L. Michael Kettel

Treatment of endometriosis with the antiprogesterone mifepristone (RU486)

OBJECTIVEnTo evaluate the safety and efficacy of an antiprogesterone (mifepristone, RU486; Roussel-Uclaf, Romaineville, France) on endometriosis.nnnDESIGNnAn open, prospective clinical trial.nnnSETTINGnThe clinical practice of an academic faculty.nnnPATIENTSnNine women with endometriosis were studied.nnnINTERVENTIONSnRU486 (50 mg/d) was administered for 6 months.nnnMAIN OUTCOME MEASURESnDaily symptom inventories and urinary steroid metabolites were assessed before, during, and after treatment. Blood for hormone analysis was obtained weekly for 4 weeks and monthly thereafter. The extent of endometriosis, bone mineral density, circadian rhythm of cortisol, and LH pulsatility were determined before and after treatment. Safety laboratory measurements were made before and at 1, 2, and 6 months of treatment.nnnRESULTSnPelvic pain and uterine cramping improved in all patients. Endometriosis regressed by 55%. All patients exhibited endocrine features of anovulatory amenorrhea without hypoestrogenism. A rise in serum LH and T levels was observed during the first month of treatment and one patient developed an elevation of liver transaminases during the last month of treatment. All other measurements were unchanged.nnnCONCLUSIONnRU486 appears to be effective in improving the symptoms and causing regression of endometriosis in the absence of significant side effects.

Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis

OBJECTIVEnTo examine endocrine and clinical responses to long-term administration of RU486 in patients with endometriosis.nnnDESIGNnProspective open trial.nnnSETTINGnFaculty practice of the authors.nnnPATIENTS, PARTICIPANTSnSix normally cycling women with endometriosis were recruited.nnnINTERVENTIONSnSubjects received RU486 100 mg/d for 3 months.nnnMAIN OUTCOME MEASURE(S)nHormonal changes during RU486 were compared with control data obtained in the preceding cycle during the early follicular phase. Clinical responses were determined by patient assessment and second-look laparoscopy.nnnRESULTSnAll women became amenorrheic, and daily urinary levels of ovarian steroid metabolites remained acyclic. Mean luteinizing hormone (LH) (P less than 0.02) and LH pulse amplitude (P less than 0.05) were increased without changes in LH pulse frequency. An antiglucocorticoid effect was demonstrated by an increase in serum cortisol (P less than 0.01) and adrenocorticotropic hormone (P less than 0.05) levels. Treatment resulted in an improvement in pelvic pain in all subjects without significant change in the extent of disease as evaluated by follow-up laparoscopy.nnnCONCLUSIONSnDaily administration of RU486 results in acyclic ovarian function and improvement in the subjective painful symptoms of endometriosis.

Expanded polytetrafluoroethylene (Gore-Tex Surgical Membrane) is superior to oxidized regenerated cellulose (Interceed TC7 ) in preventing adhesions

OBJECTIVEnTo compare the impact of expanded polytetrafluoroethylene (PTFE; Gore-Tex Surgical Membrane; W. L. Gore & Associates, Inc., Flagstaff, AZ) and oxidized regenerated cellulose (Interceed TC7, Johnson & Johnson Medical, Inc., Arlington, TX) on the development of postsurgical adhesions.nnnDESIGNnA multicenter, nonblinded, randomized clinical trial.nnnSETTINGnUniversity medical centers.nnnINTERVENTIONSnEach barrier was allocated randomly to the left or right sidewall of every patient.nnnPATIENTSnThirty-two women with bilateral pelvic sidewall adhesions undergoing reconstructive surgery and second-look laparoscopy.nnnMAIN OUTCOME MEASURESnAdhesion score (on a 0- to 11-point scale), the area of adhesion (cm2), and the likelihood of no adhesions.nnnRESULTSnThe use of both barriers was associated with a lower adhesion score and area of adhesion postoperatively. However, those sidewalls covered with PTFE had a significantly lower adhesion score (0.97 +/- 0.30 versus 4.76 +/- 0.61 points, mean +/- SEM) and area of adhesion (0.95 +/- 0.35 versus 3.25 +/- 0.62 cm2). Overall, more sidewalls covered with PTFE had no adhesions (21 versus 7) and, when adhesions were present on the contralateral sidewall, the number of sidewalls covered with PTFE without adhesions was greater than those covered with oxidized regenerated cellulose (16 versus 2).nnnCONCLUSIONnExpanded polytetrafluoroethylene was associated with fewer postsurgical adhesions to the pelvic sidewall than oxidized regenerated cellulose.

Rapid regression of uterine leiomyomas in response to daily administration of gonadotropin-releasing hormone antagonist * †

Objective The efficacy of acute and sustained pituitary gonadotropin down-regulation by the Nal-Glu GnRH antagonist (Nal-Glu) was evaluated in the treatment of uterine leiomyomas. Design Prospective, open clinical trial. Patients Seven normally cycling women with symptomatic leiomyomas. Interventions Nal-Glu (50 μ g/kg per day) was administered subcutaneously for 3 months. Main Outcome Measures Baseline ultrasound examinations were obtained and repeated monthly throughout treatment. Each leiomyoma was mapped and measured in three dimensions. Blood samples were drawn daily for 7 days, weekly for 4 weeks, and monthly for the remaining 2 months. Results Mean leiomyoma size decreased 52.8 ± 7.3% (means ± SD) after 1 month of therapy and remained unchanged for the remainder of the study. Serum levels of E 2 (35.9 ± 11.8 to 9.3 ± 0.8 pg/mL, 131.7 ± 43.3 to 34.0 ± 1.4 pmol/L), estrone (37.3 ± 7.5 to 13.0 ± 2.5 pg/mL, 138.1 ± 27.7 to 48.1 ±9.1 pmol/L), and P (1.6 ± 1.1 to 0.3 ± 0.01 ng/mL, 5.0 ± 3.6 to 0.9 ± 0.04 nmol/L) declined rapidly (within 48 hours) and remained suppressed throughout treatment. Serum LH, FSH, andro-stenedione, T, and DHEA levels did not change significantly. In two subjects who did not have surgical removal, leiomyomas grew to original size within the 1st month off drug. Six patients remained amenorrheic and the other subject spotted during the last 2 months of therapy. Conclusions Continuous treatment with Nal-Glu induces immediate and sustained pituitary-gonadal down-regulation that results in regression in leiomyoma size. By circumventing GnRH agonist-induced pituitary-ovarian up-regulation, GnRH antagonists may prove to be superior tools in the medical management of leiomyomas.

Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome * †

OBJECTIVEnTo examine the hypothalamic-pituitary sites of clomiphene citrate (CC) action in women with polycystic ovarian syndrome (PCOS).nnnDESIGNnProspective controlled trial.nnnPATIENTS, PARTICIPANTSnSeventeen women with PCOS and 9 normal-cycling women.nnnINTERVENTIONSnSubjects with PCOS received CC, 150 mg/d for 5 days.nnnMAIN OUTCOME MEASURESnFollicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and LH pulse characteristics and their response to gonadotropin-releasing hormone (GnRH, 10 micrograms) were examined before and after 3 days of CC in PCOS subjects during a 12-hour frequent sampling study (n = 8). Daily urinary estrone glucuronide and pregnanediol glucuronide levels after CC were compared with concentrations in normal-cycling women through one menstrual cycle. In another nine PCOS subjects, pituitary and ovarian hormonal cyclicity was monitored by daily blood sampling.nnnRESULTSnThirteen of 17 treated cycles were ovulatory with normal luteal phases. In the ovulatory cycles, serum LH, FSH, estradiol (E2), and estrone levels increased after CC. Luteinizing hormone pulse frequency was unchanged, but LH pulse amplitude increased significantly after CC. Both LH and FSH response to exogenous GnRH was significantly attenuated after CC treatment. In anovulatory cycles, serum LH, FSH, and E2 increased initially and then returned to baseline and remained unchanged for the ensuring 40 days.nnnCONCLUSIONSnClomiphene citrate-induced ovulation in women with PCOS is accompanied by increased secretion of LH and FSH with enhanced estrogen secretion. The increased LH pulse amplitude after CC, together with decreased pituitary sensitivity to GnRH, suggests a hypothalamic effect.

Circulating levels of follistatin from puberty to menopause.

OBJECTIVEnTo determine the changes in circulating levels of follistatin, a binding protein for activin and inhibin, through the reproductive life cycle in women.nnnDESIGNnAn open, prospective descriptive study.nnnSETTINGnAn academic endocrine research unit.nnnPATIENTSnPrepubertal (n = 10), midpubertal (n = 7), and postpubertal (n = 25) (early adolescent) girls, normal cycling adult women (n = 8), postmenopausal women (n = 17), and men (n = 13) were studied.nnnINTERVENTIONSnNormal cycling women were given Nal-Glu GnRH antagonist for 3 days in the follicular phase of the cycle.nnnMAIN OUTCOME MEASUREnSerum concentrations of follistatin determined in a heterologous RIA.nnnRESULTSnMean follistatin levels did not change during puberty but were higher in adult and postmenopausal women. Levels of immunoreactive follistatin in men were lower than levels found in normal cycling women and postmenopausal women. Daily immunoreactive follistatin levels during the menstrual cycle remained constant and did not change significantly after ovarian suppression with GnRH antagonist.nnnCONCLUSIONnBecause dynamic changes of serum immunoreactive follistatin do not occur during ovarian activation (puberty), suppression, and age-related ovarian failure, the increase in immunoreactive follistatin levels in adult and postmenopausal women may implicate sources of follistatin other than the ovary.

Clinical efficacy of highly purified urinary FSH versus recombinant FSH in volunteers undergoing controlled ovarian stimulation for in vitro fertilization: a randomized, multicenter, investigator-blind trial

OBJECTIVEnTo compare the efficacy of highly purified human urinary follicle stimulating hormone (HP-hFSH) versus human recombinant follitropin-alpha (rFSH) in volunteers undergoing controlled ovarian stimulation for IVF.nnnDESIGNnA randomized, controlled, investigator-blind trial.nnnSETTINGnFour assisted reproductive technology centers.nnnPATIENT(S)nOne hundred fifty-two IVF patients.nnnINTERVENTION(S)nVolunteers, aged 18-39, were randomized to HP-hFSH (n = 76) versus rFSH (n = 76) at a starting dose of 300 IU in down-regulated cycles.nnnMAIN OUTCOME MEASURE(S)nNumber of oocytes, clinical pregnancy rate, and live birth rate with HP-hFSH versus rFSH.nnnRESULT(S)nThe total IU of gonadotropin used did not differ between the two groups. There was no difference in number of oocytes retrieved with HP-hFSH (mean = 16.3) compared with rFSH (mean = 17.1), confidence interval (CI) of difference = -3.79 to +2.18. Clinical pregnancy rate, as defined by the presence of a gestational sac, was 48.7% (CI = 37.0%-60.4%) with HP-hFSH versus 44.7% (CI = 33.3%-56.6%) with rFSH (CI of difference = -11.9% to +19.8%). Live birth rate was 38.2% (29 of 76) in both groups (CI = 27.2%-50.0%), for a difference between groups of 0.0% (CI of the difference = -15.4% to +15.4%).nnnCONCLUSION(S)nThere were no statistically significant differences in mean oocyte number, clinical pregnancy rate, or live birth rate between HP-hFSH versus rFSH.

Accelerated dissolution of luteal-endometrial integrity by the administration of antagonists of gonadotropin-releasing hormone and progesterone to late-luteal phase women.

Sequential blockade of gonadotropin-releasing hormone (GnRH) and progesterone (P) receptors by potent antagonists (Nal-Glu GnRH antagonist and RU486) was conducted in late-luteal phase women to develop a once-a-month birth control method by timed advancement of ongoing luteolysis and endometriolysis. Hormonal dynamics and timing of uterine bleeding during the antagonists imposed luteal-follicular transition were compared with spontaneous (1st to 2nd) and recovery (2nd to 3rd) cycles in 10 normally cycling women. Serum luteinizing hormone (LH) and follicle-stimulating hormone levels declined (47 +/- 4.3% and 24 +/- 3.0%, respectively) by 24 hours after Nal-Glu injection, which accelerated the ongoing luteolytic process, as evidenced by more rapid declines of serum concentrations of estradiol, P, and ir-inhibin, as compared with the corresponding control cycle. This was accompanied by the prompt (16 +/- 3.2 hours after RU486) onset of a single episode of uterine bleeding, which was advanced by 2 days. Whereas the luteal phase length was foreshortened by 2 days, the subsequent follicular phase duration was prolonged by 2 days with a normal sequence of follicular maturation, LH surge, and luteal function during the recovery cycle. We conclude that the late-luteal sequential administration of antagonists of GnRH and P resulted in acceleration of the ongoing luteolytic and endometriolytic processes without functional alterations of the subsequent cycle.

Precision of progesterone measurements with the use of automated immunoassay analyzers and the impact on clinical decisions for in vitro fertilization

OBJECTIVEnTo compare the precision of progesterone measurements obtained with the use of immunoassays and of liquid chromatography-tandem mass spectrometry (LC-MS/MS).nnnDESIGNnComparative study.nnnSETTINGnAcademic, private practice, and in vitro fertilization (IVF) research centers.nnnPATIENT(S)nA total of 189 human serum samples were collected during controlled ovarian hyperstimulation and early pregnancy in women undergoing IVF.nnnINTERVENTION(S)nSerum progesterone pools (n = 10; 0.2-4 ng/mL) were sent to four laboratory centers that used four different automated immunoassay analyzers. Progesterone was measured by immunoassay in triplicate at three separate time points (n = 9 per pool) and by LC-MS/MS in triplicate once (n = 3 per pool).nnnMAIN OUTCOME MEASURE(S)nInter- and intraassay coefficients of variation (CVs) of progesterone measurements were compared for each analyzer and LC-MS/MS.nnnRESULT(S)nProgesterone measurements by immunoassay were highly correlated with those by LC-MS/MS. Only two analyzers had intraassay CVs <10% at all three experimental time points, and only two analyzers had an interassay CV <10%. Mean progesterone levels by the analyzers were different across multiple progesterone pools.nnnCONCLUSION(S)nOur results indicate that progesterone threshold measurements used for IVF clinical decisions should be interpreted cautiously and based on laboratory- and method-specific data. A validated progesterone standard incorporated into daily immunoassays could improve medical decision accuracy.

Rapid Regression of Uterine Leiomyomas in Response to Daily Administration of Gonadotropin-Releasing Hormone Antagonist

OBJECTIVEnThe efficacy of acute and sustained pituitary gonadotropin down-regulation by the Nal-Glu GnRH antagonist (Nal-Glu) was evaluated in the treatment of uterine leiomyomas.nnnDESIGNnProspective, open clinical trial.nnnPATIENTSnSeven normally cycling women with symptomatic leiomyomas.nnnINTERVENTIONSnNal-Glu (50 micrograms/kg per day) was administered subcutaneously for 3 months.nnnMAIN OUTCOME MEASURESnBaseline ultrasound examinations were obtained and repeated monthly throughout treatment. Each leiomyoma was mapped and measured in three dimensions. Blood samples were drawn daily for 7 days, weekly for 4 weeks, and monthly for the remaining 2 months.nnnRESULTSnMean leiomyoma size decreased 52.8 +/- 7.3% (means +/- SD) after 1 month of therapy and remained unchanged for the remainder of the study. Serum levels of E2 (35.9 +/- 11.8 to 9.3 +/- 0.8 pg/mL, 131.7 +/- 43.3 to 34.0 +/- 1.4 pmol/L), estrone (37.3 +/- 7.5 to 13.0 +/- 2.5 pg/mL, 138.1 +/- 27.7 to 48.1 +/- 9.1 pmol/L), and P (1.6 +/- 1.1 to 0.3 +/- 0.01 ng/mL, 5.0 +/- 3.6 to 0.9 +/- 0.04 nmol/L) declined rapidly (within 48 hours) and remained suppressed throughout treatment. Serum LH, FSH, androstenedione, T, and DHEA levels did not change significantly. In two subjects who did not have surgical removal, leiomyomas grew to original size within the 1st month off drug. Six patients remained amenorrheic and the other subject spotted during the last 2 months of therapy.nnnCONCLUSIONSnContinuous treatment with Nal-Glu induces immediate and sustained pituitary-gonadal down-regulation that results in regression in leiomyoma size. By circumventing GnRH agonist-induced pituitary-ovarian up-regulation, GnRH antagonists may prove to be superior tools in the medical management of leiomyomas.