Improved bleeding profile and tolerability of tibolone versus transdermal E2/NETA treatment in postmenopausal women with female sexual dysfunction.

OBJECTIVES: To compare the incidence of vaginal spotting/bleeding events and breast pain between therapy with tibolone 2.5 mg and continuous combined transdermal estradiol (E(2))/norethisterone acetate (NETA) 50 microg/140 microg after 24 weeks of treatment. METHODS: A double-blind, double-dummy, randomized, controlled trial was performed and assessments were performed at baseline, week 12 and week 24. Bleeding/spotting events were recorded in a daily diary. Breast signs and symptoms were collected as adverse events. RESULTS: A total of 403 women (mean age 56 years) were randomized. Bleeding/spotting events during weeks 1-12 with tibolone and E(2)/NETA were experienced by 16% and 56% of women, respectively (p < 0.001). The corresponding percentages during weeks 13-24 were 12% and 51%, respectively (p < 0.001). E(2)/NETA was significantly more likely than tibolone to be associated with vaginal hemorrhage (11% vs. 0%; p < 0.001) and breast signs and symptoms (11% vs. 4%; p = 0.015). Early discontinuations resulting from adverse events were significantly more common in the E(2)/NETA group than in the tibolone group (20% vs. 12%), primarily related to withdrawal due to vaginal hemorrhage (8% vs. 0%). CONCLUSIONS: Tibolone has a significantly better tolerability profile than transdermal E(2)/NETA as measured by vaginal bleeding, breast pain and treatment continuation.

Treatment with percutanous testosterone gel in postmenopausal women with decreased libido--effects on sexuality and psychological general well-being.

OBJECTIVES: To elucidate if percutanous treatment with 10mg testosterone per day could enhance sexuality and psychological well-being in postmenopausal women presenting problems with low libido. Secondary to study the influence on blood lipids, hemoglobin and erythropoietin levels. METHODS: Fifty-three postmenopausal women participated. As a complement to their already on-going HRT, 10mg of a testosterone gel (Testogel, Besins-Iscovesco) or placebo was administered. Treatment continued for three plus three months in a double blind, randomized, crossover design. RESULTS: The scores concerning "frequency of sexual activity, orgasm and intercourse", "sexual arousal, fantasies and enjoyment", "satisfaction with orgasms", and "interest in sex" were all significally improved for testosterone addition as compared to placebo both before and after crossover. Testosterone levels increased more than 10-fold during treatment while DHT-levels were more than doubled. Estrogen levels were not affected during the addition of testosterone. Liver enzymes, total cholesterol, triglycerides, HDL and LDL revealed no significant differences between any of the periods or groups. Endometrial thickness did not change significantly during treatment. Hemoglobin and erythropoietin remained unchanged. No significant differences in the number of experienced side effects were found. CONCLUSION: Testosterone gel of 10mg had positive effects on several aspects of sexual life such as frequency of sexual activity, orgasm, arousal, fantasies and sexual interest in postmenopausal women on HRT. Several psychological variables were positively influenced. The given dose resulted in too high serum levels. Even if no negative effects were observed, monitoring of serum levels and a decreased dose should be considered in future studies.

Effects of combined estrogen/testosterone therapy on bone and body composition in oophorectomized women.

OBJECTIVE: To evaluate the effect of adding testosterone undecanoate 40 mg daily to estrogen therapy on bone markers, bone mineral density and body composition in oophorectomized women. METHODS: Fifty women, 45-60 years old, who had undergone a hysterectomy and bilateral salpingo-oophorectomy for benign disorders, were randomly assigned to oral treatment with testosterone undecanoate 40 mg plus estradiol valerate 2 mg daily or placebo plus estradiol valerate 2 mg daily. Twenty-four weeks later, cross-over was performed to the other treatment regimen. Forty-four women completed the study. Their serum concentrations of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, osteocalcin, carboxyterminal telopeptide aminoterminal (ICTP), of type I collagen propeptide of type I procollagen (PICP) and interleukin (IL)-1 receptor antagonist were measured at baseline and after 24 weeks of both treatments, as were also their body mass index (BMI) and blood pressure. Bone mineral density of the total body, spine and hip and total body fat, total lean body mass, trunk fat and trunk lean mass were determined by dual-energy X-ray absorptiometry measurements at baseline and after 24 weeks of both regimens. RESULTS: During treatment, the addition of testosterone counteracted the decrease in IGF-I and PICP seen with estrogen therapy alone. Osteocalcin and ICTP were significantly reduced to the same extent by both therapies. No change ocurred in the IL-1 receptor antagonist. A significant increase was seen in total lean body mass with the estrogen/testosterone regimen, but the total fat mass, trunk lean or fat mass remained unchanged after 24 weeks of both treatments. No effect was detected on total, hip or spinal bone mineral density after treatment with estrogen alone or estrogen/testosterone. Likewise, BMI and blood pressure were unaffected. CONCLUSIONS: The addition of testosterone to oral estrogen might have positive effects on bone as suggested by the fact that it counteracted the decline in IGF-I and PICP levels. An anabolic effect on muscle was reflected by an increase in the total lean body mass. No adverse effects were noted on BMI, fat distribution or blood pressure during the 6-month treatment with oral testosterone undecanoate.

Serum lipids in oophorectomized women during estrogen and testosterone replacement therapy.

OBJECTIVE: To evaluate the effects of giving testosterone undecanoate (TU) in addition to estrogen replacement on serum lipids in oophorectomized women. METHOD: Women with surgically induced menopause (n = 50) were randomly assigned to oral treatment with 2 mg of estradiol valerate in combination with 40 mg of TU or placebo for 24 weeks. The study was double-blind with cross-over to the other regimen for further 24 weeks of treatment. Forty-four women completed the study. Their serum concentrations of total, high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol, triglycerides, lipoprotein-(a) (Lp-(a)), total testosterone, estradiol and sex hormone-binding globulin (SHBG) were analyzed at baseline and after 24 weeks of each treatment. RESULTS: Serum levels of total testosterone increased markedly from a baseline mean of 0.8-4.9 nmol/l during testosterone addition. The levels of free testosterone significantly increased during the combined treatment and fell when given estrogen alone. Total and LDL-cholesterol levels were significantly reduced by both treatments as also were those of Lp-(a) although the difference was not significant. We found a 13% reduction in HDL-cholesterol levels when testosterone was added, but no change with estrogen alone. Triglyceride levels were increased by estrogen treatment, but not affected by the combination of estrogen plus testosterone. CONCLUSIONS: These findings suggest that 40 mg of TU can be given in addition to estrogen replacement with only little side-effects on the pattern of circulating lipids. Although supraphysiological concentrations of testosterone were induced a significant reduction in total and LDL-cholesterol levels occurred.

Addition of testosterone to estrogen replacement therapy in oophorectomized women: effects on sexuality and well-being.

OBJECTIVE: To evaluate the effect of adding testosterone undecanoate 40 mg daily to estrogen replacement on sexual function, psychological well-being and self-esteem in surgically postmenopausal women. METHODS: A letter of invitation to participate in the study was mailed to women who had undergone hysterectomy and bilateral oophorectomy for benign disorders during 1990-98. Fifty women, 45-60 years old, were consecutively recruited and randomly assigned to oral treatment with testosterone undecanoate 40 mg plus estradiol valerate 2 mg daily or placebo plus estradiol valerate 2 mg daily for 24 weeks. A double-blind design was chosen, with cross-over to the other regimen for another 24 weeks of treatment. Forty-four women completed the study. Outcome included scores on McCoy's sex scale questionnaire, the Psychological General Well-Being index and a self-esteem questionnaire, at baseline and after 24 weeks of either treatment. Serum concentrations of total testosterone, sex hormone binding globulin, free testosterone, dihydrotestosterone, androstenedione, estradiol, follicle stimulating hormone and luteinizing hormone were analyzed at baseline and after 24 weeks of both treatment regimens. RESULTS: After 24 weeks, both treatment regimens had significantly improved some of the sexual variables. The addition of testosterone had a significantly better effect on the sex variables 'enjoyment of sex', 'satisfaction with frequency of sexual activity' and 'interest in sex'. The total McCoy score was significantly increased by both treatments, but there was a stronger effect when testosterone was also given. Although both regimens improved psychological well-being and self-esteem, we found no significant differences between testosterone-estrogen or estrogen alone at 24 weeks. Serum levels of all androgens, with considerable individual variation, increased significantly from baseline after 24 weeks of testosterone-estrogen treatment. Supraphysiological levels were achieved in a significant proportion of the women. Increases in estradiol and sex hormone binding globulin were less marked when testosterone was also given. Both treatments reduced gonadotropin levels. CONCLUSIONS: The addition of testosterone undecanoate improved specific aspects of sexual function more than treatment with estrogen alone. Improvements in well-being and self-esteem were similar for both treatments. If testosterone undecanoate 40 mg daily should be used for clinical treatment, regular monitoring of androgen serum levels is needed.

An evaluation of the QSP and the QPP: two methods for measuring patient satisfaction.

BACKGROUND: Patient satisfaction is a function of several variables addressing reasons why it is important to use methods in which these different factors can be isolated and their importance analysed. OBJECTIVE: In this project, two methods using this approach were used: the 'Quality from the Patient's Perspective' and the 'Quality, Satisfaction, Performance' models. The aim of the present study is to evaluate these two different methods with respect to application, strengths and weaknesses. DESIGN: In the Quality from the Patient's Perspective model, the patient judges the different domains in two dimensions: perceived reality and subjective importance. The Quality, Satisfaction, Performance model uses a multivariate analysis to capture the patient's priorities. Four hundred and sixty forms for each model were distributed to a random sample of patients at the Department of Obstetrics and Gynecology at Karolinska Hospital. MAIN MEASURES: The quality factors 'treatment by the nurse', 'participation', 'information', 'environment' and 'accessibility' were measured. RESULTS: On both forms, 'medical care', 'treatment by the doctor' and 'access to nursing treatment' received high scores in perceived reality' while 'accessibility' and 'participation' received low scores. 'Subjective importance' measured directly and indirectly, respectively, in the two models showed high values for 'medical care' and 'treatment by the doctor'. CONCLUSION: The advantages of the Quality from the Patient's Perspective model are that it has a comprehensive and solid question bank. The Quality, Satisfaction, Performance model's advantage is its immediate usefulness and its clear graphic presentation. An integration and further development of these two approaches may prove useful.

Administration of testosterone undecanoate in postmenopausal women: effects on androgens, estradiol, and gonadotrophins.

OBJECTIVE: To investigate serum androgens, estradiol, and gonadotrophins after treatment with testosterone undecanoate 40 mg daily in postmenopausal women. DESIGN: Ten postmenopausal women received 40 mg testosterone undecanoate orally every day for 4 days. Blood samples were drawn before and 2, 4, 6, and 8 hours after administration on the first day and then at 24, 48, 72, and 96 hours after administration of the first dose. Serum concentrations of testosterone, dihydrotestosterone, androstenedione, estradiol, sex hormone-binding globulin, follicle-stimulating hormone, and luteinizing hormone were analyzed. RESULTS: A rapid absorption of testosterone undecanoate was found with the highest concentrations of testosterone, dihydrotestosterone, and androstenedione 2-4 hours after administration. Significant increases from basal values were found for serum testosterone, dihydrotestosterone, androstenedione, and estradiol and a slight but significant decrease for sex hormone-binding globulin. Serum follicle-stimulating and luteinizing hormone levels were unchanged. Median levels of 3.2 nmol/L for testosterone and 3.6 nmol/L for dihydrotestosterone were recorded after the first day. CONCLUSIONS: Testosterone undecanoate displayed a rapid absorption and turnover and may offer an alternative for androgen treatment in women. Expanded pharmacokinetic studies in larger and more homogeneous groups of postmenopausal women should be performed. The individual variations were considerable, and regular monitoring of testosterone serum levels to avoid overtreatment is recommended.

[Patient preferences or cost-effectiveness? Priorities are highly affected by introduction of economic dimension]. / Patientönskemål eller kostnadseffektivitet? Prioriteterna påverkas högst påtagligt då en ekonomisk dimension införs.

In recent years various methods to measure patient satisfaction have been applied as part of quality improvement programmes in the health services. However, the statistical quality as well as the applicability and change-orientation of the methods have been questioned. Furthermore, most methods pay no attention to economic aspects. Even a methodologically well-founded measurement of patient satisfaction may lead to wrong conclusions unless economic consequences are taken into consideration. It is possible to carry out an integrated analysis that includes patient preferences as well as economic aspects.

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 17beta-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.

Effect on sexual life--a comparison between tibolone and a continuous estradiol-norethisterone acetate regimen.

OBJECTIVES: to compare the effects of tibolone 2.5 mg (Livial) with those of 17 beta-estradiol 2 mg plus norethisterone acetate 1 mg (Kliogest) on sexual life. METHODS: in a 48 week, double blind, multicenter study, 437 postmenopausal women were randomised to treatment with either tibolone or 17 beta-estradiol 2 mg plus norethisterone acetate. Treatment groups were compared with respect to different aspects of sexual life with a questionnaire covering sexual experience and responsiveness during the last 30 days. RESULTS: a total of 315 subjects completed 48 weeks treatment. In the E2/NETA group an improvement after 48 weeks compared to baseline was observed in five out of seven items assessing sexual life. In the tibolone group an improvement regarding all seven items assessing sexual life was seen. When tibolone was compared to E2/NETA significantly higher scores were found for the items assessing 'frequency', 'satisfaction' and 'enjoyment'. CONCLUSIONS: this study indicate that tibolone and E2/NETA -which both have an androgenic profile-affect several aspects of sexual life positively. The difference with respect to satisfaction with sexual enjoyment and frequency could be of clinical importance.

Renal elimination of ceftazidime during pregnancy.

OBJECTIVE: Our purpose was to study the pharmacokinetics of ceftazidime at different stages of pregnancy and in the nonpregnant state to determine whether glomerular filtration rate is altered and whether tubular secretions occurs. STUDY DESIGN: Twelve pregnant women with asymptomatic bacteruria were given a bolus dose of 400 mg of ceftazidime followed by a constant infusion for 4 hours. Inulin was infused simultaneously to determine glomerular filtration rate. Blood samples were drawn every 30 minutes. Urine was collected immediately after the bolus dose and then every hour. The same study procedure was then repeated twice: 2 weeks before the expected delivery and after termination of breast-feeding. RESULTS: At term clearance values were raised by 50% to 100% compared with the values found in the postpartum period. At all observation points a close correlation between inulin and ceftazidime clearance values were found. CONCLUSION: The results strongly indicate that ceftazidime is excreted exclusively by glomerular filtration with no tubular reabsorption. During pregnancy the excretion pattern is unaltered, but renal elimination is increased.

Effects of oophorectomy and estrogen treatment on basal levels and 24-h profiles of oxytocin.

The regulation of oxytocin is incompletely understood and data indicate that in addition to several neurotransmitters, estrogens may be involved. The aim of the present study was to investigate the effects of oophorectomy and hormonal replacement therapy (HRT) on basal levels and 24-h profiles of oxytocin. Basal levels of oxytocin were measured in 95 women who had undergone hysterectomy and who were divided into three groups: group A (n = 30), oophorectomized (BSO), not on HRT; group B (n = 32), BSO, receiving HRT; and group C (n = 33), ovaries preserved and not receiving HRT. The 24-h profiles of oxytocin were measured in nine women before and after hysterectomy. Continuous venous blood sampling was performed 1 week before surgery and 6-7 weeks after surgery for all nine women. Thereafter, three of the four oophorectomized women started replacement therapy with transdermal estradiol 50 micrograms/day. After 10 weeks of treatment, a third sampling was performed. Exogenous estrogen administration was associated with increased oxytocin levels and negative correlation between oxytocin and follicle stimulating hormone/luteinizing hormone levels was found. Removal of the ovaries did not reduce oxytocin levels in any of the investigated groups. When 24-h values were analyzed, no specific rhythmic or pulsatile pattern before or after hysterectomy, with or without simultaneous oophorectomy, was found.

Elective ovarian removal and estrogen replacement therapy--effects on sexual life, psychological well-being and androgen status.

Conflicting data have been reported on the psychosexual impact of hysterectomy combined with bilateral oophorectomy. Three age-matched, hysterectomized groups of women were investigated: Group A (n = 33): oophorectomized, not receiving estrogen replacement therapy (ERT); Group B (n = 33): oophorectomized, receiving ERT; and Group C (n = 35): ovaries preserved and not receiving ERT. The McCoy Sexual Rating Scale and the Psychological General Well-Being Index as well as a semi-structured interview were used to assess postoperative experience with respect to libido, vaginal lubrication, ability of getting pleasure from intercourse, and ability to achieve orgasm. Serum concentrations of total and free testosterone, insulin-like growth factor I (IGF-I), sex hormone binding globulin, dehydroepiandrosterone sulfate and 4-androstene-3,17-dione were determined. In oophorectomized women sexual life was impaired as compared to those with intact ovaries and these women complained about less pleasure from coitus, impaired libido and lubrication. Regardless of whether estrogens were administered or not a similar pattern was found, indicating that estrogens are of little value in treating these specific sexual dysfunctions. Oophorectomized women receiving ERT reported less anxiety and depression and more well-being similar to women whose ovaries had been preserved. No correlation was found between psychosexual variables and biochemical androgen markers. However, the IGF-I levels were strongly correlated to sexual activity and responsiveness.

Is sexual life influenced by transdermal estrogen therapy? A double blind placebo controlled study in postmenopausal women.

Two hundred and forty-two postmenopausal women between 45 and 65 years of age requiring hormone replacement therapy for climacteric symptoms were blindly and randomly allocated to treatment either with transdermal estradiol therapy (Estraderm 50 micrograms/24h) (E) or placebo (P). The patches were changed twice a week and treatment continued for 12 weeks. No progestogen supplement therapy was given during the study. No previous hormone replacement therapy had been given for the last six months and the women had had their last menstruation more than six months ago. As a part of a larger study assessing women's quality of life, a Swedish version of 'McCoy's Sex Scale Questionnaire' was administered at the start of treatment and after 12 weeks. This questionnaire contains nine items regarding different aspects of sexual life. The difference between the scorings at the start of treatment and after 12 weeks were calculated for each item and the values of the E and the P groups were compared. Items regarding 'satisfaction with frequency of sexual activity, sexual fantasies, degree of enjoyment, vaginal lubrication and pain during intercourse' were positively influenced in the E group compared to the P group. Items not affected were 'frequency of orgasm and sexual arousal'. A correlation between improved sexual life and quality of life was also found when the results from the McCoy scale were compared with a battery of quality of life questionnaires.

Consumer's attitude to hysterectomy. The experience of 678 women.

A total of 678 women were interviewed about symptoms before as well as advantages and disadvantages after abdominal hysterectomy. Medical complications, side effects, days of hospitalization and some possible differences between supravaginal hysterectomy (SVH) and total hysterectomy (TH) were also investigated. TH had been performed in 79% and SVH in 21% of the women. Leiomyoma was the most frequent diagnosis (79%). Heavy menstrual bleeding and dysmenorrhea were the dominant symptoms before surgery. After the operation, 71% of the women had no subjective gynecological complaints. Relief from heavy bleeding and pain was considered the major advantage and as many as 29% of the women experienced no disadvantage at all with the operation. Regarding sexual life, 39% experienced intercourse as much improved or better and 40% as unchanged. An intraabdominal abscess was more often found postoperatively in patients operated with TH than with SVH but with this exception no objective finding favoured one method more than the other. When new, alternative treatments such as endometrial ablation and GnRH analogues are introduced and promoted they should be subjected to careful evaluation and compared with the therapeutic efficacy of hysterectomy.

Psychological reactions and sexual life after hysterectomy with and without oophorectomy.

A total of 678 women were interviewed about psychological reactions and sexual adjustment after abdominal hysterectomy with and without simultaneous oophorectomy. The response rate was high and complete questionnaires were returned by 86% of the women. A more positive attitude towards the operation was found in the group of women where the ovaries had been preserved. Women who had undergone oophorectomy experienced a deteriorated sexual life compared to women with preserved ovaries. This was observed regardless of age and in different parameters such as 'coital frequency' and 'experience of intercourse'. The negative effects of sexual life as a result of hysterectomy with simultaneous oophorectomy are important to bear in mind and should be discussed with the woman prior to surgery.