Practical Prediction Model for Ovarian Insufficiency after Radiation / Modelo prático de predição para insuficiência ovariana após radiação

Abstract Objective The present study aimed to develop a useful mathematical model that predicts the age at which premature ovarian insufficiency might occur after teletherapy radiation. A diagnosis of premature or early menopause has physical and psychological consequences, so women may need support and long-term medical follow-up. Methods To correlate ovarian radiation dose with ovarian function, we used the formula described by Wallace et al.: √g(z) = 10(2-0,15z), where "g(z)" and "z" represent oocyte survival rate and the radiation dose (in Gray), respectively. By simulating different ages and doses, we observed a pattern that could be used to simplify the relationship between radiation dose and remaining time of ovarian function. Results We obtained a linear function between ovarian radiation dose and loss of ovarian function (LOF) that is the percentage of decrease in the time to the ovarian failure compared with the time expected for a woman at the same age without irradiation exposition. For patients <40 years old and with ovarian radiation doses < 5 Gy, the equation LOF = 2.70 + (11.08 × Dose) can be applied to estimate the decrease in time to premature ovarian insufficiency. Conclusion The present study reports a practicable theoretical method to estimate the loss of ovarian function. These findings can potentially improve the management and counseling of young women patients submitted to radiotherapy during their reproductive years.

Resumo Objetivo O presente estudo teve como objetivo desenvolver um modelo matemático útil que prediz a idade na qual a insuficiência ovariana prematura pode ocorrer após a radioterapia externa (teleterapia). O diagnóstico de menopausa prematura ou precoce tem consequências físicas e psicológicas; portanto, as mulheres podem precisar de apoio e acompanhamento médico de longo prazo. Métodos Para correlacionar a dose de radiação ovariana com a função ovariana, foi usada a fórmula descrita por Wallace et al.: √g(z) = 10(2-0,15z), na qual "g(z)" e "z" representam a taxa de sobrevivência do oócito e a dose de radiação (em Gray), respectivamente. Ao simular diferentes idades e doses, observamos um padrão que poderia ser usado para simplificar a relação entre a dose de radiação e o tempo restante da função ovariana. Resultados Obtivemos uma função linear entre a dose de radiação ovariana e a perda da função ovariana (LOF, na sigla em inglês) que é a porcentagem de diminuição no tempo até a falência ovariana em relação ao tempo esperado para uma mulher da mesma idade sem exposição à radiação. Para pacientes<40 anos de idade e com doses de radiação ovariana < 5 Gy, a equação LOF = 2,70 + (11,08 × Dose) pode ser aplicada para estimar a redução no tempo até a insuficiência ovariana. Conclusão O presente estudo relata um método teórico viável para estimar a perda da função ovariana. Estes achados podem melhorar potencialmente o manejo e o aconselhamento de pacientes jovens submetidas à radioterapia durante seus anos reprodutivos.

Local application of low level laser therapy in mice ameliorates ovarian damage induced by cyclophosphamide.

The aim of the present study is to assess whether low level laser therapy (LLLT) can protect ovaries from chemotherapy-induced gonadotoxicity using a mice model of premature ovarian failure induced by cyclophosphamide (CTX). LLLT (64 J/cm2) increased the number of antral follicles whilst decreasing the number of atretic follicles compared to CTX alone. LLLT increased the number of primordial follicles compared with those in the CTX group but they did not differ from those in the control group. LLLT treatment increased the number of AMH-positive follicles compared to CTX alone. LLLT application increased ovarian weight, serum progesterone concentration and P450scc protein levels compared to CTX alone. LLLT reduced the apoptosis in antral follicles and the BAX/BCL-2 ratio compared to CTX alone. Vascular morphology, analysed by CD31 and α-SMA immunostaining, was restored in LLLT-treated ovaries compared to CTX alone. In conclusion, application of LLLT prior to CTX might serve as a promising and novel protocol to preserve female fertility in cancer survivors.

Effect of 150 kHz electromagnetic radiation on the development of polycystic ovaries induced by estradiol Valerate in Sprague Dawley rats.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common complex endocrine disorder affecting approximately 2-20% of reproductive aged females. Tumour Treating Fields (100-300 kHz) is a recent innovative, non-invasive therapeutic approach to cancer therapy. This frequency as an alternative therapy for the management of polycystic ovaries has not yet been explored. OBJECTIVES: To explore the effect of full-body exposure of 150 kHz Electromagnetic Radiation (EMR), on the development of polycystic ovaries in an estradiol valerate-induced PCO rat model. METHOD: Twenty-one female adult rats were divided into three groups (n = 7 each): control, Estradiol Valerate (EV) and EV + EMR groups. The EV + EMR group was subjected to full body exposure at 150 kHz EMR continuously for eight consecutive weeks. Estradiol valerate was administered orally to induce polycystic ovaries in EV and EV + EMR groups. Body and ovarian weights were recorded and analysed. The regularity of the estrous cycle was assessed in all three groups. The histological study of ovarian tissue was carried out by haematoxylin and eosin staining. The serum concentration levels of Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH) and testosterone were measured using the ELISA method. RESULTS: The body and ovary weights did not differ significantly between the EV and EV + EMR groups. The estrous cycle was found to be irregular in both the EV and EV + EMR groups. Ovarian histology revealed near normal morphology with little or no degenerative and morphological changes in developing follicles in the exposed group. Histometrical analysis showed an increased number of developing follicles and a significant reduction in the number and size of follicular cysts (p < 0.05) in the EV + EMR group. Hormonal analysis revealed no significant difference in the testosterone and FSH levels between the EV + EMR and EV groups. However, the LH, LH/FSH ratio decreased significantly in the EV + EMR group compares to the EV group. CONCLUSION: The 150 kHz EMR appear to have little or no degenerative and morphological changes in the developing follicles, an increased number of typical developing follicles and a significant reduction in the number and size of the follicular cysts (p < 0.05).

Simple variance reduction in Monte Carlo calculations of specific absorbed fractions: Russian roulette and splitting at the source organ.

PURPOSE: To investigate the capabilities of several variance reduction techniques in the calculation of specific absorbed fractions in cases where the source and the target organs are far away and/or the target organs have a small volume. METHODS: The specific absorbed fractions have been calculated by using the Monte Carlo code PENELOPE and by assuming the thyroid gland as the source organ and the testicles, the urinary bladder, the uterus, and the ovaries as the target ones. A mathematical anthropomorphic phantom, similar to the MIRD-type phantoms, has been considered. Photons with initial energies of 50, 100 and 500 keV were emitted isotropically from the volume of the source organ. Simulations have been carried out by implementing the variance reduction techniques of splitting and Russian roulette at the source organ only and the interaction forcing at the target organs. The influence of the implementation details of those techniques have been investigated and optimal parameters have been determined. All simulations were run with a CPU time of 1.5 · 105 s. RESULTS: Specific absorbed fractions with relative uncertainties well below 10% have been obtained in most cases, agreeing with those used as reference. The best value for the factor defining the application of the Russian roulette technique was r = 0.3. The best value for the splitting number was between s = 3 and s = 10, depending on the specific energies and target organs. CONCLUSIONS: The proposed strategy provides an effective method for computing specific absorbed fractions for the most unfavorable situations, with a computing effort that is considerably reduced with respect to other methodologies.

Photobiomodulation can improve ovarian activity in polycystic ovary syndrome-induced rats.

Follicular cystic ovary disease is a common reproductive disorder in women and females of domestic animals, characterized by anovulation and the persistence of follicle is a common cause of reproductive failure in mammalian. Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism (HA), chronic anovulation and polycystic ovaries, and it is a common reproductive endocrine disease with clinical manifestations including hirsutism, acne, infertility and obesity that can affect 5-20% of women in their reproductive age. Photobiomodulation (PBM) has been investigated and used in clinical practice, related to biomodulatory influences on cellular functions in animals and humans, both in vivo and in vitro. In this study, we include endocrine and reproductive features in a rat model for PCOS and the effects of PBM on ovarian activities. Forty-five adult female Wistar rats PCOS-induced by a single dose of the estradiol valerate (EV) were used in the study. After the EV injection for PCO induction, rats were divided into 9 groups (n = 5/group) named C30, C45 and C60 (Control group), S30, S45 and S60 (PCO group) and L30, L45 and L60 (PCO/Laser group). The rats were irradiated with laser 3 times/week. The results shown that EV PCO-induced rats had increased body mass, reduced ovary mass, and reduced GSI. The plasma levels of P4 and T were increased, and the LH plasma level was decreased by PBM stimulation. The number of ovarian follicles and corpus luteum were increased, and the number of ovarian cysts was decreased by PBM stimulation. Thus, reproductive and endocrine characteristics were modulated by PBM.

Low level laser therapy (LLLT) modulates ovarian function in mature female mice.

It is known that LLLT has beneficial effects on several pathological conditions including wound healing, pain and inflammation. LLLT modulates biological processes, including cell proliferation, apoptosis and angiogenesis. In the present study, we examined the effect of local application of LLLT on follicular dynamics, ovarian reserve, AMH expression, progesterone levels, apoptosis, angiogenesis, and reproductive outcome in adult mice. LLLT (200 J/cm2) increased the percentage of primary and preantral follicles, whilst decreasing the percentage of corpora lutea compared to control ovaries. LLLT-treated ovaries did not exhibit any changes regarding the number of primordial follicles. We observed a higher percentage of AMH-positive follicles (in early stages of development) in LLLT-treated ovaries compared to control ovaries. LLLT reduced the P4 concentration and the apoptosis in early antral follicles compared to control ones. LLLT caused a reduction in the endothelial cell area and an increase in the periendothelial cell area in the ovary. Additionally, LLLT was able to improve oocyte quality. Our findings suggest that local application of LLLT modulates follicular dynamics by regulating apoptosis and the vascular stability in mouse ovary. In conclusion, these data indicate that LLLT might become a novel and useful tool in the treatment of several pathologies, including female reproductive disorders.

Optimization of the sterilizing doses and overflooding ratios for the South American fruit fly.

The Sterile Insect Technique (SIT) is an autocidal control method that relies on inundative releases of sterilized mass-reared insects. This technology has been used in several area-wide programmes for the suppression/eradication of fruit fly populations. Choosing the optimum sterilizing dose and the sterile release density is an essential step of the SIT. Considering unsolved issues related to the application of this technique against Anastrepha fraterculus (Wiedemann), this study aimed to define accurately the central target dose for both sexes of this species and to verify the induction of sterility in fertile flies at different sterile:fertile ratios. The results from the regression analyses proved that the sterilization process for the A. fraterculus Brazilian-1 morphotype (the most common in southern Brazil and Argentina) could consist of irradiating pupae 72 h before adult emergence at 40 Gy, with no detrimental effects to standard quality control parameters. The ovarian development in irradiated females was characterized, demonstrating that doses equal to or higher than 25 Gy cause complete and irreversible ovarian atrophy. The laboratory and field cage tests showed that the sterility induction increased with the proportion of sterile flies, and a sterile:fertile ratio of 50:1 should be appropriate in SIT field trials. The sterile females apparently did not distract the sterile males, despite of the slightly higher reductions in pupal yield for all ratios in their absence. The data generated in this study have a great practical value and will help decision-makers in planning field trials to evaluate the efficacy of the SIT against A. fraterculus populations.

Effects of Irradiation Dose on Sterility Induction and Quality Parameters of Drosophila suzukii (Diptera: Drosophilidae).

Drosophila suzukii (Matsumura, 1931) (Diptera: Drosophilidae) is a widely distributed pest of soft-skinned and stone fruits that is controlled mainly with pesticides. An alternative to the chemical control is the sterile insect technique (SIT), an ecologically friendly method of pest management that could be used against D. suzukii. The objective of the present study was to evaluate the effects of gamma radiation on reproductive sterility, ovarian morphometry, and quality parameters of D. suzukii. Full female sterility was achieved at 75 Gy, while an adequate level of male sterility (99.67%) was obtained at 200 Gy. The ovarian size showed an exponential decay in function of irradiation dose increase. There was no significant influence of irradiation dose on the quality parameters evaluated. Our data suggest that gamma radiation can be recommended to be used in an SIT program for D. suzukii.

Effect of different light sources on reproductive anatomy and physiology of Japanese quail (Coturnix coturnix japonica).

Artificial lights are essential for controlling the reproductive tract development of birds during puberty and therefore influence reproductive quality. The aim of this study was to evaluate the effect of different light sources on reproductive anatomic and physiological characteristics of female Japanese quail (Coturnix coturnix japonica). A total of 270 birds from one day of age were housed in a masonry shed divided into six rooms with light isolation. Each room was equipped with a different type of light bulb and contained seven cages with five birds in each. The light bulbs tested were: incandescent; compact fluorescent; and light-emitting diode (LED) in the colors white, blue, red and green. The experimental design was completely randomized with six treatments and seven replications of individual birds each. The anatomic and physiological condition of the birds was evaluated at four, eight and 12 weeks of age. The white LED bulb advanced (P<0.05) the sexual maturity by one week, resulted (P<0.05) in higher live weights and greater weight and relative percentage of ovarian stroma, oviduct and ovarian tissue at eight weeks of age. Higher plasma concentrations of estradiol and lipids were also observed (P<0.05) at eight weeks under the white LED bulb. At 12 weeks of age, the magnum and isthmus folding characteristics were better (P<0.05) with the red LED bulb. In conclusion, the photostimulation with the white LED bulb was more efficient at activating the reproductive cycle, hastening the onset of sexual maturity and increasing the development of reproductive organs after puberty.

O impacto da radioterapia e da quimioterapia no aparelho genital feminino / Radiotherapy and chemotherapy impact on female genital apparatus

O tratamento de diversos tipos de câncer poderá muitas vezes condicionar as pacientes a redução no seu potencial reprodutivo. As pacientes com diferentes neoplasias deverão ser informadas das opções terapêuticas e também das medidas necessárias para preservar sua fertilidade, dos possíveis danos no aparelho reprodutor feminino e das possibilidades futuras quanto à reprodução, antes de receberem qualquer orientação terapêutica. Esse foi o propósito deste estudo.

Treatment of several types of cancer, in many cases, lead to a reduction of the patients' reproductive potential. Such patients must be informed of different therapeutic options and possible resulting damage to the female reproductive tract, as well as all measures necessary for preserving their fertility and future possibilities to reproduce, prior to receiving any therapeutic orientation geared toward this goal. This was the basic purpose of this study.

Hirsutism: from Brazil to a place near you.

IMPORTANCE OF THE FIELD: Hirsutism is the excess of terminal hairs in females and can result in immense distress. Women often spend significant time and funds seeking permanent hair removal. Commercially available physical therapies have usually already been accessed before presenting to the clinician for treatment. AREAS COVERED IN THE REVIEW: We give a brief outline of physical therapies in the treatment of hirsutism with an emphasis on recently emerging hand-held laser hair removal devices for home use, which will become an increasingly important hair removal modality. The current evidence for topical ornithine decarboxylase inhibitor, oral antiandrogens, ovarian suppression and insulin sensitizers in the treatment of hirsutism is also reviewed. WHAT THE READER WILL GAIN: With advances in home laser hair removal systems the role of the clinician will increasingly become the use of pharmacotherapy in the treatment of resistant hirsutism. This article provides a review of the current literature for the use of pharmacotherapy. TAKE HOME MESSAGE: Despite the availability of a range of physical and pharmacotherapies for the treatment of hirsutism, permanent hair removal remains elusive.

New approaches to female fertility preservation.

Survival rates have been improved in young cancer patients due to advances in oncologic treatments. It is necessary to focus on the consequences of cancer treatments and try to elude or at least prevent them. Menopause and infertility are two of the main causes for concern to those patients who survive cancer. When a solution is offered to these patients, their quality of life and self-esteem can be dramatically increased after therapy. Results observed in vitrified oocytes are similar to those achieved with fresh oocytes, giving this method great potential. Recommendations on fertility preservation should be focused on the oocyte vitrification method, which should be considered as the first option. Limitations of this approach are the need for ovarian stimulation, which means a 2-3 week period prior to chemotherapy and the possibility of high oestradiol levels when tumours are hormone dependent.

The Valencia Programme for Fertility Preservation.

INTRODUCTION: Fertility preservation needs have increased dramatically in recent years due to a rising cancer incidence and also a significant increase in survival rates. MATERIALS AND METHODS: We report on 200 women participating in the Valencia Programme for Fertility Preservation, of whom 55% were breast cancer patients, 25% Hodgkin's disease patients, and the remaining 20% suffered from other nonmalignant and malignant diseases. Mean age was 28.2 years (11-39). Before patients were submitted to oncological treatment, the right ovarian cortex was extracted by laparoscopy and cryopreserved. Once the patient was free of disease, the right ovarian cortex was thawed and implanted onto the left ovarian medulla (after extraction at the same surgical time of left ovarian cortex). RESULTS: In 95% of cases, a piece approximately 2 x 3 cm was obtained. The procedure did not cause any change in the cancer therapy schedule. Four implants had been performed (all of them in women who underwent chemotherapy prior to ovarian cortex extraction), from which two of the case achieved ovarian function resumption, in one case a month after the implant and in the other 5.5 months after. The remaining two implanted cases were performed 5 and 6 months prior to the writing of this paper, respectively. CONCLUSIONS: Ovarian tissue cryopreservation is a feasible option to preserve ovarian function and possibly fertility in adolescents and young women at risk of developing premature ovarian failure (POF) due to chemotherapy and/or radiotherapy.

Genetic instability induced by low doses of x-rays in hamster cells.

PURPOSE: Genomic instability involves time delayed events and can be manifested as elevated rates of heritable changes in the progeny of irradiated cells. To study the induction of chromosomal instability by very low doses of radiation Chinese Hamster Ovary (CHO) cells were exposed to 10-50 milisieverts (mSv) (approximately 10-50 miligrays (mGy)) of x-rays. MATERIALS AND METHODS: Control and irradiated cell populations were assayed for chromosomal aberrations and assessed using a micronucleus test and anaphase-telophase analysis at the first cell division post-irradiation and at every four population doublings thereafter up to 16 population doublings post-irradiation. RESULTS: Frequencies of micronuclei, anaphase-telophase alterations and chromosomal aberrations were increased when the cells were analysed immediately after x-ray exposure. Micronuclei and anaphase-telophase alterations showed significantly increased frequencies when they were analysed at 12 and 16 population doublings after exposure to 50 mSv. Chromosomal aberrations increased significantly at 12 and 16 population doublings after exposure to 10 mSv and 50 mSv. CONCLUSIONS: Our results are consistent with the presence of a phenomenon by which the initial DNA damage in the surviving cells is memorized. Micronuclei and achromatic lessions were the main cytogenetic damage observed in cells exposed to very low doses of x-rays, indicating that these low doses are able to induce genetic instability.

Malformations in the offspring of women with thyroid cancer treated with radioiodine for the ablation of thyroid remnants.

RATIONALE: Since ovarian function is only temporarily compromised by radioiodine therapy, many women with thyroid cancer treated with radioiodine can become pregnant. The present study evaluated the evolution of these pregnancies and the consequences for the offspring. PATIENTS AND METHODS: We retrospectively analyzed 78 pregnancies of 66 women submitted to total thyroidectomy, followed by radioiodine therapy 3.75-5.5 GBq (131)I, mean 4.64 GBq). In all patients, conception occurred one year after ablative therapy (mean of 30 months). Age ranged form 19 to 36 years (mean of 30.6 years) at the time of radioiodine treatment and from 23 to 39 years (mean of 32.8 years) at the time of conception. RESULTS: Four (5.1%) of the 78 pregnancies resulted in spontaneous abortions. Three (4%) of the 74 deliveries were preterm and there was no case of stillbirth. The birthweight was > 2500 g in 94.6% of the children (+/- SD: 3350 +/- 450 g) and only one infant (1.3%) presented an apparent malformation at birth (intraventricular communication). No difference in the age at the time of radioiodine therapy or conception or in radioiodine dose was observed between pregnancies with an unfavorable outcome and those with a favorable outcome. CONCLUSION: We conclude that pregnancies that occur 12 months after ablative therapy are safe.

Malformations in the offspring of women with thyroid cancer treated with radioiodine for the ablation of thyroid remnants / Malformações na prole de mulheres com câncer de tireóide tratadas com radioiodo para ablação de remanescentes tireoideanos

RATIONALE: Since ovarian function is only temporarily compromised by radioiodine therapy, many women with thyroid cancer treated with radioiodine can become pregnant. The present study evaluated the evolution of these pregnancies and the consequences for the offspring. PATIENTS AND METHODS: We retrospectively analyzed 78 pregnancies of 66 women submitted to total thyroidectomy, followed by radioiodine therapy (3.7­5.5 GBq 131I, mean 4.64 GBq). In all patients, conception occurred one year after ablative therapy (mean of 30 months). Age ranged form 19 to 36 years (mean of 30.6 years) at the time of radioiodine treatment and from 23 to 39 years (mean of 32.8 years) at the time of conception. RESULTS: Four (5.1 percent) of the 78 pregnancies resulted in spontaneous abortions. Three (4 percent) of the 74 deliveries were preterm and there was no case of stillbirth. The birthweight was > 2500 g in 94.6 percent of the children (mean ± SD: 3350 ± 450 g) and only one infant (1.3 percent) presented an apparent malformation at birth (intraventricular communication). No difference in the age at the time of radioiodine therapy or conception or in radioiodine dose was observed between pregnancies with an unfavorable outcome and those with a favorable outcome. CONCLUSION: We conclude that pregnancies that occur 12 months after ablative therapy are safe.

ARRAZOADO: Uma vez que a função ovariana está apenas temporariamente comprometida pela terapia com radioiodo, muitas mulheres com câncer de tireóide tratadas com radioiodo podem engravidar. O presente estudo avaliou a evolução dessas gravidezes e suas conseqüências para a prole. PACIENTES E MÉTODOS: Analisamos retrospectivamente 78 gravidezes de 66 mulheres submetidas a tiroidectomia total seguida de radioiodoterapia (3,7­5,5 GBq 131I, média 4,64 GBq). Em todas, a concepção ocorreu um ano após a terapia ablativa (média de 30 meses). A idade variou de 19 a 36 anos (media de 30,6) à época do tratamento com radioiodo e de 23 a 39 anos (média de 32,8) na época da concepção. RESULTADOS: Quatro (5,1 por cento) das 78 gravidezes resultaram em abortamento espontâneo. Três (4 por cento) dos 74 partos foram pré-termo, mas não houve nenhum natimorto. O peso ao nascer foi >2.500 g em 94,6 por cento das crianças (média ± DP: 3.350 ± 450 g) e somente uma delas (1,3 por cento) apresentou uma malformação aparente ao nascimento (comunicação intraventricular). Nenhuma diferença quanto à idade na época da radioiodoterapia ou na concepção ou na dose de radioiodo foi observada entre as gravidezes com ou sem um desfecho favorável. CONCLUSÃO: Gravidezes que ocorrem 12 meses após terapia ablativa com radioiodo são seguras.

Ovarian function after radioiodine therapy in patients with thyroid cancer.

OBJECTIVE: To assess ovarian function in young women treated with radioiodine. METHODS: The study was conducted on 50 women with thyroid carcinoma aged less than 40 years (mean, 29.8 years), with regular menstrual cycles and normal FSH levels prior to radioiodine therapy. FSH determination was repeated 6 and 12 months after radioiodine therapy (mean, 4.24 GBq iodine-131) and menstrual cycles were monitored during this period. RESULTS: Twenty percent of the patients reported amenorrhea during the first year. FSH levels increased after 6 months (from 5.1 +/- 1.8 to 10.6 +/- 2.2 IU/l, p < 0.00 001) and 28 % of the patients showed elevated values, which had returned to normal by the end of the first year. CONCLUSION: Radioiodine causes transitory alterations in ovarian function even in younger women and after a mean activity of 4.2 GBq (115 mCi).

Recovery of fertility after grafting of cryopreserved germinative tissue in female rabbits following radiotherapy.

BACKGROUND: Many cancer survivors face infertility as a consequence of the aggressive treatment they must undergo. Cryopreservation of ovarian tissue before chemotherapy or radiotherapy may allow for tissue transplantation after the treatment, and restoration of fertility. We tested the potential of an orthotopic autografting of cryopreserved germinative tissue in female rabbits with ovarian failure following radiotherapy. METHODS: Ten adult multiparous female rabbits were randomly allocated into two groups, five in group I (control) and five in group II (transplant). All rabbits underwent right oophorectomy with cryopreservation of the germinative tissue, followed by sterilization of the remaining left ovary by radiotherapy. Later, group II rabbits received in the irradiated left ovary an implant of the frozen germinative tissue from the right ovary, whose small pieces were freely spread intracortically in a procedure we named 'intracortical sowing of germinative tissue' (ISGT). RESULTS: All group II rabbits conceived following spontaneous mating within 6 months of the transplant, whereas none of the remaining rabbits in group I had conceived up to 11 months after transplant. CONCLUSIONS: This study suggests that fertility can be restored in rabbits by sowing cortical tissue in a previously irradiated ovary. The clinical feasibility of this technique remains to be determined.

Recovery of natural fertility after grafting of cryopreserved germinative tissue in ewes subjected to radiotherapy.

OBJECTIVE: To recover natural fertility of ewes that were subjected to ovarian failure induced by radiotherapy with an autologous orthotopic graft of cryopreserved germinative tissue. DESIGN: Experimental surgery study. SETTING: University hospital unit. ANIMAL(S): Adult ewes. INTERVENTION(S): Four ewes were submitted to right oophorectomy and posterior dissecting and freezing of the germinative tissue. Afterward, they were administered radiotherapy to induce infertility on the remaining left ovary. Later, two of the ewes had the thawed fragments of the right ovary injected inside the cortex of the irradiated left ovary in a "sowing" procedure that eliminated the need for sutures. MAIN OUTCOME MEASURE(S): Recovery of fertility in ewes after transplantation of germinative tissue into the ovary destroyed by radiotherapy. RESULT(S): The ewes were housed with fertile rams. Six months following the grafting, the rams impregnated the transplanted ewes. More than 2 years after radiotherapy, the nongrafted (control) ewes have not become pregnant. CONCLUSION(S): Intracortical grafting of the germinative tissue circumvents the obstacle of vascular anastomosis with autologous ovarian implants. Patients could benefit from the subcortical grafting of germinative tissue in one of the ovaries, recovering fertility after radiotherapy treatment for malignancy.

Gonadal function after bone marrow transplantation for acute leukemia during childhood.

OBJECTIVE: To examine the impact of bone marrow transplantation (BMT), using high-dose chemotherapy and hyperfractionated total body irradiation, on gonadal function in survivors of acute leukemia treated during childhood. STUDY DESIGN: We conducted a retrospective study of 33 subjects (17 boys) who underwent a BMT for acute leukemia (acute lymphoblastic leukemia, n = 20; acute myelogenous leukemia, n = 13) at a single institution. All patients were prepubertal at the time of BMT (median age, 7.1 years (3.7 to 11.6 years)); at the time of their last examination the boys were a median of 14 years (10.4 to 17.1 years) of age and the girls were a median of 16.9 years (9.5 to 21.9 years) of age. RESULTS: Of 17 boys, 14 (82%) entered puberty spontaneously and 13 demonstrated age-appropriate plasma concentrations of testosterone. Two boys (aged 10.5 and 11 years) remain clinically and hormonally prepubertal, and one boy has overt Leydig cell failure requiring androgen replacement therapy. Thirty-six percent of pubertal boys have elevated plasma concentrations of luteinizing hormone and 64% have raised levels of follicle-stimulating hormone. Boys with increased levels of luteinizing hormone were significantly younger at BMT (5.4 +/- 0.8 vs 7.8 +/- 0.8 years; p = 0.024). Of 16 girls, 9 (56%) had spontaneous puberty with onset of menarche at a median age of 13 years (9.5 to 15.8 years). Though six (67%) of these nine girls have had increased plasma concentrations of luteinizing and follicle-stimulating hormones, normalization has occurred in two during a period of 4 to 7 years. The remaining seven subjects required hormone replacement because of clinical and biochemical evidence of ovarian failure. One of these subjects has recovered ovarian function after 5 1/2 years. Female patients with ovarian failure were significantly older at BMT compared with female patients with spontaneous puberty/menarche (8.6 +/- 23 years vs 6.1 +/- 1.8; p = 0.03). CONCLUSION: Our results indicate that most prepubertal boys undergoing BMT with chemotherapy and hyperfractionated total body irradiation can expect to enter and progress normally through puberty. For prepubertal girls treated with these regimens, at least 50% retain adequate ovarian function to enter puberty and menstruate regularly.