Antenatal management of recurrent fetal goitrous hyperthyroidism associated with fetal cardiac failure in a pregnant woman with persistent high levels of thyroid-stimulating hormone receptor antibody after ablative therapy.

High titer of maternal thyroid-stimulating hormone receptor antibody (TRAb) in patients with Graves' disease could cause fetal hyperthyroidism during pregnancy. Clinical features of fetal hyperthyroidism include tachycardia, goiter, growth restriction, advanced bone maturation, cardiomegaly, and fetal death. The recognition and treatment of fetal hyperthyroidism are believed to be important to optimize growth and intellectual development in affected fetuses. We herein report a case of fetal treatment in two successive siblings showing in utero hyperthyroid status in a woman with a history of ablative treatment for Graves' disease. The fetuses were considered in hyperthyroid status based on high levels of maternal TRAb, a goiter, and persistent tachycardia. In particular, cardiac failure was observed in the second fetus. With intrauterine treatment using potassium iodine and propylthiouracil, fetal cardiac function improved. A high level of TRAb was detected in the both neonates. To the best of our knowledge, this is the first report on the changes of fetal cardiac function in response to fetal treatment in two siblings showing in utero hyperthyroid status. This case report illustrates the impact of prenatal medication via the maternal circulation for fetal hyperthyroidism and cardiac failure.

A medium-chain fatty acid as an alternative energy source in mouse preimplantation development.

To further optimize the culturing of preimplantation embryos, we undertook metabolomic analysis of relevant culture media using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). We detected 28 metabolites: 23 embryo-excreted metabolites including 16 amino acids and 5 media-derived metabolites (e.g., octanoate, a medium-chain fatty acid (MCFA)). Due to the lack of information on MCFAs in mammalian preimplantation development, this study examined octanoate as a potential alternative energy source for preimplantation embryo cultures. No embryos survived in culture media lacking FAs, pyruvate, and glucose, but supplementation of octanoate rescued the embryonic development. Immunoblotting showed significant expression of acyl-CoA dehydrogenase and hydroxyacyl-CoA dehydrogenase, important enzymes for ß-oxidation of MCFAs, in preimplantation embryo. Furthermore, CE-TOFMS traced [1-(13)C(8)] octanoate added to the culture media into intermediate metabolites of the TCA cycle via ß-oxidation in mitochondria. These results are the first demonstration that octanoate could provide an efficient alternative energy source throughout preimplantation development.

Green tea extracts attenuate doxorubicin-induced spermatogenic disorders in conjunction with higher telomerase activity in mice.

PURPOSE: The aim of this study was to investigate the protective effect of green tea extracts against doxorubicin-induced damage in the mouse testes correlating with telomerase activity. METHODS: Green tea extracts were administered orally. Doxorubicin was coadministered intraperitoneally. These testes were evaluated histologically and the telomerase activity was analyzed. Additional immunostaining was carried out. RESULTS: Both the sperm density and sperm motility were significantly increased in green tea extracts coadministration groups as compared to the doxorubicin-treated groups. By histological analysis, germ cell damage was greatly attenuated by green tea extracts coadministration. Telomerase activity significantly increased in association with the coadministration of green tea extracts as compared to that of doxorubicin-only groups. In all groups, human telomerase reverse transcriptase signals were mainly observed in the spermatocytes and spermatids. CONCLUSIONS: These findings suggest that green tea extracts exert protective effects against doxorubicin-induced spermatogenic disorders in conjunction with higher telomerase activity levels.

Hypothalamic dysfunction in a female with isolated hypogonadotropic hypogonadism and compound heterozygous TACR3 mutations and clinical manifestation in her heterozygous mother.

BACKGROUND/AIMS: TAC3 and TACR3 have recently been shown to be causative genes for an autosomal recessive form of isolated hypogonadotropic hypogonadism (IHH). Here, we report a Japanese female with IHH and compound heterozygous TACR3 mutations and her heterozygous parents, and discuss the primary lesion for IHH and clinical findings. CASE REPORT: This female was identified through mutation analysis of TAC3 and TACR3 in 57 patients with IHH. At 24 years of age, an initial standard GnRH test showed poor gonadotropin response (LH <0.2-0.6 IU/l), whereas the second GnRH test performed after GnRH priming (100 microg i.m. for 5 consecutive days) revealed ameliorated gonadotropin responses (LH 0.3-6.4 IU/l; FSH 2.2-9.6 IU/l). The mother exhibited several features suggestive of mild IHH, whereas the father showed an apparently normal phenotype. RESULTS: She had a paternally derived nonsense mutation at exon 1 (Y145X) and a maternally inherited single nucleotide (G) deletion from the conserved 'GT' splice donor site of intron 1 (IVS1+1delG). CONCLUSIONS: The results suggest hypothalamic dysfunction as the primary cause for IHH in patients with biallelic TACR3 mutations and clinical manifestation in heterozygous females, together with the rarity of TAC3 and TACR3 mutations in patients with IHH.

Impairment of decidualization in SRC-deficient mice.

Many signaling events induced by ovarian steroid hormones, cytokines, and growth factors are involved in the process of decidualization of human and rodent endometrium. We have reported previously that tyrosine kinase activation of SRC functionally participates in decidualization of human endometrial stromal cells. To address its essential role in decidualization, we examined, using wild-type and Src knockout mice, whether the process of decidualization was impaired in the absence of SRC. Immunohistochemistry using an antibody specific for the active form of SRC revealed that the active SRC was expressed prominently in the decidualizing stromal cells of the pregnant wild-type mouse. Moreover, the active SRC was upregulated in the uterine horn with artificially stimulated decidual reaction. In comparison with wild-type and Src heterozygous mice, the uterus of Src null mice showed no apparent decidual response following artificial stimulation. Ovarian steroid-induced decidualization in vitro, as determined by morphological changes and expression of decidual/trophoblast prolactin-related protein and prostaglandin-endoperoxide synthase 2 (also known as Cox2), both of which are decidualization markers, did not occur in a timely fashion in endometrial stromal cells isolated from the uteri of SRC-deficient mice compared to those from wild-type and Src heterozygous mice. Our results collectively suggest that SRC is an indispensable signaling component for maximal decidualization in mice.

Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress.

Stress-induced downregulation of spermatogenesis remains poorly understood. This study examined the induction of heme oxygenase-1 (HO-1), a carbon monoxide-generating inducible enzyme, in modulation of spermatogenesis. Rats were exposed to cadmium chloride (CdCl(2)), a stressor causing oligozoospermia, and HO-1-induction was monitored by following HO isozyme expression. CdCl(2)-treated testes increased HO-1 activity and suppressed microsomal cytochromes P450, which are required for steroidogenesis. CdCl(2)-elicited HO-1 occurred mostly in Leydig cells and coincided with CO generation, as judged by bilirubin-IXalpha immunoreactivity. Under these circumstances, germ cells in peripheral regions of seminiferous tubules exhibited apoptosis; laser flow cytometry revealed that these apoptotic cells involve diploid and tetraploid germ cells, suggesting involvement of spermatogonia and primary spermatocytes in CdCl(2)-elicited apoptosis. Pretreatment with zinc protoporphyrin-IX, an HO inhibitor, but not copper protoporphyrin-IX, which does not block the enzyme, attenuated the CdCl(2)-induced apoptosis. Such antiapoptotic effects of zinc protoporphyrin-IX were repressed by supplementation of dichloromethane, a CO donor. Upon CdCl(2)-treatment, both Sertoli cells and the germ cells upregulated Fas ligand; this event was also suppressed by zinc protoporphyrin-IX and restored by dichloromethane. Thus, Leydig cells appear to use HO-1-derived CO to trigger apoptosis of premeiotic germ cells and thereby modulate spermatogenesis under conditions of stress.