Pituitary and ovarian suppression rate after high dosage of gonadotropin-releasing hormone agonist

FERTILITY AND STERILITY

Vol. 51, No.4, April1989

Copyright" 1989 The American Fertility Society

Printed in U.S.A.

Pituitary and ovarian suppression rate after high dosage of gonadotropin-releasing hormone agonist David Bider, M.D. Zion Ben-Rafael, M.D.* JosefShalev, M.D.

Mordechai Goldenberg, M.D. Shlomo Mashiach, M.D. Josef Blankstein, M.D.

Department of Obstetrics and Gynecology, the Chaim Sheba Medical Center (affiliated with the Sackler Faculty of Medicine, Tel-Aviv University), Tel-Hashomer, Israel

Ten infertile menstruating women were treated with daily injections of gonadotropinreleasing hormone agonist (GnRH-a). The GnRH-a (Buserelin; Hoe 766, Hoechst-AG, Frankfurt/Main, West Germany) was administered subcutaneously (SC) from day 9 of the cycle for 6 days, and intranasally (1.2 mg) for 15 days. Before treatment, all ten women had a normal response to Buserelin challenge test and the GnRH test, and seven of the ten responded to estradiol (E 2 ) benzoate test (2 mg intramuscularly). The SC administration ofBuserelin (1.5 mg) for 6 days resulted in suppression of pituitary activity. Continuous treatment with Buserelin (1.2 mg for 3 weeks) was effective as demonstrated by decreasing serum E 2 levels to below 20 pg/ml, and in the absence of ovarian follicles in ultrasonographic scanning. Three days after cessation of Buserelin treatment, the pituitary again responded to the GnRH test. Thus, the authors concluded that the administration of Buserelin in very high doses can induce medical hypophysectomy within 6 days, but over 3 weeks of suppression therapy are required to abolish ovarian findings. Desensitization of the pituitary was reversible within 3 days of cessation of the treatment. Fertil Steril51:578, 1989

An increasing interest has recently been shown concerning the use of gonadotropin-releasing hormone agonists (GnRH-a) for suppression of pituitary and ovarian activity before and during gonadotropin treatment. 1•2 The continuous administration of GnRH-a in women with regular menstrual cycles induces a state of hypogonadotropic hypogonadism, which facilitates the more precise control of follicular growth stimulated by human menopausal gonadotropin (hMG). This situation is analogous to patients with hypopituitary amenorrhea in whom the success rate when treated by hMG is considered to be maximal. a-6 In addition to a more uniform stimulation and the prevention of premature luteinizing horReceived June 9, 1988; revised and accepted December 20, 1988. *Reprint requests: Zion Ben-Rafael, M.D., Department of Obstetrics and Gynecology, The Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. 578

Bider et al.

Suppression with high doses of Buserelin

mone (LH) rise, 7 it is hoped that therapy by GnRH-a also will prevent ovarian hyperstimulation syndrome.8 The standard protocols prescribe variable dosages of GnRH -a for a period ranging from 15 to over 30 days, until medical hypophysectomy is proven either by estradiol benzoate (EB) or by GnRH test. Although it is known that the dosage and frequency of administration of this analog can affect pituitary suppression,9 •10 there is little information on the rate of pituitary or ovarian suppression after very high doses of GnRH-a in humans. The intention of our study was to establish whether rapid suppression of the pituitary and ovarian response could be achieved by high doses of Buserelin (Hoe 766, Hoechst-AG-Frankfurt/Main, West Germany) (D-SER[t Bu] 6-DES-Gly-NH2 GnRH etylamide) and to evaluate the time required for the pituitary and ovary to recover after cessation of Buserelin. Rapid suppression would allow for a decreased time span between initiation Fertility and Sterility

Table 1

Treatment Protocol and Test Performed

analyses were performed by Student's t-test and paired t-test.

Days 4

GnRHtest Buserelin test EBtest Buserelin suppression

+

5

+ +

9

15

+ +

22

29

+ +

32

35

+

+

From day 9 through day 29

of treatment with the analog and the treatment with hMG for ovulation induction. MATERIALS AND METHODS

The study group comprised ten infertile ovulatory menstruating women. Prolactin levels were normal in all of these patients, and their mean age was 32.1 years (range, 26 to 36 years). All provided written consent confirming their participation in the study. Before suppression therapy was started, all the patients were tested by Buserelin, GnRH, and EB for clinical response of the pituitary. In a preliminary study we found that the increase in LH and follicle-stimulating hormone (FSH) levels after Buserelin injection was similar to that of native GnRH. Buserelin (0.5 mg) was administered subcutaneously (SC) on the morning of the fifth day of the cycle. Subsequently, FSH and LH levels we:re assayed at 0, 60, 90, 120, and 180 minutes. Estradiol benzoate (2 mg intramuscularly [IM]) was administered following the Buserelin test, and estradiol (E 2), FSH, and LH were measured daily at 8:00 A.M. from day 5 to day 9 of the cycle. Commencing on day 9 of the cycle, Buserelin was administered SC, each patient receiving an initial dose of 1.5 mg (0.5 mg every 8 hours for 6 days followed by 1.2 mg [0.4 mg every 8 hours]) administered by means of a nasal spray until day 29 of the cycle. On days 15 and 22, Buserelin and EB tests were repeated as described (Table 1). Ultrasonic assessment of the ovarian follicular response was carried out on alternative days, using a mechanical sector scanner (Diasonics, Milpitas, CA) with a 3.5 MHz transducer. On day 29 of the cycle, Buserelin treatment was discontinued. Three and 7 days later, the pituitary response to native GnRH (100 J,Lg) was evaluated. We measured E 2 , FSH, and LH levels by standard radioimmunoassay. The interassay and intra-assay coefficients of variation were <9% for E 2 and <6% for FSH and LH. The results are presented as mean ± standard error of the mean. Statistical Vol. 51, No.4, April1989

RESULTS

The administration of 0.5 mg Buserelin at 8:00 A.M. on cycle day 5 resulted in a sharp increase in LH and FSH levels (Fig. 1). Similar increases were noted when GnRH 100 J,Lg was injected on day 4 of the cycle. After the Buserelin test, 2 mg of EB was injected IM, and blood levels of E 2 , LH, and FSH were measured on each of the successive four mornings. During the first day, all of the women had a sharp increase in E 2 , which then decreased slowly. Luteinizing hormone was triggered to 80 ± 16 miU/ml in only seven women on day 3 or 4 after EB injection (Fig. 2). Luteinizing hormone was not triggered in the other three women in the group. After 6 days of daily administration of high doses of Buserelin (1.5 mg), the following provocative tests indicated that complete suppression of the pituitary LH levels remained unchanged after injection of either Buserelin or EB. Buserelin (0.5 mg) resulted in LH levels of 5 to 11 miU/ml and FSH between 6.8 to 7.1 after 0, 60, 120, and 180 minutes 80

LH

i

;60 i

rn

;;l

40

FSH

>

"'

.J

~ 20

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Ill 0

60

120

180

120

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TIME

20

0

60 MINUTES

Figure 1 Serum LH and FSH levels on time 0, 60, 120, and 180 minutes after injection ofBuserelin (0.5 mg) on day 5 of the cycle (top), and after 6 days of pituitary desensitization with high dose ofBuserelin (1.5 mg/day) (bottom). Bider et al.

Suppression with high doses of Buserelin

579

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400

120 100

~!00

..."'

§200 0

"'"'t; 100

1&1

80 ~ 31 60

c

u

.....

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31 40 -

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2. 3 4 5 DAYS AFTER EB ADMINISTRATION

300

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DAYS AFTER EB ADMINISTRATION

Figure 2 Estradiol benzoate test on day 5 of the cycle before pituitary desensitization. Note the sharp rise in LH levels (top), and after 6 days of pituitary desensitization with high doses of Bueerelin (1.5 mg/day) (bottom).

(Fig. 1). Estradiol benzoate administration resulted in increased mean blood levels of E 2 from 30 to 290 pg/ml (Fig. 2). Although these levels were maintained for 4 days, neither LH nor FSH secretion of the pituitary were triggered. A similar response to provocative tests during Buserelin suppression were achieved on days 15 and 22 of the cycle. On day 29, mean basal E 2 levels were below 20pg/ml. Three days after cessation of daily Buserelin administration, the pituitary again was responsive to GnRH test. Administration of GnRH 100 ,.,g resulted in an increase of LH from 5 to 15 miU/ml after 60 minutes. A more pronounced response was achieved 7 days after termination of Buserelin (Fig. 3). The total number of ovarian follicles (>5 mm) observed by ultrasound performed every other day, was 4 ± 1 before treatment, and this remained unchanged in the first 2 weeks (5 ± 2 after 7 days and 4 ± 3 after 14 days) of suppression. After 3 weeks of suppression by Buserelin, these ovarian findings were totally absent on ultrasonograms. DISCUSSION

The response of the hypothalamic pituitary ovarian axis to high doses of Buserelin in humans 580

Bider et al.

Suppression with high doses of Buserelin

has not been studied extensively. Most studies report the administration of Buserelin ranging from a few weeks up to 6 months. 10- 12 The quantities administered ranged between 500 to 900 ,.,g per day . Our study shows that complete suppression of the pituitary can be achieved within 6 days of treatment with high doses of Buserelin. We agree with other conclusions 1•9 that suppression of the pituitary with this analog is not only time-dependent but also dose-dependent, and that a high dose of Buserelin can result in prompt pituitary suppression. This is particularly important in cases in which Buserelin is administered to prevent early luteinization. There is a fundamental difference between the administration of GnRH-a for treatment of gynecologic diseases (e.g., endometriosis, uterine !yomyomata) or the use of the analog for treatment of infertility. In gynecologic diseases, a longer time of treatment with the analog is required to bring about a change in the morpho-anatomic state of the lesion. Hence, GnRH-a is given for longer periods. Nevertheless, if rapid suppression is required, administration of an initial high dose is recommended also for treatment of gynecologic diseases. However, in infertility treatments, the aim is the reversible suppression of pituitary secretion; therefore, the shortest suppression that can achieve this goal should be used. Six days of pretreatment with a high dose of GnRH -a is probably sufficient before the initiating of combined analog/hMG therapy for infertility to prevent early luteinization, or for the abolition of endogenous hormonal secretion. In our study, 1.5 mg of Buserelin was administered continuously for 6 days, followed by 1.2 mg for a further 15 days. We observed that the number and size of the ovarian follicles remained unchanged for 3 weeks despite 30

-20 E

..... :::>

e

~ 10

0

30

60

MINUTES

90

Figure 3 Gonadotropin-releasing hormone test (100 ~tg) 3 and 7 days after Buserelin discontinuation. A more pronounced response was achieved on day 7 after Buserelin cessation. Luteinizing hormone rose significantly (P < 0.05) after 60 minutes on days 3 and 7 (P < 0.001). Fertility and Sterility

good suppression of the pituitary and ovarian hormones. The low level of ovarian steroids indicates that these follicles were not functional. After 3 weeks of suppression with high doses of Buserelin, ovarian follicles disappeared. In summary, we were able to determine that suppression of the pituitary can be achieved within 1 week by administration of a high dose of Buserelin. However, it takes approximately 3 weeks for the ovarian findings to subside entirely. After discontinuation of Buserelin, rapid recovery of the pituitary was observed. REFERENCES

6.

7.

8.

9.

10.

1. Kenigsberg D, Littman BA, Hodgen GD: Induction of ovu·

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Vol. 51, No.4, April1989

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B, Serr DM: Abortion rate in pregnancies following ovulation induced by human menopausal gonadotropin/human chorionic gonadotropin. Fertil Steril39:157, 1983 Wentz AC: Syndromes of anosmia with hypogonadotropic hypogonadism (Kallmann Syndrome). Clinical and laboratory studies in 23 cases. Obstet Gynecol Surv 38:489, 1983 Fleming R, Coutts JRT: Induction of multiple follicular growth in normally menstruating women with endogenous gonadotropin suppression. Fertil Steril 45:226, 1986 Fleming R, Haxton MJ, Hamilton MPR, McCure GS, Black WB, Macnaughton MC, Couthy JRT: Successful treatment of infertile women with oligomenorrhea using a combination of an LH-RH agonist and exogenous gonado· tropins. Br J Obstet Gynaecol 92:369, 1985 Vickery BH: Comparison of the potential for therapeutic utilities with gonadotropin-releasing hormone agonist and antagonist. Endocr Rev 7:115, 1984 Lemay A, Maheux R, Faune N, Jean C, Fazekas ATA: Reversible hypogonadism induced by a luteinizing hormonereleasing hormone (LH-RH) agonist (Buserelin) as a new therapeutic approach for endometriosis. Fertil Steril4:863, 1984 Maheuz R, Guillotean C, Lemay A, Bastide A, Fazekas ATA: Regression of leiomyomata utei following hypoentrogenism induced by repetitive LHRH agonist treatment; preliminary report. Fertil Steril 42:644, 1984 Maheux R, Guilloteau C, Lemay A, Bastide A, Fazekas ATA: Luteinizing hormone-releasing hormone agonist an.d uterine leiomyoma. A pilot study. Am J Obstet Gynecol 152:1034, 1985

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