, therefore, perform any
strict correlation between these data issued from different methods of determination.
However, the 34 available determinations of E2 by the specific RIA have resulted
in a mean plasma level of 67.5 ± 42 pg/ml. In the 'High E-P' group, the mean plasma
E2 level was 131 ± 36.2 pg/ml.
3.3. Conformity to the protocol
Among the patients of group II, five of them were considered as major deviants
from the protocol since the endometrial histologic or ultrasonographic data were
missing, due to either an insufficient recovery of endometrial tissue (n = 2) or a physical
impossibility (n = 3) to get through the cervix (atresia, conization) and the
absence of sonographic thickness measurements. Altogether, 83 patients were considered
consistent with the protocol because they had been able to undergo a successful
biopsy and/or an adequate ultrasonography.
3.4. Endometrial biopsies
Biopsies were taken on the mean day of 21.4. The morphological double
assessments by the independent pathologists were compared. Seventy-eight biopsies
were obtained in the 'Low E-P' group (see above) and 2 biopsies in the 'High E-P'
^oup (one woman of the latter group having a cervical atresia could not have any
tissue obtained). In none of these 80 biopsies was a spread of focal hyperplasia
noted. The 2 biopsies of group I revealed a quiescent, without any mitosis and a
mildly active endometrium with 1 mitosis/1000 cells, respectively. The evaluations
from the local pathologists, for group II are illustrated in Table 1. It is important
to stress that none of these biopsies showed a complete progestational maturation
and 74.4% revealed an underdeveloped endometrium remaining inactive or atrophic.
The inadequate amount of tissue obtained in 19 patients (24.3%) may reflect the
degree of atrophy of the endometrial mucosa.
The assessment from the coordinator pathologist is also presented in Table 1. One
can notice that he has considered fewer biopsies (3 vs. 20) as inadequate for diagnosis.
The endometrium was considered as subatrophic when the stroma and the glands
showed no activity. The blocked quiescent endometrium, the most frequent feature
observed, was characterized by a less cellular stroma than in the proliferative phase.
Glands were small and rectilinear with non-pseudo-stratified cyhndro-cubical cells
havmg round or ovoid nuclei. No secretory change was seen. The vessels were
underdeveloped (Fig. 1). The mildly active endometrium differed from the previous
one since the glands had quite a normal size, cylindric cells, glands were pseudostratified
and had oblong nuclei and the vessels were more visible (Fig. 2). The secretory
endometrium showed marginal secretory changes like the supra or subnuclear
vacuoles or a weak decidualization. There were no spiral arterioles (mean day: 20.5;
range: 17-25). The biopsies showing secretory changes were not performed later
than the other biopsies. In the 75 adequate endometrial samples, the glandular epithelium
had a mean of 0.53 mitoses/1000 cells (S.D.: 1.1) No mitosis was observed
neither in the subatrophic nor the quiescent or secretory endometria. The very rare
mitoses observed were exclusively noted in relation to weak activity features and
were 6-30-fold more reduced than during a physiological cycle. Among the 71 biopsies
of p-oup Ila, we observed the same four groups of endometrium with the same
respective percentage. The comparison of morphological data from group Ila and
lib (progesterone exposure during 25 days/month or 21/28 days) did not show any
marked difference: 57% of patients from group lib had a blocked, quiescent endometrium,
28% showed a restrained, mildly active endometrium (maximum number
of mitosis < 3.5/1000 cells). The last patient had a subatrophic endometrium.
3.5. Endometrial ultrasonography
In the cases of inadequate or impossible biopsy, an endovaginal ultrasonography
was performed and revealed a mean thickness of the endometrial mucosa of
3.96 ± 2.32 nun (n = 8). In women with insufficient sample, diagnosed by the first
pathologist, we observed a mean thickness of 5.25 ± 2 mm (« = 10).
3.6. Bleeding pattern
The bleeding pattern reported for 6 cycles is illustrated in Table 2 and Fig. 3. Spotting
was defined as any light blood discharge per vagina, starting after the first 20
days of the treatment cycle and ending prior to the last 2 days of the cycle. Cyclic
withdrawal bleeding was defined as any blood discharge per vagina between the last
2 days of a treatment cycle and the first 2 days of the next cycle (i.e. from days 20
and 24 for treatment groups lib and Ila, respectively). From a total of 543 cycles,
data from 18 cycles were incomplete and had thus been eliminated. Among the remaining
525 cycles, cyclic withdrawal bleeding was reported in 6.6% at the 3rd
month and 9.4% of the cases at the 6th month. Spotting (1 or several days)
unassociated with a cyclic bleeding episode was noted in 20% of the patients at the
3rd month and decreased to 8.2% at the 6th month. No bleeding was observed in
73.3 and 80.9% of the cycles at the 3rd and 6th month, respectively. Amenorrhea was
recorded in 93.3 and 91.6% of the cases (Table 2). No parallelism was observed between
the morphological findings — particularly the degree of mitoses inhibition —
and the occurrence or duration of overall bleeding. Only two episodes of spotting
were noted in the patient with the higher number of mitoses. Conversely, the two
patients with frequent and prolonged irregular bleedings had blocked quiescent and
secretory endometrium.
The three patients of 'High E-P' treatment group had the desired cyclic regular
bleeding.
3.7. Acceptability of therapy
Among the patients of the 'Low E-P' group having completed the study, 93.1%
did not think the percutaneous application of the E2 gel and the oral absorption of
Pg was a constraint. At the end of the 6th-13th month of combined administration,
88% of women were willing to continue the same therapy.
4. Discussion
Unopposed estrogen therapy in post-menopausal women over stimulates endometrial
proliferation and is, thus, responsible for an increase in abnormal vaginal
bleeding and a 5-7-fold greater frequency of endometrial cancer than in nonestrogen
treated women [6].
Administration of percutaneous E2 without any progestin has shown a similar
growth of endometrial cells to that of conjugated equine estrogens (PREMARIN®)
with a 10% rate of cystic hyperplasia [7], which is in accordance with the described
rate after 12 months use of different posologies of estrogens [8,9]. Simple or complex,
without atypia hyperplasia is known to have little risk of progression to carcinoma
unlike the atypical hyperplasia. A working group of the Fertility and
Maternal Health Drug Advisory Committee of the Food and Drug Administration
(FDA) [10] has emphasized that certain 'bordeline' lesions should be excluded from
the category of hyperplasia such as 'persistent proliferative endometrium' and 'proliferative
endometrium with focal hyperplasia' (i.e. < 10% of enlarged glands in the
sample examined). Indeed, these features rapidly disappear spontaneously and have
no clinical significance in predicting endometrial risk.
Endometrial over-stimulation has to be reduced by the cyclic use of an appropriate
dose of a progestin. Added to estrogen replacement therapy (ERT), the progestin
given during 12 or more days/month can prevent the occurrence of new cases of hyperplasia
[5,8,11,12] and significantly decrease endometrial carcinoma risk [11,13].
These epidemiological data strongly suggest that a minimal duration of 12 days [5,8]
and a dose of the progestin sequence are the key points for efficiently preventing endometrial
hyperplasia [5,8,14,15] and cancer [5,13,16].
The identification of the precise histological and cytological characteristics reflecting
the optimal control of endometrial growth during ERT [5,17-19] has allowed
to strictly define the required pattern of endometrial response for optimal safety in
the long term [20,21]. Several authors have described a non-parallelism between the
biochemical anti-proliferative and the morphological secretory differentiation effects
induced by progestins on the endometrium [22-24], Recently, Moyer et al. [5] in a
5-7-year follow up of 236 post-menopausal patients treated by percutaneous estradiol
opposed by oral micronized Pg (200-300 mg daily) for 10-14 days/28 days have
confirmed the previous works [17-19]: complete secretory maturation and consequent
regular withdrawal bleeding are not required for the prevention of endometrial
hyperplasia. The appropriate dose and duration of progesterone is that
which reduces the glands mitoses to a very low rate within 10 days, the resultant
being a lack of endometrial cyclic growth and regression, a marginal secretory transformation
and a high incidence of amenorrhea [5,20,21,25].
This study was therefore designed to evaluate if a low dose of oral micronized Pg
(100 mg/day) simultaneously administered with percutaneous E2 during a long
period (21 or 25 days) can exert the same safe protection on endometrium as the
usual dose (200 mg/day), given cyclically during the last 12-14 days of ERT
[5,24-26] and avoid the maximum regular and irregular bleeding. The mean therapy
duration (6.6 ± 1.4 months) is considered as too short for detecting any hyperplasia
feature. However, we choose to focus on the most characteristic markers of endometrial
proliferation, i.e. the mitotic activity of glandular epithelial cells. One of
the major impacts of progestins on estrogen-primed endometrium is the arrest of the
epithehal cells cycle, reflected by the number of mitoses. In this open, noncomparative
study, the endometriae have been submitted to an adequate estrogenic
stimulation, i.e. reflected to mean plasma E2 of 109.9 and 83.7 pg/ml at the 3rd and
6th month of therapy, respectively. All the available endometrial biopsies, assessed
by two independent pathologists, have shown an adequate suppression of proliferation
since no endometrium reached the same stage of proliferation as during the late
normal proliferative phase and gland mitoses were reduced to a very low level (mean
< 0.53 ± 1.1/1000 cells). It is interesting to stress that for three patients having 2
or 4 mitoses/1000 cells, their mean age was 52 years and the time elapsing since
menopause was only 12 months. They can, therefore, be considered as perimenopausal
women with a substantial residual estrogenization leading to a slight
degree of persistent mitoses which always remains, nevertheless, very much below
the threshold of 18-30 mitoses/1000 cells of the follicular phase [27]. Therefore this
finding does not represent a clinical significance for any endometrial pathology risk.
As for morphological data, a slight difference in the precise assessments of each
pathologist has been observed due to mild differences in the diagnostic terminology
from one pathologist to another: the coordinator has considered a single gland and
its surrounding stroma was sufficiently representative of the endometrium hormonal
status. A comparison of data of Table 1 shows that among the 20 tissue samples
judged insufficient or inadequate for analyses by the local pathologists (since they
only comprised few strips of epithelial glands), 16 of them were assessed as a quiescent
or a secretory endometrium by the coordinator pathologist. One can compare
the category of blocked, quiescent endometriae (61%), defined by the coordinator
the groups of quiescent and atrophic or subatrophic endometriae (56.4%), with that
of the local pathologists (Table 1). We confirmed previous works [5,24] by showing
the absence of parallelism between complete secretory maturation and efficient control
of mitoses and, consequently, prevention of endometrial hyperplasia.
Our observations of restrained under-developed endometrium are in full accordance
with the findings of Foidart et al. [28] in patients receiving the same therapy
during 12 months. In women for which no tissue was available, the mean thickness
(3.96 mm) of endometrial mucosa corresponds with the atrophic endometrium and
is, thus, not predictive of any endometrial pathology [29].
A low dose of progesterone given during 25 days/month can, therefore, induce an
endometrium with a very slight potential of cyclic activity. This characteristic is
distinct from the endometrial response obtained with a continuous combined HRT:
indeed, totally inactive endometrium have been described in >90% of patients on
daily norethindrone (NEA) or medroxyprogesterone acetate (MPA) [30-33] and in
100% of the patients on daily micronized E2 and progesterone during 12 months
[34]. We have shown that this mild endometrial activity minimizes irregular bleeding
in comparison with the severe atrophy described with some continuous therapy [32]:
indeed, 57% of irregular bleeding has been reported before the 78th week of administration
as being mainly responsible for the 62% rate of therapy discontinuation.
Amenorrhea, wished by a majority of women, appears easier to achieve and maintain
by therapy discontinuation during a few days each month, even after the 5th
year of ERT [5]. In these 126 patients receiving percutaneous E2 (1.5 mg E2/day)
and micronized progesterone (200 mg/day) during 14 days, amenorrhea was obtained
in >90% of patients which can be compared with the 100% amenorrhea incidence
observed in the 1 year study of Foidart [28].
It is important to stress that in our study incidence of spotting markedly decreased
from the 3rd month (20%) to the 6th month (8.2%). This fact has also been described
by Foidart [28], reporting a progressive decrease in spotting from the 2nd month
(13.3%) until the 9th month of therapy and a persisting zero incidence up to the 12th
month. The resultant of the spotting decrease and frequent amenorrhea observed in
our study is a high rate (80.9%) of absence of any bleeding at the 6th month of therapy.
This finding allows us to expect, in the long-term, a satisfactory compliance since
the latter is shown to be closely related to the absence of the cyclic bleeding. A
discontinuation rate because of withdrawal bleeding has been indeed reported in
27-83% of the cases [35,36]. Moreover, this very frequent amenorrhea obtained with
micronized progesterone matches the needs of women [1,37] and particularly French
women today, as attested by data of a large recent inquiry by the SOFRES Institute,
public opinion poll [38], showing that > 50% of all interviewed women would prefer
a therapy inducing no bleeding.
The low incidence of irregular bleedings observed in our population seems to be
explained by the effect of progesterone on the stroma, distinct from other progestins;
in view of the fact that the hysteroscopic study of the endometrium, under the influence
of micronized progesterone, shows a distinctive endometrium, very pale,
without any vascular dilation, unlike pregnane or norpregnane progesterone derivatives
[39]. The specific action of the progesterone on the stroma, and in particular
on its vascularization, is confirmed by the histological aspect characterized by slightly
atrophic arterioles and non-dilated capillaries.
The general attitude of postmenopausal women is illustrated in this study by the
minority of women (3 out of 101) that preferred the 'High E-P' treatment regimen.
frequently inducing cyclic bleeding [5,24]. One has to notice that ~50% of the
women had previously received the sequential association of percutaneous E2 and
micronized progesterone. These women were therefore inclined to choose the therapy
giving at least the same chance of amenorrhea. It is interesting to note that 11
out of the 13 physicians selected to test the therapy of 25 days/calendar month duration.
This mode of administration may appear easier to handle than the regimen over
21/28 days.
Two patients discontinuing the therapy reported transient adverse events possibly
related to progesterone (one nausea and one vertigo). However, these events have
been described to the same extent in women with E2 levels > 50 pg/ml, receiving at
bedtime oral progesterone (200 or 300 mg/day) or the placebo [40]. Two patients
with metrorrhagia probably had a pre-existing endometrial pathology (a polyp for
one and a submucosa fibromyoma for another). The two early episodes of mastodynia
disappeared after the necessary adjustment of the E2 dosage. Of the 88 patients
who completed the study, the acceptability of therapy was very satisfactory
since 93% thought the treatment was easy and 88% expressed the wish to continue
on with the same treatment after completion of the study. This encouraging shortterm
option of the women is crucial since the discontinuation of HRT is known to
occur on average within the first 12-18 months of therapy. However, this favourable
appreciation requires a further evaluation during a long-term follow-up study.
We conclude that a low dose of oral micronized progesterone (100 mg/day) given
for 25 days/calendar month is able to fully control endometrial proliferation induced
by an adequate dose of percutaneous E2, by efficiently inhibiting mitoses in glands.
This study confirms doses of progesterone necessary to fully suppress mitoses are inferior
to those necessary to induce secretory changes and withdrawal bleeding. The
use of a low dose of progesterone allows, therefore, to maintain a low incidence in
spotting and a very frequent amenorrhea which optimizes compliance to this longterm
therapy and avoids the stress and costs of repeated intra-uterine investigations.
Acknowledgements
We wish to thank Dr H. Aubert, Dr M. Dress, Dr B. Thoreau and Dr M.C.
Dulucq for their contribution from the centers of investigation. We are very grateful
to S. Foumier, Dr E. Joubert and Dr R. Pignal for their great assistance and B.
Morieult for her editorial help.
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