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An intrauterine progesterone contraceptive system (52 mg) used in pre- and peri-menopausal patients with endometrial hyperplasia
Maturitas, 4 (1982) 73-79 Elsevier Biomedical Press
73
An intrauterine progesterone contraceptive system (52 mg) used in pre- and peri-menopausal patients with endometrial hyperplasia A. Volpe ‘, A. Botticelli 2, M. Abrate ‘, E. Dalla Vecchia ‘, M. Mantovani ‘, C. Carani 3, A. Grass0 ‘, V. Mazza ’ and G.C. Di Renzo ’ Depurtment of Ohestetrics und Gynecologv ‘, Institute of Pathological Anutomy ‘, Institute of Endocrinology 3, Unioersi
12 June 198 1; accepted
after revision 6 January
1982)
An intrauterine progesterone contraceptive system @PCS) (52 mg) was inserted in 25 women with cystic endometrial hyperplasia. Among these women, 11 complained of heavy climacteric symptoms and also received an oestrogen replacement therapy consisting of conjugated oestrogens (0.625 mg/day) administered cyclically for 3 out of 4 wk. Prior to the therapy and after 6 mth of treatment, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oestrone (Et) and oestradiol (E,) plasma levels were measured and endometrial histology was evaluated. In the women receiving IPCS treatment alone, there were no significant changes in FSH, LH, PRL, E, and E, plasma levels. However, there were remarkable changes found in their endometrial histology. In the remaining women receiving both treatments, there was a sharp decrease in FSH and LH plasma levels and an increase in Et and Es plasma levels, while the prolactin levels remained unchanged. With the exception of two of these women. the endometrial histology changed remarkably. The endometrial morphology of the two exceptions remained unchanged. All climacteric symptoms disappeared after the administration of both IPCS and the oestrogen replacement therapy. The remarkable changes which did occur in the endometrial histology resulted in a less active glandular epithelium and stromal decidual formation, thus proving a useful effect of treatment. (Key words:
IUD. Progesterone.
Endometrium,
Hyperplasia)
introduction It is now apparent that oestrogens normally stimulate endometrial proliferation while progesterone limits endometrial growth. Prolonged and unbalanced oestrogenie stimuli frequently occur during the pre-menopause. Accordingly, this can cause excessive endometrial proliferation, leading to hyperplasia of various degrees,
Address for correspondence: Dr. A. Volpe, Clinica de1 Pozzo, 71. Modena, Italy.
0378-5122/82/0000-0000/$2.75
Q 1982 Elsevier
Ostetrica
Biomedical
e Ginecologica,
Press
Policlinico
Universitario.
Via
14
frequently associated with menometrorrhagia. In these cases, treatment usually includes the combined administration of oestrogens and progestogens, progestogens alone, or a D and C; the last being both a therapeutic and a diagnostic aid. The availability of an IUD which releases progesterone suggests the possibility of using this device in patients with endometrial hyperplasia. The rationale of this is the fact that there, is evidence for the efficacy of a directly applied progesterone or progestogens to endometrial hyperplasia and adenocarcinoma [l-4]. There is also evidence of the usefulness of topic progestogens as a pre-hysterectomy or pre-radium packing treatment for women with stage IA endometrial cancer [5]. This study was aimed at proving the usefulness of combining an intrauterine progesterone contraceptive system (IPCS) with an oestrogen replacement therapy to relieve patients of their severe climacteric symptoms and cystic endometrial hyperplasia.
Patients and methods A total of 25 women, ranging between the ages of 41 and 54 yr, had cystic endometrial hyperplasia and were willing to undergo IPCS treatment. Among these women, 11 complained of severe climacteric symptoms and were also given oestrogen replacement therapy (conjugated oestrogens - Premarin, administered cyclically: 0.625 mg/day, 3 out of 4 wk). These 11 women, receiving both treatments, were in the peri-menopausal period, aged 47-54 yr; the 14 women receiving only JPCS treatment were in the pre-menopausal period, aged 41-48 yr. Before treatment, the average weight of the per&menopausal women was 68 (-~9) kg, and of the premenopausal women, 63 (* 11) kg. Systolic blood pressure before treatment was 125 f. 15 and 110 -C 20, respectively. The weight and blood pressure were measured again after treatment. All 25 women experienced irregular menstruation before treatment and none was amenorrhoeic more than 6 mth. Prior to and after 6 mth of treatment, plasma follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oestradiol (E,), and oestrone (E,) levels were measured and endometrial biopsies were evaluated. Blood sampling was done either 6-10 days after a D and C or in the early follicular phase. Endometrial tissues were obtained by a D and C before IPCS insertion and by vacuum curettage after IPCS removal. The endometrial specimens were examined for either cellular or structural findings in the glands and stroma (always by a single observer). FSH, LH and PRL levels were measured by radioimmunoassay (Biodata, Milan, Italy). The normal range for FSH is 5-20 mIU/mg, 5-15 mu/ml for LH and 5-20 mg/ml for PRL. Intra-assay variations are 5.4, 5.8, and 6.1% respectively. Inter-assay variations are 9.1, 7.6 and 10.88, respectively. Plasma 17/3-oestradiol (Ea) and oestrone (E,) levels were also measured by radioimmunoassay. The procedure involved extraction of plasma with ether and Sephadex LH-20 chromatography for separation of E, and Ea. The assay employed highly specific antisera, raised in rabbits either against 6-carboxymethylaxin-oestradiol conjugated to human thyroglobulin or against oestrone 3-hemosuccinate conjugated to bovine serum albumin
(Sorin-Biomedica, Saluggia, Italy). Separation of the antibody bound and free oestrogens was accomplished with dextran-coated characoal. The normal range in the follicular phase for E, is 22- 120 pg/ml, and 24- 110 pg/ml for E,. Intra-assay variations are 7 and 7.58,’ respectively, and inter-assay variations are 16 and 15.5%. In the 11 peri-menopausal women with climacteric complaints, the symptoms were evaluated according to the Kuppermann Index (KI) [6]. The IUD (the Progestasert IUD was supplied by the Alza Corporation, Palo Alto, Calif.) used in this study contained 52 mg of progesterone, released continuously at an average rate of 65 pg/day. All of the 25 women in this investigation completed a menstrual blood loss record for each 2 wk period which tabulated the amount of duration of blood loss. Particular attention has been given to evidence of inflammation, decidualization, suppression or proliferation of the endometrium and presence and condition of ciliated cells.
Results Hormonal analysis did not indicate any significant change in plasma levels of FSH, LH or PRL in the 14 women treated only with IPCS. In the 11 patients treated with IPCS plus oestrogen replacement therapy only the prolactin levels did not change significantly. FSH and (less markedly) LH levels decreased sharply, from 75
BEFORE
IPCB
INSERTION
AFTER
IPCS
INSERTION
140.
12Q
ES on/ml
120_
100.
SO_
00,.
40_
20_
Fig. I. Plasma FSH, LH, PRL, E,, E, levels in 14 women (aged 41-48 insertion.
1
Et PO,ml
yr) before and after 6 mth
of IPCS
76
100
BEFORE
AFTER
TREATMENT
TREATMENT
80
T
I
60
r
40
20
1
Fig. 2. Plasma FSH, LH, PRL, Es, E, levels and Kuppermann Index (KI) in 1I women (aged treated with conjugated oestrogens (0.625 mg/day) for 3 wk out of 4. plus IPCS insertion.
47-54
yr)
and 82 mIU/ml to 42.7 and 62.8 mIU/ml, respectively. There was an increase in E, and E, levels from 18 * 5 and 37 * 10 pg/ml 61 k 13 and 52 * 13 pg/ml, respectively (Fig. 1). All climacteric symptoms disappeared in the 11 women as shown by the sharp decrease of the KI (Fig. 2). In 2 of the 11 patients receiving both treatments, the endometrial morphology did not change after 6 mth of treatment (Table I). In the other 9 women as well as in the 14 women treated with IPCS alone, remarkable changes in endometrial histology were observed with findings of less active glandular epithelium, stromal decidua formation, secretory activity and endometrial suppression (Tables I and II).
TABLE
I
HISTOLOGICAL FINDINGS IN I I WOMEN TREATMENT WITH IPCS PLUS CONJUGATED
WITH ENDOMETRIAL OESTROGENS.
Endometrial
survey of histological
morphology
Qualitative Increase
No. of glands Size of glands Proliferative glandula pattern Nuclear pseudo-stratification Secretory activity Stromal activity Stromal edema Decidual change + =Light;
+ + =mild;
+ + + =intense.
(2+ f. 2+) (4+ +. 3+) (2+ +, 7+) (2+)
8 (8+) l,(l+)
AFTER
changes
Decrease 4, 7. 9, 2.
3 (3+) 8 (5+ +, 3+)
HYPERPLASIA
No change 7 4
2 9 3 IO 8 3
TABLE
II
HISTOLOGICAL FINDINGS IN 14 WOMEN TREATMENT WITH IPCS ALONE. Endometrial
Qualitative
morphology
WITH
survey of histological
Increase No. of glands Size of glands Proliferative glandula pattern Nuclear pseudo-stratification Secretory activity Stromal activity Stromal edema Decidual change + =Light;
+ + =mild;
ENDOMETRIAL
AFTER
changes
Decrease
No change
8,(4+++,4++) lO,(4+++,6++) 10,(6++,4++) 6, (2+ +> 4+)
6 4 4 8 2 10 6 2
12 4, (4-c) 8, (4+ +, 4+) 12,(4+++,4++,4+)
HYPERPLASIA
-
+ + + =intense.
There was no change in arterial blood pressure or body weight after 6 mth of therapy in all women. No expulsion of the IPCS occurred, nor was there any troublesome cramping reported. Spotting was reported in 36% of the women (4 pre-menopausal and 3 peri-menopausal) during the first and second month of treatment. In one pre-menopausal patient irregular spotting lasted 4 mth. Only one pre-menopausal patient experienced intermenstrual bleeding during the first month of treatment, which did not necessitate IUD removal.
Discussion In 14 patients treated with IPCS alone, no significant change in plasma hormone levels was observed, thus confirming the results of Spellacy and Buhi [7] who found no change in plasma prolactin in 26 women after 6 and 12 mth of using a progesterone-type IUD. In the present study metabolic parameters were not evaluated; therefore, systemic effects related to the treatment schedule cannot be excluded. In another study of IPCS users, no change in triglyceride or cholesterol plasma levels were reported (81. Although the micro-dose amounts of progesterone released by this system have no measurable systematic effect [9,10], the high local intq-uterine concentration has an astonishing influence on endometrial morphology. Reversing hyperplasia to a normal secretory pattern was also noted when oral or [ 11,121. There is a scientific basis for intra-muscular progesterone was administered the efficacy of topical progesterone/progestogens in averting endometrial tissue overgrowth. Kohorn and Thao [I] reported a direct, dose-related toxic effect of progesterone on endometrial adenocarcinoma cells in tissue culture. In human studies [5], intra-uterine treatment with medroxyprogesterone acetate (MAP) has been evaluated as a pre-hysterectomy treatment for women diagnosed with stage IA
78
endometrial cancer; intrauterine MAP for 4 to 5 wk pre-operatory destroyed the endometrial cancer in 60% of these women (all were without myometrial invasion). The suppressed endometrium seen with the progesterone releasing system, in many ways, is similar to that seen in women using the combined oestrogen-progestogen oral contraceptives, especially those containing large amounts of progestogen [ 131. The changes are also similar to those described in women receiving depot progestogens [ 141: the glandular involution’ and vascular alterations are almost identical. The stromal response also shows many similarities but the pre-decidual reaction is not only more frequent but also more diffuse. In this study cystic hyperplasia disappeared in all patients treated with IPCS alone. Basham, Feanca and De Lima (unpubl. obs.) have used intra-uterine progesterone in treating 8 women with. adenomatous hyperplasia. In the course of treatment, all 8 women had a reversion to the normal endometrial pattern. Glandular atrophy and decidual reaction was also observed by Wan et al. [ 15). In the 11 patients with heavy climacteric symptoms, the association of IPCS with oestrogen replacement therapy has resulted in a complete relief of climacteric symptoms, confirming the efficacy of oestrogen therapy in these cases [16]. Conjugated oestrogens significantly decreased plasma gonadotrophin levels, mainly FSH [ 171, and increased E, and E, levels. No change was observed in prolactin levels, thereby supporting this slight effect of conjugated oestrogens on prolactin secretion, as we reported previously [ 181. The IPCS insertion resulted in a balance of oestrogen effect on the endometrium, modifying histologic features in 9 out of 11 women. The endometrial histological finding was unchanged in 2 of the 11 patients treated with IPCS plus oestrogens. This could be explained by the anti-oestrogenic effect of progesterone. On the contrary, in vitro studies have shown that the addition of high concentrations of oestradiol potentiated the inhibitory effects of progesterone in vitro [2,19]. The discrepancy in these observations warrants further investigations. The only frequent side effect of IPCS users in this study was spotting during the first and the second month of treatment. From these findings IPCS treatment seems to cause more frequent inter-menstrual spotting, mainly during the first months of treatment, while also being related to a decrease of menstrual blood loss [20,21]. From our results it seems that short-term application of IPCS has useful effects on endometrial hyperplasia and in post-menopausal patients treated with an oestrogen replacement therapy. We feel it is worthwhile to continue these studies in order to evaluate the long-term effects of IPCS.
References Kohom, E.J. and Thao, R. (1968) The effect of hormones on endometrial carcinoma in organ culture. J. Obstet. Gynaecol. Br. Commonw. 75, 1262-1267. Nordqvist, S. (1970) Survival and hormonal repsonsiveness of endometrial carcinoma in organ culture. Acta Obstet. Gynaecol. Stand. 49. 275-283. Nordqvist, S. (1970) The synthesis of DNA and RNA in normal human endometrium in short-term incubation in vitro and its response to oestradiol and progesterone. J. Endocrinol. 48. 17-28.
4 Nordqvist, S. (I 972) Effect of progesterone on human experimental carcinoma in different experimental systems. Acta Obstet. Gynaecol. Stand. Suppl. 19. 25-29. 5 Hustin, J. (1970)Endometrial carcinoma and synthetic progestogens: results of intrauterine treatment. J. Obstet. Gynaecol. Br. Commonw. 77, 915-921. 6 Kuppermann, H.S., Wetheler, B.B. and Blatt, M.H.G. (1952) Contemporary therapy of the menopausal syndrome. J. Am. Med. Assoc. 171, 1627-1637. 7 Spellacy, W.N. and Buhi, W.C. (1979) A prospective study of plasma prolactin levels in women using the progesterone releasing intrauterine device (IUD). Contraception 19, 91-94. 8 Spellacy, W.N., Buhi, W.C. and Birk, S.A. (1978) Studies of carbohydrate and lipid metabolism in women using the progesterone intrauterine device for six months: blood glucose, insulin, cholesterol and triglyceride levels. Fertil. Steril. 29, 505-508. 9 Martinez-Manautou, J., Aznar, R., Maqueo, M. and Pharriss, B. Cited in: Martinez-Manautou, J., Maqueo, M., Aznar, R., Pharriss, B.B. and Zaffaroni, A. (1974) Endometrial morphology in women exposed to uterine systems releasing progesterone. Am. J. Obstet. Gynecol. 15, 175- 179. 10 Pharriss, B.B., Erickson, R., Bashaw, J., Hoff, S., Place, V.A. and Zaffaroni, A. Cited in: MartinezManautou, J., Maqueo, M., Aznar, R., Pharris, B.B. and Zafaroni, A. (1974) Endometrial morphology in women exposed to uterine systems releasing progesterone. Am. J. Obstet. Gyned., 15, 175-179. I 1 Wenti, W.B. (1964) Effect of a progestational agent on endometrial hyperplasia and endometrial cancer. Obstet. Gynaecol. 24, 370-375. 12 King, R.J.B.. Whitehead, M.I., Campbell, S. and Minardi, J. (1979) Effect on estrogens and progestinic treatment on endometrium from post-menopausal women. Cancer Res. 39, 1094- 1101. 13 Martinez-Manautou, J., Maqueo, M., Aznar, R., Pharris, B.B. and Zaffaroni, A. (1974) Endometrial , morphology in women exposed to uterine systems releasing progesterone. Am. J. Obstet. Gynecol. 15, 175-179. of endometrial I4 Ronald, M., Martin, J., Clyman, I., Decker, A. and Ober, W.M. (1964)Classification response to synthetic progestogen-estrogen compounds. Fertil. Steril. IS, l43- 163. IS Wan, S.L., Hsu, Y.C., Ganguly. M. and Bigelow, B. (1977) Effects of the progestasert on the menstrual pattern. ovarian steroids and endometrium. Contraception 16,417-434. 16 Campbell, S. and Whitehead. MI. (1980) Double-blind studies on the effects of natural oestrogens on post-menopausal women: a follow-up report. In: Menopause and postmenopause, pp. 75-84. Editors: N. Pasetto, R. Paoletti and J.L. Ambnts. MTP Press, Lancaster. I7 Franchimont, P.. Legros. J.J. and Meutice, J. (1972) Effect of several estrogens on serum gonadotrophin levels in post-menopausal women. Horm. Metab. Res. 4. 288-295. I8 Volpe, A., Pellegri, P.P.. Boselli, F.. Mazza. V., Grasso, A., Maccarrone, G., Goles, A. and Montanari, G.D. (1979) Prolactin in post-menopausal endometrial hyperplasia and adenocarcinoma. In: The Menopause and post-menopause, pp. 1l3- 125. Editors: N. Pasetto, R. Paoletti and J.L. Ambrus. MTP Press, Lancaster. I9 Anderson, D.G. (1972) The possible mechanism of action of progestins on endometrial adenocarcinema. Am. J. Obstet. Gynaecol. 113, 195-21 I. 20 Rybo, C. (1980) IUDs and endometrial bleeding: qualitative and quantitative agents. In: IUD Press, pathology and management, pp. 63-73. Editors: E.S.E. Hafez and W.A.A. van OS. MTP Lancaster. 2 1 Guillebaud. J. and Bonnar, J. (1980) Estimation and prediction of IUD related increased duration and amount of menstrual blood loss. In: Pathology and Management, pp. 75-92. Editors: E.S.E. Hafez and W.A.A. van OS. MTP Press. Lancaster.
73
An intrauterine progesterone contraceptive system (52 mg) used in pre- and peri-menopausal patients with endometrial hyperplasia A. Volpe ‘, A. Botticelli 2, M. Abrate ‘, E. Dalla Vecchia ‘, M. Mantovani ‘, C. Carani 3, A. Grass0 ‘, V. Mazza ’ and G.C. Di Renzo ’ Depurtment of Ohestetrics und Gynecologv ‘, Institute of Pathological Anutomy ‘, Institute of Endocrinology 3, Unioersi
12 June 198 1; accepted
after revision 6 January
1982)
An intrauterine progesterone contraceptive system @PCS) (52 mg) was inserted in 25 women with cystic endometrial hyperplasia. Among these women, 11 complained of heavy climacteric symptoms and also received an oestrogen replacement therapy consisting of conjugated oestrogens (0.625 mg/day) administered cyclically for 3 out of 4 wk. Prior to the therapy and after 6 mth of treatment, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oestrone (Et) and oestradiol (E,) plasma levels were measured and endometrial histology was evaluated. In the women receiving IPCS treatment alone, there were no significant changes in FSH, LH, PRL, E, and E, plasma levels. However, there were remarkable changes found in their endometrial histology. In the remaining women receiving both treatments, there was a sharp decrease in FSH and LH plasma levels and an increase in Et and Es plasma levels, while the prolactin levels remained unchanged. With the exception of two of these women. the endometrial histology changed remarkably. The endometrial morphology of the two exceptions remained unchanged. All climacteric symptoms disappeared after the administration of both IPCS and the oestrogen replacement therapy. The remarkable changes which did occur in the endometrial histology resulted in a less active glandular epithelium and stromal decidual formation, thus proving a useful effect of treatment. (Key words:
IUD. Progesterone.
Endometrium,
Hyperplasia)
introduction It is now apparent that oestrogens normally stimulate endometrial proliferation while progesterone limits endometrial growth. Prolonged and unbalanced oestrogenie stimuli frequently occur during the pre-menopause. Accordingly, this can cause excessive endometrial proliferation, leading to hyperplasia of various degrees,
Address for correspondence: Dr. A. Volpe, Clinica de1 Pozzo, 71. Modena, Italy.
0378-5122/82/0000-0000/$2.75
Q 1982 Elsevier
Ostetrica
Biomedical
e Ginecologica,
Press
Policlinico
Universitario.
Via
14
frequently associated with menometrorrhagia. In these cases, treatment usually includes the combined administration of oestrogens and progestogens, progestogens alone, or a D and C; the last being both a therapeutic and a diagnostic aid. The availability of an IUD which releases progesterone suggests the possibility of using this device in patients with endometrial hyperplasia. The rationale of this is the fact that there, is evidence for the efficacy of a directly applied progesterone or progestogens to endometrial hyperplasia and adenocarcinoma [l-4]. There is also evidence of the usefulness of topic progestogens as a pre-hysterectomy or pre-radium packing treatment for women with stage IA endometrial cancer [5]. This study was aimed at proving the usefulness of combining an intrauterine progesterone contraceptive system (IPCS) with an oestrogen replacement therapy to relieve patients of their severe climacteric symptoms and cystic endometrial hyperplasia.
Patients and methods A total of 25 women, ranging between the ages of 41 and 54 yr, had cystic endometrial hyperplasia and were willing to undergo IPCS treatment. Among these women, 11 complained of severe climacteric symptoms and were also given oestrogen replacement therapy (conjugated oestrogens - Premarin, administered cyclically: 0.625 mg/day, 3 out of 4 wk). These 11 women, receiving both treatments, were in the peri-menopausal period, aged 47-54 yr; the 14 women receiving only JPCS treatment were in the pre-menopausal period, aged 41-48 yr. Before treatment, the average weight of the per&menopausal women was 68 (-~9) kg, and of the premenopausal women, 63 (* 11) kg. Systolic blood pressure before treatment was 125 f. 15 and 110 -C 20, respectively. The weight and blood pressure were measured again after treatment. All 25 women experienced irregular menstruation before treatment and none was amenorrhoeic more than 6 mth. Prior to and after 6 mth of treatment, plasma follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), oestradiol (E,), and oestrone (E,) levels were measured and endometrial biopsies were evaluated. Blood sampling was done either 6-10 days after a D and C or in the early follicular phase. Endometrial tissues were obtained by a D and C before IPCS insertion and by vacuum curettage after IPCS removal. The endometrial specimens were examined for either cellular or structural findings in the glands and stroma (always by a single observer). FSH, LH and PRL levels were measured by radioimmunoassay (Biodata, Milan, Italy). The normal range for FSH is 5-20 mIU/mg, 5-15 mu/ml for LH and 5-20 mg/ml for PRL. Intra-assay variations are 5.4, 5.8, and 6.1% respectively. Inter-assay variations are 9.1, 7.6 and 10.88, respectively. Plasma 17/3-oestradiol (Ea) and oestrone (E,) levels were also measured by radioimmunoassay. The procedure involved extraction of plasma with ether and Sephadex LH-20 chromatography for separation of E, and Ea. The assay employed highly specific antisera, raised in rabbits either against 6-carboxymethylaxin-oestradiol conjugated to human thyroglobulin or against oestrone 3-hemosuccinate conjugated to bovine serum albumin
(Sorin-Biomedica, Saluggia, Italy). Separation of the antibody bound and free oestrogens was accomplished with dextran-coated characoal. The normal range in the follicular phase for E, is 22- 120 pg/ml, and 24- 110 pg/ml for E,. Intra-assay variations are 7 and 7.58,’ respectively, and inter-assay variations are 16 and 15.5%. In the 11 peri-menopausal women with climacteric complaints, the symptoms were evaluated according to the Kuppermann Index (KI) [6]. The IUD (the Progestasert IUD was supplied by the Alza Corporation, Palo Alto, Calif.) used in this study contained 52 mg of progesterone, released continuously at an average rate of 65 pg/day. All of the 25 women in this investigation completed a menstrual blood loss record for each 2 wk period which tabulated the amount of duration of blood loss. Particular attention has been given to evidence of inflammation, decidualization, suppression or proliferation of the endometrium and presence and condition of ciliated cells.
Results Hormonal analysis did not indicate any significant change in plasma levels of FSH, LH or PRL in the 14 women treated only with IPCS. In the 11 patients treated with IPCS plus oestrogen replacement therapy only the prolactin levels did not change significantly. FSH and (less markedly) LH levels decreased sharply, from 75
BEFORE
IPCB
INSERTION
AFTER
IPCS
INSERTION
140.
12Q
ES on/ml
120_
100.
SO_
00,.
40_
20_
Fig. I. Plasma FSH, LH, PRL, E,, E, levels in 14 women (aged 41-48 insertion.
1
Et PO,ml
yr) before and after 6 mth
of IPCS
76
100
BEFORE
AFTER
TREATMENT
TREATMENT
80
T
I
60
r
40
20
1
Fig. 2. Plasma FSH, LH, PRL, Es, E, levels and Kuppermann Index (KI) in 1I women (aged treated with conjugated oestrogens (0.625 mg/day) for 3 wk out of 4. plus IPCS insertion.
47-54
yr)
and 82 mIU/ml to 42.7 and 62.8 mIU/ml, respectively. There was an increase in E, and E, levels from 18 * 5 and 37 * 10 pg/ml 61 k 13 and 52 * 13 pg/ml, respectively (Fig. 1). All climacteric symptoms disappeared in the 11 women as shown by the sharp decrease of the KI (Fig. 2). In 2 of the 11 patients receiving both treatments, the endometrial morphology did not change after 6 mth of treatment (Table I). In the other 9 women as well as in the 14 women treated with IPCS alone, remarkable changes in endometrial histology were observed with findings of less active glandular epithelium, stromal decidua formation, secretory activity and endometrial suppression (Tables I and II).
TABLE
I
HISTOLOGICAL FINDINGS IN I I WOMEN TREATMENT WITH IPCS PLUS CONJUGATED
WITH ENDOMETRIAL OESTROGENS.
Endometrial
survey of histological
morphology
Qualitative Increase
No. of glands Size of glands Proliferative glandula pattern Nuclear pseudo-stratification Secretory activity Stromal activity Stromal edema Decidual change + =Light;
+ + =mild;
+ + + =intense.
(2+ f. 2+) (4+ +. 3+) (2+ +, 7+) (2+)
8 (8+) l,(l+)
AFTER
changes
Decrease 4, 7. 9, 2.
3 (3+) 8 (5+ +, 3+)
HYPERPLASIA
No change 7 4
2 9 3 IO 8 3
TABLE
II
HISTOLOGICAL FINDINGS IN 14 WOMEN TREATMENT WITH IPCS ALONE. Endometrial
Qualitative
morphology
WITH
survey of histological
Increase No. of glands Size of glands Proliferative glandula pattern Nuclear pseudo-stratification Secretory activity Stromal activity Stromal edema Decidual change + =Light;
+ + =mild;
ENDOMETRIAL
AFTER
changes
Decrease
No change
8,(4+++,4++) lO,(4+++,6++) 10,(6++,4++) 6, (2+ +> 4+)
6 4 4 8 2 10 6 2
12 4, (4-c) 8, (4+ +, 4+) 12,(4+++,4++,4+)
HYPERPLASIA
-
+ + + =intense.
There was no change in arterial blood pressure or body weight after 6 mth of therapy in all women. No expulsion of the IPCS occurred, nor was there any troublesome cramping reported. Spotting was reported in 36% of the women (4 pre-menopausal and 3 peri-menopausal) during the first and second month of treatment. In one pre-menopausal patient irregular spotting lasted 4 mth. Only one pre-menopausal patient experienced intermenstrual bleeding during the first month of treatment, which did not necessitate IUD removal.
Discussion In 14 patients treated with IPCS alone, no significant change in plasma hormone levels was observed, thus confirming the results of Spellacy and Buhi [7] who found no change in plasma prolactin in 26 women after 6 and 12 mth of using a progesterone-type IUD. In the present study metabolic parameters were not evaluated; therefore, systemic effects related to the treatment schedule cannot be excluded. In another study of IPCS users, no change in triglyceride or cholesterol plasma levels were reported (81. Although the micro-dose amounts of progesterone released by this system have no measurable systematic effect [9,10], the high local intq-uterine concentration has an astonishing influence on endometrial morphology. Reversing hyperplasia to a normal secretory pattern was also noted when oral or [ 11,121. There is a scientific basis for intra-muscular progesterone was administered the efficacy of topical progesterone/progestogens in averting endometrial tissue overgrowth. Kohorn and Thao [I] reported a direct, dose-related toxic effect of progesterone on endometrial adenocarcinoma cells in tissue culture. In human studies [5], intra-uterine treatment with medroxyprogesterone acetate (MAP) has been evaluated as a pre-hysterectomy treatment for women diagnosed with stage IA
78
endometrial cancer; intrauterine MAP for 4 to 5 wk pre-operatory destroyed the endometrial cancer in 60% of these women (all were without myometrial invasion). The suppressed endometrium seen with the progesterone releasing system, in many ways, is similar to that seen in women using the combined oestrogen-progestogen oral contraceptives, especially those containing large amounts of progestogen [ 131. The changes are also similar to those described in women receiving depot progestogens [ 141: the glandular involution’ and vascular alterations are almost identical. The stromal response also shows many similarities but the pre-decidual reaction is not only more frequent but also more diffuse. In this study cystic hyperplasia disappeared in all patients treated with IPCS alone. Basham, Feanca and De Lima (unpubl. obs.) have used intra-uterine progesterone in treating 8 women with. adenomatous hyperplasia. In the course of treatment, all 8 women had a reversion to the normal endometrial pattern. Glandular atrophy and decidual reaction was also observed by Wan et al. [ 15). In the 11 patients with heavy climacteric symptoms, the association of IPCS with oestrogen replacement therapy has resulted in a complete relief of climacteric symptoms, confirming the efficacy of oestrogen therapy in these cases [16]. Conjugated oestrogens significantly decreased plasma gonadotrophin levels, mainly FSH [ 171, and increased E, and E, levels. No change was observed in prolactin levels, thereby supporting this slight effect of conjugated oestrogens on prolactin secretion, as we reported previously [ 181. The IPCS insertion resulted in a balance of oestrogen effect on the endometrium, modifying histologic features in 9 out of 11 women. The endometrial histological finding was unchanged in 2 of the 11 patients treated with IPCS plus oestrogens. This could be explained by the anti-oestrogenic effect of progesterone. On the contrary, in vitro studies have shown that the addition of high concentrations of oestradiol potentiated the inhibitory effects of progesterone in vitro [2,19]. The discrepancy in these observations warrants further investigations. The only frequent side effect of IPCS users in this study was spotting during the first and the second month of treatment. From these findings IPCS treatment seems to cause more frequent inter-menstrual spotting, mainly during the first months of treatment, while also being related to a decrease of menstrual blood loss [20,21]. From our results it seems that short-term application of IPCS has useful effects on endometrial hyperplasia and in post-menopausal patients treated with an oestrogen replacement therapy. We feel it is worthwhile to continue these studies in order to evaluate the long-term effects of IPCS.
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