MATURWAS JOURNAL OF THE CLIMACTERIC & POSTMENOPAUSE ELSEVIER Maturitas 20 (1995) 191-198 Endometrial hyperplasia: efficacy of a new treatment with a vaginal cream containing natural micronized progesterone Pietro Affinito*“, Costantino Di Carloa, Pasquale Di Mauroa, Valerio Napolitano”, Carmine Nappi b aDeparrment of Obstetrics and Gynecology, School of Medicine, University “Federico II” of Naples, Via Pansini. 5, 80131 Napoli. Italy bDeparrment of Gynecological Endocrinology, School of Medicine, University of Turin, Turin, Ital) Received 16 June 1993; revision received 9 May 1994; accepted 13 May 1994 Abstract Seventy-eight premenopausal women affected by benign endometrial hyperplasia (60 simple and 18 complex) were treated from the 10th to the 25th day of the menstrual cycle with a vaginal cream containing 100 mg of natural micronized progesterone in polyethylene glycol base. The treatment lasted 3 months in 58 patients and 6 in the other 16 patients. Four patients were lost from the study. We observed a total of 67 complete regressions (90.5%) of which 58 (78.3%) occurred in the first 3 months and 9 (11.5%) after 6 months of treatment. Simple hyperplasia showed a significantly higher response to treatment in comparison with the complex type (P < 0.001). The most frequent endometrial pattern detected in the patients in whom hyperplasia regressed was of a secretive type. Recurrence of hyperplasia occurred in 1 out of 58 (1.72%) patients at the 3rd month and in 3 out of 49 (6.1%) patients at the 6th month after treatment. There were no significant differences between the two hystological groups in the percentage of recurrence. During treatment we observed a significant reduction of the amount, duration and frequency of the menstrual bleeding. Minimal side-effects were observed. In conclusion, for its effectiveness and safety, vaginal administration of natural micronized progesterone seems to be an interesting approach to benign endometrial hyperplasia, particularly indicated in women also affected by metabolic disorders. Keywords: Progesterone; Endometrial hyperplasia; Vaginal administration 1. Introduction It is generally reported that patients affected by benign endometrial hyperplasia may be satisfactorily treated with drugs that counteract the prolif* Corresponding author. 0378-5122/95/%09.50 0 1995 Elsevier Science Ireland SSDl 0378-5122(94)00851-W erative effect of estrogen on the endometrium. This hormonal approach induces regression of endometrial hyperplasia and is also able to control the frequently associated menometrorrhagia [l-6]. The main drugs available today for the treatment of endometrial hyperplasia such as danazol Ltd. All rights reserved 192 P. Affiniro et al. / Maturitas 20 (1995) 191-198 and synthetic progestins (in particular the C-19 nortestosterone derivatives) are reported to present physical, psychological and metabolic sideeffects [7,8]. This may discourage long term treatment with such drugs, particularly since many women with endometrial hyperplasia are obese and diabetic or affected by disturbances of liver function. On the contrary, it has been reported that natural progesterone is devoid of adverse metabolic effects [9-121. However, oral administration of natural progesterone is followed by a rapid and extensive intestinal and hepathic metabolization of the hormone, leading to low serum concentrations of the active steroid [ 131. Indeed, in one study, orally administered micronized progesterone failed to induce a full secretory endometrium when administered for 13 days in a dose of 100 mg three times a day [ 141. Conversely, the vaginal administration of natural micronized progesterone is followed by a very efficient absorption with longlasting concentrations due to the avoidance of the first pass effect through the liver [15-211. A vaginal cream containing natural micronized progesterone has recently become available. It might offer an alternative treatment with undeniable metabolic advantages. In order to better evaluate this point, we performed an open trial to evaluate the clinical and hystological effects of vaginal administration of natural micronized progesterone in patients affected by endometrial hyperplasia. 2. Materials and methods Premenopausal women (78) with benign endometrial hyperplasia were selected among those referred to our clinic for menometrorrhagia. The mean age of the patients (* SD.) was 48.6 f 2.17 years (range 42-51). The mean body mass index (BMI) (f S.D.) was 28.4 & 1.9 (range 24.8-32.5). Sixty-eight were parous and 6 were nulliparous. History of atypical uterine bleeding had lasted in 25 of the patients for more than 1 year and in the remaining 53 for more than 6 months. Patients with uterine fibroids or other gynecological pathologies were excluded from the study. Twenty patients (27%) were affected by other medical conditions such as mild obesity (85%), cardiovascular disease (50%) or diabetes mellitus treated with insulin (30%). None of the women had received hormonal treatment for menometrorrhagic symptomatology before starting progesterone therapy. The study had been approved by the ethics committee of the Medical School of University “Federico II” of Naples. The nature of the study was explained to each subject in detail and consent was received. Treatment consisted in the self-application (by means of a special graduated device) of 4 g of vaginal cream, each evening from the 10th to the 25th day of the menstrual cycle, for 3 cycles. The cream contained 2.5% natural micronized progesterone (100 mg/application) in polyethylene glycol base and was purchased from Angelini ACRAF (Rome, Italy). The patients who did not show a regression of endometrial hyperplasia after 3 cycles of treatment were treated for a further 3 months. Endometrial biopsies were performed by means of a Masterson cannula (4 mm diameter) (Gynova Inc., USA) before therapy and between ti 22nd and the 25th day of the third cycle of treatment. A period of 6 months of postreatment follow-up, with biopsies at the 3rd and 6th months was performed. Hyperplasia was classified according to the International Society of Gynecological Pathology [22]. All participants were instructed in the use of a menstrual diary card where they recorded the menstrual bleeding characteristics for the cycle immediately before treatment and for each cycle during treatment. The type of bleeding was evaluated by frequency, amount and duration. The frequency was calculated as the number of days between the bleeding episodes. The amount was classified, according to the patient, as normal, heavy or very heavy. The duration was assessed as days of bleeding for each cycle. Patients were asked to record all side-effects during treatment. Body weight was measured before and after therapy. Statistical analysis for the evaluation of regression and recurrence of hyperplasia according to the type and the amount of the menstrual bleeding, P. AfJiniro et al. / Maruritas 20 ( 1995) I91 - I98 193 Table 1 Complete regression of endometrial hyperplasia according to the type of hyperplasia Hyperplasia type Simple Complex Total Pretreatment Cycles of treatment 3 56 18 74 6 Total N W) N (“VI) N (“/;a) 50 8** 58 89.3 44.4 78.3 6 3*** 9 10.7 16.7 12.2 56 II 67 loo* ti1.1* 90 5 *P < 0.001, **+2 (11.1%) partial regression, ***+5 (27.8%) partial regression. before and during the treatment, was performed by the x*-test. Frequency and duration of menstrual bleeding, before and during therapy were compared with the Wilcoxon Matched pairs signed ranks test. Student’s t-test for unpaired and paired data was used for the evaluation of the differences in mean BMI and mean body-weight values, before and after treatment in the various histologic groups. 3. Results Before treatment, 60 patients (76.9%) presented simple hyperplasia and 18 patients (23.1%) complex hyperplasia. There were no significant differences in the BMI of the subjects in the two hystological groups. Four patients presenting simple hyperplasia failed to attend the first biopsy post-treatment and were lost from the trial. After 3 cycles of treatment, we observed the complete regression of hyperplasia in 58 (78.3%) patients. Hyperplasia persisted in 16 (21.6%) cases. However, a partial regression of the complex hyperplasia was seen in 2 (11.1%) patients. Nine (56.2%) of the 16 patients with persistence of hyperplasia at the 3rd month showed the complete regression of the endometrial lesion after 3 other cycles of treatment. At this time, only a partial regression of the picture of complex hyperplasia could be detected in 5 (31.2%) patients. Table 1 reports the percentage of regression according to the type of hyperplasia. The percentage of response of simple hyperplasia resulted significantly higher in comparison with the complex type (P < 0.001). Indeed, the picture of sim- ple hyperplasia completely regressed in 89.3% of cases after 3 cycles and in 100% after 6 cycles. On the contrary, the picture of complex hyperplasia completely reverted in 8 (44.4%) cases after 3 cycles and in 3 (16.7%) more patients after 6 cycles of therapy. Overall, the complex hyperplasia completely regressed in 61.1% of patients while 27.7% of cases showed a partial resolution. Only in 2 (11.1%) cases did we not observe any effect. The hystological findings in the patients showing regression of hyperplasia are reported in Table 2. The most frequent hystologic pattern (85”%)proved to be secretive endometrium. Proliferative endometrium was seen in the remaining 15% of the patients. Among the 67 patients who showed regression of hyperplasia, we were able to perform a followup endometrial biopsy in 58 cases at the 3rd month and in 49 cases at the 6th month of post-treatment. It was not possible to perform any endometrial assessment on the other patients as they failed to attend the follow-up visits. These patients were contacted by telephone and reported as being in good health. They failed to attend the follow-up visits for personal reasons. Table 2 Histological findings in the patients with regression of endometrial hyperplasia Endometrium N (‘Xi) Proliferative Secretive Atrophic IO 57 15 85 194 P. Affinito et al. /Maturitas Table 3 Recurrence of the endometrial hyperplasia according to the type of hyperplasia Type of hyperplasia before treatment Months of follow-up post-treatment 3rd Simple Complex Total 6th N W) N (W 0143 1115 1158 (6.6) (1.72) 2l36 1113 3149 (5.5) (7.7) (6.1) Recurrence of the endometrial lesion was detected in 1 (1.7%) patient at the 3rd month and in 3 (6.1%) patients at the 6th month (Table 3). These data, when correlated to the type of hyperplasia, did not show a significant difference in the percentage of recurrence between the two hystological groups. During the follow-up period, we detected a spontaneous regression of hyperplasia in 3 of the 5 patients who responded only partially 20 (1995) 191-198 to 6 cycles of progesterone treatment (2 at the 3rd and 1 at the 6th month). Progesterone treatment significantly reduced the percentage of patients who subjectively reported to have heavy or very heavy menstrual bleeding (P < 0.001) (Fig. 1). Indeed, before treatment, according to a subjective statement, 30% of patients presented heavy menstrual bleeding and the remaining 70% had very heavy menstrual bleeding. Starting from the 1st cycle of treatment, the percentage of patients with normal amount of menstrual bleeding began to progressively increase and that with heavy or very heavy amount of bleeding to decrease. Indeed, by the third cycle of treatment a normal amount of menstrual bleeding was reported by more than 80% of patients. A heavy amount of menstrual bleeding persisted in lo-20% of patients but none of them had a very heavy amount of bleeding (Fig. 1). The mean duration (A S.D.) of menstrual bleeding before treatment was 7.79 f 2.01 days. It reduced significantly during therapy (P < 0.001 ??Normal Before 2nd cycle 3rd cycle 4th cycle 5th cycle 0 Heavy E Vecy Heavy 6th cycle Treatment t p < 0.001 versus basal values Fig. I. Subjective statement of the amount of menstrual bleeding before and during treatment. P. Affiniro et al. /Mart&as 10 20 (1995) 191-198 195 - 9 -- a -7 -B 6 -+I s 5 ii ;" g 3 -2 -- 1 -O-1 before lth 2nd 4th 3rd 5th 6’h Cycle of treatment ?? tt p < 0.005 versus basal value p < 0.001 versus basal value Fig. 2. Duration of menstrual for cycles l-3 and 5 and P < 0.005 for cycles 4 and 6 vs. basal value). Indeed, for cycle 2-6 the mean duration of menstrual bleeding was approximately 4 days (Fig. 2). The mean frequency (& S.D.) of menstrual bleeding before treatment was 20.93 f 3.92 days. This parameter was also significantly improved during treatment (for all cycles during treatment P s 0.001 vs. basal value), resulting for cycles 2 to bleeding before and during treatment. 6 approximately 25 days (Fig. 3). Absence of progesterone withdrawal bleeding occurred only in 10 out of 270 total cycles (3.7%). The incidence of this event was higher during the first month in comparison to the following months of treatment. Minimal side-effects were observed (Table 4). We did not detect a significant weight-gain in the patients. Among the 74 patients who completed the treatment, 62 described it as perfectly accept- 35 30 -25 -B +I 20 -s ; 15-i lo-5 -- o+ before lth 2nd 3rd 4th 5th Cycle of treatment ?? p < 0.001 versus basal value Fig. 3. Frequency of menstrual bleeding before and during treatment. 6’h 196 P. Affinito et al. /Maturitas Table 4 Side-effects observed during treatment Type Headache Insomnia Mood disturbances Vulvovaginal itching Gastralgia N 8 6 5 4 3 (“W 10.8 8.1 6.1 5.4 4.0 able, 9 as slightly unpleasant and only 3 as extremely difficult to accept. All patients reported to have strictly followed our prescription. 4. Discussion The rationale for the use of progesterone in endometrial hyperplasia is supported by its antimitotic and antigrowth effects on endometrial cells. This is mainly achieved by a modulation of the growth-stimulatory effects of estrogen. Indeed, progesterone reduces the estrogen secretion (by acting either on hypothalamo-pituitary axis or directly at the site of synthesis). Moreover, it inhibits the estrogen-receptor replenishment and induces an increase of the estradiol metabolization to less active forms via effects on 17&hydroxysteroid dehydrogenase and sulforylase [23-261. It has also recently been hypothesized that progesterone may affect the secretion and action of estrogen-induced paracrine or autocrine growth factors and may directly antagonize the estrogen action at the postreceptor level [26]. In addition, progesterone might inhibit endometrial proliferation by a direct growth-inhibitory effect [26]. These effects, together with the shedding of the endometrium induced by progesterone withdrawal, prevent the estrogen prolonged stimulation of this tissue. In our study, we observed that vaginal administration of natural micronized progesterone reverted endometrial hyperplasia in 58 (78.3%) patients after 3 cycles of treatment. Nine (12.2%) other patients needed 6 cycles of therapy for regression. We found a total of 67 cases of complete regression (90.5%). During the period of follow-up we also detected 20 (1995) 191-198 a spontaneous regression of the hyperplasia in 3 of the 5 patients who were responsive only partially to 6 cycles of treatment. If these cases could be considered as a positive response to progesterone we would achieve a global regression in 94.5% of cases. Simple hyperplasia showed a more favourable pattern of response to treatment in comparison to the complex type. In most of the patients in whom hyperplasia disappeared, we have observed a secretive endometrium. This was considered as a full response to treatment. The finding of a proliferative endometrium may be interpreted as the consequence of inadequate dosage of progesterone administration, although a poor absorption of the hormone in these patients can not be excluded. In the follow-up period, we observed a recurrence of hyperplasia in 4 patients in a period of 6 months. This suggests that some patients may need repeated courses of treatment. The effectiveness of progesterone on the hyperplastic endometrium is also evident by the analysis of the menstrual bleeding characteristics. Indeed, we observed a reduction of the menstrual blood losses and the number of days of menstrual bleeding together with a synchronyzation of the sloughing of the endometrium. Even if these effects were evident from the first cycle, they showed to be more evident in the following cycles of treatment. After the first cycle of therapy, we also observed a dramatic reduction of the percentage of cycles with absence of progesterone withdrawal bleeding. Natural micronized progesterone may be administered by oral, intramuscular, rectal and vaginal routes. The vaginal route is, however, the most attractive for clinical supplementation due to its easy administration, the avoidance of the hepatic first pass effect and the large potential area for absorption [16]. In a preliminary study [20], the vaginal administration of 100 mg of natural micronized progesterone ensured long lasting plasma progesterone levels in perimenopausal anovulatory patients, which resulted in the range of values of a normal luteal phase. These pharmacokinetical data are in good accordance with those reported by Villanueva et al. [ 151 and by Kimzey et al. [21]. P. Affinito et al. / Maturitas In this study, confirming our previous data [ 121 on the tolerance of natural progesterone, we did not observe any important side-effects. The metabolic neutrality of natural progesterone on the lipid metabolism has been largely demonstrated. Indeed, it has been reported that natural progesterone does not reduce the plasma concentrations of HDL-cholesterol [9- 11,201. On the contrary, both danazol and synthetic progestins (either C- 1Pnortestosterone or C-2 1 derivates) may have a negative impact on the lipid profile as a consequence of their androgenic activity. Indeed, these drugs have been reported to reduce the concentration of HDL-cholesterol and in particular the HDL2 subfraction [27-311. In conclusion, vaginal administration of natural micronized progesterone showed to be clinically and hystologically effective without having important adverse effects. For these reasons, we believe that it may be considered as a serious alternative to synthetic progestins in clinical practice, particularly in women with metabolic disorders. 20 (199s) J, Riis BJ, Strom U, Christiansen C. Continuous estrogen-progestin treatment and serum lipoprotein in postmenopausal women. Br J Obstet Gynaecol 1987: 94: 130-5. 1111Moorjani 1121 [I31 1141 [I51 [I61 References plasia and carcinoma effects of progestins on hyperin situ of the endometrium. Cancer 1959; 12: 1106-22. Eichner E, Abellera M. Endometrial hyperplasia treated by progestins. Obstet Gynecol 1971; 38: 739-42. therapy in endometrial hyper131 Wentz WB. Progestin plasia. Gynecol Oncol 1974; 2: 362-7. 141 Kurman RJ, Kaminisky P-F, Norris H-J. The behaviour of endometrial hyperplasia. Cancer 1985; 56: 403-12. VM, Tabanelli S, Balducci M, [51 Bulletti C, Jasonni Fuschini G, Flamigni C. Danazol reverses endometrial hyperplasia to normal endometrium. Acta Eur Fertilitatis 1987; 18: 185-7. 161 Gal D, Edman CD, Vellios F, Forney P. Long-term effect of megestrol acetate in the treatment of endometrial hyperplasia. Am J Obstet Gynecol 1989; 146: 316-22. Contemporary concepts in 171 Schenken RS. Endometriosis: clinical management. Philadelphia: JB Lippincott, 1989: 175-83. 181 Whitehead MI, Hillard TC, Crook D. The role and use of progestogens. Obstet Gynecol 1990; 75: 59-76s. BG, von Schoultz B. Subfrac[91 Ottoson UB, Johansson tions of high-density lipoprotein cholesterol during estrogen replacement therapy: A comparison between progestogens and natural progesterone. Am J Obstet Gynecol 1985; 151: 746-50. PI 197 1101Jensen 1171 [II Kistner RW. Histological 191-198 S, DuPont A, Cabrie F et al. Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association witb utrogestan in menopausal women. J Clin Endocrinol Metab 1991; 73: 373-9. Nappi C, Aftinito P, Di Carlo C, Esposito G. Montemagno U. Double-blind controlled trial of progesterone vaginal cream treatment for cyclical mastodynia in women with benign breast disease. J Endoer Invest 1992; 15: 801-6. Maxson WB, Hargrove JT. Bioavailability of oral micronized progesterone. Fertil Steril 1985; 44: 622-6. Devroey P, Palermo G, Bourgain C, Van Waesberghe L, Smitz J, Van Steirteghem AC. Progesterone administration in patients with absent ovaries. Int J Fertil 1989; 34: 188-93. Villanueva B, Casper RF, Yen SSC. Intravaginal administration of progesterone: enhanced after estrogen treatment. Fertil Steril 1981; 35: 433-7. Price JH. Ismail H, Gorwill RH, Sarsa IR. Effect of the suppository base on progesterone delivery from the vagina. Fertil Steril 1983; 39: 490-3. Glazener CMA, Bailey I, Hull MGR. Effectiveness of vaginal administration of progesterone. Br J Obstet Gynaecol 1985; 92: 364-8. ZH, Zachariah NY. Bioavailability of pro1181 Chakmakjian gesterone with different modes of administration. J Reprod Med 1987; 32: 443-8. SJ, Freeman EW, Strauss JF, [I91 Myers ER, Sondheimer Rickels K. Serum progesterone levels following vaginal administration of progesterone during the luteal phase. Fertil Steril 1987; 47: 71-5. [2Ol Nappi C, Mercorio F, Afflnito P, Lepore L, Nicotra A, Montemagno U. Vaginal administration of progesterone (211 [221 1231 1241 in premenopausal women with endometrial hyperplasia. In: Genazzani AR, Petraglia F, Volpe A, eds. Research reports on gynecology and obstetrics. Carnforth: The Parthenon Publishing Group, 1990; 543-8. Kimzey LM. Gumowski J, Merriam GR. Grimes GJ, Nelson LM. Absorption of micronized progesterone from a nonliquefying vaginal cream. Fertil Steril 1991: 56: 995-6. Kurman RJ. Norris HJ. Endometrial hyperplasia and metaplasia. In: Kurman RJ ed. Blaustein’s pathology of the female genital tract. 3rd ed. New York: SpringerVerlag. 1987; 322-37. antagoHsueh AJW, Peck EJ, Clark JH. Progesterone nism of the oestrogen receptor and oestrogen-induced uterine growth. Nature 1975; 254: 337-9. Gurpide E, Marks C. Influence of endometrial 17& hydroxysteroid dehydrogenase activity on the binding of estradiol 252-5 to receptors. J Clin Endocrinol Metab 198 I: 52: 198 P. Affinito et al. /Maturitas [25] Tseng L, Liu HC. Stimulation of arylsulfotransferase activity by progestins in human endometrium in vitro. J Clin Endocrinol Metab 1981; 53: 418-21. 126) Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocr Rev 1990; 11: 266-301. [27] Bradley DD, Wingerd J, Petitti DB. Serum high density lipoprotein cholesterol in women using oral contraceptives, estrogens and progestins. N Engl J Med 1978; 229: 17-20. [28] Allen JK, Fraser IS. Cholesterol, high density lipoprotein and danazol. J Clin Endocrinol Metab 1981; 53: 149-52. 20 (1995) 191-198 [29] Himoven E, Malkonen M, Manninen V. Effects of different progestogens on lipoproteins during postmenopausal replacement therapy. N Engl J Med 1981; 304: 560-3. [30] Luciano AA, Hauser KS, Chapler FK, Davis WA, Wallace RB. Effects of danazol on plasma lipid and lipoprotein levels in healthy women and in women with endometriosis. Am J Obstet Gynecol 1983; 145: 422-6. [31] Fahraeus L, Larsson-Cohn U, Wallentin L. L-norgestrel and progesterone have different influences on plasma lipoproteins. Eur J Clin Invest 1983; 30: 447-53.