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Factors associated with withdrawal bleeding after administration of oral micronized progesterone in women with secondary amenorrhea
Citations from the Literature
tion syndrome is related to marked arteriolar vasodilation that leads to underfilling of the arterial vascular compartment and stimulation of endogenous vasoconstrictor systems and (2) the increased urinary excretion of PGs probably represents a homeostatic response to antagonize the renal effects of these systems.
Endocriilogy
of gonadotropin-releasing hormooe hhced
cycles
in hypothalamic amenorrhea: The role of the pulse dose
Braat DDM; Schoemaker J Departmeni of Obstetrics and Gynecology, Academic Hospital Vrge Universiteit. P.O. Box 7OS7. 1007 MB Amsterdam, NLD
FERTIL STERIL 1991 56/6 (1054-1059) Objective: To find the treatment regimen giving a maximum chance of ovulation and a minimal chance of multiple follicular development in pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with hypothalamic amenorrhea. Design: We prospectively studied the endocrinology of cycles induced with 5, IO and 20 pg GnRH pulse doses, randomly assigned per patient, comparing this with the endocrinology of spontaneous menstrual cycles. Setting: All patients were treated at the Academic Hospital of the Vrije Universiteit, Division of Reproductive Endocrinology and Fertility. Patients: Fifteen patients with hypothalamic amenorrhea were treated for one to three cycles; I4 normally cycling volunteers were studied for one cycle. Main Outcome Measure: Number of ovulations per pulse dose; luteinizing hormone, follicle-stimulating hormone, total urinary estrogens (Es) and pregnanediol were measured per cycle day and per stimulation day. Results: The endocrinology of all ovulatory cycles remained within the normal range. First treatment cycles showed significantly higher ovulation rates compared with subsequent cycles. Significantly more anovulation was observed in cycles with 5-kg pulse doses. Luteal Es were significantly higher in induction cycles compared with controls. Conclusions: The optimum treatment regimen should be to start induction with 5 &pulse in the first cycle and to raise the dose to IO &pulse in subsequent cycles, regardless of the outcome of the first cycle. After ovulation, the pulse interval should be changed to 240 min.
Results of ovulation induction using human menopausal gonadotropin or purified foIlicle-stimulating hormone in hypogonadotropic bypogonadism patients
Shoham Z; Balen A; Pate1 A; Jacobs HS Cobbold Laboratories, Middlesex Hospital, Morrimer Street. London WIN 8AA, GBR
FERTIL STERIL 1991 56/6 (1048-1053) Objective: To compare ovarian performance and hormonal levels, after ovulation induction, in patients with isolated hypogonadotropic hypogonadism, using two different gonadotropin drugs. Design: Patients were treated during consecutive cycles, using the same stimulation protocol, with human menopausal gonadotropin (hMG) in the first treatment cycle and purified follicle-stimulating hormone (FSH) in the second one. Setting: Specialist Reproductive Endocrine Unit. Patients, Participants: Nine patients with isolated hypo-
335
gonadotropic hypogonadism. Main Outcome Measure: Duration of stimulation, number of leading follicles, serum estradiol (E2) concentration and endometrial thickness at the time of human chorionic gonadotropin administration and the occurrence of ovulation. Results: Compared with hMG, treatment with purified FSH required significantly more ampules of drug (P < 0.04) but resulted in a significant reduction in the number of leading follicles (P < 0.05) serum E, concentrations (P < 0.002), endometrial thickness (P < 0.02) and the occurrence of ovulation (P < 0.05). Conclusion: This study in isolated hypogonadotropic hypogonadism patients is consistent with the two-cell two-gonadotropin hypothesis, that both gonadotropins are required to accommodate their synergistic action for appropriate steroidogenesis. In treating this group of patients, the superior efficacy of hMG compared with purified FSH preparation is beyond question. Factors associated with withdrawal bleeding after administration of oral micronized progesterone in women with secondary amenorrhea
Shangold MM; Tomai TP; Cook JD; Jacobs SL; Zinaman MJ; Chin SY; Simon JA Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Hahnemann University, 1427 Vine Street, Philadelphia, PA 19102, USA
FERTIL STERIL 1991 56/6 (1040-1047) Objective: To compare two dosages of oral micronized progesterone (P) and placebo for withdrawal bleeding and side effects. Design: Prospective, randomized, double-blind. Setting: Academic institution. Participants: Out of 190 screened with oligomenorrhea/amenorrhea, 60 who qualified completed the study. Interventions: A IO-day course of (I) oral micronized P 300 mg, (2) oral micronized P 200 mg, or (3) placebo. Main Outcome Measures: Withdrawal bleeding, side effects and changes in lipids. Endogenous estradiol (Ez) concentrations at baseline and P concentrations during treatment were correlated with bleeding response. Results: Withdrawal bleeding occurred in 90% of women taking 300 mg, 58% of women taking 200 mg and 29% of women taking placebo (P < 0.0002 for 300 mg versus placebo). Side effects occurred similarly among the groups (P = not significant). Lipid concentrations were unchanged. Endogenous E, and treatment P concentrations were of limited predictive value for withdrawal bleeding. Conclusions: Progesterone 300 mg induced significantly more withdrawal bleeding than placebo, with similar side effects. Bleeding response cannot be predicted reliably from E, and P concentrations. Prevention of premature luteinizii
hormone nod progesterone rise with a gonadotropin-releasing hormone antagonist, NaI-Glu, in cont~olIed ovarian hyperstimulation
Frydman R; Cornel C; De Ziegler D; Taieb J; Spitz IM; Bouchard P Hopital Antoine Beclere. Maternite. Trivaux, 92141 Clamari, FRA
157 rue de la Porte de
FERTIL STERIL 1991 56/5 (923-927) Objective: To report a preliminary study on the efficacy of a gonadotropin-releasing hormone antagonist (Nal-Glu) for Ini J Gynecol Obstet 38
336
Citations from the Literature
preventing premature luteining hormone (LH) and progesterone (P) rise in controlled ovarian hyperstimulation using clomiphene citrate (CC) and human menopausal gonadotropin (hMG). Design: Participants in the study formed two groups. Both groups received CC-hMG and Nal-Glu. Group II differs from group I for receiving human chorionic gonadotropin (hCG) and blood samples for 10 days after the second Nal-Glu injection. Setting: Centre de Fecondation in Vitro, Hopital Antoine Beclere. Patients: Eleven women 25-34 years of age and having normal menstrual cycles using barrier method of contraception not attempting pregnancies participated in the study. Intervention: Daily blood samples, Pelvic ultrasound and CC-hMGMal-GluibCG administration. Main Outcome Measures: (1) Spontaneous LH surge and P rise, follicular growth and plasma E, levels in cycles with CC-hMG/Nal-Glu administration and (2) luteal phase after hCG injection in subjects previously treated with CC-hMGiNal-Glu. Results: Plasma E, level increased from 983 * 80 pg/ml (mean ?? SEM) on the day of the first Nal-Glu administration to 1,159 * 102 and 1610 * 114 pg/mL (mean f SEM) 24 and 48 h later. In 10 women, LH and P remained low for at least 96 h after the first Nal-Glu administration. In one subject, plasma LH was already elevated at the time of the first Nal-Glu injection. In women who received hCG, plasma Ez and P reached a maximum of 1258 + 313 pg/ml and 50.3 * 12.8 ng/ml (mean f SEM), respectively, on the 6th day of the luteal phase. Conclusion: Our results suggest that timely Nal-Glu injections can prevent LH and P rise for at least 96 h, in spite of increasing levels of plasma E,. Moreover, Nal-Glu had no adverse effect on the kinetic of E2 rise, the follicular growth, or on the post-hCG hormonal profile. CoatroBed preparation of tbe endometrium with exogenous e&radio1 and progesteroneio women baviog fooctioning ovaries De Ziegler D, Come1 C; Bergeron C; Haxout A; Bouchard P; Frydman R Department of Obstetrics and Gynecology, Hopital A. Beclere, 157 Rue de la Porte de Trivaux, 92141 Clamart, FRA
FERTIL STERIL 1991 56/5 (851-855) Objective: To determine if controlled preparation of the endometrium with exogenous estradiol (E2) and progesterone (P) could be achieved in women retaining their ovarian function without requiring prior ovarian suppression with a longacting agonist of gonadotropin-releasing hormone (GnRH-a). Design: Prospective feasibility study of a new simplified hormone regimen for preparation of endometrium receptivity. Six volunteer women received transdermal E, and vaginal P without prior suppression of their ovarian function with GnRH-a. The control group consisted of previously reported cases receiving GnRH-a and E, and P. Setting: Academic tertiary care institution. Patients: Six volunteer women. Main Outcome Measures: Participants received transdermal Ez and P after a regimen designed to duplicate the plasma E2 and P levels seen in the menstrual cycle. Intervention: Endometrial biopsy. Results: Plasma luteinixing hormone increased to surge levels in one woman on day 1I, in two on day 12 and on day 14 in the remaining three women. No follicular growth was Int J Gynecoi Obstet 38
noticed on ultrasound and no increase in plasma P occurred before the onset of P administration on day 15. Day 20 endometrium specimens showed early secretory changes as previously reported in women deprived of ovarian function receiving similar hormonal treatment. Conclusions: Our results indicate that controlled preparation of the endometrium can be achieved with exogenous E2 and P without prior ovarian suppression with a GnRH-a in women having functioning ovaries. Hence, administration of exogenous E2 and P appears to be a viable simpler alternative to the combined administration of GnRH-a and exogenous E2 and P, which avoids the side effects and the cost of GnRH-a. Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring?The importance of endometrial measurements Shoham Z; Di Carlo C; Pate1 A; Conway GS; Jacobs HS Cobbold Laboratories, Middlesex London WIN 8AA. GBR
Hospital,
Mortimer
Street,
FERTIL STERIL 1991 56/5 (836-841) Objective: To attempt the monitoring of ovulation induction solely with ultrasound (US). Design: Using serial US measurements to monitor ovulation induction using human menopausal gonadotropin and human chorionic gonadotropin (hCG), in comparison with estradiol (Ea) concentrations that became available at the end of each cycle. Setting: Specialist Reproductive Endocrine Unit. Patients, Participants: Twenty hypogonadotropic and 29 ultrasonically diagnosed polycystic ovary patients. Main Outcome Measure: Follicular growth, uterine measurements, endometrial thickness and serum E, concentrations. Results: Follicular growth, uterine measurements, and endometrial thickness correlated strongly with Ez concentrations (P < 0.0001). The endometrium on the day of hCG administration was significantly thicker (P < 0.01) in the conception (n = 27) compared with the nonconception cycles (n = 87), whereas no significant difference were observed in serum E2 concentrations. No pregnancy was observed when hCG had been administered when the endometrial thickness was s 7 mm. Midluteal endometrial thickness of 2 11 mm was found to be a good prognostic factor for detecting early pregnancy (P < 0.008). Conclusions: Serial US examinations used alone have proven to be safe and highly efftcient. It also has a unique ability to detect pregnancy in the midluteal phase. Tbe combioation of a depot gonadotrophin releasing hormone agonist and cyclical hormone replacement therapy for dystimctional uterioe bleediag Thomas EJ; Okuda KJ; Thomas NM Department
of Obstetrics
and Gynaecology,
Hospital, Westgate Road, Newcastle-upon-Tyne
Newcastle
General
NE4 6BE, GBR
BR OBSTET GYNAECOL 1991 98/l 1 (1155-I 159) Objective: To observe if a combination of a depot GnRH agonist and cyclical hormone replacement therapy decreases menstrual blood loss. Design: An open, observational study comparing the objective assessment of menstrual blood loss before, during and after 3 months treatment. Subjects: 20 women with a subjective complaint of heavy menstrual loss in
tion syndrome is related to marked arteriolar vasodilation that leads to underfilling of the arterial vascular compartment and stimulation of endogenous vasoconstrictor systems and (2) the increased urinary excretion of PGs probably represents a homeostatic response to antagonize the renal effects of these systems.
Endocriilogy
of gonadotropin-releasing hormooe hhced
cycles
in hypothalamic amenorrhea: The role of the pulse dose
Braat DDM; Schoemaker J Departmeni of Obstetrics and Gynecology, Academic Hospital Vrge Universiteit. P.O. Box 7OS7. 1007 MB Amsterdam, NLD
FERTIL STERIL 1991 56/6 (1054-1059) Objective: To find the treatment regimen giving a maximum chance of ovulation and a minimal chance of multiple follicular development in pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with hypothalamic amenorrhea. Design: We prospectively studied the endocrinology of cycles induced with 5, IO and 20 pg GnRH pulse doses, randomly assigned per patient, comparing this with the endocrinology of spontaneous menstrual cycles. Setting: All patients were treated at the Academic Hospital of the Vrije Universiteit, Division of Reproductive Endocrinology and Fertility. Patients: Fifteen patients with hypothalamic amenorrhea were treated for one to three cycles; I4 normally cycling volunteers were studied for one cycle. Main Outcome Measure: Number of ovulations per pulse dose; luteinizing hormone, follicle-stimulating hormone, total urinary estrogens (Es) and pregnanediol were measured per cycle day and per stimulation day. Results: The endocrinology of all ovulatory cycles remained within the normal range. First treatment cycles showed significantly higher ovulation rates compared with subsequent cycles. Significantly more anovulation was observed in cycles with 5-kg pulse doses. Luteal Es were significantly higher in induction cycles compared with controls. Conclusions: The optimum treatment regimen should be to start induction with 5 &pulse in the first cycle and to raise the dose to IO &pulse in subsequent cycles, regardless of the outcome of the first cycle. After ovulation, the pulse interval should be changed to 240 min.
Results of ovulation induction using human menopausal gonadotropin or purified foIlicle-stimulating hormone in hypogonadotropic bypogonadism patients
Shoham Z; Balen A; Pate1 A; Jacobs HS Cobbold Laboratories, Middlesex Hospital, Morrimer Street. London WIN 8AA, GBR
FERTIL STERIL 1991 56/6 (1048-1053) Objective: To compare ovarian performance and hormonal levels, after ovulation induction, in patients with isolated hypogonadotropic hypogonadism, using two different gonadotropin drugs. Design: Patients were treated during consecutive cycles, using the same stimulation protocol, with human menopausal gonadotropin (hMG) in the first treatment cycle and purified follicle-stimulating hormone (FSH) in the second one. Setting: Specialist Reproductive Endocrine Unit. Patients, Participants: Nine patients with isolated hypo-
335
gonadotropic hypogonadism. Main Outcome Measure: Duration of stimulation, number of leading follicles, serum estradiol (E2) concentration and endometrial thickness at the time of human chorionic gonadotropin administration and the occurrence of ovulation. Results: Compared with hMG, treatment with purified FSH required significantly more ampules of drug (P < 0.04) but resulted in a significant reduction in the number of leading follicles (P < 0.05) serum E, concentrations (P < 0.002), endometrial thickness (P < 0.02) and the occurrence of ovulation (P < 0.05). Conclusion: This study in isolated hypogonadotropic hypogonadism patients is consistent with the two-cell two-gonadotropin hypothesis, that both gonadotropins are required to accommodate their synergistic action for appropriate steroidogenesis. In treating this group of patients, the superior efficacy of hMG compared with purified FSH preparation is beyond question. Factors associated with withdrawal bleeding after administration of oral micronized progesterone in women with secondary amenorrhea
Shangold MM; Tomai TP; Cook JD; Jacobs SL; Zinaman MJ; Chin SY; Simon JA Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Hahnemann University, 1427 Vine Street, Philadelphia, PA 19102, USA
FERTIL STERIL 1991 56/6 (1040-1047) Objective: To compare two dosages of oral micronized progesterone (P) and placebo for withdrawal bleeding and side effects. Design: Prospective, randomized, double-blind. Setting: Academic institution. Participants: Out of 190 screened with oligomenorrhea/amenorrhea, 60 who qualified completed the study. Interventions: A IO-day course of (I) oral micronized P 300 mg, (2) oral micronized P 200 mg, or (3) placebo. Main Outcome Measures: Withdrawal bleeding, side effects and changes in lipids. Endogenous estradiol (Ez) concentrations at baseline and P concentrations during treatment were correlated with bleeding response. Results: Withdrawal bleeding occurred in 90% of women taking 300 mg, 58% of women taking 200 mg and 29% of women taking placebo (P < 0.0002 for 300 mg versus placebo). Side effects occurred similarly among the groups (P = not significant). Lipid concentrations were unchanged. Endogenous E, and treatment P concentrations were of limited predictive value for withdrawal bleeding. Conclusions: Progesterone 300 mg induced significantly more withdrawal bleeding than placebo, with similar side effects. Bleeding response cannot be predicted reliably from E, and P concentrations. Prevention of premature luteinizii
hormone nod progesterone rise with a gonadotropin-releasing hormone antagonist, NaI-Glu, in cont~olIed ovarian hyperstimulation
Frydman R; Cornel C; De Ziegler D; Taieb J; Spitz IM; Bouchard P Hopital Antoine Beclere. Maternite. Trivaux, 92141 Clamari, FRA
157 rue de la Porte de
FERTIL STERIL 1991 56/5 (923-927) Objective: To report a preliminary study on the efficacy of a gonadotropin-releasing hormone antagonist (Nal-Glu) for Ini J Gynecol Obstet 38
336
Citations from the Literature
preventing premature luteining hormone (LH) and progesterone (P) rise in controlled ovarian hyperstimulation using clomiphene citrate (CC) and human menopausal gonadotropin (hMG). Design: Participants in the study formed two groups. Both groups received CC-hMG and Nal-Glu. Group II differs from group I for receiving human chorionic gonadotropin (hCG) and blood samples for 10 days after the second Nal-Glu injection. Setting: Centre de Fecondation in Vitro, Hopital Antoine Beclere. Patients: Eleven women 25-34 years of age and having normal menstrual cycles using barrier method of contraception not attempting pregnancies participated in the study. Intervention: Daily blood samples, Pelvic ultrasound and CC-hMGMal-GluibCG administration. Main Outcome Measures: (1) Spontaneous LH surge and P rise, follicular growth and plasma E, levels in cycles with CC-hMG/Nal-Glu administration and (2) luteal phase after hCG injection in subjects previously treated with CC-hMGiNal-Glu. Results: Plasma E, level increased from 983 * 80 pg/ml (mean ?? SEM) on the day of the first Nal-Glu administration to 1,159 * 102 and 1610 * 114 pg/mL (mean f SEM) 24 and 48 h later. In 10 women, LH and P remained low for at least 96 h after the first Nal-Glu administration. In one subject, plasma LH was already elevated at the time of the first Nal-Glu injection. In women who received hCG, plasma Ez and P reached a maximum of 1258 + 313 pg/ml and 50.3 * 12.8 ng/ml (mean f SEM), respectively, on the 6th day of the luteal phase. Conclusion: Our results suggest that timely Nal-Glu injections can prevent LH and P rise for at least 96 h, in spite of increasing levels of plasma E,. Moreover, Nal-Glu had no adverse effect on the kinetic of E2 rise, the follicular growth, or on the post-hCG hormonal profile. CoatroBed preparation of tbe endometrium with exogenous e&radio1 and progesteroneio women baviog fooctioning ovaries De Ziegler D, Come1 C; Bergeron C; Haxout A; Bouchard P; Frydman R Department of Obstetrics and Gynecology, Hopital A. Beclere, 157 Rue de la Porte de Trivaux, 92141 Clamart, FRA
FERTIL STERIL 1991 56/5 (851-855) Objective: To determine if controlled preparation of the endometrium with exogenous estradiol (E2) and progesterone (P) could be achieved in women retaining their ovarian function without requiring prior ovarian suppression with a longacting agonist of gonadotropin-releasing hormone (GnRH-a). Design: Prospective feasibility study of a new simplified hormone regimen for preparation of endometrium receptivity. Six volunteer women received transdermal E, and vaginal P without prior suppression of their ovarian function with GnRH-a. The control group consisted of previously reported cases receiving GnRH-a and E, and P. Setting: Academic tertiary care institution. Patients: Six volunteer women. Main Outcome Measures: Participants received transdermal Ez and P after a regimen designed to duplicate the plasma E2 and P levels seen in the menstrual cycle. Intervention: Endometrial biopsy. Results: Plasma luteinixing hormone increased to surge levels in one woman on day 1I, in two on day 12 and on day 14 in the remaining three women. No follicular growth was Int J Gynecoi Obstet 38
noticed on ultrasound and no increase in plasma P occurred before the onset of P administration on day 15. Day 20 endometrium specimens showed early secretory changes as previously reported in women deprived of ovarian function receiving similar hormonal treatment. Conclusions: Our results indicate that controlled preparation of the endometrium can be achieved with exogenous E2 and P without prior ovarian suppression with a GnRH-a in women having functioning ovaries. Hence, administration of exogenous E2 and P appears to be a viable simpler alternative to the combined administration of GnRH-a and exogenous E2 and P, which avoids the side effects and the cost of GnRH-a. Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring?The importance of endometrial measurements Shoham Z; Di Carlo C; Pate1 A; Conway GS; Jacobs HS Cobbold Laboratories, Middlesex London WIN 8AA. GBR
Hospital,
Mortimer
Street,
FERTIL STERIL 1991 56/5 (836-841) Objective: To attempt the monitoring of ovulation induction solely with ultrasound (US). Design: Using serial US measurements to monitor ovulation induction using human menopausal gonadotropin and human chorionic gonadotropin (hCG), in comparison with estradiol (Ea) concentrations that became available at the end of each cycle. Setting: Specialist Reproductive Endocrine Unit. Patients, Participants: Twenty hypogonadotropic and 29 ultrasonically diagnosed polycystic ovary patients. Main Outcome Measure: Follicular growth, uterine measurements, endometrial thickness and serum E, concentrations. Results: Follicular growth, uterine measurements, and endometrial thickness correlated strongly with Ez concentrations (P < 0.0001). The endometrium on the day of hCG administration was significantly thicker (P < 0.01) in the conception (n = 27) compared with the nonconception cycles (n = 87), whereas no significant difference were observed in serum E2 concentrations. No pregnancy was observed when hCG had been administered when the endometrial thickness was s 7 mm. Midluteal endometrial thickness of 2 11 mm was found to be a good prognostic factor for detecting early pregnancy (P < 0.008). Conclusions: Serial US examinations used alone have proven to be safe and highly efftcient. It also has a unique ability to detect pregnancy in the midluteal phase. Tbe combioation of a depot gonadotrophin releasing hormone agonist and cyclical hormone replacement therapy for dystimctional uterioe bleediag Thomas EJ; Okuda KJ; Thomas NM Department
of Obstetrics
and Gynaecology,
Hospital, Westgate Road, Newcastle-upon-Tyne
Newcastle
General
NE4 6BE, GBR
BR OBSTET GYNAECOL 1991 98/l 1 (1155-I 159) Objective: To observe if a combination of a depot GnRH agonist and cyclical hormone replacement therapy decreases menstrual blood loss. Design: An open, observational study comparing the objective assessment of menstrual blood loss before, during and after 3 months treatment. Subjects: 20 women with a subjective complaint of heavy menstrual loss in