Seppo Kivinen

Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women.

Objective: To compare ospemifene and raloxifene regarding their effects on hormones, lipids, genital tract, and tolerability in postmenopausal women. Design: A randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) of ospemifene or 60 mg (n = 29) of raloxifene for 3 months. Results: There were no significant differences in the baseline characteristics between study groups. In comparison with raloxifene, follicle-stimulating hormone levels decreased significantly more in the 90-mg ospemifene group and sex hormone-binding globulin levels increased more in all ospemifene groups. Total cholesterol and low-density lipoprotein cholesterol levels decreased more in raloxifene than in ospemifene groups, although the difference in low-density lipoprotein cholesterol between 90-mg ospemifene and raloxifene was not significant. Endometrial thickness did not change in any study group and endometrial biopsies showed atrophy in the majority of subjects at 3 months. All ospemifene groups demonstrated a clear estrogenic effect on the vaginal epithelium, as seen in Pap smears. This was in sharp contrast to the raloxifene group, which had no effect on the vaginal epithelium. Kupperman index decreased in all study groups during treatment. The adverse events were mild, mainly single cases, and no clustering of events was observed. There were no clinically significant abnormal findings in laboratory safety parameters. Conclusions: Ospemifene, at the dose of 90 mg/day, was more estrogenic than raloxifene, as shown by changes in serum follicle-stimulating hormone and sex hormone-binding globulin levels. Neither agent stimulated endometrium, but in contrast to raloxifene, ospemifene had a clear estrogenic effect in the vagina. Further studies with ospemifene are needed in subjects with vaginal atrophy.

Antenatal Detection of Congenital Malformations by Routine Ultrasonography

&NA; Routine ultrasound examination was performed in 9012 fetuses of a general pregnant population to detect fetal malformations. The examination was done on 3098 fetuses at 18 weeks, and on 5914 fetuses it was repeated at 34 weeks. Ninety‐three infants (1.03%) showed 123 major malformations, of which 65 (52.8%) in 54 children were visualized in utero. The sensitivity of detection of malformed fetuses was 58.1% (54 of 93), specificity 99.9%, positive predictive value 91.5%, and negative predictive value 99.6%. Five fetal hydronephroses were the only false‐positive cases (0.06%), with apparent spontaneous resolution after birth. Fetal growth retardation, polyhydramnios, or oligohydramnios was observed in 43% of the malformed cases, suggesting the importance of these conditions in ultrasound screening. Abnormality of pregnancy was suspected clinically in only 25.8% of the cases at the time of diagnosis of fetal malformation, emphasizing the necessity for ultrasound examination of all pregnancies. (Obstet Gynecol 73:947, 1989)

Comparison of the gonadotropin-releasing hormone agonist goserelin acetate alone versus goserelin combined with estrogen-progestogen add-back therapy in the treatment of endometriosis * †

OBJECTIVE To investigate whether the addition of low-dose estrogen-P combination hormone replacement therapy (HRT) to GnRH agonist (GnRH-a) treatment for endometriosis reduces the pharmacologic side effects of such treatment without reducing efficacy and to determine the endocrinologic changes during treatment. DESIGN Prospective, randomized, double-blind, placebo-controlled, comparative study of two drug regimens: 3.6 mg goserelin acetate in a 28-day SC depot formulation once monthly for 6 months plus either a combination of 2 mg 17 beta-E2 and 1 mg norethisterone acetate (NET) 1 mg or matching placebo tablets once daily for 6 months. SETTING Multicenter study in three tertiary referral centers at university teaching hospitals and two central hospitals. PATIENTS Women with laparoscopically confirmed symptomatic endometriosis were included in the study. RESULTS Of the total of 109 patients screened, 93 were recruited and 88 patients were randomized to either the HRT or the placebo group. Four women were withdrawn because of various medical reasons, and 76 patients were followed-up for a total of 12 months. In terms of efficacy, there was no difference between the two drug regimens for objective or subjective response. There were significantly less postmenopausal symptoms in the patients treated with goserelin plus HRT compared with those treated with goserelin plus placebo. CONCLUSION Goserelin diminished significantly the symptoms and laparoscopic scores of endometriosis. The addition of HRT did not reduce the efficacy of goserelin but diminished the postmenopausal symptoms during treatment.

A DOSE RESPONSE RELATION BETWEEN IMPROVED LACTATION AND METOCLOPRAMIDE

In a placebo-controlled, cross-over study, thirty-seven puerperal women with inadequate production of breast-milk were treated with 5, 10, or 15 mg of metoclopramide three times a day for 2 weeks. Doses of 10 or 15 mg significantly raised maternal serum prolactin; they also increased breast-milk secretion by 42.5 +/- 34.7 (SD) ml and 50.0 + 35.9 ml per feed, respectively. This effect was unrelated to the phase of the puerperium during which treatment was started. The increase in milk secretion was associated with a decreased need for supplementary feeds, and 33% of the infants of these mothers needed no supplementary feeds during treatment. 5 mg doses did not stimulate prolactin milk secretion. Although placebo had no objective effect on the milk yield, 24% of the women judged its effect to be good, and 89% of women on metoclopramide reported a good effect. Seven women on metoclopramide and three women on the placebo complained of slight side-effects. No adverse effects upon the infants were observed. Metoclopramide therapy may be useful for improving poor lactation.

Metoclopramide and breast feeding: efficacy and anterior pituitary responses of the mother and the child

The purpose of this randomized, double-blind clinical study was to evaluate the efficacy of the antidopaminergic agent metoclopramide (MC) in the treatment of puerperal lactational insufficiency, and prolactin, TSH and free thyroxine responses of the mother and the child to this therapy. Therefore, 11 women received MC (10 mg 3 times daily orally) and 14 a placebo for 3 wk. MC increased the serum concentration of PRL from 57.5 + 45.5 U/l to 315.0 + 300.0 U/l (P less than 0.001), and the amount of daily milk yield in 8 women with established lactational deficiency rose from 285 + 75 ml to 530 + 162 ml (P less than 0.01) while the placebo was ineffective. Serum concentrations of TSH and free thyroxine did not change during either of the treatments. Serum concentrations of PRL, TSH and free thyroxine in the infants were similar in both groups and remained unchanged throughout the study. Our results suggest that MC is useful in the treatment of deficient puerperal lactation, and it does not stimulate the pituitary lactotropes or thyrotropes of the nursing infants.

Zoladex (goserelin acetate) and the anemic patient: results of a multicenter fibroid study * † ‡ § ∥

OBJECTIVE To compare the effects of goserelin acetate treatment with or without iron with iron alone. DESIGN Multinational, multicenter, prospective, randomized, double-blind study. PATIENTS Premenopausal women with menorrhagia or metrorrhagia and anemia associated with uterine leiomyomata awaiting hysterectomy. INTERVENTION Patients were randomized to one of three 12-week treatment groups namely goserelin acetate 3.6 mg once monthly plus placebo iron; 3.6 mg goserelin acetate once monthly plus 600 mg/d iron; or sham injection once monthly plus 600 mg/d iron. MAIN OUTCOME MEASURE Preoperative hemoglobin concentration; preoperative uterine and fibroid volumes and operative blood loss. RESULTS Considering the entry and preoperative hemoglobin concentrations, there was a difference in least square means of just over 1 g/dL between the goserelin acetate plus iron and iron only groups and 2.6 g/dL between the goserelin acetate plus iron and goserelin acetate only group. These differences were both statistically significant. Uterine and fibroid volumes were decreased in the goserelin acetate-treated patients by between 37% and 40% and 44% and 47%, respectively, compared with 7% decreases for both in the iron only group. The differences in absolute changes were statistically significant for both the goserelin acetate-treated groups versus the iron-treated group. The least square geometric mean operative blood loss was greatest in the iron only group. CONCLUSION In the patient with uterine leiomyomata and anemia, goserelin acetate in combination with iron therapy has shown significant advantages over the iron alone in restoring hematologic normality, decreasing uterine and fibroid volumes, and reducing operative blood loss.

Postmenopausal hormone replacement therapy with estrogen periodically supplemented with antiestrogen

To inhibit endometrial stimulation during postmenopausal estrogen therapy, 25 women with climacteric symptoms were treated with a daily dose of 1.25 mg of conjugated estrogens for 7 weeks followed by a period of 10 days with clomiphene citrate administration (50 mg per day). This combination was repeated three times during the 6-month trial. The marked relief of climacteric symptoms with estrogen was slightly less during clomiphene treatment. Uterine bleeding occurred five times during estrogen treatment periods but never during or after clomiphene supplementation. Histologic examination revealed endometrial atrophy in 41% of the samples after the first estrogen treatment, whereas after the first and third clomiphene periods this was increased to 77% and 73%, respectively. The first clomiphene treatment significantly decreased the concentrations of cytosol estrogen and progestin receptors in endometrium, as compared with the levels recorded at the end of the preceding estrogen therapy. The depression in the cytosol estrogen receptor concentration was persistent, whereas cytosol progestin receptor concentration tended to increase during the subsequent estrogen-plus-clomiphene treatment. Estrogen declined serum concentration of follicle-stimulating hormone (FSH), whereas the concentration of luteinizing hormone (LH) and prolactin remained unchanged. Clomiphene did not change the levels of these hormones from those observed during the estrogen treatment. The concentration of free fatty acids in serum was increased during the estrogen and clomiphene treatments, whereas the levels of cholesterol and high-density lipoprotein--cholesterol did not change. Our results suggest that this treatment regimen relieves climacteric symptoms without endometrial stimulation or other adverse effects. Thus, clomiphene appears to be a practical alternative to progestin for interruption of the postmenopausal endometrial effect of estrogen.

Comparison of Heyman packing and Cathetron afterloading methods in the treatment of endometrial cancer

The five-year survival and the complication rate were evaluated in 307 patients with endometrial carcinoma treated from 1966 to 1977. The distribution of the patients into clinical stages I, II, III and IV was 68.7, 20.8, 6.5 and 3.9%, respectively. In stage I 87.2% and in stage II 67.2% of the patients were operated on. All patients received oral medroxyprogesterone acetate for two years, and all patients with stage I or II disease were also irradiated, mostly intracavitary before operation. The crude 5-year survival in the total material was 72.0%, and for clinical stages I, II, III and IV 83.8, 54.7, 40.0 and 8.3%, respectively. 167 patients in stage I received intracavitary irradiation, 86 using the Heyman packing method and 81 using the Cathetron after-loading technique. The corresponding figures for 54 patients in stage II were 38 and 16. In clinical stage I the crude (83.9% and 84.2%, respectively) and corrected (92.9 and 88.9%, respectively) 5-year survivals were similar in the Heyman and Cathetron groups. In stage II better results were obtained using the Cathetron technique (crude 75.0 vs. 42.1%) but in the corrected material, excluding the unoperated cases, there was no significant difference (81.3 vs. 74.4%, respectively). Serious late complications requiring surgical correction were less common in the Cathetron group (2.9% vs. 11.1%; p less than 0.05). The intracavitary irradiation of endometrial carcinoma can thus be well accomplished by remote afterloading technique.

Detection of small for gestational age fetuses by the combination of clinical risk factors and ultrasonography

Clinical risk factors of fetal growth retardation and targeted ultrasound examinations were combined to detect small for gestational age (SGA) fetuses below the 10th percentile weight for age in 1122 unselected singleton pregnancies, in which the true gestational age was confirmed by ultrasonography at 18 weeks. The prevalence of SGA infants was 6.0% in this population. A risk group of 236 (21%) mothers was referred for an ultrasound examination of fetal growth by the midwives of maternity welfare centers on the basis of low symphysis-fundal height or five other major maternal risk factors (pregnancy associated hypertension, loss of weight gain, a previous SGA infant, pre-pregnancy weight below 50 kg, any smoking during pregnancy). The sensitivity and positive predictive value of the clinical part of the study were 83.6 and 23.7%, respectively. Fetal growth was assessed by measuring both biparietal diameter (BPD) and transverse abdominal diameter. In the clinically selected risk group, 83.9% of the SGA fetuses could be detected by this method using a cutoff level of -1 standard deviation (SD). The two-step screening combining clinical and ultrasonographic methods in the detection of SGA fetuses in general population showed a sensitivity of 70.1%, a specificity of 95.5%, a positive predictive value of 49.5%, and a negative predictive value of 98.1%. After ultrasound examination, the definitive risk group for SGA was 8.5% of the total material of 1122.(ABSTRACT TRUNCATED AT 250 WORDS)

Tamoxifen and Natural Progesterone as Supplements to Low-Dose Postmenopausal Estrogen Therapy

Postmenopausal women received 1 mg estrone sulfate a day for 3 weeks in 12 sequences separated by a 7-day interval without medication and every second time by a 10-day treatment with natural progesterone, 100 mg 2 times daily (n = 16), or tamoxifen, 10 mg 2 times daily (n = 17). Both treatments alleviated climacteric symptoms, maturated the vaginal epithelium, and decreased follicle-stimulating hormone, luteinizing hormone, and prolactin concentrations while lipid metabolism remained unaltered. In the estrogen-progesterone group 4 women (25%) were persistently amenorrheic, 12 (75%) experienced 1-5 bleedings per year, and 4 women had proliferative endometrium after treatments. In the estrogen-tamoxifen group 11 women (65%) were amenorrheic, 6 (35%) had 1-4 bleedings per year, and 5 had proliferative endometrium. With the present treatment schedules, tamoxifen was more effective than natural progesterone in inhibiting estrogen stimulation of postmenopausal endometrium.