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Objective: To determine bleeding patterns and endometrial response in postmenopausal women taking low-dose (1 mg) estradiol in a sequential combined formulation with 5 or 10 mg dydrogesterone., Methods: A total of 151 postmenopausal women were allocated randomly to 5 or 10 mg dydrogesterone during cycle days 15-28 in a sequential oral formulation with 1 mg estradiol continuously during 13 cycles of 28 days. Occurrence of vaginal bleeding was recorded daily and analyzed in accordance with World Health Organization (WHO) standards. Endometrial biopsies, obtained at baseline and cycle days 25-27 of the final treatment cycle, were interpreted independently by two pathologists., Results: The study was completed by 131 women (87%). The percentage of women with bleeding (mean +/- SD) was 57.2 +/- 3.6% in the 1/5-mg group and 65.8 +/- 4.2% in the 1/10-mg group (p < 0.001); cross-sectional analysis showed that, in every cycle, there were more women with bleeding in the 1/10-than in the 1/5-mg group (p < 0.001). With regard to the day of onset of bleeding, the mean difference between groups was 1.4 +/- 1.1 days (p < 0.001). There was no difference in duration of bleed (5 days), or intensity or incidence of intermittent bleeding (3-14% per cycle). Both regimens resulted in high rates of amenorrhea in each cycle (26-49%), but only 14/151 (9%) women were amenorrheic throughout. Three patients (2%) discontinued owing to bleeding problems. Endometrial protection was adequate in 98.3% (1/5-mg group) and 98.5% (1/10-mg group) with only one case of proliferation (1/10-mg group) and one of simple hyperplasia (1/5-mg group)., Conclusions: The bleeding pattern associated with low-dose (1 mg) estradiol sequentially combined with 5 or 10 mg dydrogesterone shows a high rate of amenorrhea in each cycle; there is a dydrogesterone dose effect on the occurrence and day of onset of bleeding. Bleeding episodes that occur show a regular pattern and are of slight intensity. The endometrial safety of both regimens is high.

Objectives: To compare transvaginal ultrasonography with histological findings in endometrial evaluation of postmenopausal women using hormone replacement therapy and to evaluate endometrial safety of three hormone replacement therapy regimens., Methods: In a randomized, comparative study in postmenopausal women, endometrial safety was evaluated using (1) no hormone replacement therapy, (2) oral micronized 17 beta-estradiol/oral sequential dydrogesterone, (3) transdermal 17 beta-estradiol/oral sequential dydrogesterone, or (4) oral tibolone. 85 Non-hysterectomised subjects underwent transvaginal ultrasonography immediately before Pipelle biopsy at baseline and subsequently after 12 and 24 months. Endometrial thickness and uterine dimensions were determined by transvaginal ultrasonography, and endometrial thickness (double-layer) was compared with biopsy results., Results: Endometrial evaluation was conveniently performed by transvaginal ultrasonography, and endometrial thickness correlated well with biopsy findings. If endometrial thickness was < 5 mm, the endometrial biopsy sample was either inactive/atrophic or insufficient for histopathological diagnosis. Hyperplastic or malignant changes were not reported. After 24 months, endometrial thickness was increased both in the oral (P < 0.001) and transdermal (P < 0.001) 17 beta-estradiol/dydrogesterone groups, whereas with tibolone the change in endometrial thickness was not different from controls., Conclusion: transvaginal ultrasonography of the endometrium reliably predicts the histological picture in hormone replacement therapy users. Using 5 mm endometrial thickness as cut-off point, more than 75% of biopsies could be avoided. All three hormone replacement therapies were safe with respect to the endometrium. With sequential 17 beta-estradiol/dydrogesterone the expected progestogen-induced secretory pattern was observed, whereas endometrial histology under tibolone closely mimicked the natural atrophic postmenopausal state.

Objectives: To determine the endometrial response and bleeding patterns in post-menopausal women who were given a sequential hormone replacement regimen with estradiol 2 mg and dydrogesterone 10 mg., Methods: One-hundred-and-eighty-eight (188) post-menopausal women with amenorrhea of 6 months or longer, with FSH/estradiol (E2) levels in the post-menopausal range and normal endometrium were entered in the study. All patients received a daily dose of 2 mg E2 during day 1-14 of each 28 day cycle and 2 mg E2 combined with 10 mg dydrogesterone during cycle day 15-28. The total duration of treatment was 12 months (13 cycles of 28 days)., Results: The rate of adequate progestational response (secretory or atrophic) in the 146 patients who remained in the study for at least 356 days with 90% study medication compliance and received an endometrial biopsy after 13 cycles of study medication was 97.2%. Three patients had proliferative endometrium and one simple hyperplasia. Cyclic bleedings in the 153 women who remained on study medication for at least 76 days occurred in over 85% of all cycles; the day of onset occurring regularly on day 13 or 14 of the combined period; the mean duration of bleeding per cycle was approximately 5 days with most patients having (very) slight bleeding. Sixty percent of patients had no intermittent bleedings over the whole 12-month study period. The average incidence of intermittent bleeding in the remaining patients was only 2.7 and generally of very slight quantities and of short duration. Per evaluable cycle the percentage of patients with an intermittent bleeding varies from 4.6 to 9.8%. Only two patients discontinued therapy because of bleeding problems. A clear decrease in the incidence of typical menopausal symptoms, i.e. hot flushes and night sweats was observed by the first visit after 6 weeks of treatment., Conclusions: The endometrial safety of 2 mg E2 sequentially combined with 10 mg dydrogesterone is very good as determined by the histologic response of the endometrium. The incidence of cyclic bleedings with this combination therapy is very high as is the regularity of day of onset and duration of bleeding. Blood loss during intermittent bleedings was mild and of short duration.

The effects of 6 months of hormone replacement therapy by transdermal estradiol patches (0.05 mg/day for 21 days) and oral progestogens (10 mg/day for 10 days) on hypothalamic-pituitary-ovarian function was evaluated in 32 perimenopausal women, aged 42-47 years, with irregular anovulatory cycles and menopausal symptoms. Hormone levels evaluated on the 8th and 24th day of the cycle preceding therapy showed follicle-stimulating hormone (FSH) levels above 15 mIU/ml, estradiol less than 45 pg/ml and progesterone less than 800 pg/ml. During therapy, there was an improvement in menopausal symptoms, a decrease in luteinizing hormone (LH) and FSH levels, an increase in estradiol levels and the transdermal patches were well tolerated. At the end of therapy, 19 women continued to have regular ovulatory cycles with progesterone levels similar to those in luteal phase. FSH and LH concentrations were significantly lower than before therapy. This study shows that hormone replacement therapy not only improves menopausal symptoms but may also restore the hypothalamic-pituitary-ovarian function.

The effectiveness of two treatment regiments in inducing withdrawal bleeding in secondary amenorrhea was compared and correlated with the endometrial thickness and endogenous E2 and progesterone concentrations. A prospective, randomized and double-blind study was designed at the Outpatient Clinic of Reproductive Endocrinology, Central Emek Hospital, Afula, Israel. Seventy-seven premenopausal women with oligomenorrhea or amenorrhea, 48 of whom qualified for the study, underwent a 5-day course of either medroxyprogesterone acetate (MPA) 5 mg b.i.d. or dydrogesterone (DG) 10 mg b.i.d. Endogenous pretreatment values of E2 and progesterone and endometrial thickness (by transvaginal ultrasonography) were correlated with the bleeding response. Withdrawal bleeding occurred in 93% of women taking either MPA or DG. Side effects occurred similarly among the groups. Lipid concentrations were unchanged. Endogenous E2 and progesterone were limited predictive value for withdrawal bleeding. Endometrial thickness as measured by transvaginal sonography correlated significantly with the bleeding response.

Objective: To compare the influence on lipid metabolism of two discontinuous, sequentially combined hormone replacement therapy (HRT) regimens., Study Design: In an open, randomized study in 60 women, a full lipid profile including Lp(a) and liver function tests were assessed in a fasting state at the end of treatment cycles 6 and 12. Group A was treated with 2 mg oestradiol valerate (days 1-21) sequentially combined with 1 mg cyproterone acetate (days 12-21); group B was treated with a patch releasing 50 micrograms oestradiol daily, twice a week (3 weeks), sequentially combined with 20 mg dydrogesterone (days 12-21) orally. Statistical analysis by two-sided one-way analysis of covariance (covariable is baseline) for adjusted means of lipid parameters and rank transformation analysis for lipoprotein(a) (Lp(a)) was performed., Results: Both groups were statistically comparable. The trial was completed by 45 subjects. Protocol violations occurred in 3 cases. Twelve subjects, equally divided between the groups, dropped out mainly because of adverse reactions. Both treatments were equally effective in the treatment of climacteric complaints. Liver function tests during the treatment period were normal in both groups. In group A, a statistically significant (P < 0.05) decrease versus baseline was observed in the serum levels (adjusted means) of the following parameters after 6 and 12 treatment cycles: total cholesterol (TC)-5% and -7%, respectively; low-density lipoprotein cholesterol (LDL-C) -13% and -14%, respectively; low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C ratio) -16% and -18%, respectively. Triglycerides (TG) levels were significantly increased by 28% and nearly significantly (P = 0.07) by 25% after 6 and 12 treatment cycles, respectively. In group B, all lipid parameters (with the exception of apolipoprotein A-II which was significantly decreased after 12 treatment cycles) remained unchanged during therapy. Statistically significant differences for all aforementioned variables were found between the groups after 6 and 12 treatment cycles, respectively, with the exception of TC after 12 treatment cycles. After 6 treatment cycles, Lp(a) was decreased significantly (-18%) in group A as compared with baseline; after 12 months the decrease was -17% without reaching statistical significance. In group B, Lp(a) showed a slight but not statistically significant tendency to increase by 2% and 12% after 6 and 12 treatment cycles, respectively. Differences between both groups did not reach the level of significance., Conclusion: In this randomized, comparative study, a sequentially combined oral HRT regimen consisting of oestradiol valerate (2 mg daily on days 1-21) and cyproterone acetate (1 mg daily on days 12-21), induced a lipid pattern and probably also a change in Lp(a) levels, which is generally viewed to be more beneficial with regard to the prevention of cardiovascular disease than the lipid pattern induced by a sequentially combined regimen of transdermal 17 beta-oestradiol (50 micrograms twice weekly during three weeks) and oral dydrogesterone (20 mg daily on days 12-21).

Two-hundred and fourteen (214) menopausal women with moderate to severe vasomotor symptoms, aged 40-65 years, were randomised. After a 4-week treatment-free period, each women received a continuous regimen of Menorest 50 twice weekly or Premarin 0.625 mg daily, for 12 weeks. Didrogesterone 10 mg was also given to all women for 12 days of every 28-day cycle. The objectives were to compare the efficacy and safety profiles of Menorest and an oral estrogen. A statistically significant reduction in the mean number of hot flushes occurred in each group compared to baseline with a decrease from 7.1 at baseline to 0.9 at 12 weeks in the Menorest group, and from 6.7 to 0.5 in the oral estrogen group; there was no statistically significant difference between the two groups (P = 0.36). With each successive treatment cycle, there was a continuous improvement in the number of hot flushes. The incidence and severity of menopausal symptoms were reduced in the same manner in both groups. There were no statistically significant differences in the mean plasma estradiol and estrone concentrations between the two treatment groups after 10 weeks of therapy. The mean estradiol to estrone ratio was similar in both groups, as was the number of adverse events observed. In summary, Menorest was as effective as an oral estrogen in alleviating menopausal symptoms.

Objective: To establish the lowest dose of cyclical dydrogesterone that protects against endometrial hyperplasia induced by continuous 2 mg 17 beta oestradiol, and to study the dose effect on vaginal bleeding and side effects., Design: Double-blind, prospectively randomised dose-ranging study., Setting: Menopause clinics in the UK and The Netherlands., Subjects: Three hundred and seventy-one postmenopausal women with intact uteri, aged 40 to 60., Interventions: Administration of six 28-day treatment cycles of continuous daily micronised 17 beta oestradiol with a randomly allocated dose of 5 to 20 mg of dydrogesterone added for the last 14 days of each., Main Outcome Measures: Histological assessment of adequate progestational endometrial response, bleeding patterns and adverse effects., Results: The study was completed by 320 subjects (86%). Endometrial transformation occurred in over 94% of those taking 5 mg of dydrogesterone, and in over 97% of those on higher doses, without significant differences between the 10, 15 and 20 mg groups. Acceptable bleeding patterns were found at all doses, with the incidence of withdrawal bleeding rising with increasing dose. The day of onset of bleeding was predictable from cycle to cycle, and occurred later in the 20 mg group than in the others. The incidence of noncyclic bleeding was about 6% at all doses. Withdrawal occurred in 3.3% due to unacceptable bleeding and in 5.4% due to side effects. There was no relation with dose., Conclusions: A dydrogesterone-17 beta oestradiol combination hormone replacement therapy confers endometrial protection with an acceptable bleeding pattern and few side effects At least 10 mg of dydrogesterone for 14 days is required for acceptable endometrial protection.

Objective: To describe changes in the withdrawal bleeding pattern and endometrial histology during a sequential 17 beta-estradiol-dydrogesterone regimen in postmenopausal women., Design: Open-label, non-comparative, prospective study., Setting: Gynecological outpatient department of a university hospital., Patients: Twenty-seven healthy non-hysterectomized postmenopausal women., Interventions: Continuous micronized 17 beta-estradiol supplementation, 2 mg daily, and cyclic administration of dydrogesterone, 10 mg daily for the first half of each 28 day treatment cycle., Main Outcome Measures: Changes in the characteristics of the withdrawal bleeding pattern and the endometrial biopsy histology during 2 years of treatment., Results: The initial withdrawal bleeding was comparable to normal menstruation with respect to amount and duration. During the 2 years of treatment the bleeding showed a significant tendency to become shorter with less blood loss. This was mainly the result of the decrease (P < 0.001) in the number of days per cycle with bleeding grade II (normal menstruation). None of the women developed endometrial hyperplasia, and in almost all women the given hormone replacement therapy regimen induced secretory or atrophic changes of the endometrium., Conclusions: This sequential 17 beta-estradiol-dydrogesterone regimen can be regarded as safe with respect to the prevention of endometrial disease and appeared to foster patient compliance.

We studied prospectively during one year temporary drug use by mothers donating breast milk to assess the problem of drug treatment of donors. Sixty-four of the 284 mothers (22.5%) had to abstain from donating due to medication. The indication was infection in 50/56 treatments (89.3%). Antimicrobial agents were prescribed 44/52 times (84.6%). The channelling of milk from mothers in early phases of lactation to premature and newborn infants was identified as a special risk situation, if mothers on medication are not excluded. The limited number of such donors leads to use of milk unpooled or pooled to small volumes with increased risk for adverse effects to babies as a consequence. We recommend a wash-out period of 5 half-lives of the drug after the last ingested dose. For the majority of drugs in this study, with some important exceptions, a wash-out period of 1 day was sufficient.

Oral oestrogen treatment in postmenopausal women causes a decrease of insulin-like growth factor I (IGF-I) serum level, probably through a hepatocellular effect. To explore the possibility that the androgenic progestogens oppose this effect, serum IGF-I and sex hormone binding globulin (SHBG) were evaluated in two groups of patients treated respectively with oral conjugated oestrogens (oCE) or transdermal oestradiol (tdE2), in a first phase with the addition of dydrogesterone (DYDR), a non-androgenic progestogen, and subsequently with the addition of norethisterone acetate (NETA). With respect to basal values, treatment with oCE+DYDR caused an increase of SHBG (P < 0.002) and a decrease of IGF-I serum levels (P < 0.05); the shift to NETA addition opposed both effects: SHBG levels decreased partially but significantly (P < 0.01 vs. oCE + DYDR) and IGF-I returned to basal values with a significant increase with respect to the oCE + DYDR phase (P < 0.02). No changes were observed in the tdE2 + DYDR treated women; in this group the shift to NETA addition caused a significant decrease of SHBG values (P < 0.001 vs. before treatment and vs. tdE2 + DYDR phase) and a slight increase of IGF-I values. These differential effects on IGF-I and SHBG serum levels might be relevant as far as breast cancer risk is concerned.

Introduction: Postmenopausal hormone replacement therapy (HRT) has been described to reduce the risk of developing cardiovascular disease (CVD), which can be attributed at least in part to beneficial effects of oestrogens on serum lipoproteins. Little is known about a possible counteracting effect by the progestogen integrated in modern HRT regimens., Objective: To study the possible changes in serum lipids, lipoproteins and apolipoproteins during HRT with special emphasis on the possible progestational effect., Study Design: In an open-label longitudinal non-comparative study 23 healthy non-hysterectomized postmenopausal women were treated with continuous micronized 17 beta-oestradiol, 2 mg daily, in combination with cyclic dydrogesterone, 10 mg daily, the first 14 days of each 28-day treatment cycle. The women were followed for up to 2 years., Results: After 2 years serum total cholesterol and low-density lipoprotein cholesterol had decreased by 9.0% and 18%, respectively (P < 0.01), while high-density lipoprotein cholesterol had increased by 13% (P < 0.01). The latter change was accompanied with similar increases in apolipoprotein A-I (+16%; P < 0.01) and A-II (+13%; P < 0.01), while apolipoprotein B remained unchanged. Serum very low-density lipoprotein (VLDL) cholesterol and VLDL-triglycerides increased by 28% and 21%, respectively, the latter reflecting the slight increase in serum triglycerides by 21%. These values, however, remained within the normal range. Serum lipoprotein(a) decreased by 16% (P < 0.01). All calculated atherogenic indices decreased (P < 0.01) during the study period. Serum lipids and (apo)lipoproteins did not change after withdrawal of dydrogesterone for 14 days during the combination therapy in the last cycle studied. Serum fibrinogen decreased by 8.4% (P < 0.01) in the first 12 cycles, after which it increased to 13% above baseline value (P < 0.01 vs. baseline). Antithrombin III did not change and serum glucose decreased by 5.7%., Conclusions: This HRT regimen induces (and also when given for a longer period) beneficial changes in the lipid profile, without affecting important indicators of thrombosis. Also, the glucose metabolism does not seem to be interfered with. Cyclic administration of dydrogesterone does not unfavourably affect serum lipids and (apo)lipoproteins when combined with 17 beta-oestradiol supplementation. Therefore, this combination hormone regimen can be recommended for use in HRT.

Thirty post-menopausal, non-hysterectomised women received a 50 mg oestradiol implant subcutaneously and either 10 mg or 20 mg dydrogesterone daily for 14 days every 28 days for 6 months. Endometrial biopsies were taken during the initial oestrogen-only phase and again during the final progestogen phase. Of the ten initial samples which were adequate for histological diagnosis, nine showed proliferative and one non-secretory endometrium. Of the 28 samples obtained at the end of the study during the progestogen phase, all except one showed satisfactory conversion, irrespective of dose. Acceptable bleeding patterns were seen in both dosage groups. Tolerance was good and no patient discontinued treatment. This study has shown that both 10 mg and 20 mg dydrogesterone for 14 days are potent enough to oppose the proliferative effects of the 50 mg oestradiol implant. In view of the wide inter-patient variation in endometrial response to progestogens, it appears appropriate to choose the dosage of dydrogesterone on the basis of cycle control and tolerability, whilst being able to maintain confidence in endometrial protection.

Ten non-hysterectomised, post-menopausal women received the 100 mg oestradiol implant which was opposed by 20 mg dydrogesterone (nocte) for 14 days each 28-day cycle, for 6 cycles. Plasma oestradiol was measured at baseline and on three further occasions over 6 cycles. Endometrial biopsies were taken 5 weeks after implant, during the unopposed oestrogen and at week 24 during the progestogenic phase (sampling failed on both occasions in one patient). Secretory endometrium was seen in all women at the end of treatment. Cycle control was good and the mean day of onset of bleeding occurred on or after day 11 of the dydrogesterone dosage by the 5th cycle. Dydrogesterone 20 mg for 14 days every 28 days seemed to be sufficiently potent to counteract the proliferative effects of the high dose oestrogen implant.

Fifty patients with simple glandular cystic hyperplasia of the endometrium-GCHE (one with partly adenomatous and two with partly atypical GCHE) were treated with Dabroston through 6 cycles. Daily dosage was 20-30 mg, higher dosage for those with exceeded optimal body weight. After 6 cycles of therapy curettage was repeated in 18 patients and histologic picture of the endometrium was analysed. The post-treatment curettage revealed GCHE in 5 patients, proliferative endometrium in 6 patients and secretory endometrium in 7 patients. In spite of GCHE neurovegetative perimenopausal symptoms were present in 62% before treatment and were even exaggerated in 34% of the patients during the treatment.

A double-blind, cross-over, placebo-controlled study of dydrogesterone (10 mg b.d.) in the treatment of premenstrual syndrome is described. Two groups of women were studied: secondarily referred hospital clinic patients, and self-referred patients. Only one-third of patients screened completed the study. All patients showed significant improvements in symptom scores during the course of the study, the only significant difference between placebo- and dydrogesterone-treated patients being an increase in frequency of breast tenderness and a decrease in pain with menstrual bleeding in the latter.

Lipoprotein levels were measured in 11 women who had been treated with 0.625 mg/day conjugated equine oestrogens with the addition of 0.15 mg/day DL-norgestrel for the last 12 days of each 28 day cycle for 48 wk. Treatment was then changed to an identical oestrogen regimen with dydrogesterone, 10 mg/day, as progestogen and monitoring continued for a further 24 wk. The oestrogen plus norgestrel regimen caused a significant reduction in low density lipoprotein (LDL) cholesterol levels. During the 24 wk after the change of therapy, levels of high density lipoprotein (HDL) increased significantly due to an increase in the HDL2 fraction and there was an upward trend in LDL cholesterol which did not attain statistical significance. We conclude that, when used in combination with conjugated equine oestrogens, changing from norgestrel, 0.15 mg/day, to dydrogesterone, 10 mg/day, does not lead to any significant improvement in lipoprotein profile.

A case of holoprosencephaly is reported in which the mother was prescribed high doses of oestroprogestins during the first 5 months of the pregnancy. Investigation of the family failed to reveal any sign of physical abnormality. A normal karyotype was detected in the proband. The authors suggest that this case may shed some light on the normal and abnormal way in which embryonic fields develop.