Fertility biomarkers to estimate metabolic risks in women with polycystic ovary syndrome.

PURPOSE: We sought to evaluate the relationship between the polycystic ovary syndrome (PCOS)-defining characteristics and the risk of developing metabolic complications in women presenting with complaints of infertility and/or menstrual irregularities and subsequently diagnosed with PCOS. METHODS: This was a cross-sectional study. Women presenting with complaints of infertility and/or irregular menses and diagnosed with PCOS by the Rotterdam criteria, underwent endocrine, metabolic, and ultrasound assessment in the early follicular phase. Reproductive and metabolic parameters were included in regression analysis models with the PCOS-defining characteristics; ROC curves were calculated for the significant predictors. RESULTS: Three hundred and seventy-four women with PCOS were included in our study. Oligo-anovulation, menstrual irregularities, and hirsutism were not predictive of any of the variables. Ovarian volume, follicle count, and biochemical hyperandrogenism were predictors for hormonal, metabolic, and endometrial complications. The relationships were independent of age and body mass index. ROC curves identified lower cut-off values of the PCOS-defining characteristics to predict patients' risks of hyperinsulinemia, dyslipidemia, and glucose intolerance. CONCLUSIONS: Adverse metabolic effects of PCOS are already present in women at the time they present complaining of infertility and/or irregular menses. Hyperandrogenism and ultrasound can assist in predicting the patients' concomitant metabolic abnormalities and can aid physicians in tailoring counseling for effective preventive strategies.

Serum markers of ovarian reserve and ovarian histology in adult mice treated with cyclophosphamide in pre-pubertal age.

PURPOSE: AMH is used to quantify the extent of follicular pool in postpubertal women, but its value after chemotherapy is unclear. We tested AMH as a marker of follicular reserve in adult mice treated with cyclophosphamide (CTX) in prepubertal age. METHODS: Mice received placebo or CTX at age 18 days. AMH and FSH were assessed on day 43, 56, and 95 of life. Ovaries were fixed in formalin, embedded in paraffin, and stained with H&E and TUNEL. Follicular apoptosis was graded. RESULTS: All mice exposed to CTX had a decreased number of follicles/mm(2) and significantly decreased AMH, but only 48 % of pubertal and 81 % of adult mice had increased FSH. Over time, there was an increase in FSH (p < 0.05), but not a concurrent decrease in AMH, while in controls, FSH remained stable and AMH decreased. There was no correlation between histological and serological markers. CONCLUSIONS: CTX administration to pre-pubertal mice caused various degrees of residual function, which were reflected by FSH, but not by AMH or by the number of ovarian follicles. AMH served as a marker of quantitative, and FSH of qualitative, residual ovarian function.

Applicability of adult techniques for ovarian preservation to childhood cancer patients.

PURPOSE: To appraise the feasibility of current adult medical and surgical techniques for ovarian preservation in pre-pubertal and adolescent girls with cancer. METHODS: Literature search using PubMed and SCOPUS up to February 2012. In addition, the reference lists of selected studies and all identified systematic and narrative reviews were scanned for relevant references. Inclusion criteria were ovarian preservation and cancer. Exclusion criteria were non-English publications, letters, personal communications, and ovarian preservation for conditions other than cancer. RESULTS: Data from the selected publications was interpreted and discussed in the relevant sections. Cryopreservation of ovarian tissue followed by autologous transplant represents the only surgical option available for pre-pubertal girls and adolescents who cannot delay the start of chemotherapy. Few studies report on pre-pubertal and adolescent girls undergoing ovarian preservation surgeries with good harvesting, and no follow-up has been conveyed, to date. Outcomes of ovarian function after ovarian suppression with GnRH-analogs in adults have been controversial and no reports are available for pre-pubertal girls. CONCLUSIONS: Autologous transplantation of cryopreserved ovarian cortex probably represents the best option for preservation of fertility and hormonal function in childhood cancer females; however, future research needs to address the safety of this technique, especially in patients with blood-borne cancers. Ovarian suppression with GnRH-analogs at the time of chemotherapy treatment has not proven to be superior to non-suppression for fertility preservation purposes in adults. Not enough evidence is presently available in childhood cancer patients.

Goserelin fosters bone elongation but does not prevent ovarian damage in cyclophosphamide-treated prepubertal mice.

OBJECTIVE: To evaluate whether administration of goserelin, a gonadotropin-releasing hormone (GnRH) agonist, could prevent acute or chronic ovarian insufficiency from cyclophosphamide (CTX) administration to prepubertal mice. DESIGN: Animal study. SETTING: University center. ANIMAL(S): C57BL/6J mouse strain. INTERVENTION(S): Goserelin administered on day 13 of life, CTX on day 18 of life, euthanasia on day 20 (prepubertal), 56 (pubertal), or 92 of life (mature), measurements of body weight, length, uterine weight, serum antimüllerian hormone and follicle-stimulating hormone, and histologic assessment of ovarian follicles and femur growth, and apoptotic rates by TUNEL. MAIN OUTCOME MEASURE(S): Assessment of prevention of ovarian insufficiency and defective bone elongation from CTX administration. RESULT(S): Prepubertal mice were randomly assigned to three groups: control (G1), CTX (G2), and goserelin + CTX (GG). A total of 63 mice were euthanized in the three groups. Body weight and length, and uterine weight did not differ among groups at any age. Ovarian size was not different in the three groups. There were fewer primordial and primary follicles/mm(2) in groups GG and G2 than in group G1 at all ages, but there was no difference between groups GG and G2. Corpora lutea/mm(2) were decreased in group GG versus G2. Femur length was statistically significantly greater in groups G1 and GG than group G2. CONCLUSION(S): Goserelin administered to prepubertal mice during CTX treatment fosters maintenance of bone elongation but does not protect the ovaries from follicular depletion.

Somatic and reproductive development in pre-pubertal mice treated with cyclophosphamide and subsequent estrogen replacement.

We tested the hypothesis that chemotherapy would prevent the expected pubertal development of uterus, ovaries, and long bones, and that estrogen replacement subsequent to treatment with chemotherapy would restore uterine and bone development to expected sizes. Pre-pubertal female C57BL/6J mice (n = 78) were assigned to receive placebo (controls), 200 mg/kg (group A), or 120 mg/kg (group B) of cyclophosphamide (CTX) on postnatal day 18. Mice were subsequently randomized to receive estradiol placebo or long-release estradiol pellet insertion on day 22 (early estradiol dose), day 45 (mid estradiol dose), or day 67 (late estradiol dose) of life. Body weight and length, uterine and ovarian weight, and right femur length and weight were measured. Mice treated with CTX had shorter and lighter femurs and lighter ovaries than controls (13.46 cm ± 1.51 cm vs. 15.00 cm ± 1.10 cm, 57.70 mg ± 9.71 mg vs. 65.30 mg ± 3.68 mg, and 5.16 mg ± 3.00 mg vs. 10.05 mg ± 2.31 mg, respectively; p < 0.05). Mice receiving estrogen replacement had a larger average body weight, BMI, and uterine weight than those that received placebo estrogen (19.56 g ± 1.82 g vs. 18.10 g ± 2.08 g, 26.53 g/cm(2) ± 2.91 g/cm(2) vs. 23.47 g/cm(2) ± 3.06 g/cm(2), 101.19 mg ± 41.69 mg vs. 50.00 mg ± 9.49 mg, respectively; p < 0.05). Cyclophosphamide treatment in pre-pubertal mice negatively affected femur and reproductive development. Estrogen treatment restored expected uterine development by maturity, regardless of the timing of administration. However, there was no similar recovery of femur length and bone mass was only partially recovered.

Somatic and reproductive outcomes in mice treated with cyclophosphamide in pre-pubertal age.

Disruption in the normal timing of female puberty, such as in pre-pubertal cancer treatments, can cause abnormal somatic development. We sought to evaluate the impact of cyclophosphamide (CTX) on the somatic, uterine, and ovarian, development of pre-pubertal mice. Pre-pubertal (day 18 of life) C57BL/6J female mice were randomized to receive placebo (group 1A and 1B), 200 mg/kg CTX (group 2A), or 120 mg/kg CTX (group 2B). Mice were euthanized on day 56 (A groups) or 95 (B groups) of life. Body weight and length, uterine and ovarian weight and right femur length and weight were measured, and ovarian insufficiency was assessed. Data were analyzed using ANOVA and t-test. Body weight and length did not differ among groups at time of euthanasia. The femur was shorter and weighed less in mice treated with CTX than in controls. Uterine weight was lower in group 2B than 1B (46.1 mg, 95% CI: 42.9-49.4, vs. 62.2 mg, 95% CI: 58.5-65.8, respectively; p = 0.005) and was lower in mice that developed ovarian insufficiency than in mice that did not (p < 0.05). Ovarian weight was lower in mice treated with CTX, regardless of whether they developed ovarian insufficiency. Even with no observable effect on adult body length and weight, CTX treatment in pre-pubertal mice appears to negatively affect femur, uterine, and ovarian development. However, uterine development seems to be dependent on the hormonal status created by CTX more than on its direct effect.