Ovulatory Response Rate with Human Menopausal Gonadotropins of Varying FSH/LH Ratios ARNOLD JACOBSON, M.D.,* and JOHN R. MARSHALL, M.D.
of the ratio of follicle-stimulating hormone to luteinizing hormone (FSHjLH) in human menopausal gonadotropins (HMG) administered prior to human chorionic gonadotropin (HCG) for ovulation induction has been controversial. The prevalent concept has been that the FSHjLH ratio is of little importance. 2 • 3, 9,10 A major reason for the present uncertainty has been the variability in response noted both between cycles in a single patient and between different patients. We have previously shown that much of this between-patient variability can be eliminated by examining response in terms of a standard threshold HMG dose, the first ovulatory dose. H Additionally, we have shown that this standard threshold dose results in approximately a 60% ovulatory rate. S Thus, comparison of the effectiveness of various IIMG preparations in individuals with varying thresholds is possible. In this study three HMG preparations with widely differing LH contents were compared by treating patients with comparable FSH doses. The HMG preparation with the lowest LH content was significantly less effective. THE IMPORTANCE
MATERIALS AND METHODS Six oligo-ovulatory and two anovulatory women were treated with HMG JHCG to induce ovulation. I-IMG was given as a single injection on From the Heproductive Hesearch Branch, National Institutes of Child Health and Human Development, Surgery Branch, National Cancer Institute, U. S. Public Health Service. Presented at the 24th Annual Meeting of The American Fertility Society, San Francisco, Calif., Mar. 28-30, 1968. The HMG used in this study was supplied as Humegon by Organon, Inc., West Orange, N. J., and as Pergonal by Cutter Laboratories, Berkeley, Calif. *Present address: Department of Obstetrics and Gynecology, University of Miami School of Medicine, Miami, Fla.
Day 1 of an arbitrary cycle; 10,000 LU. of HeG was given on Day 9. A standard threshold dose, the first ovulatory dose, was obtained as previously described,8 using a preparation containing HMG with 75 LU. FSH and 530 LU. LH (IRP No.2) per ampule. An FSH dose which was usually slightly greater than the first ovulatory dose was selected for each patient. Patients were then randomly treated in succeeding cycles at the selected dose with 3 HMG preparations: HMG-530, containing 75 LU. FSH and 530 LU. LH (Humegon 66/2, 1/0.5); HMG-84, containing 75 I.U. FSH and 84 LU. LH (Pergonal PR 2128); and HMG-28, containing 82 LU. FSH and 28 LU. LH (Pergonal PR 2119). The bioassays had been performed by the manufacturers. Each patient was treated at least once with each preparation. Since the dosage was always given jn whole ampules and since no correction was made for the difference between 75 and 82 1. U. of FSH, the FSH dose of HMG-28 was actually 9% greater than that of the other 2 FSH preparations. Ovulatory response rates to each HMG preparation were calculated. RESULTS
The FSH doses in LU. (IRP No.2) HMG for each individual patient and results of the treatment cycles with 3 HMG preparations are shown in Table 1. The FSH doses ranged from 750 to 3900 I.U., with a mean dose of 1175 LU. When HMG was repetitively administered at nearly equal FSH doses, the ovulatory rate for HMG-530 was 67%, with 6 of 9 cycles ovulatory; for HMG-84, 67%, with 8 of 12 cycles ovulatory; and for HMG-28, 0%, with 0 of 9 cycles ovulatory. Despite the greater FSH content of the HMG-28 material, the ovulatory rate for this preparation was significantly less (p < 0.01) TABLE 1. Ovulatory Response Rates to DiHerent HMG Preparations
L.G. Z.M. E.M. P.J. J.S. D.P. H.C. K.N. ALL
FSH dose (l.U.,IRP No.2)
750 750 900 1125 1125 1650 1725 3900 1175
0/1 1/1 0/1 1/1 0/1 2/2 1/1 1/1 6/9(67%)
2/2 3/3 0/1 1/1 0/1 0/2 1/1 1/1 8/12(67%)
0/1 0/2 0/1 0/1 0/1 0/1 0/1 0/1 0/9(0%)
* FSH dose actually 9% greater;
VOL. 20, No.1, 1969
OVULATORY RESPONSE TO
than for either HMG-84 or HMG-530. Considering only results from the first treatment with each preparation at nearly equal FSH doses, the ovulatory rate for HMG-28 is still significantly less (p < 0.05) than for either HMG-84 or HMG-530. DISCUSSION
In this comparison of various HMG preparations differing over a 20-fold range in their LH content, each patient served as her own control. Ovulatory response rates at nearly equal FSH doses were not different for HMG preparations having an FSHjLH ratio of 0.14 or 0.90; both had ovulatory rates of 67%. However, the HMG preparation with the low LH content and a FSHjLH ratio of 3.0 was ineffective at this FSH dosage. The present 67% ovulatory rate for HMG-530, at doses slightly greater than the first ovulatory dose, confirms our previous findings based on the triple injection schedule and using a HMG preparation similar to HMG84. 8 We demonstrated that ovulatory rates are positively dose-related and that the first ovulatory dose repetitively administered will result in an ovulatory rate of approximately 60%. Using such a dose allows perception of either significant increases or decreases in the ovulatory rate. In addition, this dose provides an acceptable ovarian enlargement rate. 8 The prevalent concept concerning FSHjLH ratios of gonadotropins administered prior to HCG for ovulation induction is that the FSHjLH ratio is of little importance. 2 , 3, 9, 10 However, in animals, highly purified FSH has been shown ineffective in producing normal follicular growth. 1 , 4-6 The failure of prior clinical studies to demonstrate the importance of FSHjLH ratios in HMG preparations can be attributed to several factors. Firstly, patients have not served as their own controls, and significant differences have thereby been masked by the inherent and large betweenpatient variability. Secondly, patients have not been treated at doses which give a comparable response rate; this adds another uncontrolled source of variation. Thirdly, patients have been treated with excessive doses so that differences in ovulatory rates would be difficult to appreciate. Treatment of many patients could possibly overcome the first and second factors, but not the third. We have subsequently treated patients with larger doses of HMG-28 relative to their first ovulatory dose and have shown an increased ovulatory rate which is more difficult to distinguish from that evoked by other HMG preparations at equally large FSH doses. 7 The possibility that total gonadotropin content is of major importance in determining ovulatory rate can be excluded by noting that the administration of both HMG-530 and HMG-84 at equal FSH doses, but at a fourfold
difference in total gonadotropin content, resulted in equal ovulatory rates. Our previous studies demonstrating a positive dose response relationship between HMG dose and ovarian response have not differentiated between FSH and LH, but have shown the relationship to total HMG dose. s Most probably, in any individual a separate ovulatory threshold dose exists for FSH and LH. The margin of safety associated with a given gonadotropin preparation is more important than its ovulatory effectiveness. It is possible that one preparation with a given FSHjLH ratio might be less effective in inducing ovulation when compared at equal doses to another preparation. However, the first preparation, when given at equally effective doses, for ovulation induction might provide a lower incidence of ovarian enlargement and multiple pregnancy and might, therefore, be the preferable preparation. Additional study will be directed toward this area. We have shown that the LH content of an HMG preparation is an impOltant determinant of the ovulatory response rate. There appears to be a threshold content for LH above which increases do not result in an increased ovulatory rate. This has been shown by noting that an HMG preparation known to be effective in causing ovulation was ineffective at equal FSH doses when compared with HMG preparations having a moderate and high LH content and the same ovulatory rate.
SUMMARY In a study of the importance of the FSHjLH ratio in human menopausal gonadotropins, HMG, used to induce ovulation,HMG was given as a single injection to oligo-ovulatory and anovulatory women on Day 1, and HeG, on Day 9. A FSH dose for each patient was selected which would give an ovulatory rate of 60-70% for an HMG preparation with an FSHjLH ratio of 0.14. Then, in each patient, 3 HMG preparations with FSHjLH ratios of 0.14, 0.9, and 3.0, respectively, were compared at the selected FSH doses. The HMG preparation with least LH or highest FSHjLH was significantly less effective in inducing ovulation than were the other preparations. It was postulated that each individual has an ovulatory threshold dose for both FSH and LH. Department of Opstetric8 & Gynecology University of Miami School of Medicine • Miami, Fla. 33136
CARTER, F., WOODS, M. C., and SIMPSON, M. E. "The Role of the Pituitary Gonadotropins in Induction of Ovulation in the Hypophysectomized Rat." In Control of Ovulation. Pergamon Press, New York, 1961, p. 1.
VOL. 20, No.1, 1969
OVULATORY RESPONSE TO HMG
2. CROOKE, A. C., BUTT, vV. R., and BERTRAND, P. V. Treatment of infertility and secondary amenorrhea with follicle-stimulating hormone and chorionic gonadotropin. Lancet 2:636, 1967. 3. DICZFALUSY, E. In Estrogen Assays in Clinical Medicine, Paulsen, C. A., Ed. Univ. Washington Press, Seattle, 1965, p. 20l. 4. CREEP, R. 0., VAN DYKE, H. B., and CHOW, B. F. Gonadotropin of the swine pituitary. 1. Various biological effects of purified FSH and pure ICSH. Endocrinol:Jgy 30:6.35, 1942. 5. HISAW, F. J., FEVOLD, H. L., and GREEP, R. O. The pituitary gonadotropic hormones. Prec Ass Res Nerv Dis 17:247, 1936. 6. LOSTROH, A. J., and JOHNSON, R. E. Amounts of interstitial cell-stimulating hormone and follicle-stimulating hormone required for follicular development, uterine growth and ovulation in the hypophysectomized rat. Endocrinology 79:991, 1966. 7. ~1ARSHALL, J. R., and JACOBSON, A. lTnpublished data. 8. MARSHALL, J. R., JACOBSON, A., and HAl\IMOND, C. B. Dose-response relationships in ovulation induction with human menopausal gonadctropin. ] C lin Endoer In press. 9. TAYMOR, M. L., and STURGIS, S. H. Induction of ovulation with human menopausal gonadotropin. II. Probable causes of overstimulation. Fertil Steril 17:736, 1966. 10. VANDE \VIELE, R., and TURKSOY, R. N. Treatment of amenorrhea and of anovulation with human menopausal and chorionic gonadotropins. ] Clin Enduer 25: 369, 1965.