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Cytologic evaluation of hormonal dynamic in the postmenopause
Maturitas, 1 (1979) 269-277
0 Elsevier/North-Holland
269
Biomedical Press
CYTOLOGIC EVALUATION OF HORMONAL DYNAMIC IN THE POSTMENOPAUSE
A. SCHACHTER, A. SEGALL, E. AVRAM and C. BAHARY Gynecologic Gynecology, Israel
Cytology and Colposcopy Unit ‘Marie Cohen”, Department of Obstetrics and Beilinson Medical Center, Tel Aviv University, Sackler School of Medicine, Tel Aviv,
(Received 21 August 1978, accepted 7 February 1979)
There is increasing evidence that the postmenopausal ovary retains some endocrine function and thus can contribute a certain extent to the persistence of the vaginal epithelium proliferation a long time after the cessation of menstruations. Vaginal cytology plays an important role in the assessment of the vaginal epithelium response to hormonal stimuli, though less accurate than the blood and the urine estimations. It was established that there was a good correlation between the vaginal cytology and the biochemical estimations [ 21. The fact that vaginal cytology cannot distinguish the proliferative patterns induced by estrogens, progesterone and androgens is true. With this in mind we did a cytological study in postmenopausal women, using our classification for the cytological typing based on the depth of the epithelial atrophy. The findings are discussed with special reference to the ethnic origin, reproductive life and concurrent illnesses. (Key words: Postmenopause,
Ethnic origin, Cytohormonal
evaluation)
MATERIALS AND METHODS Vaginal smears were taken from 1022 postmenopausal women who were referred to the Gynecological Cytology Unit of the Beilinson Medical Center for cytopathological and cytohormonal investigations, by gynecologists from all over the country during the period between the years 1975-1977. They were divided into three ethnic groups: Western, Eastern and Israeli born. Clinical data were obtained regarding age, parity, the onset of the menarche, the menopause and general or gynecological illnesses. None of the women took hormonal treatment 3 mth prior to the tests. The cytohormonal smears were taken from the upper third of the lateral wall of the vagina, as it is the least traumatized by coitus and it is considered a more accurate reflector of the hormonal activity. Smears showing marked inflammatory changes were excluded from the study. In some cases that received local treatment the urocytogram was utilized according to Lencioni’s technique. The papanicolau-stained smears were interpreted according to our new classification which was derived from de Neefs classical description [9] and based on Meisels’ Maturation Index. Unlike other classifications described in the literature, we could include all the women in a well-defined frame in our classification. According to our classification, there are 5 “usual” postmenopausal types and one “unusual” type. The 5 usual types are: 1. Beginning postmenopausal with a good proliferative activity. MI O/80/20.
2. Mild postmenopausal, in which there are intermediate cells only or sometimes a few parabasal and superficial cells, both of them under 10%. MI O/100/0 or 10/80/10. 3. Advanced postmenopausal, containing an increased number of parabasal cells but not more than 40%. MI 40/60/O. 4. Deep postmenopausal, showing parabasal cells which exceed those of the intermediate cells in number. The general image became poor and dirty due to the very common senile vaginitis. MI 60/40/O. 5. Absolute postmenopausal, characterized by parabasal cells only, sometimes eosinophilic as an expression of depth of atrophy. MI 100/O/O. The exception is the “unusual” hyperestrogenic smear, which contains more than 20% superficial cells. The patients were divided into groups depending on ethnic origin, parity and the cytohormonal patterns in each group were compared. The cytological postmenopausal type was established depending on the time elapsed since the menopause. A special interest was taken in the hyperestrogenic postmenopausal type in women who were postmenopausal for 11 yr or more. These were divided into two ethnic groups, Western and Eastern (the Israeli born women of 60-70 yr of age form a group too small for separate analysis) and we tried to learn something from the prolonged proliferative effect in their smears. It must be mentioned that 20 out of the 1022 women studied, underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. These were treated as a separate group. RESULTS
The patients were divided into three groups according to their ethnic origin: Western 73.6%, Eastern 16.9% and Israeli born 9.5% (Table I). Table I shows the mean age of every group with the mean age of the total sample 55.47: the mean age of menarche 13.07 and the mean age of menopause 47.98. The mean age of menarche in the Western and Israeli born group is lower than that of Eastern women, The length of reproductive life, which is counted from the menarche till the menopause minus 1 yr for every delivery, was more prolonged in the Western women than in the Eastern, mainly because of the lower incidence of multiparity amongst the Western women (7.0%). There was no difference between the nulliparous women of the two mentioned groups. The distribution of smears according to cytological postmenopausal types in relation to age shows a high percentage of women between the age of 5 l-60 yr in every cytological pattern group (Fig. 1). In the older groups, i.e., 61-70 yr and 71 and more, the percentage of deep and absolute postmenopausal types remains constant, while the percentage of the beginning and the mild postmenopausal types decreased. The increased percentage of the hyperestrogenic pattern was unexpected in women of 66 yr of age and older. The cytological postmenopausal types in relation to the time elapsed since the onset of menopause are shown in Fig. 2. The percentage of patients with advanced, deep and absolute postmenopausal types increased steadily with the passage of years. The percentage of patients with a mild postmenopausal pattern remains quite stable in the first decade of the postmenopasual life, but increases in the next decades. The percentage of
No.
152 I73 91 1022
Ethnic groups
Western Eastern Israeli born Total
13.6 16.9 9.5 100
%
51.4 55.02 53.99 55.47
Age
f f f +
1.30 8.12 8.16 8.06
12.98 13.45 12.78 13.07
* f * f
1.6 1.56 1.95 1.70
Age of menarche
Distribution of patients according to their ethnic origin and anamnestic data
TABLE I
48.97 47.04 41.94 41.98
f 5.04 _+5.54 f 4.82 f 5.13
Age of menopause
33.92 29.12 32.44 32.83
? 5.43 + 5.75 f 5.45 f 5.54
Length of reproductive life
105 24 7 136
14.0 13.6 7.0 13.3
53 67 11 131
7.0 38.8 11.6 12.9
%
No.
No.
%
Multiparity
Nulliparity
272
-45
51-55
46-50
56-60
61-65
66-70
71 -
AGE
Fig. 1. Percentual distribution of patients according to cytological postmenopausal type and age. Hyperestrogenic: PI = over 20%, -. beginning postmenopausal: MI = O/80/20, - - -; mild MI = 40/60/O, - - - - - -; deep postmenopausal: MI = O/100/0, . - . - .’ advanced postmenopausal: postmenopausal: MI = 60/40/O, -X-X -; absolute postmenopausal: MI = 100/O/O, -.
the hyperestrogenic type decreases during the first 10 yr, after the menopause as it was expected, but it did not come to zero after 11 yr. There were 9.7% of patients with a hyperestrogenic smear, in this very interesting group.
l-2 YEARS
3-5 AFTER
MENOPAUSE
6-10
11 -
TOTAL MENOPAUS
F’OSTAL
WOMEN
Fig. 2. Percentual distribution of patients according to cytological menopausal type and the elapsed time since menopause. Hyperestrogenic, 0; beginning postmenopausal, 8; mild postmenopausal, Q; advanced postmenopausal,@;deep postmenopausal,O; absolute postmenopausal,@.
213 TABLE II Distribution of high proliferative and atrophic cytological patterns in patients menopause according to ethnic origin. Cytologic pattern
11 yr and more after
Ethnic groups Western %
Eastern %
Proliferative Hyperestrogenic Beginning postmenopausal
8.9 24.0
Total
32.9
2.5 2.8 5.3
Atrophic Deep postmenopausal Absolute postmenopausat
1.3 4.4 5.1
11.9 16.4 -
Total
28.3
The factors involved in the persistence of the high proliferative smears in the older patients and so many years after the menopause, is a field of various theoretical speculations. We compared the Western and Eastern groups as concerning the high proliferative and atrophic cytological postmenopausal types (Table II). In the Western group the percentage of proliferative smears is higher than that of the atrophic smears (4.5%), while in the Eastern group the percentage of proliferative smears is lower (0.4%) than that of atrophic smears. This inverse relationship reflects a rather prolonged estrogenic effect in the Western group as compared to the Eastern. The parity does not seem to play a role in our 6 cytological postmenopausal types (Table III). The same percentage of proliferative
TABLE III Percentual distribution
of parity according to cytological postmenopausal
Cytological pattern
Parity NulIiparity No.
Multiparity %
No.
%
13 45 33 9 10 26
9.4 32.8 24.0 6.3 1.4 20.1
15 31 33 10 12 24
11.1 28.3 25.3 8.0 9.1 18.2
136
100.0
131
100.0
Hyperestrogenic Beginning postmenopausal Mild postmenopausal Advanced postmenopausal Deep postmenopausal Absolute postmenopausal Total
type of smear.
Total
Hyperestrogenic Beginning postmenopause Mild postmenopause Advanced postmenopause Deep postmenopause Absolute postmenopause
Cytological pattern
1022
9.1 27.5 24.6 10.8 11.7 15.7 234
32 88 23 21 45 25
No.
No.
99 281 251 110 120 160
Obesity
Patients %
13.7 37.6 9.8 9.0 19.2 10.0
%
Distribution of patients according to cytological postmenopausal
TABLE IV
23
1 3 2 1 5 11
No.
4.4 13.0 8.7 4.4 21.7 47.8
%
Diabetes
86
22 16 10 4 7 27 25.6 18.6 11.6 4.7 8.1 31.4
Hypertension ~ No. %
35
6 I 6 4 10 2
17.1 20.1 17.1 11.4 28.6 5.1
Gynecological carcinoma ~ No. %
type and associated pathological conditions.
64
10 15 11 3 11 14
15.6 23.4 17.2 4.1 17.2 21.9
Breast ca. ____ No. %
20
0 6 5 1 2 6
No.
0 30.0 25.0 5.0 10.0 30.0
%
State after panhysterectomy
215
and atrophic smears is found in the hypertensive women, in cases with genital and breast cancer (Table IV). The diabetic patients did not show a higher percentage of proliferative smears in this study. Only obese women were found to have more proliferative smears. The group of patients after panhysterectomy still shows a cytological pattern of beginning and mild postmenopause in more than 50% of the cases. In all age groups there was a number of hyperestrogenic smears which tended to increase in the older women in whom there was a higher incidence of ovarian, breast and endometrial carcinoma, diabetes and obesity. DISCUSSION The physiologic transition in woman’s life from the reproductive function to its complete cessation, reveals significant cytological changes as an expression of the permanent and inevitable decreasing activity of the ovary. Papanicolau and Shorr [l] were the first to establish a colpocytologic classification for the postmenopause. They believed that the vaginal epithelium is a very sensitive target tissue for the sex-steroids. It is also known that the cytohormonal smear cannot distinguish between the proliferative patterns induced by estrogens, progesterone or androgens which may act on the vaginal epithelium independently or synergistically. Therefore, we have to consider the vaginal smear as a sum reflection of influences of sex-steroids, mainly the estrogens. The use of the Maturation Index shows the percentual relations between parabasal, intermedial and superficial cells which build the squamous vaginal epithelium, and thus an evaluation of the clinical status of the postmenopausal woman through the vaginal cytology becomes feasible. Recent investigations showed that the postmenopausal ovary is not a “dead” structure but that it maintains some endocrine function for many years after the cessation of menses. The ovarian stroma continues to play some role in steroidogenesis, especially in the production of androgens [3]. Evidence that an appreciable number of women retain a cytological detectable proliferative activity has been revealed in many studies [5-81. There are two hypotheses regarding the source of this strong estrogenic activity in the postmenopause. The first hypothesis is based on the presumption that there is a direct secretion of estrogens from the ovaries and the adrenals [3,12,13]. The second hypothesis deals with the peripheral conversion of androgens such as androstenedione from ovarian and adrenal stroma into estrogens, mainly estrone [14,15]. It is also observed that women, losing weight, begin to suffer from the postmenopausal syndrome [16]. Our findings confirm previous cytohormonal evaluations of postmenopausal vaginal smears. Three main patterns of proliferation were found: (1) 38.1% of our patients showed a progressive decrease of the estrogenic activity with the passing of years, reaching complete epithelial atrophy in 15.7% of cases. Equal percentage of women showed a very low proliferative activity (noted by advanced and deep postmenopausal patterns). (2)Half of the group under study (52.1%) displayed a moderate proliferative activity (beginning and mild postmenopausal patterns). (3) About 10% of the cases had hyperestrogenic smears in old age. This type of smear may indicate the possible presence of an ovarian, estrogen-secreting
216
tumor or another pathological situation in which estrogenic-like substances are secreted [ 10,111, but it can also be the result of an increase in the conversion of androgens to estrone. We will discuss the latter. Similar findings, especially regarding the high estrogenic levels, were reported in Meisels’study on 5920 menopausal women. There is full correlation between our results and those of others [6-81, as to the high levels of estrogenic activity in old postmenopausal women. We did not find a strong correlation between proliferative activity and ethnic origin. In two previous studies presented in New York in 1976 and in Las Vegas in 1978, in relation to breast and endometrial cancer, we found prolonged estrogenic activity in postmenopausal women of Western origin, as well as a significant difference between the Western and Eastern groups of patients regarding hyperestrogenism. In the present study we found that prolonged proliferative activity was more common in the Western women (32.8%) than in the Eastern (5.4%). (We prefer to use the term proliferative and estrogenic activity because of the multi-steroid influenc,es on the vaginal epithelium after the menopause.) De Waard et al.‘s study (1972) [12] concluded that the estrogens secreted in the urine correlated quite well with the vaginal proliferation. Procope and Adlercreutz’s theory (1973) considers urinary and blood estrogen determination as inexact because they measure only a part of the biologically active estrogens. Thus we believe that the cytology is a more accurate method for the evaluation of the proliferative response to endogenous and exogenous estrogens, in spite of the fact that the target organ (the vaginal epithelium) can have a variable quantitative sensitivity to estrogen at different levels. The vagina, which was described by Zondek et al. [17], in the early 50’s as “the most sensitive indicator of estrogen effect of all hormone responsive tissues in the body” and thus its epithelial changes can be used effectively in the diagnosis, treatment and followup of the postmenopausal woman, if the cytologists and the clinicians understand the unusual and sometimes surprising hormonal dynamics of this interesting period of life. REFERENCES
I
[l ] Papanicolau,
G. and Shorr, E. (1936) The action of ovarian follicular hormone in the menopause as indicated by vaginal smears. Am. J. Obstet. Gynecol. 31.806831. [2] Waard, F. de, Pot, H., Tonckens-Nanninga, N., Baanders-van Halewijn, E. and Thijssen, J. (1972) Longitudinal studies on the phenomenon of postmenopausal estrogen production. Acta Cytol. 16213-218. i] Poortman, J., Thijssen, J.H. and Schwartz, F. (1974) Androgen production and conversion to estrogens in normal postmenopausal women and in selected breast carcinoma patients. J. Clin. Endocrinol. Metabol. 37, 101-109. I4 .] Asch, R.A. and Greenblatt, R.B. (1977) Steroidogenesis in the postmenopausal ovary. In: Clinics in obstetrics and gynecology, Vol. 4, no. 1, p. 85. Editors: R.B. Greenblatt and J. Studd, W.B. Saunders Company Ltd., London. (51 Masukawa, T. (1960) Vaginal smears in women past 40 years of age, with emphasis on their remaining hormonal activity. Obstet. Gynecol. 16,407-413. [6] Meisels, A. (1966) The menopause: a cytohormonal study. Acta Cytol. 10,49-55. [7] Kistner, R.W. (1973) The menopause. Clin. Obstet. Gynecol. 164,106-129. [8] Ziliotto, G. and Cortella, A. (1968) Aspetti della citologica vaginale in donne ultrasettientenm, i sulla presenza di repertia morfologia estrogenica. Acta Gerontol. 18, 181-l 91.
v
,
211 [9] Neef, J. de (1965) Clinical endocrine cytology. Harper and Row Publishers, New York.
[ 10) Siiteri, P.K. and MacDonald, P.C. (1973) In: Handbook of physiology, Sect. 7, Vol. II, Part I, p. 615. Editor: R.O. Greep and E.B. Astwood, American Physiology Society.
[ 111 Siiteri, P.K., Schwartz, B.F. and MacDonald, P.C. (1974) Estrogen receptors
and the estrone hypothesis in relation to endometrial and breast cancer. Gynecol. Oncol. 2,228-238. [ 121 Waard, F. de and Thijssen, J. (1970) Relationship between hormonal cytology and steroid excretion in postmenopausal women. J. Endocrinol. 48, 36. [ 131 Hammond, D.O. (1977) Cytological assessment of climacteric patients. Clin. Obstet. Gynecol. 4,49-70. (141 Procope, B.J. and Adlercreutz, H. (1973) Oestrogen production in postmenopausal women. In: Ageing and estrogens. Frontiers of hormone research, Vol. 2, pp. 57-73. Karger, Basel. [ 151 Schindler, A.E., Ebert, A. and Friederich, E. (1972) Conversion of androstenedione to estrone by human fat tissue. J. CIin. Endocrinol. Metabol. 35,627-630. [ 161 Waard, F. de and Baanders-van Halewijn, E.A. (1961) Further cytological observations concerning estrogenic activity in postmenopausal women. Acta Endocrinol. 38, 5 15-526. [17] Zondek, B., Toaff, R. and Rozin, S. (1950) Cyclic changes in the vaginal but not in the uterine mucose of amenorrheic women, induced by a single injection of estrone and progesterone precipitates. J. Chn. Endocrinol. 10,615-622.
0 Elsevier/North-Holland
269
Biomedical Press
CYTOLOGIC EVALUATION OF HORMONAL DYNAMIC IN THE POSTMENOPAUSE
A. SCHACHTER, A. SEGALL, E. AVRAM and C. BAHARY Gynecologic Gynecology, Israel
Cytology and Colposcopy Unit ‘Marie Cohen”, Department of Obstetrics and Beilinson Medical Center, Tel Aviv University, Sackler School of Medicine, Tel Aviv,
(Received 21 August 1978, accepted 7 February 1979)
There is increasing evidence that the postmenopausal ovary retains some endocrine function and thus can contribute a certain extent to the persistence of the vaginal epithelium proliferation a long time after the cessation of menstruations. Vaginal cytology plays an important role in the assessment of the vaginal epithelium response to hormonal stimuli, though less accurate than the blood and the urine estimations. It was established that there was a good correlation between the vaginal cytology and the biochemical estimations [ 21. The fact that vaginal cytology cannot distinguish the proliferative patterns induced by estrogens, progesterone and androgens is true. With this in mind we did a cytological study in postmenopausal women, using our classification for the cytological typing based on the depth of the epithelial atrophy. The findings are discussed with special reference to the ethnic origin, reproductive life and concurrent illnesses. (Key words: Postmenopause,
Ethnic origin, Cytohormonal
evaluation)
MATERIALS AND METHODS Vaginal smears were taken from 1022 postmenopausal women who were referred to the Gynecological Cytology Unit of the Beilinson Medical Center for cytopathological and cytohormonal investigations, by gynecologists from all over the country during the period between the years 1975-1977. They were divided into three ethnic groups: Western, Eastern and Israeli born. Clinical data were obtained regarding age, parity, the onset of the menarche, the menopause and general or gynecological illnesses. None of the women took hormonal treatment 3 mth prior to the tests. The cytohormonal smears were taken from the upper third of the lateral wall of the vagina, as it is the least traumatized by coitus and it is considered a more accurate reflector of the hormonal activity. Smears showing marked inflammatory changes were excluded from the study. In some cases that received local treatment the urocytogram was utilized according to Lencioni’s technique. The papanicolau-stained smears were interpreted according to our new classification which was derived from de Neefs classical description [9] and based on Meisels’ Maturation Index. Unlike other classifications described in the literature, we could include all the women in a well-defined frame in our classification. According to our classification, there are 5 “usual” postmenopausal types and one “unusual” type. The 5 usual types are: 1. Beginning postmenopausal with a good proliferative activity. MI O/80/20.
2. Mild postmenopausal, in which there are intermediate cells only or sometimes a few parabasal and superficial cells, both of them under 10%. MI O/100/0 or 10/80/10. 3. Advanced postmenopausal, containing an increased number of parabasal cells but not more than 40%. MI 40/60/O. 4. Deep postmenopausal, showing parabasal cells which exceed those of the intermediate cells in number. The general image became poor and dirty due to the very common senile vaginitis. MI 60/40/O. 5. Absolute postmenopausal, characterized by parabasal cells only, sometimes eosinophilic as an expression of depth of atrophy. MI 100/O/O. The exception is the “unusual” hyperestrogenic smear, which contains more than 20% superficial cells. The patients were divided into groups depending on ethnic origin, parity and the cytohormonal patterns in each group were compared. The cytological postmenopausal type was established depending on the time elapsed since the menopause. A special interest was taken in the hyperestrogenic postmenopausal type in women who were postmenopausal for 11 yr or more. These were divided into two ethnic groups, Western and Eastern (the Israeli born women of 60-70 yr of age form a group too small for separate analysis) and we tried to learn something from the prolonged proliferative effect in their smears. It must be mentioned that 20 out of the 1022 women studied, underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. These were treated as a separate group. RESULTS
The patients were divided into three groups according to their ethnic origin: Western 73.6%, Eastern 16.9% and Israeli born 9.5% (Table I). Table I shows the mean age of every group with the mean age of the total sample 55.47: the mean age of menarche 13.07 and the mean age of menopause 47.98. The mean age of menarche in the Western and Israeli born group is lower than that of Eastern women, The length of reproductive life, which is counted from the menarche till the menopause minus 1 yr for every delivery, was more prolonged in the Western women than in the Eastern, mainly because of the lower incidence of multiparity amongst the Western women (7.0%). There was no difference between the nulliparous women of the two mentioned groups. The distribution of smears according to cytological postmenopausal types in relation to age shows a high percentage of women between the age of 5 l-60 yr in every cytological pattern group (Fig. 1). In the older groups, i.e., 61-70 yr and 71 and more, the percentage of deep and absolute postmenopausal types remains constant, while the percentage of the beginning and the mild postmenopausal types decreased. The increased percentage of the hyperestrogenic pattern was unexpected in women of 66 yr of age and older. The cytological postmenopausal types in relation to the time elapsed since the onset of menopause are shown in Fig. 2. The percentage of patients with advanced, deep and absolute postmenopausal types increased steadily with the passage of years. The percentage of patients with a mild postmenopausal pattern remains quite stable in the first decade of the postmenopasual life, but increases in the next decades. The percentage of
No.
152 I73 91 1022
Ethnic groups
Western Eastern Israeli born Total
13.6 16.9 9.5 100
%
51.4 55.02 53.99 55.47
Age
f f f +
1.30 8.12 8.16 8.06
12.98 13.45 12.78 13.07
* f * f
1.6 1.56 1.95 1.70
Age of menarche
Distribution of patients according to their ethnic origin and anamnestic data
TABLE I
48.97 47.04 41.94 41.98
f 5.04 _+5.54 f 4.82 f 5.13
Age of menopause
33.92 29.12 32.44 32.83
? 5.43 + 5.75 f 5.45 f 5.54
Length of reproductive life
105 24 7 136
14.0 13.6 7.0 13.3
53 67 11 131
7.0 38.8 11.6 12.9
%
No.
No.
%
Multiparity
Nulliparity
272
-45
51-55
46-50
56-60
61-65
66-70
71 -
AGE
Fig. 1. Percentual distribution of patients according to cytological postmenopausal type and age. Hyperestrogenic: PI = over 20%, -. beginning postmenopausal: MI = O/80/20, - - -; mild MI = 40/60/O, - - - - - -; deep postmenopausal: MI = O/100/0, . - . - .’ advanced postmenopausal: postmenopausal: MI = 60/40/O, -X-X -; absolute postmenopausal: MI = 100/O/O, -.
the hyperestrogenic type decreases during the first 10 yr, after the menopause as it was expected, but it did not come to zero after 11 yr. There were 9.7% of patients with a hyperestrogenic smear, in this very interesting group.
l-2 YEARS
3-5 AFTER
MENOPAUSE
6-10
11 -
TOTAL MENOPAUS
F’OSTAL
WOMEN
Fig. 2. Percentual distribution of patients according to cytological menopausal type and the elapsed time since menopause. Hyperestrogenic, 0; beginning postmenopausal, 8; mild postmenopausal, Q; advanced postmenopausal,@;deep postmenopausal,O; absolute postmenopausal,@.
213 TABLE II Distribution of high proliferative and atrophic cytological patterns in patients menopause according to ethnic origin. Cytologic pattern
11 yr and more after
Ethnic groups Western %
Eastern %
Proliferative Hyperestrogenic Beginning postmenopausal
8.9 24.0
Total
32.9
2.5 2.8 5.3
Atrophic Deep postmenopausal Absolute postmenopausat
1.3 4.4 5.1
11.9 16.4 -
Total
28.3
The factors involved in the persistence of the high proliferative smears in the older patients and so many years after the menopause, is a field of various theoretical speculations. We compared the Western and Eastern groups as concerning the high proliferative and atrophic cytological postmenopausal types (Table II). In the Western group the percentage of proliferative smears is higher than that of the atrophic smears (4.5%), while in the Eastern group the percentage of proliferative smears is lower (0.4%) than that of atrophic smears. This inverse relationship reflects a rather prolonged estrogenic effect in the Western group as compared to the Eastern. The parity does not seem to play a role in our 6 cytological postmenopausal types (Table III). The same percentage of proliferative
TABLE III Percentual distribution
of parity according to cytological postmenopausal
Cytological pattern
Parity NulIiparity No.
Multiparity %
No.
%
13 45 33 9 10 26
9.4 32.8 24.0 6.3 1.4 20.1
15 31 33 10 12 24
11.1 28.3 25.3 8.0 9.1 18.2
136
100.0
131
100.0
Hyperestrogenic Beginning postmenopausal Mild postmenopausal Advanced postmenopausal Deep postmenopausal Absolute postmenopausal Total
type of smear.
Total
Hyperestrogenic Beginning postmenopause Mild postmenopause Advanced postmenopause Deep postmenopause Absolute postmenopause
Cytological pattern
1022
9.1 27.5 24.6 10.8 11.7 15.7 234
32 88 23 21 45 25
No.
No.
99 281 251 110 120 160
Obesity
Patients %
13.7 37.6 9.8 9.0 19.2 10.0
%
Distribution of patients according to cytological postmenopausal
TABLE IV
23
1 3 2 1 5 11
No.
4.4 13.0 8.7 4.4 21.7 47.8
%
Diabetes
86
22 16 10 4 7 27 25.6 18.6 11.6 4.7 8.1 31.4
Hypertension ~ No. %
35
6 I 6 4 10 2
17.1 20.1 17.1 11.4 28.6 5.1
Gynecological carcinoma ~ No. %
type and associated pathological conditions.
64
10 15 11 3 11 14
15.6 23.4 17.2 4.1 17.2 21.9
Breast ca. ____ No. %
20
0 6 5 1 2 6
No.
0 30.0 25.0 5.0 10.0 30.0
%
State after panhysterectomy
215
and atrophic smears is found in the hypertensive women, in cases with genital and breast cancer (Table IV). The diabetic patients did not show a higher percentage of proliferative smears in this study. Only obese women were found to have more proliferative smears. The group of patients after panhysterectomy still shows a cytological pattern of beginning and mild postmenopause in more than 50% of the cases. In all age groups there was a number of hyperestrogenic smears which tended to increase in the older women in whom there was a higher incidence of ovarian, breast and endometrial carcinoma, diabetes and obesity. DISCUSSION The physiologic transition in woman’s life from the reproductive function to its complete cessation, reveals significant cytological changes as an expression of the permanent and inevitable decreasing activity of the ovary. Papanicolau and Shorr [l] were the first to establish a colpocytologic classification for the postmenopause. They believed that the vaginal epithelium is a very sensitive target tissue for the sex-steroids. It is also known that the cytohormonal smear cannot distinguish between the proliferative patterns induced by estrogens, progesterone or androgens which may act on the vaginal epithelium independently or synergistically. Therefore, we have to consider the vaginal smear as a sum reflection of influences of sex-steroids, mainly the estrogens. The use of the Maturation Index shows the percentual relations between parabasal, intermedial and superficial cells which build the squamous vaginal epithelium, and thus an evaluation of the clinical status of the postmenopausal woman through the vaginal cytology becomes feasible. Recent investigations showed that the postmenopausal ovary is not a “dead” structure but that it maintains some endocrine function for many years after the cessation of menses. The ovarian stroma continues to play some role in steroidogenesis, especially in the production of androgens [3]. Evidence that an appreciable number of women retain a cytological detectable proliferative activity has been revealed in many studies [5-81. There are two hypotheses regarding the source of this strong estrogenic activity in the postmenopause. The first hypothesis is based on the presumption that there is a direct secretion of estrogens from the ovaries and the adrenals [3,12,13]. The second hypothesis deals with the peripheral conversion of androgens such as androstenedione from ovarian and adrenal stroma into estrogens, mainly estrone [14,15]. It is also observed that women, losing weight, begin to suffer from the postmenopausal syndrome [16]. Our findings confirm previous cytohormonal evaluations of postmenopausal vaginal smears. Three main patterns of proliferation were found: (1) 38.1% of our patients showed a progressive decrease of the estrogenic activity with the passing of years, reaching complete epithelial atrophy in 15.7% of cases. Equal percentage of women showed a very low proliferative activity (noted by advanced and deep postmenopausal patterns). (2)Half of the group under study (52.1%) displayed a moderate proliferative activity (beginning and mild postmenopausal patterns). (3) About 10% of the cases had hyperestrogenic smears in old age. This type of smear may indicate the possible presence of an ovarian, estrogen-secreting
216
tumor or another pathological situation in which estrogenic-like substances are secreted [ 10,111, but it can also be the result of an increase in the conversion of androgens to estrone. We will discuss the latter. Similar findings, especially regarding the high estrogenic levels, were reported in Meisels’study on 5920 menopausal women. There is full correlation between our results and those of others [6-81, as to the high levels of estrogenic activity in old postmenopausal women. We did not find a strong correlation between proliferative activity and ethnic origin. In two previous studies presented in New York in 1976 and in Las Vegas in 1978, in relation to breast and endometrial cancer, we found prolonged estrogenic activity in postmenopausal women of Western origin, as well as a significant difference between the Western and Eastern groups of patients regarding hyperestrogenism. In the present study we found that prolonged proliferative activity was more common in the Western women (32.8%) than in the Eastern (5.4%). (We prefer to use the term proliferative and estrogenic activity because of the multi-steroid influenc,es on the vaginal epithelium after the menopause.) De Waard et al.‘s study (1972) [12] concluded that the estrogens secreted in the urine correlated quite well with the vaginal proliferation. Procope and Adlercreutz’s theory (1973) considers urinary and blood estrogen determination as inexact because they measure only a part of the biologically active estrogens. Thus we believe that the cytology is a more accurate method for the evaluation of the proliferative response to endogenous and exogenous estrogens, in spite of the fact that the target organ (the vaginal epithelium) can have a variable quantitative sensitivity to estrogen at different levels. The vagina, which was described by Zondek et al. [17], in the early 50’s as “the most sensitive indicator of estrogen effect of all hormone responsive tissues in the body” and thus its epithelial changes can be used effectively in the diagnosis, treatment and followup of the postmenopausal woman, if the cytologists and the clinicians understand the unusual and sometimes surprising hormonal dynamics of this interesting period of life. REFERENCES
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[l ] Papanicolau,
G. and Shorr, E. (1936) The action of ovarian follicular hormone in the menopause as indicated by vaginal smears. Am. J. Obstet. Gynecol. 31.806831. [2] Waard, F. de, Pot, H., Tonckens-Nanninga, N., Baanders-van Halewijn, E. and Thijssen, J. (1972) Longitudinal studies on the phenomenon of postmenopausal estrogen production. Acta Cytol. 16213-218. i] Poortman, J., Thijssen, J.H. and Schwartz, F. (1974) Androgen production and conversion to estrogens in normal postmenopausal women and in selected breast carcinoma patients. J. Clin. Endocrinol. Metabol. 37, 101-109. I4 .] Asch, R.A. and Greenblatt, R.B. (1977) Steroidogenesis in the postmenopausal ovary. In: Clinics in obstetrics and gynecology, Vol. 4, no. 1, p. 85. Editors: R.B. Greenblatt and J. Studd, W.B. Saunders Company Ltd., London. (51 Masukawa, T. (1960) Vaginal smears in women past 40 years of age, with emphasis on their remaining hormonal activity. Obstet. Gynecol. 16,407-413. [6] Meisels, A. (1966) The menopause: a cytohormonal study. Acta Cytol. 10,49-55. [7] Kistner, R.W. (1973) The menopause. Clin. Obstet. Gynecol. 164,106-129. [8] Ziliotto, G. and Cortella, A. (1968) Aspetti della citologica vaginale in donne ultrasettientenm, i sulla presenza di repertia morfologia estrogenica. Acta Gerontol. 18, 181-l 91.
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