l FERTLTY AND STERLTY Vol. 62, 6, December 1994 Copyright e 1994 The American Fertility Society Printed on acid-free paper in U. S. A. Endometrial ablation for refractory postmenopausal bleeding with continuous hormone replacement therapy Lyman B. Spaulding, M.D., Ph.D.* Department of Obstetrics and Gynecology, St. Joseph Hospital, and Colorado Permanent Medical Group, Denver, Colorado Objective: To determine the role of endometrial ablation and benign uterine pathology in menopausal women with refractory bleeding who were treated with continuous hormone replacement therapy (HRT). Design: Prospective. Setting: Health maintenance organization. Patients: One hundred seventy-one menopausal women with an average age of 55 were enrolled in an algorithm of continuous HRT, endometrial biopsy for bleeding with initial therapy, doubling of the progestin dose, hysteroscopy, and endometrial resection-ablation for continued refractory bleeding. ntervention: Endometrial biopsy, hormone manipulation, office hysteroscopy, and hysteroscopic resection -ablation. Main Outcome Measures: Refractory menopausal bleeding and benign uterine pathology. Results: One hundred sixty-two women completed the study. One hundred six (65.4%) remained free of bleeding at the end of the initial 3 months of hormone therapy. Fifty-six (34.6%) had one or more bleeding episodes and required office biopsy and an increase in dosage of progestin. Bleeding ceased in an additional 35 (87%) while 21 (13%) continued to bleed. Those patients underwent endometrial resection-ablation. Surgical specimen demonstrated endometrial polyps, submucous leiomyomas, and adenomyosis in 85.7% of the cases. All patients are now free of bleeding. Conclusion: Many women become amenorrheic on the initial dose of continuous HRT; however, if bleeding continues, most stop when the dosage of progestin is doubled. Benign uterine pathology may cause refractory bleeding in a small group of patients but may be eliminated with endometrial resection-ablation. Fertil Steril1994;62:1181-1185 Key Words: Hormone replacement therapy, menopausal bleeding, endometrial ablation The beneficial effects of estrogen (E) replacement therapy in postmenopausal women are now accepted widely. Relief of vasomotor symptoms, decreased risk of cardiovascular disease, prevention of osteoporosis, and relief of genitourinary symptoms are recognized benefits (1). One of the major drawbacks fore replacement is the need for the addition of a progestin in those women with an intact uterus. Received January 28, 1994; revised and accepted July 22, 1994. * Reprint requests: Lyman B. Spaulding, M.D., Ph.D., Department of Obstetrics and Gynecology, Colorado Permanente Medical Group, 8383 West Alameda Avenue, Lakewood, Colorado 80226 (FAX: 303-239-7568). Troublesome bleeding may be the factor that causes many women to discontinue therapy. Continuous administration of an E and progestin potentially offers elimination of all bleeding. Although bleeding with continuous hormone replacement therapy (HRT) has been reported in 30% to 40% of patients within the first 4 months of use, it usually has decreased to approximately 12.5% after 9 months of therapy (2). This refractory bleeding may provoke patient anxiety, dissatisfaction, and decreased compliance (3). Resectoscopic therapy for abnormal bleeding has been used for approximately 20 years. Endometrial polyps and submucous myomas have been described in a high percentage of women undergoing Vol. 62, 6, December 1994 Spaulding Endometrial ablation and HRT 1181
surgical therapy for refractory bleeding (4). The current study was begun to investigate and treat refractory bleeding in patients treated with continuous HRT. The uterine pathology, as well as the effect of endometrial resection and ablation, in this clinical setting were evaluated. MATERALS AND METHODS One hundred seventy-one consecutive patients with an average age of 55 years (range, 43 to 72) presented with menopausal symptoms or dissatisfaction with their current hormone regimen from a large health maintenance organization serving the Denver metropolitan area between June 1991 and May 1993 and were seen by the author in a single clinic. The diagnosis of menopause was made if the patients presented with nocturnal vasomotor symptoms and failed to have withdrawal bleeding for 2 consecutive months after a progestational challenge (medroxyprogesterone acetate A], 10 mg for 10 days) or a serum FSH and LH 40 miu/ml (conversion factor to S unit, 1.00). This process identified 78 patients ( 45.6%) of the cohort. The remaining 93 patients (54.4%) had never been on HRT, with a number of years of no menses, or had been tried on cyclic replacement and were desirous of no more monthly withdrawal bleeding. The average age of the study population was 55 years (range 43 to 72 years), gravidity 2.7 (range 0 to 8), parity 2.35 (range 0 to 6), and weight 67.9 kg (range 42.3 to 122.3 kg). The ethnic breakdown was Anglo, 160 (93.5%); Hispanic, 9 (5.3%); and Asian, 2 (1.2%). All patients were begun on daily conjugated equine E (Premarin; Ayerst Laboratories, nc., Philadelphia, PA) 0.625 mg and MPA (Provera; The Upjohn Company, Kalamazoo, M) 2.5 mg. Those with no bleeding after the first 3 months of therapy were requested to return in another 6 months, whereas those with bleeding underwent an endometrial biopsy and the dose of MPA was increased to 5.0 mg/d. After biopsy, patients were seen again in 3 months. Patients without bleeding were scheduled to be seen in another 6 months. Those who continued to bleed underwent office hysteroscopy (Olympus HYF Type P, Lake Success, NY) and were counseled individually and provided with written material outlining their options: stopping all hormone therapy, endometrial resection-ablation, or hysterectomy. All patients requested resection-ablation (Fig. 1). An outpatient ambulatory surgical center was used for all ablations. Anesthesia was induced using the general endotracheal technique. nitially, the patient's bladder was emptied by catheter and the cervical stroma infiltrated with 2 ml of a dilute vasopressin solution (20 U of vasopressin in 30 ml of saline) at the 2, 4, 8, and 10 o'clock position. The internal cervical os was dilated to 9 Hegar, and the continuous flow 22FR resectoscope (Olympus Hystero-resectoscope, Malpitas, CA) was used for all procedures. Chilled sorbitol solution (3.3%) with the CDS rrigation System (Zimmer Patient Care Division, Dover, OH) was used to distend the uterine cavity with intrauterine pressure no greater than 78 mm Hg. No endometrial preparation was used, and HRT was continued before and immediately after the surgical procedure. The ablation technique was accomplished in two steps. First, endometrial polyps, submucous myomas, and endometrial strips, from the entire cavity to a depth of 3 to 4 mm were resected using the loop electrode at loow of cutting current. These tissue samples were removed from the endometrial cavity using the Synevac Vacuum Curettage (Berkeley Medevices, nc., Berkeley, CA). Second, the entire uterine cavity was coagulated using the rollerbarrel electrode at loow of coagulation current. The electrical generator used was the Force 2 (Valley Lab, n., Boulder, CO). All tissue specimens were submitted to pathology. Patients were observed in the outpatient facility and discharged to home within 3 hours. All patients in this study were followed for at least 9 months, and the longest follow-up was 32 months. RESULTS One hundred seventy-one menopausal patients were entered into the study. Nine patients did not complete the study. Four women stopped hormone therapy because of unacceptable bleeding. One stopped because of a newly diagnosed breast cancer, 1 because of emotional problems, 1 lost her health insurance, and 2 patients were lost to follow-up. At the end of the initial 3 month phase 106 (65.4%) women reported no bleeding and experienced no further bleeding during the study. Fifty-six women (34.6%) reported bleeding and underwent office endometrial biopsy. The dosage of progestational agent (MP A) was then increased to 5 mg. All biopsies were benign (Table 1). The single patient with insufficient tissue underwent a second office biopsy plus ultrasound imaging of the endometrial stripe. The second biopsy was reported also as insufficient tissue and the endometrial strip was 3 mm in 1182 Spaulding Endometrial ablation and HRT Fertility and Sterility
Diagnosis of menopause (n = 171) Continuous hormone replacement therapy* Discontinued patients (n = 9) Three months (n = 162) Bleeding (n =56) Office biopsy (nonmalignant) + Progestational agentt Three months No bleeding (n = 106) Followup at six months Figure 1 Management protocol for continuous HRT. Bleeding (n = 21) Office hysteroscopy Endometrial ablation No bleeding (n = 35) Followup at six months thickness. These 56 patients were seen again after a second 3-month interval. After increasing MPA to 5.0 mg, 35 additional patients became amenorrheic (87%) but 21 (12.9%) continued to bleed. Endometrial histology from these 21 women were similar to those previously sampled. (Table 2). Endometrial polyps, submucous leiomyomas, and normal cavities were observed in this subset of patients at office hysteroscopy. One patient was noted to have polyps and leiomyomas. All patients with refractory bleeding underwent endometrial resection-ablation with the exception of 1 patient. Because of equipment malfunction, this patient only had resection performed. The pathological specimens were benign with endometrial polyps (47.6%) and submucous Table 1 Endometrial Histology After the First 3 Months of Treatment* Diagnosis nactive endometrium Atrophic nsufficient tissue * n =56. 43 (76.8)t 6 (10.7) 6 (10.7) 1 (1.8) leiomyomata (33.3%) predominating (Table 3). A number of specimens contained more than a single pathological entity. Sorbitol (3.3%) uptake averaged 337 ml (range, 0 to 1,300 ml). Blood loss was minimal, and there were no complications in this series. None of these patients are bleeding at this time. DSCUSSON Approximately 36 million American women could spend one third of their lives in a hypoestrogenic state. With modern HRT, this condition can be avoided. Estrogen replacement can be accomplished by pills, patches, subdermal capsules and M injections. However, endometrial hyperplasia and uterine cancer have been associated with prolonged use of unopposed E (5). By decreasing nuclear E receptors (6), blocking DNA synthesis (7), and decreasing cell multiplication (8), progestins offer a protective effect when combined with E. Replacement therapy has been prescribed to mimic the natural monthly withdrawal cycle, but after 40 years of monthly menses, most menopausal women would like to eliminate these bleeding episodes. Daily ingestion of an E and a progestin (con- Vol. 62, 6, December 1994 Spaulding Endometrial ablation and HRT 1183
Table 2 Patient Characteristics With Refractory Bleeding* Endometrial histology Office hysteroscopy nactive endometrium Atrophic endometrium nsufficient tissue 16 (76.2)t Endometrial polyps Submucous leiomyoma Normal cavity 12 (54.5)t 7 (31.8) 3 (13.6) * n = 21. tinuous HRT) has the potential to eliminate all bleeding. Although 90% of women on cyclic HRT experience withdrawal bleeding (9), only 30% to 40% have bleeding on daily therapy. This incidence of bleeding has decreased to 12.5% by 9 months (2) and approximately 10% by 1 year. Perimenopausal status (10), dosage of E (11), patient weight (12), progestational dose (13), and progestational type (14) have all been reported to influence bleeding with daily combined therapy. Any bleeding while on replacement therapy limits compliance. n one study 57% of women stopped taking cyclic therapy because of withdrawal bleeding. n hysterectomized women, only 21% discontinued E therapy (15). Bleeding appears to be the number one reason for discontinuing HRT. Because of this common problem, a protocol of biopsy, hormone manipulation, office hysteroscopy, and endometrial ablation was initiated (Fig. 1). Medroxyprogesterone acetate was increased to 5.0 mg/d after 3 months of irregular bleeding. Although Weinstein et al.(16) noted no difference in bleeding patterns between 2.5 and 5.0 mg, many women in our patient population stopped bleeding on the 5.0-mg dose, yielding an 87% level of amenorrhea at 6 months of therapy. Weinstein et al. (16) also demonstrated that the higher dose of MP A did not cause deterioration of lipid profile. No hyperplasia or overt cancers were noted on office biopsy Table 3 Histologic Features at Endometrial Resection-Ablation* Diagnosis Endometrial polyps Leiomyomata nactive endometrium Adenomyosis Cystic atrophy * n = 21. 10 (47.6) 7 (33.3) 3 (14.3) or surgical specimens. This finding is consistent with other reports (17) and is thought to be due to the antiestrogen effect of the progestins. Recent reports that have included a few postmenopausal women, describing abnormal bleeding due to benign uterine pathology are consistent with this study. n Loffer's (4) report on large symptomatic intrauterine growths, he included 6 postmenopausal women who were noted to have polyps ( 4/ 16) and leiomyoma (2/16) as the cause of their bleeding. Brooks and Serdan (18) included 13 postmenopausal women in their report of 26 women bleeding after the age of 50. Overall, 58% of their patients demonstrated adenomyosis, whereas only 35% and 4% were found to have leiomyoma and polyps, respectively. The series by tzkowic (19) contained 5 postmenopausal patients in his report of 37 women with bleeding because of submucous leiomyomas. These women accounted for 13.5% of his population. Similarly, lndman (20) described 7 postmenopausal women in his 51 patients treated for menorrhagia for a similar rate of 13.7%. The results in this portion ofthe study of 21 menopausal women more closely match Loffer's work with our finding of adenomyosis in only one patient. Although benign uterine pathology causing clinical problems is diminished in frequency at the menopause, there appears to be a small group of patients who when challenged by HRT respond with unacceptable uterine bleeding. Whether this bleeding is due to hormonal stimulation of polyps and submucous leiomyomas that were present before HRT or the induction of new growths remains to be determined. Even though this study was not randomized and lacked a control group, the protocol described may select for those postmenopausal patients who can best benefit from removal of benign uterine pathology. Conclusions to be drawn from this study include the following: [l]many women will cease or continue to have no menses on the initial dose of continuous hormone therapy (65.4%); [2]increasing 1184 Spaulding Endometrial ablation and HRT Fertility and Sterility
- the dose of progestin may enhance levels of amenorrhea (87%); [3]benign uterine pathology may cause refractory bleeding in a small group of patients (13%); and [4]endometrial resection-ablation may correct the bleeding, thus encouraging them to maintain compliance with HRT. REFERENCES 1. American College of Obstetricians and Gynecologists, Hormone replacement therapy. ACOG Technical Bulletin no. 166. Washington, DC: American College of Obstetricians and Gynecologists, 1992. 2. Prough SG, Aksel S, Wiebe H, Shepherd, J. Continuous estrogen/progestin therapy in menopause. Am J Obstet Gynecol 1987;157:1449-53. 3. Derman SG, Rehnstrom J, Neuwirth, RS. The long-term effectiveness of hysteroscopic treatment of menorrhagia and leiomyomas. Obstet Gynecol1991;77:591-4. 4. Loffer FD. Removal of large symptomatic intrauterine growth by the hysteroscopic resectoscope. Obstet Gynecol 1990;76:836-40. 5. World Health Organization. Research on the menopause. World Health Organization Technical Report Series 670. Geneva: WHO, 1981. 6. Hsveh AJW, Peck EJ, Clark JH. Control of uterine estrogen receptor levels by progesterone. Endocrinology 1976;98: 438-44. 7. Whitehead Ml, Townsend PT, Pryse-Davies J, Ryder JA, King RJB. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. N Eng! J Med 1981;305:1599-605. 8. Gerschenson LE, Berliner J, Yang JJ. Diethylstilbestrol and progesterone regulation of cultured rabbit endometrial cell growth. Cancer Res 1974;34:2873-80. 9. Whitehead Ml, Hillard TC, Crook D. The role and use of progestogens. Obstet Gynecol 1990;75:59S-76S. 10. Mattson L, Samsioe G. Estrogen-progestogen replacement in climacteric women, particularly as regards a new type of continuous regimen. Acta Obstet Gynecol Scand Suppl 1985;130:53-8. 11. Magos AL, Brincat M, Studd JWW, WardLE, Schlesinger P, O'Dowd T. Amenorrhea and endometrial atrophy with continuous oral estrogen and progestogen therapy on postmenopausal women. Obstet Gynecol 1985;65:496-9. 12. Sporrong T, Samsioe G, Larsen S, Mattson LA. A novel statistical approach to analysis of bleeding patterns during continuous hormone replacement therapy. Maturitas 1989;11:209-15. 13. Yancey MK, Hannan CJ Jr, Plymate SR, Stone K, Friedl KE, Wright JR. Serum lipids and lipoproteins in continuous or cyclic medroxyprogesterone acetate treatment in postmenopausal women treated with conjugated estrogens. Fertil Steril 1990;54:778-82. 14. Jensen J, Riis BJ, Strom V, Christiansen C. Continuous estrogen-progestogen treatment and serum lipoproteins in postmenopausal women. Br J Obstet Gynaecol 1987;94: 130-5. 15. Hemminki F, Brambilla DJ, MacKinlay SM, Posner JG. Use of estrogens among middle-aged massachusetts women. DCP 1991;25:418-23. 16. Weinstein L, Bewtra C, Gallagher JC. Evaluation of a continuous combined low dose regimen of estrogen progestin for treatment of the menopausal patient. Am J Obstet Gynecol 1990;162:1534-42. 17. Bewtra C, Kable WT, Gallagher JC. Endometrial histology and bleeding patterns in menopausal women treated with estrogen and continuous or cyclic progestin. J Reprod Med 1988;33:205-8. 18. Brooks PG, Serden SP. Endometrial ablation in women with abnormal uterine bleeding aged fifty and over. J Reprod Med 1992;37:682-4. 19. tzkowic D. Submucous fibroids: clinical profile and hysteroscopic management. Aust NZ J Obstet Gynecol 1993; 33:630-7. 20. ndman PD. Hysteroscopic treatment of menorrhagia associated with uterine leiomyomas. Obstet Gynecol 1993;81: 716-20. Vol. 62, 6, December 1994 Spaulding Endometrial ablation and HRT 1185