†Rue de l’Assomption 31, Paris XVIe, France ‡Department of Gynecology and Obstetrics, St. Joseph Hospital, Eindhoven, The Netherlands §Department of Gynecology and Obstetrics, Clinical Centre Dedinje, Beograd, Yugoslavia

Partly presented at the International Symposium on the Menopause, Viareggio, Italy, May 25 2 8, 19 80 and at the 3rd International Congress on the Menopause, Ostend, Belgium, 9-12 June, 1982.

Eighty-two postmenopausal women with vaginal atrophy and associated symptoms were treated with either Ovestin® vaginal cream (54 women) or vaginal suppositories (28 women) containing 0.5mg of E3/dose, daily for 3 weeks, A maintenance dose of 0.5 mg of E3 twice weekly was applied by all patients for 5 weeks, and by 27 of them for up to 16 weeks. Variables studied were clinical and colposcopic findings, the Maturation Index (MI) and Maturation Value (MV), cervical mucus ferning (F) and spinnbarkeit (S) and endometrial biopsies (obtained pretreatment and after 3 weeks in 15 of the patients). Furthermore, the bio-availability of circulating unconjugated E3 for up to 8 hours following a single dose of Ovestin cream was studied in 10 of the patients.

Clinical and colposcopic findings indicated that the treatment had a very favourable effect in all patients. This was reflected in the pronounced change in vaginal smears, indicating a strong oestrogenic effect. There was a slight to moderate effect on cervical mucus. Endometrial biopsies showed that endometrium remained atrophic in all 15 patients in whom biopsies were obtained. A maintenance dose of 0.5 mg of E3 twice weekly appeared to be sufficient to maintain the beneficial effect. Tolerance was good, and patients commented favourably on the treatment.


Postmenopausal vaginal atrophy with associated clinical symptoms is the most frequent problem in wom,en of this age group. According to Kicovic et al.1 about 20% of postmenopausal women refer to the Menopause Clinic because of some of these symptoms, and require topical treatment with creams containing oestrogens.

Until recently creams containing conjugated oestrogens were used frequently in clinical practice. However several recent studies have shown that vaginal administration of these creams led towards marked rise in circulating Ei and E2 levels with resultant high urinary oestrogen levels and pronounced endometrial stimulation2-5. It is not therefore, surprising, that current clinical interest is focusing on E3 which has very recently been shown to cure post-menopausal vaginal atrophy efficiently without any undesirable general effects1-5. The present study was undertaken to extend recent clinical experience in treating this syndrome with the new Ovestin® vaginal cream or suppositories containing 0.5mg of E3/dose1.

Materials and methods


Eighty-two postmenopausal or ovariectomized women aged 36-79 years and presenting with vaginal atrophy and related symptoms, participated in the study. The menopause had occurred 4-28 years (mean 14.6 years) prior to the present study. None of the patients had used any hormonal treatment for at least 12 months preceding the present investigation; furthermore, no other therapy or self-medication that might have interfered with the present medication was allowed. Patients with a history of malignancies were excluded. The patients were divided into two groups: 54 of them were treated with Ovestin vaginal cream and 28 were treated with Ovestin vaginal suppositories, both containing 0.5 mg of E3 per dose. The patients applied a daily dose of 0.5 mg of E3 (0.5g of cream by a plastic calibrated applicator, or one suppository) each day before retiring for 3 weeks. A maintenance dose of 0.5 mg of E3 twice .weekly was applied by all patients for 5 weeks, and by 27 of them for up to 16 weeks.


Vaginal smears obtained by drawing a disposable wooden spatula down the upper half of both lateral vaginal walls, were fixed in 95% alcohol and stained according to Papanicolaou. Results were expressed as the Maturation Index (MI). By multiplying the percentages of basal-parabasal cells, intermediate cells and superficial cells by factors 0, 0.5 and 1, respectively, the values of the MI were transformed into the Maturation Value (MV). Ferning (F) was scored as 0,1,2 or 3; spinnbarkeit (S) was measured immediately in centimetres. Endometrial biopsies were evaluated by means of light microscopy. The plasma levels of unconjugated E3 were measured by radioimmunoassay according to Rotti et al.6; reagents were obtained from Medical Systems. For enzymatic hydrolysis β-glucuronidase, isolated from Helix pomatia, was used. Assays were carried out in duplicate, at the same time and with the same batches of reagents.

Clinical and colposcopic examinations were performed pretreatment and at weeks 3, 5, 8,12 and 16. Besides patients’ claims on the clinical symptomatology, particular attention was paid to the appearance of cervico-vaginal mucosa (colour, petechiae, elasticity, etc.). Furthermore, in 15 of the patients endometrial biopsies were obtained prior to, and after 3 weeks of, treatment.


The treatments with both cream and suppositories had a beneficial effect in all patients at 3 weeks, the improvement being maintained during the maintenance therapy. A good clinical effect was reflected in the change of the MV from 44.5 and 39.1 at pretreatment to 73.8 and 69.8 at 3 weeks following daily administration of the cream or suppositories, respectively. During the maintenance therapy MV remained more or less unchanged, thus demonstrating that the twice-weekly maintenance treatment appeared to be sufficient. As can be seen from Table 1, both cream and suppositories induced slight to moderate effect on cervical mucus F and S.

Table 1. Mean values of the MI, MV, F and S in patients using Ovestin cream and Ovestin suppositories.


In ten of the patients absorption and bioavailability of E3 following a single admin-istration of Ovestin vaginal cream (0.5g of cream, i.e. 0.5mg of E3) were studied by means of frequent measurements of the plasma levels of unconjugated E3. Table 2 shows that there was a sharp rise in unconjugated E3 levels to a mean peak value of 113.5pg/mlat 1 hour, followed byagradual decline during the following 7hours, the mean value being 34.6pg/ml at 8hours.

Table 2. Individual and mean (± SD) plasma levels of unconjugated E3 (pg/ml) following single i-vaginal administration of Ovestin cream.


Clinical examinations showed the treatments to have had a beneficial effect in all patients at 3 weeks, the improvement being maintained during maintenance therapy. A remarkable improvement in dyspareunia was reported by all 28 patients presenting with this complaint. A similar beneficial effect was reported by all patients who complained of vaginal dryness. Improvement of the local condition led toward a change in the libido and sexual activity in a number of patients, and this was indeed remarkable. Kraurosis vulvae was considerably improved in two patients presenting with this complaint, whilst pruritus vulvae et ani remained unchanged in one patient. Colposcopic examinations confirmed that the treatments had an excellent effect on vaginal mucosa: subepithelial petechiae disappeared completely and mucosa had normal appearance. Endometrial biopsies, obtained in 15 of the patients, showed that endometrium remained atrophic at 3 weeks in all of them.

Tolerance was very good and all 82 patients were satisfied with the treatments. Only one patient experienced slight, transient mastodynia at the beginning of treatment and one patient complained of a sensation of “fire in vagina” during the first 2-3 days of therapy with suppositories, but this side-effect was only transitory and did not re-occur. No other untoward effects were reported.


The present study confirms the recent data on efficacy and safety of Ovestin vaginal cream and/or suppositories for the treatment of postmenopausal vaginal atrophy, as well as on the absorption pattern of E3 from these preparations through vaginal mucosa1. In view of the well-known facts about untoward effects of vaginal creams containing conjugated oestrogens2-5, particularly with regard to unopposed endometrial stimulation, the natural hormone E3 appears to be an ideal alternative for the treatment of this local condition which is so frequent in the older group of postmenopausal women. E3 is a short-acting oestrogen and its long-term oral or intra- vaginal administration in individual daily doses leads toward normalization of the cervico-vaginal mucosa, whereas the endometrium remains unaffected. This is not surprising in view of (a) the pharmacokinetic profile of E3 (rapid absorption following oral or intravaginal administration, rapid metabolism and excretion together with weak binding to plasma proteins), and (b) the finding that the E3-receptor complex is much less stable than that of oestradiol (E2)7,8.

We found it very practical and suitable to have both pharmaceutical forms of this excellent preparation available for clinical practice as some patients do not accept or have difficulties in manipulating an applicator for the cream, while others nevertheless prefer the cream. Tolerance of both pharmaceutical forms was shown to be very good and we recommend these preparations as therapy of choice for postmenopausal vaginal atrophy and associated complaints.


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Whitehead, M. I., Minardi, J., Kitchin, Y. and Sharpies, Systemic absorption of estrogen from Premarin vaginal cream. In Cooke, I. D. (ed.) The Role ofEstrogen/Progestogen in the Management of the Menopause, pp. 63-70. (Lancaster: MTP Press) (1978) 

Englund, D. E. and Johansson, E. D. B. Plasma levels of oestrone, oestradiol and gonadotrophins in postmenopausal women after oral and vaginal administration of conjugated equine oestrogens (Premarin). Br. J. Obstet. Gynaecol., 85, 957 (1978) 

Widholm, O. and Vartiainen, E. The absorption of conjugated oestrogen and sodium sulphate from vagina. Ann. Chir. Gynaecol. Fenn., 63, 186 (1974) 

Rotti, K., Stevens, J., Watson, D. and Longcope, C. Estriol concentration in plasma of normal, non-pregnant women. Steroids, 25, 807 (1975)  

Schiff, I., Wentworth, B., Koos, B., Ryan, K. J. and Tulchin.sky, D. Effect of estriol fadministration on the hypogonadal woman. Fertil. Steril., 30, 278 (1978). 

Bergink, E. W. Oestriol receptor interactions: their biological importance and therapeutic implications. Acta Endocrinol., Suppl., 233, 9 (1980)