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BACKGROUND: Approximately half of all pregnancies in the United States are unintended. However, women who are diagnosed with cancer in their reproductive years may be a unique population. This study examines the prevalence of and identifies factors associated with unplanned pregnancy among cancer survivors. MATERIALS AND METHODS: Female cancer survivors aged 22–45 years, diagnosed between ages 20–35 years and at least 2 years postdiagnosis, and women with no history of cancer were interviewed about their reproductive histories, including pregnancy intention. Using a random matching process, comparison women were assigned an artificial age at cancer diagnosis equal to that of her cancer survivor match. An adjusted Cox model was fit examining time to unintended pregnancy after cancer for each of 1,000 matches. Cox proportional hazards models were also fit to assess associations between participant characteristics and unplanned pregnancy after cancer among survivors. RESULTS: Cancer survivors (n = 1,282) and comparison women (n = 1,073) reported a similar likelihood of having an unplanned pregnancy in models adjusted for race, income, history of sexually-transmitted infection, and history of unplanned pregnancy before diagnosis (adjusted hazard ratio [aHR] 1.06, 95% simulation interval 0.85–1.36). After adjusting for confounders, unplanned pregnancy among survivors was associated with age

Objective To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). Design Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. Setting Participants were recruited from academic and clinical settings. Patient(s) Women with a premutation (PM) who experienced FXPOI at the age of 35 years or younger (n = 63) and women with a PM who experienced menopause at the age of 50 years or older (n = 51) provided clinical information and a deoxyribonucleic acid sample for whole genome sequencing. The functional screen was on the basis of Drosophila TRiP lines. Intervention(s) Clinical information and a DNA sample were collected for whole genome sequencing. Main Outcome Measures A polygenic risk score derived from common variants associated with natural age at menopause was calculated and associated with the risk of FXPOI. Genes associated with the risk of FXPOI were identified on the basis of the P-value from gene-based association test and an altered level of fecundity when knocked down in the Drosophila PM model. Results The polygenic risk score on the basis of common variants associated with natural age at menopause explained approximately 8% of the variance in the risk of FXPOI. Further, SUMO1 and KRR1 were identified as possible modifying genes associated with the risk of FXPOI on the basis of an untargeted gene analysis of rare variants. Conclusions In addition to the large genetic effect of a PM on ovarian function, the additive effects of common variants associated with natural age at menopause and the effect of rare modifying variants appear to play a role in FXPOI risk.

PURPOSE: Oocyte donor in vitro fertilization (IVF) represents an ideal model to study the effects of embryo stage on reproductive success, as embryos come from young women with high-quality oocytes. Our study aimed to determine if embryo transfer stage affected outcomes in oocyte donor IVF, including the common scenario where only a limited number of quality embryos are available after culture. METHODS: This retrospective cohort analyzed anonymous vitrified donor oocyte cycles at a single clinic between 2008 and 2015. Overall, 983 recipients underwent 1178 warming cycles resulting in fresh transfer of one-to-two embryos. Our primary outcome was live birth; secondary outcomes included multiple birth, birthweight, and gestational age. Log binomial regression with cluster-weighted generalized estimating equations were used to calculate adjusted risk ratios (aRR) accounting for recipient age, race, and transfer year. RESULTS: Among 132 cleavage and 1046 blastocyst transfer cycles, cleavage transfers were associated with lower probability of live birth (aRR 0.72, 95% CI 0.59–0.88). Subgroup analysis focused on cycles with a limited number of quality embryos 3 days post-fertilization (≤2), as clinically these women were most likely to be considered for cleavage transfers. Among these cycles (120 cleavage, 371 blastocyst), cleavage transfers were still associated with lower live birth rates compared to blastocyst (aRR 0.66, 95% CI 0.51–0.87) CONCLUSIONS: Even in a donor oocyte model with high-quality oocytes, there was a benefit to extended culture and blastocyst transfer, including when only one-to-two quality embryos were available after early culture. This is possibly owed to improved uterine synchronicity or decreased contractility.

Objective Some treatments for systemic lupus erythematosus (SLE) can cause infertility, but the effect of SLE itself on fertility, particularly in African American women, is less clear. We undertook this study to examine infertility experiences in African American women with SLE compared to healthy women. Methods We enrolled women ages 22-40 years living in the Atlanta metropolitan area who were diagnosed with SLE after age 17 years. Women who had ever been treated with cyclophosphamide or who had a hysterectomy were excluded. African American women ages 22-40 years who were from the same area and recruited from a marketing list were used for comparison. Women were interviewed about their reproductive histories and goals. Periods of infertility were identified as times when women had regular, unprotected sex for ≥12 months without conceiving after 20 years of age. We separately considered any period of infertility and periods of infertility when attempting pregnancy. We used Cox proportional hazards regression to examine the association between SLE and time to infertility. Models were adjusted for age, nulliparity, and smoking. An age-matched analysis was also conducted to examine periods of infertility occurring after SLE diagnosis. Results Our sample included 75 women with SLE and 154 women without SLE. SLE was associated with any infertility (adjusted hazard ratio [HRadj ] 2.08 [95% confidence interval (95% CI) 1.38-3.15]), but less so with infertility when attempting pregnancy (HRadj 1.30 [95% CI 0.62-2.71]). The matched analysis generated similar point estimates. Conclusion Women with SLE may be more likely to experience episodes of infertility, but this may not translate to an inability to meet reproductive goals.

In 1973, accidental contamination of Michigan livestock with polybrominated biphenyls (PBBs) led to the establishment of a registry of exposed individuals that have been followed for > 40 years. Besides being exposed to PBBs, this cohort has also been exposed to polychlorinated biphenyls (PCBs), a structurally similar class of environmental pollutants, at levels similar to average US exposure. In this study, we examined the association between current serum PCB and PBB levels and various female reproductive health outcomes to build upon previous work and inconsistencies. Participation in this cross-sectional study required a blood draw and completion of a detailed health questionnaire. Analysis included only female participants who had participated between 2012 and 2015 (N = 254). Multivariate linear and logistic regression models were used to identify associations between serum PCB and PBB levels with each gynecological and infertility outcome. Additionally, a generalized estimating equation (GEE) model was used to evaluate each pregnancy and birth outcome in order to account for multiple pregnancies per woman. We controlled for age, body mass index, and total lipid levels in all analyses. A p-value of β = −0.11, 95% CI = −0.21 to −0.005, p = 0.04). There were no correlations between serum PCB levels and the self-reported gynecological outcomes (pelvic inflammatory disease, endometriosis, polycystic ovarian syndrome, or uterine fibroids). No associations were identified between serum PCB levels and the prevalence of female infertility in women reporting ever having sexual intercourse with a male partner. There were no associations identified between serum PCB levels and pregnancy outcomes (singleton live births or miscarriages) or birth outcomes (preterm birth, birth weight, birth defects, hypertensive disorders of pregnancy, or gestational diabetes). PBB was not associated with any outcome. Further research is needed to determine if and how PCB may reduce pregnancy number.

BACKGROUND: Brominated flame retardants, including polybrominated biphenyls (PBB), are persistent compounds reported to affect sex hormones in animals; less is known about potential effects in humans. An industrial accident in 1973–1974 exposed Michigan residents to PBB through contaminated food. We examined whether this exposure to PBB had long-term effects on menstrual cycle function. METHODS: In 2004–06, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications. Participants kept daily diaries and provided daily urine for up to 6 months. We assayed urine samples for estrone 3-glucuronide (E(1)3G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). We fit linear mixed models among women aged 35–42 years to describe the relation between serum PBB levels and log-transformed, creatinine-adjusted daily endocrine levels among women who were premenarchal during the exposure incident in 1973–74 (n=70). RESULTS: We observed that high (>3.0 parts per billion (ppb)) and medium (>1.0–3.0 ppb) PBB exposure were associated with lower E(1)3G levels across the menstrual cycle and lower FSH levels during the follicular phase, compared with low PBB exposure (≤1.0 ppb). High PBB exposure was also associated with lower Pd3G levels across the cycle compared with low PBB exposure, whereas Pd3G levels were similar in women with medium and low PBB exposure. CONCLUSIONS: Our results are consistent with a hypothesized effect of exposure to an exogenous estrogen agonist but the modest sample size of the study requires cautious interpretation.

Background Michigan residents were directly exposed to endocrine-disrupting compounds, polybrominated biphenyl (PBB) and polychlorinated biphenyl (PCB). A growing body of evidence suggests that exposure to certain endocrine-disrupting compounds may affect thyroid function, especially in people exposed as children, but there are conflicting observations. In this study, we extend previous work by examining age of exposure’s effect on the relationship between PBB exposure and thyroid function in a large group of individuals exposed to PBB. Methods Linear regression models were used to test the association between serum measures of thyroid function (total thyroxine (T4), total triiodothyronine (T3), free T4, free T3, thyroid stimulating hormone (TSH), and free T3: free T4 ratio) and serum PBB and PCB levels in a cross-sectional analysis of 715 participants in the Michigan PBB Registry. Results Higher PBB levels were associated with many thyroid hormones measures, including higher free T3 (p = 0.002), lower free T4 (p = 0.01), and higher free T3: free T4 ratio (p = 0.0001). Higher PCB levels were associated with higher free T4 (p = 0.0002), and higher free T3: free T4 ratio (p = 0.002). Importantly, the association between PBB and thyroid hormones was dependent on age at exposure. Among people exposed before age 16 (N = 446), higher PBB exposure was associated with higher total T3 (p = 0.01) and free T3 (p = 0.0003), lower free T4 (p = 0.04), and higher free T3: free T4 ratio (p = 0.0001). No significant associations were found among participants who were exposed after age 16. No significant associations were found between TSH and PBB or PCB in any of the analyses conducted. Conclusions This suggests that both PBB and PCB are associated with thyroid function, particularly among those who were exposed as children or prenatally. Electronic supplementary material The online version of this article (10.1186/s12940-019-0509-z) contains supplementary material, which is available to authorized users.

Background A growing literature suggests that minority races, particularly Black women, have a lower probability of live birth and higher risk of perinatal complications after autologous assisted reproductive technology. However, questions still remain as to whether these racial disparities have arisen because of associations between race and oocyte/embryo quality, the uterine environment, or a combination of the two. Oocyte donation assisted reproductive technology represents a unique approach to examine this question. Objective This study aimed to evaluate the associations between the race of female oocyte donors and recipients and live birth rates following vitrified donor oocyte assisted reproductive technologies. Study Design This was a retrospective study conducted at a single, private fertility clinic that included 327 oocyte donors and 899 recipients who underwent 1601 embryo transfer cycles (2008–2015). Self-reported race of the donor and recipient were abstracted from medical records. Live birth was defined as the delivery of at least 1 live-born neonate. We used multivariable cluster weighted generalized estimating equations with binomial distribution and log link function to estimate the adjusted risk ratios of live birth, adjusting for donor age and body mass index, recipient age and body mass index, tubal and uterine factor infertility, and year of oocyte retrieval. Results The racial profile of our donors and recipients were similar: 73% white, 13% Black, 4% Hispanic, 8% Asian, and 2% other. Women who received oocytes from Hispanic donors had a significantly higher probability of live birth (adjusted risk ratio, 1.20; 95% confidence interval, 1.05–1.36) than women who received oocytes from white donors. Among Hispanic recipients, however, there was no significant difference in probability of live birth compared with white recipients (adjusted risk ratio, 1.07; 95% confidence interval, 0.90–1.26). Embryo transfer cycles using oocytes from Black donors (adjusted risk ratio, 0.86; 95% confidence interval, 0.72–1.03) and Black recipients (adjusted risk ratio, 0.84; 95% confidence interval, 0.71–0.99) had a lower probability of live birth than white donors and white recipients, respectively. There were no significant differences in the probability of live birth among Hispanic, Asian, and other race recipients compared with white recipients. Conclusion Black female recipients had a lower probability of live birth following assisted reproductive technology, even when using vitrified oocytes from healthy donors. Female recipients who used vitrified oocytes from Hispanic donors had a higher probability of live birth regardless of their own race.

Context Menstrual cycle function is determined by a complex endocrine axis that controls the ovaries and endometrium. While the late luteal phase is characterized by declining progesterone and estrogen, how these hormonal profiles relate to menstrual bleeding patterns is not well understood. Objective Characterize associations between luteal phase hormonal profiles and subsequent menstrual bleeding patterns, specifically spotting before bleeding. Design, Setting, and Participants We examined creatinine-adjusted urinary estrone 3-glucuronide (E13G) and pregnanediol 3-glucuronide (Pd3G) levels in relation to spotting in 116 premenopausal women (ages 20–47) who kept daily menstrual diaries and collected first morning urine samples for ≥ 2 consecutive cycles or 1 luteal-follicular transition (n = 283 transitions). We used linear mixed models to estimate associations between luteal phase hormone levels and spotting before bleeding. Main Outcome Measure(s) and Results Transitions with ≥ 1 days of spotting before menstrual bleeding (n = 118) had greater luteal phase Pd3G levels vs nonspotting transitions (n = 165). Differences in Pd3G between spotting and nonspotting transitions were largest at menses onset (34.8%, 95% confidence interval, 18.9%, 52.7%). Pd3G levels for spotting transitions dropped to similar levels as nonspotting transitions an average of 1 day later, which aligned with the first day of bleeding for transitions with contiguous spotting. Spotting transitions were preceded by slower rates of Pd3G decline than nonspotting transitions, whereas E13G declines were similar. Conclusions Self-reported bleeding patterns may provide insight into luteal phase Pd3G levels. First bleed appears to be the best choice for defining the end of the luteal phase and achieving hormonal consistency across transitions.

Gender affirming procedures adversely affect the reproductive potential of transgender people. Thus, fertility preservation options should be discussed with all transpeople before medical and surgical transition. In transwomen, semen cryopreservation is typically straightforward and widely available at fertility centers. The optimal number of vials frozen depends on their reproductive goals and treatment options, therefore a consultation with a fertility specialist is optimal. Experimental techniques including spermatogonium stem cells (SSC) and testicular tissue preservation are technologies currently under development in prepubertal individuals but are not yet clinically available. In transmen, embryo and/or oocyte cryopreservation is currently the best option for fertility preservation. Embryo cryopreservation requires fertilization of the transman's oocytes with a donor or partner's sperm prior to cryopreservation, but this limits his future options for fertilizing the eggs with another partner or donor. Oocyte cryopreservation offers transmen the opportunity to preserve their fertility without committing to a male partner or sperm donor at the time of cryopreservation. Both techniques however require at least a two-week treatment course, egg retrieval under sedation and considerable cost. Ovarian tissue cryopreservation is a promising experimental method that may be performed at the same time as gender affirming surgery but is offered in only a limited amount of centers worldwide. In select places, this method may be considered for prepubertal children, adolescents, and adults when ovarian stimulation is not possible. Novel methods such as in-vitro activation of primordial follicles, in vitro maturation of immature oocytes and artificial gametes are under development and may hold promise for the future.

Objective In female cancer patients anticipating chemotherapy or radiation, oocyte retrieval for fertility should be performed as efficiently as possible to avoid postponing cancer treatments. Our objective was to compare clinical outcomes among female cancer patients who underwent a conventional early follicular phase-start ovarian stimulation cycle and those who underwent a random-start ovarian stimulation cycle. Evidence review A systematic review of the literature was performed in accordance with PRISMA guidelines. Medline, Embase.com, Scopus, Cochrane Library, and Clinicaltrials.gov databases were searched to identify all original research published in English through July 2020 on the topic of female cancer patients undergoing ovarian stimulation with a random or conventional start. Studies lacking a comparison group or including women who had already undergone chemotherapy at the time of ovarian stimulation were excluded. The primary author assessed all identified article titles and abstracts, and two independent reviewers assessed full-text articles and extracted data. A meta-analysis with a random-effects model was used to calculate weighted mean differences (WMDs) for outcomes of interest. The primary outcome was the number of mature (meiosis II) oocytes retrieved. Secondary outcomes included duration of stimulation, total dose of gonadotropins, total number of oocytes retrieved, fertilization rate, and number of embryos or zygotes cryopreserved. Results A total of 446 articles were screened, and 9 full-text articles (all retrospective cohort or prospective observational) were included for review. Additionally, pooled primary retrospective data from two institutions were included. In total, data from 10 studies including 1653 women were reviewed. Five studies reported the number of embryos cryopreserved, and four reported fertilization rates. Random-start cycles were slightly longer (WMD 0.57 days, 95 % confidence interval [CI] 0.0–1.14 days) and used more total gonadotropins (WMD 248.8 international units, 95 % CI 57.24–440.40) than conventional-start cycles. However, there were no differences in number of mature oocytes retrieved (WMD 0.41 oocytes, 95 % CI −0.84–1.66), number of total oocytes retrieved (WMD 0.90 oocytes, 95 % CI −0.21–2.02), fertilization rates (WMD −0.12, 95 % CI −1.22–0.98), or number of embryos cryopreserved (WMD 0.12 embryos, 95 %CI −0.98–1.22) between random-start and conventional-start cycles. All outcomes except for the parameter “total oocytes retrieved” yielded an I2 of over 50 %, indicating substantial heterogeneity between studies. Conclusion(s) Although random-start cycles may entail a longer duration of stimulation and use more total gonadotropins than conventional-start cycles, the absolute differences are small and likely do not significantly affect treatment costs. The similar numbers of mature oocytes retrieved, fertilization rates, and number of embryos cryopreserved in the two start-types suggest that they do not differ in any clinically important ways. Given that random-start cycles can be initiated quickly, they may help facilitate fertility preservation for cancer patients.

It is unclear whether cancer and its treatments increase the risk of adverse pregnancy outcomes. Our aim was to examine whether cancer survivors have higher risks of poor outcomes in pregnancies conceived after diagnosis than women without cancer, and whether these risks differ by cancer type and race. Diagnoses from cancer registries were linked to pregnancy outcomes from birth certificates in three U.S. states. Analyses were limited to the first, live singleton birth conceived after diagnosis. Births to women without a previous cancer diagnosis in the registry were matched to cancer survivors on age at delivery, parity, race/ethnicity and education. Log-binomial regression was used to estimate risk ratios. Cervical cancer survivors had higher risks of preterm birth (Risk ratio = 2.8, 95% Confidence interval: 2.1, 3.7), as did survivors of invasive breast cancer (RR = 1.3, 95% CI: 1.1, 1.7) and leukemia (RR = 2.1, 95% CI: 1.3, 3.5). We observed a higher risk of small for gestational age (SGA) infants (

Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence-based guidelines for the treatment and follow-up of CG are currently lacking, and treatment and follow-up have been demonstrated to vary worldwide. To provide patients around the world the same state-of-the-art in care, members of The Galactosemia Network (GalNet) developed an evidence-based and internationally applicable guideline for the diagnosis, treatment, and follow-up of CG. The guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. A systematic review of the literature was performed, after key questions were formulated during an initial GalNet meeting. The first author and one of the working group experts conducted data-extraction. All experts were involved in data-extraction. Quality of the body of evidence was evaluated and recommendations were formulated. Whenever possible recommendations were evidence-based, if not they were based on expert opinion. Consensus was reached by multiple conference calls, consensus rounds via e-mail and a final consensus meeting. Recommendations addressing diagnosis, dietary treatment, biochemical monitoring, and follow-up of clinical complications were formulated. For all recommendations but one, full consensus was reached. A 93 % consensus was reached on the recommendation addressing age at start of bone density screening. During the development of this guideline, gaps of knowledge were identified in most fields of interest, foremost in the fields of treatment and follow-up. Electronic supplementary material The online version of this article (doi:10.1007/s10545-016-9990-5) contains supplementary material, which is available to authorized users.

PURPOSE: Endocrine disrupting compounds (EDCs) have been shown to affect multiple biologic processes especially steroid-hormone processes. We sought to determine differences in DNA methylation exists between women with and without endometriosis following exposure to polybrominated biphenyl (PBB). METHODS: Cross-sectional study of 305 females in the Michigan PBB Registry. DNA was extracted, and DNA methylation was interrogated using the MethylationEPIC BeadChip (Illumina, San Diego, California). Demographic data was analyzed using Chi-squared and T tests. Linear regressions were performed for each cytosine-guanine dinucleotide (CpG) site, modeling the logit transformation of the β value as a linear function of the presence of endometriosis. Sensitivity analyses were conducted controlling for estradiol levels and menopausal status. Replication study performed evaluating for any association between CpGs reported in the literature and our findings. RESULTS: In total, 39,877 CpGs nominally associated with endometriosis (p

Objective: Supraphysiologic estradiol (E2) levels associated with controlled ovarian hyperstimulation in high in vitro fertilization (IVF) responders may alter implantation and placentation and increase the risk of preeclampsia. Our hypothesis is that elevated E2 levels in vitro significantly alter endometrial decidualization, sFlt1, and HOXA10 expression. Methods: Human endometrial stromal cells were treated with a decidualization cocktail of medroxyprogesterone, cyclic adenosine monophosphate, and 3 concentrations of E2 10 nM (standard), 100 nM (intermediate), or 1000 nM E2 (high). Effects on sFlt1, prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP-1), vascular endothelial growth factor (VEGF), and HOXA10 were studied. Results: Prolactin, IGFBP-1, and VEGF significantly increased at all 3 E2 concentrations. While IGFBP-1 and VEGF did not change with increasing E2, PRL was less with high E2 (6.0 ng/mL + 1.4 standard error of the mean) compared to standard (21.4 + 3.2) and intermediate (19.8 + 3.8). sFlt1 decrease was similar at all E2 concentrations. HOXA10 was lower at standard (10%) and intermediate (30%) as expected, but did not change with high E2. Conclusions: Supraphysiologic E2 levels associated with high IVF responders that exceed in vivo levels may impair in vitro endometrial decidualization. Although PRL did increase with high E2, the levels were, however, attenuated and 3.4-fold lower than standard and intermediate E2. sFlt1 was decreased under all 3 conditions with no differences between concentrations. Reduced HOXA10 was not observed with high E2. These findings suggest that elevated E2 levels in vitro may alter endometrial decidualization and subsequently affect implantation and placentation.

Objective Approximately 20% of women with a premutation in the FMR1 gene experience primary ovarian insufficiency (POI). We explored diagnostic patterns, frequency of appropriate hormone replacement, obstetric outcomes, fertility treatment, reproductive decisions, and counseling of women with fragile X-associated POI (FXPOI). Methods Semistructured interviews with 79 women with FXPOI were conducted by a single interviewer. FMR1 cytosine-guanine-guanine repeat size was determined from a blood, saliva, or buccal sample. Results The median age of POI onset for women in our study was 33 years. Seventy-two percent of the women had an FMR1 cytosine-guanine-guanine repeat length of 80 to 100. Mean length of time from symptom onset to POI diagnosis was 1.12 years, longer in women with a younger age of POI onset and shorter in women who knew they were carriers. After diagnosis, 52% of women never took hormone therapy, started it years after POI diagnosis, or stopped it before 45 years of age. Forty-nine percent of the women had infertility, but 75% had had at least one genetically related child. Obstetric outcomes were similar to the general population. Forty-six percent of women had a diagnosis of low bone mineral density or osteoporosis, and an additional 19% had never had a bone density assessment. Conclusions Women with FXPOI are at significant risk for delayed POI diagnosis and undertreatment with hormone therapy. Although approximately 50% of women had infertility, most were able to conceive at least one child and had no elevated risk of adverse obstetric outcomes.

Objective To examine the degree to which paternal variables of age, body mass index (BMI), and sperm parameters affect vitrified donor oocyte IVF outcomes. Previous studies examining the impact of male partner characteristics on in-vitro fertilization (IVF) have found conflicting results. Concerns are rising over the potential effects of paternal factors, such as age and obesity, on pregnancy and child health. Frozen donor oocyte IVF offers an ideal model to study these effects. Design Retrospective chart review. Setting Private fertility clinic. Patient(s) Nine hundred forty-nine recipients undergoing transfer of blastocyst embryo(s) from a vitrified oocyte donor bank between 2008-2015. Intervention(s) None. Main Outcome Measure(s) Implantation rate, clinical pregnancy rate, live birth rate, rate of low birth weight singleton infants (≤2500 g), and preterm deliveries (PTD) of singleton infants ( Results After adjusting for covariates known to affect oocyte donation cycle success, male age, BMI and sperm parameters were not associated with differences in IVF outcomes. There were higher PTD rates for men ≥51 years and BMI ≥35 kg/m2, however, these were not significant after adjustment. There were no differences in rates of low birth weight infants with men >35 years or BMI >25 kg/m2. Lastly, there were no differences in rates of PTD or low birth weight infants with abnormal sperm parameters. Conclusions Neither advancing male age, elevated BMI, nor poor sperm quality were associated with outcomes in frozen donor oocyte IVF cycles in this study. Intracytoplamic sperm injection and “oocyte quality” likely mitigate some of the effects of male variables on outcomes following cryopreserved oocyte donation.

BACKGROUND: Previous studies have reported that hyperthyroid and hypothyroid women experience menstrual irregularities more often compared with euthyroid women, but reasons for this are not well understood and studies on thyroid hormones among euthyroid women are lacking. In a prospective cohort study of euthyroid women, this study characterized the relationship between thyroid hormone concentrations and prospectively-collected menstrual function outcomes. METHODS: Between 2004–2014, 86 euthyroid premenopausal women not lactating or taking hormonal medications participated in a study measuring menstrual function. Serum thyroid hormones were measured before the menstrual function study began. Women then collected first morning urine voids and completed daily bleeding diaries every day for three cycles. Urinary estrogen and progesterone metabolites (estrone 3-glucuronide (E(1)3G) and pregnanediol 3-glucuronide (Pd3G)) and follicle-stimulating hormone were measured and adjusted for creatinine (Cr). RESULTS: Total thyroxine (T(4)) concentrations were positively associated with Pd3G and E(1)3G. Women with higher (vs. lower) T(4) had greater luteal phase maximum Pd3G (Pd3G=11.7 μg/mg Cr for women with high T(4) vs. Pd3G=9.5 and 8.1 μg/mg Cr for women with medium and low T(4), respectively) and greater follicular phase maximum E(1)3G (E(1)3G=41.7 ng/mg Cr for women with high T(4) vs. E(1)3G=34.3 and 33.7 ng/mg Cr for women with medium and low T(4), respectively). CONCLUSIONS: Circulating thyroid hormone concentrations were associated with subtle differences in menstrual cycle function outcomes, particularly sex steroid hormone levels in healthy women. Results contribute to the understanding of the relationship between thyroid function and the menstrual cycle, and may have implications for fertility and chronic disease.

Gonadal hypofunction is described in male and female patients with sickle cell anemia (SCA) after bone marrow transplant (BMT) and in males treated with hydroxyurea (HU). Anti-Müllerian hormone (AMH) is a serum marker of ovarian reserve. This study describes AMH and follicle-stimulating hormone (FSH) levels in female SCA subjects treated with supportive care (SCA-SC), HU (SCA-HU) and BMT (SCA-BMT). SCA (SS/Sβ(0)) subjects not on HU, on HU and status-post BMT, ages 10-21 years were recruited. SCA-HU subjects were treated with HU ≥ 20 mg/kg for ≥ 12 consecutive months. SCA-BMT subjects had received busulfan and cyclophosphamide. Serum AMH and random FSH levels were obtained. Diminished ovarian reserve (DOR) was defined as AMH level5th percentile for age-matched controls. Subjects also with FSH40 IU/L were classified as having premature ovarian insufficiency (POI). 14 SCA-SC (14.5 ± 2.7 years), 33 SCA-HU (14.4 ± 2.4 years) and 9 SCA-BMT (14.3 ± 2.7 years) females were included. AMH was undetectable in all SCA-BMT subjects and5th percentile in 24% of SCA-HU subjects. FSH was menopausal (40 IU/L) in 88.9% of SCA-BMT subjects. All SCA-BMT subjects and 24% of subjects on HU had DOR; 89% of SCA-BMT subjects had POI. AMH and FSH may be useful tools in assessing ovarian reserve and function.

Objective To compare markers of fertility and ovarian reserve between cancer survivors and cancer-free women with and without polycystic ovary syndrome (PCOS). Design Furthering Understanding of Cancer, Health, and Survivorship in Adult (FUCHSIA) Women's Study—a population-based cohort study. Setting Not applicable. Patient(s) Female cancer survivors (n = 1,090) aged 22–45 years, diagnosed between ages 20 and 35 years, and at least 2 years after diagnosis; 369 participated in a clinic visit. Three hundred seventy-four reproductive-aged women without cancer also completed a clinic visit. Intervention(s) None. Main Outcome Measure(s) Infertility, time to first pregnancy after cancer diagnosis, and measures of ovarian reserve (antimullerian hormone [AMH] and antral follicle count [AFC]). Results Seventy-eight cancer survivors (7.2%) reported a PCOS diagnosis, with 41 receiving gonadotoxic treatment. Survivors with PCOS exposed to gonadotoxic treatment (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.2–4.5) and unexposed (OR 3.4, 95% CI 1.7–6.9) were more likely to report infertility than unexposed survivors without PCOS and were more likely to have fewer children than desired (exposed: OR 2.1, 95% CI 1.0–4.2; unexposed: OR 3.0, 95% CI 1.4–6.8). After adjusting for age, comparison women with PCOS had the highest markers of ovarian reserve (AMH: 2.43 ng/mL, 95% CI 1.22–4.82 ng/mL; AFC: 20.7, 95% CI 15.3–27.8), and cancer survivors without PCOS treated with gonadotoxic agents had the lowest levels (AMH: 0.19 ng/mL, 95% CI 0.14–0.26 ng/mL; AFC: 7.4, 95% CI 6.4–8.5). Conclusion(s) Despite having higher AMH and AFC on average after cancer treatment, cancer survivors with PCOS were less likely to meet their reproductive goals compared with survivors without PCOS.

Preeclampsia (PE) is a major complication of pregnancy in which the placenta is known to have shallow implantation into the uterine decidua. Studies have implicated soluble fms-like tyrosine kinase-1 (sFlt1), a soluble vascular endothelial growth factor (VEGF) receptor protein, in the pathogenesis of PE. sFlt1 has the ability to bind to and neutralize the angiogenic functions of VEGF and placental growth factor (PlGF). The presence of sFlt1 and its action in the endometrium is yet to be determined. We hypothesize that endometrial stromal cells (ESC) at the maternal-fetal interface may play a role in sFlt-1 regulation during pregnancy. In this study, we seek to understand the dynamic regulation of sFlt1 production in primary human ESC as a result of hormone stimulation and withdrawal. To mimic a biphasic menstrual cycle, ESC were treated with cAMP to induce endometrial decidualization that occurs during the luteal secretory phase, followed by cAMP withdrawal reflecting the follicular proliferative phase. Here, we present data to show that (1) ESC produce detectable amounts of sFlt1, (2) sFlt1 expression is turned off during decidualization at both the protein and RNA level (3) ESC decidualization and resulting sFlt1 expression are reversible phenomenon, and (4) Decidualization markers prolactin (PRL) and VEGF expressions in ESC are negatively correlated with sFlt1. These findings may have important implications in diseases such as PE that involve abnormal decidualization, implantation and angiogenesis at the maternal-fetal interface.

PURPOSE: To evaluate the difference in tubal ligation use between rural and urban counties in the state of Georgia, USA. METHODS: The study population included 2,160 women aged 22–45. All participants completed a detailed interview on their reproductive histories. County of residence was categorized using the National Center for Health Statistics Urban-Rural Classification Scheme. We estimated the association between urbanization of county of residence and tubal ligation using Cox regression. Among women with a tubal ligation, we examined factors associated with prior contraception use and the desire for more children. FINDINGS: After adjustment for covariates, women residing in rural counties had twice the incidence rate of tubal ligation compared with women in large metropolitan counties (adjusted Hazard Ratio (aHR) = 2.0, 95% Confidence Interval (CI) = 1.4–2.9) and were on average 3 years younger at the time of the procedure. No differences were observed between small metropolitan and large metropolitan counties (aHR = 1.1, CI = 0.9–1.5). Our data trend to suggest that women from large metropolitan counties are slightly more likely than women from rural counties to use hormonal contraception or long-acting reversible contraception (LARC) prior to tubal ligation and to desire more children after tubal ligation. CONCLUSIONS: Women from rural counties are more likely to undergo a tubal ligation than their urban counterparts. Our results suggest that circumstances regarding opting for tubal ligation may differ between urban and rural areas, and recommendations of alternative contraceptive options may need to be tailored differently for rural areas.

Objective To identify factors associated with cancer treatment–induced amenorrhea and time to return of menses. Design Population-based cohort study. Setting Not applicable. Patient(s) Female cancer survivors who were diagnosed with cancer between the ages of 20 and 35 and were at least 2 years postdiagnosis at the time of recruitment (median = 7 years; interquartile range, 5–11). Intervention(s) None. Main Outcome Measure(s) Amenorrhea (≥6 months without menses) and resumption of menses. Result(s) After excluding women with hysterectomies before cancer diagnosis, 1,043 women were eligible for analysis. Amenorrhea occurred in 31.6% of women. Among women treated with chemotherapy (n = 596), older age at diagnosis (30–35 vs. 20–24 years: adjusted odds ratio [aOR] = 2.37; 95% confidence interval [CI], 1.30, 4.30) and nulligravidity (vs. gravid: aOR=1.50; 95% CI, 1.02, 2.21) were risk factors for amenorrhea. Among amenorrheic women, menses resumed in most (70.0%), and resumption occurred within 2 years of treatment for 90.0% of women. Survivors of breast cancer were more likely to resume menses at times greater than 1 year compared with lymphoma and pelvic-area cancers. Women diagnosed at older ages, those exposed to chemotherapy, and those exposed to any radiation experienced longer times to return of menses. Women who were older at diagnosis were more likely to have irregular cycles when menses returned. Conclusion(s) Treatment-induced amenorrhea is common in cancer survivors, although most women resume menses within 2 years. However, once resumed, older women are more likely to have irregular cycles. Age at diagnosis and pregnancy history affect the risk of amenorrhea.

Objective To assess which characteristics are associated with failure to receive fertility counseling among a cohort of young women diagnosed with cancer. Design Population-based cohort study. Setting Not applicable. Patient(s) A total of 1,282 cancer survivors, of whom 1,116 met the inclusion criteria for the analysis. Intervention(s) None. Main Outcome Measure(s) The main outcome in this study was whether or not women reported receiving any information at the time of their cancer diagnosis on how cancer treatment might affect their ability to become pregnant. Result(s) Forty percent of cancer survivors reported that they did not receive fertility counseling at the time of cancer diagnosis. Women were more likely to fail to receive counseling if they had only a high school education or less or if they had given birth. Cancer-related variables that were associated with a lack of counseling included not receiving chemotherapy as part of treatment and diagnosis with certain cancer types. Conclusion(s) Counseling about the risk of infertility and available fertility preservation options is important to cancer patients. Additionally, counseling can make women aware of other adverse reproductive outcomes, such as early menopause and its associated symptoms. Less-educated women and parous women are at particular risk of not getting fertility-related information. Programs that focus on training not just the oncologist, but also other health care providers involved with cancer care, to provide fertility counseling may help to expand access.

Single-nucleotide polymorphisms (SNPs) are the most frequent type of variation in the human genome, and they provide powerful tools for a variety of medical genetic studies. In a large-scale survey for SNPs, 2.3 megabases of human genomic DNA was examined by a combination of gel-based sequencing and high-density variation-detection DNA chips. A total of 3241 candidate SNPs were identified. A genetic map was constructed showing the location of 2227 of these SNPs. Prototype genotyping chips were developed that allow simultaneous genotyping of 500 SNPs. The results provide a characterization of human diversity at the nucleotide level and demonstrate the feasibility of large-scale identification of human SNPs.

Classic galactosemia is a potentially lethal genetic disorder resulting from profound impairment of galactose-1P uridylyltransferase (GALT). More than 80% of girls and women with classic galactosemia experience primary or premature ovarian insufficiency despite neonatal diagnosis and rigorous lifelong dietary galactose restriction.The goal of this study was to test the relationship between markers of ovarian reserve, cryptic residual GALT activity, and spontaneous pubertal development in girls with classic galactosemia.This was a cross-sectional study with some longitudinal follow-up in a university research environment.Patients included girls and women with classic galactosemia and unaffected controls,1 month to 30 years old.We evaluated plasma anti-Müllerian hormone (AMH) and FSH levels, antral follicle counts ascertained by ultrasound, and ovarian function as indicated by spontaneous vs assisted menarche.More than 73% of the pre- and postpubertal girls and women with classic galactosemia in this study, ages3 months to 30 years, demonstrated AMH levels below the 95% confidence interval for AMH among controls of the same age, and both pre- and postpubertal girls and women with classic galactosemia also demonstrated abnormally low antral follicle counts relative to age-matched controls. Predicted residual GALT activity ≥ 0.4% significantly increased the likelihood that a girl with classic galactosemia would demonstrate an AMH level ≥ 0.1 ng/mL.A majority of girls with classic galactosemia demonstrate evidence of diminished ovarian reserve by 3 months of age, and predicted cryptic residual GALT activity is a modifier of ovarian function in galactosemic girls and women.

Secondary amenorrhea in women of reproductive age may be an indication of an undiagnosed, chronic condition and appropriate treatment is dependent upon accurate diagnosis of the underlying etiology. A thorough clinical assessment and a few common laboratory tests can easily identify the most frequent causes of secondary amenorrhea. However, once these have been ruled out, the more uncommon pathophysiologies can be difficult to diagnose due to similarities in presentation and appropriate laboratory testing and interpretation become critical. In these cases, misdiagnosis is unfortunately common and often the result of poor laboratory utilization in the form of a failure to employ indicated tests, the use of obsolete tests, or erroneous interpretation in the face of interfering factors or co-morbidities. Consequently, the algorithmic approach to laboratory evaluation in the context of secondary amenorrhea described in this review can minimize the risk of diagnostic error as well was decrease test volume, cost, and time to diagnosis.

Objective To determine whether developing hypothyroidism after cancer treatment is associated with a decreased probability of women being able to meet their reproductive goals. Design A population-based cohort study. Setting Not applicable. Patient(s) A total of 1,282 cancer survivors, of whom 904 met the inclusion criteria for the analysis. Intervention(s) None. Main Outcome Measure(s) Three outcomes that may indicate reduced fertility, which include failure to achieve desired family size, childlessness, and not achieving pregnancy after at least 6 months of regular unprotected intercourse. Result(s) We used data from the Furthering Understanding of Cancer Health and Survivorship in Adult (FUCHSIA) Women's Study to examine the association between being diagnosed with hypothyroidism after cancer and meeting reproductive goals. After adjusting for age and other potential confounders, women reporting hypothyroidism after cancer treatment were twice as likely to fail to achieve their desired family size (adjusted odds ratio [aOR] 1.91; 95% confidence interval [CI], 1.09, 3.33) and be childless (aOR 2.13; 95% CI, 1.25, 3.65). They were also more likely to report having unprotected intercourse for at least 6 months without conceiving (aOR 1.37; 95% CI, 0.66, 2.83). Conclusion(s) Although cancer treatments themselves are gonadotoxic, it is important to consider other medical conditions such as hypothyroidism that occur after cancer treatment when counseling patients on the risks for impaired fertility or a shortened reproductive window.

Objective To determine if girls with Duarte variant galactosemia (DG) have an increased risk of developing premature ovarian insufficiency based on prepubertal anti-Mullerian hormone (AMH) levels. Design Cross-sectional study. Setting University research laboratory. Patient(s) Study volunteers included 57 girls with DG, 89 girls with classic galactosemia (GG), and 64 control girls between the ages of Intervention(s) Blood sampling. Main Outcome Measure(s) We determined AMH and FSH levels in study volunteers with and without Duarte variant or GG. Result(s) FSH levels were significantly higher and AMH levels significantly lower in girls with GG than in age-stratified control girls, but there was no significant difference between FSH and AMH levels in girls with DG and control girls. Conclusion(s) Although >80% of girls with GG in this study demonstrated low to undetectable AMH levels consistent with diminished ovarian reserve, 100% of girls with DG in our study demonstrated no apparent decrease in AMH levels or increase in FSH levels, suggesting that these girls are not at increased risk for premature ovarian insufficiency.

Primary or premature ovarian insufficiency (POI) is the most common long-term complication experienced by girls and women with classic galactosemia; more than 80% and perhaps more than 90% are affected despite neonatal diagnosis and careful lifelong dietary restriction of galactose. In this review we explore the complexities of timing and detection of galactosemia-associated POI and discuss potential underlying mechanisms. Finally, we offer recommendations for follow-up care with current options for intervention.

Background Administration of recombinant luteinizing hormone (rLH) in controlled ovarian hyperstimulation may benefit a subpopulation of patients. However, late follicular phase administration of high doses of rLH may also reduce the size of the follicular cohort and promote monofollicular development. Methods To determine if rLH in late follicular development had a negative impact on follicular growth and oocyte yield, IVF patients in our practice who received rFSH and rLH for the entire stimulation were retrospectively compared with those that had the rLH discontinued at least two days prior to hCG trigger. Results The two groups had similar baseline characteristics before stimulation with respect to age, FSH level and antral follicle count. However, the group which had the rLH discontinued at least two days prior to their hCG shot, had a significantly higher number of oocytes retrieved, including a higher number of MII oocytes and number of 2PN embryos. Conclusions When using rLH for controlled ovarian hyperstimulation, administering it from the start of stimulation and stopping it in the late follicular phase, at least two days prior to hCG trigger, may increase oocyte and embryo yield.

Objective To determine whether premature ovarian insufficiency (POI) associated with classic galactosemia results from a true impairment of ovarian function or from aberrant FSH. Design Cross-sectional study. Setting University research laboratory. Patient(s) Study subjects included 35 girls and women with galactosemia and 43 control girls and women between the ages of Intervention(s) Blood sampling and medical and reproductive histories were obtained. Main Outcome Measurement(s) We determined FSH and anti-Mullerian hormone (AMH) levels in subjects with and without classic galactosemia. FSH bioactivity was measured in a subset of girls and women with and without galactosemia who were not on hormone therapy. Result(s) FSH levels were significantly higher and AMH levels were significantly lower in our galactosemic cases relative to controls. FSH bioactivity did not significantly differ between cases and controls. Conclusion(s) Close to 90% of girls and women with classic galactosemia have a profound absence of ovarian function, a deficit that is evident shortly after birth, if not before. These patients have no evidence of abnormally functioning FSH. AMH levels can be assessed before menarche or after initiation of hormone therapy and may supplement FSH as a useful blood biomarker of ovarian function for patients with classic galactosemia.

The effect of race and obesity on the age-associated decline of androgens in reproductive-aged and menopausal women has not been well characterized.Our objective was to determine the impact of racial differences and body mass index (BMI) on the change in androgen levels during a woman's reproductive and early menopausal years.We conducted a frequency-matched cross-sectional study at a tertiary academic medical center.Subjects included 260 healthy, nonhirsute and eumenorrheic, self-identified Black and White women, ages 15-60 yr.A medical and reproductive history, physical exam, and blood sampling were determined in the fasting state during the early follicular phase.Serum levels of androgens or androgen metabolites (dehydroepiandrosterone sulfate, androstenedione, and total and free testosterone) and SHBG were measured and the BMI, the waist-to-hip ratio (WHR), and the basal insulin resistance estimated by the homeostasis model assessment for insulin resistance determined.After controlling for differences in BMI, insulin resistance, and WHR, Black women had lower androgen levels than age-matched White women. All androgens, or androgen metabolites, declined similarly across the reproductive lifespan and menopausal transition in both Black and White women. Race was a significant predictor of dehydroepiandrosterone sulfate, androstenedione, and total and free testosterone but not SHBG.Eumenorrheic, nonhirsute Black women have a lower range of normal androgen levels than White women of the same age, BMI, WHR, and homeostasis model assessment index for insulin resistance. Race and age-adjusted data should be considered when evaluating androgen levels in women between the ages of 15 and 60 yr.