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

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1 FERTILITY AND STERILITY Copyright 985 The American Fertility Society Vol. 44, No.5, November 985 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 Adistration 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 exaations; and group C consisted of eight patients who exhibited anovulation or irregular ovulation. GnRH was adistered subcutaneously or intravenously in dosages varying from 5 M to 0 fj,g, with pulse frequency of to 3 hours in 53 cycles. Forty-one cycles were ovulatory. Four pregnancies resulted, one ending in miscarriage at 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, 985 Recent advances in adistration of gonadotropin-releasing hormone (GnRH) have offered an alternative in the treatment of hypothalamic amenorrhea. Since it was demonstrated that GnRH needs to be adistered in pulses to restore pituitary gonadotropin secretion in mon- Received August 0, 984; revised and provisionally accepted November 6, 984; accepted July &, 985. *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 550. *Department of Medicine, Veterans Adistration Hospital. keys with hypothalamic lesions, l effective regimens have been developed for therapeutic use of GnRH in infertile women. Pulsatile adistration of GnRH has been highly effective in inducing ovulation and achieving pregnancy in patients with hypothalamic amenorrhea. -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 infertile women. MATERIALS AND METHODS Twenty-one infertile women, 4 to 36 years of age, with infertility were treated with pulsatile Vol. 44, No.5, November 985 Phansey et ai. Alternative indications for GnRH therapy 589

adistration 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).

2 adistration 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 days during late luteal phase (days 4 to 6) of at least two cycles, as detered 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 exaations. Ultrasound exaations were performed daily or alternate days during a imum of two cycles in women with unexplained infertility who had apparent ovulatory cycles, as evidenced by biphasic basal body temperature (BBT) rise and normal (~ 000 ng/dl) midluteal serum P levels. Follicular dysfunction was diagnosed as follows o : Luteinized Unruptured Follicle (LUF). Increase in the size of the doant 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 exaations were also performed. Luteinization of the Doant Follicle Before Rupture. Rise in BBT with multiple echoes seen in the doant follicle without increase in size, followed by rupture, as documented by ultrasound exaation. Absence of a Normal Doant Follicle. Growth of multiple follicles with a failure to develop a doant follicle with or without any evidence of rupture of a follicle of < 3 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 50-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 ) and were subgrouped as C, whereas those with a normal LH to FSH ratio were included in group Cl. One woman from C 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 imal 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 ASC, 6H, Auto Syringe, Inc., Hooksett, NH). A pulse dose of 0 f-lg every hours was used for subcutaneous adistration of GnRH. The dose was changed to 0 f-lg every 3 hours in the same or subsequent cycle if there was an absence of follicular growth evident on ultrasound exaation and/or rise in the serum estradiol (E) level. Once the response was seen, pulse frequency was changed to every 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 hours was used for intravenous adistration. Ovulation was achieved with an intramuscular injection of human chorionic gonadotropin (hcg) in a dose of 0,000 IU in women who did not ovulate with a doant follicle of ~ 7 mm in size and serum E level of ~ 300 pg/ml. GnRH was discontinued at the time of hcg injection or after ovulation was documented on ultrasound exaation. Follow-up hcg injections were given to all women during the luteal phase (500 to 500 IU) every 3 days starting on the third day of ovulation for a total of four doses. Follicular growth was monitored by serial ultrasound exaations and frequent serum E deterations (every third or fourth day during Fertility and Sterility

3 Table. Results ofgnrh Therapy in Three Groups of Patients Treat GnRH therapy Ovula Patient ment tory cycles Dose Frequency Method a cycles JJ.g hrs Group A M.K. 0 J. G.b 0 5 D. H.b 0 96, B. S. 0 S.B. 0 A. H. 0 3, B. B. 0 96, B. M.e D. Z.b 0 96, 5, 0 96, Group B M.E.d 0 3, C.W. 0 K. M.e 0 J.N. 0 3, 3 5 Group C L. L. 0 3, D. B.d 5 0 3, J.O.' 0,0 3, 5,0 3, K. B.' 0, 0 3, K. E.' 0,0 3, K. S. 96 S. T.d 4 0 0, 0, 3, A.N.d 5,0 3, 0 U, subcutaneous;, 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 doant follicle (~ 7 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 ~ 000 ng/dl. Endometrial biopsies were performed during the GnRH treatment cycle 0 to 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 E was measured by radioimmunoassay (RIA) with the Pantex immuno-estradiol 5 extraction method kit, and P was measured by Pantex immuno-direct progesterone 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). RESULTS Pulsatile GnRH was adistered 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 adistered intravenously in 3 cycles. Eleven cycles were ovulatory (78%). One of the six patients who received intravenous GnRH (Table ) failed to respond in a total of two cycles. Group A Nine women were treated for cycles, 7 subcutaneously and 4 intravenously. Duration of therapy ranged from 4 to 7 days. In all ovulatory cycles (subcutaneous, 4 of7; intravenous, 4 of 4), the luteal phase length was 4 to 7 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 exaation during all but one of the seven cycles treated with subcutaneous adistration of GnRH, and one conceived. Persistent follicular dysfunction was seen Vol. 44, No.5, November 985 Phansey et ai. Alternative indications for GnRH therapy 59

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

4 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 C were treated with a total of subcutaneous and 4 intravenous treatment cycles. Ten of the cycles treated with subcutaneous adistration 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 0,...,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 hours, mild ovarian hyperstimulation resulted, with enlarged ovaries (43 x 4 mm, seen on ultrasound exaation) and a serum E level of 300 pg/ml.ll Ovulation was achieved with a 0-j.Lg pulse of intravenous GnRH at 3-hour intervals. Three women in group C had no response to four subcutaneous and two intravenous GnRH treatment cycles. Patient J. O. was then treated with GnRH intravenously (.5 j.lg every 8 utes) 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 imal reduction (from 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 adistration thereafter failed to stimulate either LH or FSH during the next 0 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 adistration. Superficial phlebitis occurred in one woman with intravenous therapy with no other complications. During subcutaneous therapy, small subcutaneous hematomas were observed in 3 of patients when heparinized solution was used. No complications were seen when heparin was deleted. Hyperstimulation occurred in one woman during intravenous therapy. 59 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 literature 5-8,- (Table ) lends credence to this hypothesis because GnRH therapy in women with hypothalamic amenorrhea is successful in inducing ovulation and pregnancy. Leyendecker and Wildt 7 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. 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 adistration 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 adistration of GnRH were observed in subsequent cycles in some women. However, if results from three women who had no response to GnRH adistered 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. Review of the literature (Table ) shows comparable responses of subcutaneous and intravenous routes of GnRH adistration in terms of ovulation (83.9%, versus 80.7%) and pregnancies (46%, versus 5%). Because of convenience, low-risk potential, and comparable success rates, the subcutaneous route of adistration re- Fertility and Sterility

5 Table. Summary of Pulsatile GnRH Adistration (Literature Reviewr No. of No. of Dose and No.ofovu- No. of Reference patients cycles Method frequency latory cycles pregnancies Reid et al ILg every 0 0 /'- hrs ILg ev~ry P/-.hrs Schoemaker et al ILg every 3 hrs Keogh et al. 5 4 ILg every 6,5 Skarin et al ILg every 90 9 Miller et al ILg every in 5 patients 0 Skarin et al.4 4? -0 ILg every 36 8 Hurley et al ILg every Berg et ap ILg every 90 3 ( set of twins) Ley~itdecker and ILg every 3 7 ( sets of twins) Wildt ILg every Seibel et al ??? ILg every 3 hrs Loucopoulos et al ILg, Hypergonadotropic 5-0 ILg, hypogonadism ILg, Polycystic ovary 9-0 ILg, syndrome Hurley et al ILg every 30 3 in patients ( 90 set of twins) Mason et al ILg every in 8 patients (8 90 spontaneous abortions) ILg every 6 ( set of triplets) Reid and Sauerbrei ILg every 7.5- hrs ILg every 9-4 hrs aovulatory patients, 8.5%; pregnant patients, 49.%; pregnant/cycle,.7%. Ovulation and pregnancy rate in subcutaneous () and intravenous () treatment cycles as available data permits: ovulation rate, 80.7%; ovulation rate, 83.9%; pregnancy rate, 5%; 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 exaations 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 cy- de specifically in women with unexplained infertility. Four women from group C and one woman with LUF required GnRH adistration at a decreased frequency for ovulation. One of these women, who was hyperstimulated with intravenous GnRH at a frequency of 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 Vol. 44, No.5, November 985 Phansey et ai. Alternative indications for GnRH therapy 593

FSH secretion without an appreciable increase in LH.3 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.

6 FSH secretion without an appreciable increase in LH.3 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 exaation), 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 ). 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. Knobil E: The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 36:53, 980. Crowley WF, McArthur JW: Simulation of the normal menstrual cycle in Kallman's syndrome by pulsatile adistration of luteinizing hormone-releasing hormone (LHRH). J Clin Endocrinol Metab 5:73, Leyendecker G, Struve T, Plotz EJ: Induction of ovulation with chronic intermittent (pulsatile) adistration of LH-RH in women with hypothalamic amenorrhea. Arch Gynecol 9: 77, Leyendecker G, Wildt L, Hansmann M: Pregnancies following chronic intermittent (pulsatile) adistration of GnRH by means of a portable pump ("Zyklomat"): a new approach to the treatment of infertility in hypothalamic amenorrhea. J Clin Endocrinol Metab 5:4, Keogh EJ, Mallal SA, Giles PFH, Evans DV: Ovulation induction with intermittent subcutaneous LHRH. Lancet :47, Schoemaker J, Simons AHM, van Osnabrugge GJC, Lugtenburg C, van Kessel H: Pregnancy after prolonged pulsatile adistration of luteinizing hormone-releasing hormone in a patient with clomiphene-resistant secondary amenorrhea. J Clin Endocrinol Metab 5:88, 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, Seibel MM, Kamrava M, McArdle C, Taymor ML: Ovulation induction and conception using subcutaneous pulsatile luteinizing hormone releasing hormone. Obstet Gynecol 6:9, Noyes RW, Hertig AT, Rock J: Dating the endometrial biopsy. Fertil Steril :3, Phansey SA: Follicular dysfunction by ultrasound. Abstract presented at the Minnesota Obstetrical and Gynecological Society Meeting, Minneapolis, MN, December 984. 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, 973, p 35. 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) 0:78, Miller DS, Reid RL, Cetel NS, Rebar RW, Yen SSC: Pulsatile adistration of low dose gonadotropin releasing hormone. JAMA 50:937, Skarin G, Nillius SJ, Wide L: Pulsatile subcutaneous lowdose gonadotropin-releasing hormone treatment of anovulatory infertility. Fertil Steril 40:454, 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, Berg D, Mickan H, Michael S, Doring K, Gloring K, Janicke F, Rjosk HK: Ovulation and pregnancy after pulsatile adistration of gonadotropin releasing hormone. Arch Gynecol 33:05, Leyendecker G, Wildt L: Induction of ovulation with chronic intermittent (pulsatile) adistration of GnRH in women with hypothalamic amenorrhea. J Reprod Fertil 69:397, Loucopoulos A, Ferin M, Vande Wiele RL, Dyrenfurth I, Linkie D, Yeh M, Jewelewicz R: Pulsatile adistration of gonadotropin-releasing hormone for induction of ovulation. Am J Obstet Gynecol 48:895, 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 30:069, 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 88:8, 984. Reid RL, Sauerbrei E: Evaluation of techniques for induction of ovulation in outpatients employing pulsatile gonadotropin releasing hormone. Am J Obstet Gynecol 48:648, 984. Wilks JW, Hodgen GD, Ross GT: Luteal phase defect in the rhesus monkey, the significance in serum FSH:LH ratios. J Clin Endocrinol Metab 43:6, 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 09:376, Phansey et al. Alternative indications for GnRH therapy Fertility and Sterility

Induction of multiple ovulation by pulsatile administration of gonadotropin-releasing hormone*

FERTILITY AND STERILITY Copyright 1983 The American Fertility Society VoL 40, No.1, July 1983 Printed in UBA. Induction of multiple ovulation by pulsatile administration of gonadotropin-releasing hormone*