G. Wright Bates

Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome

BACKGROUND Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. METHODS In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. RESULTS Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. CONCLUSIONS As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).

Fertility preservation in women of reproductive age with cancer.

Advances in cancer care have improved survival, driving the need to mitigate the side effects of cancer therapy to improve the quality of life of cancer survivors. Use of fertility preservation has grown given the potential gonadotoxicity of chemotherapy and radiation, the increasing rate of treatment success, and the strong desire for childbearing in cancer survivors. Current options include embryo and oocyte cryopreservation, ovarian tissue cryopreservation, gonadal suppression, and ovarian transposition. Consultation with a reproductive endocrinology and infertility specialist trained in fertility preservation provides cancer patients an individualized risk assessment for future gonadal failure and discussion of potential fertility preservation options.

The Pregnancy in Polycystic Ovary Syndrome II study: baseline characteristics and effects of obesity from a multicenter randomized clinical trial

OBJECTIVE To summarize baseline characteristics from a large multicenter infertility clinical trial. DESIGN Cross-sectional baseline data from a double-blind randomized trial of two treatment regimens (letrozole vs. clomiphene). SETTING Academic Health Centers throughout the United States. PATIENT(S) Seven hundred fifty women with polycystic ovary syndrome (PCOS) and their male partners took part in the study. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Historic, biometric, biochemical, and questionnaire parameters. RESULT(S) Females averaged 30 years and were obese (body mass index [BMI] 35) with ∼20% from a racial/ethnic minority. Most (87%) were hirsute and nulligravid (63%). Most of the women had an elevated antral follicle count and enlarged ovarian volume on ultrasound. Women had elevated mean circulating androgens, LH-to-FSH ratio (∼2), and antimüllerian hormone levels (8.0 ng/mL). In addition, women had evidence for metabolic dysfunction with elevated mean fasting insulin and dyslipidemia. Increasing obesity was associated with decreased LH-to-FSH levels, antimüllerian hormone levels, and antral follicle counts but increasing cardiovascular risk factors, including prevalence of the metabolic syndrome. Men were obese (BMI 30) and had normal mean semen parameters. CONCLUSION(S) The treatment groups were well matched at baseline. Obesity exacerbates select female reproductive and most metabolic parameters. We have also established a database and sample repository that will eventually be accessible to investigators. CLINICAL TRIAL REGISTRATION NUMBER NCT00719186.

Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS

CONTEXT In overweight/obese women with polycystic ovary syndrome (PCOS), the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown. OBJECTIVE We compared the results of two, multicenter, concurrent clinical trials treating infertility in women with PCOS. DESIGN, SETTING, AND PARTICIPANTS This was a secondary analysis of two randomized trials conducted at academic health centers studying women 18-40 years of age who were overweight/obese and infertile with PCOS. INTERVENTION We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (N = 187) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives, lifestyle modification (Lifestyle: including caloric restriction, antiobesity medication, behavioral modification, and exercise) or the combination of both (combined) from the Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL PCOS) trial (N = 142). MAIN OUTCOME MEASURES Live birth, pregnancy loss, and ovulation were measured. RESULTS In PPCOS II, after four cycles of clomiphene, the cumulative per-cycle ovulation rate was 44.7% (277/619) and the cumulative live birth rate was 10.2% (19/187), nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial (ovulation 45% [67/149] and live birth: 8.5% [4/47]). In comparison, deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene. (Lifestyle: 62.0% [80/129]; risk ratio compared to PPCOS II = 1.4; 95% confidence interval [CI], 1.1-1.7; P = .003; combined: 64.3% [83/129]; risk ratio compared to PPCOS II = 1.4; 95% CI, 1.2-1.8; P < .001 and a significantly better live birth rate lifestyle: 25.0% [12/48]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.7; P = .01 and combined: 25.5% [12/47]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.8; P = .01). CONCLUSIONS These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment. Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment.

Early pregnancy loss in in vitro fertilization (IVF) is a positive predictor of subsequent IVF success

OBJECTIVE To determine the significance of biochemical pregnancy losses and clinical spontaneous abortion (SAB) on outcomes of future IVF cycles. DESIGN Retrospective cohort study. SETTING Academic IVF program. PATIENT(S) Women with a history of unsuccessful IVF attempts undergoing IVF. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Clinical pregnancy rate. RESULT(S) Patients with an early pregnancy loss had a greater ongoing clinical pregnancy rate in the immediate next cycle when compared with those women who had a negative pregnancy test (37.3% vs. 27.3%). Patients with a history of a biochemical pregnancy or a clinical spontaneous abortion had an ongoing clinical pregnancy rate in the next cycle of 38.4% and 42.3%, respectively, compared with 27.3% in women who had a history of a negative pregnancy test. The cumulative pregnancy rate after the first IVF attempt was 54.1% in patients with a previous biochemical pregnancy loss, 61.4% in those with a previous clinical SAB, and 46.5% in women with a previous negative pregnancy test. CONCLUSION(S) Women who experience an early pregnancy loss after IVF have a greater likelihood of success in subsequent IVF cycles when compared with patients who fail to conceive.

Self-assessed knowledge of treatment and fertility preservation in young women with breast cancer

Young women with breast cancer do not identify themselves as knowledgeable about the effect of cancer treatment on fertility or fertility preservation treatments and resources. These women need access to high-quality health information to support their participation in medical decision making about fertility preservation.

Favourable metabolic effects of a eucaloric lower‐carbohydrate diet in women with PCOS

Diet‐induced reduction in circulating insulin may be an attractive nonpharmacological treatment for women with polycystic ovary syndrome (PCOS) among whom elevated insulin may exacerbate symptoms by stimulating testosterone synthesis. This study was designed to determine whether a modest reduction in dietary carbohydrate (CHO) content affects β‐cell responsiveness, serum testosterone concentration and insulin sensitivity in women with PCOS.

Effects of a eucaloric reduced-carbohydrate diet on body composition and fat distribution in women with PCOS☆

OBJECTIVE To determine if consumption of a reduced-carbohydrate (CHO) diet would result in preferential loss of adipose tissue under eucaloric conditions, and whether changes in adiposity were associated with changes in postprandial insulin concentration. METHODS In a crossover-diet intervention, 30 women with PCOS consumed a reduced-CHO diet (41:19:40% energy from CHO:protein:fat) for 8 weeks and a standard diet (55:18:27) for 8 weeks. Body composition by DXA and fat distribution by CT were assessed at baseline and following each diet phase. Insulin AUC was obtained from a solid meal test (SMT) during each diet phase. RESULTS Participants lost 3.7% and 2.2% total fat following the reduced-CHO diet and STD diet, resp. (p<0.05 for difference between diets). The reduced-CHO diet induced a decrease in subcutaneous-abdominal, intra-abdominal, and thigh-intermuscular adipose tissue (-7.1%, -4.6%, and -11.5%, resp.), and the STD diet induced a decrease in total lean mass. Loss of fat mass following the reduced CHO diet arm was associated with lower insulin AUC (p<0.05) during the SMT. CONCLUSIONS In women with PCOS, consumption of a diet lower in CHO resulted in preferential loss of fat mass from metabolically harmful adipose depots, whereas a diet high in CHO appeared to promote repartitioning of lean mass to fat mass.

Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics

OBJECTIVE To identify baseline characteristics of women with unexplained infertility to determine whether treatment with an aromatase inhibitor will result in a lower rate of multiple gestations than current standard ovulation induction medications. DESIGN Randomized, prospective clinical trial. SETTING Multicenter university-based clinical practices. PATIENT(S) A total of 900 couples with unexplained infertility. INTERVENTION(S) Collection of baseline demographics, blood samples, and ultrasonographic assessments. MAIN OUTCOME MEASURE(S) Demographic, laboratory, imaging, and survey characteristics. RESULT(S) Demographic characteristics of women receiving clomiphene citrate (CC), letrozole, or gonadotropins for ovarian stimulation were very consistent. Their mean age was 32.2 ± 4.4 years and infertility duration was 34.7 ± 25.7 months, with 59% primary infertility. More than one-third of the women were current or past smokers. The mean body mass index (BMI) was 27 and mean antimüllerian hormone level was 2.6; only 11 women (1.3%) had antral follicle counts of <5. Similar observations were identified for hormonal profiles, ultrasound characterization of the ovaries, semen parameters, and quality of life assessments in both male and female partners. CONCLUSION(S) The cause of infertility in the couples recruited to this treatment trial is elusive, as the women were regularly ovulating and had evidence of good ovarian reserve both by basal FSH, antimüllerian hormone levels, and antral follicle counts; the male partners had normal semen parameters. The three treatment groups have common baseline characteristics, thereby providing comparable patient populations for testing the hypothesis that use of letrozole for ovarian stimulation can reduce the rates of multiples from that observed with gonadotropin and CC treatment. CLINICAL TRIAL REGISTRATION NUMBER NCT 01044862.

Evaluation and Treatment of Anovulatory and Unexplained Infertility

Anovulatory disorders are a primary cause of female infertility. Polycystic ovarian syndrome is the major cause of anovulation and is generally associated with obesity. Lifestyle changes to encourage weight loss are the initial therapy for overweight and obese patients, followed by clomiphene citrate for ovulation induction. For those patients who fail to ovulate on clomiphene citrate, alternatives, such as letrozole; gonadotropins; and complimentary agents to enhance clomiphene citrate, such as metformin and glucocorticoids, are reviewed. Women with unexplained infertility (no identifiable cause of infertility on a routine evaluation) may benefit from ovulation induction with clomiphene citrate, letrozole, or gonadotropins.