Efficacy on climacteric symptoms and safety of low dose estradiol transdermal matrix patches. A randomized, double-blind placebo-controlled study.

Two estradiol (E2) transdermal patches releasing 25 micrograms/day E2 (D-25) or 37.5 micrograms/day E2 (D-37.5) were compared to a placebo patch on 156 patients in natural or surgical menopause suffering from at least 5 hot flushes per day, randomly and blindly assigned to three parallel groups of 52 patients each, to be treated continuously for 12 weeks, without progestin opposition. "Responders" (patients with less than 3 hot flushes per day at the end of treatment), were 82% and 90% under D-25 or D-37.5, respectively, both significantly (p < 0.001) more than under placebo (44%). Comparable efficacy was observed on severity of hot flushes, Kupperman Index and on the self-rated efficacy. Systemic adverse events occurred in 10%, 10% and 8% of patients, respectively, under D-25, D-37.5 or placebo. Occasional mild and transient itching and/or erythema on the site of application was reported by few patients and did never require discontinuation of application. In conclusion D-25 and D-37.5 were significantly more effective than placebo in relieving climacteric symptoms and were systemically and locally as well tolerated as placebo. D-25 (Demestril 25) releasing 25 micrograms/day E2 can therefore be recommended for low-dosed estrogen replacement therapy.

[Postmenopausal osteoporosis in the Emilia-Romagna region. Extent of the problem]. / L'osteoporosi postmenopausale nella regione Emilia-Romagna. Dimensioni del problema.

BACKGROUND: The purposes of this paper are to summarise the epidemiological data concerning the frequency of postmenopausal osteoporosis and its related fractures in Emilia-Romagna, a province of northern Italy, and to determine the future impact of this disease. METHODS: To evaluate how many people suffer from postmenopausal osteoporosis it was decided to calculate the number of hospital admissions due to this disease or to its related fractures in postmenopausal women--included and excluded according to the ICD9-CM codes relative to the hospital discharges--during the years 1994 and 1995. RESULTS: The results show that incidence rates of these hospital admissions increase with age, as well as the number of osteoporotic fractures. Hip fractures, which represent a major problem due to their costs and consequences, are the more frequent osteoporotic fractures which need hospital admission, while it is possible that a large part of other fractures (which do not need hospitalisation or have been treated in private structures) has not been calculated. CONCLUSIONS: When projected to the population of women living in Emilia-Romagna in the future decade, also keeping the age-specific fracture rates constant, these data suggest that the occurrence of postmenopausal osteoporosis and of osteoporotic fractures will increase, with a dramatic escalation of economic and human costs. Finally, direct costs related to postmenopausal osteoporosis have been calculated for the decade 1995-2004.

Amenorrhea frequency with continuous combined hormone replacement therapy: a retrospective analysis. Menopause Study Group.

OBJECTIVES: The study retrospectively determined in postmenopausal women the cumulative amenorrhea patterns with continuous conjugated equine estrogens (CE) with or without continuous medroxyprogesterone acetate (MPA), and withdrawal bleeding patterns with cyclic therapy. METHODS: During a 1-year, prospective trial, all patients took CE. Groups A and B also took continuous MPA 2.5 and 5 mg, respectively, C and D took MPA 5 and 10 mg for the last 14 cycle days, respectively, and E took placebo to match MPA. RESULTS: By cycle 7, 40.4, 52.6 and 53.8% of women in Groups A, B and E, respectively, became amenorrheic. Percentages increased at each subsequent cycle. Of the remaining women in Groups A and B, 42.1 and 46.2%, respectively, experienced only spotting at cycle 7. In Groups C and D, 80 and 65.9%, respectively, had a mean change of equal to or less than 3 days in the onset of withdrawal bleeding/spotting from cycle to cycle for all 13 evaluable cycles. CONCLUSIONS: Amenorrhea is often desirable, and a continuous combined daily regimen of CE 0.625 mg + MPA 2.5 or 5 mg, which resulted in progressive increases in amenorrheic frequency during the 1-year treatment period, may promote compliance. In some women, however, the cyclic regimens, which produced fairly predictable withdrawal bleeding, may be preferable.

Bone density changes in postmenopausal women with the administration of ipriflavone alone or in association with low-dose ERT.

Ipriflavone is a synthetic flavonoid that has been shown to exert a direct inhibitory effect on osteoclastic activity and possibly stimulate the osteoblast activity in different experimental models. The aim of the present study was to evaluate the effects of either ipriflavone alone or ipriflavone plus low dose hormone replacement therapy (HRT) in the prevention of postmenopausal bone loss. Patients were randomly allocated to different treatment groups receiving calcium (500 mg/day, control group), continuous HRT (25 or 50 micrograms/day of transdermal 17 beta-estradiol) plus medrogestone 5 mg/day for 12 days/month, ipriflavone at the standard dose of 600 mg/day, or finally ipriflavone 600 mg/day plus 17 beta-estradiol 25 micrograms/day plus medrogestone 5 mg/day for 12 days/month. No significant differences in basal levels of biochemical markers of bone turnover or in basal bone mineral density (BMD) values were evident in the different groups. In the control group after 12 months, spine BMD showed a significant (p < 0.05) 3.41% decrease. The pattern of BMD modification was significantly different from controls in the high dose HRT group (+1.84%), the ipriflavone group (+0.11%), and the combined ipriflavone/HRT group (-0.22%). Conversely, the BMD pattern in the low dose HRT group (-0.55%) was similar to that observed in controls. Thus, present results confirm that ipriflavone and 50 micrograms/day of transdermal 17 beta-estradiol are effective measures in the prevention of postmenopausal osteopenia. A lower transdermal estrogen dose is unable to increase the antiresorptive effect of ipriflavone and did not exert any further action in the prevention of postmenopausal osteopenia.

Premenopause-dependent changes.

The authors retrospectively evaluated 1,773 climacteric outpatients in order to establish: (a) criteria able to distinguish different conditions in the transitional phase before menopause (advanced fertile age and premenopause) and (b) premenopause-related changes during the transition from one to the other of several clinical and laboratory parameters. Results showed an increase in gonadotropin plasma levels, a decrease in estrogen plasma levels and a greater frequency of women complaining of hot flushes in premenopause compared to advanced fertile age, as an expression of the progressive decline of ovarian function. Premenopause-related changes were a decrease in thyroid function and an increase in the body mass index, the beginning of bone loss, an increase in glucose, total cholesterol and triglyceride serum levels and a greater frequency of women complaining of hypertension and urinary stress incontinence. An increase in total proteins, uric acid and aminotransferase serum levels was also noted.

Effects of cyclic therapy with intranasal carbocalcitonin in healthy spontaneous postmenopausal women.

Carbocalcitonin spray administered for 12 months at a daily dosage of 80 U MRC according to five schedules has been tested on 150 normal spontaneous postmenopausal women for its influence on bone mineral density (BMD), bone metabolism and osteoarticular pain. BMD was monitored before and at the end of treatment in comparison with BMD of untreated control women. Metabolic markers (serum alkaline phosphatase, serum osteocalcin and urinary hydroxyproline) were also evaluated before and during treatment (at the 9th or 10th month of treatment). Osteoarticular pain was assessed by an analogic visual scale. Intranasal carbocalcitonin, administered according to cyclic schedules at a high frequency dosage, was able to maintain bone mass only in the earlier postmenopausal women. BMD percent increase after 12 months of treatment was 1.10 and 1.31 in women with low (< 0.870 mg/cm2) and high baseline BMD (> or = 0.870 mg/cm2), respectively. In advanced menopause the maintaining effect of carbocalcitonin on BMD seemed evident only if the baseline bone mass was lower than the BMD of the age matched control group. At least six months of treatment/year is necessary for effective therapy. Both systemic and local tolerance were optimal. No significant side-effects were detected.

Intramuscular interferon-beta treatment of cervical intraepithelial neoplasia II associated with human papillomavirus infection.

A placebo-controlled trial to evaluate the efficacy and the safety of intramuscular injection of interferon-beta has been performed on 37 patients suffering from cervical intraepithelial neoplasia II (CIN II) associated with human papillomavirus (HPV) infection of the cervix: twenty-two patients were treated with interferon-beta (2 x 10(6) I.U. daily) for ten days; fifteen received placebo (2 ml of saline solution daily) for ten days. Prior to therapy, and at day 70, 190, 370, 550, 730 after the beginning of treatment, patients were examined by colposcopy and punch biopsies of the cervix. Results showed a progressive amelioration in the interferon-beta treated patients, which was statistically significant at any control station (70, 190, 370, 550, 730 days) as compared to placebo treatment. Percentages of lesions that regressed, persisted or progressed were 36.4%, 54.5%, 9.1% respectively in the Interferon-beta group, and 0%, 67.7% and 33.3% respectively in the placebo group. Interferon-beta administered intramuscularly has shown to be an efficacious treatment of CIN II (cervical intraepithelial neoplasia II) associated with HPV infection, without evident side effects; it can be used in patients requiring medical treatment with at least one-year monitoring by cervical biopsies or as an adjuvant surgical treatment (which remains the principal treatment) in the management of patients suffering from CIN II associated with HPV infection.

Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Menopause Study Group.

OBJECTIVE: To compare the bleeding patterns obtained with two continuous combined and two sequential regimens of conjugated estrogens with medroxyprogesterone acetate (MPA) and conjugated estrogens alone. METHODS: This was a 1-year double-blind, randomized study done with 1724 postmenopausal women at 99 sites in the United States and Europe. All five treatment groups received 0.625 mg/day of conjugated estrogens. Groups A and B also took continuous daily doses of 2.5 and 5.0 mg of MPA, respectively. Groups C and D took 5.0 and 10.0 mg of MPA, respectively, for the last 14 days of each 28-day cycle. Group E took continuous daily doses of placebo to match MPA. RESULTS: The two continuous combined regimens (A and B) produced amenorrhea in 61.4 and 72.8%, respectively, of all evaluable cycles. Generally, the incidence of amenorrhea increased and irregular bleeding decreased with longer duration of treatment. In addition, amenorrhea occurred for at least the last seven consecutive cycles of the treatment year for about 40% of the patients taking the lower-dose continuous combined regimen (A), about 50% of the patients taking the higher-dose continuous combined regimen (B), and about 50% of the patients taking conjugated estrogens alone. About 5% of the patients who took either of the sequential regimens (C or D) had amenorrhea during that time. Most of the cycles (81.3 and 77.0% in groups C and D, respectively) for patients taking the sequential conjugated estrogens-MPA regimens had regular withdrawal bleeding or withdrawal spotting. There was no bleeding or spotting in 75.5% of the cycles for patients who took conjugated estrogens alone. CONCLUSIONS: Approximately half of the women who took the continuous combined conjugated estrogens-MPA regimens had amenorrhea, and the incidence tended to increase during the study. Women who took the sequential regimens had good cycle control with minimal irregular bleeding. More than half of those who took conjugated estrogens alone had amenorrhea.

Effects of an oral contraceptive combination containing 0.150 mg desogestrel plus 0.020 mg ethinyl estradiol on healthy premenopausal women.

Twenty-six healthy premenopausal outpatients from the Menopause Clinic of the University of Bologna were treated with a combination pill containing 0.020 mg of ethinyl estradiol and 0.150 mg of desogestrel for one year. Throughout the treatment period, clinical and laboratory monitoring was periodically performed, and women were asked about the occurrence of climacteric symptoms. This formulation relieved climacteric symptoms, and did not adversely affect lipids and clotting factors, except for a slight increase in serum triglycerides. Laboratory data also suggest a beneficial effect on bone metabolism.

[Italian multicenter study for the verification of the efficacy and tolerability of short-term substitution hormone therapy using conjugated estrogens and progestagens administered orally in the postmenopausal a period]. / Studio multicentrico italiano di verifica in merito all'efficacia ed alla tollerabilità della terapia ormonale sostitutiva a breve termine con estrogeni coniugati e progestinici per via orale nella postmenopausa.

Three hundred and sixty-three postmenopausal women received 6 months of cyclic hormone replacement therapy with conjugated estrogens in differing doses (0.625 mg and 1.25 mg) associated in a sequential pattern lasting 12 days with progestagens (medroxyprogesterone acetate or medrogestone) in 16 italian health centres. The results of the multicentre study confirm the efficacy of this conjugated estrogen-progestogen regimen in resolving climacteric syndrome, offering cardiovascular protection and vaginal trophic effect and preventing postmenopausal osteoporosis, as well as confirming its tolerability in relation to blood pressure, body weight, breast, endometrium, blood coagulation and hepato-renal function.

A randomized comparative study for the clinical evaluation of hormone replacement by transdermal and oral routes.

During a six-month randomized study involving 460 post-menopausal women, transdermal estradiol has proved to be as effective as oral conjugated equine estrogens in the control of menopausal symptoms and to produce similar estrogenic effects on the endometrium. The group of patients treated with transdermal estradiol showed better compliance and had fewer drop-outs. Moreover, the quality and duration of menstrual bleeding were considered more physiological in the transdermal estradiol group than in the orally treated patients. The trial was carried out with the co-operation of 17 Italian University Centres, under the supervision of Ciba-Geigy Italy S.p.A. Medical Department.

Analysis of the climacteric syndrome.

The climacteric syndrome (CS) was investigated in a large sample of women (over 4000) who spontaneously attended the Menopause Clinic at the University of Bologna between 1976 and 1986. The participants selected had received no hormonal replacement therapy for at least 6 mth or any other drug for at least 3 mth previously. They were all free from any disease that could influence any of the CS symptoms. The frequency of 12 symptoms considered typical of the CS was investigated. The interrelationships between these symptoms were determined as well as the frequency of the occurrence of individual symptoms in association with various climacteric complaints. The results indicated (a) that the CS is not uniform but both variable and individual, (b) that the frequency of its constituent symptoms remains high in advanced fertile age and the advanced postmenopause, (c) that the symptoms are preferentially interlinked, (d) that many, but not all, symptoms exhibit a differentiated pattern during the course of the natural and surgical menopause/age progression, and (e) that hot flushes and sweating, and to some extent insomnia and headache, are menopause-dependent.

Body mass index distribution in climacteric women.

Body Mass Index (BMI) was calculated in 2481 climacteric women selected from among the outpatients attending the Menopause Clinic at Bologna University in absence of hormonal replacement therapy and diseases that could cause weight gain. Analysis of variance of the W/H2 (weight/height squared) distribution in different age and climacteric situations demonstrates that the pre-menopause is a weight-gain inducing state and that ageing seems to cause a progressive increase in W/H2.

Dihydroergocristine in stopping lactation: double-blind study vs bromocriptine.

In a double-blind study vs bromocriptine, 30 women who wished to interrupt breast-feeding after a physiological delivery and at least 3 months of nursing were given at random 10 mg dihydroergocristine capsules or 2.5 mg bromocriptine capsules twice a day for 5 days, then 3 times a day for 5 days if treatment had failed to produce an effect. The parameters considered were PRL plasma levels, which were measured at baseline, on the 5th day and, where necessary, on the 10th day of treatment. Milk secretion, breast swelling and pain were recorded at baseline and daily during treatment. The appearance of any side-effect was accurately reported. A prolactin decrease was observed in both groups (p less than 0.01). After 5 days milk secretion was reduced more significantly in the dihydroergocristine group; after 10 days of treatment 6 cases treated with bromocriptine and 1 case treated with dihydroergocristine still revealed a low milk secretion. Breast congestion and pain were absent in both groups. As regards side-effects, a significant decrease in systolic blood pressure (standing position) was reported in the bromocriptine group. Other symptoms, such as nausea, vomiting, insomnia and headache, were reported in 8 patients in the bromocriptine group vs 6 patients in the dihydroergocristine group.

Non-invasive 24-hr monitoring of high blood pressure in climacteric outpatients.

Blood pressure (BP) monitoring was carried out over a period of 24 hr in 28 hypertensive women selected among the outpatients attending the Menopause Clinic at Bologna University. Seven (7) of the women (mean age 50 +/- 1 yr) were in the pre-menopause, 7 had undergone a natural menopause at 6 to 36 mth previously (mean age 52 +/- 4 yr) and a further 7 had had a natural menopause 37-120 months previously (mean age 56 +/- 5 yr). The control group was made up of 7 women in late fertile age (mean age 47 +/- 1 yr). It was found that: high blood pressure was not confirmed in all patients; there was a significant increase in systolic and diastolic BP values in natural post-menopause subjects (P less than 0.01) temporarily related to ovarian failure, but BP reached a steady state in elderly women when a new hormonal balance is established; 24-hr monitoring made it possible to identify a group of climacteric outpatients at higher cardiovascular risk whose suitability for antihypertensive treatment could thus be assessed.

Use of Org OD 14 for the treatment of climacteric complaints.

The effects of treating climacteric complaints in post-menopausal women were studied in an open trial in which Org OD 14, a placebo and no treatment were compared. In addition to the symptomatic effects, clinical and laboratory parameters were also studied. One hundred and twenty-four women who had undergone a natural or surgical menopause completed 4 mth of randomized treatment; 35 received Org OD 14 (2.5 mg/day, per os), 46 a placebo, and 43 no treatment. The mean ages and time in years since menopause were comparable for each group. The parameters were assessed before treatment and after 4 mth. The results in the group treated with Org OD 14 were compared statistically with those for the other two groups using the chi 2 test, Student's t test or analysis of variance. A beneficial effect on clinical parameters was seen following Org OD 14 treatment. The results as regards hot flushes and sweating were significantly better statistically than those in the other groups. Org OD 14 was found to have no effect on the endometrium, breasts, body weight or blood pressure, while vaginal atrophy was slightly improved. Serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and phosphate were slightly reduced by Org OD 14. Liver function tests, clotting factors and the other routine laboratory parameters were not affected by Org OD 14 treatment. It was concluded that Org OD 14 is an effective and safe compound for the treatment of climacteric syndrome.

Physiopathological aspects of body overweight in the female climacteric.

The correlation between overweight and the climacteric was studied in 550 menopause clinic patients by investigating certain clinical and sociocultural parameters (age, marital status, educational level, occupation and type of work, calorie intake, smoking habits, parity, blood pressure, previous hormonal therapy and climacteric symptoms), evaluating plasma levels of various hormones (17 beta-oestradiol, follicle-stimulating hormone (FSH), luteinizing (LH), testosterone, hydrocortisone, adrenocorticotrophic hormone (ACTH), triiodothyronine (T3), thyroxine (T4), growth hormone (GH) and insulin), glucose and various lipid fractions (total lipids, total cholesterol, nonesterified fatty acids (NEFA), triglycerides and phospholipids) and exploring the blood-clotting pattern ( Owren 's test, euglobulin lysis time, antithrombin III and prothrombin agglutination time (PAT). The subjects were classified as normal weight or overweight by reference to Broca's Index, as modified by Brusch , and the degree of overweight was determined by means of the Body Mass Index (BMI). Of the subjects examined, 49% were overweight and, in successive years following the menopause, there was a growing bipolarization of the weight increase. The correlation between overweight in the climacteric and the parameters considered was found to be significant only in regard to calorie intake, age and educational level. Post-menopausal gonadotrophin levels in blood were significantly lower in the overweight than in the normal-weight women. With the onset of menopause, the plasma level of testosterone fell in the normal-weight women, while it increased, along with that of hydrocortisone, in the overweight women. In the normal-weight women at menopause, it was found that there was a tendency towards a substantial increase in lipid fractions and glycaemia, as well as a state of hypercoagulability. In the overweight women, the tendency was towards an even more marked increase in both glycaemia and the various lipid fractions, and, besides the hypercoagulative state, there was an associated reduction in fibrinolytic activity. It is concluded that the menopause not only causes metabolic changes but also aggravates the metabolic and endocrine tendencies which characterize overweight subjects and thus, clinically, constitutes an obesity risk factor in those women who already demonstrate a tendency towards overweight in the pre-menopausal phase.

A study of thyroid function in the pre- and post-menopause.

Serum levels of thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), free triidotthyronine (FT3), free thyroxine (FT4) and thyroxine-binding globulin (TBG) were measured in 382 healthy women who were attending a menopause clinic. Of these women, 140 were in the pre-menopausal phase, 162 had been post-menopausal for less than 3 yr and 60 had been post-menopausal for greater than 3 yr. Analysis of the results as a function of climacteric situation, revealed that the only significant difference was a lower serum concentration of FT3 in the women who had been post-menopausal for over 3 yr than in the women who were in the pre-menopausal phase. Statistical analysis of the results as a function of both climacteric situation and age showed that the serum level of TBG increases with age, while serum levels of circulating thyroid hormones decrease, and that although the menopause does not bring about marked changes in thyroid function, it nevertheless tends to reduce that function, especially when menopause occurs at the expected time. Finally, by correlating values with T4 values on an individual basis, it was possible to ascertain that when physiological changes in thyroid function do occur in the climacteric, they are not caused by primary changes in TSH secretion.

Female sexual activity as a function of climacteric conditions and age.

By establishing a statistical profile of the average sexual behaviour of women during the climacteric period, an attempt was made to determine what influence the climacteric had on female sexual activity. With the advancement of age, the sexual activity of women tends to decline. The menopause itself tends to further reduce the retrogression of the sexual activity in women.