Michael M. Alper

A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial

OBJECTIVE To determine the value of gonadotropin/intrauterine insemination (FSH/IUI) therapy for infertile women aged 21-39 years. DESIGN Randomized controlled trial. SETTING Academic medical center associated with a private infertility center. PATIENT(S) Couples with unexplained infertility. INTERVENTION(S) Couples were randomized to receive either conventional treatment (n=247) with three cycles of clomiphene citrate (CC)/IUI, three cycles of FSH/IUI, and up to six cycles of IVF or an accelerated treatment (n=256) that omitted the three cycles of FSH/IUI. MAIN OUTCOME MEASURE(S) The time it took to establish a pregnancy that led to a live birth and cost-effectiveness, defined as the ratio of the sum of all health insurance charges between randomization and delivery divided by the number of couples delivering at least one live-born baby. RESULT(S) An increased rate of pregnancy was observed in the accelerated arm (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.00-1.56) compared with the conventional arm. Median time to pregnancy was 8 and 11 months in the accelerated and conventional arms, respectively. Per cycle pregnancy rates for CC/IUI, FSH/IUI, and IVF were 7.6%, 9.8%, and 30.7%, respectively. Average charges per delivery were

The impact of acupuncture on in vitro fertilization outcome.

9,800 lower (95% CI,

Ovarian reserve screening in infertility: Practical applications and theoretical directions for research

25,100 lower to

Pregnancies after premature ovarian failure

3,900 higher) in the accelerated arm compared to conventional treatment. The observed incremental difference was a savings of

Impact of a group mind/body intervention on pregnancy rates in IVF patients

2,624 per couple for accelerated treatment and 0.06 more deliveries. CONCLUSION(S) A randomized clinical trial demonstrated that FSH/IUI treatment was of no added value.

Gonadotropin-releasing hormone antagonist versus agonist administration in women undergoing controlled ovarian hyperstimulation: Cycle performance and in vitro steroidogenesis of granulosa-lutein cells

OBJECTIVE To replicate previous research on the efficacy of acupuncture in increasing pregnancy rates (PR) in patients undergoing IVF and to determine whether such an increase was due to a placebo effect. DESIGN Prospective, randomized, controlled, single blind trial. SETTING Private, academically affiliated, infertility clinic. PATIENT(S) One hundred fifty patients scheduled to undergo embryo transfer. INTERVENTION(S) Subjects were randomized to either the acupuncture or control group. Acupuncture patients received the protocol, as first described by Paulus and his colleagues, for 25 minutes before and after embryo transfer. Control subjects laid quietly. All subjects then completed questionnaires on anxiety and optimism. The IVF staff remained blind to subject assignment. MAIN OUTCOME MEASURE(S) Clinical PRs, anxiety, optimism. RESULT(S) Before randomization both groups had similar demographic characteristics including age and psychological variables. There were no significant differences in PRs between the two groups. Acupuncture patients reported significantly less anxiety post-transfer and reported feeling more optimistic about their cycle and enjoyed their sessions more than the control subjects. CONCLUSION(S) The use of acupuncture in patients undergoing IVF was not associated with an increase in PRs but they were more relaxed and more optimistic.

Multivariate Analysis of Factors Predictive of Successful Live Births in In Vitro Fertilization (IVF) Suggests Strategies to Improve IVF Outcome

The concept of ovarian reserve describes the natural oocyte endowment and is closely associated with female age, which is the single most important factor influencing reproductive outcome. Fertility potential first declines after the age of 30 and moves downward rapidly thereafter, essentially reaching zero by the mid-40s. Conceptions beyond this age are exceedingly rare, unless oocytes obtained from a younger donor are utilised. How best to estimate ovarian reserve clinically remains controversial. Passive assessments of ovarian reserve include measurement of serum follicle stimulating hormone (FSH), oestradiol (E(2)), anti-Müllerian hormone (AMH), and inhibin-B. Ultrasound determination of antral follicle count (AFC), ovarian vascularity and ovarian volume also can have a role. The clomiphene citrate challenge test (CCCT), exogenous FSH ovarian reserve test (EFORT), and GnRH-agonist stimulation test (GAST) are provocative methods that have been used to assess ovarian reserve. Importantly, a patients prior response to gonadotropins also provides highly valuable information about ovarian function. Regarding prediction of reproductive outcome, in vitro fertilisation (IVF) experience at our centres and elsewhere has shown that some assessments of ovarian reserve perform better than others. In this report, these tests are discussed and compared; we also present practical strategies to organise screening as presently used at our institutions. Experimental challenges to the long-held tenet of irreversible ovarian ageing are also introduced and explored. While pregnancy rates after IVF are influenced by multiple (non-ovarian) factors including in vitro laboratory conditions, semen parameters, psychological stress and technique of embryo transfer, predicting response to gonadotropin treatment nevertheless remains an important aim in the evaluation of the couple struggling with infertility.

The relationship of semen parameters to fertilization in patients participating in a program of in vitro fertilization.

&NA; Six women who conceived after a diagnosis of premature ovarian failure are discussed. Two pregnancies occurred while the women were receiving conjugated estrogen therapy, two while taking oral contraceptives, and two women conceived spontaneously. The possible role of exogenous estrogens in sensitizing the granulosa cells to the effect of follicle‐stimulating hormone and thereby inducing ovulation and conception in some women with premature ovarian failure is examined. (Obstet Gynecol 67:59S, 1986)

A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over Treatment Trial (FORT-T)

OBJECTIVE To determine if women who were randomized to a mind/body program before starting their first IVF cycle would have higher pregnancy rates than control subjects. DESIGN Randomized, controlled, prospective study. SETTING Private academically affiliated infertility center. PATIENT(S) A total of 143 women aged≤40 years who were about to begin their first IVF cycle. INTERVENTION(S) Subjects were randomized to a ten-session mind/body program (MB) or a control group and followed for two IVF cycles. MAIN OUTCOME MEASURE(S) Clinical pregnancy rate. RESULT(S) Only 9% of the MB participants had attended at least one-half of their sessions at cycle 1 start. Pregnancy rates for cycle 1 were 43% for all subjects; 76% of the MB subjects had attended at least one-half of their sessions at cycle 2 start. Pregnancy rates for cycle 2 were 52% for MB and 20% for control. CONCLUSION(S) MB participation was associated with increased pregnancy rates for cycle 2, prior to which most subjects had attended at least half of their sessions.

Luteal support with vaginal micronized progesterone gel in assisted reproduction.

OBJECTIVES We sought to determine the effectiveness of a gonadotropin-releasing hormone antagonist compared with an agonist in suppressing a spontaneous luteinizing hormone surge in women undergoing controlled ovarian hyperstimulation for in vitro fertilization and gamete intrafallopian transfer and to examine whether in vivo administration of these analogs effects granulosa-lutein cells steroidogenesis in vitro. STUDY DESIGN This prospective case-control study included 30 healthy women undergoing ovarian hyperstimulation with human menopausal gonadotropins. Fifteen women received the Nal-Glu antagonist, 5 mg intramuscularly daily, when the lead follicle was > or = 15 mm or serum estradiol level was > or = 500 pg/ml. The control group included 15 women who underwent oocyte retrieval on the same day as the study subjects and were given the agonist leuprolide acetate, 250 micrograms subcutaneously daily, starting on cycle day 1. Granulosa-lutein cells were purified from follicular aspirates from six subjects and six controls and cultured in parallel, evaluating basal progesterone production, progesterone response to follicle-stimulating hormone or luteinizing hormone and aromatase activity. RESULTS No difference was demonstrated in the total amount of gonadotropins received by the two groups. Overall, the gonadotropin-releasing hormone antagonist was given for only 2.5 +/- 0.2 (mean +/- SEM) days before human chorionic gonadotropin administration. The antagonist group showed significantly lower levels of serum luteinizing hormone than did the agonist group, 1.0 +/- 0.2 versus 4.2 +/- 0.5 mIU/ml (p = 0.0001) on the day of human chorionic gonadotropin administration. Serum estradiol levels were significantly lower in the antagonist than the agonist group, 820 +/- 120 versus 1361 +/- 110 pg/ml (p = 0.003) on the day of human chorionic gonadotropin administration. There was no difference in the number of retrieved oocytes, but the antagonist group had a higher proportion of mature oocytes, 82% +/- 4% versus 62.4% (p = 0.02), and a higher proportion of embryos of good quality, 69.8% +/- 9.8% versus 44.3% +/- 7.2% (p = 0.03) in the agonist group. Granulosa-lutein cells from antagonist-treated women showed significantly lower aromatase activity the first 6 hours after retrieval, 17.6 +/- 1.6 versus 31.3 +/- 7.4 ng/ml per 6 hours estradiol (p = 0.03), whereas basal and gonadotropin-stimulated with progesterone responses were similar. CONCLUSION Gonadotropin-releasing hormone antagonist administration during the late follicular phase resulted in lower serum luteinizing hormone and estradiol levels and more mature oocytes and embryos of better quality compared with gonadotropin-releasing hormone agonist administration. These results suggest that gonadotropin-releasing hormone antagonist administration in ovarian hyperstimulation has practical advantages over the agonist regimen. Gonadotropin-releasing hormone analogs may have direct action on ovarian function with differential effects on granulosa-lutein cell aromatase activity. This could explain the lower serum estradiol levels routinely observed in women given gonadotropin-releasing hormone antagonist.