Richard P. Buyalos

Ovulation induction in women age 40 and older: the importance of basal follicle-stimulating hormone level and chronological age *

OBJECTIVES To determine pregnancy and livebirth rates for women age 40 and older undergoing ovulation induction and to assess the impact of basal follicle-stimulating hormone (FSH) on outcome in these patients. DESIGN Prospective, observational. SETTING Fertility service of university medical center. PATIENTS Infertile couples in whom the female partner was age 40 or older referred for ovulation induction therapy. INTERVENTION Assessment of basal hormonal status; ovulation induction. MAIN OUTCOME MEASURES Clinical pregnancy rate (PR), livebirth rate. RESULTS Analysis of 402 cycles in 85 women age 40 and older demonstrated a clinical PR of 3.5% per cycle (95% confidence interval [CI] 1.7% to 5.3%). The livebirth rate was 1.2% per cycle (95% CI 0.1% to 2.3%). Women with a basal FSH < 25 IU/L and age < 44 years had a clinical PR of 5.2% per cycle (95% CI 2.5% to 7.9%) compared with 0.0% per cycle (95% CI 0.0% to 2.1%) in cases in which either basal FSH was > or = 25 IU/L or age was > or = 44 (P < 0.005). The prognostic importance of basal FSH and chronological age was confirmed by multivariate logistic regression analysis. The predictive value of the resulting regression equation was high (R2 = 0.94; P < 0.01). CONCLUSIONS Pregnancy and livebirth rates are generally low during ovulation induction in women age 40 and older. In combination, basal FSH and chronological age are accurate predictors of PR, in these couples and can define a subset of patients with a more favorable prognosis. The spontaneous abortion rate in women who do conceive is high, substantially lowering the livebirth rate.

Elevated interleukin-6 levels in peritoneal fluid of patients with pelvic pathology * †

OBJECTIVE To determine if interleukin 6 (IL-6) is a normal constituent of peritoneal fluid (PF), and if various types of pelvic pathology influence its presence within the PF microenvironment. STUDY DESIGN Peritoneal fluid from 73 women obtained at the time of laparoscopy was examined for the presence of IL-6 using an IL-6 specific sandwich enzyme-linked immunosorbent assay. Thirty-nine patients had pelvic endometriosis, 17 had nonendometriotic pelvic adhesive disease, and 17 subjects undergoing tubal sterilization without evidence of pelvic pathology served as controls. RESULTS Immunoreactive IL-6 was observed in the PF of all 73 subjects (range 0.26 to 11.16 ng/mL). The mean concentration of IL-6 was higher in women with nonendometriotic pelvic adhesions as compared with control subjects (1.28 +/- 0.16 versus 0.80 +/- 0.06 ng/mL, P less than 0.03). There was no difference in the mean peritoneal concentrations of IL-6 between women with endometriosis (1.16 +/- 0.28 ng/mL) and controls, P = 0.38. Twenty-seven of 73 patients (37%) demonstrated elevated levels (greater than 1.0 ng/mL) of IL-6. Patients with pelvic adhesions were significantly more likely to have elevated concentrations of IL-6 than controls (10/17 [59%] versus 3/17 [18%], P less than 0.02). Alternatively, the percentage of patients with elevated IL-6 concentrations did not differ between patients with endometriosis or controls (14/39 [36%] versus 3/17 [18%], P greater than 0.10). CONCLUSIONS These findings demonstrate that IL-6 is a normal constituent of PF and that elevated levels are found in many patients with pelvic adhesions.

The profound impact of patient age on pregnancy outcome after early detection of fetal cardiac activity

OBJECTIVE To evaluate the influence of maternal age on pregnancy loss rates after early documentation of fetal cardiac activity by transvaginal ultrasound (US) in previously infertile women. DESIGN Retrospective, observational study. SETTING Tertiary fertility center. PATIENTS One hundred eighty-six previously infertile women 20 to 43 years of age undergoing ovulation induction. MAIN OUTCOME MEASURE We analyzed 201 clinical pregnancies in which cardiac activity had been documented by transvaginal US 35 to 42 days after ovulation in a previously infertile population treated at a tertiary fertility center. Patient age, infertility diagnosis, ovulation induction protocol, and mode of insemination were analyzed by chi 2, Fishers exact test and logistic regression analyses. RESULTS A profound increase in spontaneous abortion rates occurred as a function of maternal age in this population (chi 2 for trend = 15.1). A spontaneous abortion rate of 2.1% was observed for maternal ages < or = 35 years but this rate increased to 16.1% for patients > or = 36 years (odds ratio, 8.72; 95 percent confidence interval 2.3 to 32.9). A fivefold increase in spontaneous abortion rate was observed in women > or = 40 years compared with women 31 to 35 years (3.8% versus 20.0%. Infertility diagnosis, mode of insemination, and ovulation induction protocol were not associated with an increased risk of spontaneous abortion. CONCLUSIONS The incidence of pregnancy loss after confirmation of early fetal cardiac activity by transvaginal US is substantially greater in infertile patients than previously reported, when considered as a function of maternal age. In particular, patients > or = 36 years should be counseled that their risk of spontaneous abortion is significant even after fetal heart motion is present on transvaginal US. Cautious optimism and greater surveillance may be required during the first trimester of pregnancy in these women.

Polycystic ovary syndrome: pathophysiology and outcome with in vitro fertilization

OBJECTIVE To assess the efficacy of IVP-ET in infertile women with the polycystic ovary syndrome (PCOS) and to provide a comprehensive review of contemporary therapeutic options and their complications as reflected in the current literature. DESIGN Pertinent studies in medical literature identified through computerized bibliographic search and via manual review of relevant scientific publications. RESULTS In vitro fertilization and ET is an effective therapy for PCOS patients who are refractory to ovulation induction in vivo or who have coexisting infertility factors. The use of GnRH agonist (GnRH-a) is associated with significant reductions in the incidence of pregnancy loss and may improve fertilization and cleavage rates. In the PCOS patient, the use of purified FSH preparations does not appear to improve pregnancy rates nor other clinical parameters when compared with hMG. Severe ovarian hyperstimulation syndrome (OHSS) is an important consideration when PCOS patients undergo superovulation protocols. Strategies for OHSS prevention include the use of intravenous albumin immediately after oocyte retrieval, triggering of ovulation with a GnRH-a, or withholding menotropin therapy for several days before hCG administration. Cryopreservation of all embryos for future transfer in an artificial cycle has also proven to be an effective alternative in PCOS patients at high risk for severe OHSS. CONCLUSIONS Pregnancy rates for PCOS patients undergoing IVF-ET are comparable with those for women with tubal factor infertility. Therefore, IVF-ET should be offered to patients with PCOS who are refractory to conventional infertility modalities.

Detection of interleukin-6 in human follicular fluid * †

OBJECTIVE To determine if interleukin-6 (IL-6) is a normal constituent of human follicular fluid (FF) after ovarian hyperstimulation and to assess whether IL-6 levels differ in conditions associated with immunological causes of infertility. DESIGN After ovarian hyperstimulation for an in vitro fertilization (IVF) treatment cycle, FF samples were obtained at the time of oocyte retrieval. SETTING Referral center at a tertiary care hospital. PATIENTS Thirty women referred for IVF, including 10 patients with significant titers (greater than 40%) of antisperm antibodies and 10 with pelvic endometriosis. Ten patients with tubal infertility without antisperm antibodies or endometriosis served as controls. MAIN OUTCOME MEASURES Analysis of FF levels for IL-6 using both bioassay and immunoassay. RESULTS Bioactive (range 0.32 to 32.2 U/mL) and immunoreactive (range 0.34 to 13.6 ng/mL) IL-6 levels were detected in FF of all subjects after ovarian hyperstimulation. Follicular fluid IL-6 levels were substantially higher (3 to 30-fold) than that reported in serum. There was no difference in the mean concentrations of IL-6 levels between patients with antisperm antibodies, endometriosis, or tubal infertility. CONCLUSIONS Bioactive and immunoreactive IL-6 are present in human FF after ovarian hyperstimulation, supporting a potential autocrine or paracrine role within the follicular microenvironment.

Decreased 34K insulin-like growth factor binding protein in polycystic ovarian disease *

Insulin and insulin-like growth factor I (IGF-I) have been implicated in ovarian androgen production. Insulin is closely related to IGF-I and cross-reacts with its receptor. The 34K IGF-binding protein (34K IGF-BP) has been shown to inhibit the binding of IGF-I to its receptor. The authors evaluated the role of insulin in the regulation of serum levels of 34K IGF-BP in patients with polycystic ovarian disease (PCOD). 34K IGF-BP levels during an oral glucose tolerance test (OGTT) were measured in 15 PCOD (8 obese and 7 nonobese) patients and in 10 healthy control subjects. The fasting level of 34K IGF-BP was decreased in nonobese PCOD patients (2.4 +/- 0.3 micrograms/l) (mean +/- standard error) (P = 0.02) and obese PCOD patients (0.59 +/- 0.2 micrograms/l) (P less than 0.001) as compared with healthy controls (4.8 +/- 0.9 micrograms/l). Both nonobese PCOD patients and normal controls demonstrated a significant decrease in 34K IGF-BP following OGTT. An insulin-related decrease in 34K IGF-BP may allow an increased pool of IGF-I able to bind to its receptor. This would provide a mechanism for increased ovarian androgen production via IGF-I stimulation of its receptor.

Basal estradiol and follicle-stimulating hormone predict fecundity in women of advanced reproductive age undergoing ovulation induction therapy

OBJECTIVE To determine the prognostic value of single basal E2 and FSH levels as predictors of fecundity in women of advanced reproductive age who are undergoing ovulation induction with IUI therapy. DESIGN Prospective, observational. SETTING Fertility service of university medical center. PATIENT(S) Infertile couples in which the female partner was > or = 38 years old. INTERVENTION(S) Single assessment of basal E2 and FSH levels and ovulation induction with IUI. MAIN OUTCOME MEASURE(S) Cumulative and clinical pregnancy rates and live birth rates. RESULT(S) All live births occurred in patients with a basal E2 < or = 80 pg/mL (conversion factor to SI unit, 3.671), a basal FSH < or = 13 mIU/mL (conversion factor to SI unit, 1.00), and a chronological age < or = 42 years. In women 38 to 42 years of age, 10.3% had elevated basal E2 (> 80 pg/mL) in combination with normal basal FSH (< or = 13 mIU/mL), and no live births occurred in these couples. The cumulative live birth rate after four treatment cycles in women 38 to 42 years of age with both normal basal E2 (< or = 80 pg/mL) and FSH levels (< or = 13 mIU/mL) was 43.9%. CONCLUSION(S) Basal E2 improves the ability to predict fertility potential compared with basal FSH and chronological age alone. Basal E2, in combination with basal FSH and chronological age, has useful prognostic value in prospectively counseling patients of advanced reproductive age who are considering ovulation induction and IUI therapy.

The effect of clomiphene citrate and menopausal gonadotropins on cervical mucus in ovulatory cycles

OBJECTIVE To determine the effect of clomiphene citrate (CC) and hMG on cervical mucus (CM), optimally sampled in the periovulatory period from confirmed ovulatory cycles, in the dosage range commonly employed for ovulation induction. DESIGN Controlled, observational. SETTING Infertility treatment center at a university medical center. PATIENTS One hundred fifty-four infertile patients undergoing 161 treatment cycles in which postcoital test was performed in a documented ovulatory cycle. INTERVENTION One hundred six patients received CC at dosages of 50 to 200 mg. Twenty patients received hMG at dosages of 75 to 225 IU. Thirty-seven patients sampled during spontaneous ovulatory cycles served as controls. MAIN OUTCOME MEASURE Cervical mucus score using standardized scoring criteria. RESULTS Subjects receiving CC at all dosages had significantly lower CM scores 8.6 +/- 0.5, compared with patients receiving hMG 11.0 +/- 0.6 or spontaneous cycles 12.1 +/- 0.5. The incidence of unfavorable CM (score < 10/15) was similar in patients receiving CC at dosages of 50 mg (48.1%), 100 mg (48.6%), and 150 to 200 mg (60%). CONCLUSIONS Cervical mucus scores are reduced in ovulatory cycles after CC administration compared with both spontaneous ovulatory cycles and in patients undergoing superovulation with hMG. The reduction in CM scores was similar at all dosages of CC studied. The lack of adverse effects on CM during hMG therapy supports a local antiestrogenic effect of CC at the level of the cervix.

Clomiphene citrate with intrauterine insemination: is it effective therapy in women above the age of 35 years?*

OBJECTIVES To evaluate the influence of female age on clomiphene citrate (CC) with IUI therapy and to compare the efficacy of this therapy between patients with ovulatory and anovulatory infertility. SETTING A university fertility clinic. SUBJECTS Six hundred sixty-four CC with IUI cycles from 290 women aged 22 to 48 years. MAIN OUTCOME MEASURES Cumulative and clinical pregnancy rates (PRs). RESULTS Both cumulative and clinical PRs declined substantially in women > 35 years when compared with those < or = 35 years. In addition, no difference in these parameters was noted between patients with ovulatory and anovulatory infertility diagnoses. The vast majority of pregnancies occurred within the first four treatment cycles, irrespective of age or ovulatory versus anovulatory infertility diagnoses. CONCLUSIONS The age-related decline in clinical PR is most rapid beginning at the age of 35 years. For any given age group, CC with IUI therapy has similar cumulative and clinical PRs for both ovulatory and anovulatory infertility diagnoses. This therapy usually should not extend beyond four cycles. Couples should be counseled about the dramatic fall in PRs occurring beyond the age of 35 years.

The influence of supraphysiologic estradiol levels on human nidation

ObjectiveExogenous estradiol (E2) has a well-recognized interceptive action when administered shortly after ovulation. The influence of extremely elevated levels of endogenous E2 on human oocyte fertilization and implantation are unclear. The purpose of this study was to evaluate a potential antinidatory role of extremely high endogenous E2 concentrations on implantation and pregnancy duringin vitro fertilization-embryo transfer (IVF-ET).MethodsTwenty-five patients receiving human menopausal gonadotropins (hMG) following midluteal GnRHa administration for IVF-ET, in which the maximal E2 concentration was >5000 pg/ml (range 5358–16,344 pg/ml) were studied. Cycle parameters including oocyte and embryo characteristics, fertilization, cleavage, and implantation rates as well as pregnancy outcomes were compared to those of 25 patients treated contemporaneously whose treatment cycles had peak E2 values <3500 pg/ml. Patients groups were matched for age, infertility diagnoses, duration of infertility and stimulation protocol.ResultsCycles characterized by very high endogenous E2 levels resulted in significantly more oocytes per retrieval (21.4± 1.7 versus 8.4± 0.6;P < 0.0001), fewer postmature oocytes (1.6%± 1.0% versus 14%± 5.0%;P < 0.03), and a decreased fertilization rate (63%±4.0% versus 73%±3.0%;P < 0.04) compared to control cycles. There were no differences in the overall mean morphologic grade or cleavage rates between groups. However, high E2 cycles were associated with a significantly increased implantation rate (14%±4.0% versus 8.0%±4.0%;P < 0.01) and pregnancy rate per embryo transfer (62%±16% versus 36%±16%;P < 0.01) compared to controls. The incidence of spontaneous abortion did not differ between groups.ConclusionsExtremely high endogenous E2 levels do not appear to adversely affect implantation or overall cycle pregnancy rates in IVF-ET cycles. However, impaired fertilization rates in such cycles support a potential adverse effect on oocyte quality.