Does it make sense to refreeze ovarian tissue after unexpected occurrence of endometriosis when transplanting the tissue?

BACKGROUND: Ovarian insufficiency is a major concern for long-term cancer survivors. Ovarian tissue cryopreservation for fertility preservation is an emerging technique that has proven successful over the past decade through transplantation of frozen-thawed ovarian tissue. Compared to other established techniques, such as oocyte freezing, ovarian tissue cryopreservation preserves actual organ function and thus the production of sex hormones. Endometriosis in perimenopausal women is rare, however it can be surprising diagnosis in the planned transplantation of cryopreserved ovarian tissue and the already thawed tissue may not be transplanted, so that it has to be refrozen. RESULTS: Ovarian function returned in the patient two months after transplantation, as shown by estrogen production. Ten months after the ovarian tissue transplantation mild stimulation with FSH was initiated in accordance with a low-dose protocol. When ultrasonography revealed a follicle 17 mm in size in the ovarian graft, hCG was added and after follicular puncture one oocyte was obtained. The oocyte could be fertilized by IVF and transferred to the uterus. On day 14 after embryo-transfer, a positive hCG-Level was detected and after an uncomplicated pregnancy a healthy child was delivered. CONCLUSIONS: We report the first pregnancy and live birth achieved using transplantation of thawed and refrozen ovarian tissue in a woman treated by chemotherapy and subsequent endometriosis surgery. Refreezing of cryopreserved ovarian tissue is not a hindrance to successful transplantation of ovarian tissue. Against the background of increasing numbers of candidates for transplantation of ovarian tissue is expected that the combination chemotherapy followed by endometriosis will increase.

Critical evaluation of human endometrial explants as an ex vivo model system: a molecular approach.

The human endometrium is unique among adult tissues. Its functions are modulated by numerous hormones and mediators. The aim of this study was to evaluate the suitability of human endometrial explants for studying functional effects of chemicals and drugs on gene expression biomarkers. Endometrial tissues were obtained by aspiration curettage and cultivated for up to 24 h. Relative mRNA concentrations were determined by reverse transcription quantitative real-time PCR. Viability was assessed by light microscopy, lactate dehydrogenase assay and scanning electron microscopy. It was acceptable after 6 h of culture but reduced after 24 h. Culture-induced alterations of mRNA levels were found for progesterone receptor, estrogen receptor(α), leukemia inhibitory factor and cyclooxygenase-2 in tissues from all cycle stages. The suitability of the model to detect chemical effects was demonstrated by the down-regulation of cyclooxygenase-2 mRNA by chlormadinone acetate in proliferative and secretory endometrium. The model is mainly restricted by interindividual variations and varying tissue quality. An advantage is the preservation of tissue composition. We conclude that human endometrial explants are a complex model due to limited viability, difficult standardization and intrinsic alterations during culture. Experiments with this model should be performed over a limited time period under strictly controlled conditions.

Metformin versus acarbose therapy in patients with polycystic ovary syndrome (PCOS): a prospective randomised double-blind study.

The objective of this study was to investigate the effect of metformin versus acarbose in terms of ovulation rate, their impact on hormonal and metabolic status and tolerability of both drugs in patients with polycystic ovary syndrome (PCOS). Seventy-five patients with PCOS were included in this prospective randomised controlled double-blinded clinical study. According to randomisation, patients were allocated to receive either metformin 2550 mg/day (n = 37) or acarbose 300 mg/day (n = 38) for 12 weeks. Primary study outcomes were ovulation rate, restoration of a regular menstrual cycle and the incidence of side effects. Secondary outcomes included treatment-related hormonal and metabolic changes. Comparable high rates of regular menstrual cycles as well as ovulation could be achieved in both groups (70% and 73% for metformin vs. 78% and 59% for acarbose, p = 0.330 and p = 0.185, respectively). In contrast, only in patients treated with metformin a statistically significant decrease in fasting insulin and cholesterol levels as well as BMI was observed. However, comparing both groups at the end of treatment, no significant differences in metabolic and/or hormonal parameters could be detected. Regarding side effects, the rate of flatulence and/or diarrhoea was significantly lower for acarbose compared to metformin (38% vs. 80%, p < 0.001).

Ovarian transplantation for fertility preservation in a sheep model: can follicle loss be prevented by antiapoptotic sphingosine-1-phosphate administration?

AIMS: The aim of this study was to investigate whether sphingosine-1-phosphate (S1P), an apoptosis-inhibitor would be able to protect ovarian follicles from hypoxia-induced cell death in ovarian transplantation. METHODS: In four sheep, both ovaries were removed and immediately transplanted back into the abdominal wall. In two of them, one ovary was treated with S1P locally by injection and incubation after dissecting the ovarian cortex. The contra lateral ovary of both sheep and both ovaries of the remaining sheep served as controls. After 2 weeks, all grafts were evaluated histologically. RESULTS: Although the mean number of apoptotic cells were increased after grafting compared with fresh tissue, we were not able to demonstrate a significant difference regarding the follicular density in tissue with S1P treatment (mean number of follicles per field of view: 0.21 vs. 0.23, p = 0.909). CONCLUSION: Apoptosis seems to play a role in follicular loss during ovarian transplantation; however, local application of S1P does not prevent primordial/primary follicles from hypoxia-induced cell death in cortical grafts in our study.

Efficacy, safety and sustainability of treatment continuation and results of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg chlormadinone acetate, in long-term usage (up to 45 cycles)--an open-label, prospective, noncontrolled, office-based Phase III study.

BACKGROUND: This open-label, noncontrolled study assessed the long-term efficacy and tolerability of the monophasic combined low-dose oral contraceptive (OC) ethinyl estradiol (EE) 30 mcg+chlormadinone acetate (CMA) 2 mg (Belara). STUDY DESIGN: In total, 781 women who had already taken EE 30 mcg+CMA 2 mg for 24 cycles in a previous Phase III study were assessed for up to 45 cycles. RESULTS: Over 23,033 cycles, the Pearl Index was 0.16 (95% confidence interval, 0.04-0.42). Approximately 86% of women had regular withdrawal bleeding in each cycle, while incidence of intracyclic bleedings (1.6-6.4%) and proportion of women with amenorrhea (4%) were low. The incidence of acne decreased from 13.8% to 5.7%, while rates of hirsutism, alopecia and seborrhea remained low (< or =4%) throughout this study. The most frequent adverse events were consistent with OC treatment, and no unexpected events occurred. No changes in mean blood pressure and pulse rate were observed during the study, and there were no clinically relevant changes in liver or hematological parameters, hemostasis or carbohydrate metabolism. The incidence of pathological findings in gynecological examination was low and decreased over time. CONCLUSION: EE 30 mcg+CMA 2 mg was an effective and well-tolerated OC, with beneficial effects on cycle stability, intracyclic bleeding, amenorrhea and signs of androgenization that were maintained during long-term treatment for up to 5 years. There was no evidence of an increased risk of thromboembolic events, atherogenic disease or cervical cancer, suggesting that 30 EE mcg+CMA 2 mg is highly suitable for long-term use.

Chlormadinone acetate suppresses prostaglandin biosynthesis in human endometrial explants.

OBJECTIVE: To elucidate the mode of action of chlormadinone acetate (CMA) in reducing dysmenorrheic pain by studying the effects of CMA and dexamethasone (DEX) on messenger RNA (mRNA) abundance of cyclo-oxygenase-2 (COX-2), annexin-1 (ANXA1), glucocorticoid receptor (GR), progesterone receptor (PR), and concentrations of prostaglandin F(2α) (PGF(2α)) and leukotrienes B(4) (LTB(4)) and C(4) (LTC(4)) in human endometrial explants. DESIGN: Ex vivo study. SETTING: University hospital. PATIENT(S): Fifteen premenopausal patients undergoing surgery for benign gynecologic disorders. INTERVENTION(S): Endometrial explants were obtained by aspiration curettage and stimulated ex vivo with interleukin-1ß before exposure to CMA or DEX; mRNA levels were determined via reverse transcription-quantitative real-time polymerase chain reaction, and concentrations of arachidonic acid metabolites by enzyme immunoassays. MAIN OUTCOME MEASURE(S): Messenger RNA levels of COX-2, ANXA1, PR, and GR; concentrations of PGF(2α), LTB(4), and LTC(4) in endometrial explants treated with CMA or DEX. RESULT(S): In IL-1ß-treated explants COX-2 mRNA and PGF(2α), concentrations were significantly down-regulated by CMA but not by DEX. Chlormadinone acetate did not affect mRNA abundance of ANXA1, PR, and GR. CONCLUSION(S): Our data suggest that CMA is a suppressor of COX-2 expression. Comparison with DEX revealed that progestin-specific activity of CMA may mainly be responsible for suppression of prostaglandin biosynthesis in human endometrium.

Nonsteroidal anti-inflammatory drugs and hormonal contraceptives for pain relief from dysmenorrhea: a review.

BACKGROUND: This article is a comprehensive overview of dysmenorrhea and a systematic review of the available literature on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and hormonal contraceptives for the therapy and management of dysmenorrhea. STUDY DESIGN: A comprehensive search of the PubMed database for clinical trials and observational studies of dysmenorrhea treatments from 2004 onwards. RESULTS: Eighteen publications were identified. Ten randomized controlled trials (RCTs) assessing NSAIDs for treating primary dysmenorrhea demonstrated superior pain relief compared with placebo, but no superiority was established among different NSAIDS. Two RCTs and six nonrandomized observational or prospective studies assessing the effect of hormonal contraceptives on dysmenorrhea strongly suggest a beneficial effect for dysmenorrheic pain relief and were conducted mainly in larger populations (N=41-6169) than those in the NSAID trials (N=10-337). Ethinylestradiol/chlormadinone acetate was the only formulation that provided a more pronounced relief of dysmenorrheic pain compared with a parallel alternative or previously used hormonal contraceptive. Methodological inconsistencies were widespread between the hormonal contraceptive studies. CONCLUSIONS: The findings of this review support the use of NSAIDs as a first-line therapy for pain relief from dysmenorrhea in women without wish for contraception. For women who wish contraception, combined oral contraceptives (COCs) are the preferential therapy for pain relief from dysmenorrhea as the additional noncontraceptive benefit of pain relief from dysmenorrhea is not linked to additional risks, eliminates the risks associated with taking NSAIDs and is a more suitable long-term option. Recommendations are made to strengthen the impact of future trials through improved methodology.

Beneficios no anticonceptivos de 0, 02 mg de etinilestradiol/2 mg de acetato de clormadinona administrados en un régimen de 24+4 días / Non-contraceptive benefits of 0.02 mg ethinylestradiol /2 mg chlormadinone acetate in a 24 +4 days intake regimen

Objetivo: Demostrar la influencia sobre las molestias emocionales y físicas (beneficios no anticonceptivos) experimentadas durante el primer año de uso de un anticonceptivo oral combinado (AOC) que contiene 0,02 mg de etinilestradiol (EE) y 2 mg de acetato de clormadinona (ACM) administrado en un régimen de 24 + 4 días de placebo. Diseño del estudio: Análisis adicional de las sensaciones subjetivas registradas en los diarios de 1665 participantes de un estudio de Fase III multicéntrico, no controlado, de administración múltiple, después de 13 ciclos de EE/ACM en un régimen de administración de 24 + 4 días, publicado previamente. Resultados: Se informó de menor frecuencia de molestias emocionales y físicas en el ciclo de medicación 13 en comparación con los datos en la admisión y en el ciclo 1. La incidencia de ánimo depresivo se redujo en 84,5 por ciento y 72,2 por ciento respectivamente, y la irritabilidad en 87,3 por ciento y 66,0 por ciento. Las cefaleas se redujeron en 75,5 por ciento y 74,7 por ciento, las molestias mamarias en 77,1 por ciento y 66,1 por ciento, y la dismenorrea preexistente en 77,9 por ciento y 67,6 por ciento respectivamente. El abandono prematuro del estudio a causa de las molestias fue marginal, y el perfil del sangrado fue aceptable. Conclusiones: Un AOC de baja dosis que contiene 0,02 mg de EE + 2 mg de ACM, administrado en un régimen de 24 + 4 días, reduce significativamente la mayor parte de las molestias emocionales y físicas que se presentan durante los ciclos espontáneos de las mujeres, y se combina con un adecuado perfil de sangrado.

Objective: To demonstrate the influence on physical and psychological complaints during the first year of intake of the combined oral contraceptive (COC) 0.02 mg ethinylestradiol (EE)/2 mg chlormadinone acetate (CMA), administered in a regimen of 24 days of CMA/EE intake followed by 4 days of placebo intake. Study design: The subjective feelings of non-contraceptive benefits registered in women's diaries of 1,665 subjects participating in a multicentre, uncontrolled, multiadministration, Phase III trial, published elsewhere, were analyzed post-hoc after 13 cycles intake of EE/CMA in a 24 +4 days intake regimen. Results: Emotional complaints were reported less frequently at medication cycle 13 compared with admission and cycle 1. Depressive mood was reduced by 84.5 percent and 72.2 percent, irritability by 87.3 percent and 66.0 percent; physical complaints were also reduced: headaches by 75.5 percent and 74.7 percent, breast discomfort by 77.1 percent and 66.1 percent; pre-existing dysmenorrhea by 77.9 percent and 67.6 percent. Premature termination due to complaints was only marginal, the bleeding profile was accepted. Conclusions: The low-dose COC, 0.02 mg EE/2 mg CMA, administered in a 24 +4 day regimen, reduces significantly most of the emotional and physical complaints occurring during spontaneous cycles of women, combined with an adequate bleeding profile.