The effect of gonadotropin suppression on the induction of ovulation in premature ovarian failure patients *†

FERTILITY AND STERILITY

Vol. 52, No.1, July 1989

Copyright © 1989 The American Fertility Society

Printed in U.S.A.

The effect of gonadotropin suppression on the induction of ovulation in premature ovarian failure patients*t

Eric S. Surrey, M.D.:!: Marcelle I. Cedars, M.D.§ Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of California Los Angeles School of Medicine, Los Angeles, California

Ovulation induction in patients with hypergonadotropic premature ovarian failure is rarely successful. The authors have attempted to reproduce the results of recent case reports that suggest that ovulation and pregnancy can be successfully achieved when estrogen therapy precedes or coincides with ovarian stimulation with human menopausal gonadotropins (hMG). Fourteen patients with idiopathic premature ovarian failure underwent gonadotropin suppression and attempted ovulation induction with at least one of three regimens, which were as follows: 1) Group A: estrogen-induced suppression followed by hMG stimulation (n = 4). 2) Group B: estrogen-induced suppression followed by hMG stimulation with concomitant estrogen therapy (n = 10).3) Group C: gonadotropinreleasing hormone agonist-induced gonadotropin suppression followed by concomitant hMG stimulation (n = 6). Despite complete gonadotropin suppression and high-dose hMG therapy in all three groups, ovulation occurred in only a single patient in group C. Pregnancy did not ensue. These data fail to corroborate previous case reports. Fertil Steril 52:36,1989

Attempting to induce ovulation in patients with idiopathic hypergonadotropic premature ovarian failure is a frustrating task. Scattered case reports have described pregnancies during or immediately after cyclic estrogen and progestin therapy. 1-7 Others have achieved pregnancy after attempted ovulation induction with human menopausal gonadotropins (hMG) in only a handful of these patients. 8- 11 Much more encouraging results have Received December 27,1988; revised and accepted March 27, 1989. * Presented in part at the Forty-Third Annual Meeting of The American Fertility Society, September 28 to 30, 1987, Reno, Nevada. t Supported in part by a grant from the Ortho Pharmaceutical Corporation, Raritan, New Jersey. :j: Reprint requests and present address: Eric S. Surrey, M.D.; Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, 444 South San Vicente Boulevard, Los Angeles, California 90048. § Present address: Department of Obstetrics and Gynecology, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267. 36

Surrey and Cedars Ovulation induction in ovarian failure

been recently described by Check and Chase,12 who reported a 60% ovulation rate and a 40% pregnancy rate in a small series of premature ovarian failure patients stimulated with hMG during and after exogenous estrogen administration. These variable results can be explained by the fact that chronically high levels of circulating gonadotropins in premature ovarian failure patients and subsequent granulosa cell receptor down-regulation may render any remaining follicles unresponsive to stimulation. Gonadotropin suppression induced by exogenous estrogens may replenish follicular follicle-stimulating hormone (FSH) and luteinizing hormone (LH) receptor concentrations and allow for the enhanced responsiveness of any existing follicles. However, if pituitary gonadotropin levels rapidly rebound after cessation of estrogen therapy, receptor concentrations may quickly become depleted once again. Thus, continuation of estrogens after suppression has been achieved may prevent such a rebound and allow for successful follicular recruitment with exogenous gonadotropins. Fertility and Sterility

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Table 1

Baseline Clinical and Laboratory Data

Patient

Gravidity

Parity

Age at diagnosis

Age at study

1

1

1

29

34

2 3 4 5 6 7 8 9

0 2 0 0 0 1 0 0

0 0 0 0 0 0 0 0

21 35 32 20 22 37 20 32

10 11

2 2

0 0

12 13 14

0 0

1 0 0

FSH

Estradiol

mIu/ml

pg/ml

40

42

35 36 33 23 27 39 28 38

100 102 133 163 200 100 201 84

8 7 21 10 10 10 10 11

36 33

35 34

107 54

20 40

38 25 13

41 26 25

108 229 146

18 7 10

Antithyroglobulin antibody

Antimicrosomal antibody

Antiadrenal cortical antibody

N/A

N/A

Significant history

Partial thyroidectomy

N/A N/A

1:100

1:400

Hyperthyroidism Bicornuate uterus Chorioadenoma destruens. Treatment, methothexate. Age 24 Partial right oophorectomy

Treatment groups

A" A A,Bb A,B B B B B,C' B

B,C B,C B,C C C

"Group A: estrogen-induced suppression followed by hMG stimulation (n = 4). b Group B: estrogen-induced suppression followed by hMG stimulation with concomitant estrogen therapy (n = 10). 'Group C: gonadotropin-releasing hormone agonist-induced gonadotropin suppression followed by concomitant hMG stimulation (n = 6).

In an effort to substantiate the encouraging results reported by Check and Chase,12 we have attempted ovulation induction with hMG in premature ovarian failure patients in conjunction with three methods of gonadotropin suppression: direct negative feedback on gonadotropin secretion by either preceding or concomitant estrogen therapy; or desensitization of pituitary gonadotropes with a highly potent gonadotropin-releasing hormone agonist (GnRH_a).13,14 MATERIALS AND METHODS

Fourteen patients with hypergonadotropic amen0rrhea of onset prior to age 40 were studied. All desired pregnancy and were required to have a baseline serum FSH level of >40 mIU Iml. Baseline clinical data are presented in Table 1. Serum levels of calcium, phosphorous, antimicrosomal, antithyroglobulin, and antiadrenal cortical antibodies, as well as red blood cell indices and thyroid functions, were measured. With the exception of one patient (no. 7) with elevated titers of antithyroglobulin antibody and a second with elevated titers of antimicrosomal antibody (no. 9), no evidence of active autoimmune processes could be determined. Chromosomal analyses performed on patients under 30 Vol. 52, No.1, July 1989

years of age were all normal. Routine infertility evaluation, including semen analysis, hysterosalpingography, and laparoscopy, when indicated, was normal in all patients. Ovarian biopsies were not performed. The patients were divided into three therapy groups. Four patients assigned to group A received cyclic therapy with conjugated estrogens (CEE) (Premarin, Ayerst, New York, NY) in an orally administered dose of 2.5 mg a day for 25 days along with medroxyprogesterone acetate (MP A) (Provera, Upjohn, Kalamazoo, MI) 10 mg a day during the last 10 days of the treatment cycle. Doses of CEE were increased in subsequent cycles until adequate pituitary gonadotropin suppression was achieved. This was defined as a value of serum FSH of <20 mIU Iml obtained on day 14 ofthe treatment cycle prior to initiation of the progestin. Conjugated estrogen therapy was discontinued on the day before initiation of gonadotropin therapy. The ten patients assigned to group B received cyclic therapy with ethinyl estradiol (EE 2) (Estinyl, Schering Corp., Kenilworth, NJ) and MPA. All patients received an initial daily dose of 50 ,."g ofEE2, which was increased in subsequent cycles by increments of 25 ,."g until gonadotropin suppression was achieved, as previously defined. In Surrey and Cedars Ovulation induction in ovarian failure

37

an attempt to avoid a rebound of endogenous FSH and LH to presuppression levels, EE2 was continued throughout hMG therapy. Unlike conjugated equine estrogens, EE2 does not cross-react with the radioimmunoassay for estradiol (E 2) employed in our laboratory. Six patients were assigned to group C. These women self-administered a highly potent GnRH-a [D-His6 (imBzI), Pro9 -NET]-GnRH (Histrelin, Ortho Pharmaceutical Corp., Raritan, NJ) in a 100 f.lg daily subcutaneous dose for a minimum of 14 days or until gonadotropin suppression was achieved. Once hMG therapy was begun, GnRH-a was continued concomitantly in a reduced daily dosage of 50 f.lg daily to prevent rebound of endogenous gonadotropins. Two patients participated in both groups A and B. Four patients participated in both groups Band C. No patients participated in all three treatment groups. Human menopausal gonadotropins (Pergonal, Serono, Randolph, MA) were administered in a high-dose "step-up" regimen that was similar to that employed in our in vitro fertilization program. I5 Patients received 2 to 4 ampules of hMG daily beginning after gonadotropin suppression was achieved (group C) or on the second day of the withdrawal bleed after suppression was documented (groups A and B). The patients then were reassessed on day 5 and the dosage was increased to a maximum of 8 ampules daily as indicated. Follicular development was monitored with serial pelvic ultrasonography and rapid E2 radioimmunoassay. Ovulation was triggered with human chorionic gonadotropin (Pregnyl, Serono, Randolph, MA) 10,000 units when mean follicular diameter and serum E2 reached a minimum of 15 mm and 150 pgj ml, respectively. RESULTS

Characteristics ofthe patients studied are shown in Table 1. The mean age ± standard error (SE) at initial diagnosis was similar among the three groups (group A: 29.3 ± 3.01 years; group B: 30.6 ± 2.1 years; group C: 27.3 ± 4.05 years). In addition, there were no statistically significant differences in mean age ± SE at initiation of therapy (group A: 34.5 ± 0.65 years; group B: 33.5 ± 1.8 years; group C: 31.7 ± 2.6 years). Prior reproductive performance also was similar. Mean ± SE serum levels of gonadotropins and E2 before institution of suppressive therapy were similar among the three groups 38

Surrey and Cedars Ovulation induction in ovarian failure

as well (Table 2). All patients demonstrated marked elevations of FSH. Estradiol levels were within the range for menopausal women. As a result of suppressive therapy, the elevated baseline FSH levels were significantly reduced in each group to within the follicular range (Table 2). The degree of suppression was similar within each of the three treatment groups. Three patients in group A required 2.5 mg of CEE to achieve gonadotropin suppression, whereas one required 5.0 mg. Among the patients participating in group B, adequate suppression was obtained after treatment with varying doses of EE 2: 100 f.lg in four patients, 75 f.lg in five, and 50 f.lg in one. Suppression was accomplished in a mean of 50 ± 10.2 and 70 ± 2.4 days in groups A and B, respectively. Gonadotropin-releasing hormone agonist 100 f.lg daily effectively suppressed all patients in group C more rapidly within a mean of 30.3 ± 1.8 days. The premature ovarian failure patients in group C received slightly more hMG over a similar period of time than did patients in the other two groups. This increase represented an attempt to provide doses ofhMG similar to those described in previous case reports. 9- I2 There were no significant differences between groups A or B. No member of either group of ovarian failure patients treated with estrogens demonstrated a significant rise in E2 or sonographic evidence of follicular development after hMG therapy. The presence of even small resting follicles could only rarely be identified sonographically. Only a single patient in group C (no. 12) treated with GnRH-a and hMG mounted a rapid and dramatic response to hMG (E 2 of 410 pgjml and a single follicle with a mean diameter of 29 mm by the sixth day of therapy). This patient had failed to respond to 3,150 IU (42 ampules) of hMG as a previous participant in group B. Unfortunately, no pregnancy ensued, and the patient failed to respond in a subsequent trial as well. DISCUSSION

In this study, we have prospectively attempted to induce ovulation employing high-dose hMG therapy in 14 consecutive patients with hypergonadotropic amenorrhea after three separate regimens of pituitary gonadotropin suppression. The current study design was based on the assumption that chronically elevated gonadotropin levels in patients with premature ovarian failure down-regulate granulosa cell FSH receptors, rendering any Fertility and Sterility

Table 2

Clinical Response FSH Suppression Patient

Group A

1

2 3 4

Regimen

CEE 2.5 mg" MPA10mg b CEE 2.5 mg MPA10mg CEE2.5mg MPA10mg CEE 5.0 mg MPA10mg

hMG Days

3

4 5 6 7

8 9 10 11

12 Mean ±SE GroupC

8 10 11

12 13 14

GnRH-a' 1OOl'g GnRH-a lOOl'g GnRH-a lOOl'g GnRH-a lOOl'g GnRH-a 1OOl'g GnRH-a lOOl'g

Mean ±SE

mIu/ml

mIu/ml

Pretherapy

Maximum on hMG

pg/ml

Maximum follicular diameter

pg/ml

mm

15

2,775

12

42

12

<10

50

100

16

l,BOO

12

8

10

<10

25

102

10

2,100

8

7

40

<10

100

133

7

1,950

9

21

13

<10

19.5 8.1

18.8 7.1

93.8 19.4

12' 4.2

2,156.3 d 215.1

10.25 1.0

50

104

10

1,575

6

75

129

15

3,000

50

163

10

100

200

100

9

10

<10

11

20

15

<10

2,400

10

10

14

<10

11

2,400

9

10

15

<10

100

2

2,700

9

10

13

<10

75

201

6

1,950

8

10

10

<10

50

84

10

2,700

9

11

12

<10

100

107

17

3,600

10

20

10

<10

50

54

11

2,475

7

40

10

<10

50

108

8

3,150

9

18

24

<10

70 d 7.3

125 15.3

10' 1.3

2,595 d

8.8 0.5

15.8 3.0

13.3 1.4

48

286

24

4,650

11

GnRH-a50 l'g

10

18

<10

22

101

17

4,200

11

GnRH-a501'g

10

14

<10

28

44

6

4,650

11

GnRH-a501'g

18

18

<10

30

111

3

l,BOO

6

GnRH-a501'g

12

410

29

33

229

5

3,825

11

GnRH-a501'g

7

10

<10

21

146

19

3,375

9

GnRH-a501'g

10

12

<10

30.3 4.0

152.8 36.8

12.3' 3.6

3,750 438.6

9.8 0.8

" CEE = Conjugated equine estrogens. b MPA = Medroxyprogesterone acetate. 'GnRH-a = GnRH agonist.

remaining resting follicles refractory to exogenous stimulation. It was hypothesized that pretreatment of these patients with estrogens would allow regeneration of ovarian FSH receptors and result in a positive response to exogenous gonadotropins Vol. 52, No.1, July 1989

Days

IV

Concurrent therapy

40

50 17.7 CEE751'g MPA10mg CEE 1OOl'g MPA10mg CEE50 I'g MPA10mg CEE100l'g MPA10mg CEE lOOl'g MPA10mg CEE751'g MPA10mg CEE751'g MPA10mg CEE751'g MPA10mg CEE75 I'g MPA10mg CEE 1OOl'g MPA10mg

Postsuppression

25

Mean ±SE GroupB

Pretherapy

184

EE2 77l'gf

11.2 1.5

BO.3 65.9 Nonresponders: 14.4 ± 1.6

d P < 0.5 versus group C. • P < 0.05 versus pretherapy.

f

EE2

=

Ethinyl estradiol.

(group A). To prevent a rebound of endogenous gonadotropins to baseline levels and subsequent receptor down-regulation once estrogen administration was stopped, we continued estrogen therapy throughout the course of hMG therapy in a second Surrey and Cedars Ovulation induction in ovarian failure

39

1

Table 3

Previously Reported hMG-Induced Pregnancies in Premature Ovarian Failure Total hMGdose

hMG duration

units

days

1,125 750 1,500 3,000

15 10 10 NRa

Reference

No. of patients

12 10 15

1 1 2

13 14

1 1

1,500 4,500

NR NR

Mean a

Pre-hMG Estrogen (Both patients)

Outcome

IUp b Spontaneous abortion !UP !UP !UP !UP

1,935

NR, not reported.

group of patients (group B). Other investigators also have shown that the presence of exogenous estrogens significantly enhances the stimulatory effect of FSH on granulosa cell FSH receptors. 16-18 Before hMG administration, a third group of patients (group C) received a highly potent agonist of GnRH, which achieves gonadotropin suppression primarily by pituitary gonadotrope receptor downregulation, and is not felt to interfere directly with ovarian function. 13 Several investigators have demonstrated improved ovarian responses when employing GnRH-a before gonadotropin stimulation in patients who were poor responders to hMG alone for superovulation in conjunction with in vitro fertilization or gamete intrafallopian transfer .19-21 On the whole, these interventions were unsuccessful in that ovulation was not achieved in any patient treated with estrogens either before or concomitant with hMG. A single patient who had failed to respond to 3,150 IV (42 ampules) of hMG after estrogen-induced suppression as a member of group B did demonstrate adequate follicular development and ovulatory response without conception to 1,500 IV (20 ampules) ofhMG after GnRHa-induced gonadotropin suppression. These data conflict with those of Check and Chase,12 who reported a 60% ovulation rate and 40% pregnancy rate in a small series of five patients treated with hMG and either preceeding or concomitant estrogen therapy. Other authors have also described occasional pregnancies in premature ovarian failure patients after hMG-induced ovulation (Table 3),8-11 or in conjunction with GnRHa administration. 22 ,23 These differences in outcome compared with the present study cannot be attributed to administration of inadequate amounts of hMG. The mean dose ofhMG employed to achieve ovulation and subsequent pregnancy in the five pa40

Concurrent therapy

Surrey and Cedars Ovulation induction in ovarian failure

b

IUP, intrauterine pregnancy.

tients previously reported was 1,935 IV, which was less than that employed in any of the treatment groups in our series. However, the inadequacy of sample sizes studied, as well as the inherent heterogeneity of the patient population with hypergonadotropic amenorrhea, may serve as more reasonable explanations for these variable results. In contrast with the current series, other reports do not appear to have been designed as prospective analyses of consecutive patients, but rather as case reports. As a result, the true incidence of successful ovulation induction among the total number of premature ovarian failure patients treated in these studies is difficult to ascertain. Thus, despite previously published case reports to the contrary,12 we were able to induce ovulation, without subsequent pregnancy, in only 1 of 14 patients with premature ovarian failure treated with high-dose gonadotropins following pituitary gonadotropin suppression (20 cycles). In our experience, there was no benefit to concomitant estrogen therapy. Prior and concurrent use of highly potent agonists of gonadotropin-releasing hormone provided more rapid gonadotropin suppression and may hold some slight promise. We can only conclude that such a generally poor response may result from either complete absence of residual follicles, an inherent gonadotropin receptor abnormality, or the presence of an unsuppressed factor inhibiting gonadotropin-follicular interactions. 24,25 It therefore would appear that fertilization and transfer of donated oocytes might provide a more successful means of achieving pregnancy in this unfortunate group of patients. Acknowledgments. Special thanks to the Ortho Pharmaceutical Corporation for generously providing Histrelin; to Howard L. Judd, M.D. for his helpful critique of this manuscript; to Joseph C. Gambone, D.O. and David R. Meldrum, M.D., for paFertility and Sterility

tient referrals; and to Ms. Laurie Levine for her typographical skills.

REFERENCES 1. Voigt S: Pregnancy in a young woman with hypergonadotropic "ovarian failure." Acta Obstet Gynecol Scand 63: 733, 1984 2. Alper MM, Jolly EE, Garner PR: Pregnancies after premature ovarian failure. Obstet Gynecol (suppl) 67:59S, 1986 3. Ohsawa M, Wu M, Masahashi T, Asai M, Narita 0: Cyclic therapy resulted in pregnancy in premature ovarian failure. Obstet Gynecol 66:645, 1985 4. Petsos P, Buckler H, Mamtora H, Anderson DC: Ovulation after treatment with ethinyl-oestradiol and medroxyprogesterone acetate in a woman approaching premature menopause: case report. Br J Obstet Gynaecol 93:1,155, 1986 5. Starup J, Philip J, Sele V: Oestrogen treatment and subsequent pregnancy in two patients with severe hypergonadotropic ovarian failure. Acta Endocrinol (Copenh) 89:149, 1978 6. Shangold MM, Turksoy RN, Bashford RA, Hammond CB: Pregnancy following the "insensitive ovary syndrome." Fertil SteriI28:1,179, 1977 7. Szlachter BN, Nachtigall LE, Epstein J, Young BK, Weiss G: Premature menopause: a reversible entity? Obstet Gynecol 54:397, 1979 8. Amos WL: Pregnancy in a patient with gonadotropin resistant ovary syndrome. Am J Obstet GynecoI153:154, 1985 9. Johnson TR, Peterson EP: Gonadotropin-induced pregnancy following "premature ovarian failure." Fertil Steril 31:351, 1979 10. Tanaka T, Sakuragi N, Fujimoto S, Ichinoe K: HMG-HCG therapy in patients with hypergonadotropic ovarian anovulation: one pregnancy case report and ovulation and pregnancy rate. Int J Fertil 27:100, 1982 11. Zourlas P, Mantzavinos T: Pregnancies in primary amenorrhea with normally developed secondary sex characteristics. Fertil SteriI34:112, 1980 12. Check JH, Chase JS: Ovulation induction in hypergonadotropic amenorrhea with estrogen and human menopausal gonadotropin therapy. Fertil Steril42:919, 1984 13. Yen SSC: Clinical applications of gonadotropin-releasing hormone and gonadotropin-releasing hormone analogs. Fertil SteriI39:257, 1983

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14. Meldrum DR, Chang RJ, Lu J, Vale W, Rivier J, Judd HL: "Medical oophorectomy" using a long-acting GnRH agonist-a possible new approach to the treatment of endometriosis. J Clin Endocrinol Metab 54:1,081,1982 15. Meldrum DR, Chetkowski R, Steingold KA, de Ziegler D, Cedars MI, Hamilton M: Evolution of a highly successful in vitro fertilization-embryo transfer program. Fertil Steril 48:86,1987 16. Ireland JJ, Richards JS: Acute effects of estradiol and follicle-stimulating hormone on specific binding of human [ 125 Iliodo-follicle-stimulating hormone to rat ovarian granulosa cells in vivo and in vitro. Endocrinology 102:876, 1978 17. Richards JS, IrelandJJ, Rao MC, Bernath GA, Midgley AR Jr, Reichart LE: Ovarian follicular development in the rat: hormone receptor regulation by estradiol, follicle stimulating hormone and luteinizing hormone. Endocrinology 99: 1,562,1976 18. Bradbury JT: Direct action of estrogen on the ovary of the immature rat. Endocrinology 68:115, 1961 19. de Ziegler D, Cedars MI, Randle D, Lu JKH, Judd HL, Meldrum DR: Suppression of the ovary using a gonadotropin releasing hormone agonist prior to stimulation for oocyte retrieval. Fertil SteriI48:807, 1987 20. Palermo R, Amodeo G, Navot D, Rosenwaks Z, Cittadini E: Concomitant gonadotropin-releasing hormone agonist and menotropin treatment for the synchronized induction of multiple follicles. Fertil SteriI49:290, 1988 21. Serafini P, Stone B, Kerin J, Batzofin J, Quinn P, Marrs RP: An alternate approach to controlled ovarian hyperstimulation in "poor responders": pretreatment with a gonadotropin-releasing hormone analog. Fertil Steril 49:90, 1988 22. Fleming R, Hamilton MPR, Barlow DH, Cordiner JW, Coutts JRT: Pregnancy after ovulation induction in a patient with menopausal gonadotropin levels after chemotherapy. Lancet 1:399, 1984 23. Check JH, Wu CH, Check ML: The effect ofleuprolide acetate in aiding induction of ovulation in hypergonadotropic hypogonadism: a case report. Fertil Steril49:542, 1988 24. Chiauzzi V, Cigorraga S, Escobar ME, Rivarola MA, Charreau EH: Inhibition of follicle-stimulating hormone receptor binding by circulating immunoglobulins. J Clin Endocrinol Metab 54:1,221,1982 25. Tang VW, Faiman C: Premature ovarian failure: a search for circulating factors against gonadotropin receptors. Am J Obstet GynecoI146:816, 1983

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Ovulation induction in ovarian failure

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