Antimüllerian hormone and antral follicle count are lower in female cancer survivors and healthy women taking hormonal contraception.

OBJECTIVE: To determine the impact of hormonal contraception (HC) on markers of ovarian reserve, including antimüllerian hormone (AMH) and antral follicle count (AFC). DESIGN: Longitudinal prospective cohort. SETTING: University hospital. PATIENT(S): Young adult female cancer survivors and healthy similar-age women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Participants were followed annually to determine hormone levels and for transvaginal ultrasound. Subjects who used HC within the preceding 3 months were considered to be exposed. Linear mixed effects models were used to incorporate repeated measures and adjust for potential confounders. RESULT(S): A total of 249 women (126 survivors, 123 control subjects; average age 25.5 years) were followed for an average of 2.1 visits and 2.15 years. After adjusting for confounders, AMH was found to be 21% lower among survivors using HC and 55% lower among control subjects using HC (relative risk [RR] 0.79, 95% confidence interval [CI] 0.68-0.93; and RR 0.45, 95% CI 0.30-0.68; respectively). AFC was 20% lower among survivors and control subjects using HC (RR 0.80, 95% CI 0.69-0.93). When considering an individual subject, AMH was 17%-35% lower when a subject had recently used HC than when she had not (survivors: RR 0.83, 95% CI 0.75-0.93; control subjects: RR 0.65, 95% CI 0.55-0.78), and AFC was 11% lower (RR 0.89, 95% CI 0.82-0.96). Additive HC exposure across multiple visits was not associated with differences in AMH or AFC. CONCLUSION(S): AMH and AFC are significantly lower among women with recent exposure to HC. AMH and AFC should be interpreted with caution when measured in the setting of recent hormone use.

Quality of life in female cancer survivors: is it related to ovarian reserve?

PURPOSE: The purpose of the study is to assess the quality-of-life scores and possible association with measures of ovarian reserve in female cancer survivors compared to healthy controls of similar age. METHODS: In this prospective cohort study, fifty-nine cancer survivors aged 16-39 years and 66 healthy, similarly aged unexposed women were recruited at the University of Pennsylvania. The primary outcome measures are the generic and cancer-specific domain scores on the Quality of Life in Adult Cancer Survivors (QLACS) instrument, early follicular phase serum hormones, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), inhibin B (INH), anti-Mullerian hormone (AMH), and ovarian ultrasound measurements [ovarian volume and antral follicle count (AFC)]. RESULTS: Cancer survivors had significantly higher total and cancer-specific domain scores compared to unexposed participants. Serum AMH, INH, ovarian volume, and AFC were lower while serum FSH was higher in cancer survivors. Although survivors exhibited diminished ovarian reserve, these markers were not independently associated with total QLACS score. Cancer survivors with irregular menstrual function were found to have lower quality-of-life (QOL) scores than those with regular cycles. CONCLUSIONS: We found that QOL appears to be significantly impaired in cancer survivors compared to controls, even when remote from initial cancer diagnosis. In addition, our study suggests that reproductive aging contributes to QOL in the setting of irregular menses and likely profound impairment of ovarian function.

What is normal ovarian reserve?

While hormonal and ultrasonographic measures of ovarian reserve are often used to counsel patients about their fertility potential, normative data for these markers in the general population are lacking. Most studies are cross sectional and take place within specific subpopulations. Antral follicle count and anti-Mullerian hormone have been shown to be the best indicators of a woman's total follicular reserve. Ovarian volume, inhibin B, estradiol, and follicle-stimulating hormone are less helpful. Antral follicle count and anti-Mullerian hormone decrease with age and have been used to attempt to predict the length of the fertile window. Additional longitudinal data are needed for these biomarkers in populations of young, healthy, multiethnic women to assess for the presence of cofactors and determine the rate of age-related decline. Currently, these biomarkers are insufficient as predictors of fertility potential or advancement to menopause and no definitive determinations can be made about what constitutes "normal" levels of each measure.

Pregnancy after cancer: results from a prospective cohort study of cancer survivors.

BACKGROUND: Future fertility is an important concern for many cancer survivors. Cancer therapies have been shown to adversely impact reproductive function. However, it is difficult to predict the extent to which reproductive dysfunction will occur. The purpose of this study was to compare measures of ovarian reserve (MOR) and pregnancy rates in young female cancer survivors and similar-aged controls. PROCEDURES: A prospective cohort study was conducted in a university-hospital setting. Participants were followed annually for a mean 25 months to assess reproductive history, the incidence of pregnancy, and MOR (serum follicle-stimulating hormone, luteinizing hormone, estradiol, inhibin B, anti-mullerian hormone (AMH), antral follicle counts and mean ovarian volume). RESULTS: Eighty-four female survivors (average age 26, and 14 years post-treatment) and 98 similar-aged controls that were sexually active with men were included. At baseline, 27/84 survivors and 42/98 controls reported a prior pregnancy. Adjusted models showed that anti-mullerian hormone (AMH) and antral follicle count (AFC) were impaired in survivors with a prior pregnancy compared to controls with a prior pregnancy (P < 0.01, P = 0.03). During follow-up in 56 survivors and 74 controls, 19 pregnancies occurred in survivors and 18 in controls. Comparison of MOR between survivors who became pregnant and controls who became pregnant revealed that AMH and AFC were impaired in survivors (P < 0.05). Compared to survivors who did not become pregnant, survivors who did were older (P < 0.01) and more likely to be cohabitating (P < 0.01), but had similar MOR and exposure to alkylators (P = 0.34). CONCLUSIONS: Survivors achieved pregnancy at a rate similar to controls despite impaired MOR.

Response to ovarian stimulation in patients facing gonadotoxic therapy.

Chemotherapy naïve patients undergoing embryo/oocyte banking for fertility preservation (FP) were assessed for response to ovarian stimulation. Fifty FP patients facing gonadotoxic therapy were matched by age, race, cycle number, date of stimulation and fertilization method to patients undergoing IVF for infertility or oocyte donation. There were no differences in baseline FSH, anti-Müllerian hormone, antral follicle count and total gonadotrophin dose. FP patients had more immature oocytes (2.2 versus 1.1; P=0.03) and lower fertilization rates per oocyte retrieved (52% versus 70%; P=0.002). There were no differences in numbers of oocytes retrieved, mature oocytes or fertilized embryos. Subgroup analysis revealed that FP patients taking letrozole required higher gonadotrophin doses (3077IU versus 2259IU; P=0.0477) and had more immature oocytes (3.4 versus 1.2; P=0.03) than matched controls. There were no differences in gonadotrophin dose or oocyte immaturity among FP patients not taking letrozole. Overall, chemotherapy naïve FP patients had similar ovarian reserve, response to stimulation and oocyte and embryo yield compared to controls. Patients who received letrozole required higher gonadotrophin doses and produced more immature oocytes, suggesting that response to ovarian stimulation may be impaired in patients with hormone-sensitive cancers receiving letrozole. With improvement in cancer survival rates, there has been a shift in attention toward management of long-term consequences of cancer therapy, including infertility. Many young women with cancer, particularly those who will be treated with chemotherapy, pursue fertility preservation (FP) strategies for the purpose of banking oocytes or embryos for future use. We examined patients with no prior exposure to chemotherapy who underwent IVF to freeze embryos or oocytes for FP. Fifty FP patients were identified and matched to healthy controls by age, race, cycle number, date of stimulation and fertilization method. There were no differences in baseline measures of ovarian reserve or amount of medication needed to stimulate the ovaries. FP patients had more immature oocytes and lower fertilization rates than controls. There were no differences in number of oocytes retrieved, number of mature oocytes, rate of maturity or number of fertilized embryos. Subgroup analysis revealed that FP patients taking letrozole required higher gonadotrophin doses and had more immature oocytes compared with matched controls. There were no differences in gonadotrophin dose or oocyte immaturity among FP patients not taking letrozole. We demonstrated that FP patients not previously exposed to chemotherapy have similar ovarian reserve, response to stimulation and oocyte and embryo yield compared with infertile and donor controls. Patients who received letrozole required higher gonadotrophin doses and produced more immature oocytes, suggesting that response to ovarian stimulation may be impaired in patients with hormone-sensitive cancers receiving letrozole.

Pretreatment antimüllerian hormone levels determine rate of posttherapy ovarian reserve recovery: acute changes in ovarian reserve during and after chemotherapy.

OBJECTIVE: To identify factors associated with ovarian reserve impairment during and immediately after chemotherapy. DESIGN: Prospective cohort study. SETTING: Four university hospitals. PATIENT(S): Forty-six adolescent and young adult women with a new diagnosis of cancer requiring chemotherapy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Measurements of ovarian reserve via levels of serum follicle-stimulating hormone, luteinizing hormone, estradiol, inhibin B, and antimüllerian hormone (AMH) as well as antral follicle counts and mean ovarian volume at 3-month intervals. RESULT(S): Changes in ovarian reserve were quantified for both the acute impact of treatment using linear regression and the longitudinal recovery after therapy using mixed-effects models adjusted for baseline ovarian reserve, use of alkylating agent, and hormone use. The women had at least one pretreatment and two posttreatment study visits (mean follow-up interval: 12 months). All measures of ovarian reserve demonstrated statistically significant changes during chemotherapy. Alkylating agent exposure and baseline ovarian reserve were acutely associated with the magnitude of impairment, and pretreatment AMH levels were associated with the rate of recovery of AMH after treatment. In adjusted models, participants with a pretreatment AMH level > 2 ng/mL recovered at a rate of 11.9% per month after chemotherapy, whereas participants with pretreatment AMH levels ≤ 2 ng/mL recovered at a rate of 2.6% per month after therapy. CONCLUSION(S): Baseline ovarian reserve and alkylating agent exposure effect the magnitude of acute changes in ovarian reserve from chemotherapy. The rate of recovery of AMH is impacted by pretreatment levels. This should be considered during pretreatment fertility preservation counseling.

Sperm and oocyte cryopreservation: comprehensive consent and the protection of patient autonomy.

Sperm cryopreservation and increasingly oocyte cryopreservation are common forms of fertility preservation for oncology patients facing gonadotoxic therapy. Both procedures present challenging ethical issues with regard to informed consent, given that the context for these procedures is a disease that carries a significant risk of mortality. We argue that the current consent process does not allow for adequate collection of information about a patient's wishes for the custody of cryopreserved gametes in the case of premature death. After review of the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine guidelines we propose that a new, comprehensive consent procedure for sperm and oocyte cryopreservation including a 'roll-down' option is imperative to protect the autonomy of these oncology patients. This 'roll-down' option should allow for the transfer of custody of gametes to a pre-selected alternative recipient(s) if the original recipient no longer intends to use the gametes to create a child. We also demonstrate that objections over non-spousal custody of gametes can be overcome with sound ethical arguments.

How and when human chorionic gonadotropin curves in women with an ectopic pregnancy mimic other outcomes: differences by race and ethnicity.

OBJECTIVE: To investigate the hCG profiles in a diverse patient group with ectopic pregnancy (EP) and to understand when they may mimic the curves of an intrauterine pregnancy (IUP) or spontaneous abortion (SAB). DESIGN: Retrospective cohort study. SETTING: Three university hospitals. PATIENT(S): One hundred seventy-nine women with symptomatic pregnancy of unknown location. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Slope of log hCG; days and visits to final diagnosis. RESULT(S): Of women with an EP, 60% initially exhibited an increase in hCG values, with a median slope of 32% increase in 2 days; 40% of subjects initially had an hCG decrease, with the median slope calculated as a 15% decline in 2 days. In total, the hCG curves in 27% of women diagnosed with EP resembled that of a growing IUP or SAB. Of the EP hCG curves, 16% demonstrated a change in the direction of the slope of the curve. This was more common in African Americans and less evident in Hispanics. Furthermore, it was associated with more clinical visits and days until final diagnosis. CONCLUSION(S): The rate of change in serial hCG values can be used to distinguish EP from an IUP or SAB in only 73% of cases. The number of women who had a change in direction of serial hCG values was associated with race and ethnicity.

Pediatric and young adult patients and oncofertility.

OPINION STATEMENT: With improving survival rates for pediatric and young adult cancer patients, considerations regarding the long-term effects of therapy have become more important. Cancer therapies are known to pose reproductive risks, though the effects may be unpredictable. All at-risk patients should have a discussion about potential treatment-related infertility before the onset of cancer therapy, and should be offered appropriate fertility preservation options. Embryo and sperm cryopreservation are considered standard therapy, though oocyte cryopreservation is gaining acceptance. Ovarian tissue cryopreservation, while still experimental, is showing great promise. It is the only option currently available to prepubertal girls. No fertility preservation options exist for prepubertal boys though some institutions may offer experimental testicular tissue cryopreservation.

Imported Lassa fever, Pennsylvania, USA, 2010.

We report a case of Lassa fever in a US traveler who visited rural Liberia, became ill while in country, sought medical care upon return to the United States, and subsequently had his illness laboratory confirmed. The patient recovered with supportive therapy. No secondary cases occurred.