THE USE OF HUMAN GONADOTROPINS FOR THE INDUCTION OF OVULATION IN WOMEN WITH POLYCYSTIC OVARIAN DISEASE*

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1 FERTILITY AND STERILITY Copyright e 1980 The American Fertility Society Vol. 33, No.5, May 1980 Printed in U.SA. THE USE OF HUMAN GONADOTROPINS FOR THE INDUCTION OF OVULATION IN WOMEN WITH POLYCYSTIC OVARIAN DISEASE* CHUN FU WANG, M.D.t CARL GEMZELL, M.D. Department of Obstetrics and Gynecology, Downstate Medical Center, State University of New York, Brooklyn, New York During the years 1974 to 1977, a total of 77 treatment cycles of human menopausal gonadotropin (hmg)-human chorionic gonadotropin (hcg) were administered to 41 infertile patients with polycystic ovarian disease who failed to conceive on clomiphene. Twenty-seven patients (65.9%) conceived, two of them twice, making twenty-nine pregnancies. The abortion rate was 24.1% and the multiple pregnancy rate was 36.3%. Of the 77 treatment cycles, 7.8% were complicated by mild hyperstimulation and 3.9% by severe hyperstimulation. In six treatment cycles (7.8%), ovulation occurred spontaneously prior to the hcg injection. hmg-hcg is an additional safe and effective, nonsurgical treatment for women with polycystic ovarian disease who have failed to respond to clomiphene therapy. The reaction to exogenous gonadotropins is unpredictable and probably depends on the stage of follicular development prior to the stimulation. Therefore, daily estrogen determinations from the 1 st day of treatment are mandatory in order to avoid hyperstimulation and/or multiple births. Fertil Steril 33:479, 1980 Ovarian wedge resections have been performed on patients with polycystic ovarian disease (POD) who either do not ovulate or do not conceive with clomiphene citrate. However, this type of surgery involves a major operative intervention with variable results in restoration of normal ovulatory cycles and conception.! In addition, some patients who do ovulate remain infertile because of significant postoperative pelvic adhesions. 2 Although induction of ovulation using human gonadotropins is an established method of treating anovulatory infertility, women with POD are more likely to develop the hyperstimulation syndrome 3, 4 and Received October 25, 1979; revised December 27, 1979; accepted January 3, *Presented at the Thirty-Fifth Annual Meeting of The American Fertility Society, February 3 to 7,1979, San Francisco, Calif. treprint requests: Chun Fu Wang, M.D., Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, N. Y therefore have been considered to be high-risk patients. With recent availability of monitoring techniques by rapid urinary or plasma estrogen determinations, the untoward effects of human gonadotropin treatment can be minimized. The purpose of this report is to review our results on the induction of ovulation with human gonadotropins in 41 infertile women with POD. Selection of Patients MATERIALS AND METHODS During the years 1974 to 1977, a total of 77 treatment cycles of human menopausal gonadotropin (hmg)-human chorionic gonadotropin (hcg) were administered to 41 infertile patients with POD who failed to ovulate or conceive with clomiphene. The diagnosis of POD was made by laparoscopy, culdoscopy, or laparotomy or with clinical and hormonal findings. All patients were thoroughly studied in search of other infertility factors but none were found. Clomiphene failure

2 480 WANG AND GEMZELL May 1980 TABLE 1. Profiles of Forty-One Patients No. of patients Age (range 23-34, mean 28.7) Parity (range 0-2) Nullipara 34 One 5 Two 2 Diagnosis made by Wedge resection of ovaries 11 Endoscopy (laparoscopy, culdoscopy) 9 Endoscopy and ovarian biopsy 7 Clinical and hormonal findings 14 % was defined as absence of an ovulatory response or conception to a clomiphene dose of at least 150 mg for 5 days with additional hcg treatment, 10,000 IU, on the day of maximal cervical mucus production. Hormone Determinations Plasma Estradiol (E:J: Daily plasma samples were obtained between 9:00 and 9:30 A.M. by venipuncture. The plasma samples were assayed on the same day, according to the radioimmunoassay method of Enqvist and Johansson. 5 The sensitivity of the assay was 50 pg/ml and the interas say variation was 13%. The coefficient of variation between 50 and 150 pg was 10% to 20%. Plasma Progesterone (P): Plasma samples were kept frozen until the time of determination. The assay procedure was that described by Thorneycroft and Stone 6 with slight modification by Bosu et a1. 7 The antiserum was raised against ll-hydroxyprogesterone succinyl-bovine serum albumin in sheep. The sensitivity of the assay was 0.5 ng/ml. Methods of Treatment Gonadotropin therapy was started following a spontaneous menstrual period or a progesteroneinduced flow. During the first course, treatment began with 2 ampules ofhmg (Pergonal [75 IU of follicle-stimulating hormone and 75 IU of luteinizing hormone/ampule], Serono Laboratories, Braintree, Mass.)Iday. In subsequent cycles, the starting dose was the number of ampules per day required to initiate follicular development during the previous cycle. If the patient's plasma E2level did not increase after 4 or 5 days, the dose ofhmg was increased by a factor of 0.3 to 0.5. The dosage of hmg required to initiate a rise in E2 was administered daily. When the E2 level reached 600 to 800 pg/ml, ovulation was induced with hcg (Pregnyl; Organon Inc., West Orange, N. J.), 5,000 or 10,000 IU, 24 to 48 hours after the last hmg injection. Ovulation was confirmed by an elevation of the basal body temperature and/or a progesterone level above 10 ng/ml. If the ovaries were not enlarged, a second injection of 5,000 IU of hcg was given 1 week later. The patient was instructed to have intercourse the day before, the day during, and the day after the first hcg injection. Assessment of Complications The main complications of gonadotropin therapy were hyperstimulation of the ovaries and/or multiple births. Ovarian enlargement due to hyperstimulation was classified as (1) mild, ovarian enlargement less than 7 cm without ascites or hydrothorax, or (2) severe, ovarian enlargement greater than 7 cm with or without ascites or hydrothorax. Abortion and multiple pregnancy were also considered complications. The abortion rate was defined as the number of abortions in relation to the total number of pregnancies. The multiple TABLE 2. Results of hmg-hcg Treatment ( ) POD Other infertility factorsa Total No. of women No. of treatment cycles No. of ovulatory 75 (97.4%) 87 (98.9%) 162 (98.2%) cycles No. of pregnant 27 (65.9%) 27 (64.3%) 54 (65.1%) women No. of pregnancies 29 (37.7%) 35 (39.8%) 64 (38.8%) No. of multiple 8 (36.3%) 7 (25%) 15 (30%) pregnanciesb No. of abortions 7 (24.1%) 7 (20%) 14 (21.9%) No. of complicated 9 (11.7%) 4 (4.5%) 13 (7.9%) treatments Mild hyperstim ulation Severe hyperstim ulation No. of cycles with 6 (7.8%) 6 (6.8%) 12 (7.3%) "premature" ovulationc alncludes hypogonadotropic hypogonadism, hyperprolactinemic anovulation, hypopitutarism, gonadotropin-resistant ovary, and corpus luteum insufficiency. bmultiple pregnancy rate is calculated as the number of multiple pregnancies in relation to the total number of pregnancies less abortions. CSpontaneous ovulation during hmg treatment without hcg.

3 Vol. 33, No.5 INDUCTION OF OVULATION IN POLYCYSTIC OVARIAN DISEASE 481 TABLE 3. Results and Complications of hmg-hcg Treatment in Women with POD POD with primary amenorrhea POD after wedge resection No. of women 4 11 No. of treatment cycles No. of pregnant women 1 (25%) 5 (45.5%) No. of pregnancies 1 (8.4%) 5 (21.7%) No. of multiple pregnancies 0 0 No. of abortions, 0 1 (20%) No. of complicated treatments 1 (8.3%) 2 (8.7%) Mild hyperstimulation 1 2 Severe hyperstimulation 0 0 POD with hyperprolactinemia Others Total (50%) 16 (80%) 27 (65.9%) 6 (31.6%) 18 (51.4%) 29 (35.8%) 1 (16.6%) 7 (38.9%) 8 (27.6%) 2 (33.3%) 4 (22.2%) 7 (24.1%) 2 (10.5%) 4 (11.4%) 9 (11.7%) (7.8%) (3.9%) pregnancy rate was defined as the number ofmultiple pregnancies in relation to the number of pregnancies less abortions. Definition of POD POD was defined as anovulation in a woman with active estrogen-producing ovaries, who experienced vaginal bleeding following an injection of progesterone. Her ovaries might be enlarged or of normal size, she might have hirsutism but also lack abnormal hair growth. She was infertile and had to be treated in order to conceive. RESULTS Table 1 summarizes the profiles of 41 infertile women included in this study. The average age of the patients was 28.7 years with a range of 23 to 34; 82.9% were nulliparous. Eleven patients (26.8%) had undergone ovarian wedge resections; in seven women (17.1%) the diagnosis was made from an endoscopic ovarian biopsy specimen. In nine patients, polycystic ovaries were seen on laparoscopy or culdoscopy. The diagnosis was based on clinical and hormonal findings in 14 patients (34.1%). The over-all results of hmg-hcg treatment in these women were compared with those in an- No. of women No. of treatment cycles No. of pregnant women No. of pregnancies No. of multiple pregnancies No. of abortions No. of complicated treatments Mild hyperstimulation Severe hyperstimulation No. of cycles with "premature" ovulation TABLE 4. Clomiphene Failures Ovulation (68%) 18 (40%) 5 (35.7%) 4 (22.2%) 7 (15.5%) (13.3%) No ovulation (62.5%) 11 (34.4%) 3 (37.5%) 3 (27.2%) 2 (6.3%) 2 o other group of anovulatory patients (Table 2). Of women with POD, 27 (65.9%) conceived, two of them twice, making 29 pregnancies. No differences were noted in the rates of ovulation, pregnancy, and spontaneous ovulation between the two groups. Higher rates of multiple pregnancies, abortions, and complications occurred in patients with POD, although no statistically significant difference was found. None of the infants showed any congenital malformations at the time of birth or 1 year later. Four of the patients with POD had primary amenorrhea, eleven had undergone ovarian wedge resection, and ten had mildly elevated prolactin levels with or without galactorrhea (Table 3). The pregnancy rates in these three groups of women with POD were 25%, 45.5%, and 50%. In women with POD without any of these conditions, the pregnancy rate was 80% associated with a lower multiple birth rate. The results of hmg-hcg treatment in patients with POD who ovulated on clomiphene treatment as compared with those who did not ovulate are shown in Table 4. No significant difference was found between rates of pregnancy, multiple pregnancies, or abortions. However, a higher complication rate was found in the group of patients who ovulated on clomiphene, and all "premature" ovulations occurred in this group. Table 5 summarizes the findings on patients who developed ovarian hyperstimulation following hmg-hcg treatment. Three patients had to be hospitalized because of severe ovarian hyperstimulation, and all recovered following conservative treatment. Two of them had term deliveries and one aborted at 7 weeks of gestation. One patient (C. 0.) with mild hyperstimulation was hospitalized because of severe lower abdominal pain and was operated upon for ectopic pregnancy. She also had an intrauterine pregnancy and delivered a male infant at full term. None of the patients with mild ovarian hypersttmulation had to be

4 482 WANG AND GEMZELL Mav 1980 TABLE 5. Ovarian Hyperstimulation following hmg-hcg Treatment in Women with POD Ovarian Urine Hemocon- Hospitalization Outcome of Patient Age' Parity enlargement Ascites Hydrothorax output centration time Treatment pregnancy days Severe hyperstimlation L. B R: 10 x Normal 7 Conservative Triplet, term L: 5 x 5 H.G Unclear Anuria + 20 Conservative Twin, term S. J R: 10 x 10 Normal 6 Conservative Aborted, 7 wk L: 4 x 4 Mild hyperstimulation R. D R: 4 x 4 Normal No treatment Single, term L: 4 x 5 D. K R: 4 x 4 Normal No treatment Not pregnant L: 5 x 5 D.K R: 5 x 5 Normal No treatment Not pregnant L: 5 x 4 C.O R: 7 x 6 Normal 7 Operated upon for One ectopic, L: 4 x 5 ectopic pregnancy one term M.R R: Normal No treatment Not pregnant L: 4 x 5 M.R R: 5 x 6 Normal No treatment Single, term L: 5 x 5 hospitalized or needed special treatment. Two patients (D. K. and M. R) had mild ovarian hyperstimulation in two treatment cycles. The daily administration of hmg resulted in rising E2 levels. In patients with POD, the ovarian response to hmg was quite unpredictable and, according to the rise in E 2, four different patterns of response could be identified (Table 6). Figures 1 to 7 show the pattern of basal body temperature (BBT) and levels of E2 and P in some representative cycles following gonadotropin administration. Patient L. K. (Fig. 1) showed signs of follicular development beginning on day 5 ofhmg stimulation. hmg stimulation was discontinued when plasma estradiol reached 950 pg/ml, and ovulation was induced 24 hours later with hcg. The patterns of E2 and P were similar to those of a normal spontaneous menstrual cycle (type I). Following treatment she conceived a single pregnancy without ovarian enlargement. In patient C. M. (Fig. 2) the increase in E2 was immediate and rapid following the daily administration of two ampules ofhmg (type 11). On day 4, the E2 level reached 600 pg/ml, and in order to avoid hyperstimulation the hmg was discontinued and no hcg was given. However, ovulation took place as indicated by rises in the BBT and P level to 13 ng/ml. At this time, no intercourse took place and the patient did not conceive. In patient L. B. (Fig. 3) the E2 increased immediately and rapidly following the daily administration of two ampules ofhmg (type 11). On day 7, E2 reached 875 pg/ml; on day 8 ovulation was induced by hcg. She conceived a single pregnancy. No ovarian enlargement was noticed. In patient K. B. (Fig. 4) E2 started to rise on day 4 ofhmg administration and gradually increased to 500 pg/ml on day 8. Despite continuous hmg stimulation, E2 decreased (type III). An hcg injection on day 12, when E2 had fallen to 50 pg/ml, did not result in ovulation. She experienced vaginal bleeding on day 13, indicating that no ovulation had taken place. In patient R R. (Fig. 5) hmg administration resulted in an irregular pattern of E2 with repeated inadequate increases followed by decreases (type 111), eventually rising again on day 11 and reaching 750 pg/ml on day 14. On day 15, ovulation was induced with hcg. She conceived a single pregnancy. Patient I. P. (Fig. 6) also showed an irregular pattern of E2 with repeated inadequate increases followed by decreases (type III). However, following the daily administration of four ampules of hmg, the E2 started to increase. Ovulation was induced by hcg 24 hours after the E2 reached 580 pg/ml. The ovaries of this patient required 300 IU of hmg/day in order to bring about follicular development and ovulation (type IV). She conceived a single pregnancy. Patient H. S. (Fig. 7) ovulated spontaneously during the hmg therapy. On day 14 the E2 was 425 pg/ml, and on day 15 she ovulated. According

5 Vol. 33, No.5 INDUCTION OF OVULATION IN POLYCYSTIC OVARIAN DISEASE 483 TABLE 6. Patterns of Estradiol Rise following hmg Stimulation in Women with POD Type I: Type ll: Typem: Type IV: Similar to a nonnal cycle Immediate and steep rise Repeated inadequate increase followed by a decrease Rise only following 300 IU or more ofhmg l' &At p.e-o. ~Itli 55 to the retrospective plasma progesterone determination, she ovulated prior to the heg injection. She conceived during this treatment. The ovulation was probably triggered by endogenous luteinizing hormone (LH) released by the rising estrogen levels. At term, she delivered normal twins. DISCUSSION The treatment of women with POD who desire pregnancy has always been a difficult and serious medical problem. Before ovulation-inducing drugs became available, most of these women were subjected to wedge resection of the ovaries. This surgical procedure yielded widely divergent results in different hands. 1 Also, an important problem was the occurrence of postoperative adhesions and the possibility of ectopic pregnancies occurring during the subsequent therapy. 2 Following the report by Gemzell et al. 3 about the induction of ovulation with human pituitary l.k HMO _III,;;:c:o ~~~liliimlli ~. 'HeG ~IU 4-:!---+--~--~ - fi 17 II D FIG. 2. Treatment cycle of patient C. M. The pattern of E2 rise was immediate and rapid following hmg stimulation (type ll). The hmg stimulation was discontinued, but she ovulated spontaneously. gonadotropins (hpg), it was found that some women had more complications as a result of treatment than others. With further experience and the treatment of more anovulatory women, it became obvious that women with active estrogensecreting ovaries were more vulnerable to hpg treatment's resulting in a higher rate of super-,, 1..8 peg HeG I0,00O RJ HeG ~/U _ ",,, 8 FIG. 1. Treatment cycle of patient L. K. The pattern of E2 rise following hmq stimulation was similar to that of a normal spontaneous menstrual cycle (type I). FIG. 3. Treatment cycle of patient L. B. The pattern Qf E2 rise was immediate and rapid (type ll). Ovulation was induced by hcg on day 8.

6 484 WANG AND GEMZELL May 1980 HMG ampule. HI " IL I III., iiiiiiiii, HCG 10,000 IU 1500 II 10 1 " ~I FIG. 4. Treatment cycle of patient K. B. The E2 gradually increased to 500 pglml on day 8, then decreased in spite of continuous hmg stimulation (type III). No ovulation took place. ovulation and/or hyperstimulation. Women with POD belonged to this group and at one time it was advised that the first course of treatment should only be explorative and the second should be aimed at conception. In 1961, clomiphene citrate became available and many women with POD ovulated and conceived following this treatment. 8 However, a few women with POD failed to respond to clomiphene, and human gonadotropins became a second and only choice if surgery was to be avoided. In 1968, Brown et a!. 9 reported a rapid technique to determine total urinary estrogens, and it became almost mandatory to use this technique for the daily monitoring ofhpg or hmg therapy. Later, E2 levels in plasma were used to monitor treatment. As a consequence, the risk involved decreased and severe hyperstimulation rarely occurred. Women with POD who were clomiphene failures were treated more frequently and were also allowed to become pregnant without any explorative course of treatment. With hpg or human menopausal gonadotropins (hmg), ovulation can be induced in almost 100% FIG. 5. Treatment cycle of patient R. R. An irregular pattern ofe 2 was noted with repeated inadequate rise followed by a decrease (type III). of women with POD. The pregnancy rate as shown in this study was the same as in women who did not ovulate because of other reasons, but they had higher rates of abortion and hyperstimulation. The treatment also required some experience as the response to hpg or hmg varied considerably from patient to patient. This was probably due to the fact that the status of the ovaries varied from course to course and was more or less unknown at the onset of treatment. FIG. 6. Treatment cycle of patient I. P. An irregular pattern of E2 was noted initially with repeated inadequate rise followed by a decrease (type III). However, E2 started to rise following daily 4 ampules of hmg stimulation (type IV).

7 Vol. 33, No.5 INDUCTION OF OVULATION IN POLYCYSTIC OVARIAN DISEASE 485 J ~I FIG. 7. Treatment cycle of patient H. S. She ovulated spontaneously during the hmg administration, according to the retrospective plasma progesterone determination. It has been found repeatedly that women with POD have follicles in various stages of function and development. Some follicles seem to be active while others show signs of degeneration or atresia. It is most likely that these follicles would respond differently to the exogenous gonadotropins and produce different amounts of estrogens. As some of these patients with POD had elevated serum levels of LH it was not surprising that quite a few ovulated without additional hcg. This has a practical implication, as intercourse has to be advised accordingly, usually throughout the administration of hmg.10 A number of studies have indicated U - 13 that androgen may playa role in the rate of follicular atresia. Especially the intrafollicular ratio of androgen to estradiol might be of importance in the determination of the fate of the follicles. 13, 14 It might, therefore, be of some advantage to suppress the endogenous production of LH and/or androgen before attempts are made to induce ovulation with human gonadotropins. A study performed in rats 15 has indicated that danazol can inhibit steroidogenesis and cause regression of cystic follicles in polycystic ovaries. Clinical trial with danazol before the gonadotropic therapy is in progress. The clinical results of hmg-hcg treatment in POD patients from various treatment centers are summarized in Table The number of patients reported is actually quite limited. It is hoped that, when daily estrogen determinations in blood or urine become more easily available, more patients will be treated. The pregnancy rate of65.9% is either better than or at least as good as those after wedge resection. Furthermore, two women in this series started to ovulate spontaneously following a single treatment with hmghcg and eventually became pregnant without further therapy. In our opinion, patients with POD who have an infertility problem and who are clomiphene failures are good candidates for human gonadotropin treatment before an eventual wedge resection is performed. By careful monitoring of treatment, complications can be avoided, although at the present time abortions and multiple births cannot be completely avoided. REFERENCES 1. Goldzieher JW: Polycystic ovarian disease. Clin Obstet Gynecol 16:82, 1973 TABLE 7. Summary of Clinical Results with hmg-hcg Treatment in Women with POD No. of No. of Ovulation Pregnancy Abortion Multiple Complication Author patienta treatment rate (% rate (% rate pregnancy rate (% cycles patienta) patienta) rate Q cycles) Thompson and (76%) 50 (26%) 21 (39%) 8 (24.2%) 6 (1.1%) Hansen16 Gemzellb (45.6%) 27 (26.2%) 14 (13.6%) Raj et ai Mild 50% Severe 10% Tsapoulis et a (87.5%) 13 (32.5%) Oelsner et a1. b (21.4%) Mild 4.03% Severe 0.16% Present series (95.1%) 27 (65.9%) 7 (24.1%) 8 (36.3%) Mild 9.1% Severe 2.6% amultiple pregnancy rate is calculated as the number of multiple pregnancies in relation to the total number of pregnancies less abortions. blncludes all patients with endogenous estrogen activity and anovulation.

8 486 WANG AND GEMZELL May Kistner RW: Induction of ovulation with clomiphene citrate. In progress in Infertility, Edited by SJ Behrman, RW Kistner. Boston, Little, Brown andco, 1968, p Gemzell CA, Diczfalusy E, Tillinger KG: Clinical effect of human pituitary follicle-stimulating hormone (FSH). J Clin Endocrinol Metab 18:1333, Crooke AC, Butt WR, Palmer R, Morris R, Edward RL, Taylor EW, Short RV: Effect of human pituitary follicle stimulating hormone and chorionic gonadotropin in Stein-Leventhal syndrome. Br Med J 1:1119, Enqvist LE, Johansson EDB: Radioimmunoassay of oestrone and oestradiol in human and bovine peripheral plasma. Acta Endocrinol (Kbh) 71:716, Thomeycroft IH, Stone SC: Radioimmunoassay of serum progesterone in women receiving oral contraceptive steroids. Contraception 5:129, Bosu WTK, Enqvist LE; Lindbert P, Martinsson K, Johansson EDB: The effects of various dosages of lynestrol on the plasma levels of oestrogens and progesterone during the menstrual cycle in the rhesus monkey. Contraception 13:677, Greenblatt RB, Barfield WE, Jungck EC, Roy AW: Induction of ovulation with MRL-41. JAMA 178:101, Brown JB, MacLeod SC, MacNaughton C, Smith MA, Smith B: A rapid method for estimating estrogens in urine using a semiautomatic extractor. J Endocrinol 42:5, Gemzell CA, Kemmann E, Jones JR: "Premature" ovulation during administration of human menopausal gonadotropins in non-ovulatory women. Infertility 1:1, Ingram DL: Atresia. In The Ovary, Vol 1, Edited by S Zuckerman. New York, Academic Press, 1962, p Harman SM, Louvet JP, Ross GT: Interaction of estrogen and gonadotropins on follicular atresia. Endocrinology 96:1145, Louvet JP, Harman SM, Schreiber JM, Ross GT: Evidence for a role of androgens in follicular maturation. Endocrinology 97:366, Armstrong DT, Papkoff H: Stimulation of aromatization of exogenous and endogenous androgens in ovaries of hypophysectomized rats in vivo by follicle-stimulating hormone. Endocrinology 99:114, Raj SG, Raj MHG, Talbert LM, Chen R: Structural and functional regression of polycystic ovaries by danazol. Fertil Steril 30:731, Thompson CR,' Hanson LM: Pergonal (menotropins): a summary of clinical experience in the induction of ovulation and pregnancy. Fertil Steril 21:844, Gemzell CA: Induction of ovulation with human gonadotropins. J Reprod Med 18:155, Raj SG, Berger MJ, Grimes EM, Taymor ML: The use of gonadotropins for the induction of ovulation in women with polycystic ovarian disease. Fertil Steril 28:1280, Tsapoulis AD, Zourlas PA, Comninos AC: Observations on 320 infertile patients treated with human gonadotropins (human menopausal gonadotropin/human chorionic gonadotropin). Fertil Steril 29:492, Oelsner G, Serr DM, Mashiach S, Blankstein J, Snyder M, Lunenfeld B: The study of induction of ovulation with menotropins: analysis of results of 1897 treatment cycles. Fertil Steril 30:538, 1978