Intranasal peptide contraception by inhibition of ovulation with the gonadotropin-releasing hormone superagonist nafarelin: six months' clinical results

Forty-seven woman volunteers used a new highly potent stimulatory analog of the hypothalamic gonadotropin-releasing hormone (GnRH) for contraception. The superagonist nafarelin acetate, D-Nal(2)6-GnRH, was administered intranasally in one daily dose of 125 micrograms to 25 women and 250 micrograms to 22 women. Ovulation was consistently inhibited during 261 of 262 treatment months. No pregnancy occurred during 222 months in which no additional contraceptives were used. The mean plasma estradiol level after 6 months of treatment was 162 pmol/l. The predominant bleeding pattern was oligomenorrhea. Three women on the lower dose and six women on the higher dose discontinued the trial prematurely, mainly because of hot flushes. No serious side effects were reported. Ovulatory menstruations returned after a median time of 43 days after discontinuation of therapy. Daily intranasal nafarelin treatment for inhibition of ovulation proved to be an effective and rapidly reversible method of contraception.     

A randomized,double-blind,placebo-controlled,multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone

OBJECTIVE: The purpose of this study was to determine the incidence of endometrial hyperplasia in subjects who receive continuous norethindrone acetate and ethinyl estradiol combinations versus unopposed ethinyl estradiol. STUDY DESIGN: Nine hundred forty-five postmenopausal women were randomly selected for 12 months of treatment with one of six blinded norethindrone acetate/ethinyl estradiol combinations (milligrams of norethindrone acetate/micrograms of ethinyl estradiol: 0/5, 0.25/5, 1/5, 0/10, 0.5/10, or 1/10) or to open-label 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate. Endometrial hyperplasia and endometrial proliferation were assessed by biopsy at screening, months 6 and 12. RESULTS: Endometrial hyperplasia developed in 26 subjects: Placebo, 0/5 and 0.25/5 (1 subject each) and 0/10 (23 subjects). Significantly less endometrial proliferation was measured in the 1/5 norethindrone acetate/ethinyl estradiol and other norethindrone acetate/ethinyl estradiol combination groups and in the 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate group, than in unopposed ethinyl estradiol groups (6 months: P <.004; 12 months: P <.001). Treatment with 1/5 norethindrone acetate/ethinyl estradiol and with other norethindrone acetate/ethinyl estradiol combinations significantly reduced endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate (6 and 12 months: P <.02). CONCLUSION: Norethindrone acetate protects the endometrium from estrogen-induced hyperplasia and changes in proliferative status. In addition, norethindrone acetate/ethinyl estradiol-treated subjects had significantly less endometrial proliferation compared with 0.625 mg conjugated equine estrogens/2.5 mg medroxyprogesterone acetate-treated subjects.     

Intrauterine therapy with levonorgestrel releasing IUD of women with hypermenorrhea secondary to uterine fibroids

OBJECTIVES: The aim of the study was to evaluate the effectiveness of Mirena IUD (Schering) treatment in women with severe menstrual bleedings secondary to uterine fibroids. MATERIAL AND METHODS: The study comprised 12 women in the age of 30 to 43 years (average 36.4) with uterine fibroids and severe menstrual bleedings. Eight patients developed anemia with hemoglobin levels below 12 g/dL. All women were treated with the levonorgestrel releasing IUD. Half of the group was observed for 6, and the remaining women for 12 months. Intensity of menstrual bleedings was evaluated prior and after the treatment. US evaluation comprised measurements of endometrium and the fibroids. RESULTS: No early complications were observed following the insertion of the IUD. Six weeks following the insertion, one patient had persisted menstrual bleedings and was operated, the remaining 11 noted decrease in the intensity of menstruation. After twelve weeks 3 out of 6 women with intramural fibroids developed ammenorrhea, the remaining 3 had scanty menstrual bleedings. Hemoglobin levels were normal in 11 women already 6 months after the insertion of IUD. Post treatment US revealed endometrium thickness of no more then 4 mm, and no change in the fibroids volume. CONCLUSION: Insertion of levonorgestrel releasing Mirena IUD (Schering) reduces intensity of menstrual bleedings secondary to uterine fibroids.     

Long-term effect of megestrol acetate in the treatment of endometrial hyperplasia

Fifty-two postmenopausal women who were poor surgical risks and had histologically proved adenomatous hyperplasia, atypical hyperplasia, or adenocarcinoma in situ of the endometrium were treated with megestrol acetate, 40 mg per day, continuously for 9 to 104 months (mean, 42 months). More than 90% of these women had complete remissions of the hyperplasia. Three women with carcinoma in situ were followed up for 57, 65, and 104 months, without recurrence of the disease. Four women required hysterectomy; none had invasive adenocarcinoma. No adverse side effects of the drug were observed. Thus, we conclude that the continuous use of megestrol acetate is an effective, safe, alternative form of therapy for endometrial hyperplasia in postmenopausal women.     

Evidence of similar increases in bone turnover during nafarelin and danazol use in women with endometriosis

Medical 'oophorectomy' by GnRH agonist or danazol is an effective treatment for endometriosis. Since increased bone loss is a potential risk of hypoestrogenism, we compared the effect of nafarelin and danazol treatment on bone metabolism. Twelve patients with laparoscopically confirmed endometriosis received nafarelin (400 micrograms day intranasally) and six patients danazol (600 mg day orally) for 6 months. Both treatments had already led to hypoestrogenism (E2 less than 21.6 pg/ml) after 3 months. They both were accompanied by an approximately 50% rise in 24-h urinary hydroxyproline output, suggesting accelerated bone resorption at 6 months; yet urinary calcium output did not change significantly. Serum osteocalcin rose by 80-120% and bone alkaline phosphatase activity by 34-40%, suggesting stimulated bone formation at the same time. No detectable changes ensued in cortical bone mineral content in the distal radius or in serum levels of calcium, calcitonin, parathyroid hormone, or aminoterminal propeptide of type III collagen. Three months after treatment, hydroxyproline output, serum osteocalcin and bone alkaline phosphatase were still elevated in women taking nafarelin, whereas only serum osteocalcin was elevated in women taking danazol. Our data thus suggest that bone turnover was increased during nafarelin and danazol therapy and that this effect was reversible.     

Treatment of endometriosis with a potent agonist of gonadotropin-releasing hormone (nafarelin)

Administration of superactive agonistic analogs of gonadotropin-releasing hormone (GnRH) has been shown to induce a paradoxic and reversible suppression of gonadotropins, resulting in suppressed gonadal steroid concentrations. Because there currently is no uniformly successful and acceptable medical therapy for endometriosis, we examined the effects of 6 months of nasal administration (500 micrograms every 12 hours) of the agonistic analog of GnRH, nafarelin, on clinical signs and symptoms and hormonal profiles in eight women with endometriosis. All patients had prompt and near-complete relief from their painful symptoms of endometriosis. Laparoscopy or laparotomy, performed both before and after treatment in seven of the women, revealed complete resolution of active endometriotic lesions in five patients and only a single, small cul-de-sac implant in a sixth woman. A large ovarian endometrioma decreased slightly in response to treatment in the seventh woman. Serum luteinizing hormone and follicle-stimulating hormone concentrations, after a transitory stimulation at the onset of treatment, declined and were suppressed (P less than 0.001) during the remainder of treatment. Serum estradiol concentrations fell to approximately menopausal levels (less than 30 pg/ml) after 1 to 4 weeks. Reversibility of drug effect was prompt, with ovulatory menses returning 47 +/- 8 days (+/- standard deviation) after treatment. Thus, nasal administration of agonistic analogs of GnRH may represent a new treatment modality for endometriosis.     

Effect on endometrium of combined oestrogen-progestogen replacement therapy of 1 mg 17beta-estradiol and 0.5 mg norethisterone acetate

The purpose of the study was to determine the effects of low-dose hormone replacement therapy (HRT) on ultrasound thickness of the endometrium and on endometrial histology in postmenopausal women. Two hundred and fifty-four postmenopausal women were included in the study; 124 completed three years of treatment with continuous HRT containing 1 mg oestradiol and 0.5 mg norethisterone acetate daily, and 130 women did not take HRT during the same time (control group). Ultrasound scan showed that the mean thickness of the endometrium was similar between the groups under investigation at the end of the study. Ninety-one percent of the women in the HRT group and 78% in the control group had an atrophic or unassessable endometrium and no cases of endometrial hyperplasia or malignancy were detected in either group at endometrial biopsy at the end of the study. It seems that low-dose continuous HRT of moderate duration is not associated with either endometrial hyperplasia or malignancy.     

Therapeutic efficacy and bone mineral density response during and following a three-month re-treatment of endometriosis with nafarelin (Synarel)

OBJECTIVE: Our goal was to determine the effects of a repeated course of the gonadotropin-releasing hormone agonist nafarelin on symptoms and signs of endometriosis and lumbar and distal radius bone mineral density. STUDY DESIGN: Forty-five women previously treated for 6 months with nafarelin, who had recurrent symptoms and signs of endometriosis, received 400 mcg/day of nafarelin intranasally for 3 months. Efficacy was evaluated by changes in severity of symptoms and signs. Lumbar bone mineral density was measured by dual-energy x-ray absorptiometry and distal radius bone mineral density by single-photon absorptiometry. Bone mineral density was also measured in 10 control volunteers. RESULTS: Repeated 3-month treatment significantly alleviated recurrent symptoms and signs of endometriosis. Lumbar bone mineral density decreased significantly by a mean of 2% at the end of treatment; this loss was restored within 3 to 6 months after treatment completion. No bone mineral density decline occurred in the radius. Bone mineral density changes in the control group were statistically insignificant. CONCLUSIONS: A repeated 3-month course of nafarelin treatment significantly relieved recurrent endometriotic symptoms and signs without sustained loss of bone mineral density.(Am J Obstet Gynecol 1997;177:8)     

Anastrozole, an aromatase inhibitor, and medroxyprogesterone acetate therapy in premenopausal obese women with endometrial cancer: a report of two cases successfully treated without hysterectomy

BACKGROUND: Hormonal therapy for endometrial cancer is occasionally warranted in the premenopausal woman who is interested in maintaining fertility. Combining progesterone with an agent that eliminates the adipose production of estrogen will theoretically be more effective than progesterone alone. CASES: Two cases of reproductive-aged women with grade 1 endometrial cancer who were treated with medroxyprogesterone acetate and anastrozole daily for 3 and 6 months subsequently reverted to normal endometrium. CONCLUSION: Progesterone combined with the elimination of adipose production of estrogen may be an effective therapy in well-differentiated endometrial cancer in the obese premenopausal woman.     

Treatment of hyperplasia endometrium with GNRH agonists

OBJECTIVES: Untreated hormonal disturbances connected with unbalanced estrogen serum concentrations can influence on pathological proliferation of endometrium. The aim of the study is to assess the effect of GnRH agonists on endometrium in women consulted due to simple hyperplasia endometrium. MATERIAL AND METHODS: 15 women in the mean age 48.5 +/- 3.5 years with the histopathological diagnosis of simple hyperplasia were treated with trioptorelin during 3 months. After therapy all patients were undergone transvaginal ultrasonography and endometrial biopsy. RESULTS: Atrophic endometrium were observed in all women after a 3-month therapy. The thickness of endometrium decreased from 10.21 +/- 3.2 mm to 3.94 +/- 1.56 mm. CONCLUSIONS: The efficacy of the therapy of simple hyperplasia in women with GnRH agonist was 100%.     

Mechanical preparation of the endometrium prior to endometrial ablation.

Of 143 women who underwent endometrial ablation between May 1986 and August 1991, 16 also had repeat procedures. Medical preparation of the endometrial lining (danazol, leuprolide acetate, or nafarelin acetate) was used in 109 patients; mechanical preparation in the form of suction curettage, in 28 patients; and no preparation, in 6 postmenopausal patients. Evaluation of the results following endometrial ablation showed that the results in mechanically prepared patients were comparable to those in patients receiving traditional medical preparation; thus mechanical preparation can make the procedure simpler, enhance patient compliance, and reduce side effects considerably.     

Sequential combined transdermal and oral postmenopausal hormone replacement therapies: effects on bleeding patterns and endometrial histology

Objectives: To determine the endometrial response and bleeding patterns in postmenopausal women taking a sequential combined hormone replacement regimen either orally or transdermally. Methods: Seventy-two postmenopausal women with amenorrhea of 6 months or longer with follicle stimulating hormone and estradiol levels in the postmenopausal range and normal endometrium were included in the study. The patients randomly received sequential combined hormone replacement regimen with oral (n=37) or transdermal route (n=35). The total duration of treatment was 6 months (6 cycles of 28 d). The subjects kept daily bleeding diaries, and endometrial biopsies were taken at baseline and after 6 months of therapy. Results: The rates of adequate progestational response (secretory or atrophic) were 83.8% and 82.9% in the oral and transdermal hormone replacement groups, respectively (p>0.05). In the oral hormone replacement group, there were 16.2% of inadequate progestational response, 2.7% had endometrial hyperplasia and 13.5% proliferative endometrium. In the transdermal hormone replacement group, there were 17.1% of inadequate progestational response, 2.9% had endometrial hyperplasia and 14.3% proliferative endometrium. Cyclic bleedings occurred in 92.4% and 92% of all cycles in the oral and transdermal treatment groups, respectively. The mean duration of bleeding per cycle were 3.9±0.9 and 3.8±0.9 d in the oral and transdermal treatment groups, respectively. Conclusion: Sequential combined transdermal hormone replacement therapy is as effective as oral therapy in preventing the development of endometrial hyperplasia. Satisfactory control of bleeding is achieved with both regimens. Received: 6 June 2001 / Accepted: 12 July 2001     

Uterine effects of raloxifene in comparison with continuous-combined hormone replacement therapy in postmenopausal women

OBJECTIVE: We sought to compare the uterine effects of raloxifene with those of continuous-combined hormone replacement therapy. STUDY DESIGN: This randomized, double-blind 24-month study involved 136 postmenopausal women who received raloxifene 150 mg/d or conjugated equine estrogens 0.625 mg/d with medroxyprogesterone acetate 2.5 mg/d. After baseline evaluations, endometrial biopsy specimens were obtained, and endometrial thickness was measured annually by means of transvaginal ultrasonography. Statistical analyses were performed with an intention-to-treat approach. RESULTS: In the raloxifene group at the end point of the study 94.4% of biopsy specimens showed normal benign postmenopausal endometrium and 5.6% were classified as benign stimulatory endometrium. In the continuous-combined hormone replacement therapy group at the end point of the study 78.7% of biopsy specimens showed normal benign postmenopausal endometrium, 19. 1% were classified as benign stimulatory endometrium, and 2.1% showed benign abnormal postmenopausal endometrium. Mean endometrial thickness was unchanged from baseline with raloxifene and was increased significantly by 0.5 mm at 12 months with continuous-combined hormone replacement therapy. CONCLUSION: Raloxifene 150 mg/d did not increase endometrial thickness or cause endometrial proliferation in healthy postmenopausal women.     

Presence of corpus luteum as evidence of ovulation in women treated with low doses of chlormadinone acetate

50 women under continuous treatment for 1-31 months with 500 mcg chlormadinone acetate daily were studied. Culdoscopy was performed between Day 14 and 23 of their menstrual cycles. A corpus luteum was thought to be observed in 37 cases. In 18 with suspected corpus luteum a wedge resection of the ovary was done. Examination of patients 10 days after operation revealed no complications. In 4 cases subsequent culdoscopic examinations revealed no traces of biopsy damage. In 5 an endometrial biopsy was obtained the same day as the ovarian one or shortly thereafter. The 18 ovarian biopsies showed recent corpora lutea in 12, old corpus luteum in 1, follicular and theca-lutein cysts in 2, and normal follicles without corpus luteum in 3. Endometrial biopsies revealed 2 instances of normal secretory endometrium and 1 case of irregular endometrium with corpora lutea. Evidence of ovulation occurred in 70%. The reported pregnancy rate with low-dose progestogen therapy has been 3.7/100 years of woman exposure. The exact mechanism of contraception by chlormadinone acetate has not been determined.     

Intrauterine release of levonorgestrel--a new way of adding progestogen in hormone replacement therapy.

Forty perimenopausal women with climacteric complaints were randomly allocated to one of two estrogen-progestogen regimens. One group was treated cyclically for 3-week periods with 2 mg of estradiol (E2) valerate; during the last 10 days 250 micrograms of levonorgestrel was added. Another group was given 2 mg of E2 valerate a day and had a 20-micrograms/24-hour levonorgestrel-releasing intrauterine device (IUD) inserted. The study period was 1 year. Climacteric symptoms, bleeding patterns, and endometrial histopathology were recorded during the study. Subjective symptoms were equally diminished in both groups. In the IUD group, bleeding disturbances were gradually reduced, and 15 of 18 women became amenorrheic after 12 months, compared with the group given cyclic treatment in which all women bled regularly. No endometrial proliferation was found in any woman after 12 months. Thus, intrauterine release of 20 micrograms of levonorgestrel per day, in combination with orally administered E2, prevented endometrial proliferation and reduced uterine bleeding. This new approach to continuous combined hormone replacement therapy may be a well-tolerated treatment alternative in perimenopausal women.     

Continuous oestrogen-progestogen treatment and serum lipoproteins in postmenopausal women

Summary. Serum lipids and lipoproteins were examined in 44 healthy postmenopausal women every 3 months during 1 year of treatment with either continuous oestrogen-norethisterone acetate or placebo. Total serum cholesterol and LDL-cholesterol levels were reduced by approximately 15% and 20% ( P <0.001), respectively in the hormone group but were unchanged in the placebo group. Serum triglycerides levels remained constant in both groups. HDL-cholesterol levels were significantly reduced by approximately 10% in the hormone group but significant reductions of 5–10% also occurred in the placebo group so that differences between the two groups were only significant after 3 months of treatment. Vaginal bleedings were experienced during the first 3 months by eight of the 21 women receiving hormones, but in only one woman after 9 months of therapy. The addition of norethisterone acetate to postmenopausal oestrogen therapy in clinically relevant doses had no adverse effects on lipoproteins as previously reported, even though administered continuously. Moreover, the low frequency of bleeding with continuous oestrogen-progestogen therapy would make this an appropriate alternative in postmenopausal replacement therapy.     

Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis

Objective: To evaluate the efficacy of the GnRH agonist (GnRH-a) nafarelin compared with placebo administered for 6 months after reductive laparoscopic surgery for symptomatic endometriosis.Design: Randomized, prospective, placebo-controlled, multicenter clinical trial.Setting: Thirteen clinics including private practice and university centers.Patient(s): One hundred nine women aged 18–47 with laparoscopically proven endometriosis and pelvic pain who had undergone reductive laparoscopic surgery for endometriosis.Intervention(s): Patients were randomized to receive either the GnRH-a nafarelin (200 μg twice daily) or placebo for 6 months.Main Outcome Measure(s): Time to initiation of alternative treatment (the length of time from beginning study medication to receiving alternative therapy or to deeming that the study drug was ineffective) and patient-reported and physician-assessed pelvic pain scores.Result(s): The median time to initiation of alternative treatment was > 24 months in the nafarelin group versus 11.7 months in the placebo group. Fifteen (31%) of 49 nafarelin-treated patients required alternative therapy, compared with 25 (57%) of 44 placebo-treated patients. The patients' pelvic pain scores dropped significantly in the nafarelin and placebo groups after 6 months of treatment. Physician summary ratings showed significant improvement in the nafarelin group and no significant changes in the placebo group after 6 months of treatment.Conclusion(s): Compared with placebo, nafarelin administered after reductive laparoscopic surgery for endometriosis significantly delays the return of endometriosis symptoms requiring further treatment.     

Tamoxifen and endometrial pathologies: a prospective study.

OBJECTIVE:The purpose of this study was to prospectively follow a group of women with breast cancer, on tamoxifen, for the development of endometrial pathologies. MATERIALS AND METHODS: Eighty women with breast cancer, on tamoxifen, were prospectively followed every 6 months with pelvic examination, Pap smear, vaginal ultrasound, and endometrial biopsy. RESULTS: Nine women were lost to follow-up prior to initiation of treatment and 4 refused biopsies, leaving 67 patients for evaluation. Fifty (74.6%) of the 67 patients were already on tamoxifen for a mean duration of 15.8 +/- 16.6 months and had a baseline benign, unremarkable endometrium at the time of entry into the study. The total duration of treatment was 32.5 +/- 19.6 months (median 30 months). The mean age of the patients was 51.7 +/- 9.9 years (median 52 years). Of the patients, 56.7% were postmenopausal. Sixty-three patients had a benign endometrium (mean age 51.8 +/- 10.1 years, mean duration 33.1 +/- 19.6 months). Two patients had simple hyperplasia (mean age 43.5 years, duration 28.5 +/- 33.2 months), 1 patient had complex hyperplasia with atypia (age 57 years, duration 13 months), and another patient developed adenocarcinoma (grade 3) after 22 months. These 4 patients had abnormal vaginal bleeding. Seven patients developed endometrial polyps (mean age 54.0 +/- 8.5 years, duration 36 +/- 24.2 months). The mean endometrial thickness for patients with histologically unremarkable and abnormal endometrium was not significantly different (7.6 +/- 3.9 vs 8.8 +/- 5.0 mm, respectively) (median 7.0 mm for both groups). No endometrial thickness cutoff point reached statistical significance. The patient who developed endometrial cancer had a thickness of only 3 mm. CONCLUSION: All patients who developed an abnormal endometrium had abnormal vaginal bleeding. There was no correlation between endometrial thickness and endometrial pathology; thus the value of routine screening remains controversial.     

Endometrial findings in long-term treatment with synthetic sex steroids in Turner syndrome

In 9 patients with Turner's syndrome (karyotype 45/X0) aged from 23 to 50 years (average age 34 years) a curettage was performed. In these women there has been a treatment with mestranol 80 micrograms or ethinylestradiol 50 micrograms and chlormadinome acetate 2 mg as a sequential therapy in a cyclic manner for 5 to 22 years. Additionally in 3 patients a biopsy from the uterine cervix was performed because of abnormal colposcopic findings. Only in one patient an atrophic endometrium was found, whereas in the other patients the endometrium showed a weak proliferation or a slight secretion. Ectasia of the endometrial glands was observed in 4 patients. A hyperplastic endometrium wasn't found in any patient.     

Intrauterine levonorgestrel delivered by a frameless system, combined with systemic estrogen: acceptability and endometrial safety after 3 years of use in peri- and postmenopausal women.

OBJECTIVE: To evaluate the acceptability and endometrial safety of a novel intrauterine drug delivery system, FibroPlant-levonorgestrel (LNG), combined with estrogen therapy (ET) in 150 peri- and postmenopausal women, followed-up for at least 3 years. DESIGN: This was a prospective, non-comparative study in peri- and postmenopausal women. In the majority of women, treatment with the FibroPlant-LNG intrauterine system (IUS), combined with ET, was initiated during the perimenopausal transitional phase to establish a smooth transition to menopause and suppress the endometrium to prevent endometrial proliferation and bleeding. A 3.5-cm long coaxial fibrous delivery system, delivering approximately 14 microg LNG/day, was used. The calculated duration of release of the system is at least 3 years. The majority of women received percutaneous 17beta-estradiol (Oestrogel), 1.5 mg daily on a continuous basis, which provides sufficient blood levels of estrogen in most women to suppress climacteric symptoms and protect against bone loss. OUTCOME MEASURES: To measure acceptability, women were asked, after they had the IUS in place for a minimum of 3 years, if they would like to continue the combined regimen and if they would accept renewal of the IUS. Endometrial safety was evaluated by transvaginal ultrasound examination and endometrial biopsy in a subset of 101 women prior to replacement of the IUS. RESULTS: Ninety-four insertions were done in perimenopausal and 56 in postmenopausal women aged between 33 and 78 years. Of the total group of 150 women, 132 women (88.0%) accepted replacement of the IUS and ten are waiting for replacement. This group includes nine women who will receive a second replacement. The number of women continuing the method is 142 (94.6%). Histological examinations conducted on endometrial biopsies from 101 postmenopausal women prior to replacement, after an average period of use of the regimen of 40 months (range 25-50 months), showed predominantly inactive endometrium characterized by pseudodecidual reaction of the endometrial stroma with endometrial atrophia, which is in keeping with the effects seen with a progestogenic compound. There were no specimens showing signs of proliferation. CONCLUSIONS: Results suggest that the frameless FibroPlant-LNG IUS is safe, well tolerated, well accepted and effective in suppressing the endometrium during ET. Intrauterine progestogen administration in postmenopausal women can be regarded as fundamentally advantageous compared with systemically applied progestogens, which may have potentially inherent ill side-effects, especially on the breast and cardiovascular system, as reported in the recent literature.