Jessica B. Spencer

The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries

Pudgy (pu) homozygous mice exhibit clear patterning defects at the earliest stages of somitogenesis, resulting in adult mice with severe vertebral and rib deformities. By positional cloning and complementation, we have determined that the pu phenotype is caused by a mutation in the delta-like 3 gene (Dll3), which is homologous to the Notch-ligand Delta in Drosophila. Histological and molecular marker analyses show that the pu mutation disrupts the proper formation of morphological borders in early somite formation and of rostral-caudal compartment boundaries within somites. Viability analysis also indicates an important role in early development. The results point to a key role for a Notch -signalling pathway in the initiation of patterning of vertebrate paraxial mesoderm.

Ovarian function in girls and women with GALT-deficiency galactosemia

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.

Biomarkers of ovarian function in girls and women with classic galactosemia

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 <1 and 51 years. INTERVENTION(S) Blood sampling and medical and reproductive histories were obtained. MAIN OUTCOME MEASUREMENT(S) We determined FSH and anti-Müllerian 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.

Modifiers of Ovarian Function in Girls and Women With Classic Galactosemia

CONTEXT 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. OBJECTIVE 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. DESIGN AND SETTING This was a cross-sectional study with some longitudinal follow-up in a university research environment. PATIENTS Patients included girls and women with classic galactosemia and unaffected controls, <1 month to 30 years old. MAIN OUTCOME MEASURES 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. RESULTS More than 73% of the pre- and postpubertal girls and women with classic galactosemia in this study, ages >3 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. CONCLUSIONS 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.

Menses resumption after cancer treatment–induced amenorrhea occurs early or not at all

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.

Reproductive and gynecologic care of women with fragile X primary ovarian insufficiency (FXPOI).

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.

Ovarian function in Duarte galactosemia

OBJECTIVE To determine if girls with Duarte variant galactosemia (DG) have an increased risk of developing premature ovarian insufficiency based on prepubertal anti-Müllerian 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 <1 month and 10.5 years. 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.

The effects of hydroxyurea and bone marrow transplant on Anti-Müllerian hormone (AMH) levels in females with sickle cell anemia.

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 level <5th percentile for age-matched controls. Subjects also with FSH >40 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 and <5th 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.

Racial Disparities in Seeking Care for Help Getting Pregnant

BACKGROUND Fertility counselling and treatment can help women achieve their desired family size; however, disparities exist in the utilisation of this care. METHODS This study examines the persistence of a racial disparity in visiting a doctor for help getting pregnant by estimating the direct effect of this association using data from the Furthering Understanding of Cancer Health and Survivorship in Adult Womens Study, a population-based cohort study. This cohort included 1073 reproductive age women (22-45 years) with 28% reporting infertility. We fit log binomial models to quantify the magnitude of the racial difference in reported care seeking after adjustment for hypothesised mediators using inverse probability weighting. RESULTS Compared with white women, black women were less likely to visit a doctor in the total population [adjusted risk ratio (RR) 0.57, 95% confidence interval (CI) 0.41, 0.80] and in the subgroup of women with infertility [RR 0.75, 95% CI 0.56, 0.99]. In addition, black women waited twice as long, on average, before seeking help compared with white women. CONCLUSIONS There were notable racial differences in visiting a doctor for help getting pregnant in this study although reports of infertility were similar by race. These differences may be mitigated through improved communication about the range of counselling and treatment options available.

Discontinuation of rLH two days before hCG may increase the number of oocytes retrieved in IVF

BackgroundAdministration 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.MethodsTo 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.ResultsThe 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.ConclusionsWhen 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.