Göran Cullberg

Evaluation of a continuous oestrogen-progestogen regimen for climacteric complaints

Subjective complaints, endometrial histopathology, vaginal cytology and bleeding patterns were recorded in 26 patients treated with a continuous oestrogen-progestogen regimen for 12 mth. A marked reduction of hot flushes and sweats were noted and the evaluation of endometrial specimens revealed that the mucosae were mostly inactive-atrophic. The karyopyknotic index proved to be a poor indicator of oestrogenic activity. The number of recorded bleedings in the peri-menopausal women differed markedly from the post-menopausal women during treatment; they were very slight in the latter group. Even in those cases where bleeding occurred, the endometrial samples were found to be atrophic. Vaginal bleeding seemed to be an unreliable indicator of endometrial histopathology. The present combination of hormones used in a continuous regimen is a good alternative for post-menopausal women in need of hormonal therapy.

Pharmacodynamic Studies on Desogestrel Administered Alone and in Combination with Ethinylestradiol

Most progestogens in oral contraceptives are testosterone derivatives and have androgenic side effects such as weight increase, acne and hirsutism. They pose a problem to many women just like the clinical picture of the polycystic ovary syndrome (PCO) with obesity, hirsutism, acne and amenorrhea.

Two oral contraceptives, efficacy, serum proteins, and lipid metabolism: A comparative multicentre study on a triphasic and a fixed dose combination

A triphasic, combined oral contraceptive containing 30 - 40 - 30 micrograms ethinyloestradiol (EE), and 50 - 75 - 125 micrograms levonorgestrel was compared with a fixed dose combination containing 30 micrograms EE and 150 micrograms desogestrel in a randomized multicentre trial in 193/199 women and 1 063/1 073 cycles, respectively. The duration of the trial was six months. Eleven centres in Denmark, Sweden, and Norway participated. Contraceptive reliability, bleeding control and side effects were evaluated. Influence on serum sex hormone binding globulin (SHBG) and transcortin was assayed as well as lipid metabolism. Three pregnancies occurred in the group using the triphasic regimen but none in the fixed dose regimen. Two of the three pregnancies were considered drug failures and the third a possible interaction. Possible reasons for the triphasic contraceptive failure are discussed with special reference to a British report on eight pregnancies. Bleeding control appeared to be equally good for the two preparations. However, the number of cycles with spotting, breakthrough bleeding and missed withdrawal bleeding were above the levels reported earlier on the triphasic regimen. About 80 per cent of the women completed the planned six months on either combination. Side effects were generally mild and in accordance with earlier reports on low dose oral contraceptives. Metabolically the triphasic levonorgestrel combination increased SHBG 100 per cent versus 200 per cent for the fixed desogestrel combination. Transcortin rose about 98 and 110 per cent, respectively. Both preparations induced similar changes in the levels of lipids and lipoproteins with the exception of a significant increase in the arachidonic content of cholesterol during treatment with the desogestrel-containing preparation.

Effects of a low-dose desogestrel-ethinylestradiol combination on hirsutism, androgens and sex hormone binding globulin in women with a polycystic ovary syndrome.

Abstract. Twenty women suffering from a polycystic ovary syndrome (PCO) accompanied by hirsutism were given a low‐dose oral contraceptive combination containing 0.150 mg desogestrel plus 0.030 mg ethinylestradiol for 8 months. The pretreatment situation regarding hair and hormone profiles in the PCO group was compared with that in 22 regularly menstruating women. Serum levels of free and total testosterone and androstenedione were significantly elevated in PCO women, as were body weight, blood pressure, hair diameter and depilation frequency. Sex hormone binding globulin (SHBG) binding capacity was lower. Following treatment of the PCO group for 8 months, total and free testosterone levels were depressed, but androstenedione had not changed significantly. SHBG binding capacity was increased five‐fold. Body weight decreased in the obese women. Hair growth was significantly suppressed and the hair itself was less coarse. Depilation intervals were longer. Acne, present before the treatment had now disappeared. Blood pressure did not change. Few and mild side effects were recorded. After treatment, 3 women succeeded in becoming pregnant and in 8 others spontaneous menstruations had recurred.

On the use of Plasma Proteins as Indicators of the Metabolic Effects of Combined Oral Contraceptives

Abstract. Ethinylestradiol (EE, 17α‐ethynyl‐1,3,5(10)‐es‐tratriene‐3,17β‐diol) 30 μg daily, in combination with 150μg per day of desogestrel (Org 2969,17α‐ethynyl‐18‐methyl‐11‐methylene‐4‐estrene‐17β‐ol) or levonorgestrel (17α‐ethynyl‐18‐methyl‐4‐estrene‐17β‐ol‐3‐one), was administered to two groups of 10 healthy human women who had been without hormonal treatment during 3 months prior to the study. The preparations were given for three 21‐day cycles with 7‐day intervals. Blood samples were taken before treatment and at the end of the third treatment period. Serum sex‐hormone binding globulin (SHBG), ceruloplasmin, ornsomucoid, C1‐esterase inhibitor and C4 were analyzed by electroimmunoassay and transcortin was assayed as cortisol‐binding capacity. Serum testosterone was assayed by radioimmunoassay of methylenedichloride extracts using an antiserum with about 20% cross‐reactivity for dihydrotestosterone (DHT).

Vaginal administration of low-dose oestradiol — effects on the endometrium and vaginal cytology

Twenty (20) post-menopausal women, mean age 62.4 yr, presenting with symptoms associated with urogenital atrophy were treated intravaginally with daily doses of 25 and 50 micrograms oestradiol (E2) in a double-blind, cross-over study. After randomization, the patients started daily treatment with pessaries containing either 25 or 50 micrograms E2 for 3 wk, followed by a maintenance period of 6 wk during which the pessaries were used only twice a week. A 4-wk wash-out period was followed by another treatment period of 9 wk. The effects on the karyopyknotic index (KPI) and on endometrial histopathology were assessed before and after 3, 9, 16 and 22 wk of treatment. In the case of the 25 micrograms dose the mean KPI values were 34.7 and 20.9% after 3 and 9 weeks of treatment, respectively, the corresponding figures after treatment with 50 micrograms E2 being 39.2 and 22.7%. No dose-effect relationship was apparent from the vaginal cytology findings. Endometrial biopsies could not be taken systematically in all patients. Weak proliferation of the endometrium was observed in 1 woman after 3 wk of daily treatment with the 50 micrograms dose. No endometrial stimulation was detected in any of the patients after treatment with 25 micrograms daily. Beneficial clinical and cytological effects were obtained with both dosage regimens. Daily intravaginal administration of 25 micrograms E2 can accordingly be advocated for the treatment of urogenital symptoms attributable to oestrogen deficiency in post-menopausal women.

A clinical evaluation of treatment with estriol vaginal cream versus suppository in postmenopausal women

Abstract. Thirty postmenopausal women with vaginal atrophy were treated with a vaginal cream or vaginal suppositories containing 0.5 rag estriol (OvestinR, Organon, The Netherlands). The preparations were given daily for 14 days and then during the next 6 weeks a maintenance dose was applied twice a week.

Vaginal absorption of two estriol preparations: A comparative study in postmenopausal women

Abstract. In a comparative randomized cross‐over study the absorption of a single dose of 0.5 mg estriol from a vaginal cream or a vaginal suppository (OvestinR, Organon, The Netherlands) was studied. Eight healthy postmenopausal women participated and the preparations were given with an interval of 14 days. Blood sampling was performed twice before application and then after 1/4, 1/2, 1, 2, 4, 6, 8, 24 and 48 hours. Serum was analysed for unconjugated and conjugated estriol (E3), FSH and LH by radio‐immunoas‐say. Considerable interindividual variations in serum levels of unconjugated E3 were found but mean values were about equal throughout the study for the two preparations. Peak levels of 0.5 — 0.6 nmol/1 were achieved 1 — 2 hours after application of the preparations and after 24 hours no unconjugated E3 was measurable. Conjugated E3 rose rapidly but within 48 hours serum concentrations reached baseline levels. A maximum decrease in serum LH levels of about 40% was obtained with both preparations after 6 hours and the return to baseline within 24 hours indicates a relationship to unconjugated E3. FSH in serum was maximally suppressed 6—12%. Estriol is thus readily absorbed by the vaginal route and peak levels of unconjugated E3 after insertion of 0.5 mg estriol seem to be comparable to those obtained after 8‐12 mg estriol given orally.

Ovulation Inhibition with 17β‐Estradiol Cyclo‐Octyl Acetate and Desogestrel

Ovulation inhibition and bleeding control with a combination of 0.5 mg 17β‐estradiol cyclo‐octyl acetate (E2COA) and 0.15 mg desogestrel was investigated in 10 regularly menstruating women for 21 days. In half the group the treatment was extended for 7 days (days 22 − 28) with 0.03 mg desogestrel in order to evaluate any posttreatment influence on the gonadotropin levels. E2COA, beeing a long‐chain fatty ester dissolved in oil, was expected to be resorbed from the intestinal wall via the lymphatic system. By incorporating it in the chylomicrons, E2COA would thereby avoid the unfavourable first liver pass. The serum levels of progesterone were suppressed during treatment. No increase in 17β‐estradiol (E2) concentration was found; levels remained low and even during medication. No peak values of gonadotropins were seen. Thus follicular hormonal activity and ovulation was inhibited by this combination. Bleeding control was, however unacceptable in all volunteers. The addition of desogestrel during the fourth investigation week apparently did not induce any hormonal differences. The estrogenic activity is shown by the low, even S‐E2 levels, but the dosage of E2COA seems to be too low in relation to progestogen dosage. Further studies will have to be performed in order to find the ideal combination.

A Continuous Estrogen - Progestogen Regimen for Climacteric Complaints: Effects on Lipid and Lipoprotein Metabolism

Abstract. The lipid composition of serum and the lipoprotein fractions, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) were determined in 26 peri‐ and postmenopausal women treated with a daily dose of 2 mg 17‐β‐estradiol, 1 mg estriol and 1 mg norethisteroneacetate in a continuous regimen for 12 months. A decrease was noted in all serum lipids, triglycerides, cholesterol and phospholipids during treatment. When comparing the lipid values after 3 and 12 months of treatment a tendency was found to approach pre‐treatment values with time. A reduction of triglycerides in VLDL after 3 months, concomitant with a decrease in HDL‐cholesterol, was interpreted as an effect mainly of the progestogen component. A decrease of free cholesterol in LDL was found during treatment. The ratio of LDL‐choles‐terol/HDL‐cholesterol was unaltered when comparing values before vs. after 3 and 12 months of treatment. Decreased levels of HDL‐cholesterol and elevated levels of LDL‐cholesterol are considered to be risk factors for coronary heart disease. The significance of lipid metabolic effects induced by treatment in the present study on a long‐term basis is hard to evaluate in terms of atherogenicity.