The acute feedback action of exogenously administered oestrogens on the serum-gonadotropin-levels in pre- and postmenopausal women (author's transl)

The effects of estradiol benzoate (EB), ethinyl estradiol (EE), and mestranol in different dosages on serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were measured by dioxane-radioimmunoassay at intervals of hours and days. All postmenopausal women studied here reacted with a pronounced suppression of both FSH and LH. The LH decline starts 4-10 hours earlier than FSH and returns - after the minumum on Days 2-3 - to the controls on Days 5-6, while the FSH levels show a longer suppression. Neither in the type of estrogen nor in the administered dose a marked qualitative difference could be observed. Only after 3 mg EE and 15 mg mestranol a prolonged inhibitory effect on FSH and LH became evident. Results in premenopausal women were quite different. In 7 women with a history of amenorrhea or anovulatory cycles 5 mg EB was given. A small decline after 24 hours was followed by a sharp rise of LH 1 day later which is comparable to the preovulatory LH peak. In the subsequent days values returned to control levels. The FSH curve did not show a similar peak. Only 1 woman ovulated and became pregnant. In another group of 11 women with normal menstrual cycles, 5 mg EB was injected at different times of the follicular, periovulatory, and luteal phases. The patterns of serum LH and FSH were comparable to the results in amenorrheic patients. In all cases an LH peak appeared on Days 2-3, which seemed to be higher in the preovulatory than in the postovulatory phase. The FSH curves remained uncharacteristic with small oscillations. The role of the physiological follicular estrogen peak for triggering the LH surge is discussed as well as the possibility of checking the response of the hypothalamic-hypophyseal system by exogenous estrogen application.     

Induction of ovulation in amenorrheic patients with gonadotropin-releasing hormone and human menopausal gonadotropin

In five hypothalamic amenorrhea patients who underwent chronic intermittent gonadotropin-releasing hormone (GnRH) therapy for induction of ovulation, small doses (2 to 4 ampules/day) of human menopausal gonadotropin (hMG) were administered 9 to 32 days after the start of GnRH treatment. In seven treatment cycles, the addition of hMG initiated a sudden rise of 17 beta-estradiol concentrations, followed by a luteinizing hormone and follicle-stimulating hormone surge and ultrasonographic evidences of ovulation. Four of five patients conceived (singleton pregnancies) after the first or second treatment course. There were no clinical signs of ovarian hyperstimulation. Combined therapy of GnRH and hMG may be useful, therefore, for the treatment of hypothalamic amenorrhea patients who demonstrate prolonged follicular phases or luteinized unruptured follicle syndrome under chronic treatment with pulsatile GnRH alone.     

Indications for and limitations of laparoscopic ovarian biopsy

A series of 213 patients with different menstrual patterns underwent laparoscopic visualization of the ovaries and ovarian biopsy in order to evaluate ovarian function. Menstrual patterns were classified in four groups: regular menstrual cycles, oligoamenorrhea, secondary amenorrhea and primary amenorrhea. Laparoscopic gross ovarian appearance was classified in four groups, also. Microscopic picture of the ovaries was also placed in four categories. Laparoscopic vision of the ovaries is not justified in regular menstrual cycle patients. Laparoscopic vision of the ovaries might be useful when menstrual disorders exist, especially in secondary amenorrhea. There is some controversy about whether primary amenorrhea patients should be biopsied. Histology may be important in x,y karyotype primary amenorrhea. Biopsy should be avoided in oligoamenorrhea patients. Premature menopause might be diagnosed histologically in patients with secondary amenorrhea. Gross ovarian appearance may help in the selection of patients for ovarian biopsy. Sclerocystic polycystic ovaries should be biopsied, but the procedure must be bloodless and correctly performed. Streak gonad biopsy is not without hazard, and ureteral injury has been reported. The diagnostic, prognostic and therapeutic value of ovarian biopsy should be balanced against the risk and expense of the procedure.     

Endocrinology of gonadotropin-releasing hormone induced cycles in hypothalamic amenorrhea: the role of the pulse dose.

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 propectively studied the endocrinology of cycles induced with 5, 10, and 20 micrograms 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; 14 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-micrograms 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 micrograms/pulse in the first cycle and to raise the dose to 10 micrograms/pulse in subsequent cycles, regardless of the outcome of the first cycle. After ovulation, the pulse interval should be changed to 240 minutes.     

Pulsatile intravenous gonadotropin-releasing hormone for ovulation-induction in infertile women. II. Analysis of follicular and luteal phase responses

Pulsatile intravenous gonadotropin releasing hormone (IV-GnRH) was used in 36 infertile patients with primary amenorrhea (n = 5), secondary amenorrhea due to hypothalamic chronic anovulation (HCA) (n = 22), hyperprolactinemia (n = 1) or polycystic ovary syndrome (PCOS) (n = 5), and oligomenorrhea (n = 3), using several dosage and timing regimens. Early follicular phase responses showed four patterns: type 1 consisted of a delayed follicle-stimulating hormone (FSH) peak and was seen with severe hypothalamic suppression (n = 4); type 2 consisted of a brisk and dominant FSH peak on the first day of treatment, and occurred with mild to moderate hypothalamic suppression (n = 19); type 3, which consisted of an FSH peak accompanied by an immediate and exaggerated luteinizing hormone (LH) rise, occurred with mild PCOS and some cases of HCA (n = 5); and type 4, in which LH levels were high to begin with and neither FSH nor LH levels rose with GnRH, occurred with severe PCOS (n = 2). Exaggerated estradiol responses within 24 hours of therapy were seen in eight cycles: in four cases no ovarian abnormality was apparent; in three cases a dominant follicle was already present; and in one case ovarian hyperstimulation was diagnosed ultrasonographically. With standard human chorionic gonadotropin luteal phase support, luteal phase defects were rare with HCA but common with PCOS.     

Mechanism of action of narcotics in the production of menstrual dysfunction in women.

The ability of morphine to block ovulation in animals prompted investigation of the frequency and mechanisms of menstrual abnormalities in women addicted to narcotic analgesics. Menstrual histories obtained from 76 former heroin addicts receiving daily methadone maintenance revealed that more than one-half of these women had experienced menstrual abnormalities while taking heroin or methadone. In order to determine the specific physiologic effects of narcotic analgesics on reproductive function, detailed endocrinologic studies were carried out in seven of these patients who complained of amenorrhea or irregular menses while receiving methadone. Four of the seven women manifested abnormalities of the control of gonadotropin secretion. Three of these four failed to exhibit cyclic gonadotropin release, as evidenced by an absence of increased levels of follicular phase follicle-stimulating hormone, midcycle gonadotropin peaks or luteal phase progesterone increments. In the fourth patient a prolonged follicular phase (30 days) of the menstrual cycle was detected. One of these four patients also had low basal gonadotropin levels and failed to exhibit luteinizing hormone increments greater than control levels in response to ethinyl estradiol (positive feedback). The remaining three women exhibited normal patterns of gonadotropin secretion during the observation period. In these women, menstrual bleeding occurred in response to withdrawal from luteal phase (10 to 20 ng/ml) progesterone levels and to exogenous ethinyl estradiol, suggesting normal uterine responsivity to progesterone and estrogen. Although not documented, it is likely that oligo-ovulation was the cause of the irregular menses in these three patients. Amenorrhea is commonly associated with methadone ingestion or heroin addiction and appears to be related to an alteration of the hypothalamic mechanisms controlling gonadotropin secretion. Tolerance to these effects of methadone may develop after chronic ingestion.     

Pituitary sarcoidosis causing secondary amenorrhea. A case report

A 32-year-old woman with hypogonadotropic amenorrhea and sarcoidosis had an enlarged pituitary stalk and gland on computed tomography. Concentrations of luteinizing and growth hormone did not increase after the administration of gonadotropin releasing hormone and insulin-induced hypoglycemia, respectively. The absence of response possibly was the consequence of the patient's estrogen deficiency. The response of thyroid stimulating hormone, prolactin and cortisol was normal after provocative pituitary stimulation. Central nervous system sarcoidosis occurs in 3.5-5.0% of patients with systemic sarcoidosis. Hypothalamic or pituitary sarcoidosis occurs in approximately 0.5% of patients. Diabetes insipidus and hyperprolactinemia are the most frequent manifestations of hypothalamic-pituitary sarcoidosis, occurring in one-half and one-third, respectively, of such patients. Menstrual disturbances, including amenorrhea, are reported infrequently. Computed tomography and provocative pituitary-hypothalamic testing are useful in detecting central nervous system sarcoidosis and in delineating the site of involvement.     

The risk of post-pill amenorrhea: a preliminary report from the Menstruation and Reproduction History Research Program

Menstrual cycle lengths prior to and after oral contraceptive use were prospectively recorded for 245 women. In this preliminary study, a difference in the distributions in the pre- and post-pill cycle lengths was observed. An increase of 5 days in the medial cycle length occurred after oral contraceptive use had been discontinued. Although there was an approximately twofold relative risk of amenorrhea of 90 days' duration or more after discontinuing pill use, the differences in the rates of amenorrhea between the pre-pill and post-pill cycles were not statistically significant.     

Clinical and endocrinological studies on anovulatory women treated with two-step administration of clomiphene citrate

The two step clomiphene citrate (CL) administration therapy was performed in 89 patients with first grade amenorrhea during 1980 through 1983, and clinical data in 89 patients and daily serum hormone levels in 20 patients were investigated. Out of the 89 women, ovulation occurred in 71 (79.8%). As to the treatment cycles, ovulation occurred in 158 cycles (53.4%) out of the total 296 cycles. Pregnancy was achieved in 16 women, among whom 2 women ended in spontaneous abortion and one had a multiple pregnancy. (1) As for 9 women in whom ovulation was induced by this treatment, the serum level of LH in the follicular phase and that of estradiol in the late follicular phase and luteal phase were higher than those of women who had normal ovulatory cycles. (2) No significant differences were observed between the serum levels of FSH and progesterone of the 9 women and those of women with normal ovulatory cycles. (3) As for 11 women in whom ovulation was not induced by this treatment, a transient increase in serum levels of LH and estradiol were observed after the first step administration of CL. This change also appeared soon after completion of the second step administration of CL and became more significant as additional stepwise administration of CL was performed. In view of observations, it was concluded that CL two step administration is effective for anovulatory women who did not respond to one step use of CL. As previously reported, CL exerts its action on the central nervous system to promote ovulation, but it is also strongly suggested that CL has its direct action on the ovary too.     

Cisplatin/5-Fluorouracil Treatment of Recurrent Cervical Carcinoma: A Phase II Study with Long-Term Follow-up

Objective: To evaluate the response rate and corrected survival in patients with recurrent cervical carcinoma (RCC) treated with 100 mg/m²cisplatin (CDDP) iv on Day 1 and 1000 mg/m²5-fluorouracil (5-FU) iv on Days 1 to 5. Methods: A phase II study of CDDP/5-FU in RCC was initiated in 1986. Up to December 1991, a total of 72 patients were enrolled. Of these, 65 were evaluable for response. Results: The overall response rate was 49%. For 9 patients with complete remission, the median duration of response was 16 months, range 6 to 79+. The corresponding figures for 26 patients with partial remission were 10 months, range 3 to 80 months. By multivariate analysis, FIGO stage, disease-free interval, WHO performance status, and number of lesions at recurrence were independent prognostic variables. Twenty-two percent of the patients survived for more than 2 years and 9% for more than 5 years. Toxicity was tolerable. Leucopenia, ototoxicity, and neurotoxicity were the main problems. Conclusion: A high response rate (49%) was observed with CDDP/5-FU treatment in patients with RCC with 9% of the patients surviving for more than 5 years.     

Pulsatile intravenous gonadotropin-releasing hormone for ovulation-induction in infertile women. I. Safety and effectiveness with outpatient therapy

Pulsatile intravenous gonadotropin-releasing hormone (IV-GnRH) was used in 36 infertile patients with primary amenorrhea (n = 5), secondary amenorrhea due to hypothalamic chronic anovulation (HCA) (n = 22), hyperprolactinemia (n = 1) or polycystic ovary syndrome (PCOS) (n = 5), and oligomenorrhea (n = 3). Treatment was commonly initiated in the hospital but was then continued outside, with patients and local physicians accepting responsibility for maintaining IV-GnRH delivery systems. Twenty-eight of 113 treatment cycles (24.8%) resulted in pregnancy, with four spontaneous abortions (14.3%) and four twin pregnancies (16.7%) among 24 births. Probability of pregnancy per treatment cycle was significantly higher for primary amenorrhea (0.30) and for HCA (0.33) than for PCOS (0.07; P less than 0.05) and for oligomenorrhea (no conceptions; P = 0.01). Ovulatory cycles were not achieved in five patients (primary amenorrhea, n = 1; PCOS, n = 3; oligomenorrhea, n = 1). There were no serious complications; six patients recorded eight febrile episodes, which responded quickly to antibiotic therapy and cannula change. The authors conclude that outpatient IV-GnRH is safe, practical, and effective for follicular stimulation and ovulation induction in women presumed to have GnRH deficiency and in whom clomiphene therapy fails, and that less intensive monitoring is needed compared with gonadotropin ovulation induction therapy.     

Induction of multiple follicular growth in normally menstruating women with endogenous gonadotropin suppression

Patients with normal menstrual rhythm and normal luteinizing hormone were treated with exogenous gonadotropins to induce multiple follicular development. This was effected in the absence (34 cycles in 12 patients) or with concurrent suppression of endogenous gonadotropin levels with a gonadotropin-releasing hormone analog (84 cycles in 18 patients). In the absence of the analog, "premature" luteinization occurred in 51% of cycles before the ultrasonic visualization of a follicle with a diameter of 20 mm. In the analog-treated cycles, premature luteinization was almost totally eliminated and progesterone elevations were delayed until after administration of human chorionic gonadotropin. Follicular estrogen production was unaffected by the analog treatment, compared with hypogonadal patients treated with exogenous gonadotropins. The characteristics of follicular development showed that two to three follicles of mature size were induced with this technique, and the capacity for the induction of a larger number of follicles was evident.     

Body mass index and fertility: is there a correlation with human reproduction outcomes?

Considering the existing conflicts about how an elevated body mass index (BMI) affects fertility, this study had the objective of evaluating the impact of overweight and obesity on the results of IVF/ICSI (in-vitro fertilisation/intracytoplasmatic sperm injection) performed at the Human Reproduction Centre of Faculdade de Medicina do ABC. Retrospective data from 208 IVF cycles of 191 women, performed at our laboratory from February through June, 2008, were used to calculate their BMI. On the basis of the results, the patients were divided into two groups: Group 1: BMI?<25?kg/m² and Group 2: BMI?≥25 kg/m². Of the 208 cycles, 137 were from patients with BMI?<25?kg/m² and 71 cycles from patients with BMI?≥25?kg/m². Patients' ages and the number of cycles with gonadotrophin-releasing hormone agonist and antagonist were similar in both groups. The doses of follicle-stimulating hormone used for ovarian induction per cycle, the number of retrieved oocytes, fertilisation rate, embryo quality and number of transferred and frozen embryos, the hyperstimulation, pregnancy rates, miscarriage rate and live birth rates showed no statistically significant differences. BMI does not appear to be a good parameter for the definition of IVF success. The association with other methodologies may produce more consistent data about body composition and its impact on fertility.     

The treatment of luteal phase defects with pulsatile infusion of gonadotropin-releasing hormone

Because pulsatile administration of gonadotropin-releasing hormone (GnRH) can initiate normal follicular maturation and corpus luteum function in women with hypothalamic amenorrhea, the authors attempted to treat five women with inadequate and one with short luteal phase with GnRH therapy. Pulsatile administration of GnRH (5 micrograms intravenously every 90 minutes) was begun on days 1 to 4 and continued throughout the cycle. Blood levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, and progesterone were monitored daily throughout the control and treatment cycles. There were 12 GnRH treatment cycles, all of them ovulatory. The length of the induced luteal phases varied from 11 to 17 days in all patients. Mean progesterone levels during GnRH treatment were significantly increased over those of the matched control cycles (control cycle 3.5 +/- 0.5 ng/ml; treatment cycle 8.2 +/- 1.45 ng/ml [mean +/- standard error]). Endometrial biopsies obtained during the luteal phase (days 25 to 27) in five women were in phase during the GnRH treatment cycle, in contrast to the control cycle in which they were two or more days out of phase. One patient achieved pregnancy during the treatment cycle, but aborted spontaneously at 8 1/2 weeks. The data demonstrate that pulsatile GnRH infusion, when initiated in the early follicular phase, can restore normal corpus luteum function in women with luteal phase defects.     

Role of dehydroepiandrosterone sulfate as a prehormone for ovarian steroidogenesis

The endocrine effects of induction of ovulation with menotropins were studied in 43 patients: 11 with hypothalamic amenorrhea and 32 with the polycystic ovary syndrome. Patients with polycystic ovary syndrome had higher base-line values of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-estradiol, dehydroepiandrosterone sulfate, testosterone, and a higher testosterone-free index than those with hypothalamic amenorrhea. During treatment with menotropins, patients with polycystic ovary syndrome had higher values of serum LH, prolactin, dehydroepiandrosterone sulfate, testosterone, percent free testosterone, testosterone-free index, and body weight than those with hypothalamic amenorrhea; serum FSH, dose of menotropins per kilogram body weight, and total follicular volume were higher in patients with hypothalamic amenorrhea than in those with polycystic ovary syndrome. Multiple linear regression after log transformation demonstrated that the testosterone-free index was predicted statistically by total ovarian volume and dehydroepiandrosterone sulfate and that serum 17 beta-estradiol was predicted statistically by total ovarian volume and testosterone-free index. Adding dexamethasone to menotropins in six patients with polycystic ovary syndrome produced significant decreases in 17 beta-estradiol, dehydroepiandrosterone sulfate, testosterone, and testosterone-free index. Higher concentrations of endogenous serum LH and dehydroepiandrosterone sulfate in patients with polycystic ovary syndrome in comparison with those with hypothalamic amenorrhea were associated with higher concentrations of serum testosterone, a lower total follicular volume, and an effective response to menotropins at a lower serum FSH and a lower dose of menotropins per kilogram body weight. These data suggest that serum dehydroepiandrosterone sulfate may be a precursor for ovarian steroidogenesis.     

Effects of low day 3 luteinizing hormone levels on in vitro fertilization treatment outcome.

In a previous study we demonstrated that women with day 3 luteinizing hormone (LH) values < 3 IU/l subjected to controlled ovarian hyperstimulation without pituitary desensitization responded with a lower number of follicles > 15 mm compared to women with a higher basal LH level. The aim of this study was to determine whether in patients with day 3 LH levels < 3 IU/l a further reduction of serum LH concentration by gonadotropin-releasing hormone (GnRH) analog impairs follicular response to follicle stimulating hormone (FSH) and treatment outcome in in vitro fertilization (IVF) cycles. For this purpose we retrospectively studied 249 consecutive women subjected to standard IVF treatment employing pituitary desensitization with buserelin and follicular stimulation with urinary highly purified FSH. The patients were divided into two groups according to their day 3 LH value. The first group (group A) showed day 3 LH levels < 3 IU/l and the second (group B) had day 3 LH levels > 3 IU/l. Group A and B patients did not show statistically significant differences in the ovarian response to FSH, nor in IVF treatment outcome, showing that in FSH treated GnRH analog suppressed cycles, the ovarian responsiveness and IVF outcome do not differ according to basal LH values. However, the high dosage of FSH we employed in group A and B patients could account, at least in part, for this result. Indeed, comparative evaluations with unsuppressed cycles (our previous study) strongly suggest that a reduced ovarian responsiveness to gonadotropins in patients with day 3 LH values < 3 IU/l should be considered in clinical practice.     

Growth hormone deficiency as the only identifiable cause for primary amenorrhea

Background: There is much evidence that growth hormone plays an important role in the development and function of the reproductive system of both males and females. Growth hormone exerts its effects on the ovarian follicular cycle directly or by local production of insulin-like growth factor 1 (IGF-1). It is known that growth hormone deficiency during childhood may delay pubertal development, but there is limited data about primary amenorrhea in GH-deficient girls with sufficient stimulated gonadotropin levels.Methods: Case series.Results: In the evaluation of primary amenorrhea and delayed puberty, 3 cases of adolescent females aged 17-19 years were identified as isolated GH-deficiency. Among the 3 patients, 2 had history of intracranial surgery due to hydrocephalus (shunt operation) or prolactin-secreting pituitary macro-adenoma (transphenoidal surgery, one year before). 17-year-old patient with shunted hydrocephalus and 19-year-old patient with primary amenorrhea showed short statue (< 5%) and delayed bone maturation. The patient undertaken transphenoidal surgery for prolactinoma showed normal height and bone maturation. There was no familial history of delayed puberty. On physical examination, 3 patients showed variable degree of breast development from Tanner stage II to IV without sex-steroid replacement. In sella MRI, small pituitary gland were identified in 2 patients with short statue and delayed bone maturation. All of the 3 patients underwent combined pituitary function test. After insulin-induced hypoglycemia, peak growth hormone levels of the 3 patients were 0.08, 1.4 and 1.4 ng/ml and were compatible with growth hormone deficiency. Peak LH after intravenous gonadrelin (FACTREL) were 19.0 to 56.1 mIU/ml and LH % responses were 217 to 1100% and were hence defined as not being gonadotropin deficiency. Other anterior pituitary functions were normal in all of the 3 patients.Conclusions: We found isolated growth hormone deficiency as the only identifiable cause for primary amenorrhea in three patients with sufficient gonadotropins secretion. These findings suggest a complementary role of GH to gonadotropins in the occurrence of menarche.     

Effects of gonadotropin-releasing hormone (GnRH) agonist on pituitary and ovarian responses to pulsatile GnRH therapy in polycystic ovarian disease

Nine clomiphene citrate-resistant polycystic ovarian disease (PCOD) patients received intravenous gonadotropin-releasing hormone (GnRH) pulses before and immediately after 1 month of GnRH agonist (GnRH-a) therapy. Circulating gonadotropin and ovarian steroid levels, as well as follicular development, were measured throughout therapy. Results were compared with those obtained from five hypogonadotropic patients treated with GnRH pulses only who ovulated during six of seven treatment cycles. Only two PCOD patients ovulated normally with GnRH pulses before GnRH-a therapy. Aberrant gonadotropin and ovarian steroid secretory patterns were noted in the others. After GnRH-a, gonadotropin and ovarian steroid hormone levels were similar to those of the hypogonadotropic patients. Subsequent secretory responses to GnRH pulses were partially normalized. However, only two additional PCOD patients ovulated.     

A study of postpill amenorrhea

Levels of follicle-stimulating hormone, luteinizing hormone and prolactin were evaluated in 52 cases of postpill amenorrhea at the Institute of Post Graduate Medical Education and Research, Calcutta, India. All 52 patients had experienced amenorrhea for one year since discontinuation of oral contraceptive therapy. The incidence of postpill amenorrhea was much higher in patients with histories of oligomenorrhea or irregular menstrual periods. No relationship was seen between the number of cycles of pills used and the incidence of postpill amenorrhea. The ratio of luteinizing hormone to follicle-stimulating hormone in all cases exceeded unity, indicating that postpill amenorrhea is a type of functional secondary amenorrhea.     

Phase II study of high-dose cisplatin, etoposide, and cyclophosphamide for refractory ovarian cancer

OBJECTIVES: A phase II trial of high-dose cyclophosphamide, etoposide, and cisplatin was done. STUDY DESIGN: Forty-eight patients with progressive or persistent disease and previous cisplatin-based chemotherapy and no paclitaxel therapy were entered for treatment on the basis of two cycles of cyclophosphamide (4500 mg/m²), etoposide (750 mg/m²), and cisplatin (120 mg/m²). RESULT: Seventy-four cycles were delivered. Six patients died during treatment (12.5%). Of 28 with measurable disease, there was a 25% response rate and 32% had stable disease. Median time to recurrence and survival were significantly different for minimal versus bulky disease (p = 0.0089, p = 0.0008, log-rank) and for platinum-sensitive versus platinum-resistant disease (p = 0.18, p = 0.0012, log-rank). The number of prior regimens was not correlated with time to progression or survival. CONCLUSION: This study shows little advantage for high-dose protocols except for patients with a response to platinating agents and minimal residual disease. (Am J Obstet Gynecol 1996;174:1688-94.)