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Medroxyprogesterone acetate with Zoladex for long-term treatment of fibroids: effects on bone density and patient acceptability


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Human Reproduction vol.12 no.3 pp.436–440, 1997

Medroxyprogesterone acetate with Zoladex™ for

long-term treatment of fibroids: effects on bone density

and patient acceptability



, C.P.West


, M.A.Lumsden



oestradiol concentrations and amenorrhoea (West and Baird, 1987).



and S.M.Gow


However, there is concern about the long-term use of these 1Department of Obstetrics and Gynaecology, University of

agents because it has been shown that a reduction in bone Edinburgh, Centre for Reproductive Biology,2Department of

density occurs (Johansen et al., 1988). In addition, users Medical Physics and Medical Engineering, University of

Edinburgh, Western General Hospital and3Department of Clinical effectively experience a pseudo-menopause associated with Chemistry, Royal Infirmary of Edinburgh, Edinburgh, UK unwanted side-effects, such as vasomotor symptoms and vaginal atrophy. The use of ‘add-back’ therapies, such as 4To whom correspondence should be addressed

hormone replacement therapy or progestogens, may reduce

A randomized trial was carried out to investigate the effect these unwanted effects without reducing efficacy (West et al., of 12 months administration of the gonadotrophin-releasing 1992). Mandel et al. (1982) have shown that medroxyproges-hormone agonist (GnRHa) Zoladex™ in combination with

terone acetate (MPA) may inhibit bone resorption. We were

either placebo or medroxyprogesterone acetate (MPA) from

interested to add this to the Zoladex treatment to observe its

the third month. Bone density, markers of bone resorption,

effect on bone mineral density (BMD) and the cross-links

symptoms and uterine volume were monitored in 24 women

pyridinoline (PYD) and deoxypyridinoline (DPD), valid

with symptomatic fibroids or menstrual problems. A total

markers of collagen degradation. West et al. (1992) reported

of 21 women were recruited to act as controls for the

that adding MPA at the start of therapy prevents the rapid

assessment of bone parameters. Vasomotor side-effects

reduction in uterine volume required for the treatment of

were reduced significantly in the MPA-treated group. The

fibroids, but that its introduction after 3 months of gonadal

reduction in uterine volume in women with fibroids was suppression by Zoladex does not interfere with further fibroid not impaired by the addition of MPA. The bone markers shrinkage. This study also showed that the suppression of osteocalcin and alkaline phosphatase were assessed in luteinizing hormone, follicle stimulating hormone and oestra-plasma, and the cross-links pyridinoline and deoxy- diol was maintained when progestogens were added.

pyridinoline measured in urine. Changes in these markers We designed a study to observe changes in bone density and are reported which suggest increases in bone resorption metabolism in a randomized placebo-controlled trial conducted during the period of observation. Bone mineral density over 12 months, comparing the effect of the GnRHa Zoladex™ (BMD) was assessed by dual energy X-ray absorptiometry (3.6 mg goserelin acetate; Zeneca Pharmaceuticals, at the spine and forearm. The net reduction in BMD at

Macclesfield, UK) in women with symptomatic fibroids and/

the spine in the treated groups was 4.30 6 0.59% at 6

or menorrhagia, with sequential MPA or a placebo ‘added

months and 7.506 0.78% at 1 year, with no change in the

back’ at 3 months. The subjects and 21 age-matched controls

control group. No change was seen in forearm BMD. No

were followed up for 1 year after the Zoladex depots were

protective effect was observed when MPA was added. At


1 year after the completion of treatment, BMD remained significantly below baseline, and this has implications for the prolonged use of GnRHa.

Materials and methods

Key words: bone/bone density/fibroids/GnRH agonist/

Pre-menopausal women who wished to avoid surgical treatment for medroxyprogesterone acetate

symptomatic fibroids or menstrual problems were recruited from the outpatient department of Edinburgh Royal Infirmary (Edinburgh, UK), where a full gynaecological assessment had been made. The presence of fibroids was confirmed by ultrasound. Women who had conditions affecting bone metabolism or who had taken any hormonal


agent within the past 3 months were excluded from the study. Women Sex hormone-dependent gynaecological conditions, including

whose initial BMD (Z score) was .1.6 SD below age-matched endometriosis, menorrhagia and uterine leiomyomata

controls were also excluded from the study. Once the women had (fibroids), are increasingly managed by the suppression of

given informed consent in writing, they were randomized to receive cyclical ovarian activity using gonadotrophin-releasing hor- sequential therapy with either Zoladex plus placebo or Zoladex plus mone agonists (GnRHa). This allows the sustained inhibition MPA. The Zoladex depot was injected s.c. into the lower anterior of pituitary gonadotrophins with a reduction in gonadal steroid abdominal wall using a pre-packed syringe. Treatment was initiated output. Single s.c. injections of goserelin acetate (Zoladex), on days 2–5 of the menstrual cycle and given every 28 days thereafter. After the first 3 months and at the time of administration of the 3.6 mg depot, have been shown to result in post-menopausal


fourth implant, adjunctive therapy in the form of MPA, 15 mg daily, graphic data and the monthly scores in the two patient groups were made using the non-parametric Mann–Whitney U-test. BMD results or a placebo was commenced. The actual treatment given to individual

patients was determined by a random scheme prepared by the were expressed as the percentage change from baseline value at 48 (end of treatment) and 96 weeks (end of follow-up). Each analysis Biometrics Group, Zeneca Pharmaceuticals. The randomization was

was conducted using an analysis of covariance. held in the hospital pharmacy. In all, 12 depots were given to each

of the subjects. Full approval for the study was obtained from the Lothian Health Board Paediatrics/Reproductive Medicine Ethics of

Medical Research Sub-Committee (Edinburgh, UK). Results

On admission to the study, a full history was taken and an A total of 24 women were recruited to the study: 12 patients examination performed. An endometrial biopsy was taken when were randomized to receive Zoladex plus MPA and 12 to considered to be indicated clinically. Height and weight were

receive Zoladex plus placebo. In the Zoladex plus MPA group measured. A blood sample was obtained on entry to the study to

10 women presented with symptomatic uterine fibroids and exclude renal dysfunction and conditions affecting bone turnover. All

two with menorrhagia, whereas in the Zoladex plus placebo subjects completed a daily diary chart throughout the study, in which

group 11 women had symptomatic uterine fibroids and one menstrual bleeding, dysmenorrhoea, breast discomfort, abdominal

had menorrhagia. In all, 21 women were recruited locally to bloating, irritability, depression, hot flushes and night sweats were

act as normal controls. These women were matched for age, recorded individually. Symptom severity was assessed

semi-quantitat-ively on a four-point scale using a visual system of shading in parity and smoking habits. Only BMD and bone turnover were individual boxes. Diaries were collected and reissued at each assessed in these control women.

monthly visit. The mean age of the subjects was 42 years (range 29–49)

Bone turnover was assessed pretreatment, after 24 and 48 weeks and their weight was 68.5 kg (range 54–145). There was no of treatment and at 24 weeks after the completion of treatment, by significant difference in age or weight between the two measuring plasma calcium, alkaline phosphatase and osteocalcin.

treatment groups. The 21 women enrolled in the control group Urine was collected for the markers of collagen degradation: PYD

had a mean age of 42 years (range 31–48) and a mean and DPD. Calcium and alkaline phosphatase were measured using a

weight of 62.1 kg (range 47.4–77.9). The control group was SMAC 2 analyser (Technicon). Osteocalcin was measured in plasma

significantly lighter. Smoking habit was similar in each of the using an in-house radioimmunoassay developed in the Department

groups and did not change over the study period. of Clinical Chemistry at the Royal Infirmary of Edinburgh (Edinburgh,

UK). The method uses antiserum raised in rabbits against bovine


osteocalcin. Tracer (125I-labelled osteocalcin) and the standards were

prepared against bovine osteocalcin. The antiserum cross-reacted with Of the 24 women initially recruited to the study, two (one human osteocalcin and was used to measure osteocalcin in plasma. from each group) withdrew prior to randomization. Their data The assays were performed in batches for each study. The intra-assay were not included in the final analysis. Two withdrew during variation was 4.5% and the interassay variation was 12.1%. Urine

the course of the treatment phase of the study: one (MPA samples were analysed for creatinine, PYD and DPD using

solid-group) at 5 months on account of exacerbation of ulcerative phase extraction and reversed-phase high-performance liquid

colitis, and the other (placebo group) because of excessive chromatography after acid hydrolysis, as described by Pratt et al.

bone loss. Data from both subjects were included fully in the (1992). A fully automated method was used which has improved the

analysis of bone density and until withdrawal in the analysis reproducibility of the technique [coefficient of variation (CV),3%].

of uterine volume. Only one of the two continued to complete Analyses were performed at the Rowett Research Institute, Aberdeen,

UK. The results are expressed relative to the urinary creatinine daily diary charts, and these results were included in the

concentration (nmol/mmol creatinine). analysis.

BMD was measured by dual energy X-ray absorptiometry using a

Hologic QDR 1000W densitometer (Hologic Inc., Waltham, USA). Analysis of symptom charts BMD was measured at the lumbar spine (L1–L4) and the ultradistal

Following administration of the last depot, menses returned at forearm. Measurements were made pretreatment and at 24, 48, 72

a median of 90 days (range 33–133) in the MPA group and and 96 weeks. This system is described in detail by Wahner et al.

110 days (range 82–161) in those treated with placebo. The (1988). Measurement of a spine phantom was performed daily and

difference was not significant. During treatment, 14 (81%) of the long-term precision was excellent (the mean BMD was 1.0384

the subjects (six in the placebo group and eight in the MPA g/cm2with a SD of 0.0054 and a CV of 0.52%). Short-term in-vivo

precision (duplicate measurements of 12 subjects with repositioning group) developed either complete amenorrhoea or documented between scans) was measured and the CV at the lumbar spine was only minimal spotting. The eight remaining subjects all had 0.80% and at the forearm was 0.46%. significant episodes of breakthrough bleeding which, in seven Uterine volume was monitored at 12 week intervals using real- (three placebo, four MPA), was documented predominantly as time ultrasound expressed as the mean percentage change from the intermittent light spotting with occasional heavier days. One baseline value as described previously (West et al., 1987).

subject treated with placebo experienced episodes of prolonged, Power calculations were made based on an earlier pilot study of

sometimes heavy, almost continuous bleeding which required the effect of Zoladex on bone density and the appropriate number of

further investigation. Overall, bleeding patterns did not differ subjects recruited to detect significant changes in bone density. All

between the two groups. analyses were conducted on an intention-to-treat principle (all patients

Analysis of the daily diary charts showed that symptoms of receiving the treatment to which they were allocated). For the analysis

dysmenorrhoea, breast discomfort and abdominal bloating of symptom diaries, total monthly scores were calculated for each


recur-Figure 3. Urinary concentration of the cross-links Figure 1. Severity of hot flushes (lower figure) and night sweats

(upper figure) during the study period expressed as the mean deoxypyridinoline (DPD; upper figure) and pyridinoline (PYD; lower figure) during the study period. Results are expressed in (6SEM) of total 4 weekly scores.

nmol/mmol creatinine. **P, 0.01; *P , 0.05 versus baseline. either of the treatment groups or the controls at baseline. At baseline there was a highly significant variability between subjects in the overall mean baseline level (P, 0.0001), and within subjects there was a significant difference between the five time points in each group (P , 0.0001). The nature of these differences was examined using t-test comparisons. There was found to be no difference between the rates of either bone loss or bone increase after treatment was discontinued in either group. Apparently MPA offered no protective effect. There was no obvious relationship between the percentage change in BMD and body weight, pretreatment BMD or age. By 1 Figure 2. Change in bone mineral density (mean6 SEM) at the year after treatment was discontinued, spine BMD remained lumbar spine during and 1 year after the completion of treatment. at 5.3% (placebo group) and 4.5% (MPA group) below that measured before treatment, and this still represented a highly significant reduction (P , 0.001). The study design did not rence as menses returned. No differences between the two

treatment groups were apparent (data not shown). There were include measurements beyond that time. The rate of bone loss at the ultradistal forearm during treatment was no different no apparent overall differences in the levels of depression or

irritability recorded during the treatment and post-treatment between the two groups at 1.4%, and this did not reach statistical significance. By 1 year after the completion of months, and no significant differences between the two groups.

Mean severity data of vasomotor symptoms of hot flushes treatment forearm BMD was not significantly different than at baseline and was within the reproducibility of the machine. and night sweats throughout the study are shown in Figure 1.

Data indicate that such symptoms were experienced by both There was no significant change in BMD at either the spine or forearm in the control group. This is as we would expect groups during therapy, with resolution once menses returned.

The severity of hot flushes was significantly greater in the in pre-menopausal women. group treated with placebo compared with those treated with

Biochemical parameters

MPA; differences reached statistical significance (P , 0.05)

during the 4 week periods ending at weeks 20, 24, 28, 32 and The results of the cross-links PYD and DPD are shown in Figure 3. Results are expressed as nmol/mmol creatinine. At 40 of therapy. In the case of night sweats, differences reached

statistical significance (P, 0.05) during weeks 28–32. baseline there was a highly significant variability between subjects in the overall mean baseline level (P, 0.008), and

Bone density within subjects there was a significant difference between the

four time points in each group. The nature of these differences Changes in BMD at the lumbar spine are shown in Figure 2.


Figure 5. Mean percentage change (6SD) in uterine volume during and 1 year after the completion of treatment.

agonist. However, we have failed to confirm the hypothesis Figure 4. Plasma osteocalcin (µg/l) (upper figure) and plasma that adjunctive use of MPA delays uterine fibroid regrowth alkaline phosphatase (IU/l) (lower figure) during the study period.

following the cessation of therapy. Indeed Carr et al. (1993) ***P, 0.001; **P , 0.01; *P , 0.05 versus baseline.

have suggested that progestagens may have a trophic effect. The duration of follow-up after the pilot study was only 6 Figure 3. There was no difference in the rate of change of

months; at 6 months the results of the present study show a DPD excretion between the placebo and MPA groups. PYD

similar delay in uterine regrowth, which may be related to the excretion did not change significantly in the MPA-treated

delay in the return of ovarian function, and was not sustained group. It can be seen that excretion of PYD and DPD peaks

at 12 months. Our finding that only 80% of the subjects at 48 weeks (at the end of active treatment) and falls thereafter.

achieved amenorrhoea during therapy is similar to that of other The cross-links at this time remain higher than at baseline and

studies using GnRHa alone. were not measured beyond this time point. No relationship

Zoladex therapy results in a steady reduction in BMD at was found between the rate of bone loss and cross-link

the lumbar spine. Adjunctive therapy with the progestogen excretion at any time point. In the control group there was no

MPA does not prevent the bone loss associated with GnRHa, difference in cross-link excretion throughout the study period.

in this case Zoladex. The beneficial effects of MPA on bone There was no change in plasma calcium throughout the

metabolism were suggested by Mandel et al. (1982) following study period. The alkaline phosphatase and osteocalcin results

the finding that a reduction in urinary excretion of calcium are shown in Figure 4. Alkaline phosphatase increased similarly

and hydroxyproline was seen in post-menopausal women on in both the placebo and MPA groups, and the nature of these

20 mg MPA daily. However, bone mass was not measured in differences from baseline is shown in Figure 4. Plasma

that study. In contrast, Gallagher et al. (1991) found that MPA osteocalcin paralleled these increases, and these highly

sig-failed to prevent post-menopausal bone loss as assessed by nificant increases were observed in each group. There was no

the direct measurement of spinal and radial bone density. change in any of these parameters in the control group.

Friedman (1989) observed radial bone density (using single photon absorptiometry) in 16 women who were receiving the

Uterine response

agonist in addition to 20 mg MPA or placebo. Bone loss was Uterine response was expressed in terms of the mean percentage

not observed in either group; however, this is not unexpected change in volume, taking the pretreatment baseline

measure-because only cortical bone was observed. ment for each woman as 100% (Figure 5). There was a

The fall in circulating oestrogen in the first treatment cycle sustained reduction in uterine volume during therapy which

may initiate bone loss. The rate of decline in BMD is no did not differ between the two groups, with gradual regrowth

different in the period from pretreatment to 6 months, and that of the fibroids over the 12 months following its cessation.

from 6 to 12 months. The net reduction in BMD at the spine Two women (both with fibroids; one from each group) had

in the treatment groups was 4.306 0.59% at 6 months and hysterectomies during the 12 month follow-up period, and six

7.506 0.78% at 1 year, similar to that seen by Bianchi et al. subsequently required surgical treatment of their fibroids during

(1995). Progesterone receptors are known to be present on the 2 years after cessation of treatment. They were equally

osteoblasts, but are only found in the presence of oestrogen distributed between the two treatment groups.

(Eriksen et al., 1988). Thus the inability of MPA to protect bone may be because of the absence of progesterone receptors

Discussion in hypo-oestrogenic states. These rates of bone loss at 6 months

are similar to those seen during breastfeeding (equivalent loss In a previous pilot study (West et al., 1992) we reported that

the use of MPA as an adjunct to Zoladex reduces vasomotor 4.9 6 1.5%), a physiological hypo-oestrogenic state (Caird et al., 1994).

side-effects without impairing the uterine or clinical response

to the GnRHa. This has now been confirmed in the present The use of other agents has been explored with a view to protecting against loss of bone mineral while on GnRHa randomized study, which also illustrates that a further reduction


contraception may protect against loss of bone mass in breast feeding shown to be bone sparing by Friedman (1989) and Maheux

women. Clin. Endocrinol., 41, 739–745.

et al. (1991), who added adjunctive therapy at 3 months, as Carr, B.R., Marshburn, P.B., Weatherall, P.T. et al. (1993) An evaluation of in this study. Leather and Studd (1992) noted that bone the effect of gonadotrophin-releasing hormone analogues and medroxyprogesterone acetate on uterine leiomyomata volume by magnetic loss was prevented when hormone replacement therapy was

resonance imaging: a prospective, randomised, double-blind, placebo-commenced at the time of the first implant in sufferers of pre- controlled crossover trial. J. Clin. Endocrinol. Metab., 76, 1217–1223. menstrual syndrome. In their study no change in BMD was Eriksen, E., Colvard, D.S., Berg, N.J. et al. (1988) Evidence of oestrogen

receptors in normal human osteoblast-like cells. Science, 241, 84–86. seen in hormone replacement therapy users, while a bone loss

Friedman, A.J. (1989) Treatment of leiomyomata uteri with short term of 4.8% in 6 months was seen in the Zoladex-alone group,

leuprolide followed by oestrogen–progestin hormone replacement therapy which is similar to the bone loss found here. No data are for two years, a pilot study. Fertil. Steril., 51, 526–528.

available concerning the effect of the synthetic steroid Tibolone Gallagher, J.C., Kable, W. and Goldgar, D. (1991) Effect of progestin therapy on cortical and trabecular bone: comparison with oestrogen. Am. J. Med., (Livial; Organon) in association with GnRHa on bone mineral

90, 171–177. or fibroids. However, Tibolone does prevent post-menopausal

Johansen, J.S., Riis, B.J., Hassager, C. et al. (1988) The effect of a bone loss (Lindsay et al., 1980). gonadotrophin-releasing hormone agonist analogue (Naferelin) on bone

metabolism. J. Clin. Endocrinol. Metab., 67, 701–706. The elevation in alkaline phosphatase and osteocalcin seen

Leather, A.T. and Studd, J.W. (1992) The prevention of GnRH analogue bone at 6 and 12 months in the treatment groups would suggest an

loss in young women by ‘add back’ oestrogen therapy. In Ring, E.F.J. (ed.), increase in bone turnover during Zoladex therapy. This was Current Research in Osteoporosis and Bone Mineral Measurement 2. Proceedings of the Third Bath Conference on Osteoporosis and Bone paralleled by an increased excretion of the cross-links PYD

Mineral Measurement, British Institute of Radiology, London, UK, pp. and DPD. By 24 weeks after the treatment was discontinued


none of these markers of bone activity had returned to normal, Lindsay, R., Hart, D.M. and Kraszewski, A. (1980) Prospective double-blind suggesting a continuing increase in bone turnover. However, trial of synthetic steroid (Org OD 14) for preventing postmenopausal

osteoporosis. Br. Med. J., 280, 1207–1209. osteocalcin remained relatively higher than the cross-links

Maheux, R., Lemay, A., Blanchet, P. et al. (1991) Maintained reduction of compared with baseline, suggesting increased bone formation

uterine leiomyoma following addition of hormonal replacement therapy to at this time as BMD was in fact increasing. The above findings a monthly luteinizing hormone-releasing hormone agonist implant: a pilot

study. Hum. Reprod., 6, 500–505. are in agreement with those of Scharla et al. (1990), who

Mandel, F.P., Davidson, F.P., Erlik, Y. et al. (1982) Effects of progestins on found an increase in alkaline phosphatase and phosphate in

bone metabolism in postmenopausal women. J. Reprod. Med., 27, 511–514. women treated with Zoladex alone. It was suggested that this Pratt, D.A., Daniloff, Y., Duncan, A. et al. (1992) Automated analysis of the simply reflected enhanced bone turnover. These results are pyridinium crosslinks of collagen in tissue and urine using solid-phase extraction and reversed-phase high-performance liquid chromatography. similar to those reported by others for the use of a GnRHa

Anal. Biochem., 207, 168–175. alone (Johansen et al., 1988; Waibel-Treber et al., 1989).

Scharla, S., Minne, H.W., Waibel-Treber, S. et al. (1990) Bone mass reduction In summary, this study confirms that a significant loss of after oestrogen deprivation by long-acting gonadotrophin releasing hormone agonists and its relation to pretreatment serum concentrations of 1,25-bone mineral occurs with Zoladex therapy. This loss is similar

dihydroxyvitamin D. J. Clin. Endocrinol. Metab., 70, 1055–1061. to that seen during breastfeeding, which is a physiological

Wahner, H.W., Dunn, W.L., Brown, M.L. et al. (1988) Comparison of dual-situation. In addition, biochemical changes suggesting altered energy X-ray absorptiometry and dual photon absorptiometry for bone mineral measurements of the lumbar spine. Mayo Clin. Proc., 63, 1075–1084. skeletal metabolism do occur. The changes in bone mass at

Waibel-Treber, S., Minne, H., Scharla, S.H. et al. (1989) Reversible bone loss the spine are not prevented with adjunctive progestogen therapy

in women treated with GnRH-agonists for endometriosis and uterine (MPA). This is in contrast to its already proven symptomatic leiomyoma. Hum. Reprod., 4, 384–388.

benefits (West et al., 1992). A more useful alternative may be West, C.P. and Baird, D.T. (1987) Suppression of ovarian activity by Zoladex depot (ICI 118630), a long acting luteinizing hormone releasing hormone the addition of conventional hormone replacement therapy,

agonist analogue. Clin. Endocrinol., 26, 3–220. and Maheux et al. (1991) have shown that low-dose oestrogen

West, C.P., Lumsden, M.A., Lawson, S. et al. (1987) Shrinkage of uterine and sequential progesterone may protect against bone loss fibroids during therapy with goserelin (Zoladex); a luteinising hormone-releasing agonist administered as a monthly subcutaneous depot. Fertil. with no apparent increase in the growth of fibroids.

Steril., 48, 45–51.

West, C.P., Lumsden, M.A., Hillier, H. et al. (1992) Potential role for medroxyprogesterone acetate as an adjunct to goserelin (Zoladex) in the

Acknowledgements medical management of uterine fibroids. Hum. Reprod., 7, 328–332. We thank Sister Joan Creiger for her assistance with data collection

Received on July 23, 1996; accepted on November 15, 1996 and patient supervision. We are grateful to the staff at the Ultrasound

Department for their assistance with scanning. Thanks are due to Steve Cowan and Carol Miller at the Department of Medical Physics at the Western General Hospital for their assistance with dual energy X-ray absorptiometry scanning. This research was supported by financial assistance from Zeneca Pharmaceuticals, Macclesfield, UK. L.E.C. was sponsored by a Faculty of Medicine Research Fellowship at Edinburgh University (Edinburgh, UK).


Bianchi, S., Fedele, L., Vignali, M. et al. (1995) Effects on bone mineral density of 12-month goserelin treatment in over 40 year old women with uterine myomas. Calcif. Tissue Int., 57, 78–80.


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