Mary Ann Lumsden

Shrinkage of uterine fibroids during therapy with goserelin (Zoladex * ): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot

Thirteen premenopausal women with uterine fibroids were treated for a maximum of 6 months with a long-acting agonist of luteinizing hormone-releasing hormone (LH-RH), goserelin (Zoladex depot, ICI Pharmaceuticals, Macclesfield, UK) 3.6 mg, administered subcutaneously every 28 days. A 55% reduction (range, 38% to 84%) in uterine volume assessed by ultrasound was obtained. The greatest reduction (30%) was apparent within the first treatment cycle regardless of whether treatment was started in the early follicular or the luteal phase. Fibroid regression was inversely correlated with urinary estrogen concentration. Treatment was well tolerated and only one subject withdrew from the study before its scheduled completion. Following cessation of therapy, ovulatory menstruation returned within 3 months in the majority of the subjects, but this was accompanied by a rapid regrowth of the fibroids. This medical approach to the management of fibroids merits further investigation but as yet cannot be regarded as an alternative to surgery.

The binding of epidermal growth factor to the human uterus and leiomyomata in women rendered hypooestrogenic by continuous administration of an LHRH agonist

Summary. The binding of epidermal growth factor (EGF) to human myometrium and leiomyomata was assessed in a group of women rendered hypo‐oestrogenic with the LHRH agonist Zoladex (ICI118630). The results were compared with those obtained with tissues from women with normal cycles. Tn normal women, the specific binding of radiolabelled [125I] EGF to both myometrial and fibroid homogenates did not vary during the menstrual cycle, but the specific binding of [125I] EGF to fibroid in women treated with LHRH agonist was significantly less than in the untreated group. Since the hypo‐oestrogenic state induced by the agonist is associated with a decrease in fibroid size, the results suggest that the effect of oestrogen on fibroid tissue may partly be mediated by EGF.

Primary dysmenorrhoea: the importance of both prostaglandins E2 and F2α

Summary. Menstrual fluid was collected in a contraceptive diaphragm from 16 women with primary dysmenorrhoea and 12 matched control subjects without dysmenorrhoea. Prostaglandins F2α (PGF2α), E2 (PGE2) and 6‐oxo‐prostaglandin F1α (6‐oxo‐PGFlα) were extracted and measured using gas‐chromatography: mass spectrometry (GC:MS). The concentrations of both PGF2α and PGE2 were higher on days 1 and 2 in the dysmenorrhoea group than in the control group and the concentration of PGF2α was higher on day 1 than on day 2 in the dysmenorrhoea group. The concentrations of 6‐oxo‐PGF1α (the stable metabolite of PGI2) were low in both groups. These results confirm suggestions that PGF2α is important in the aetiology of dysmenorrhoea and also indicate that PGE2 may be involved.

Treatment with the gonadotrophin releasing hormone-agonist goserelin before hysterectomy for uterine fibroids

Objective To investigate the effect of the gonadotrophin releasing hormone (GnRH)‐agonist goserelin, given by monthly subcutaneous injection for three months prior to total abdominal hysterectomy for uterine leiomyomata, on the pre‐operative symptoms, difficulty of operation and operative blood loss.

Estrogenic action of tamoxifen in women treated with luteinizing hormone-releasing hormone agonists (goserelin)—lack of shrinkage of uterine fibroids

Six premenopausal women with uterine fibroids were treated with a combination of tamoxifen, 20 mg/d, and goserelin, 3.6mg every 28 days, for a total of 24 weeks. Results were compared with those from six women, matched for pretreatment uterine volume, who had been treated with goserelin alone. During combined therapy, plasma and urinary estrogen concentrations were significantly lower than during goserelin alone, whereas sex hormone binding globulin concentrations were significantly higher. Plasma luteinizing hormone and follicle stimulating hormone (FSH) concentrations were both suppressed, in contrast with results during goserelin alone when FSH levels remained within the pretreatment range. None of the women on combined therapy bled in response to the endocrine changes of the initial treatment cycle. Despite this profound pituitary-ovarian suppression, there was no significant change in uterine volume during combined therapy. These results suggest that tamoxifen is acting as an estrogen agonist in women rendered hypoestrogenic with luteinizing hormone-releasing hormone agonists.

Tamoxifen prolongs luteal phase in premenopausal women but has no effect on the size of uterine fibroids

Tamoxifen (20 mg per day) was administered for at least 3 months to six premenopausal women with uterine fibromyomata. In all the women there was an increased variability in the length of the menstrual and ovarian cycle associated with a significant lengthening of the luteal phase (16.9 ± 3.5 vs 12.5 ± 1.5 days, mean ± SD, P < 0.02). The concentration of oestradiol and progesterone in plasma and their metabolites in urine (oestrone glucuronide and pregnanediol) increased reflecting multiple follicular development and ovulation. There was a significant rise in the concentration of FSH during the luteal phase of the cycle (8.0 ± 2.9 vs 2.0 ± 1.7 U/I, P < 0.01). There was no change in the size of the uterine leiomyomata. These results demonstrate that the antioestrogen tamoxifen results in an increased secretion of gonadotrophins by antagonizing the effects of oestradiol at the hypothalamus and anterior pituitary. The lengthening of the luteal phase suggests oestradiol may play a role in the mechanism of luteal regression either locally or via feedback effect on gonadotrophins.

Is prostaglandin F2α involved in the increased myometrial contractility of primary dysmenorrhoea

The concentrations of prostaglandin F2 alpha (PGF2 alpha) and E2 (PGE2) in menstrual fluid collected daily from 13 women with primary dysmenorrhoea and 11 matched controls, were compared with the pattern of uterine contractility during the hour following the menstrual fluid collection. The intra-uterine pressure (IUP) was measured using a micro-transducer catheter and the tracings analysed. On Day 2 the concentration of PGF2 alpha correlated with the peak area, but not with amplitude, duration or rate of contraction. These findings add additional support to the hypothesis that increased production of PGF2 alpha could contribute to the increased uterine contractility in primary dysmenorrhoea.

Long-term suppression of ovarian function by a luteinizing-hormone releasing hormone agonist implant in patients with endometriosis

Ten endometriosis patients received luteinizing hormone releasing hormone (LH-RH) agonist (buserelin) implant injections (6.6 mg subcutaneously) at days 0, 42, 84 and 126. Serum LH and follicle-stimulating hormone (FSH) were lowered by day 14. Luteinizing hormone remained at basal concentrations while FSH returned to values in the low-normal range of the menstrual cycle by day 35. At the end of the luteal phase during which treatment commenced, estrone and pregnanediol declined and remained at postmenopausal or early follicular phase values until days 305 to 460. Time to first ovulation ranged from 321 to 481 days after starting treatment. After the initial menstruation, only three instances of bleeding occurred during treatment. Pelvic pain was relieved or markedly reduced by day 42 and remained absent throughout the period of ovarian suppression. These results indicate the potential of a long-acting LH-RH agonist implant to form the basis for the treatment of symptomatic endometriosis.

Goserelin (Zoladex®) in the treatment of fibroids

C . P. W E S T M. A . L U M S D E N D . T. B A I R D hysterectomy specimens from women who had been pretreated for 3 months with goserelin, compared with untreated controls4. This finding was not attributable to changes in receptor occupancy. Binding of progesterone to fibroids was, however, significantly reduced and was correlated with the degree of reduction of plasma oestradiol concentrations in the treated women. It is possible that this rise in oestrogen-receptor conDepartment of Obstetrics and Gynaecology, University of Edinburgh, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh, UK

The relationship between menstrual blood loss and prostaglandin production in the human: evidence for increased availability of arachidonic acid in women suffering from menorrhagia

In this study we have obtained endometrium and myometrium from women whose menstrual blood loss had been measured objectively. Samples of tissue were snap frozen in liquid nitrogen for the estimation of PG content and tissue was homogenized and incubated with and without added arachidonic acid. PGE, PGF2 alpha and 6-oxo PGF1 alpha were measured by gas chromatography - mass spectometry. We confirm that the F2 alpha/E2 ratio in the snap frozen samples was significantly lower in women with a high blood loss although this was not reflected in the production by incubated homogenates. Incubation of endometrial tissue with myometrium from the same patient and with a pool of myometrium showed that the source of myometrium was not important. This suggests that previous observations of increased 6 oxo F1 alpha production in incubations of endometrium and homologous myometrium from women with high MBL, resulted from differences in endometrium. When prostaglandin E and F production by endometrium is studied there is a significant inverse correlation between the percentage difference in production with and without added arachidonic acid and menstrual blood loss which suggests that women with high MBL have relatively high levels of available arachidonic acid in their endometrium.