Add-back medrogestone does not prevent bone loss in premenopausal women treated with goserelin.

To investigate the effect of medrogestone on bone mineral density (BMD) and bone turnover under conditions of estrogen withdrawal, premenopausal women with endometriosis were treated with goserelin (Zoladex), combined with either placebo (group A, n = 12) or 10 mg medrogestone (Prothil, group B, n = 11) for six months, and followed for an additional six months. Lumbar spine BMD was measured at 0 and 6 month. Markers of bone turnover were serum bone alkaline phosphatase (sBAP) and osteocalcin (sOC) by ELISA, and urinary total pyridinoline (uPYD) and deoxypyridinoline crosslinks (uDPD) by HPLC. Patients in both groups had a similar and significant decrease in BMD after 6 months (4%, p < 0.01). The time course of changes in bone turnover, in contrast, was different in both groups. In group A, crosslink excretion increased from one month onwards, while no changes were seen in group B. In group A, sBAP levels rose during treatment, while in group B, this rise was delayed until treatment was terminated. Additionally, group B showed an initial suppression of sBAP and sOC. In both groups, sOC increased after treatment was discontinued. Medrogestone at 10 mg/d does not prevent lumbar bone loss in premenopausal women under estrogen deprivation. In the medrogestone add back group, the changes in bone turnover are compatible with low turnover bone loss,as ooposed to a state of high turnover seen in the unopposed goserelin group. This effect may be due to glucocorticoid receptor mediated actions of medrogestone on bone.

Efficacy and tolerability of a new 7-day transdermal estradiol patch versus placebo in hysterectomized women with postmenopausal complaints.

OBJECTIVES: To investigate the efficacy and tolerability of a continuously applied 7-day-Estradiol patch (Fem7, Merck KGaA, Germany) delivering 50 microg estradiol per day in the treatment of hysterectomized women with postmenopausal complaints compared with placebo. DESIGN: A multicentre, randomized, double-blind study with an initial screening phase (phase I), a 3-month double-blind placebo-controlled phase (phase II) and a 3-month open follow-up phase (phase III). METHODS: 186 patients were randomized for a 3-cycle placebo-controlled study followed by a 3-cycle open follow-up (total duration; 6 months). The changes in Kupperman Index (primary efficacy variable), hot flushes and urogenital symptom score were studied from baseline to the end of the study. In addition, skin tolerability was assessed and patients were also asked to grade the subjective acceptance of therapy. RESULTS: A reduction in Kupperman Index was observed in both groups, and at each cycle of the placebo-controlled treatment phase the 7-day-Estradiol patch was superior compared with placebo (last value vs. baseline P = 0.0006). From the second treatment week onwards a distinct difference was noted in the reduction of hot flushes from baseline between the 7-day-Estradiol patch group and the placebo group. The difference between the groups was statistically significant for each cycle and at the end of the controlled treatment phase (mean weekly hot flush reduction at the end of the placebo-controlled treatment phase: -32.5 for the 7-day-Estradiol patch vs. -22.0 for placebo, P = 0.0025). The efficacy of the 7-day-Estradiol patch within the application period did not show any difference between days 1-3 and 4-7. Subjective acceptance of the 7-day-Estradiol patch was good and 72.4% of patients who took active medication throughout the study were willing to consider continuing its use. CONCLUSIONS: The 7-day-Estradiol patch is well tolerated and provides effective relief of moderate to severe vasomotor symptoms in hysterectomized women, with a rapid onset of action and 7-day duration of therapeutic effect. Although a placebo effect was observed, the 7-day-Estradiol patch significantly reduced hot flushes and other menopausal symptoms throughout the application period.

Serum concentrations of FSH, oestradiol, oestrone and androstenedione in normal and obese women.

The normal ranges of the concentrations of follicle stimulating hormone (FSH), oestradiol (E2), oestrone (E1), and androstenedione (A) were established in 257 healthy women. The hormone levels of 84 normal post-menopausal women were compared with those from a group of 46 post-menopausal women with severe obesity (36.3 +/- 15.2 kg over the ideal weight). The increase of the FSH concentrations during the peri- and post-menopause occurs about 4 yr earlier in the obese than in the normal women. There is no significant difference, however, between the E2 levels of the normal and obese women. In the obese women, A (P less than 0.001) and E1 (P less than 0.05) levels are significantly lower than in the normal women. A weight reduction in the obese women had no influence on the concentrations of A and E2, whereas E1 levels tended to increase. FSH levels also increased significantly during weight reduction.

Endometrial safety and tolerability of AERODIOL(R) (intranasal estradiol) for 1 year.

OBJECTIVE: the purpose of this study was to assess the endometrial safety and patient acceptability of a pulsed estrogen therapy provided by S21400 (intranasal 17 beta-estradiol) in the treatment of postmenopausal symptoms. DESIGN: postmenopausal women (n=408) entered an open-label, community based, multicentre trial. Patients received S21400 plus sequential (>90% of patients) or continuous progestogen. Treatment was initiated with a standard daily dose of 300 microg but dose adaptation was possible every 3 months from 150 to 600 microg daily. Endometrial biopsies were performed at entry and at 12 months, and bleeding patterns were recorded at 3-monthly intervals throughout the trial. RESULTS: 71% of patients received 300 microg per day S21400 throughout the study, 3% had their dose decreased, 19% had their dose increased and 7% had their dose both decreased and increased. Three hundred and eleven biopsies were obtained after 12 months of treatment, there were no cases of endometrial hyperplasia. The 95% confidence interval [CI] for the rate of incidence was 0-1.2%. Cyclical bleeding occurred in 82% of sequential treatment cycles. Unexpected bleeding occurred in 5% of the treatment cycles. Presence of unexpected bleeding varied according to the treatment regimen, 15 and 4% of the cycles with combined continuous and sequential regimen, respectively. Unexpected bleeding was mostly spotting. Nasal treatment was well accepted. Nasal symptoms (itching sensation, rhinorrhea and sneezing) were mostly mild in intensity and they led to treatment withdrawal in approximately 3% of patients. The rate of treatment continuation was 85% at 1 year. CONCLUSIONS: S21400, in combination with continuous or sequential progestogen, exhibits good endometrial safety and patient acceptability in postmenopausal women.

Serum leptin levels and body weight in postmenopausal women under transdermal hormone replacement therapy.

Leptin, the adipocyte-specific product of the ob gene, is implicated in body weight regulation and energy balance. We investigated the influence of hormone replacement therapy (HRT) on the body mass index (BMI) and serum leptin levels in 20 postmenopausal, nonobese women treated with transdermal HRT (delivery rate 50 microg 17beta-estradiol/24 h, 1 patch per week) for 6 months. Serum leptin levels were measured by ELISA and results were compared by means of the Student's paired t-test or Pearson's correlation. The mean patient age was 55+/-6.04 years. The mean body weight prior to the start of the study was 69.39+/-9.37 kg, and the BMI before HRT was 26.92+/-4.47 kg/m2. Both parameters remained unchanged under therapy. No significant change in absolute serum leptin values (18.8+/-8.4 ng/ml; 20.47+/-9.7 ng/ml; 17.92+/-8.7 ng/ml at 0, 4 and 6 months respectively) or in adiposity-corrected values (serum leptin/BMI) (0.68+/-0.24; 0.75+/-0.29; 0.67+/-0.26 at 0, 4 and 6 months respectively) were found. Serum leptin levels correlated well with BMI (r = 0.7193, p<0.0001). There was no significant correlation of estradiol with serum leptin levels before or during therapy. In summary, low dose, transdermal HRT exhibited no influence on serum leptin levels or BMI in postmenopausal women. These data suggest that low dose HRT does not influence body weight regulation in postmenopausal women.

Influence of severe obesity on peripheral hormone concentrations in pre- and postmenopausal women.

To investigate the influence of obesity on hormonal parameters in 186 apparently healthy women and in 176 women suffering from severe obesity the serum concentrations of FSH, LH, estrone (E1), estradiol (E2), androstenedione (A) and testosterone (T) were determined radioimmunologically. The climacteric onset of increased FSH production is 4 yr earlier (P less than 0.001) in obese than in normal women. Parallel to the rise of FSH there is a significantly premature decrease of the E1 and E2 concentrations in obese women. The typical elevation of the LH was found similar and not significantly different in the two collectives. The mean A levels are significantly lower (P less than 0.01) in obese than in normal women in all age groups. The T concentrations do not depend on the age of the women during the investigated period (41 to 60 yr) and are significantly higher (P less than 0.001) in the obese than in the normal women. There is a significant (P less than 0.001) correlation between the concentrations of A and E1 both in the obese and the normal women. An increased conversion of androgens to estrogens by adipose tissue is not revealed by the peripheral serum concentrations. Our data clearly demonstrate that in obese women the onset of ovarian insufficiency is significantly earlier than in normal women.

Monitoring of HMG-stimulated follicular development by real-time ultrasound.

Monitoring of human follicular development by real-time ultrasound during HMG-HCG treatment is presented. With the aid of ultrasound monitoring, the ovulation rate is raised to 94.3% (formerly 80% without ultrasound). Serious side effects such as ascites and/or hydrothorax did not occur in this study (1.2% without ultrasound controls). The pregnancy rate was 21/47 (44%) of all hormonally treated patients. By means of real-time sector scan examination, the growing follicle could be detected in 103/106 (97.3%) of HMG-HCG treated cycles. Thus real-time ultrasound examinations provide results comparable to those achieved mostly by time-consuming compound scan in demonstration of the growing follicle.

Postmenopausal hormone replacement therapy and the vascular wall: epidemiology and clinical studies.

The clinical relevance of estrogen's multiple acute and more delayed effects on vascular wall structure and function is incompletely understood. This review attempts to reevaluate epidemiological findings and clinical studies concerning the vascular actions of estrogens and gives implications for strategies in postmenopausal hormone replacement therapy (HRT). There is large evidence from observational studies that HRT reduces the risk of cardiovascular mortality and morbidity in postmenopausal women. However, according to the only large randomized, placebo-controlled, secondary prevention Heart and Estrogen/progestin Replacement Study (HERS), women with prevalent cardiovascular disease (CVD) have increased CVD events within the first year after onset of HRT. The net effects of HRT on atherosclerosis, coagulation, fibrinolysis or the inflammatory response are unproven. Randomized trials of intermediate outcomes reveal that HRT has favorable effects on isolated cardiovascular risk factors, e.g. lipoproteins, carbohydrate metabolism and vasodilatation, but the impact of this effects on clinical endpoints is still not clear. The basis of "evidenced based medicine" is currently not sufficient to provide exact recommendation who will benefit from HRT and who might not. Therefore, the decision about hormone use should consider individual benefit-risk profiles.

[Alternatives to hormone replacement therapy: raloxifene and tibolone]. / Alternativen zur Hormonersatztherapie: Raloxifen und Tibolon.

The bone is an active metabolic organ influenced by many substances like calcium, vitamin D, bisphosphonates etc. The postmenopausal osteoporosis is mainly caused by estrogen deficiency and hormone replacement therapy (HRT) has been shown to prevent the progress of osteoporosis. The following paper describes two alternatives to the classical HRT: raloxifen and tibolon. Raloxifen belongs to the selective estrogen receptor modulators (SERM) showing an estrogen-agonistic effect on bone. There is evidence that bone mineral density (BMD) is growing with treatment. In a three year study (MORE), a statistically significant decrease of lumbar spine fractures was demonstrated (RR 0.5-0.7). Furthermore there was a statistically significant reduction of receptor positive breast cancer (RR 0.10). Raloxifen shows beneficial effects on the lipids and does not induce endometrial proliferation. In the field of climacteric complaints, it is an estrogen-antagonist and therefore inappropriate for this indication. Tibolon--a steroid hormone--and their three metabolites have estrogenic, gestagenic and weak androgenic effects on the different target organs. As expected, there is an increase of bone mineral density comparable to that of HRT or raloxifen; data of fracture rates with long-term therapy are missing. The substance and their metabolites are equivalent to HRT in the treatment of climacteric complaints. Tibolon shows some beneficial effects on the lipids and a lower bleeding rate compared to HRT. Raloxifen and tibolon are interesting alternatives to HRT which allow a more individual treatment of patients in the postmenopause.

[Endocrinological changes in pre- and postmenopause]. / Endokrinologische Veränderungen in der Prä- und der Postmenopause.

The endocrinology of the perimenopause--the time between pre- and postmenopause--is characterized by changes in the metabolism of the steroid hormones caused by increasing insufficiency of the ovaries. Until the age of 48 the concentrations of the estrogens are relatively constant with a median level of 120 pg/ml serum for estradiol and of 75 pg/ml for estrone. Between the age of 49 and 54 the levels decrease to concentrations of 35 pg/ml for estrone and 10 pg/ml for estradiol. In the corresponding time, there is a tenfold rise of the level of FSH. The level remains constant until high age. The decrease of the estrogens causes the menopause in an age of 51 to 52. In the postmenopause the ovaries don't play a role for the concentrations of the estrogens. The concentrations are determined by the conversion of the androgens secreted by the adrenal cortex. The serum concentrations of androstenedione are five times higher than those of testosterone. The function of the adrenal cortex remains until high age; there is no 'adrenopause' comparable to the 'menopause'. The suppression of the adrenal cortex by treatment with corticoids (e.g. for asthma) causes a dramatic decrease of the androgens and consecutively for the estrogens. The lack of estrogens play an important role in the induction of osteoporosis and other disturbances of the late postmenopause, e.g. coronary heart disease. Obese women show in the pre- and the perimenopause more often dysfunctional bleedings caused by anovulation or corpus luteum insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

[On the validity of artifical homologous insemination (AIH) (author's transl)]. / Uber den therapeutischen Wert der homologen Insemination.

After examination of ovarian and tubal function 246 women underwent 1238 AIH in 847 menstrual cycles. During the treatment period 74 patients became pregnant once or several times; altogether 99 pregnancies were observed. Whereas only 22 pregnancies occurred in cycles with AIH, the other 77 occurred in cycles without AIH. The ratio of pregnancies after AIH and those occurring without insemination decreases in relation to the degree of deterioration of the semen quality. With normal semen the ratio of pregnancies with AIH and those without AIH was 1:2.5. With semen of grade I this ratio became 1:4 and with grade II 1:10. On the basis of these results the following conclusions can be drawn: (1) with more or less normal semen quality and disturbance of the cervical mucus penetration AIH appeared to be reasonable; (2) with severe or even moderate subfertile semen findings AIH is not indicated; (3) an indication for AIH is the impossibility of cohabitation or ejaculation.

[Progress in sterility therapy. Gonadotropin treatment, monitoring follicle maturation using real-time ultrasonics]. / Fortschritte der Sterilitätstherapie. Gonadotropin-Behandlung, Uberwachung der Follikelreifung mittels Real-Time-Ultraschall.

Results of prospective examination of follicle development under HMG-HCG-therapy by real time scanning are discussed. 1979-1980 37 patients were treated with HMG-HCG, 82 cycles of treatment were evaluated. In 93% of these cycles ovulation occurred, 17 patients became pregnant. Slight overstimulation was seen in 5% (4 of 82 cycles of treatment). Real time scan monitoring of follicular development allows a more efficient treatment with HMG-HCG, also multiple gravidity might theoretically be reduced.

[Prenatal diagnosis of Meckel-Gruber's syndrome by ultrasound (author's transl(]. / Pränatale Diagnose des Meckel-Gruber-Syndroms durch Ultraschall.

The article reports on the ultrasonographic diagnosis of a Meckel-Gruber's syndrome in the 17th week of pregnancy. This malformation syndrome is characterized by the triad: encephalocele, polycystic kidneys, and polydactyly. This congenital disease is compared with malformation syndromes which are distinguishable by differential diagnosis, such as Potter's renofacial syndrome. Thorough ultrasonic examination will be able to detect the severe renal changes as well as the neural tube defects associated with Meckel-Gruber's syndrome. Further diagnostic aids for detecting neural tube defects are, in the first place, the alpha-fetoprotein values obtained from the serum of the mother and/or the amniotic fluid, as well as the determination of acetyl cholinesterase.

Steroids in human myometrium and peripheral blood during the menstrual cycle.

Blood samples were collected prior to vaginal hysterectomy from nine women in the proliferative phase of the cycle and from 15 women in the secretory phase, and from each uterus five grams of the fundus were obtained. The concentrations of progesterone (P), 20alpha-dihydroprogesterone (20alpha-DHP), estradiol-17beta (E2), and estriol (E3) were determined in serum and in the tissue with the use of specific radioimmunoassays. The concentrations of P and 20alpha-DHP in serum and myometrium were significantly higher in the secretory than in the proliferative phase. Furthermore, the concentration of P in myometrium was significantly higher than in serum in the secretory phase, indicating a specific uptake of P by the myometrium. The concentration of E2 was about 10 times higher in the myometrium than in the serum during both phases of the cycle and appeared to be independent of the serum levels. This indicates a specific but limited uptake of E2 by the myometrium. The E3 levels in the tissue showed no significant differences during the menstrual cycle, whereas in the serum the E3 concentrations were higher in the secretory than in the proliferative phase of the cycle.

[Endocrinology of the climacteric]. / Endokrinologie des Klimakteriums.

The endocrinology of the menopause is determined by the decrease of estrogens. In 250 healthy patients there was an observed decrease of estrone to 35 pg/ml and of estradiol to 10 pg/ml serum between the 49th and 54th year of age. Thereafter no further decline occurred, because the androgen precursors of the estrogens were secreted by the adrenal cortex until advanced age. In a period of 30 years there was a decrease of the androgen levels of only 25%. In 200 patients with severe obesity we found no differences in peripheral steroid concentrations, but the SHBC concentrations were significantly lowered; therefore, the amount of free active estradiol and the effect on the target organ is higher in these patients.

[Oral or transdermal estrogen substitution therapy in climacteric?]. / Orale oder transdermale Ostrogensubstitutionstherapie im Klimakterium?

There are several preparations available for hormone substitution in the postmenopause. The aim of this paper is to give a short review on oral and transdermal hormone substitution therapy. Are there different effects, side effects or metabolic interactions? Both the oral and the transdermal application are similar in reduction of menopausal symptoms. Neither vaginal cytologic differences, nor different bleeding patterns and no increase in weight or blood pressure changes can be observed with either application form. Despite a local irritation of the skin (3-7%) with transdermal oestradiol, only 4% of the patients show systemic side effects either with oral or transdermal hormone substitution. The oral administration results in higher 17 beta-oestradiol levels, higher oestrone levels and an increase in some liver proteins, possibly as a result of the first pass effect of the liver. The cardioprotective effects of oral hormone substitution are well known. Furthermore transdermal oestradiol therapy results, also in a decrease of cholesterol and atherogenic LDL-C levels. In contrast to oral oestrogens, no effect on triglycerides or its decrease can be observed; in view of conflicting results regarding HDL-C, further studies are necessary. With both applications, there are no clinically relevant alterations in thyroid, carbohydrate- or blood coagulation metabolism: Even the prevention of osteoporosis in postmenopausal women, which is establish with oral hormone therapy, can also be observed with transdermal hormone substitution.

[Amenorrhea rate after switch from sequential hormone replacement therapy to continuous combined administration of low dose estradiol and norethisterone acetate]. / Blutungsfreiheit nach der Umstellung von einer sequenziellen Hormonersatztherapie auf die kontinuierlich kombinierte Gabe von niedrig dosiertem Estradiol und Norethisteronacetat.

OBJECTIVE: Patient's wishes for a hormone replacement therapy (HRT) without withdrawal bleedings are decisive for a good compliance. Systematic experience concerning the bleeding profile when switching from a sequential hormone replacement therapy (s.c.HRT) to a continuous combined hormone replacement therapy (c.c.HRT) is sparse. This non-interfering study is designed to investigate the bleeding profile after such a switch. MATERIAL AND METHODS: 1 018 gynaecological centres recruited 3 917 patients pretreated with a s.c.HRT for this study. The switch from the s.c.HRT to the c.c.HRT was performed with a low-dose combination of 1 mg estradiol plus 0.5 mg norethisterone acetate (NETA). The bleeding profile was evaluated after 6 to 9 months of treatment according to the patient's diaries. RESULTS: Amenorrhoea was reached in 74.4 % of the enrolled patients after 3 months, in 90.6 % after 6 months, and in 92.1 % after 9 months of treatment. At the time of the switch to the c.c.HRT, already 32.4 % of the women were free of withdrawal bleedings. Parameters like age of the patients, body mass index (BMI), dosage of the estrogen during pretreatment did not influence the results considerably. 92.7 % of the physicians and 92.5 % of the women rated the combined treatment of 1 mg estradiol and 0.5 mg NETA (Activelle) as satisfactory. CONCLUSION: The switch from a s.c.HRT to a continuous combined treatment with 1 mg estradiol plus 0.5 mg NETA can be performed without problems, resulting in a high rate of amenorrhoea and a high acceptance of physicians as well as patients.

Estradiol and levonorgestrel: effects on bleeding pattern when administered in a sequential combined regimen with a new transdermal patch.

OBJECTIVE: A 1-year, randomized, multicenter study was carried out to assess the effects of estradiol/levonorgestrel, delivered transdermally by 7-day patches in a sequential combined regimen, on bleeding pattern and acceptability in postmenopausal women. METHODS: A total of 468 postmenopausal women were randomized to 15-cm2, 22.5-cm2 or 30-cm2 patches containing 17 beta-estradiol alone (50, 75 or 100 micrograms/24 h, respectively) for 2 weeks followed by 17 beta-estradiol/levonorgestrel (50/10, 75/15 or 100/20 micrograms/24 h) for 2 weeks. RESULTS: The occurrence of cyclic bleeds was dose-dependent, with an increase at higher dosages; the frequency of a cyclic bleed per treatment cycle was 40% in the 50/10 micrograms/24 h patch, 62% in the 75/15 micrograms/24 h patch and 76% in the 100/20 micrograms/24 h patch. The incidence of intermittent bleeding also increased with higher doses, from 22% in the 50/10 group to 35% in the 100/20 group; 20% of women in the 50/10 group did not bleed at all; the corresponding figures for the 75/15 and 100/20 groups were 7% and 0%, respectively. Time of onset of cyclic bleeding was constant in all groups. The mean duration of cyclic bleeding was constant within each group, but increased from 4.4 days in the 50/10 to 6.3 days in the 100/20 group. The regularity and predictability of cyclic bleeding were high in all groups. Recurrence of cyclic bleeds was acceptable for most women (90%). CONCLUSIONS: Sequential combined transdermal 17 beta-estradiol/levonorgestrel shows very good cycle control that is well accepted by postmenopausal women.