Jennifer Hirshfeld-Cytron

Metabolic syndrome and oocyte quality

Metabolic syndrome affects one in four women in the USA, and the incidence is rising every year. Metabolic syndrome is strongly associated with development of coronary artery disease and diabetes. Women of reproductive age are not spared from the complications of metabolic syndrome, which overlaps with obesity and polycystic ovary syndrome (PCOS), both of which are linked to infertility and poor reproductive outcome. Therefore, the relationship between the metabolic syndrome and reproductive dysfunction is an active area of study. In this review, we discuss the animal and human data available to determine if the abnormality is at the level of the ovary and/or endometrium, and discuss the underlying mechanisms causing the associated poor reproductive outcomes.

IGF-I Signaling Is Essential for FSH Stimulation of AKT and Steroidogenic Genes in Granulosa Cells

FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes. In contrast, inhibition of IGF-I receptor (IGF-IR) activity or expression using pharmacological, genetic, or biochemical approaches prevented the FSH- and cAMP-induced expression of steroidogenic genes and estradiol production. In vivo experiments demonstrated that IGF-IR inactivation reduces the stimulation of steroidogenic genes and follicle growth by gonadotropins. FSH or IGF-I alone stimulated protein kinase B (PKB), which is also known as AKT and in combination synergistically increased AKT phosphorylation. Remarkably, blocking IGF-IR expression or activity decreased AKT basal activity and abolished AKT activation by FSH. In GCs lacking IGF-IR activity, FSH stimulation of Cyp19 expression was rescued by overexpression of constitutively active AKT. Our findings demonstrate, for the first time, that in human, mouse, and rat GCs, the well-known stimulatory effect of FSH on Cyp19 and AKT depends on IGF-I and on the expression and activation of the IGF-IR.

Fertility preservation for social indications: a cost-based decision analysis

OBJECTIVE Age-related infertility remains a problem that assisted reproductive techniques (ART) have limited ability to overcome. Correspondingly, because an increasing number of women are choosing to delay childbearing, fertility preservation strategies, initially intended for patients undergoing gonadotoxic therapies, are being applied to this group of healthy women. Studies supporting the effectiveness of this practice are lacking. DESIGN Decision analytic techniques. SETTING We compared the cost-effectiveness of three strategies for women planning delayed childbearing until age 40: oocyte cryopreservation at age 25, ovarian tissue cryopreservation (OTC) at age 25, and no assisted reproduction until spontaneous conception had been attempted. PATIENT(S) Not applicable. INTERVENTION(S) Not applicable. MAIN OUTCOME MEASURE(S) Cost-effectiveness, which was defined as the cost per live birth. RESULT(S) In this analysis, the strategy of foregoing fertility preservation at age 25 and then choosing ART only after not spontaneously conceiving at age 40 was the most cost-effective option. OTC was dominated by the other strategies. Sensitivity analyses demonstrated the robustness of the model; no analysis existed in which OTC was not dominated by oocyte cryopreservation. Increasing the cost of an IVF cycle beyond

Late postpartum eclampsia : Examples and review

22,000 was the only situation in which oocyte cryopreservation was the most preferred strategy. CONCLUSION(S) Neither oocyte cryopreservation nor OTC appear to be cost-effective under current circumstances for otherwise healthy women planning delayed childbearing. This analysis should give pause to the current practice of offering fertility preservation based only on the desire for delayed childbearing.

Nonmalignant Diseases and Treatments Associated with Primary Ovarian Failure: An Expanded Role for Fertility Preservation

Eclampsia, defined as the occurrence of seizures in pregnant women, usually in the setting of preeclampsia and in the absence of other neurologic disorders, occurs mainly before, during, or within 48 hours after delivery. When convulsions occur later postpartum, diagnosis is difficult and treatment disputed. We review the entity of late postpartum eclampsia and report 2 examples in which the serum levels of antiangiogenic and angiogenic proteins were measured. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to explain that late postpartum eclampsia can occur more than 48 hours and less than 4 weeks post delivery, state that it is important to have a comprehensive differential diagnosis, and recall that the signs and symptoms of postpartum eclampsia may differ from antepartum or intrapartum preeclampsia/eclampsia.

Characterization of Functionally Typical and Atypical Types of Polycystic Ovary Syndrome

Cancer treatments can be detrimental to fertility; recent literature has focused on the efforts of fertility preservation for this patient population. It should be recognized, however, that several nonmalignant medical conditions and therapeutic interventions could be similarly hazardous to fertility. Some of these nonmalignant diseases and their treatments that can adversely impact the reproductive axis are gastrointestinal diseases, rheumatologic disorders, nonmalignant hematologic conditions, neurologic disorders, renal disorders, gynecologic conditions, and metabolic diseases. Their negative effects on reproductive function are only now being appreciated and include impaired ovarian function, endocrine function, or sexual function and inability to carry a pregnancy to term. Complications and comorbidities associated with certain diseases may limit the success of established fertility preservation options. Recent advances in fertility preservation techniques may provide these patients with new options for childbearing. Here, we review several fertility-threatening conditions and treatments, describe current established and experimental fertility preservation options, and present three initiatives that may help minimize the adverse reproductive effects of these medical conditions and treatments by raising awareness of the issues and options: (1) increase awareness among practitioners about the reproductive consequences of specific diseases and treatments, (2) facilitate referral of patients to fertility-sparing or restorative programs, and (3) provide patient education about the risk of infertility at the time of diagnosis before initiation of treatment.

Fertility preservation outcomes may differ by cancer diagnosis

CONTEXT The typical polycystic ovary syndrome (PCOS) phenotype includes 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHag) testing. Functionally atypical PCOS lacks this feature. OBJECTIVE The hypothesis was tested that the typical PCOS ovarian dysfunction results from intrinsically increased sensitivity to LH/human chorionic gonadotropin (hCG) due to a flaw in FSH action. PARTICIPANTS/DESIGN/INTERVENTIONS/MAIN OUTCOME MEASURES: After phenotyping a cohort of 60 women, steroid and inhibin-B responses to gonadotropins were evaluated in representative typical (n = 7) and atypical (n = 5) PCOS and healthy controls (n = 8). Submaximal hCG testing before and after an FSH test dose was performed in random order before and after prolonged ovarian suppression by depot GnRHag. SETTING The study was performed at a Clinical Research Center. RESULTS Of our PCOS cohort, 68% were the typical type. Typical PCOS had 17OHP hyperresponsiveness and, unlike controls, significant androgen and estradiol responses to hCG. FSH increased inhibin-B and did not inhibit free testosterone or enhance estradiol responsiveness to hCG, all unlike controls. After ovarian suppression, 17OHP, androstenedione, and inhibin-B responsiveness to gonadotropin testing persisted. Atypical PCOS had significantly higher body mass index but lower ovarian volume and plasma free testosterone than typical PCOS. Steroid responses to hCG were insignificant and similar to controls. FSH suppressed free testosterone but stimulated inhibin-B. The estradiol level after combined hCG-FSH was subnormal. Free testosterone was less GnRHag suppressible than in typical PCOS. CONCLUSIONS Typical PCOS is characterized by intrinsic ovarian hypersensitivity to hCG to which excessive paracrine FSH signaling via inhibin-B may contribute. Atypical PCOS is due to a unique type of ovarian dysfunction that is relatively gonadotropin hyposensitive.

Comparing thaw survival, implantation and live birth rates from cryopreserved zygotes, embryos and blastocysts

CONTEXT: Cancer survival has improved significantly and maintaining fertility is both a major concern and an important factor for the quality of life in cancer patients. AIMS: To explore differences in oocyte stimulation for fertility preservation (FP) patients based on cancer diagnosis. SETTINGS AND DEIGN: Between 2005 and 2011, 109 patients elected to pursue FP at a single institution. MATERIALS AND METHOD: In vitro fertilization (IVF) outcome variables between four cancer diagnostic groups (breast, gynecologic, lymphoma/leukemia and other) and age-matched male factor or tubal factor infertility IVF control group were compared. STATISTICAL ANALYSIS: ANOVA and Chi-square analyses were employed to compare variables between the groups that were normally distributed. Kruskal–Wallis with subsequent Mann–Whitney U-test were used for data that were not normally distributed. RESULTS: Women with gynecologic malignancies were significantly older than the women in the other three groups, but tended to have a better ovarian response. Women with hematologic malignancies were most likely to have been exposed to chemotherapy and had the longest stimulations with a similar number of oocytes retrieved. The age-matched IVF controls had higher peak estradiol levels, number of oocytes obtained, and fertilization rates when compared to cancer patients with or without a history of prior chemotherapy. CONCLUSIONS: Factors including age, type of cancer and chemotherapy exposure, can influence response to ovarian stimulation. Discussing these findings with patients presenting for FP may aid in setting realistic treatment expectations.

Uterine artery embolization immediately preceding laparoscopic myomectomy

CONTEXT: Most in vitro fertilization (IVF) programs employ embryo cryopreservation to enhance pregnancies from a single ovarian stimulation. More embryos are created, some of which are not transferred to the uterus immediately, generating a need for improved cryopreservation protocols. One protocol may involve growing embryos to a further stage of development, allowing only embryos with proven developmental capabilities to be cryopreserved. Here we examined thaw survival, implantation and live birth rates of embryos cryopreserved at different stages. AIMS: We examined thaw survival, implantation and live birth rates of embryos cryopreserved at the zygote, day 3 (D3) embryos or blastocyst stage. SETTINGS AND DESIGN: This is a retrospective study from a single academic IVF program. PATIENTS AND METHODS: A retrospective study of all patients who had frozen embryos transferred to their uteri from year 2002 to 2008 at a single academic IVF program was conducted. STATISTICAL ANALYSIS USED: Analysis of variance followed by Fishers Exact Test was performed to compare the survival after thaw, implantation and live birth rates between the three groups. RESULTS: One thousand nine hundred and ninety-one zygotes, 2880 D3 embryos and 503 blastocysts were frozen using a slow freeze technique, thawed and transferred. Significantly more D3 embryos and blastocysts survived the thawing process compared to zygotes and significantly higher implantation rate per number of thawed blastocysts was achieved than that for zygotes. Live birth rates were similar between the three groups. CONCLUSIONS: Growing embryos to blastocyst stage prior to cryopreservation is associated with fewer frozen embryos but does not appear compromise patients’ chance of achieving pregnancy

Psychological Counseling of Female Fertility Preservation Patients

To determine whether performing uterine artery embolization (UAE) immediately before laparoscopic myomectomy can facilitate a minimally invasive surgical approach for larger uterine fibroids.