Comparison of pharmacokinetics of a conjugated equine estrogen preparation (premarin) and a synthetic mixture of estrogens (C.E.S.) in postmenopausal women.

OBJECTIVE: To compare the pharmacokinetics and relative bioavailabilities of key estrogen components of Premarin (Wyeth-Ayerst, Canada) with those of a generic conjugated estrogen preparation, C.E.S. (synthetic mixture of estrogens; ICN, Montreal, Canada) in healthy postmenopausal women. METHODS: We conducted a randomized, single-dose, two-treatment, three-period crossover study in 41 postmenopausal women. After an oral dose (2 x 0.625 mg) of Premarin or C.E.S., plasma concentrations of unconjugated and total estrone (E(1)), equilin (Eq), 17beta-estradiol (17beta-E(2)), 17beta-dihydroequilin (17beta-Eq), Delta(8)-esterone (Delta(8)-E(1)) and Delta(8),17beta-estradiol (Delta(8),17beta-E(2)) were measured over 72 hours using gas chromatography and mass spectroscopy. RESULTS: After administration of C.E.S., E(1), Eq, and 17beta-Eq appeared in blood at a significantly faster rate (lower t(max)) than after Premarin. The rapid appearance of estrogens after C.E.S. was associated with significantly higher (14-61%) C(max) values. In contrast to the high C(max) values, the area under the curve (AUC)(infinity) of unconjugated and total Eq, and 17beta-Eq were significantly lower after C.E.S., whereas those of E(1) were significantly higher. Although, the t(max) values for 17beta-E(2) were lower and the C(max) values higher after C.E.S., only the C(max) of unconjugated 17beta-E(2) was significantly different after Premarin. Unconjugated and total Delta(8)-E(1) and its main metabolite, Delta(8),17beta-E(2), were detectable in plasma only after administration of Premarin. The geometric mean ratio (GMR) (C. E.S./Premarin) of bioavailability parameters indicated that all C(max) and t(max) values for the unconjugated and total E(1), Eq, 17beta-E(2), and 17beta-Eq fell outside the regulatory requirement that the 90% confidence intervals of GMRs of two products be within 80% and 125%. Similarly, with the exception of total E(1) and total Eq, none of the AUC(t) or AUC(alpha) of the remaining estrogens meets the required regulatory standards of bioequivalence. CONCLUSIONS: C.E.S. is not bioequivalent to Premarin. Because C.E.S. also is not pharmaceutically equivalent to Premarin, it cannot be assumed to be therapeutically equivalent. Until long-term clinical trials with C.E.S. demonstrate its efficacy, extrapolation of the long-term benefits described for Premarin to C.E.S. would be risky and questionable.

Impact on postmenopausal symptoms of adding continuous C-21 versus C-19 progestin to estrogen.

OBJECTIVE: To compare the effects of (i) continuous low dosage C-19 progestin (dl-norgestrel, NG) plus cyclical conjugated estrogen (CEE) versus (ii) continuous low dosage C-21 progestin [medroxyprogesterone acetate (MPA)] plus CEE on postmenopausal vaginal bleeding, mood and somatic, psychosomatic and psychological symptoms. METHODS: Nine hypercholesterolemic postmenopausal women with intact uteri were randomly assigned in a prospective, double-blind, two-period cross-over study of CEE (25/28 days) plus either (i) NG, (0.05 mg/day) or (ii) MPA (2.5 mg/day) for 1 year and after an appropriate wash-out period were switched to the alternative regimen for another year. Four hysterectomized control subjects received the CEE only. RESULTS: Administration of CEE + MPA versus CEE + NG resulted in a significantly higher percent of cycles which were free of vaginal bleeding (97 vs 85%), spotting (92 vs 79%) and either spotting or bleeding (92 vs 76%, P < 0.01). All three regimens significantly reduced the overall combined scores for postmenopausal somatic, psychosomatic and psychological symptoms (P < 0.05). CONCLUSIONS: Vaginal bleeding and/or spotting were significantly less frequent with CEE + MPA versus CEE + NG. However, each of the three hormonal regimens improved mood and significantly reduced postmenopausal symptoms in comparison to untreated control values.

Effects of adding C-19 versus C-21 progestin to conjugated estrogen in moderately hypercholesterolemic postmenopausal women.

OBJECTIVE: Our purpose was to compare the effects on fasting plasma lipoprotein lipids of adding low dosage C-19 continuous progestin (dl-norgestrel) versus conventional low-dosage continuous C-21 progestin (medroxyprogesterone acetate) to cyclic conjugated estrogen therapy. STUDY DESIGN: Nine hypercholesterolemic postmenopausal women with intact uteri were randomly assigned in a prospective, double-blind, two-period crossover study of conjugated estrogen plus either (1) dl-norgestrel (0.05 mg/day) or (2) medroxyprogesterone acetate (2.5 mg/day) for 1 year and after an appropriate washout period were switched to the alternative regimen for another year. Four subjects received conjugated estrogen only. RESULTS: Compared with baselines, each of the C-19 and C-21 progestin regimens significantly increased plasma high-density lipoprotein cholesterol (15% vs 12%) and reduced the ratio of total cholesterol/high-density lipoprotein cholesterol (20% vs 15%, respectively), but only the former significantly reduced plasma triglycerides (24% vs 0.3%, p < 0.05). CONCLUSIONS: Low dosages of either dl-norgestrel (C-19) or medroxyprogesterone acetate (C-21) when combined with conjugated estrogen significantly improve plasma lipoprotein lipids of postmenopausal women.

In quest of the perfect analogy for using in vitro fertilization patients as oocyte donors.

Whether painted in totalitarian terror, like the organ farm story and The Handmaid's Tale, the science-fiction reality of Make Room! Make Room!, the cinema noir urban tragedy of prostitution, or the portrayals of slavery (Afro-American, Nazi-European, and Russian), this series of resemblances, I hope, illustrates the power of analogy to surface sensitivity to ethical issues in the efficient, and possibly entertaining, texture demanded by medical personnel. Although my quest was quixotic from the start, I hope that this exercise will encourage your consideration of using analogy as an educational tool to heighten the awareness in medical personnel to many issues, to allow our better service of patients and society.

The yellow brick road of medical education.

From the time the medical school's acceptance letter is opened, students eagerly set off on the yellow brick road in pursuit of the attributes of the good physician: intelligence, compassion and courage. The students already possess these traits, just as the Scarecrow, Tin Man and Lion did before they set out for Oz, but they may dissolve in education systems that still decree that the initiation to medicine involve tonnes of tutored words and consuming call schedules.

Future in vitro fertilization pregnancy potential of women with variably elevated day 3 follicle-stimulating hormone levels.

OBJECTIVE: To determine the IVF-ET pregnancy potential of women with variably elevated day 3 FSH. DESIGN: Cohort evaluation of 1,868 consecutive IVF-ET cycles January 1991 to December 1994. SETTING: University hospital infertility unit. PATIENTS: Four cohorts of couples were defined based on day 3 FSH determinations with an arbitrary threshold of 20 mIU/mL, only > or = 20 mIU/mL, always < 20 mIU/mL, current < 20 mIU/mL but one previous > or = 20 mIU/mL, and current < 20 mIU/mL but two or more previous > or = 20 mIU/mL (conversion factor to SI unit, 1.00). INTERVENTION: In vitro fertilization-embryo transfer. MAIN OUTCOME MEASURE: Fetal heart activity on luteal day 40 transvaginal ultrasound. RESULTS: No pregnancies occurred in 53 cycles with day 3 FSH only > or = 20 mIU/mL. In 1,750 women whose day 3 FSH levels were always < 20 mIU/mL, the pregnancy rate (PR) per cycle was 16.5%. In 54 cycles in which day 3 FSH was > or = 20 one time only, but < 20 mIU/mL during the treatment cycle, the PR was 5.6%. In 11 cycles where two or more previous FSH determinations were > or = 20 mIU/mL but with a current day 3 FSH < 20 mIU/mL, no pregnancies occurred. CONCLUSION: Our data leads us to the conclusion that day 3 FSH determination precede every IVF cycle and that cycles with FSH > or = 20 mIU/mL be canceled. It also suggests that women with two previous elevations of day 3 FSH be discouraged from future IVF cycles. The 5.6% pregnancy per cycle with one previously elevated FSH warrants extreme pessimism in discussion of further cycles.

Novel low-dosage hormonal replacement therapy complements dietary treatment of moderately hypercholesterolemic postmenopausal women.

It is not known whether female hormonal replacement therapy (HRT) influences fasting plasma lipoprotein lipids in diet-treated hypercholesterolemic subjects. Thirteen moderately hypercholesterolemic postmenopausal women were studied during dietary treatment alone with a low fat, low cholesterol diet for the 3 months and during the subsequent 2 y of HRT with dl-norgestrel (0.075 mg daily) and estradiol-17 beta (1 mg, 25 of 28 days) with maintenance of the same diet. Hormonal replacement therapy decreased plasma total cholesterol by 11 +/- 3% (5.7 vs. 6.4 mmol/L, p < 0.005), due to a 17 +/- 3% mean reduction (p < 0.001) in the concentration of plasma low density lipoprotein cholesterol (3.9 vs. 4.7 mmol/L, p < 0.001). The ratio of plasma total cholesterol to high density lipoprotein cholesterol fell significantly by 17 +/- 4% (4.1 vs. 4.9, p < 0.005). Mean fasting plasma concentrations of total triglycerides (1.1 vs. 1.6 mmol/L, p < 0.005) fell by 31 +/- 6%, and very low density lipoprotein triglycerides (0.56 vs. 0.83 mmol/L, p < 0.02) by 33 +/- 9%. Hormonal replacement therapy was well-tolerated, improved mood levels, and increased the mineral content of the vertebral spine significantly, while effectively relieving vasomotor flushing. Hormonal replacement therapy complements the dietary treatment of hypercholesterolemia.

The pregnancy rates of cohorts of idiopathic infertility couples gives insights into the underlying mechanism of infertility.

OBJECTIVES: To determine causes of "idiopathic" infertility, the IVF-ET experience of three cohorts of couples with this diagnosis was examined. DESIGN: Three cohorts of idiopathic infertility couples undergoing IVF-ET: a "failed IUI" group, three previous controlled ovarian hyperstimulation (COH)-IUI cycles with no pregnancies; a "conversion" group, patients converted during a COH-IUI cycle to IVF-ET because of excess follicle numbers; and a "direct IVF" group, patients proceeding directly to IVF-ET were compared. SETTING: A tertiary referral reproductive medicine unit. PARTICIPANTS: Forty-one idiopathic infertility couples. INTERVENTION: In vitro fertilization-ET. MAIN OUTCOME MEASURES: Number of oocytes retrieved, percent oocytes fertilized, number embryos per ET, implantation rate, percent pregnancy per cycle. RESULTS: The cohorts had similar fertilization rates and mean (+/- SD) number of pre-embryos transferred. The conversion group demonstrated a higher pregnancy rate (PR) per cycle and a higher E2 concentration than the other groups. The PR of 35.0% in the direct IVF group appeared higher than the 16.7% rate observed in the failed IUI group. CONCLUSIONS: Our observation of a lower PR in couples in the failed IUI group (16.7%) than in couples in the direct IVF group (35.0%) suggests pre-embryo developmental problems or implantation problems as likely important etiologies for a large proportion of idiopathic infertility couples. However, as the conversion group demonstrated both a significantly higher E2 concentration ([E2]) and per cycle PR than the other cohorts with similar fertilization and pre-embryo transfer rates. Subjects converted in a COH-IUI cycle to IVF-ET are thus either more likely to produce pre-embryos more genetically capable of continued development to implantation stage (i.e., better oocytes recruited and fertilized) or due to the higher [E2] to have endometrium more receptive to implantation. Neither undiagnosed tubal factors nor fertilization problems appear to be major etiologic contributors.

Residents' attitudes to training in ethics in Canadian obstetrics and gynecology programs.

OBJECTIVE: To determine residents' attitudes toward their current training in ethics, including their preferred learning format, time commitment, and the influences of training and personal background on their views and decision-making process. METHOD: All 203 residents from English-speaking Canadian obstetrics and gynecology programs were mailed an 18-question, numerical-response questionnaire in prestamped return envelopes. One hundred thirty-one residents (64.5%) responded (81 to the first mailing and 50 to the second). RESULTS: The number of hours in the residency program devoted to ethical issues correlated positively with the residents' perception of the residency program in shaping their ethical views (P = .015, r = 0.22). Of the respondents, 44.7% preferred case presentations as their learning format and 30.7% ranked seminars as their first choice. Informal discussions and rounds were less popular, and lectures were considered least appropriate by 69.3%. When asked what most influenced the residents' ethical decision-making process, 34.2% indicated family views, 17.1% undergraduate teaching, 15.4% religious background, 12.8% views of consulting staff, 11.1% residency training, and 9.4% peer attitudes. Sixty-eight percent of residents felt that their training in ethics during their residency program should be increased; this may reflect response bias. A position of conscience conflict during residency training was reported by 28.9% of residents. CONCLUSION: Findings from this survey support the benefit of more discussion of ethical issues during residency programs, particularly with the use of case presentations.

Randomized trial of partial zona dissection for male infertility.

OBJECTIVES: To compare IVF rates using partial zona dissection versus zona intact insemination in couples with male infertility. To analyze pregnancy rates relative to sperm characteristics, fertilization rates, and treatment. DESIGN: Randomized prospective comparison of fertilization in sibling oocytes. Transfer of the three best quality embryos from one or both treatments. SETTING: Department of Gynaecology and Reproductive Medicine, University Hospital, London, Ontario, Canada. PARTICIPANTS: Thirty-two couples undergoing IVF with a principal diagnosis of male infertility. INTERVENTION: Treatment with partial zona dissection. MAIN OUTCOME MEASURES: Fertilization and pregnancy. RESULTS: Fertilization rates were 26% and 9% after partial zona dissection and IVF, respectively. Polyspermy was < 1% in each treatment. There were five singleton pregnancies in 29 completed cycles, three in cycles with fertilization only by partial zona dissection and two in cycles with both partial zona dissection and IVF fertilization. There were no pregnancies after fertilization by IVF only. Stepwise logistic regression analysis indicated that pregnancy was related to partial zona dissection, initial sperm concentration, and total acrosin activity. CONCLUSION: Partial zona dissection was associated with minimal polyspermic fertilization and higher normal fertilization rates than sibling oocytes treated by modified IVF. Pregnancy occurred only after transfer of embryos from partial zona dissection or combined partial zona dissection and IVF.

Nafarelin acetate for pituitary down-regulation in in vitro fertilization. Comparison of two dosages.

The objective of this study was to evaluate the efficacy of intranasal (IN) nafarelin acetate (NA), 400 micrograms/d and 600 micrograms/d, in a luteal-phase-start, long protocol in women undergoing their first in vitro fertilization (IVF) cycle. A sequential comparison of 200 consecutive first IVF cycles, the study was performed in the Department of Gynaecology and Reproductive Medicine, University Hospital, London, Ontario, Canada. The participants were 200 first-cycle IVF patients who were regularly cycling--100 NA 400 micrograms IN followed by 100 NA 600 micrograms IN. Eighty-two percent of the NA 400 micrograms group were adequately suppressed after 11 days of treatment (serum estradiol < or = 150 pmol/L) as compared to 87% with NA 600 micrograms/d. These results compare favorably with those in a historical control group of 179 subjects receiving daily leuprolide acetate (LA), 0.5 mg subcutaneously, in their first cycle of IVF. The amount of human menopausal gonadotropin required for optimal follicular development was similar for the two NA groups. Clinical pregnancy rates were 13% per cycle and 21.7% per embryo transfer (ET) for NA 400 micrograms od and 19% per cycle and 30.1%/ET for NA 600 micrograms od (normal standard dose). No spontaneous luteinizing hormone (LH) surges occurred in any subject. Patient counseling and instruction time for NA use, which required nursing time, averaged five minutes per patient and an additional five minutes of video-viewing time. NA, 400 micrograms and 600 micrograms per day, appear to be acceptable alternate choices for pituitary down-regulation in a luteal-phase-start, long down-regulation protocol for IVF.(ABSTRACT TRUNCATED AT 250 WORDS)

Confounding variables affecting in vitro fertilization success: a decade of experience.

PURPOSE: To evaluate etiology of infertility, female age, ovarian response and stimulation protocol in affecting in vitro fertilization (IVF) success. METHODS: Retrospective analysis was used. Computer records of all 5209 cycles initiated in 2391 couples from February 1, 1984 to December 31, 1993 were analyzed. RESULTS: There were 644 intrauterine, 24 solely ectopic and 7 heterotopic pregnancies. Pregnancy rates increased with number of embryos transferred with a significant increase still found between transfer of three or four embryos. Multiple gestations also increased in association with an increasing number of embryos transferred. Pregnancy rates per cycle did not decline with repeated cycles. Reduced pregnancy rates were associated with a primary diagnosis of male infertility. Covariates associated with a better pregnancy rate were younger age of the female partner or higher peak preovulatory serum estradiol. Routine administration of GnRH-agonist was associated with a reduced cycle cancellation rate, an increase in oocytes retrieved and an improved pregnancy rate. CONCLUSIONS: Couples with male infertility and increased female age should be counselled regarding the reduced prognosis for success.

Transferring more embryos increases risk of heterotopic pregnancy.

OBJECTIVES: To analyze symptoms and signs that may distinguish heterotopic pregnancy from solely ectopic pregnancy (EP) after IVF. To determine if the number of embryos transferred is a risk factor for heterotopic compared with solely EP. DESIGN: Retrospective cohort of 587 IVF pregnancies, 328 with distorted tubal anatomy. SETTING: University Hospital, London, a referral center for Ontario provincial government-supported assisted reproductive technologies. PARTICIPANTS: Couples undergoing IVF. INTERVENTION: None. MAIN OUTCOME MEASURES: Heterotopic pregnancy, solely EP, intrauterine pregnancy, and distorted pelvic anatomy. RESULTS: Of 587 pregnancies, 7 were heterotopic pregnancies and 24 were solely EP, all in the subset of 328 women with distorted tubal anatomy. Symptoms, signs and time of diagnosis were not different between heterotopic and solely ectopic gestations. Compared with solely EP, heterotopic pregnancies were associated with transfer of more embryos. With four or more embryos transferred, the odds ratio for development of heterotopic versus solely ectopic gestation was 10.0. CONCLUSION: Heterotopic pregnancy occurred in 2% of gestations after IVF, all in women with distorted tubal anatomy. Transfer of four or more embryos was a risk factor for heterotopic pregnancy.

Long-term gonadotropin-releasing hormone agonist with standard postmenopausal estrogen replacement failed to prevent vertebral bone loss in premenopausal women.

If indeed younger women do not receive bone protection from standard postmenopausal hormone replacement, these women may also be at increased risk for heart disease, urogenital atrophy, and other effects of long-term hypoestrogenism with 0.625 mg of CE add-back. We recommend that until long-term studies using BMD of the lumbar spine are available, 1.25 mg of CE or the equivalent dosage of other Es be prescribed when planning long-term GnRH-a ovarian suppression.

Risk of repeated spontaneous luteinizing hormone surges in ovarian stimulation for in vitro fertilization.

Although spontaneous luteinizing hormone (LH) surges are preventable with gonadotropin releasing hormone agonist (GnRH-a) inclusion in ovarian stimulation protocols, GnRH-a-containing protocols are more expensive and associated with an increased risk of ovarian hyper-stimulation syndrome. The present study assessed whether spontaneous LH surges occur in predictable patterns, allowing GnRH-a to be utilized selectively. We assessed 1,103 patients receiving clomiphene citrate/human menopausal gonadotropin (CC/hMG) without GnRH-a for their first in vitro fertilization (IVF) cycle and observed spontaneous LH surges in 30.4%. When patients who demonstrated a spontaneous LH surge received a second CC/hMG stimulation protocol, 45.9% surged again. Of those patients who did not demonstrate a spontaneous LH surge in their initial CC/hMG cycle, only 23.0%, significantly less (P < .001), surged in their second cycle. Of those patients who did not surge in their first two cycles, only 15.7% had an LH surge in their third cycle (P < .001). Thus, if all patients received CC/hMG without GnRH-a as their first IVF stimulation protocol, GnRH-a could be reserved for patients who have demonstrated a spontaneous LH surge. By tailoring the treatment plan, the pregnancy rate would be optimized while decreasing cycle cancellations due to spontaneous LH surges in those patients susceptible to LH surges and limiting costs and inconvenience for patients unlikely to surge spontaneously.

An aggressive philosophy in controlled ovarian stimulation cycles increases pregnancy rates.

To assess the effect of timing of human chorionic gonadotrophin (HCG) administration in ovarian stimulation cycles, the serum oestradiol concentration and follicle profile were compared with the clinical pregnancy rate in 582 ovarian stimulation-intra-uterine insemination (OS-IUI) cycles and 3917 in-vitro fertilization-embryo transfer (IVF-ET) cycles. The pregnancy rates increased exponentially with increasing oestradiol in both OS-IUI and IVF-ET cycles (R2 = 0.720, P < 0.001) but then decreased in OS-IUI cycles when the oestradiol concentration exceeded 5000 pmol/l (R2 = 0.936, P < 0.004) at HCG administration. In OS-IUI cycles the percentages of cycles with three or more mature follicles (> or = 18 mm diameter) increased up to an oestradiol concentration of 5000 pmol/l then declined, mirroring the pregnancy rate (R2 = 0.900, P = 0.01). The exponential increase in pregnancy rate with increasing oestradiol concentration in IVF-ET cycles suggests that high oestradiol concentration does not have a deleterious effect on endometrial receptivity. The decrease in pregnancy rate in OS-IUI cycles when oestradiol concentration exceeded 5000 pmol/l reflected fewer mature follicles, resulting from premature administration of HCG to avoid severe ovarian hyperstimulation syndrome (OHSS). We recommend that HCG administration be delayed until multiple follicles have reached maturity, and reducing the risk of severe OHSS by converting high risk OS-IUI cycles to IVF-ET, or if funds or facilities are unavailable, transvaginally draining all but four or five mature follicles.

Randomized, prospective comparison of luteal leuprolide acetate and gonadotropins versus clomiphene citrate and gonadotropins in 408 first cycles of in vitro fertilization.

OBJECTIVE: To compare luteal phase leuprolide acetate (LA) initiated pituitary down regulation followed by human menopausal gonadotropins (hMG) versus clomiphene citrate (CC) and hMG for follicular recruitment and oocyte maturation before in vitro fertilization (IVF). DESIGN: Randomized, prospective comparison in first cycles of IVF. SETTING: University Hospital, a tertiary referral center offering assisted reproductive technologies. PARTICIPANTS: Participants were couples undergoing their first ever cycle of IVF and consenting to participation in the trial. RESULTS: Luteal phase initiated LA/hMG was associated with a lower probability of cycle cancellation, improved folliculogenesis, and a higher probability of embryo transfer (ET) compared with CC/hMG alone. Implantation rates were not different. CONCLUSION: A higher rate of ET with LA/hMG suggests that gonadotropin-releasing hormone agonist for the induction of folliculogenesis before IVF may be appropriate.