Effect of bisphosphonate and denosumab treatment on TBS in Japanese breast cancer patients with AIBL.

INTRODUCTION: Bisphosphonates and denosumab increase bone mineral density (BMD) for osteoporosis treatment in patients with aromatase inhibitor-associated bone loss (AIBL). This study aimed to directly compare bisphosphonates with denosumab in treating patients with AIBL and to determine the effect of denosumab on the trabecular bone score (TBS). MATERIALS AND METHODS: Thirty-nine patients with AIBL receiving osteoporosis treatment (21 in the bisphosphonates group and 18 in the denosumab group) were retrospectively evaluated for changes in lumbar spine and femoral BMD, lumbar spine bone quality (assessed by TBS), and blood bone metabolic markers. The Mann-Whitney and Wilcoxon tests were used for statistical evaluation. RESULTS: After 24 months of treatment, the lumbar spine BMD change rate was 5.82 ± 1.10% with bisphosphonates and 10.49 ± 1.20% with denosumab, with the change rate of denosumab significantly increasing over that of bisphosphonates. The change rate in femoral BMD was 2.69 ± 1.16% with bisphosphonates and 2.95 ± 1.26% with denosumab, with no significant difference between the two groups. The rate of decrease in tartrate-resistant acid phosphatase isoform 5b was significantly higher in the denosumab group. The change rate in TBS at 24 months of treatment was 0.53 ± 1.26% in the bisphosphonates group and 1.08 ± 1.33% in the denosumab group, with no significant difference between the two groups. After 24 months, TBS remained stable. CONCLUSION: Both bisphosphonates and denosumab may increase BMD, improve bone metabolism, and inhibit bone quality loss in patients with AIBL.

Factors associated with low bone mineral density in Turner syndrome: a multicenter prospective observational study.

Turner syndrome (TS) is associated with a high risk of fracture due to low bone mineral density (BMD). While hypogonadism is known to play a role in decreasing BMD, other factors have not been studied well. Focusing on diet, exercise, and bone metabolism markers, the present, multicentric, prospective, observational study aimed to identify factors contributing to decreased BMD in TS. In total, 48 patients with TS aged between 5 and 49 years comprising a pre-pubertal group (n = 9), a cyclical menstruation group (n = 6), and a hormone replacement therapy (HRT) group (n = 33) were enrolled. The cyclical menstruation group and the HRT group were referred to collectively as the post-pubertal group. The bone mineral apparent density (BMAD) Z-score was higher in the pre-pubertal group than in the post-pubertal group (-0.3 SD vs. -1.8 SD; p = 0.014). Within the post-pubertal group, the median BMAD Z-score was -0.2 SD in the cyclical menstruation group and -2.3 SD in the HRT group (p = 0.016). Spearman's rank correlation revealed no correlation between the BMAD Z-score and bone metabolism markers. No significant relationship was observed between the BMAD Z-score and either the vitamin D sufficiency rate or the step sufficiency rate. A negative correlation was found between BMAD Z-score and serum sclerostin in the pre-pubertal group and serum FSH in the post-pubertal group. In conclusion, the present study found no relationship between the vertebral BMAD Z-score and diet or exercise habits in TS, indicating that estrogen deficiency is the chief reason for low BMD in TS.

Fertility preservation immediately after therapeutic abortion results in multiple normal follicular growth with the absence of mature oocytes due to early luteinization: a case report and literature review.

Cancer therapy has priority over fertility preservation. The time available for fertility preservation in patients with cancer is often very limited and depends on the condition of the underlying disease. This case report presents the results of two rounds of controlled ovarian stimulations (COSs) performed after an induced abortion. The patient had mixed phenotype acute leukemia diagnosed during early pregnancy and underwent a surgical abortion, followed by ovarian stimulation using urinary follicle-stimulating hormone (uFSH) and gonadotropin-releasing hormone (GnRH) agonists. Oocyte retrieval was subsequently performed for oocyte cryopreservation. Despite good hormonal and ultrasonic follicular growth, no oocytes were obtained. During a second COS performed at a low human chorionic gonadotropin (hCG) level (less than 100 IU/L), several mature oocytes were obtained, suggesting that higher hCG levels during COS induce the absence of mature oocytes during normal follicular growth. It is recommended to start COS post-abortion after confirming a low hCG level while considering the timing of cancer treatment.

National survey of primary amenorrhea and relevant conditions in Japan.

AIM: In Japan, most of the patients with primary amenorrhea or related conditions, such as delayed menarche, are diagnosed by pediatricians or gynecologists; accordingly, the number of the patients and the ratio of the causes were unclear. To clarify them, we conducted a nationwide survey in both the departments for the first time. METHODS: We sent a questionnaire about the patients with chief complaint of no menarche whose first visit was from January 2015 to December 2017, to 596 training institutions for specialist physicians of the Japan Society of Obstetrics and Gynecology and 152 facilities to which councilors of the Japanese Society for Pediatric Endocrinology belong. RESULTS: We received replies from 283 (37.8%) institutions. During the 3 years, 1043 patients first visited pediatrics or gynecology for no menarche. In 303 patients under 16 years old at the first visit, 177 (58.4%) patients had menarche by the age of 16. Of them, 41 (13.5%) patients had menarche spontaneously. Among 308 patients aged 16 to 17 at the first visit, 216 patients were 18 years or older at the survey. Of them, 124 (57.4%) patients had menarche by the age of 18, and 21 (9.7%) of them had menarche spontaneously. The causes of amenorrhea were detected in 462 patients. Abnormal karyotype including Turner syndrome was the most common at 122 (26.4%), followed by Mullerian agenesis at 73 (15.8%). CONCLUSIONS: The first national survey revealed the number and causes of primary amenorrhea and related conditions. This report will provide better information for clinicians.

25-Hydroxyvitamin D profiles and maternal bone mass during pregnancy and lactation in Japanese women.

Vitamin D deficiency is observed worldwide and represents a health hazard for mothers, infants and elderly persons. We know that many young Japanese women experience vitamin D insufficiency; however, there is a lack of knowledge regarding the serum 25-hydroxyvitamin D [25(OH)D] profile of pregnant Japanese women and of the association between maternal 25(OH)D level and maternal bone mass during pregnancy and lactation. In this longitudinal study, 160 pregnant Japanese women were enrolled; of them, 68 have been followed-up from the first trimester through at least 1 year of breast-feeding. We estimated serum 25(OH)D levels, intact PTH levels, calcaneus quantitative ultrasound (QUS: T score) scores, bone mineral density at the distal one-third of the radius, dietary intakes according to the Food Frequency Questionnaire, and sunlight exposure times. We found that Vitamin D deficiency is prevalent in Japanese women, irrespective of pregnancy or lactation, and our analysis suggested that 25(OH)D levels and BMI in the first trimester were related to the lactating women's bone mass from after delivery to 1 year after delivery.

A retrospective multicenter study of bone mineral density in adolescents and adults with Turner syndrome in Japan.

Osteoporosis is one of the clinical features of women with Turner syndrome (TS). The reasons for low bone mineral density (BMD) and increased bone fragility are multifactorial, including estrogen deficiency, X-chromosome abnormalities, and environmental factors. Few, large-scale studies on bone mineral density in either adolescents or adults with TS have been done in Japan. The goal of the present study was to investigate spinal BMD in women with TS, assess its relationship with clinical parameters, especially estrogen replacement therapy, and investigate its longitudinal changes. The spinal BMD and clinical data of 149 Japanese women with TS aged 15 to 49 years who were followed at the four participating hospitals were retrospectively analyzed. The BMD Z-scores of the women with TS ranged from -5.30 to +1.89. Women with TS aged 15-39 years had lower BMD than healthy Japanese women (p < 0.01) while women with spontaneous menstruation had a significantly higher BMD Z-score than those without spontaneous menstruation (-0.73 ± 1.11 vs. -1.67 ± 1.18, p < 0.01). In women without spontaneous menstruation, BMD Z-scores correlated with the duration of their estrogen therapy (r = 0.167, p < 0.01). Women aged 15-39 years with TS had low BMD, which was associated with primary amenorrhea and short estrogen replacement therapy duration.

Current situation and outcomes of pregnancy in women with Turner syndrome in Japan.

AIM: Reports on pregnancy and delivery in women with Turner syndrome (TS) in Japan are limited to case reports, and the current situation remains unclear. Therefore, this study aimed to clarify the current situation of pregnancy and delivery in women with TS in Japan. METHODS: Our study comprised primary and secondary surveys and we included perinatal centers approved by the Ministry of Health, Labor and Welfare. RESULTS: A total of 24 cases from 19 facilities were reported, and we obtained individual information for 20 cases from 16 facilities. Of these 20 patients, 13 (65%) had become pregnant via oocyte donation. Three of these patients had received oocyte donation in Japan, while the other 10 had received donations in foreign countries. The other seven patients became pregnant with their own oocyte, with spontaneous menarche. Live babies were delivered by 18 patients, while an induced abortion was required at 18 weeks of gestation in one patient and an intrauterine fetal death from an unknown cause was detected at 38 weeks of gestation in another patient. Cesarean section was performed in 14 patients, with the most frequent indication being cephalopelvic disproportion. The rate of implementation of screening for complications related to TS was low, suggesting insufficient cooperation between facilities responsible for TS treatment, infertility and pregnancy and delivery management. CONCLUSION: To improve pregnancy outcomes in women with TS, improved cooperation between facilities and laws regarding oocyte donation in Japan are needed.

Activated vitamin D3 formulations can be safely used as concomitant medication for prevention of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis.

AIM: Denosumab prevents osteoporosis by potently inhibiting bone resorption, but requires oral therapy with calcium and vitamin D preparations to prevent the side effects of hypocalcemia. Generally, a combination drug containing calcium, natural vitamin D, and magnesium is used. However, if activated vitamin D has been used before the initiation of denosumab therapy, continued use of activated vitamin D is not uncommon. This study aimed to evaluate the combination vitamin D preparation, alfacalcidol, and eldecalcitol on the therapeutic effect on denosumab therapy, the preventive effect on hypocalcemia, and the effect on renal function, to determine the optimal choice of concomitant medication. METHODS: This is a retrospective and single-center study. Among 39 patients who had used denosumab (60 mg dose) for at least 12 months between November 2013 and October 2015, those who used the combination medication concomitantly as the standard treatment, those who used alfacalcidol concomitantly, and those who used eldecalcitol concomitantly were compared. RESULTS: Denosumab therapy markedly increased lumbar spine and femoral neck bone densities at 12 months in the three groups, showing no particular difference in the rate of increase of bone density. The three groups had marked decreases in bone metabolism markers, but had no intergroup differences. No hypocalcemia, hypercalcemia, or obvious renal dysfunction occurred over 12 months. CONCLUSION: This study indicates that the use of activated vitamin D preparations, as concomitant medications with denosumab therapy, is appropriate considering the therapeutic efficacy of denosumab, prevention of hypocalcemia, and influence on renal function.

Eldecalcitol increases bone mass in patients with Turner syndrome who have insufficient bone mass acquisition after estrogen replacement therapy.

Most patients with Turner syndrome (TS) exhibit amenorrhea due to premature ovarian failure. Therefore, estrogen replacement therapy (ERT) is required; however, even after undergoing ERT, it is not rare for bone mass acquisition to be insufficient. This study was conducted in two stages, involving a cross-sectional and a prospective interventional study. We recruited 52 TS patients undergoing ERT due to amenorrhea (categorized into low (LB group; n = 23), and normal (NB group; n = 29) bone mass groups) and 7 TS patients who maintained ovarian function (spontaneous menstrual cycle group (MC group)) as controls. We compared bone associated markers between the three groups (LB, NB, and MC). Furthermore, the LB group had concomitant treatment with eldecalcitol (ELD) and ERT for 12 months. The bone mineral density (BMD) of the lumber spine (L2-4) and the bone metabolism markers were then compared before and after the treatment. The bone metabolism markers were significantly higher in the LB group than the NB and MC groups. Furthermore, with the concomitant use of ELD and ERT in the LB group, BMD increased significantly (pre-treatment 0.710 ± 0.056 g/cm2 vs. 0.736 ± 0.062 g/cm2 after 12 months; p < 0.001). TS patients with insufficient bone mass acquisition even after ERT were characterized by a higher turnover in bone metabolism. Therefore, the concomitant use of ELD was considered an effective adjuvant therapy for increasing bone mass.

Physical and social characteristics and support needs of adult female childhood cancer survivors who underwent hormone replacement therapy.

BACKGROUND: Female childhood cancer survivors who develop gonadal dysfunction require female hormone replacement therapy (HRT) from puberty until menopause. However, the support provided in such cases has not been studied. We investigated the physical and social characteristics and support needs of adult female childhood cancer survivors who underwent HRT. METHODS: Forty-nine adult female childhood cancer survivors completed self-administered questionnaires. We compared the clinical characteristics, health status, and social conditions between a group that underwent HRT and a group that did not, and we surveyed support needs of the group that underwent HRT. RESULTS: The median age of the subjects was 25.0 years (range 20-41). Twenty subjects (40.8%) underwent HRT. A significantly high number of those who underwent HRT also underwent radiation therapy (p < 0.01) and hematopoietic stem cell transplantation (p < 0.001), and none of them had a history of pregnancy or childbirth (p < 0.05). There were no significant differences in physical symptoms and social characteristics between the groups. Those who experienced anxiety regarding fertility required information about HRT, a platform to share their concerns, and psychological support and cooperation among healthcare providers. CONCLUSIONS: Although the subjects of this survey exhibited good social adjustment regardless of whether or not they underwent HRT, they were anxious about fertility. It is important to understand the concerns and anxieties unique to female childhood cancer survivors and to enhance psychological support in addition to providing educational support so that HRT can be administered.

Nomenclature of primary amenorrhea: A proposal document of the Japan Society of Obstetrics and Gynecology committee for the redefinition of primary amenorrhea.

AIM: The aim of this study was to provide medical terms to describe the condition of a girl who should be evaluated for primary amenorrhea in order to facilitate intervention at an appropriate time. METHODS: We performed a literature and clinical guidelines search for recent practices with regard to menarche and discussed relevant cases that had been experienced by committee members. Additionally, we theoretically reviewed medical terms defined in the Glossary Book of Obstetrics and Gynecology in Japan (Japan Society of Obstetrics and Gynecology, 3rd edition). RESULTS: The committee for the redefinition of primary amenorrhea proposed the introduction of two terms and the deletion of one term that had been defined by the Japan Society of Obstetrics and Gynecology, instead of changing the age definition of primary amenorrhea. 'Delayed menarche' was introduced to describe a condition in which a girl has never experienced cyclic menstruation (menarche) by 15-17 years of age. 'Late menarche' was also introduced to describe a condition in which a girl has experienced menarche at 15 years of age or older. 'Delayed menstruation,' which was defined as a condition in which a girl experiences menarche at 15-18 years of age, was deleted. CONCLUSION: The new terms 'delayed menarche' and 'late menarche' were introduced, and the term 'delayed menstruation' was deleted. The new system might help in the early detection and appropriate treatment of primary amenorrhea.

Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth.

OBJECTIVE: Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth. STUDY DESIGN: Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients' charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry. RESULTS: EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 ± 4122 vs 1455 ± 2141; P = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (ρ = 0.294; P = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P = .013 by Fisher exact test). CONCLUSION: This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which some uterine leiomyomas reach a large size, and the understanding of EPO expression patterns in these tumors may be useful for management of the patients with leiomyomas.

Efficacy of estrogen replacement therapy (ERT) on uterine growth and acquisition of bone mass in patients with Turner syndrome.

Estrogen replacement therapy (ERT) is necessary for uterine development and bone mass acquisition in women with Turner syndrome (TS) suffering from ovarian insufficiency. However, adequate ERT regimens have not yet been established. The aim of this study was to evaluate the efficacy of ERT for both uterine development and bone mass acquisition. One hundred TS patients from Yokohama City University Hospital (88 with primary amenorrhea (PA) and 12 patients with spontaneous menstrual cycles (MC)) were enrolled after obtaining consent. Clinical profiles, uterine length (UL) measured by ultrasonic examination, and bone mineral density (BMD) of the lumbar vertebrae (L2-4) assessed by DEXA were evaluated. At the time of the first visit, the ULs of patients in the PA group were significantly shorter than those in the MC group. After receiving ERT, there were no significant differences in UL between patients with PA and MC. Forty-seven patients for whom the ERT initiation age was known were investigated to clarify the influence on BMD. The results showed that the BMD in the late initiation (18 years or older) group at the latest visit (0.770 ± 0.107 g/cm2: n = 16) was significantly lower than that in the early initiation (under 18 years) group (0.858 ± 0.119 g/cm2: n = 21) or the MC group (0.941 ± 0.118 g/cm2: n = 10). No significant differences were seen between the early initiation and MC group. ERT was effective in increasing UL and BMD. However, early initiation of ERT is necessary to increase BMD.

Case of early postoperative adhesion in a patient with molimina due to transverse vaginal septum concomitant with imperforate hymen.

Transverse vaginal septum is a residual vaginal plate composed of the Müllerian duct and urogenital sinus. Imperforate hymen results from failure of perforation of the membrane between the urogenital sinus and vaginal cavity. We report a rare case of concurrence of these two conditions. A 16-year-old girl had been treated with puncture several times for hematometra and hematocolpos from 13 years of age because of monthly occurrence of lower abdominal pain without menstrual bleeding and was referred to our hospital. Magnetic resonance imaging demonstrated hematometra, hematocolpos and expansion of the vaginal fornix. The imperforate hymen was incised and a slight adhesion at the lower vaginal cavity was detached. After that, a complete transverse vaginal septum, which was 5 mm thick, was identified. It was excised after ultrasonography-guided puncture. Although two cycles of menstrual bleeding took place, molimina recurred. Re-operation was performed 6 months after the first operation, and recurrence of adhesion in the lower vaginal cavity was identified. A silicon dilator was inserted, but she could not use it at home and instead used a tampon. Cyclic menstrual bleeding is observed 4 months after the second operation.

Dienogest was effective in treating hemorrhagic ascites caused by endometriosis: a case report.

Hemorrhagic ascites caused by endometriosis is extremely rare, and its treatment is under discussion. We report a case of recurrent endometriosis-related ascites treated with dienogest (DNG). A 35-year-old nulliparous Japanese woman with a history of infertility presented with worsening dysmenorrhea and abdominal distention caused by massive ascites. The patient underwent exploratory laparotomy, and hemorrhagic ascites (5500 mL) was drained. She had a normal-sized uterus, and the bilateral ovaries could not be observed because of extensive adhesion in the abdominal cavity. Endometriosis was diagnosed by histopathological evaluation of the omental biopsy, and this was considered to be the cause of ascites. After laparotomy, she had recurrence of ascites. For the next 8 years, the patient was treated conservatively with gonadotropin-releasing hormone agonist therapy and drainage during the intermittent periods followed by DNG administration. She has been treated continuously with DNG for 1 year with no recurrence of ascites. DNG could be an effective treatment for recurrent ascites associated with endometriosis, especially when surgical therapy is undesirable.

Study of the distribution by age group of serum cross-linked C-terminal telopeptide of type I collagen and procollagen type I N-propeptide in healthy Japanese women to establish reference values.

Osteoporosis prevention is an important public health goal. Bone turnover markers are clinically measured to assess bone strength. C-terminal telopeptide of type I collagen (CTX) is released when collagens degrade and serves as an indicator of bone resorption. Simple CTX immunoassays are now available. However, serum CTX (sCTX) reference ranges for Japanese women are lacking. Procollagen type I N-propeptide (intact P1NP) reflects osteoblast activity, serving as a marker of bone formation. Because sCTX and intact P1NP are clinically applied as bone turnover markers, we determined reference ranges for both sCTX and intact P1NP in healthy Japanese women. We collected 228 blood samples from healthy Japanese women aged 19-83 years, grouped by age and menopausal status. We measured sCTX and intact P1NP and examined their correlation. sCTX values differed significantly between the two consecutive decade groups encompassing 19-39 years of age, intact P1NP values between 20 and 30 s, between post-menopausal 50 and 60 s, and between pre-and post-menopausal women in their 50 s. The mean sCTX of 91 healthy pre-menopausal women was 0.255 (0.100-0.653) ng/mL, the intact P1NP in 90 women 33.2 (17.1-64.7) µg/L. Corresponding values for post-menopausal women were 0.345 (0.115-1.030) ng/mL and 41.6 (21.9-79.1) µg/L. sCTX correlated with intact P1NP. Bone resorption markers are measured to assess anti-resorption agents, bone formation markers to assess the effects of bone-forming agents. The sCTX and intact P1NP reference values determined herein, in healthy Japanese women, are expected to be useful for osteoporosis treatment, assessment of fracture risk, and other clinical applications.

A case of empty follicle syndrome who conceived after aspiration of an endometrial cyst.

Empty follicle syndrome (EFS) has been defined as a condition where no oocytes can be retrieved for in vitro fertilization (IVF) even though ultrasound findings and estradiol (E2) levels suggest the presence of potential follicles. The EFS is a rare condition with an incidence of 0.5-7 % of women undergoing IVF treatments. Although there are many hypotheses as to the cause of EFS, including advanced ovarian age, drug-related problems, and dysfunctional folliculogenesis, its cause remains unknown. A 37-year-old woman with endometriosis and a 5-year history of primary infertility underwent IVF treatment for 4 cycles. No oocytes were retrieved in 2 cycles and no fertilized eggs were obtained in the other 2 cycles. We assumed that endometriosis adversely affected folliculogenesis and fertilization. Aspiration of an endometrial cyst in the right ovary and subsequent administration of oral contraceptives resulted in successful folliculogenesis and fertilization. Thereafter, she conceived and delivered a 2,662 g female infant at 38 weeks of gestation. Here, we report a case of EFS who conceived in the 5th IVF cycle after aspiration of an endometrial cyst. We assumed that endometriosis might have been involved in the dysfunction of folliculogenesis and EFS.

Mitochondrial DNA mutations can influence the post-implantation development of human mosaic embryos.

Introduction: Several healthy euploid births have been reported following the transfer of mosaic embryos, including both euploid and aneuploid blastomeres. This has been attributed to a reduced number of aneuploid cells, as previously reported in mice, but remains poorly explored in humans. We hypothesized that mitochondrial function, one of the most critical factors for embryonic development, can influence human post-implantation embryonic development, including a decrease of aneuploid cells in mosaic embryos. Methods: To clarify the role of mitochondrial function, we biopsied multiple parts of each human embryo and observed the remaining embryos under in vitro culture as a model of post-implantation development (n = 27 embryos). Karyotyping, whole mitochondrial DNA (mtDNA) sequencing, and mtDNA copy number assays were performed on all pre- and post-culture samples. Results: The ratio of euploid embryos was significantly enhanced during in vitro culture, whereas the ratio of mosaic embryos was significantly reduced. Furthermore, post-culture euploid and culturable embryos had significantly few mtDNA mutations, although mtDNA copy numbers did not differ. Discussion: Our results indicate that aneuploid cells decrease in human embryos post-implantation, and mtDNA mutations might induce low mitochondrial function and influence the development of post-implantation embryos with not only aneuploidy but also euploidy. Analyzing the whole mtDNA mutation number may be a novel method for selecting a better mosaic embryo for transfer.

Breakpoint determination of X;autosome balanced translocations in four patients with premature ovarian failure.

Premature ovarian failure (POF) is a disorder characterized by amenorrhea and elevated serum gonadotropins before 40 years of age. As X chromosomal abnormalities are often recognized in POF patients, defects of X-linked gene may contribute to POF. Four cases of POF with t(X;autosome) were genetically analyzed. All the translocation breakpoints were determined at the nucleotide level. Interestingly, COL4A6 at Xq22.3 encoding collagen type IV alpha 6 was disrupted by the translocation in one case, but in the remaining three cases, breakpoints did not involve any X-linked genes. According to the breakpoint sequences, two translocations had microhomology of a few nucleotides and the other two showed insertion of 3-8 nucleotides with unknown origin, suggesting that non-homologous end-joining is related to the formation of all the translocations.