Alternative indications for pulsatile gonadotropin-releasing hormone therapy in infertile women

FERTILITY AND STERILITY Copyright © 1985 The American Fertility Society

Vol. 44, No.5, November 1985 Printed in U.SA.

Alternative indications for pulsatile gonadotropin-releasing hormone therapy in infertile women

Shaila A. Phansey, M.D.*t Roger Toffle, M.D. * John Curtin, M.D.t Theodore C. Nagel, M.D.* George E. Tagatz, M.D.* Mary A. Barnes, B.S.:!: Raghawan Nair, Ph.D.:!: Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Minnesota Medical School, Minneapolis, Minnesota, and Department of Medicine, Veterans Administration Hospital, Charleston, South Carolina

Three groups of women with different types of ovulatory dysfunction who had failed to conceive on conventional therapy were treated with pulsatile gonadotropin-releasing hormone (GnRH). Group A consisted of nine patients with luteal phase defect; group B included four patients with apparently normal menstrual cycles but disordered foliiculogenesis seen by serial ultrasound examinations; and group C consisted of eight patients who exhibited anovulation or irregular ovulation. GnRH was administered subcutaneously or intravenously in dosages varying from 5 M to 20 fJ,g, with pulse frequency of2 to 3 hours in 53 cycles. Forty-one cycles were ovulatory. Four pregnancies resulted, one ending in miscarriage at 12 weeks' gestation. Our results indicate that GnRH may be used as an alternative to the prevalent therapeutic methods for ovulatory dysfunction. Only those women who had anovulation and abnormal basal levels of serum luteinizing hormone were resistant to GnRH therapy. Fertil SteriI44:589, 1985

Recent advances in administration of gonadotropin-releasing hormone (GnRH) have offered an alternative in the treatment of hypothalamic amenorrhea. Since it was demonstrated that GnRH needs to be administered in pulses to restore pituitary gonadotropin secretion in monReceived August 10, 1984; revised and provisionally accepted November 16, 1984; accepted July 1&, 1985. *Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Minnesota Medical School. tReprint requests: Shaila A. Phansey, M.D., Department of Obstetrics and Gynecology, St. Paul Ramsey Hospital, 640 Jackson Street, St. Paul, Minnesota 55101. *Department of Medicine, Veterans Administration Hospital. Vol. 44, No.5, November 1985

keys with hypothalamic lesions, l effective regimens have been developed for therapeutic use of GnRH in infertile women. Pulsatile administration of GnRH has been highly effective in inducing ovulation and achieving pregnancy in patients with hypothalamic amenorrhea. 2 - s Little information is available regarding GnRH therapy for other forms of ovulatory dysfunction. We evaluated the role of GnRH in the treatment of three different types of ovulatory dysfunction in 21 infertile women. MATERIALS AND METHODS

Twenty-one infertile women, 24 to 36 years of age, with infertility were treated with pulsatile Phansey et aI. Alternative indications for GnRH therapy

589

administration of GnRH subcutaneously. Those who failed to respond with predictable ovulation were then treated by the intravenous route.

INDICATIONS

Group A Nine patients had luteal phase defect (LPD). The diagnosis was based on a delay in endometrial maturation of more than 2 days during late luteal phase (days 24 to 26) of at least two cycles, as determined by the criteria described by Noyes and associates 9 for histologic dating of the luteal phase endometrium. All women had been previously treated with clomiphene citrate (CC) and progesterone (P) suppositories with no conception. These treatments failed to correct LPD in four women, as documented by the delay in endometrial maturation during therapy. Five women had associated factors that may have contributed to their infertility, such as endometriosis (three women), male factor (two women), and surgically repaired tubal disease (one woman).

GroupB Four patients had follicular dysfunction diagnosed by ultrasound examinations. Ultrasound examinations were performed daily or alternate days during a minimum of two cycles in women with unexplained infertility who had apparent ovulatory cycles, as evidenced by biphasic basal body temperature (BBT) rise and normal (~ 1000 ng/dl) midluteal serum P levels. Follicular dysfunction was diagnosed as follows 1o : Luteinized Unruptured Follicle (LUF). Increase in the size of the dominant follicle without rupture (LUF) with a rise in BBT suggests apparent ovulation. One patient showed LUF in two successive cycles. This was confirmed by laparoscopic visualization of the follicle during the luteal phase of the second cycle, in which ultrasound examinations were also performed. Luteinization of the Dominant Follicle Before Rupture. Rise in BBT with multiple echoes seen in the dominant follicle without increase in size, followed by rupture, as documented by ultrasound examination. Absence of a Normal Dominant Follicle. Growth of multiple follicles with a failure to develop a dominant follicle with or without any evidence of rupture of a follicle of < 13 mm in diameter. 590

Phansey et al. Alternative indications for GnRH therapy

Group C Eight euestrogenic (positive progestin challenge test) women with anovulation or irregular ovulation who had failed to respond with predictable ovulation to CC up to a 150-mg daily dose for 5 days were entered in the study. The serum prolactin level was normal in all women. Three of the eight women had abnormal ratios of serum luteinizing hormone (LH) to follicle-stimulating hormone (FSH) (~ 3 to 1) and were subgrouped as C2, whereas those with a normal LH to FSH ratio were included in group Cl. One woman from C2 had moderately elevated androgens (testosterone and dehydroepiandrosterone sulfate). Four women had persistent poor cervical mucus during CC therapy, and other associated infertility factors such as minimal endometriosis (one woman), male factor (one woman), and surgically treated tubal disease (one woman) were present in three women. THERAPY

GnRH was infused with the help of infusion pumps (Autosyringe AS2C, 6H, Auto Syringe, Inc., Hooksett, NH). A pulse dose of 10 f-lg every 2 hours was used for subcutaneous administration of GnRH. The dose was changed to 20 f-lg every 3 hours in the same or subsequent cycle if there was an absence of follicular growth evident on ultrasound examination and/or rise in the serum estradiol (E 2) level. Once the response was seen, pulse frequency was changed to every 2 hours during the late follicular phase. Women who had aberrant response to other ovulatory agents (cyst formation on CC) were treated with a decrease in frequency of GnRH to every 3 hours. A GnRH dose of 5 f-lg every 2 hours was used for intravenous administration. Ovulation was achieved with an intramuscular injection of human chorionic gonadotropin (hCG) in a dose of 10,000 IU in women who did not ovulate with a dominant follicle of ~ 17 mm in size and serum E2 level of ~ 300 pg/ml. GnRH was discontinued at the time of hCG injection or after ovulation was documented on ultrasound examination. Follow-up hCG injections were given to all women during the luteal phase (1500 to 2500 IU) every 3 days starting on the third day of ovulation for a total of four doses. Follicular growth was monitored by serial ultrasound examinations and frequent serum E2 determinations (every third or fourth day during Fertility and Sterility

Table 1. Results ofGnRH Therapy in Three Groups of Patients Patient

Group A M.K. J. G. b D. H.b B. S. S.B. A. H. B. B. B. M.e D. Z.b Group B M.E.d C.W. K. M.e J.N. Group C L. L. D. B. d J.O.' K. B.' K. E.' K. S. S. T.d

A.N. d

Treat· ment cycles

GnRH therapy Dose

Frequency

JJ.g

hrs

1 2 2 1 2 2 2 2 3 2 2

10 10 5 10 10 10 10 10 10 10 5, 10

2 2 2 1 3

10 10 10 10 5

2 2 2 2 2 1 1 4 2 2 2

2 2 2

96 min, 2 2 2 3,2 96 min, 2 96 min 96 min, 2 96 min, 2 3,2 2 2 3,2 2

10 3,2 5 2 20 3,2 10,20 3,2 5,10 3,2 10, 20 3, 2 10,20 3,2 10 96 min, 2 10, 20 3,2 5,10 3, 2 10 2

Method a

SQ SQ IV SQ SQ SQ SQ SQ SQ SQ IV SQ SQ SQ SQ IV SQ IV SQ SQ IV SQ SQ SQ SQ IV SQ

Ovula· tory cycles

1 1

2 1

RESULTS

1

1

Pulsatile GnRH was administered subcutaneously in 40 cycles. Seventy-five percent of the cycles were ovulatory. Ten were aborted because of lack of response. Three patients, one each from groups A, B, and C, conceived during subcutaneous GnRH therapy. Pulsatile GnRH was administered intravenously in 13 cycles. Eleven cycles were ovulatory (78%). One of the six patients who received intravenous GnRH (Table 1) failed to respond in a total of two cycles.

2 2

Group A

2 1 2

3 2 2 2 2 2

3

4 1

2 2

USQ, subcutaneous; IV, intravenous. bWomen who corrected LPD during GnRH treatment. eWomen who conceived during GnRH treatment. dWomen who successfully ovulated with one single domi· nant follicle with decreased GnRH frequency (every 3 hours) during early follicular phase. eWomen with abnormal serum LH to FSH ratio.

the early and midfollicular phases and daily during the late follicular phase). Normal follicular growth and ovulation was defined as an appearance and growth of a dominant follicle (~ 17 mm) with disappearance of the follicle and simultaneous presence of cul-de-sac fluid. Midluteal serum P levels were measured, which confirmed ovulation when levels were ~ 1000 ng/dl. Endometrial biopsies were performed during the GnRH treatment cycle 10 to 12 days after ultrasound documentation of ovulation in three of the four women from group A who had persistent LPD during CC and P therapy. Laboratory Assays. Serum E2 was measured by radioimmunoassay (RIA) with the Pantex immuno-estradiol 1125 extraction method kit, and P was measured by Pantex immuno-direct progesterone Vol. 44, No.5, November 1985

1125 kit (Pantex, Division of Bioanalysis, Inc., Santa Monica, CA). LH and FSH RIA were performed with Amerlex LH and FSH RIA kits (Amersham Corporation, Arlington Heights, IL).

Nine women were treated for 21 cycles, 17 subcutaneously and 4 intravenously. Duration of therapy ranged from 14 to 17 days. In all ovulatory cycles (subcutaneous, 14 of17; intravenous, 4 of 4), the luteal phase length was 14 to 17 days' duration. All women ovulated with subcutaneous therapy in the first treatment cycle. Two women showed inconsistent response during the following subcutaneous treatment cycles. The same therapy was repeated in one of these two women after an interval of 4 weeks, which resulted in ovulation and conception. The other woman was successfully treated with intravenous GnRH. Three of the four women who had persistent LPD during CC and P therapy showed correction of LPD during GnRH treatment. The fourth woman received human menopausal gonadotropin (hMG) therapy before GnRH treatment. Dating of the endometrial biopsy showed correction of LPD, but the women failed to conceive in three treatment cycles, whereas conception occurred in the third treatment cycle with subcutaneous GnRH. GroupB

Four women in this group with follicular dysfunction showed an excellent follicular growth and ovulation by ultrasound examination during all but one of the seven cycles treated with subcutaneous administration of GnRH, and one conceived. Persistent follicular dysfunction was seen Phansey et aI. Alternative indications for GnRH therapy

591

in one woman with subcutaneous therapy who received intravenous therapy in three consecutive cycles with correction of dysfunction in every treatment cycle. Group C

Five women in group C1 were treated with a total of 12 subcutaneous and 4 intravenous treatment cycles. Ten of the 12 cycles treated with subcutaneous administration of GnRH were ovulatory. One woman conceived twice. Ovulation was achieved in four women by decreasing the frequency to 3 hours and/or increasing the dosage to 20 ,...,g/pulse. One woman had delayed response in the first subcutaneous treatment cycle, whereas there was no response in the second subcutaneous treatment cycle. When she was treated with an intravenous dose of 5 j.Lg every 2 hours, mild ovarian hyperstimulation resulted, with enlarged ovaries (43 x 41 mm, seen on ultrasound examination) and a serum E2 level of 1300 pg/ml.ll Ovulation was achieved with a 10-j.Lg pulse of intravenous GnRH at 3-hour intervals. Three women in group C2 had no response to four subcutaneous and two intravenous GnRH treatment cycles. Patient J. O. was then treated with GnRH intravenously (2.5 j.Lg every 8 minutes) to down-regulate gonadotropin responses. Serum levels of LH decreased from a baseline of 70 mIUlml to 30 mIUlml in 6 days. Serum levels of FSH showed a minimal reduction (from 12 mIU/ml to 8 mIUlml) , but a rise to the baseline level was seen during continuous therapy. A small number of samples precluded statistical analysis. Pulsatile GnRH administration thereafter failed to stimulate either LH or FSH during the next 10 days of therapy. Other Observations. Clear, copious, preovulatory cervical mucus with spinnbarkeit of ~ 7 cm and with an excellent ferning pattern on drying was noted during all ovulatory cycles, even in those women who had poor cervical mucus during therapy with other fertility drugs (e.g., CC). There were no systemic side effects to GnRH administration. Superficial phlebitis occurred in one woman with intravenous therapy with no other complications. During subcutaneous therapy, small subcutaneous hematomas were observed in 3 of 12 patients when heparinized solution was used. No complications were seen when heparin was deleted. Hyperstimulation occurred in one woman during intravenous therapy. 592

Phansey et aI. Alternative indications for GnRH therapy

DISCUSSION

Hypothalamic amenorrhea is considered to be a defect in GnRH secretion from the hypothalamus. A review of the literature5 -8 ,12-21 (Table 2) lends credence to this hypothesis because GnRH therapy in women with hypothalamiC amenorrhea is successful in inducing ovulation and pregnancy. Leyendecker and Wildt 17 have. proposed that clinically differentiated types of ovulatory dysfunction, such as inadequate luteal phase and oligoovulation or anovulation, may merely represent different degrees of deficiency in GnRH secretion from the hypothalamus. Wilks et al. 22 showed that inappropriate secretion of gonadotropins during the follicular phase can result in disordered folliculogenesis, which leads to an inadequately functioning corpus luteum. Because of difficulties in the diagnosis of LPD in women and an inadequate knowledge of the cause of LPD, several treatment regimens have been tried, including CC luteal phase P suppositories and hMG, each with some success. For these reasons, this trial was conducted to evaluate the role of GnRH therapy in women with LPD. The fact that three of the four women who had persistent LPD during CC and P therapy corrected their defect during GnRH therapy and the fourth conceived indicates that pulsatile administration of GnRH may correct LPD in infertile women, thus offering an easier alternative than hMG therapy to treat such an ill-defined entity when other modalities fail. Inconsistent responses to subcutaneous administration of GnRH were observed in subsequent cycles in some women. However, if results from three women who had no response to GnRH administered by either route are deleted, ovulation occurred in all but one patient with subcutaneous therapy during the first treatment cycle. Anovulation seen in five women during the second treatment cycle may be due to storage, sequestration, and slow release of GnRH in circulation from the subcutaneous fat, resulting in continuous rather than intermittent stimulation of the pituitary gland, as suggested by Reid and Sauerbrei. 21 Review of the literature (Table 2) shows comparable responses of subcutaneous and intravenous routes of GnRH administration in terms of ovulation (83.9%, versus 80.7%) and pregnancies (46%, versus 52%). Because of convenience, low-risk potential, and comparable success rates, the subcutaneous route of administration reFertility and Sterility

Table 2. Summary of Pulsatile GnRH Administration (Literature Reviewr No. of patients

No. of cycles

Method

2

2

SQ

2

2

IV

Schoemaker et al. 6

1

3

IV

Keogh et al. 5

1

1

SQ

Skarin et al. 12

4

9

SQ

Miller et al. 13

8

23

IV

Skarin et al. 14

14

?

SQ

Hurley et al. 15

3

7

SQ

Berg et aP6

27

40

IV

Ley~itdecker and Wildt17

18

32

IV

8

SQ

Reference Reid et al. 7

Seibel et al. 8

6 3

28 3

? SQ

Loucopoulos et al. 18

8

16

IV

Hypergonadotropic hypogonadism 4

5

SQ

9

IV

Polycystic ovary syndrome 14

9

SQ

36

SQ

28

83

SQ

2

6

IV

6

8

IV

5

11

SQ

Hurley et aL 19 Mason et al. 20

Reid and Sauerbrei 21

Dose and frequency 0.5-5 ILg every 11/2'-2 hrs 0.5-5 ILg ev~ry P/2-2.hrs 20ILg every 2 hrs 4 ILg every 62,5 min 20 ILg every 90 min 1-5 ILg every 96120 min 1-20 ILg every 90 min 1.25-10 ILg every 90 min 20 ILg every 90 min 5-20 ILg every 90 min 5-20 ILg every 90 min ? 12-20 ILg every 2 hrs 2-20 ILg, 90-180 min 2-20 ILg, 90-180 min 2-20 ILg, 90-180 min 2-20 ILg, 90-180 min 5-15 ILg every 90 min 10-25 ILg every 90 min 10-25 ILg every 90 min 2.5-5 ILg every 1.5-2 hrs 5-20 ILg every 2-4 hrs

No.ofovulatory cycles

No. of pregnancies

0

0

2

2

3

1

1

1

9

1

20

7 in 5 patients

36

8

6

3

32

11 (1 set of twins)

32

17 (2 sets of twins)

8

4

? 3

5 1

9

2

0

0

1

0

0

0

30

6

13 in 11 patients (1 set of twins) 30 in 28 patients (8 spontaneous abortions) (1 set of triplets)

7

1

80

9

aOvulatory patients, 82.5%; pregnant patients, 49.2%; pregnant/cycle, 21.7%. Ovulation and pregnancy rate in subcutaneous (SQ) and intravenous (IV) treatment cycles as available data permits: IV ovulation rate, 80.7%; SQ ovulation rate, 83.9%;· IV pregnancy rate, 52%; SQ pregnancy rate, 46%.

mains our first choice for GnRH therapy. Intravenous treatment is reserved for those women who show either inconsistent responses or fail to respond to subcutaneous therapy. The newly defined group of follicular dysfunction (group B) observed by ultrasound examinations seems to be benefited by GnRH therapy, as shown by prompt correction of such a dysfunction in all women during therapy and conception in one woman. This may warrant ultrasound observations offolliculogenesis during a menstrual cyVol. 44, No.5, November 1985

de specifically in women with unexplained infertility. Four women from group C and one woman with LUF required GnRH administration at a decreased frequency for ovulation. One of these women, who was hyperstimulated with intravenous GnRH at a frequency of 2 hours, ovulated when the frequency was decreased to 3 hours. This suggests an underlying abnormality of endogenous GnRH secretion in these women. Decreased pulse frequency was used to stimulate Phansey et aI. Alternative indications for GnRH therapy

593

FSH secretion without an appreciable increase in LH.23 It is obvious that GnRH therapy in the regimens described in this report is not indicated in women with an abnormal serum LH to FSH ratio. GnRH therapy had no deleterious effects on cervical mucus secretion. Significant improvement in cervical mucus in women who had poor mucus during CC therapy suggests another indication for GnRH treatment. To summarize, infertility due to LPD, disordered folliculogenesis (seen by ultrasound examination), irregular ovulation, or anovulation can be effectively treated with pulsatile GnRH therapy in some women. Different responses to different dose schedules and frequency intervals suggest a need for individualization of GnRH therapy in these women. Careful monitoring of the patient is mandatory until and even after each cycle, because the responses to the same dose schedule in the same individual may vary during different cycles. GnRH therapy was disappointing in anovulatory women with an abnormal ratio of basal serum levels of LH to FSH (;?!: 3 to 1). Acknowledgment. We would like to thank John A. Colwell, M.D., Ph.D., Professor of Medicine, Director, Endocrinology! Metabolism/Nutrition Division, Medical University of South Carolina, for his support and supply of gonadotropin -releasing hormone. REFERENCES 1. Knobil E: The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 36:53, 1980 2. Crowley WF, McArthur JW: Simulation of the normal menstrual cycle in Kallman's syndrome by pulsatile administration of luteinizing hormone-releasing hormone (LHRH). J Clin Endocrinol Metab 51:173, 1980 3. Leyendecker G, Struve T, Plotz EJ: Induction of ovulation with chronic intermittent (pulsatile) administration of LH-RH in women with hypothalamic amenorrhea. Arch Gynecol 229: 177, 1980 4. Leyendecker G, Wildt L, Hansmann M: Pregnancies following chronic intermittent (pulsatile) administration of GnRH by means of a portable pump ("Zyklomat"): a new approach to the treatment of infertility in hypothalamic amenorrhea. J Clin Endocrinol Metab 51:1214, 1980 5. Keogh EJ, Mallal SA, Giles PFH, Evans DV: Ovulation induction with intermittent subcutaneous LHRH. Lancet 1:147, 1981 6. Schoemaker J, Simons AHM, van Osnabrugge GJC, Lugtenburg C, van Kessel H: Pregnancy after prolonged pulsatile administration of luteinizing hormone-releasing hormone in a patient with clomiphene-resistant secondary amenorrhea. J Clin Endocrinol Metab 52:882, 1981 7. Reid RL, Leopold GR, Yen SSC: Induction of ovulation and pregnancy with pulsatile luteinizing hormone releasing factor: dosage and mode of delivery. Fertil Steril 36:553, 1981 594

Phansey et al. Alternative indications for GnRH therapy

8. Seibel MM, Kamrava M, McArdle C, Taymor ML: Ovulation induction and conception using subcutaneous pulsatile luteinizing hormone releasing hormone. Obstet Gynecol 61:292, 1983 9. Noyes RW, Hertig AT, Rock J: Dating the endometrial biopsy. Fertil Steril 1:3, 1950 10. Phansey SA: Follicular dysfunction by ultrasound. Abstract presented at the Minnesota Obstetrical and Gynecological Society Meeting, Minneapolis, MN, December 1984 11. Jewelewicz R, Dyrenfurth I, Warren MP, Vande Wiele RL: Ovarian hyperstimulation syndrome. In Gonadotropin Therapy in Female Infertility, Edited by E Rosenberg. Amsterdam, Excerpta Medica, 1973, p 235 12. Skarin G, Nillius SJ, Wide L: Pulsatile low-dose luteinizing hormone-releasing hormone treatment for induction of follicular maturation and ovulation in women with amenorrhea. Acta Endocrinol (Copenh) 101:78, 1982 13. Miller DS, Reid RL, Cetel NS, Rebar RW, Yen SSC: Pulsatile administration of low dose gonadotropin releasing hormone. JAMA 250:2937, 1983 14. Skarin G, Nillius SJ, Wide L: Pulsatile subcutaneous lowdose gonadotropin-releasing hormone treatment of anovulatory infertility. Fertil Steril 40:454, 1983 15. Hurley DM, Brian RJ, Burger HG: Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: singleton pregnancies in patients with previous multiple pregnancies after gonadotropin therapy. Fertil Steril 40:575, 1983 16. Berg D, Mickan H, Michael S, Doring K, Gloring K, Janicke F, Rjosk HK: Ovulation and pregnancy after pulsatile administration of gonadotropin releasing hormone. Arch Gynecol 233:205, 1983 17. Leyendecker G, Wildt L: Induction of ovulation with chronic intermittent (pulsatile) administration of GnRH in women with hypothalamic amenorrhea. J Reprod Fertil 69:397, 1983 18. Loucopoulos A, Ferin M, Vande Wiele RL, Dyrenfurth I, Linkie D, Yeh M, Jewelewicz R: Pulsatile administration of gonadotropin-releasing hormone for induction of ovulation. Am J Obstet Gynecol 148:895, 1984 19. Hurley DM, Brian R, Outch K, Stockdale J, Fry A, Hackman C, Clarke I, Burger HG: Induction of ovulation and fertility in amenorrheic women by pulsatile low dose gonadotropin releasing hormone. N Engl J Med 310:1069, 1984 20. Mason P, Adams J, Morris DV, Tucker M, Price J, Vougaris Z, Van der Spuy ZM, Sutherland I, Chamblis GR, White S, Wheeler MJ, Jacobs HS: Induction of ovulation with pulsatile luteinizing hormone releasing hormone. Br Med J 288:181, 1984 21. Reid RL, Sauerbrei E: Evaluation of techniques for induction of ovulation in outpatients employing pulsatile gonadotropin releasing hormone. Am J Obstet Gynecol 148:648, 1984 22. Wilks JW, Hodgen GD, Ross GT: Luteal phase defect in the rhesus monkey, the significance in serum FSH:LH ratios. J Clin Endocrinol Metab 43:1261, 1976 23. Wildt L, Hamster A, Marshall G, Hutchinson JS, Plant TM, Belchetz PE, Knobil E: Frequency and amplitude of gonadotropin releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Endocrinology 109:376, 1981

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