Peripubertal vitamin D(3) deficiency delays puberty and disrupts the estrous cycle in adult female mice.

The mechanism(s) by which vitamin D(3) regulates female reproduction is minimally understood. We tested the hypothesis that peripubertal vitamin D(3) deficiency disrupts hypothalamic-pituitary-ovarian physiology. To test this hypothesis, we used wild-type mice and Cyp27b1 (the rate-limiting enzyme in the synthesis of 1,25-dihydroxyvitamin D(3)) null mice to study the effect of vitamin D(3) deficiency on puberty and reproductive physiology. At the time of weaning, mice were randomized to a vitamin D(3)-replete or -deficient diet supplemented with calcium. We assessed the age of vaginal opening and first estrus (puberty markers), gonadotropin levels, ovarian histology, ovarian responsiveness to exogenous gonadotropins, and estrous cyclicity. Peripubertal vitamin D(3) deficiency significantly delayed vaginal opening without affecting the number of GnRH-immunopositive neurons or estradiol-negative feedback on gonadotropin levels during diestrus. Young adult females maintained on a vitamin D(3)-deficient diet after puberty had arrested follicular development and prolonged estrous cycles characterized by extended periods of diestrus. Ovaries of vitamin D(3)-deficient Cyp27b1 null mice responded to exogenous gonadotropins and deposited significantly more oocytes into the oviducts than mice maintained on a vitamin D(3)-replete diet. Estrous cycles were restored when vitamin D(3)-deficient Cyp27b1 null young adult females were transferred to a vitamin D(3)-replete diet. This study is the first to demonstrate that peripubertal vitamin D(3) sufficiency is important for an appropriately timed pubertal transition and maintenance of normal female reproductive physiology. These data suggest vitamin D(3) is a key regulator of neuroendocrine and ovarian physiology.

Increasing adiposity in normal ovulatory women affects adipocytokine expression in subcutaneous and visceral abdominal fat.

OBJECTIVE: To determine which adipocytokines are differentially expressed as a function of body mass index (BMI), to compare expression of adipocytokines in abdominal subcutaneous and omental fat, and to correlate these findings with serum levels, BMI, and parameters of insulin resistance. METHODS: Serum and subcutaneous (sc) and omental (om) tissue were obtained from lean and obese ovulatory women undergoing gynecologic surgery. We determined adipocytokine expression in sc versus om abdominal fat and related this to increasing BMI. RESULTS: Serum leptin was higher and adiponectin lower in overweight subjects. Adipocytokines had higher expression in sc abdominal versus om adipose tissue with the most significant difference observed for leptin (P=0.01). As BMI increased, sc leptin expression increased and adiponectin expression decreased. The leptin/adiponectin ratio correlated significantly with BMI (R=0.84, P=0.0001). CONCLUSION: Increased adipocytokine expression correlates with BMI. Abdominal sc tissue has greater adipocytokine expression overall. The serum leptin/adiponectin ratio is highly correlated with BMI. These data may help in our understanding of how obesity affects women in a variety of ways.

Full-sibling embryos created by anonymous gamete donation in unrelated recipients.

OBJECTIVE: To report the rare occurrence of full-sibling embryos in unrelated women using independently chosen donor sperm and donor oocytes in two different cycles unintentionally created at our IVF program, and to discuss the concept of disclosure to the patients. DESIGN: Case report. SETTING: Academic IVF program. PATIENT(S): Two women independently undergoing donor recipient cycles with anonymous donor oocytes and donor sperm. INTERVENTION(S): Both women received oocytes from the same donor several months apart and then by coincidence selected the same anonymous sperm donor to create anonymous full-sibling embryos. MAIN OUTCOME MEASURE(S): Clinical pregnancy after donor-recipient IVF cycle. RESULT(S): Both women conceived using the same donor sperm and donor oocytes in independent cycles, resulting in simultaneous pregnancy of full siblings. CONCLUSION(S): As providers with the knowledge that anonymous full sibling embryos have been created, we may have an obligation to disclose this information to the patients.

The neuroendocrine physiology of female reproductive aging: An update.

The transition into menopause is a complex process that affects fertility and increases the risk for a number of health problems in aging women that include, but are not limited to osteoporosis, heart disease, diabetes mellitus and cognitive dysfunction. Improved nutrition and enhanced access to medical care have increased the average lifespan for women in developed countries, and many will spend more than one-third of their life in a post-menopausal state. Epidemiological studies indicate that a delayed natural menopause confers longevity and decelerates the appearance of much age-related morbidity, suggesting that developing treatments to delay menopause would significantly improve quality of life for women. Although menopause is ultimately defined by ovarian follicular exhaustion, several lines of scientific evidence in humans and animals now suggest that dysregulation of estradiol feedback mechanisms and hypothalamic-pituitary dysfunction contributes to the onset and progression of reproductive senescence, independent of ovarian failure. This article provides a brief update on our current understanding of the role of the hypothalamic-pituitary axis in the onset of and transition into female reproductive senescence.

A multidisciplinary approach to fertility-sparing therapy for a rare vulvar tumor.

OBJECTIVE: Case report of a young woman with a rare vulvar malignancy who received treatment with a personalized multidisciplinary approach to balance management of her malignancy without compromising survival with her desire for future pregnancy. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 33-year-old woman, gravida 2, para 1-0-1-1, who had a diagnosis of synovial cell sarcoma of the vulva and who desired future fertility. INTERVENTION(S): At multiple steps, treatment was planned to try to maximize fertility preservation without potentially affecting initial treatment, which included a radical hemivulvectomy with bilateral lymph node dissection, brachytherapy with interstitial needles (20 Gy), and external beam radiation therapy (50 Gy). MAIN OUTCOME MEASURE(S): Treatment and eradication of the malignancy and achievement of a successful subsequent pregnancy and live birth. RESULT(S): The patient had no evidence of disease for 2 years after treatment. During that time she received preconception counseling by both a perinatologist and a reproductive endocrinologist. She conceived with the use of ultrasound monitoring to time intercourse specifically with ovulation from the contralateral ovary and had an uncomplicated pregnancy with a term delivery. CONCLUSION(S): By using several disciplines and subspecialists, this patient received personalized treatment for a rare cancer, focused at curing her cancer and optimizing her future fertility.

Evidence for a Müllerian-inhibiting substance autocrine/paracrine system in adult human endometrium.

OBJECTIVE: To determine if adult human endometrium possesses an intact müllerian-inhibiting substance (MIS) signal transduction system and, if so, whether MIS can modulate endometrial cell viability. DESIGN: Adult human endometrial tissue was subjected to reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. In addition, cultured human endometrial stromal cells were treated with recombinant MIS or transiently transfected with MIS and/or MIS type II receptor (MISRII) expression plasmids to assess for effects upon endometrial cell viability and apoptosis. The MIS in conditioned media was quantified by specific ELISA. SETTING: Academically affiliated medical center. PATIENT(S): Reproductive-age women undergoing routine infertility evaluation. INTERVENTION(S): Endometrial sampling. MAIN OUTCOME MEASURE(S): Assessment of MIS gene transcription and protein translation in human endometrial tissue in vivo and in vitro. RESULT(S): 1) The RT-PCR revealed that adult human endometrium expresses the genes for MIS, MISRII, ALK3, and Smads 1 and 9. 2) Immunohistochemistry reveals that MIS and MISRII protein are expressed in human endometrium. 3) Immunocytochemistry of cultured human endometrial cells reveals that MIS and MISRII protein are primarily restricted to mitosing cells. 4) ELISA reveals that MIS is secreted by human endometrial cells in vitro and that this process is increased by sex steroids. 5) Increasing local MIS concentration in cultured human endometrial stromal cells either by exogenous administration or transient transfection significantly decreases cell viability and increases apoptosis. CONCLUSION(S): Adult human endometrium possesses a functional MIS signal transduction system which negatively regulates cellular viability.

Cryopreservation of supernumerary high quality embryos predicts favorable outcomes for patients undergoing repeated cycles of in vitro fertilization.

OBJECTIVE: To determine whether the decline in pregnancy and implantation rates in repeated fresh IVF cycles is associated with the availability of embryo cryopreservation. DESIGN: Retrospective study. SETTING: Assisted reproductive unit at an academic institution. PATIENT(S): Women <38 years old (1,037), undergoing nondonor fresh or frozen embryo transfer (FET) cycles between January 1, 2000 and December 31, 2005. INTERVENTION(S): In fresh cycles, women used either pituitary desensitization or GnRH antagonists in combination with gonadotropin stimulation protocols before oocyte retrieval. In FET cycles, endometrial development was achieved by oral E(2) and vaginal P after pituitary desensitization. Embryo transfer occurred either on day 3 or on day 5. MAIN OUTCOME MEASURE(S): Implantation and pregnancy rates (PR). RESULT(S): Excluding FET cycles, implantation rates and PRs declined significantly in repeated cycles compared to the initial one. However, women with supernumerary embryos for cryopreservation appeared to produce embryos with higher implantation potential but were excluded from the analysis. When FET cycles were included, there were no significant declines in PRs for at least three repeated cycles. CONCLUSION(S): Embryo cryopreservation stratifies women with high quality embryos from those with low quality embryos who require repeat fresh attempts, resulting in an accelerated decline in observed PRs and implantation rates.

Triplet pregnancy after ovulation induction with an aromatase inhibitor.

OBJECTIVE: To describe the first reported case of a triplet pregnancy subsequent to the use of an aromatase inhibitor for ovulation induction. DESIGN: Case report. SETTING: Academic medical center. PATIENT(S): A 32-year-old female with polycystic ovary syndrome and primary infertility. INTERVENTION(S): Letrozole, 5 mg/day, on cycle days 2 to 6 for ovulation induction. MAIN OUTCOME MEASURE(S): Clinical pregnancy. RESULT(S): Viable triplet gestation. CONCLUSION(S): Use of an aromatase inhibitor for ovulation induction does not eliminate the risk for higher order multiple pregnancy.