A prospective, randomized trial of gonadotropin ...

0021-972x/93/7606-1439$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright cc>1993 by The Endocrme Swaety

Vol. 76. No. 6 Printed m U.S.A.

A Prospective, Randomized Trial of GonadotropinReleasing Hormone Agonist Plus Estrogen-Progestin Progestin “Add-Back” Regimens for Women with Leiomyomata Uteri* ANDREW MITCHELL

J. FRIEDMAN, MARGARET S. REIN, CALLIOPE FINE,

or

DALY, MARY JUNEAU-NORCROSS, RAY GLEASON, AND MERYL LEBOFF

Departments of Obstetrics and Gynecology (A.J.F., M.D., M.J-N., M.S.R.) and Medicine (R.G., M.L.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; and the Boston Ultrasound Associates, P.C. (C.F.), Brookline, Massachusetts 02146 ABSTRACT

Mean uterine volume decreased to 64% of pretreatment size at 12 weeks of LAD treatment in both groups. The estrogen-progestin addback group had no significant regrowth of uterine volume, which was 75% of pretreatment size at treatment week 52; in contrast, the progestin add-back group had a mean uterine volume of 92% of pretreatment size by treatment week 52. Both groups demonstrated significant improvements in mean hemoglobin concentrations and hematocrits. The progestin add-back group had a significant decline in mean high density lipoprotein-cholesterol concentration, which was not seen in the estrogen-progestin add-back group. Finally, after a significant 3% bone loss during the first 12 weeks of treatment, bone mineral density stabilized in both add-back regimen groups. GnRH-a/steroid add-back regimens provide a useful long-term treatment strategy in women with large, symptomatic uterine myomas and may obviate the need for surgical intervention in selected cases. The estrogen-progestin add-back regimen was superior or equal to the progestin add-back regimen in all efficacy and safety parameters assessed. (J Clin Endocrinol Metub 76: 1439-1445,1993)

Treatment of women with myomas with GnRH agonists (GnRH-a) for 3-6 months will result in profound hypoestrogenism, a significant but temporary reduction in uterine volume, and menstrual suppression. Long-term (i.e. >6 months) treatment with a GnRH-a is not recommended because of accelerated bone resorption and the presence of hypoestrogenic symptoms. In this 2-yr study, women with myomas were treated with GnRH-a plus one of two steroid “add-back” regimens to minimize adverse sequelae of chronic hypoestrogenism. Fifty-one premenopausal women with large, symptomatic uterine myomas all received the GnRH-a, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks at which time the women were randomized to receive LAD plus either an estrogen-progestin or progestin-only addback regimen for an additional 92 weeks. Efficacy parameters assessed included serial uterine volumes, hemoglobin concentrations, and hematocrits; safety parameters evaluated included serial bone mineral density measurements, lipid profiles, and medication-related symptoms. This report analyzes the first 52 weeks of study data.

U

TERINE myomas are estrogen-sensitive neoplasms which arise in 25-30s of women during their reproductive years (1). The majority of symptoms experienced by women with leiomyomata are due to either an enlarged pelvic massor excessiveuterine bleeding. The standard treatment options for women with large or symptomatic myomas are surgical and include hysterectomy or myomectomy. Treatment of women with myomas with a GnRH agonist (GnRH-a) for 3 months will result in profound hypoestrogenism, which in turn leads to significant and reversible reductions in uterine and myoma volumes and to menstrual suppression(2-5). However, long-term (i.e. >6 months) treatment with a GnRH-a is not recommended because of the risks of accelerated bone loss and the presence of other hypoestrogenic symptoms (e.g. vasomotor flushes, urogenital atrophy) that may affect the quality of life. It has been Received September 16, 1992. Address requests for reprints to: Andrew J. Friedman, M.D., Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, 75 Francis Street, ASBl-2-104, Boston, Massachusetts 02115. * Supported in part by a grant from TAP Pharmaceuticals, Inc., and by Grant 7-MOl-RR02635-01 from the General Clinical Research Center, Brigham and Women’s Hospital.

hypothesized that low doses of steroid hormones added to GnRH-a treatment may avert adverse effects of prolonged hypoestrogenism without causing regrowth of uterine myomas and the return of myoma-related symptoms (6-8). In this prospective clinical trial, women with large, symptomatic myomas were treated with the GnRH-a, leuprolide acetate depot (LAD), for 104 weeks; after the first 12 weeks of LAD treatment, women were randomized to receive either estrogen-progestin or progestin only “add-back” therapy in an effort to minimize hypoestrogenic symptoms and adverse effects. This report analyzes the first year data from this ongoing clinical trial. Materials Patient

and Methods

selection

Fifty-one premenopausal women, 27-53 yr of age, with leiomyomata uteri voluntarily consented to participate in this study which was approved by the Brigham and Women’s Hospital Human Research Committee. The women were offered expectant management (i.e. observation) but all declined because of the severity of myoma-related symptoms. Inclusion criteria for this study were the same as those defined in a previous study (4). In addition, if a woman’s low density lipoprotein (LDL) cholesterol was greater than or equal to 4.14 mmol/L (~160 mg/

1439

The Endocrine Society. Downloaded from press.endocrine.org by [Meryl LeBoff] on 11 November 2015. at 11:02 For personal use only. No other uses without permission. . All rights reserved.

FRIEDMAN

1440

dL) either before enrollment or at any time after study entry, her participation in the study was terminated. Thirty-four age-matched regularly cycling premenopausal women on no medications served as controls for bone density measurements over the 2-yr study period; measurements were made at 0,52, and 104 weeks. Before enrollment in the study, all patients had their histories recorded and were given a complete physical examination. Blood samples were collected in the midluteal phase of the menstrual cycle before administration of the first dose of LAD, for determinations of FSH, estradiol (E,), hemoglobin (Hgb), hematocrit (Hct), cholesterol, high density lipoprotein (HDL) cholesterol, and LDL cholesterol. Baseline bone density determinations and measurements of uterine volume by ultrasonography were also obtained in the month before initiation of LAD therapy. All women received 3.75 mg LAD (TAP Pharmaceuticals, Inc., Deerfield, IL) im every 4 weeks for 104 weeks. After the first 12 weeks of LAD treatment, women were randomized to one of two steroid addback protocols: The estrogen-progestin add-back group received 0.75 mg estropipate (Ogen 0.625, Abbott Pharmaceuticals, Inc., Abbott Park, IL) daily plus 0.7 mg norethindrone (Micronor, Ortho Pharmaceuticals Corp., Raritan, NJ) days 1 through 14 each month during treatment weeks 12 through 104. The progestin add-back group received 10 mg norethindrone (Norlutin, Parke-Davis, Morris Plains, NJ) daily during treatment weeks 12 through 104. LAD treatment was initiated in the mid- to late-luteal phase. Patients were seen at 4-week intervals during the treatment period. During each visit, myoma-related symptoms, adverse effects of medication, and menstrual histories were recorded. Bimanual examinations were performed every 3 months. Blood samples for Ez concentrations and uterine volume measurements were obtained at treatment weeks 12, 24, 52, 76, and 104. Descriptions of sonographic uterine measurements and uterine volume calculations have been reported previously (4). Blood samples for cholesterol, HDL cholesterol, LDL cholesterol, Hgb, and Hct determinations as well as bone density measurements were obtained at treatment weeks 12, 52, 76, and 104.

Bone density analysis Bone mineral density was performed by dual x-ray absorptiometry initially with a QDR-1000 and later with a QDR-1000W bone densitometer (Hologic, Inc., Waltham, MA) (see below). Each patient had a baseline measurement of the lumbar spine (Ll-L4) in duplicate with repositioning during the month before treatment initiation, with subsequent measurements at 12,52, 76, and 104 weeks. When an individual’s bone density was noted to be different from her baseline value by greater than or equal to 5%, duplicate measurements were obtained. The in viva reproducibility of our dual x-ray absorptiometry determinations of the spine in this study was 0.68 + 0.06% (n = 108 scans with repositioning). Based on this reproducibility, a change in bone density of greater than 2% should be detectable with two measurements (9). Over the course of the study, one stepwise change within 0.5% of the anthropomorphic spine phantom bone mineral content was introduced by a necessary service repair. The integrated in vitro reproducibility of our spine phantom was 0.50% (n = 832) during the entire study. Due to careful cross-calibration, no stepwise change was introduced when our QDR-1000 bone densitometer was upgraded to a QDR-1000W. Bone mineral density data are presented as grams per cm’.

Statistical

analysis

Analysis of variance was used to analyze data in this two-factor (i.e. time, treatment) experiment with repeated measures on one factor (i.e. time). Post-hoc pairwise comparisons among time means were done using the Newman-Keuls test. In analyses where a significant treatment by time interaction was observed, a repeated measure analysis of variance for each treatment group blocking by subject was performed to determine where time differences occurred within each treatment group (Newman-Keuls test). Differences in baseline data were tested for significance using an unpaired t test. Fisher’s exact test was used to test for differences in the proportion of patients in both treatment groups experiencing medication-related adverse effects and in their bleeding patterns at treatment week 12 (i.e. on LAD alone) and at treatment

ET

AL.

JCE & M. 1993 Voll6.No6

weeks 24 and 52 (i.e. on LAD plus one of two steroid add-back regimens). Patients experiencing bleeding and spotting were combined and compared to amenorrheic patients resulting in a 2 x 2 table. The statistical analyses were performed using SAS software (SAS Institute, Inc., Cary, NC) Data were analyzed and reported only for patients who completed 52 weeks of the study protocol.

Results

Demographic data and presenting symptoms for both groups of patients are reported in Table 1. Randomization resulted in the groups being well matched for age, weight, pretreatment uterine volume, and presenting symptoms. Seven patients in the estrogen-progestin add-back group and 12 patients in the progestin add-back group did not complete 52 weeks of the study protocol (P = 0.12) and are therefore not included in data analysis. The reasons for premature termination are shown in Table 2. Mean serum EZ concentrations in both treatment groups showed significant (P < 0.0001) but parallel degrees of suppression throughout the study period. Mean E2 concentrations were suppressedbelow 100 pmol/L (25 pg/mL) in both groups at treatment weeks 12, 24, and 52. Figure 1 illustrates the mean uterine volumes, as calculated by ultrasonic measurements, before therapy and at 12, 24, and 52 weeks. Mean uterine volume decreased to 64% of pretreatment size (i.e. 36% decrease in size) by treatment week 12 in both treatment groups. After estrogen-progestin add-back treatment, uterine volume was 69% of pretreatment size at week 24 and 75% of pretreatment volume at week 52 (P 5 0.05 DS.pretreatment volume). In the progestin add-back group, uterine volume increasedto 86% of pretreatment size at week 24 and to 92% of pretreatment size by week 52 (P = NS VS.pretreatment volume). Changesin the severity of myoma-related symptoms were analyzed for women completing 52 weeks of treatment and are presented in Table 3. Both add-back regimens were highly successfulin reducing excessive uterine bleeding. The estrogen-progestin add-back regimen was more successful TABLE

1. Demographic data” and presenting symptoms for 51 women with uterine myomas treated with leuprolide acetate depot and either an estrogen-progestin or a progestin-only add-hack regimen Leuprolide

acetate depot plus

Estrogen-progestin Characteristic? Age W Weight (kg) Uterine vol (cm3) Presenting symptoms’

Progestin

(n = 26)

(n = 25)

41 * 1 69 f 3 898 * 103

44 + 1

67 f 2 738 f 96

[no. (%)I Menorrhagia Pelvic pressure Pelvic/abdominal Urinary frequency Pelvic pain Constipation

mass

21 21 19 19 16 9

(81) (81) (73) (73) (62) (35)

’ Mean + SE. *P not significant for all characteristics. ‘Some patients presented with more than

23 20 19 18 19 11

one symptom.


(92) (80) (72) (72) (76) (44)

GnRH-a/STEROID

ADD-BACK

RX

FOR MYOMAS

1441

TABLE 2. Premature terminations of participation in study of 51 women with uterine myomas treated with leuprolide acetate depot plus an estrogen-progestin or a progestin-only add-back regimen Leuprolide

acetate

depot

plus Progestin (n = 12)

Estrogen-progestin (n = 7)

Reason

Week(s) terminated

No.

Excessive vaginal bleeding Uterine regrowth No uterine shrinkage Depression Personal reasons Pelvic pain Sterile abscess at injection site

Week(s) terminated

No.

3

16, 24, 28

0 1 0

5 3

16

0

2

20,32

2 1

36

0

0

20, 20, 20, 28, 28 24, 28, 28 24,40 20 24

1

1

1000 T

GnRHa/E*P

T

600 600 400 200

FIG. 1. Uterine volumes at the pretreatment visit and at treatment weeks 12, 24, and 52. *, P 5 0.05 us. pretreatment.

Vol (cm’)

I

Pre

24

52

Treatment

week

TABLE 3. Changes in the presence or severity of presenting symptoms in 32 women with uterine myomas treated with leuprolide acetate depot plus either an estrogen-progestin or a progestin-only add-back regimen Status Presenting

of presenting

symptoms

at week

52

symptom Resolved

Menorrhagia Estrogen-progestin add-back Progestin add-back (n = 17) Pelvic pressure Estrogen-progestin add-back Progestin add-back (n = 16) Pelvic/abdominal mass Estrogen-progestin add-back Progestin add-back (n = 15) Urinary frequency Estrogen-progestin add-back Progestin add-back (n = 14) Pelvic pain Estrogen-progestin add-back Progestin add-back (n = 15) Constipation Estrogen-progestin add-back Progestin add-back (n = 9)

(n = 18) (n = 19) (n = 17)

(n = 14) (n = 7)

No change

Worsened

17

1

0

0

12

2

2

1

7

9

4

5

3 5

0 2

9

5 4

3 7

0 2

4

4 4

3 4

0 2

13 12

1 1

0 0

2

7 4

0 2

0 3

0 0

2

(n = 18)

Improved

11


0

ET AL.

FRIEDMAN

1442

than the progestin add-back regimen in reducing severity of symptoms due to an enlarged uterus. Mean Hgb concentrations and Hct determinations are shown in Table 4. Both treatment groups demonstrated significant (P = 0.0004) but parallel increases over time. When only anemic women (i.e. Hct < 36%, n = 20) were analyzed during the first 12 weeks of GnRH-a treatment, mean Hct increased from 31.6 f 0.9% to 36.2 + 1.0% (P = 0.0003). Mean bone density of the lumbar spine showed significant (P = 0.0001) but parallel changes over time in both treatment groups (Table 5). In the estrogen-progestin add-back group, mean bone density decreased significantly by 2.7% during the first 12 weeks of treatment (i.e. while on LAD alone); a further small, but not statistically significant, decrement in mean bone density of 2.0% was noted between treatment weeks 12 and 52. In the progestin add-back group, mean bone density decreased significantly by 3.3% during the first 12 weeks of treatment; an increment of 0.8% in bone density was noted from treatment week 12 to 52 but was not statistically significant. In a group of 34 age-, weight-, and racematched regularly cycling controls on no medications, the mean bone density decreased by 0.3% over 52 weeks, which was not statistically significant. Serum concentrations of total cholesterol and HDL and LDL subfractions are shown in Table 6. The only significant difference between the treatment groups was a lower mean HDL cholesterol concentration in the progestin add-back group compared with the estrogen-progestin add-back group at treatment week 52. Bleeding patterns for all women were assessed at each treatment week and are illustrated for both treatment groups at weeks 12, 24, and 52 in Fig. 2. The majority of patients (66%) were amenorrheic at treatment week 12 (12%). In the estrogen-progestin add-back group, the majority of patients experienced amenorrhea at treatment weeks 24 and 52, despite administration of estrogen continuously with cyclic progestin. In contrast, the majority of women in the progestin add-back group experienced intermittent spotting at treatment weeks 24 and 52. When patients experiencing bleeding or spotting were combined and compared to amenorrheic patients by Fisher’s exact test, a significant difference was seen between the two groups only at treatment week 52

(P = 0.014). Medication-related

adverse effects are reported in Table 7

TABLE

4. Hgb concentrations and Hct determinations” estrogen-progestin or a progestin-only add-back regimen

in 32 women

JCE & M. 1993 Voll6.No6

at treatment week 12 for all patients and at weeks 24 and 52 for each treatment group. For both treatment groups, significant decreases in the proportion of patients experiencing hot flashes from treatment week 12 to 24 and from week 12 to 52 were reported (P I 0.05 for all within-group comparisons). In addition, significantly fewer women in the estrogen-progestin add-back group experienced vaginal dryness at treatment week 24 than at week 12 (5% VS. 41%, P < 0.02). Discussion In this prospective, randomized clinical trial, women with large, symptomatic uterine myomas were treated with a GnRH-a for 3 months followed by the addition of either an estrogen-progestin or a progestin-only add-back regimen to GnRH-a treatment for an additional nine months. In all patients, mean uterine volume decreased by 36% after 12 weeks of GnRH-a treatment, which is consistent with findings in previous studies (2-5). After steroid add-back therapy, the mean uterine volume in the estrogen-progestin add-back group remained significantly smaller at treatment week 52 than before treatment initiation; in contrast, mean treatment week 52 uterine volume was not significantly different from pretreatment in the progestin add-back group. No placebo group was available for comparison, eliminating the ability to observe the natural history of disease progression. These results confirm the findings from two small pilot studies in which women were treated with a GnRH-a for 3 months followed by GnRH-a plus estrogen-progestin addback therapy for 9 or 24 additional months (6, 7). In these studies, mean uterine volume decreased significantly after the first 3 months of treatment but did not change after the addition of cyclic estrogen-progestin, which prevented hypoestrogenic symptoms and significant reductions in bone density. The results of these studies support the “estrogen threshold hypothesis” of uterine growth in women with myomas (8). According to this hypothesis, low circulating estradiol levels seen with GnRH-a treatment or after menopause are associated with regression of estrogen-sensitive tissues (i.e. myomas, bone, etc.). Adding back small amounts of estrogen will increase circulating estrogens to levels high enough to maintain the integrity of some tissues (i.e. bone) with relief of vasomotor symptoms while causing other tissues (i.e. myomas) to remain in a state of regression. Thus, with

uterine

myomas

treated

with

leuprolide

Treatment

acetate

depot

week

Pretreatment 12

52

Hgb k/W Estrogen-progestin Progestin add-back Hct (%)* Estrogen-progestin Progestin add-back a Mean + SE. * Both treatment

groups

(n = 19)

11.9 f 0.5 12.0 2 0.6

12.7 f 0.6 13.0 f 0.4

13.3 + 0.3 13.6 f 0.2

add-back (n = 19) (n = 13)

35.7 + 1.7 35.9 + 1.6

37.3 f 1.7 38.1 If- 1.3

39.3 f 0.6 40.0 f 0.6

add-back (n = 13)

demonstrated

significant

(P = 0.0004)

but parallel

changes

over time.


plus either

an

GnRH-a/STEROID

TABLE either

5. Bone density an estrogen-progestin

determinations (g/cm’)’ in 34 controls or progestin-only add-back regimen

ADD-BACK

RX

and 32 women

FOR

with

MYOMAS

uterine

1443

myomas

treated

with

Treatment

leuprolide

add-back (n = 19) (n = 13)

a Mean f SE. * Both treatment groups demonstrated significant ‘P < 0.05 between pretreatment and week 52. d P = NS between pretreatment and week 52.

TABLE either

6. Total, HDL, an estrogen-progestin

and LDL cholesterol or a progestin-only

1.102 f 0.025 1.081 f. 0.022 1.081 k 0.020 (P = 0.0001)

but parallel

concentrations” in 32 women add-back regimen

changes

with

depot

plus

week

Pretreatment Estrogen-progestin’ Progestin add-back* Control (n = 34)

acetate

12

52

1.074 + 0.028 1.045 * 0.022

1.053 + 0.027 1.047 f 0.025 1.078 + 0.020d

over time.

uterine

myomas

treated

with

Treatment

leuprolide

acetate

depot

plus

week

Pretreatment 12

Total cholesterol-mmol/L* (mg/dL) Estrogen-progestin add-back (n = 19) Progestin

add-back

HDL cholesterol-mmol/L Estrogen-progestin Progestin

add-back

LDL cholesterol-mmol/L* Estrogen-progestin Progestin

add-back

(n = 13) (mg/dL) add-back (n = 19) (n = 13)

add-back

(mg/dL) (n = 19)

(n = 13)

* Both treatment groups showed significant ‘P = 0.004 between groups at week 52. d P < 0.05 between pretreatment and week

(P = 0.01) but parallel

52

4.81 f 0.18 (186 + 7) 4.68 + 0.16 (181+ 6)

5.30 + 0.21 (205 + 8) 5.20 + 0.21 (201t 8)

5.15 f 0.16 (199 + 6) 4.58 -t 0.26 (177 + 10)

1.45 (56 1.42 (55

f + + f

0.08 3) 0.10 4)

1.60 (62 1.45 (56

t -c + f

0.08 3) 0.10 4)

+ f 0 98 + i38 +

2.90 (112 2.82 (109

+ + f f

0.13 5) 0.13 5)

3.15 (122 3.28 (127

+ + + +

0.16 6) 0.18 7)

3.23 t 0.10 (125 + 4) 3.21 + 0.26 (124 f 10)

changes

1.42 (55

0.08 3)

0 08'~~ 3j

over time.

52.

GnRH-a/E+P 100 80 60 40 20 FIG. 2. Bleeding

patterns in women receiving either estrogen-progestin or progestin add-back therapy at treatment weeks 12,24, and 52.

GnRH-a/P 100 80 60 40 20 24 Treatment

week


= 0 0

Bleeding Spotting Amenorrhea

FRIEDMAN

1444 TABLE progestin

7. Medication-related or a progestin-only

adverse effects add-back regimen

in 32 women

with

uterine

ET AL. myomas

JCE8~M.1933 Vol76.No6

treated

with

No. (76) of patients with Effect

Week 12 All patients (n = 32)

Hot flashes Insomnia Vaginal dryness Mood swings Headache Arthralgias Hair loss Breast tenderness Edema Fatigue Decreased libido Weight gain Acne ’ E + P, Estrogen-progestin *P, Progestin add-back

28 (88) 13 (41) 13 (41) 10 (31)

7 (22) 6 (19) 4 4 4 1 1 1 0 add-back

(13) (13) (13) (3) (3) (3) (0)

Week

24 GnRH-a

plus

leuprolide

indicated

acetate

Week

P* (n = 13)

E+P (n = 19)

(32)

2 (15) 5 (38)

5 (26)

6 (32)

4 4 5 4 3 3 5 0 0 4 1

5 (26) 4 (21) 2 (11) 4 (21) 2 (11) 2 (11) 0 (0) 0 (0) 0 (0) 1 (5) 0 (0)

(21) (5) (21) (16) (21) (5) 2 (11) 1 (5) 0 (0) 0 (0) 0 (0) 1 (5)

(31) (31) (38) (31) (23) (23) (38) (0) (0) (31)

(8)

plus either

an estrogen-

effect

E + P” (n = 19)

6 4 1 4 3 4 1

depot

52 GnRH-a

plus (n T13)

3 4 2 4 4 3 3 2 3 0 0 5 0

(23) (31) (15) (31) (31) (23) (23) 05) (23) (0) (0) (38) (0)

group.

group.

there exists a hierarchy of tissue sensitivities to the same circulating levels of estrogens. Regrowth of mean uterine volume was more pronounced in the progestin add-back group which is consistent with the results of a previous 6 month randomized, placebo-controlled clinical trial (2). It could be that the high doses of progestins used in this and the present studies prevented the achievement or maintenance of maximal uterine shrinkage. Clearly, dose-response studies are needed to evaluate norethindrone and other progestins as potential add-back steroids. The lo-mg dose of norethindrone used in the progestin add-back group in the present study was chosen to maximize the chances of preserving bone mineral density and to reduce the incidence of hot flashes in women treated with GnRHa. Norethisterone 10 mg daily was shown to protect against bone mineral loss compared to placebo-treated controls in 43 postmenopausal women treated for 2 yr (10). However, a previous study in postmenopausal women treated with norethisterone 5 mg daily failed to demonstrate a significant improvement in urinary hydroxyproline/creatinine and calcium/creatinine ratios compared to pretreatment levels (11). The evidence on the effect of norethisterone 5 mg daily on hot flashes is conflicting. One study (12) demonstrated an improvement in this symptom whereas another (11) showed no significant reduction in the proportion of postmenopausal women experiencing hot flashes compared to placebo-treated controls. Taken together, these findings suggest that progestins, as well as estrogens, may be important for uterine growth in women with leiomyomata. Both estrogen and progesterone receptors have been demonstrated in myometrium and myomas (13, 14). Myometrial and leiomyoma tissue cultures supplemented with progesterone have demonstrated significant growth (14). In addition, women treated with a progestin-only preparation (usually depot medroxyprogesterone acetate) before hysterectomy demonstrated significantly higher mitotic activities in their myomas compared to women pretreated with either a combined estrogen-progestin prep-

aration or untreated controls (15). Finally, leiomyoma mitotic activity is higher in the early luteal phase than in the follicular phase (16). Both steroid add-back regimens successfully suppressed menses, thus leading to improved Hgb concentrations in all patients during the 52-week treatment period. An increase in mean Hct was especially apparent in women who were anemic before receiving treatment. Increases in these hematologic parameters may be explained by menstrual suppression, as a majority of women experienced either amenorrhea or intermittent vaginal spotting. Although both groups demonstrated comparable improvements in hematologic profiles, the estrogen-progestin add-back regimen was better tolerated due to a higher percentage of patients with either complete menstrual suppression or predictable withdrawal bleeds. GnRH-a/steroid add-back therapy may, therefore, be a viable long-term treatment strategy in women with myomas who experience excessive menstrual bleeding. This medical treatment strategy may be especially useful in women who are perimenopausal, those who have severe medical illness (i.e. leukemia, aplasic anemia) precluding safe surgical intervention, or for those women who wish to control excessive menstrual bleeding until surgery is scheduled electively. The results of this study corroborate those in a recently published open observational study in which 20 women with menorrhagia treated with a GnRH-a plus a cyclic estrogen-progestin combination for 3 months experienced decreases in menstrual blood loss of 56-76% (17). The majority of patients in the estrogen-progestin addback group reported improvement in or resolution of symptoms due to an enlarged uterus (i.e. pelvic pressure, appreciation of a pelvic/abdominal mass, urinary frequency, pelvic pain, constipation). However, symptoms related to enlarged uterine size failed to demonstrate a similar degree of improvement in women in the progestin add-back group. A major safety concern regarding the long-term use of GnRH-a treatment is the induction of a hypoestrogenic state leading to the acceleration of bone mineral loss, osteopenia,


GnRH-a/STEROID

ADD-BACK

and ultimately to osteoporosis. Several studies, using a variety of bone density measurement techniques, have demonstrated minimal loss of cortical bone but significant decrements in trabecular bone ranging from 5.9-8.2% after 6 months of GnRH-a treatment (18-20). Sensitive measurements of trabecular bone mineral density 6 months after completion of GnRH-a treatment have demonstrated an incomplete return of bone densities to baseline levels, with persistent decrements in lumbar bone mineral content of 4.2-5.4%. Addition of norethindrone (21) or cyclic estrogenprogestin (6) to GnRH-a treatment has been shown to have bone-sparing effects in small, short-term pilot studies. In the present study, the mean bone density of the lumbar spine was noted to decrease by approximately 3% in the first 12 weeks of GnRH-a treatment in all patients. After steroid add-back therapy, there was stabilization of bone density measurements in both treatment groups with no further significant changes between treatment weeks 12 and 52. These data suggest that both steroid add-back regimens offer protection against bone loss normally seen in hypoestrogenic states and may provide the option of long-term medical treatment of women with myomas provided close and regular monitoring of bone density in these women is performed. In the progestin add-back group, the mean HDL cholesterol level decreased significantly with no change in LDL cholesterol between weeks 12 and 52 resulting in a less favorable cholesterol profile compared to the estrogen-progestin add-back group. These findings may be explained by the relatively high dose and androgenic properties of norethindrone used in the progestin add-back group. To conclude, GnRH-a steroid add-back regimens provide a new long-term medical treatment strategy for women with large or symptomatic uterine myomas and may obviate the need for surgical intervention in selected cases. In this study, the estrogen-progestin add-back regimen yielded equal or superior results on all safety and efficacy parameters assessed when compared with a progestin-only add-back regimen. In addition to providing an alternative to the more traditional surgical options for women with myomas, this classical endocrine ablation-replacement study design aids in our understanding of the endocrine sensitivities of these common neoplasms.

RX FOR MYOMAS

4.

5.

6.

7.

500-505. 8. Friedman

9. 10.

11.

12.

13.

14.

15. 16.

17.

18.

19.

References 1. Buttram Jr VC, Reiter RC. 1981 Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 36:433-445. 2. Friedman AJ, Barbieri RL, Doubilet PM, Fine C, Schiff I. 1988 A randomized, double-blind trial of a gonadotropin releasing-hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri. Fertil Steril. 49: 404-409. 3. Friedman AJ, Barbieri RL, Benacerraf BR, Schiff I. 1987 Treatment

of leiomyomata with intranasal or subcutaneous leuprolide, a gonadotropin releasing-hormone agonist. Fertil Steril. 48:560-564. Friedman AJ, Harrison-Atlas D, Barbieri RL, Benacerraf B, Gleason RE, Schiff I. 1989 A randomized, placebo-controlled, doubleblind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata. Fertil Steril. 51:251-256. Friedman AJ, Hoffman DI, Comite F, Browneller RW, Miller JD. 1991 Treatment of leiomyomata uteri with leuprolide acetate depot: a double-blind, placebo-controlled, multicenter study. Obstet Gynecol. 77:720-725. Friedman AJ. 1989 Treatment of leiomyomata uteri with shortterm leuprolide followed by leuprolide plus estrogen-progestin hormone replacement therapy for two years: a pilot study. Fertil Steril. 51:526-528. Maheux R, Lemay A, Blanchet P, Friede J, Pratt X. 1991 Maintained reduction of uterine leiomyoma following addition of hormone replacement therapy to a monthly luteinizing hormone-releasing hormone agonist implant: a pilot study. Hum Reprod. 6:

20.

21.

AJ, Lobe1 S, Rein MS, Barbieri RL. 1990 Efficacy and safety considerations in women with uterine leiomyomata treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis. Am J Obstet Gynecol. 163:1114-1119. Cummings SR, Black D. 1986 Should perimenopausal women be screened for osteoporosis? Ann lnt Med. 104:814-823. Abdalla HI, Hart DM, Lindsay R, Leggate I, Hooke A. 1985 Prevention of bone mineral loss in postmenopausal women by norethisterone. Obstet Gynecol. 66:789-792. Nordin BEC, Jones MM, Crilly RG, Marshall DH, Brooke R. 1980 A placebo-controlled trial of ethinyl estradiol and norethisterone in climacteric women. Maturitas. 2:247-251. Paterson MEL. 1982 A randomized, double-blind, cross-over trial into the effect of norethisterone on climatetic symptoms and biochemical profiles. Br J Obstet Gynaecol. 89:464-472. Rein MS, Friedman AJ, Stuart JM, MacLaughlin DT. 1990 Fibroid and myometrial steroid receptors in women treated with the gonadotropin-releasing hormone agonist leuprolide acetate. Fertil Steril. 53:1018-1023. Cramer SF, Robertson AL, Ziats NP, Pearson OH. 1985 Growth potential of human uterine leiomyomas: some in vitro observations and their implications. Obstet Gynecol. 66:36-41, Tiltman AJ. 1985 The effect of progestins on the mitotic activity of uterine fibromyomas. Int J Gynecol Pathol. 4:89-96. Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T. 1989 Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol. 160:637-641. Thomas EJ, Okuda KJ, Thomas NM. 1991 The combination of a depot gonadotrophin releasing hormone agonist and cyclic hormone replacement therapy for dysfunctional uterine bleeding. Br J Obstet Gynaecol. 98:1155-1159. Dawood MY, Lewis V, Ramos J. 1989 Cortical and trabecular bone mineral content in women with endometriosis: effect of gonadotropin-releasing hormone agonist and danazol. Fertil Steril.52:21-26. Dodin S, Lemav A, Maheux R, Dumont M. Turcot-Lemav L. 1991 Bone m&s in kdbmetriosis patients treated with GnRfi agonist implant or danazol. Obstet Gynecol. 77:410-415. Matta WH, Shaw RW, Hesp R, Evans R. 1988 Reversible trabecular bone density loss following induced hypo-oestrogenism with the GnRH analogue buserelin in premenopausal women. Clin Endocrino1 (Oxf). 29:45-51. Riis BJ, Christiansen C, Johansen JS, Jacobson J. 1990 Is it possible to prevent bone loss in young women treated with luteinizing hormone-releasing hormone agonists? J Clin Endocrinol Metab. 70:920-924.
