Elizabeth S. Ginsburg

Transdermal Testosterone Treatment in Women with Impaired Sexual Function after Oophorectomy

BACKGROUND The ovaries provide approximately half the circulating testosterone in premenopausal women. After bilateral oophorectomy, many women report impaired sexual functioning despite estrogen replacement. We evaluated the effects of transdermal testosterone in women who had impaired sexual function after surgically induced menopause. METHODS Seventy-five women, 31 to 56 years old, who had undergone oophorectomy and hysterectomy received conjugated equine estrogens (at least 0.625 mg per day orally) and, in random order, placebo, 150 microg of testosterone, and 300 microg of testosterone per day transdermally for 12 weeks each. Outcome measures included scores on the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and a sexual-function diary completed over the telephone. RESULTS The mean (+/-SD) serum free testosterone concentration increased from 1.2+/-0.8 pg per milliliter (4.2+/-2.8 pmol per liter) during placebo treatment to 3.9+/-2.4 pg per milliliter (13.5+/-8.3 pmol per liter) and 5.9+/-4.8 pg per milliliter (20.5+/-16.6 pmol per liter) during treatment with 150 and 300 microg of testosterone per day, respectively (normal range, 1.3 to 6.8 pg per milliliter [4.5 to 23.6 pmol per liter]). Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm in the Brief index of Sexual Functioning for Women (P=0.03 for both comparisons with placebo). At the higher dose the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from base line. The positive-well-being, depressed-mood, and composite scores of the Psychological General Well-Being Index also improved at the higher dose (P=0.04, P=0.03, and P=0.04, respectively, for the comparison with placebo), but the scores on the telephone-based diary did not increase significantly. CONCLUSIONS In women who have undergone oophorectomy and hysterectomy, transdermal testosterone improves sexual function and psychological well-being.

The number of eight-cell embryos is a key determinant for selecting day 3 or day 5 transfer

OBJECTIVE To select patients for day 3 vs. day 5 embryo transfer. DESIGN Retrospective analysis of assisted reproduction technology (ART) cycles comparing outcomes of day 3 and day 5 transfers. SETTING ART program of Brigham and Womens Hospital. PATIENT(S) Patients with day 3 or day 5 embryo transfers (n = 221 and 141, respectively). INTERVENTION(S) Cycles with eight or more zygotes were stratified by the number of eight-cell embryos available on day 3 (none, one or two, or three or more). MAIN OUTCOME MEASURE(S) Number of blastocysts, implantation rates, ongoing pregnancy rates, and number of fetal heart beats. RESULT(S) With no eight-cell embryos on day 3, 0% and 33% pregnancies resulted from day 5 vs. day 3 transfers. With one or two eight-cell embryos on day 3, ongoing and high order multiple rates were not different between day 3 and day 5 transfers. With three or more eight-cell embryos, day 5 transfer resulted in a decrease in multiple gestations but no difference in ongoing pregnancy rates compared with day 3 transfer. CONCLUSION(S) With no eight-cell embryos on day 3, a day 3 transfer is warranted. With one or two eight-cell embryos, any benefit of day 5 transfer appears to be equivocal. With three or more eight-cell embryos, day 5 transfer is recommended.

Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort

BACKGROUND Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. We investigated infertility and time to pregnancy in female childhood cancer survivors, and analysed treatment characteristics associated with infertility and subsequent pregnancy. METHODS The Childhood Cancer Survivor Study (CCSS) is a cohort study including 5 year cancer survivors from 26 Canadian and US institutions who were younger than 21 years at the time of diagnosis between Jan 1, 1970, and Dec 31, 1986, and a sibling control group. We included women aged 18-39 years who had ever been sexually active. We gathered demographic, medical, and reproductive data via a baseline questionnaire, and quantified exposure to alkylating agents and radiation therapy. Self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analysed. FINDINGS 3531 survivors and 1366 female sibling controls who enrolled between Nov 3, 1992, and April 4, 2004, were included. Compared with their siblings, survivors had an increased risk (relative risk [RR] 1·48 [95% CI 1·23-1·78]; p<0·0001) of clinical infertility (ie, >1 year of attempts at conception without success), which was most pronounced at early reproductive ages (RR 2·92 [95% CI 1·18-7·20], p=0·020, in participants ≤24 years; 1·61 [1·05-2·48], p=0·029, in those aged 25-29 years; and 1·37 [1·11-1·69], p=0·0035, in those aged 30-40 years). Despite being equally likely to seek treatment for infertility, survivors were less likely than were their siblings to be prescribed drugs for treatment of infertility (0·57 [95% CI 0·46-0·70], p<0·0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (p=0·032), 292 (64%) of 455 participants with self-reported clinical infertility achieved a pregnancy. INTERPRETATION A more comprehensive understanding of infertility after cancer is crucial for counselling and decision making about future conception attempts and fertility preservation. FUNDING National Cancer Institute, American Lebanese Syrian Associated Charities, Swim Across America.

Prospective Study of Fertility Concerns and Preservation Strategies in Young Women With Breast Cancer

PURPOSE Most research regarding fertility in young women with breast cancer has focused on long-term survivors. Little is known about how fertility concerns affect treatment decisions or fertility preservation strategies at the time of initial cancer diagnosis. PATIENTS AND METHODS As part of an ongoing prospective multicenter cohort study, we surveyed women with newly diagnosed early-stage breast cancer at age ≤ 40 years. The baseline survey included sociodemographic, medical, and treatment data as well as a modified Fertility Issues Survey, including fertility concern and preservation items. Univariable and multivariable modeling were used to investigate predictors of greater fertility concern. RESULTS Among the first 620 eligible respondents included in this analysis, median age was 37 years (range, 17 to 40 years); 425 women (68%) discussed fertility issues with their physicians before starting therapy, and 319 (51%) were concerned about becoming infertile after treatment. Because of concerns about fertility, four women (1%) chose not to receive chemotherapy, 12 (2%) chose one chemotherapy regimen over another, six (1%) considered not receiving endocrine therapy, 19 (3%) decided not to receive endocrine therapy, and 71 (11%) considered receiving endocrine therapy for < 5 years; 65 (10%) used fertility preservation strategies. Greater concern about fertility was associated with younger age, nonwhite race, not having children, and receipt of chemotherapy. CONCLUSION Many young women with newly diagnosed breast cancer have concerns about fertility, and for some, these substantially affect their treatment decisions. Only a minority of women currently pursue available fertility preservation strategies in this setting.

Complications of hysteroscopic surgery: predicting patients at risk.

Objective To determine the frequency of operative complications and whether they can be predicted by specific patient characteristics or type of hysteroscopic procedure. Methods We collected demographic and medical history information on 925 women who had hysteroscopies from 1995 through 1996. We compared differences in rates of operative complications of specific hysteroscopic procedures. Operative complications were defined as uterine perforation, excessive glycine absorption (1 L or more), hyponatremia, hemorrhage (500 mL or more), bowel or bladder injury, inability to dilate the cervix, and procedure-related hospital admissions. Results Operative complications occurred in 25 (2.7%) of 925 hysteroscopies. Excessive fluid absorption was the most frequent complication. Hysteroscopic myomectomy and resection of uterine septum were associated with greater odds of complications (odds ratio [OR] 7.4, 95% confidence interval [CI] 3.3, 16.6 and OR 4.0, 95% CI 0.9, 19.6, respectively). Hysteroscopic polypectomy and endometrial ablation were associated with lower odds of complications (OR 0.1, 95% CI 0.0, 0.7 and OR 0.4, 95% CI 0.1, 3.3, respectively). Hysteroscopies done by reproductive endocrinologists and preoperative GnRH agonist therapy were associated with 4–7 times higher odds for operative complications. Conclusion Complications during hysteroscopic surgery are rare. Among hysteroscopic procedures, myomectomies and resections of uterine septa have significantly higher rates of complications, especially excessive fluid absorption. Meticulous fluid management might limit the number of serious complications of these higher-risk procedures.

Multinucleation in normally fertilized embryos is associated with an accelerated ovulation induction response and lower implantation and pregnancy rates in in vitro fertilization-embryo transfer cycles

OBJECTIVE To determine if multinucleation in normally fertilized embryos is indicative of poor developmental or clinical pregnancy prognosis and to examine the ovulation induction characteristics associated with multinucleation. DESIGN Retrospective review. SETTING A tertiary care institution. PATIENT(S) Patients undergoing IVF-ET cycles (exclusive of other assisted reproductive technologies). MAIN OUTCOME MEASURE(S) Cycles in which embryos had at least 1 multinucleated blastomere were compared with cycles in which all blastomeres exhibited no nucleus or a single nucleus (control). RESULT(S) When >50% of transferred embryos contained multinucleated blastomeres there was a significant reduction in implantation (3.4% vs. 14.7%), clinical pregnancy (9.1% vs. 29.1%), and live birth rates (7.5% vs. 27.6%) when compared with transfers of control embryos. In conjunction with this finding, multinucleate cycles had higher E2 levels and more follicles on the day of hCG administration, a higher number of oocytes retrieved, a higher fertilization rate, and more embryos transferred per patient than did the cycles that produced control embryos. When multinucleated embryos were present, but not transferred, the developmental capacity of the sibling embryo was reduced. CONCLUSION(S) The evaluation of nuclear status using simple light microscopy is predictive of embryo developmental capacity and should be included in the embryo scoring system. The presence of multinucleated blastomeres in normally fertilized embryos is associated with a more effusive response to gonadotropin therapy and is indicative of a poor developmental outcome and lower clinical pregnancy rates.

Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer

OBJECTIVE To compare markers of ovarian reserve between women exposed to cytotoxic chemotherapy for early stage breast cancer and matched controls. DESIGN Cross-sectional evaluation of markers of ovarian reserve. SETTING Dana-Farber/Brigham and Womens Cancer Center, Massachusetts General Hospital, and Faulkner Hospital in Boston, MA. PATIENT(S) Breast cancer survivors with continued menses after chemotherapy were compared with age-matched, gravidity-matched controls. MAIN OUTCOME MEASURE(S) Antral follicle count (AFC), anti-Müllerian hormone (AMH), FSH, inhibin B (InB), and E(2) on day 2, 3, or 4 of the menstrual cycle. A Bonferroni correction was performed to correct for multiple comparisons. RESULT(S) Twenty survivors and 20 controls were evaluated; 50% of survivors were currently on tamoxifen. Median AFC was 6 for survivors and 9.5 for controls. There were significant differences between the two groups in AFC, AMH, and nonsignificant differences in FSH and InB, all indicating better ovarian reserve in controls. The AFC and AMH levels were highly correlated (r = 0.72). Survivors on tamoxifen had lower AFC, AMH, InB, and higher E(2) than nontamoxifen-treated survivors. CONCLUSION(S) Premenopausal breast cancer survivors have diminished ovarian reserve compared with controls.

Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization.

OBJECTIVE: To estimate the effect of body mass index (BMI) on oocyte and embryo parameters and cycle outcomes in women undergoing in vitro fertilization (IVF). METHODS: We evaluated a retrospective cohort of 1,721 women undergoing a first IVF cycle with fresh, autologous embryos between 2007 and 2010 in an academic infertility practice. Main outcome measures included number of mature and normally fertilized oocytes, embryo morphology, estradiol on the day of human chorionic gonadotropin administration, clinical pregnancy, spontaneous abortion, and live birth. We performed multivariable analyses, adjusting for potential confounders, including age at cycle start, infertility diagnosis, type of stimulation, total gonadotropin dose, use of intracytoplasmic sperm injection, and number of embryos transferred. RESULTS: Compared with women of normal BMI, women with class II (BMI 35–39.9) and III (BMI 40 or higher) obesity had fewer normally fertilized oocytes (9.3 compared with 7.6 and 7.7, P<.03) and lower estradiol levels (2,047 pg/mL compared with 1,498 and 1,361, P<.001) adjusting for age and despite similar numbers of mature oocytes. Odds of clinical pregnancy (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.31–0.82) and live birth (OR 0.51, 95% CI 0.29–0.87) were 50% lower in women with class III obesity as compared with women of normal BMI. CONCLUSION: Obesity was associated with fewer normally fertilized oocytes, lower estradiol levels, and lower pregnancy and live birth rates. Infertile women requiring IVF should be encouraged to maintain a normal weight during treatment. LEVEL OF EVIDENCE: II

Human embryonic stem cell derivation from poor-quality embryos

During in vitro fertilization, embryos deemed clinically useless based on poor morphology are typically discarded. Here we demonstrate a statistical correlation between the developmental stage of such poor-quality embryos and the yield of human embryonic stem (hES) cell lines. Early-arrested or highly fragmented embryos only rarely yield cell lines, whereas those that have achieved blastocyst stage are a robust source of normal hES cells.

In vitro fertilization for cancer patients and survivors

OBJECTIVE To determine in vitro fertilization (IVF) outcome in cancer patients. DESIGN Retrospective record review. SETTING Academic, hospital-based assisted reproductive technology (ART) program. PATIENT(S) Sixty-nine women undergoing 113 IVF/gamete intrafallopian transfer (GIFT) cycles after cancer treatment in one partner, and 13 women undergoing 13 IVF cycles for embryo cryopreservation before chemotherapy/radiation. INTERVENTION(S) IVF, intracytoplasmic sperm injection (ICSI), assisted hatching, and gamete intrafallopian transfer as indicated. MAIN OUTCOME MEASURE(S) Delivery rate, spontaneous abortion rate, number of embryos cryopreserved, cancer diagnosis, systemic or local cancer treatment, female age, amount of gonadotropin used, treatment duration, peak estradiol level, and number of oocytes and embryos. RESULT(S) The women undergoing IVF after chemotherapy had poorer responses to gonadotropins than did the women with locally treated cancers even though they were younger (33.5 +/- 1.3 vs. 36.5 +/- 0.5 years; P<.05). The delivery rates after the women had undergone chemotherapy tended to be lower among the systemic treatment group than it was for the local cancer treatment group: (13.3% [2 of 15] vs. 40% [14 of 56, P=NS]). The women who had cryopreserved all embryos before chemotherapy produced more oocytes (18.7 +/- 3.2 vs. 14.5 +/- 1.2) and embryos (11.3 +/- 1.9 vs. 7.5 +/- 0.7) than did the women who had had a history of local cancer treatment. Male factor infertility as a result of cancer treatment is well treated with IVF or intracytoplasmic sperm injection, where indicated (32% delivery rate/cycle), with no difference between the frozen sperm banked before cancer treatment and fresh sperm produced after treatment. CONCLUSION(S) Chemotherapy diminishes the response to ovulation induction in assisted reproductive technologies. IVF with cryopreservation of embryos allows embryo banking before chemotherapy for women who have been newly diagnosed with cancer. Factors related to the partner affect the success of IVF for male factor infertility as a result of cancer treatment.