Psychological effects of hormone replacement therapy: A comparison of tibolone and a sequential estrogen therapy

Hormone replacement therapy (HRT) is effective in alleviating vasomotor symptoms but the effect on psychological symptoms is less dear. This study aimed to compare the psychological effects of two regimens of HRT in perimenopausal women in a randomized, initially double-blind, controlled trial.

Thirty-eight women reporting climacteric symptoms were randomly allocated into either oral conjugated equine estrogen 0.625mg daily plus progestogen (norgestrel) 150 μg for the last 12 days of each 28 day cycle, or tibolone 2.5 mg/day for 28 days. They were assessed using standardized psychological assessments.

There were no significant differences in changes from baseline between the two types of therapy. For both groups combined mere were significant improvements compared with baseline in vasomotor symptoms in the first month, plus anxiety, sleep, memory and somatic dysfunction by the second and third months, but not in scores of depression. Log linear analysis of weekly scores showed that depression scores were significantly related to improvement in vasomotor scores independent of type of therapy and time on HRT. Memory problems were related to vasomotor symptoms independent of depression. No difference between the two types of therapy was found, nor any direct effect of HRT on anxiety or depression. The results support the domino theory, suggesting mat psychological improvement follows alleviation of vasomotor symptoms.     

E-cadherin expression in cervical epithelial cells of postmenopausal women: association with hormone therapy, tibolone, and raloxifene

This study assesses the possible associations between postmenopausal therapy (hormone therapy, raloxifene, and tibolone) and E-cadherin expression in normal cervical Papanicolaou smears (squamous, glandular, and metaplastic cells). E-cadherin immunostaining was less intense in metaplastic cells of women on tibolone, whereas hormone therapy and raloxifene were not associated with altered E-cadherin expression.     

Psychological effects of hormone replacement therapy: a comparison of tibolone and a sequential estrogen therapy.

Hormone replacement therapy (HRT) is effective in alleviating vasomotor symptoms but the effect on psychological symptoms is less clear. This study aimed to compare the psychological effects of two regimens of HRT in perimenopausal women in a randomized, initially double-blind, controlled trial. Thirty-eight women reporting climacteric symptoms were randomly allocated into either oral conjugated equine estrogen 0.625 mg daily plus progestogen (norgestrel) 150 micrograms for the last 12 days of each 28 day cycle, or tibolone 2.5 mg/day for 28 days. They were assessed using standardized psychological assessments. There were no significant differences in changes from baseline between the two types of therapy. For both groups combined there were significant improvements compared with baseline in vasomotor symptoms in the first month, plus anxiety, sleep, memory and somatic dysfunction by the second and third months, but not in scores of depression. Log linear analysis of weekly scores showed that depression scores were significantly related to improvement in vasomotor scores independent of type of therapy and time on HRT. Memory problems were related to vasomotor symptoms independent of depression. No difference between the two types of therapy was found, nor any direct effect of HRT on anxiety or depression. The results support the domino theory, suggesting that psychological improvement follows alleviation of vasomotor symptoms.     

The differential effect of estrogen, estrogen-progestin and tibolone on coagulation inhibitors in postmenopausal women.

OBJECTIVES: Hormone therapy increases the risk of venous thromboembolism, possibly through a negative effect on coagulation inhibitors. The aim of the study was to assess the effect of conjugated equine estrogens alone or in combination with medroxyprogesterone acetate, low-dose 17beta-estradiol combined with norethisterone acetate and tibolone on inhibitors of coagulation. METHODS: Two hundred and sixteen postmenopausal women received orally either conjugated equine estrogens 0.625 mg (CEE, n=24) or tibolone 2.5 mg (n=24) or CEE+medroxyprogesterone acetate 5 mg (CEE/MPA, n=34) or 17beta-estradiol 1 mg+norethisterone acetate 0.5 mg (E2/NETA, n=66) or no therapy (control, n=68) for 12 months. Plasma antithrombin, protein C and total protein S were measured at baseline and at 12 months. RESULTS: CEE, CEE/MPA and E2/NETA treatment were associated with a significant decrease in antithrombin levels (CEE: baseline 235.6+/-47.6 mg/l, follow-up 221.3+/-48.3 mg/l, p=0.0001; CEE/MPA: baseline 251.1+/-38.6 mg/l, follow-up 225.0+/-42.6 mg/l, p=0.009; E2/NETA: baseline 257.1+/-59.4 mg/l, follow-up 227.1+/-50.4 mg/l, p=0.007; tibolone: baseline 252.6+/-62.4 mg/l, follow-up 261.9+/-59.1 mg/l, p=0.39). Protein C decreased significantly in the CEE and CEE/MPA groups (CEE: baseline 3.64+/-1.17 mg/l, follow-up 2.48+/-1.47 mg/l, p=0.004; CEE/MPA: baseline 3.24+/-1.23 mg/l, follow-up 2.61+/-1.38 mg/l, p=0.001; E2/NETA: baseline 3.24+/-1.10 mg/l, follow-up, 3.15+/-1.11 mg/l, p=0.08; tibolone: baseline 3.26+/-1.25 mg/l, follow-up 3.09+/-1.32 mg/l, p=0.37). Protein S decreased significantly only in the CEE/MPA group (CEE: baseline 19.4+/-2.76 mg/l, follow-up 18.0+/-2.45 mg/l, p=0.56; CEE/MPA: baseline 18.4+/-3.42 mg/l, follow-up 14.5+/-3.43 mg/l, p=0.005; E2/NETA: baseline 19.0+/-3.11 mg/l, follow-up 19.5+/-3.43 mg/l, p=0.18; tibolone: baseline 18.5+/-3.09 mg/l, follow-up 18.0+/-4.09 mg/l, p=0.32). CONCLUSIONS: Estrogen and estrogen-progestin therapy are associated with a reduction in coagulation inhibitors, the extent of which depends on the regimen administered. Tibolone appears to have no effect on inhibitors of coagulation.     

A randomized study of the effects of tibolone and transdermal estrogen replacement therapy in postmenopausal women with uterine myomas

OBJECTIVE: To evaluate the effects of two types of hormone replacement therapy, an estrogen-progestin combination and tibolone, on uterine myomas in menopausal women. STUDY DESIGN: Thirty-eight menopausal women with one or more uterine myomas were randomized to treatment with a transdermal system continuously releasing estradiol 50 microg/day combined with oral medroxyprogesterone acetate (MPA) 10 mg/day for 12 days/month or tibolone tablets 2.5 mg/day. The scheduled duration of both treatments was 12 months. Physical examination and abdominal/transvaginal ultrasonography were performed before entering the study and at 3, 6 and 12 months of treatment. At each ultrasonography the overall uterine volume was determined as well as the size of each myoma and the endometrial thickness and characteristics. RESULTS: No statistically significant difference was detected between the two groups at any time during treatment. However, within-group analysis showed a significant increase of uterine volume and of myoma number and size in the estrogen-progestin group, whereas no such increase occurred in the patients treated with tibolone. Also, the mean endometrium width increased significantly from baseline to the end of treatment in the estrogen-progestin group, but not in the tibolone group. CONCLUSIONS: Tibolone seems a valid alternative in menopausal patients with uterine myomas as it provides adequate relief from menopausal symptoms and avoids volume increase of the uterus and myomas.     

Effect of hormone replacement therapy and tibolone on serum total homocysteine levels in postmenopausal women

OBJECTIVE: To assess the effect of continuous combined hormone replacement therapy (HRT) or tibolone on serum total homocysteine (tHcy) levels in postmenopausal women. STUDY DESIGN: Ninety-five postmenopausal women aged 41-68 years were included in the study. Seventy-three women with climacteric complaints, osteopenia or osteoporosis received either conjugated equine estrogens 0.625 mg combined with medroxyprogesterone acetate 5 mg (CEE/MPA, n=31) or tibolone 2.5 mg (n=42). Twenty-two healthy women, matched for chronological and menopausal age, served as controls. Serum tHcy levels were assessed at baseline, 6, 12 and 18 months. RESULTS: No difference was recorded between groups regarding demographic characteristics or mean baseline serum tHcy. Serum tHcy levels decreased significantly in the CEE/MPA compared to baseline (change at 18 months: -3.9%, P<0.05). The magnitude of the decrease was higher in the subgroup of women with baseline tHcy levels above the median (change at 18 months: -15.0%, P<0.01). No change in tHcy levels was detected in the tibolone group throughout the study period, either in the whole group (change at 18 months: 1.9%, NS) or in the subgroup with baseline tHcy levels above the median (change at 18 months: -3.23%, NS). CONCLUSION: Continuous CEE/MPA reduces tHcy especially in women with high pretreatment tHcy levels. Tibolone has no effect on serum tHcy levels at least during the first 18 months of therapy. Larger studies with longer follow-up are required to confirm these results.     

The effects of soygerm extracts on blood lipoproteins, antioxidative capacity and urinary estrogen metabolites in postmenopausal women on hormone therapy.

OBJECTIVE: To evaluate the effects of soygerm isoflavones extracts on blood lipoproteins, antioxidative capacity and urinary estrogen metabolites in postmenopausal women who receive hormone therapy (HT). METHOD: Thirty-nine volunteers receiving HT were recruited, and 33 completed the study. All subjects received 6 g of soygerm extracts per day for 4 weeks. Blood and urine samples were collected for study at the beginning and at the end of study. RESULT: Plasma HDL-C levels increased markedly with significant decreases of plasma LDL-C/HDL-C ratio and LDL-TG levels. The lag time of conjugated dienes formation prolonged for 9.9% and thiobarbituric acid reactive substances production in copper-catalyzed oxidation of LDL decreased. The differences were statistically significant. Urinary ratio of 2-OHE(1) to 16alpha-OHE(1) increased without statistical significance. CONCLUSION: Soygerm extracts may improve serum lipid profile in postmenopausal Taiwanese women who receive HT, and probably provide a favorable effect on estrogen metabolism.     

Hormone replacement therapy with tibolone: effects on sexual functioning in postmenopausal women

OBJECTIVE: Because hormonal changes in postmenopausal women may be accompanied by sexual problems and a worsening of various aspects of libido, the aim of this study was to assess the effect of tibolone (Liviel(R)) on sexual life. METHODS: Postmenopausal first-time users of hormone replacement therapy (HRT) were included in this open, multicenter study. Patients were treated with tibolone 2.5 mg daily for at least 4 months. Both at baseline and after 4 months of treatment, patients were asked to complete two different questionnaires rating the women's subjective assessment of their sexual problems or desires. RESULTS: One hundred and eighty-four women were enrolled to receive HRT with tibolone. Overall, a significant increase in women's satisfaction with their sexual lives and a significant improvement in different aspects of libido was found. CONCLUSION: Tibolone has beneficial effects on several aspects of sexual life in postmenopausal women. These effects may be due to both an increase in genital blood flow and the central estrogenic/androgenic activity.     

A double-blind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms

Objective To compare the effects of two postmenopausal regimens on menopausal symptoms, bleeding episodes, side effects and acceptability.
Design Double-blind, randomised controlled trial.
Setting Twenty-nine sites in Denmark, nine in Norway and six in Sweden.
Participants Four hundred and thirty-seven postmenopausal women with menopausal complaints. None of these women had had a hysterectomy.
Interventions Daily treatment with tibolone 2.5 mg (  n = 218  ) or 17β-oestradiol 2 mg plus norethisterone acetate 1 mg (E₂/NETA) (  n = 219  ).
Main outcome measures Hot flushes, sweating episodes, vaginal dryness, assessment of sexual life and bleeding patterns; at baseline and after 4,12,24 and 48 weeks.
Results Treatment with either preparation significantly reduced mean scores for hot flushes, sweating episodes and vaginal dryness. The overall discontinuation rate was 28% (tibolone 25%, E₂/NETA 31%; P = 0.14), mostly during the first six months. There was a markedly lower cumulative incidence of bleeding or spotting episodes with tibolone compared with E₂/NETA (  P < 0.0001  ), mainly during the first six treatment cycles.
Conclusions Both tibolone and E₂/NETA effectively alleviate menopausal symptoms. However, tibolone caused significantly fewer bleeding or spotting episodes, which were reflected by lower overall rates of bleeding, as well as lower drop-out rates due to bleeding.     

Decrease of serum endothelin levels with postmenopausal hormone replacement therapy or tibolone.

Endothelin is the most potent vasoconstrictor peptide known to date. Hormone replacement therapy (HRT) with estrogen reduces plasma endothelin levels. We measured endothelin in 51 postmenopausal patients before and during HRT. Patients were randomly allocated to receive either oral tibolone, oral or transdermal 17 beta-estradiol. A group of comparable volunteers served as controls. After 24 months, endothelin levels decreased in all treatment groups: tibolone, 18.2%; oral 23.1%; transdermal, 20.8%. Endothelin levels increased in the controls by 36.6% (p < 0.01). Tibolone decreases endothelin levels to a similar degree as conventional estrogen-progestogen-replacement therapy. These data provide another potential mechanism supporting the cardioprotective effects of tibolone.     

Effects of tibolone and continuous combined hormone replacement therapy on bleeding rates,quality of life and tolerability in postmenopausal women

Objective To compare the effects of tibolone and conjugated equine oestrogens continuously combined with medroxyprogesterone acetate on bleeding rates, quality of life (QoL) and tolerability.
Design A double-blind, randomised comparative trial.
Setting Thirty-seven centres in six European countries.
Population Five hundred and one postmenopausal women, under 65 years of age with an intact uterus.
Interventions For 12 months, women received daily treatment with tibolone 2.5 mg (   n = 250  ), or conjugated equine oestrogens 0.625 mg continuously combined with medroxyprogesterone acetate 5 mg (CEE–MPA,   n = 251  ).
Main outcome measures The primary outcome was vaginal bleeding rate during cycles 4–6. The secondary outcomes were vaginal bleeding rate during cycles 1–3, 7–9 and 10–13, cumulative bleeding rate, QoL, wellbeing, climacteric symptoms, urogenital complaints and tolerability.
Results Treatment with tibolone led to a significantly lower bleeding rate during cycles 4–6 compared with CEE–MPA (15.0% vs 26.9%;   P = 0.004  ); there was a similar difference during cycles 1–3. Both treatments improved QoL, wellbeing, climacteric symptoms and urogenital complaints. By intent-to-treat analysis, tibolone significantly improved sexual drive, interest and/or performance, compared with CEE–MPA at 12 months (   P = 0.017  ). Although both treatments were well tolerated, there was a significantly lower incidence of breast tenderness with tibolone than CEE–MPA (2.4% vs 17.1%;   P < 0.001  ).
Conclusion The vaginal bleeding rate during cycles 4–6 was significantly lower in women using tibolone. Both treatments improved QoL, wellbeing, climacteric symptoms and urogenital symptoms. Breast tenderness was significantly less frequent with tibolone.     

Differential effects of unopposed versus opposed hormone therapy,tibolone, and raloxifene on substance p levels

OBJECTIVE: To evaluate the effects of unopposed therapy (conjugated equine estrogens [CEE]) vs. opposed therapy (CEE and medroxyprogesterone acetate), tibolone, and raloxifene on serum substance p levels. DESIGN: Clinical study. SETTING: University hospital. PATIENT(S): One hundred eight postmenopausal women were assigned to four treatment groups: unopposed hormone therapy (HT) (n = 30), opposed HT (n = 48), tibolone (n = 18), and raloxifene (n = 12). INTERVENTION(S): Conjugated equine estrogens, CEE and medroxyprogesterone acetate, tibolone, and raloxifene were administered orally; blood samples were collected before therapy and 3 months after. MAIN OUTCOME MEASURE(S): Serum substance p levels were measured before and at the end of the third month of the treatment.The serum substance p levels were increased in the unopposed HT group after treatment. On the contrary, substance p levels were decreased in the opposed HT group, in the tibolone group, and in the raloxifene group. CONCLUSION(S): Addition of progesterone (P) to estrogen (E) treatment significantly decreases serum substance p levels. Tibolone and raloxifene exert the same effect.     

Long-term effects of tibolone on ocular functions in postmenopausal women

Hormone replacement therapy has been widely used for the prevention of postmenopausal osteoporosis and treatment of climacteric symptoms for many years, but its effect on ocular functions remains unclear. The aim of the study was to evaluate the long-term effects of tibolone on ocular functions in postmenopausal women. A total of 77 healthy women with at least 1 year of spontaneous menopause were enrolled in the study. Forty women were treated with tibolone for 6 months and 37 women were left untreated. All these patients underwent ophthalmic examination including visual acuity, intraocular pressure (IOP), tear functions, blue-on-yellow and white-on-white Humphrey visual field (HVF), visual evoked potentials (VEP) and electroretinography (ERG). There were significant differences in mean deviation of blue-on-yellow HVF, and oscillatory potentials (O1, O2, and O4) in the ERGs of the chronic tibolone users and the control (P < 0.0001, P = 0.001, P < 0.0001 and 0.05, respectively). However, no significant differences were observed in visual acuity, IOP, tear functions, white-on-white HVF and VEP. We concluded that, although tibolone had no effects on visual acuity, IOP, tear functions and VEP, it might cause some early adverse effects on the electrophysiologic and structural characteristics of the retina, which are detected by these sensitive assays. Randomized placebo-controlled studies with larger groups are needed in future research.     

Different effects of tibolone and continuous combined estrogen plus progestogen hormone therapy on sex hormone binding globulin and free testosterone levels--an association with mammographic density.

OBJECTIVE: To compare the effects of tibolone and continuous combined hormone therapy on circulating sex steroids and their binding proteins and their relationship to mammographic density. STUDY DESIGN: A prospective, double-blind placebo-controlled study. A total of 166 postmenopausal women were equally randomized to receive tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E2/NETA) or placebo. Serum analyses of sex steroids, insulin-like growth factor (IGF-I) and binding proteins and assessment of mammographic breast density were performed at baseline and after 6 months of treatment. RESULTS: Estrogens were markedly increased and androgens decreased by E2/NETA. In contrast, tibolone had only a minor influence on circulating estrogens. Sex hormone binding globulin (SHBG) levels were reduced by 50%, while levels of androgens increased. Baseline values of estrone sulfate (E1S), around 1.0-1.1 nmol/l, were increased to 44.7 nmol/l by E2/NETA and to only 1.7 nmol/l by tibolone (p < 0.001). Mammographic breast density displayed a negative correlation with age and body mass index and a positive association with SHBG. After 6 months there was also a negative correlation with levels of free testosterone.Conclusion We found that tibolone and E2/NETA caused distinct differences in estrogen/androgen status and blood levels of possible breast mitogens. The negative association between free testosterone and mammographic density could be a possible explanation for tibolone having less influence on the breast.     

Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women

OBJECTIVE: To compare changes in mammographic density and the expression of markers of proliferation (Ki67) and apoptosis (Bcl-2) after 1 year of treatment with tibolone and continuous conjugated equine estrogens combined with medroxyprogesterone acetate (CEE-MPA). DESIGN: Comparative, randomized, evaluator-blinded study. SETTING: City research hospital. PATIENT(S): Thirty-seven postmenopausal women. INTERVENTION(S): Tibolone (2.5 mg; n = 18) or continuous conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (5 mg; n = 19) for 1 year. MAIN OUTCOME MEASURE(S): Mammographic density (BI-RADS density score), expression of immunohistochemical markers Ki67 and Bcl-2. RESULT(S): Mean breast density score decreased significantly from 2.22 to 1.67 in the tibolone group, compared with a significant increase in the CEE-MPA-treated group from 1.84 to 2.63. Ki67 expression decreased in 12 of 15, increased in 2 of 15, and remained unchanged in 1 of 15 subjects in the tibolone group, compared with 1 of 19, 15 of 19, and 3 of 19 subjects, respectively, in the CEE-MPA group. Bcl-2 expression decreased in 12 of 15, increased in 2 of 15, and remained unchanged in 1 of 15 subjects in the tibolone group, compared with 5 of 19, 9 of 19, and 5 of 19 subjects, respectively, in the CEE-MPA group. CONCLUSION(S): One-year treatment with tibolone induced a decrease in breast density, with a reduction in proliferation and a stimulation of apoptosis, whereas 1-year treatment with CEE-MPA induced an increase in breast density, with stimulation of proliferation and inhibition of apoptosis, indicating that tibolone effects on the breast are different from those of CEE-MPA.     

Effect of hormone replacement therapy,tibolone and raloxifene on serum lipids,apolipoprotein A1, apolipoprotein B and lipoprotein(a) in Greek postmenopausal women

The aim of this study was to assess the effect of estrogen, two regimens of continuous combined hormone replacement therapy (HRT), tibolone and raloxifene on serum lipid, apolipoprotein A1 and B and lipoprotein(a) levels in Greek postmenopausal women. A total of 350 postmenopausal women were studied in a prospective open design. Women were assigned to one of the following regimens depending on the presence of risk factors for osteoporosis, climacteric symptoms and an intact uterus: conjugated equine estrogen 0.625 mg (CEE, n=34), continuous combined CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 5 mg, (n=80), continuous combined 17β-estradiol 2 mg plus norethisterone acetate (NETA) 1 mg (n=58), tibolone 2.5 mg (n=83) and raloxifene HCl 60 mg (n=50). Forty-five postmenopausal women with no indications for HRT served as controls. Total cholesterol (TC), low-density lipoprotein (LDL) cholestrol and high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein A1 (ApoA₁), apolipoprotein B (ApoB) and lipoprotein(a) (Lp(a)) levels were assessed in each subject at baseline, and at 6 and 12 months of therapy. All therapy regimens lowered TC levels compared to baseline (4.2-8.0% decrease). This effect was more prominent in the subgoup of women with high baseline TC levels (9.1-20.4% decrease). LDL cholesterol decreased significantly in CEE, CEE/MPA and raloxifene groups (?11.2%, ?11.9% and ?11.0%, respectively). Hypercholesterolemic women exhibited a steeper decrease in LDL cholesterol (10.6-27.8% in all therapy groups). TG levels increased significantly in the CEE and CEE/MPA groups (23.7% and 21.8%, respectively), while estradiol/NETA had no effect on TG levels. Tibolone decreased TG levels markedly, by 20.6%, while raloxifene had no TG-lowering effect. HDL cholesterol and ApoA₁ were increased by CEE and CEE/MPA (HDL cholesterol, 7.4% and 11.8%, respectively; ApoA₁, 17.8% and 7.9%, respectively) and decreased by tibolone (HDL cholesterol, ?13.6%; and ApoA₁, ?9.9%). All therapy regimens except raloxifene lowered Lp(a) levels, with tibolone having the more pronounced effect (?13.2 to ?29.0%). In conclusion, each therapy regimen had a different effect on lipid-lipoprotein levels, exerting favorable and unfavorable modifications. Hypercholesterolemic women seemed to benefit more from the cholesterol-lowering effect of estrogen replacement therapy/HRT. The choice for a particular regimen should be based on individual needs, indications and lipid-lipoprotein profile.     

Estradiol/progesterone-releasing vaginal rings for hormone replacement therapy in postmenopausal women

In order to investigate whether vaginal rings delivering estradiol and progesterone could prevent endometrial hyperplasia and relieve climacteric symptoms ,two variants of rings were used in 20 postmenopausal women with intact uteri for 4 months. One ring designated as PI-002 (n = 8) delivered in vitro estradiol 160 μg/day and progesterone 20 mg/day ,while the other (PI-003; n = 12) delivered the same dosage of estradiol but only half the progesterone (10 mg/day). Serum estrone ,estradiol and progesterone were measured at pretreatment ,weekly for 4 weeks ,and then monthly for 4 months. The incidence of hot flushes ,frequency of night sweats ,mood scores ,vaginal discharge and bleeding profiles were recorded. Endometrial thickness was monitored by ultrasonography. The mean estrone level was 50 pg/ml for 16 weeks. The mean serum estradiol level was 75 pg/ml for the first 4 weeks and gradually decreased to 50 pg/ml at 16 weeks. The mean progesterone level with the PI-002 ring was 5 ng/ml for the first 4 weeks and decreased to 3.5 ng/ml at 16 weeks. With the PI-003 ring ,the mean progesterone level was initially 3.5 ng/ml and then decreased to 2.5 ng/ml thereafter. Significant decreases in the incidence of hot flushes and night sweats as well as a striking improvement in mood scores were noted as early as 2 weeks after insertion. Three of the 20 women discontinued the treatment ,owing to ring expulsion. Increased vaginal discharge was observed with both rings in the first 6 weeks. Vaginal bleeding was more frequently apparent among users of the PI-002 ring ,although bleeding and spotting were confined to the first 6 weeks. Ultrasonographic monitoring of the endometrium constantly revealed a thickness of < 3 mm for both variants throughout use for 16 weeks. An estradiol/progesterone-releasing vaginal ring is a potential alternative to long-term hormone replacement therapy with minimum attention required. It provides effective protection against endometrial hyperplasia.