Vol. 55, No.1, January 1991
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright© 1991 The American Fertility Society
A comparative, randomized study of low-dose human menopausal gonadotropin and follicle-stimulating hormone in women with polycystic ovarian syndrome
Margaret A. Sagle, F.R.C.S.(C)* Diana Hamilton-Fairley, M.R.C.O.G. Deborah S. Kiddy, B.A. Stephen Franks, F.R.C.P. Department of Obstetrics and Gynaecology, St. Mary's Hospital Medical School, London, United Kingdom
Treatment with low-dose follicle-stimulating hormone (FSH) is associated with a high rate of ovulation in anovulatory women with polycystic ovarian syndrome (PCOS), but it is not clear whether the success of treatment is because of the use of pure FSH or the low dose of gonadotropin. We undertook a randomized controlled study to compare the effects of urinary FSH and human menopausal gonadotropin (hMG) using a low-dose regimen in 30 women with PCOS. Each subject received a maximum of three cycles of either FSH or hMG. Ovulation occurred in 75% of subjects and in 77% of cycles induced with FSH and in 94% of women, 85% of cycles of those treated with hMG. A single dominant follicle developed in 70% (FSH) and 65% (hMG) of cycles, respectively. Five singleton pregnancies occurred in each group. This study shows that low-dose FSH and hMG are equally successful in inducing ovulation, suggesting that the success of treatment depends on the low dose of gonadotropin used rather than the presence or absence of luteinizing hormone in the preparation. Fertil Steril55:56, 1991
Treatment of clomiphene citrate (CC)-resistant anovulation in infertile patients with polycystic ovarian syndrome (PCOS) remains a considerable clinical problem. Human menopausal gonadotropin (hMG, Pergonal; Serono, Welwyn Garden City, United Kingdom) has been used for many years with variable success in terms of pregnancy rate (PR) and is associated with a high risk of multiple follicular development and multiple pregnancy.1-6 A number of recent studies have reported high rates of ovulation and pregnancy during treatment with purified follicle-stimulating hormone (FSH, Metrodin; Serono). 6- 11 We and others have Received April 11, 1990; revised and accepted September 11, 1990. * Present address: Department of Obstetrics and Gynaecology, McMaster University, St. Joseph's Hospital, Hamilton, Ontario, Canada. · t Reprint requests: Stephen Franks, F.R.C.P., Department of Obstetrics and Gynaecology, St. Mary's Hospital Medical School, London, W2 1PG, United Kingdom.
56
Sagle et al.
Low dose hMG versus FSH in PCOS
reported a much reduced rate of multiple follicle development if FSH is given in low doses8 •10- 12; however, it is not clear from such studies if the success of such treatment is primarily because of the use of purified FSH or simply the low doses of gonadotropin that are administered. A preliminary, uncontrolled study indicated that hMG given at a low dose was equally effective in inducing uniovulatory cycles. 13 The similarity between the effects of FSH and hMG has recently been confirmed by controlled studies in small groups of women, using conventional doses of hMG or FSH. 13- 15 The purpose of this study, therefore, was to perform a randomized controlled trial of the effects of low-dose hMG and FSH given to a group of anovulatory women with PCOS. MATERIALS AND METHODS
Thirty patients had presented with anovulatory infertility associated with PCOS. Five had amenorFertility and Sterility
rhoea, 25 had oligomenorrhoea, and 20 had hirsutism and/or acne. The diagnosis of PCOS was made initially on ultrasound (US). Our criteria for diagnosis were 10 or more follicles 2 to 10 mm in diameter observed in one plane and either an ovarian volume :2: 9 cm3 or an increased stromal area (or both) .16•17 Ultrasound findings were supported by at least one endocrine abnormality, i.e., elevated luteinizing hormone (LH), testosterone (T), or both. The upper limits of the normal ranges for LH (11.1 IU/L) and T (2.6 nmol/L) were determined by two SDs above the mean of measurements in 60 women with normal ovaries and regular ovulatory cycles studied in the early to midfollicular phase 7•17 using polyclonal antisera. 18 The intra-assay coefficients of variation (CVs) for LH and FSH were 5.2% and 4.5%, respectively, and the interassay CVs were 6.8% and 6.5%, respectively. 18 Testosterone was measured using a radioimmunoassay with reagents from St. Thomas' Hospital, London, United Kingdom. The interassay and intra-assay CVs were 6.5% and 5.4%, respectively. All patients were unresponsive to CC at a maximum dose of 150 mg as demonstrated by serial US scans showing lack of follicular development and low ( 25 IU/L. Clinical pregnancy was defined by US evidence of agestation sac.
RESULTS
Fifteen women were randomly assigned to each of the two treatment groups. The treatment groups were similar in terms of age and duration of infertility. The mean pretreatment concentrations of LH and T were elevated in both groups of women, but there was no difference between the groups in LH, FSH, or T. The mean (SD) serum concentrations were as follows: (1) FSH group; LH 9.1 (6.5) IU/L, FSH 4.6 (1.6) IU/L, and T 3.3 (2.0) nmol/L and (2) hMG group; LH 10.6 (6.2) IU/L, FSH 4.4 (2.0) IU/L, and T 2.5 (0.9) nmol/L. In the hMG group, 34 of 40 cycles (85%) were ovulatory; of these, 22 (65%) were single follicle ovulations diagnosed on US. In the FSH-treated group, 25 of 34 cycles (73.5%) were ovulatory; 18 Sagle et al.
Low dose hMG versus FSH in PCOS
57
r Table 1 Comparison of the Effects of Purified Urinary FSH and HMG in 30 Women With CC-Resistant PCOS FSH No. of patients No. of patients who ovulated at least once No. of cycles No.(%) of ovulatory cycles No. ofuniovulatory cycles Mean maximum dose of gonadotropin Mean (range) total dose per cycle Mean (SD) midluteal P
HMG
LH lUlL 14 12 10
15 12
15 14
35 27 (77) 19 96IU/d
40 34 (85) 22 86IU/d
19.3 (9 to 38.5) ampules 54.6 (25.0) nmol/L
14.4 (7 to 26) ampules 53.9 (16.8) nmol/L
(72%) were single follicle ovulations (Table 1). Only 3 cycles were abandoned for multifollicular development. No patients developed hyperstimulation or significant ovarian enlargement. The maximum daily dose of gonadotropin was not significantly different (Mann-Whitney U-test) for the two treatments; 86 IU /d for the hMG group, 96 IU/d for the FSH group. The mean total dose required per cycle was 14.4 ampules in the hMG group and 19.3 in the FSH group; again, there was no statistical difference between the groups. Five pregnancies occurred in each treatment group. For both FSH and hMG, two pregnancies occurred in women with secondary infertility, three in the group with primary infertility. Four pregnancies ended in early spontaneous miscarriage (i.e., before 6 weeks' gestation) three in the FSH group, and one in the hMG group. All of the remaining pregnancies were single live births (Table 2). Thus the overall PR was 30% for both FSH and hMG. The cumulative conception rate (including both FSH- and hMG-treated couples) was 36.5% at 3 months. During the course of treatment, three women were found to have persistently negative postcoital tests, despite good cervical mucus and a normal semen analysis (presumed male factor), and one woman had an intermittently raised serum Table 2 Details of Pregnancies in Women Treated With Low-Dose FSH or HMG
Total pregnancies Multiple pregnancies Miscarriages (early pregnancy loss)" Ongoing or completed pregnancies a
58
FSH (n = 15)
HMG (n = 15)
5 0 3 2
5 0 1 4
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright© 1991 The American Fertility Society
A comparative, randomized study of low-dose human menopausal gonadotropin and follicle-stimulating hormone in women with polycystic ovarian syndrome
Margaret A. Sagle, F.R.C.S.(C)* Diana Hamilton-Fairley, M.R.C.O.G. Deborah S. Kiddy, B.A. Stephen Franks, F.R.C.P. Department of Obstetrics and Gynaecology, St. Mary's Hospital Medical School, London, United Kingdom
Treatment with low-dose follicle-stimulating hormone (FSH) is associated with a high rate of ovulation in anovulatory women with polycystic ovarian syndrome (PCOS), but it is not clear whether the success of treatment is because of the use of pure FSH or the low dose of gonadotropin. We undertook a randomized controlled study to compare the effects of urinary FSH and human menopausal gonadotropin (hMG) using a low-dose regimen in 30 women with PCOS. Each subject received a maximum of three cycles of either FSH or hMG. Ovulation occurred in 75% of subjects and in 77% of cycles induced with FSH and in 94% of women, 85% of cycles of those treated with hMG. A single dominant follicle developed in 70% (FSH) and 65% (hMG) of cycles, respectively. Five singleton pregnancies occurred in each group. This study shows that low-dose FSH and hMG are equally successful in inducing ovulation, suggesting that the success of treatment depends on the low dose of gonadotropin used rather than the presence or absence of luteinizing hormone in the preparation. Fertil Steril55:56, 1991
Treatment of clomiphene citrate (CC)-resistant anovulation in infertile patients with polycystic ovarian syndrome (PCOS) remains a considerable clinical problem. Human menopausal gonadotropin (hMG, Pergonal; Serono, Welwyn Garden City, United Kingdom) has been used for many years with variable success in terms of pregnancy rate (PR) and is associated with a high risk of multiple follicular development and multiple pregnancy.1-6 A number of recent studies have reported high rates of ovulation and pregnancy during treatment with purified follicle-stimulating hormone (FSH, Metrodin; Serono). 6- 11 We and others have Received April 11, 1990; revised and accepted September 11, 1990. * Present address: Department of Obstetrics and Gynaecology, McMaster University, St. Joseph's Hospital, Hamilton, Ontario, Canada. · t Reprint requests: Stephen Franks, F.R.C.P., Department of Obstetrics and Gynaecology, St. Mary's Hospital Medical School, London, W2 1PG, United Kingdom.
56
Sagle et al.
Low dose hMG versus FSH in PCOS
reported a much reduced rate of multiple follicle development if FSH is given in low doses8 •10- 12; however, it is not clear from such studies if the success of such treatment is primarily because of the use of purified FSH or simply the low doses of gonadotropin that are administered. A preliminary, uncontrolled study indicated that hMG given at a low dose was equally effective in inducing uniovulatory cycles. 13 The similarity between the effects of FSH and hMG has recently been confirmed by controlled studies in small groups of women, using conventional doses of hMG or FSH. 13- 15 The purpose of this study, therefore, was to perform a randomized controlled trial of the effects of low-dose hMG and FSH given to a group of anovulatory women with PCOS. MATERIALS AND METHODS
Thirty patients had presented with anovulatory infertility associated with PCOS. Five had amenorFertility and Sterility
rhoea, 25 had oligomenorrhoea, and 20 had hirsutism and/or acne. The diagnosis of PCOS was made initially on ultrasound (US). Our criteria for diagnosis were 10 or more follicles 2 to 10 mm in diameter observed in one plane and either an ovarian volume :2: 9 cm3 or an increased stromal area (or both) .16•17 Ultrasound findings were supported by at least one endocrine abnormality, i.e., elevated luteinizing hormone (LH), testosterone (T), or both. The upper limits of the normal ranges for LH (11.1 IU/L) and T (2.6 nmol/L) were determined by two SDs above the mean of measurements in 60 women with normal ovaries and regular ovulatory cycles studied in the early to midfollicular phase 7•17 using polyclonal antisera. 18 The intra-assay coefficients of variation (CVs) for LH and FSH were 5.2% and 4.5%, respectively, and the interassay CVs were 6.8% and 6.5%, respectively. 18 Testosterone was measured using a radioimmunoassay with reagents from St. Thomas' Hospital, London, United Kingdom. The interassay and intra-assay CVs were 6.5% and 5.4%, respectively. All patients were unresponsive to CC at a maximum dose of 150 mg as demonstrated by serial US scans showing lack of follicular development and low ( 25 IU/L. Clinical pregnancy was defined by US evidence of agestation sac.
RESULTS
Fifteen women were randomly assigned to each of the two treatment groups. The treatment groups were similar in terms of age and duration of infertility. The mean pretreatment concentrations of LH and T were elevated in both groups of women, but there was no difference between the groups in LH, FSH, or T. The mean (SD) serum concentrations were as follows: (1) FSH group; LH 9.1 (6.5) IU/L, FSH 4.6 (1.6) IU/L, and T 3.3 (2.0) nmol/L and (2) hMG group; LH 10.6 (6.2) IU/L, FSH 4.4 (2.0) IU/L, and T 2.5 (0.9) nmol/L. In the hMG group, 34 of 40 cycles (85%) were ovulatory; of these, 22 (65%) were single follicle ovulations diagnosed on US. In the FSH-treated group, 25 of 34 cycles (73.5%) were ovulatory; 18 Sagle et al.
Low dose hMG versus FSH in PCOS
57
r Table 1 Comparison of the Effects of Purified Urinary FSH and HMG in 30 Women With CC-Resistant PCOS FSH No. of patients No. of patients who ovulated at least once No. of cycles No.(%) of ovulatory cycles No. ofuniovulatory cycles Mean maximum dose of gonadotropin Mean (range) total dose per cycle Mean (SD) midluteal P
HMG
LH lUlL 14 12 10
15 12
15 14
35 27 (77) 19 96IU/d
40 34 (85) 22 86IU/d
19.3 (9 to 38.5) ampules 54.6 (25.0) nmol/L
14.4 (7 to 26) ampules 53.9 (16.8) nmol/L
(72%) were single follicle ovulations (Table 1). Only 3 cycles were abandoned for multifollicular development. No patients developed hyperstimulation or significant ovarian enlargement. The maximum daily dose of gonadotropin was not significantly different (Mann-Whitney U-test) for the two treatments; 86 IU /d for the hMG group, 96 IU/d for the FSH group. The mean total dose required per cycle was 14.4 ampules in the hMG group and 19.3 in the FSH group; again, there was no statistical difference between the groups. Five pregnancies occurred in each treatment group. For both FSH and hMG, two pregnancies occurred in women with secondary infertility, three in the group with primary infertility. Four pregnancies ended in early spontaneous miscarriage (i.e., before 6 weeks' gestation) three in the FSH group, and one in the hMG group. All of the remaining pregnancies were single live births (Table 2). Thus the overall PR was 30% for both FSH and hMG. The cumulative conception rate (including both FSH- and hMG-treated couples) was 36.5% at 3 months. During the course of treatment, three women were found to have persistently negative postcoital tests, despite good cervical mucus and a normal semen analysis (presumed male factor), and one woman had an intermittently raised serum Table 2 Details of Pregnancies in Women Treated With Low-Dose FSH or HMG
Total pregnancies Multiple pregnancies Miscarriages (early pregnancy loss)" Ongoing or completed pregnancies a
58
FSH (n = 15)
HMG (n = 15)
5 0 3 2
5 0 1 4
