Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone.

OBJECTIVE: To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Multicenter environment. PATIENT(S): Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC. INTERVENTION(S): Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC. MAIN OUTCOME MEASURE(S): Ovulation and pregnancy rates. RESULT(S): In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant. CONCLUSION(S): In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.

Raloxifene and estrogen effects on quality of life in healthy postmenopausal women: a placebo-controlled randomized trial.

OBJECTIVE: To assess the effects of raloxifene, estrogen, and placebo on quality of life in healthy, asymptomatic, postmenopausal women. METHODS: In a multicenter, double-blind, 12-month study, 398 women were assigned randomly to one of four groups: raloxifene HCl, 60 (n = 97) or 150 mg/day (n = 100); conjugated equine estrogens, 0. 625 mg/day (n = 96); or placebo (n = 105). The Women's Health Questionnaire, a validated quality-of-life instrument for perimenopausal and postmenopausal women, was administered at baseline and 3-month intervals. RESULTS: Overall, quality of life from baseline to end point was preserved equally in all treatment groups. Six domains (depressed mood, somatic symptoms, memory/concentration, sexual behavior, sleep problems, and perceived attractiveness) were unchanged in all groups. Three domains (menstrual symptoms, vasomotor symptoms, and anxiety/fears) were statistically significantly different among groups. Mean scores for menstrual symptoms significantly worsened and vasomotor symptoms significantly improved from baseline to end point in the estrogen group. Mean scores for vasomotor symptoms did not worsen at any point in the raloxifene 60 mg/day group. Mean anxiety/fears scores improved significantly during raloxifene 60 mg/day administration throughout treatment (P <.05), irrespective of previous hormone replacement therapy, baseline estradiol (E2) levels, or years postmenopause. CONCLUSION: Most quality-of-life domains were not affected by treatment with estrogen or raloxifene. Estrogen provided relief from vasomotor symptoms but caused menstrual symptoms. Raloxifene 60 mg/day improved anxiety levels in postmenopausal women.

The cost of infertility evaluation and therapy: findings of a self-insured university healthcare plan.

OBJECTIVE: To assess the total costs of infertility coverage, determine the proportion of healthcare costs related to infertility, compare infertility costs to those of other diseases, and calculate a per member per month cost of an infertility benefit. DESIGN: Historical prospective analysis. SETTING: A university-based, self-insured, fee-for-service healthcare plan. PATIENT(S): Healthcare policy members from January 1993 through December 1995. INTERVENTION(S): General and infertility-specific healthcare that included diagnostic tests for infertility, induction of ovulation, artificial insemination, donor gametes, in vitro fertilization, gamete intrafallopian transfer, zygote intrafallopian transfer, microsurgical epididymal sperm aspiration, embryo cryopreservation, and frozen embryo transfer. MAIN OUTCOME MEASURE(S): Healthcare costs, as calculated from the International Classification of Diseases, Volume 9 codes. RESULT(S): Total healthcare and infertility-specific costs of the university healthcare plan over a 3-year period were $86,445,642 and $680,921, respectively. Therefore, infertility accounted for 0.79% of the total university healthcare costs. The mean total and infertility-specific per member per month healthcare costs were $86.15 and $0.67, respectively. CONCLUSION(S): These data reveal that infertility costs account for only a small fraction of the total healthcare costs and can be attained at a nominal monthly fee.

Sonohysterography in premenopausal women with and without abnormal bleeding.

OBJECTIVE: To estimate the prevalence of abnormalities detected by sonohysterography in premenopausal women who were asymptomatic or had abnormal uterine bleeding. METHODS: Standard sonohysterography was done in 100 asymptomatic premenopausal women age 30 and older. The prevalence of uterine abnormalities was recorded and compared with findings in 80 premenopausal women evaluated in our unit for abnormal uterine bleeding. RESULTS: Compared with asymptomatic women, premenopausal women with abnormal uterine bleeding had a higher prevalence of polyps (33 versus 10%), intracavitary myomas (21 versus 1%), and intramural myomas (58 versus 13%). Ten percent of asymptomatic women had polyps, but these polyps tended to be smaller than the polyps found in women with abnormal bleeding (8.5 versus 13.9 mm, P = .064). Polyps were associated significantly with myomas, and both were more common in older premenopausal women. CONCLUSION: Intracavitary lesions and intramural myomas are more prevalent in women with abnormal uterine bleeding than in asymptomatic women, suggesting a causative relationship. However, small endometrial polyps are common and frequently asymptomatic.

Cost-effective treatment of the infertile couple.

OBJECTIVE: To review the published literature on the cost-effective approach to infertility treatment. DESIGN: The literature on the economics and cost-effectiveness of infertility treatments was reviewed. Studies related to this topic were identified through MEDLINE. RESULT(S): Few cost-effectiveness studies about infertility treatment have been published. In the absence of tubal blockage and severe male factor, use of IUI and hMG-IUI is more cost-effective than IVF. In vitro fertilization is at least as cost-effective as tubal surgery. Although IVF costs are high, they fall well within the range of other accepted medical treatments and are below the general public's willingness to pay for these treatments. CONCLUSION(S): Cost-effectiveness analysis is an important means of improving quality of care while controlling costs. Further work regarding cost-effectiveness of treatments among different diagnostic groups is needed.

Selective early elimination of luteal support in assisted reproduction cycles using a gonadotropin-releasing hormone agonist during ovarian stimulation.

OBJECTIVE: To determine if women undergoing GnRH agonist-hMG stimulated IVF cycles can undergo successful discontinuation of luteal phase support. DESIGN: A protocol for selective discontinuation of luteal phase support was evaluated prospectively in women undergoing assisted reproduction cycles. SETTING: A tertiary care institutional-based assisted reproduction program. PATIENT(S): One hundred eighty-eight women who conceived after an IVF or zygote intrafallopian transfer cycle including a GnRH agonist between January 1994 and June 1997. INTERVENTION(S): Women with serum progesterone levels of > or = 60 ng/mL at 4 weeks' gestation were selected for discontinuation of their luteal phase support. MAIN OUTCOME MEASURE(S): Delivery rate. RESULT(S): Sixty-three women (62.4%) met the criteria for discontinuation of luteal phase support. There were no differences in the mean age, peak E2 levels, number of follicles, number of embryos transferred, or delivery rates (85.7% versus 78.9%) between the women who did and those who did not have discontinuation of their progesterone supplementation. CONCLUSION(S): These data reveal that luteal phase support can be discontinued successfully for selective women undergoing IVF who are receiving a GnRH agonist.

Ultrasound-guided aspiration of hydrosalpinges is associated with improved pregnancy and implantation rates after in-vitro fertilization cycles.

Previous reports have shown that the presence of hydrosalpinges may have a detrimental effect on in-vitro fertilization (IVF) outcomes and salpingectomy has been recommended by some authors as a means of improving IVF pregnancy rates. Our first objective was to determine the effect of hydrosalpinges diagnosed by ultrasound on IVF outcomes in our clinic. Our second objective was to examine the effects of aspiration of hydrosalpinges at the time of oocyte retrieval on IVF outcomes. Women with hydrosalpinges (n=34) were compared with women who had tubal disease but no hydrosalpinges (n=124) and were found to have a reduced clinical pregnancy rate (18 % versus 37%, P=0.053), a reduced ongoing pregnancy rate (15 versus 34%, P=0.051), and a reduced implantation rate (7 versus 18%, P=0.003) after IVF procedures. Among women with hydrosalpinges present, 16 had their hydrosalpinges aspirated at the time of oocyte retrieval and 18 did not. Aspiration of hydrosalpinges was associated with a higher clinical pregnancy rate (31 versus 5%, P=0.07), a higher ongoing pregnancy rate (31 versus 0%, P=0.015), and a higher implantation rate (14 versus 1%, P=0.015). This study confirms the association between the presence of hydrosalpinges and poor IVF outcomes. We find that aspiration of hydrosalpinges at the time of oocyte retrieval leads to improved pregnancy rates and may be an acceptable alternative to salpingectomy for treatment of these patients.

Uterine leiomyomas reduce the efficacy of assisted reproduction cycles: results of a matched follow-up study.

A matched follow-up study design was used to test the hypothesis that pregnancy rates following assisted reproduction procedures do not differ between women with or without intramural or sub-serosal uterine leiomyomas. Women undergoing their first in-vitro fertilization (IVF)-embryo transfer or zygote intra-Fallopian transfer (ZIFT) cycle between January 1993 and June 1995 were included. Cases (women with leiomyomas) were matched 1:1 with the next consecutive control (women without leiomyomas) according to age, number of embryos transferred, embryo grade, and the route of embryo transfer (uterine or Fallopian). Assisted reproduction cycles were performed in an identical manner, independent of the presence or absence of uterine leiomyomas. The main outcomes measured were clinical pregnancy and delivery rates. A total of 182 cycles was evaluated. Of the 91 assisted reproduction cycles performed in the leiomyoma group, there were 34 clinical pregnancies (37%) and 30 deliveries (33%). Of the 91 assisted reproduction cycles in the control group, there were 48 clinical pregnancies (53%) and 44 deliveries (48%). The Mantel-Haenszel estimate of relative risk indicated that the presence of a uterine leiomyoma significantly reduced the chance for a clinical pregnancy or delivery. These findings suggest that leiomyomas are associated with a reduction in the efficacy of assisted reproduction cycles.

Reactions of residency directors to primary care requirements in obstetrics and gynecology training.

OBJECTIVE: To determine the opinions of obstetrics and gynecology residency program directors regarding the Residency Review Committee mandate, requires 6 months of primary care training in obstetrics and gynecology. METHODS: A ten-question survey was mailed to the 272 accredited obstetrics and gynecology programs in the United States and Puerto Rico. Program directors were asked about the adequacy of 6 months of primary care training, whether educational deficiencies in obstetrics and gynecology will develop as a result of the mandate, and whether residency programs should be lengthened to encompass primary care. RESULTS: The response rate for the survey was 92.3% (251/272). University-affiliated, community, and military-based programs were surveyed and all geographic areas of the country were represented. Of program directors responding, 53.4% agreed with the mandate, 43.0% disagreed, and 3.6% declined to answer this question or both agreed and disagreed. Fifty-one percent considered 6 months of primary care training to be adequate, and 60.2% of program directors thought that educational deficiencies would develop in obstetrics and gynecology training programs. Whereas 66.1% responded that extension of obstetrics and gynecology training programs beyond 4 years was unnecessary, 32.7% thought program length should be increased. CONCLUSION: The results of this survey demonstrate that a substantial proportion of U.S. residency directors do not agree with the Residency Review Committee mandate for primary care training and think that deficiencies in obstetrics and gynecology training will develop as a result of these changes.

Endometriosis-associated pelvic pain: evidence for an association between the stage of disease and a history of chronic pelvic pain.

OBJECTIVE: To track the severity and location of pelvic pain associated with endometriosis throughout the reproductive-age years and to evaluate the association between these pain parameters and the stage of disease. DESIGN: Historical prospective study. SETTING: Tertiary care center. PATIENT(S): Forty-eight women with endoscopically staged endometriosis and chronic pelvic pain who had undergone medical and/or conservative surgical therapy. INTERVENTION(S): Each participant was administered a questionnaire that included a determination of the severity and location of her pain. MAIN OUTCOME MEASURE(S): The stage of disease, the area of the pelvis that contained the bulk of disease, the severity of pain, and the location of the most severe pain were recorded. RESULT(S): The mean duration from the initial diagnosis until follow-up was 15.7 +/- 3.1 years, Twenty-one (43.8%) subjects denied any symptoms of pain on follow-up evaluation. Of the 27 patients with persistent pain, 21 (78%) identified the location of their most severe pain as being the same as at initial diagnosis. The stage of disease at initial diagnosis was significantly associated with a higher degree of pain at follow-up. CONCLUSION(S): These data suggest that endometriosis-associated chronic pelvic pain commonly persists throughout the reproductive years and that endometriosis stage is directly related to the persistence of pelvic pain.

Autoantibodies and infertility: a review of the literature.

The role that autoantibodies play in infertility remains uncertain. There are conflicting data regarding the prevalence of autoantibodies in women with endometriosis. Certainly no one has demonstrated an association between the presence of antibodies in women with endometriosis and infertility. Despite intensive study, there is also no consensus on a role of autoantibodies to the zona pellucida as a cause of infertility. Recently, much attention has been focused on autoantibodies and infertility particularly with regards to phospholipid antibodies and their effect on IVF success rates. The literature suggests that women with infertility have an increased prevalence of phospholipid antibodies compared to fertile women. However, the presence of these antibodies has not been associated with a worsened prognosis for IVF cycles. Many questions remain to be answered. What is the cause of this apparently increased prevalence of autoantibodies in infertile women? Do these autoantibodies cause infertility or are they merely associated with some other condition which is actually causitive? Finally, can treatment of autoantibodies improve pregnancy rates in infertile couples after IVF or other infertility treatments? The answers to these questions should be sought by carefully conducted trials with appropriate control groups. Subjecting patients to expensive testing and 'treatments' before these answers are known is not consistent with good scientific or medical practice.

Cost-effectiveness of infertility treatments: a cohort study.

OBJECTIVE: To determine the cost-effectiveness of infertility treatments. DESIGN: Retrospective cohort study. SETTING: Academic medical center infertility practice. PATIENT(S): All patients treated for infertility in a 1-year time span. INTERVENTION(S): Intrauterine inseminations, clomiphene citrate and IUI (CC-IUI), hMG and IUI (hMG-IUI), assisted reproductive techniques (ART), and neosalpingostomy by laparotomy. MAIN OUTCOME MEASURE(S): All medical charges and pregnancy outcomes associated with the treatments were obtained. Cost-effectiveness ratios defined as cost per delivery were determined for each procedure. The effects of a woman's age and the number of spermatozoa inseminated on cost-effectiveness of the procedures was also determined. RESULT(S): Intrauterine inseminations, CC-IUI, and hMG-IUI have a similar cost per delivery of between $7,800 and $10,300. All of these were more cost-effective than ART, which had a cost per delivery of $37,000. Assisted reproductive techniques in women with blocked fallopian tubes was more cost-effective than tubal surgery performed by laparotomy, which had a cost per delivery of $76,000. Increasing age in women and lower numbers of spermatozoa inseminated were factors leading to higher costs per delivery for IUI, CC-IUI, hMG-IUI, and ART. Use of donor oocytes reduced the cost per delivery of older women to the range seen in younger women with ART. CONCLUSION(S): Our analysis supports, in general, the use of IUI, CC-IUI, and hMG-IUI before ART in women with open fallopian tubes. For women with blocked fallopian tubes, IVF-ET appears to be the best treatment from a cost-effectiveness standpoint.

The role of hysterosalpingography in the evaluation of infertility.

Hysterosalpingography is the only radiologic procedure routinely performed in the initial evaluation of the infertile woman. Hysterosalpingography is used to assess the anatomy of the uterus and the patency of the fallopian tubes, and is performed in the proliferative phase of the menstrual cycle. It can be performed with either water- or oil-soluble contrast medium. Care should be taken during the procedure that excessive amounts of contrast medium are not injected, because that could obscure the diagnostic findings. Selective salpingography can help evaluate a suspected proximal tubal occlusion. The complications associated with hysterosalpingography include pain, pelvic infection, intravasation of contrast medium and allergic reactions. Abnormal hysterosalpingographic findings include occlusion of one or both fallopian tubes, uterine filling defects and müllerian anomalies. Therapy for abnormal hysterosalpingographic findings depends on the specific clinical scenario and includes endoscopic surgery, laparotomy and in vitro fertilization.

The effects of smoking on ovarian function and fertility during assisted reproduction cycles.

OBJECTIVE: To investigate the effects of cigarette smoking on ovarian function and fertility in women undergoing assisted reproduction cycles. METHODS: We assessed the effects of smoking on ovarian function and fertility in a cohort of 499 women. Questionnaires were designed to quantify past smoking exposure and to determine whether the woman was smoking during the treatment cycle. Ovarian function characteristics and pregnancy rates were compared among current smokers, past smokers, and nonsmokers. RESULTS: Compared with nonsmokers, both current and past smokers have reduced gonadotropin-stimulated ovarian function. A history of increasing tobacco exposure was associated with decreasing serum estradiol concentrations, numbers of retrieved oocytes, and numbers of embryos. On average, for every 10 pack-years of cigarette smoking, 2.5 fewer mature oocytes and 2.0 fewer embryos were obtained. Women who smoked during their treatment cycle had approximately a 50% reduction in implantation rate and ongoing pregnancy rate compared with women who had never smoked. Women who quit smoking before their treatment cycle had the same pregnancy rate as nonsmokers. CONCLUSION: Cigarette smoking is associated with a prolonged and dose-dependent adverse effect on ovarian function. Smoking appears to have a more transient toxic effect on fertility, because current smokers, but not past smokers, had a markedly reduced pregnancy rate after treatment cycles compared with nonsmokers. Women should quit smoking before assisted reproduction cycles.

The effectiveness of sublingual progesterone administration during cryopreserved embryo transfer cycles: results of a matched follow-up study.

OBJECTIVE: To compare cryopreserved ET pregnancy rates in subjects receiving either sublingual parenteral P. DESIGN: Matched follow-up study. SETTING: University-based assisted reproduction program. PATIENTS: Women undergoing cryopreserved ET between January 1993, and December 1994. Cases received a hormone replacement protocol containing oral E2 and sublingual P and controls received a hormone replacement protocol containing oral E2 and parenteral P. Cases and controls were matched one-to-one according to age, number of embryos transferred, embryo grade, and route of ET. INTERVENTIONS: Cryopreserved embryos were thawed and transferred in all patients in an identical manner independent of the route of P administration. MAIN OUTCOME MEASURES: Clinical and ongoing pregnancy rates. RESULTS: Of 61 ET cycles performed in the sublingual P group, there were 16 clinical pregnancies (26.2%) and 12 ongoing pregnancies (19.7%). Of the 61 ET cycles in the parenteral P group, there were 14 clinical pregnancies (23.0%) and 11 ongoing pregnancies (18.0%). A chi 2 test revealed no significant differences in either clinical or ongoing pregnancy rates according to the route of P administration. CONCLUSIONS: This data suggests that sublingual P administration is an effective alternative to parenteral P administration in preparing the endometrium for the implantation of cryopreserved embryos.

The efficacy and cost effectiveness of embryo cryopreservation compared with other assisted reproductive techniques.

OBJECTIVE: To evaluate the efficacy and cost effectiveness of embryo cryopreservation compared with other assisted reproductive techniques (ARTs). DESIGN: Retrospective review of medical records and health care costs. SETTING: Tertiary care academic medical school ART program. PATIENTS: For determination of the efficacy of cryopreserved ET, we analyzed 610 patients undergoing the first 1,000 oocyte retrievals in our program. For determination of cost effectiveness, we analyzed the costs associated with 334 initiated ART cycles in 1992. MAIN OUTCOME MEASURES: The ongoing pregnancy rate (PR) per initiated cycle and per oocyte retrieval. The medical costs associated with each procedure. RESULTS: The transfer of cryopreserved embryos increased the ongoing PR per oocyte retrieval by 6.6%. Transfer of cryopreserved embryos was cost effective compared with other ARTs. The cost per delivery for cryopreserved ETs was between 25% and 45% that of a fresh cycle. CONCLUSIONS: Including embryo cryopreservation in an ART program can improve PRs and lower the ultimate cost per delivery.

Infertility evaluation in fertile women: a model for assessing the efficacy of infertility testing.

A standard infertility evaluation consists of a semen analysis, hysterosalpingogram, post-coital test, endometrial biopsy and laparoscopy. Although these tests are well grounded in clinical experience, information on their ability to discriminate between fertile and infertile couples is limited. In this study, we performed standard infertility tests plus two others--sperm antibodies and cervical culture for Mycoplasma hominis and Ureaplasma urealyticum--on fertile and infertile couples. Women in the fertile group were selected from those who had delivered a child within the previous 2 years and who were scheduled for a laparoscopic tubal ligation. Women in the infertile group were selected from those presenting for an infertility evaluation (mean duration of infertility 4.2 years), and they were matched by age (+/- 3 years) and race with fertile subjects. Subjects were recruited from both private and clinic patients. A total of 64 couples (32 matched pairs) completed the evaluation. At least one 'abnormal' infertility test was found in 69% of fertile and 84% of infertile couples. With the exception of tubal damage and endometriosis, which as expected were more common in infertile couples, no significant differences between groups for remaining infertility factors could be demonstrated. Despite the small size of the current study, these results confirm the feasibility and importance of comparisons of the prevalence of infertility factors in fertile and infertile couples.