Toremifene in premenstrual mastalgia

Abstract

Toremifeeni hankalan kuukautiskierron lopulla pahenevan rintojen kivun hoitona

Rintojen kipu (mastalgia) voi olla tois- tai molemminpuolista. Kipu voi olla jatkuvaa tai vaihdella kuukautiskierron mukaan. Kolmella naisella neljästä oireen voimakkuus on kierron vaiheen mukaan vaihtuva. Oire on yleensä hankalin kuukautiskierron jälkipuolella. Kipu voi tuntua voimakkaammalta liikuttaessa tai juostessa, jolloin oire voi varsinkin useita päiviä kestäessään haitata normaalia elämää, työntekoa ja harrastetoimintaa. Rintojen arkuutta voi helpottaa käyttämällä tukevia rintaliivejä myös ruokavaliolla voi olla merkitystä. Lääkäriin kannattaa hakeutua, jos omista toimenpiteistä huolimatta oire haitaa päivittäistä elämää. Esim. hormonihoidoilla oiretta voidaan joskus helpottaa.

Tässä väitöstutkimuksessa selvitettiin toremifeeni-lääkityksen tehoa hankalan loppukierron mastalgian hoidossa. Toremifeeni on lääkeaine, joka toimii naishormoni estrogeenin vastavaikuttajana (antiestrogeeni). Lääkettä annosteltiin kuukautiskierron lopulla hankalasta rintojen kivusta kärsiville potilaille kuukautiskierron lopulla ja sen tehoa ja sivuvaikutuksia verrattiin lumelääkkeeseen (placeboon). Toremifeenin teho rintojen kivussa osoittautui hyväksi, selvästi lumelääkettä paremmaksi. Koetut sivuvaikutukset olivat lieviä eivätkä ne eronneet lumelääkkeestä.

Tutkimuksessa selvitettiin myös naisen sukuhormonitasoissa tapahtuvia muutoksia kuukautiskierron lopulla toremifeenin käytön aikana. Estrogeeni, keltarauhashormoni ja prolaktiinitasojen havaittiin nousevan mastalgiasta kärsivillä naisilla. Rintojen magneettitutkimuksella osoitettiin rintojen verenkierron ja samalla turvotuksen vähenevän toremifeenin käytön aikana verrattuna lumelääkitykseen rintojen kivusta kärsivillä naisilla. Oireettomilla naisilla ei todettu muutoksia, kun verrattiin rintojen verenkiertoa ja tilavuutta kolmiulotteisella (3D) ultraäänellä toremifeenin ja lumelääkkeen käytön aikana. Toremifeeni 20 mg annoksella kuukautiskierron lopulla on yksi vaihtoehto hankalan mastalgian hoitona ja sen teho samoin turvallisuus lyhytaikaisessa käytössä osoitettiin tässä väitöstutkimuksessa.

Cyclic mastalgia, by definition, occurs in premenopausal women and connotes breast pain that is clearly related to the menstrual cycle. Premenstrual mastalgia may be severe enough to interfere with usual daily activities, and its effect on quality of life (QoL) is often underestimated. Hormonally active treatments are effective for patients with cyclic mastalgia. This book consists of five studies and presents the effects of the anti-oestrogen toremifene on mastalgia in the premenopausal breast.

The aim of the first study was to evaluate the potential role of toremifene in the treatment of mastalgia, and to investigate its mechanism of action in this indication. The next aim was to evaluate if there are any measurable changes in luteal phase sex hormones attributable to toremifene in women with premenstrual mastalgia. The third aim was to find out if the effect of toremifene on the breast would be detectable with dynamic magnetic resonance imaging (MRI). The fourth aim was to investigate the vascular and volume effects of toremifene on healthy premenopausal breasts by three dimensional (3D) ultrasound.

In the first study, a total of 62 premenopausal women suffering from cyclic mastalgia were randomized to receive toremifene 20 mg daily or placebo from day 15 of the menstrual cycle until menstruation for three consecutive cycles. After a wash-out cycle, the women were crossed over to receive placebo or toremifene, respectively, for three additional cycles. In the second and third study, the population was the same as previously described. However, only those participants who had given blood samples at all measuring points were included in the study. Forty-eight patients gave three blood samples during the luteal phase of the menstrual cycle: the first at baseline, the second during the third toremifene/placebo cycle and third during the third placebo/toremifene cycle, respectively. The investigated hormones in the second study were: follicle stimulating hormone (FSH), oestradiol, progesterone, prolactin (PRL), androstenedione, total and free testosterone and in the third study inhibin A and B were investigated.

In the fourth study, ten women with marked premenstrual mastalgia were randomized to receive either toremifene 20 mg or placebo from cycle day 15 until the next menstruation for three menstrual cycles. After a washout period, the treatment was crossed over for three additional cycles. The MRI evaluations were performed prior to menstruation at the end of each treatment phase. Breast pain and QoL scores were collected from one baseline cycle and from all treatment cycles. Nine participants were included in the final analysis. In the fifth study, twenty healthy premenopausal women were recruited. Following a single non-medicated baseline menstrual cycle, the participants received toremifene 20 mg/day from cycle day 15 until the second examination. The breast 3D ultrasound evaluations were performed within 5 days prior to menstruation. Both breasts were assessed as four quadrants. The power Doppler setting was used and standardized with twenty degrees volume angle and maximum quality.

In Study I, there was a 64 % reduction in median pain scores in the toremifene-treated cycles compared with a 26 % reduction in placebo-treated cycles. The median pain scores were 1.8 (during toremifene treatment), 3.7 (during placebo), and 5.0 (baseline). Although the placebo effect was also significant, toremifene reduced the pain significantly more than placebo. The adverse reactions turned out to be mild and infrequent during the treatment and were evenly distributed between the arms. The overall QoL scores remained unchanged. In study IV, the median Visual Analogue Scale (VAS) scores were 1.83 during toremifene and 6.33 during placebo. Once again, toremifene alleviated breast pain, but the difference was only of borderline significance (P=0.078). However, the QoL scores appeared to be slightly lower during toremifene when compared with placebo (P=0.047). This is likely to be a coincidental result due to the much smaller sample size in Study IV compared with Study I (9 vs. 56 patients, respectively).

The median serum oestradiol and progesterone levels were significantly higher in the toremifene-treated cycles. The median serum PRL concentration was significantly higher during the toremifene treatment when compared with the baseline. There were no significant changes in other hormone concentrations evaluated. The concentrations of both inhibins were within normal range for the luteal phase and remained unchanged throughout the treatment cycles. The mechanism by which toremifene has a therapeutic effect in cyclic mastalgia does not seem to involve inhibition or stimulation of ovarian inhibin production.

Both the enhancement ratio and the maximum slope of enhancement tended to be lower during the toremifene cycles when compared with placebo. These findings indicate that the therapeutic effect of toremifene in alleviating premenstrual mastalgia may at least partly be mediated though diminished blood flow to the breast. The 3D measured volumes and all vascular indices in healthy breasts remained unchanged during the treatment with toremifene when compared with the baseline.

The finding that toremifene significantly alleviated premenstrual breast pain over placebo with few mild adverse effects encourages its use for this indication. The short-term safety of 20 mg of toremifene administered daily during the luteal phase was addressed. The present results imply that the mechanism of action of toremifene in mastalgia is at least partly based on local effects, although the luteotropic effect was also evident.