ErbB4 point mutation in CU3 inbred rats affects gonadotropin-releasing-hormone neuronal function via compromised neuregulin-stimulated prostaglandin E2 release from astrocytes.

Gonadotropin releasing hormone (GnRH)-secretion is not only regulated by neuronal factors but also by astroglia cells via growth factors and ErbB receptors of the epidermal growth factor family. Studies in transgenic mice carrying mutations in the ErbB receptor system experience impaired reproductive capacity. In addition, some of these animals show a typical skin phenotype with wavy hair and curly whiskers. The rat strain SPRD-CU3 (CU3), examined in this study, displays a similar skin phenotype and a significant impairment of the timing of puberty onset and reproductive performance, suggesting a disruption in the astrocytic to GnRH neuronal communication. To address this issue, we analyzed astrocytic prostaglandin E2 (PGE2 ) release from primary hypothalamic astrocytic cell cultures after stimulation with transforming growth factor α (TGFα), ligand for ErbB1/ErbB2, or Neuregulin 1 beta 2 (NRG1ß2 ), ligand for ErbB4/ErbB2 signaling pathway. Compared to cultures from wild type animals, astrocytic cultures from CU3 rats were unable to respond to NRG stimulation, suggesting a disruption of the ErbB4/ErbB2 signaling pathway. This is confirmed by mutational analysis of ErbB4 that revealed a single point mutation at 3125 bp resulting in an amino acid change from proline to glutamine located at the carboxy-terminal region. As a consequence, substantial conformational changes occur in the transmembrane and intracellular domain of the protein, affecting the ability to form a receptor dimer with a partner and the ability to function as a transcriptional regulator. Thus, astroglia to GnRH neuronal signaling via ErbB4 is essential of timely onset of puberty and reproductive function.

Ambiguous Genitalia Associated with an Extremely Rare Syndrome: A Case Report of XLAG Syndrome and Review of the Literature.

X-linked lissencephaly, absent corpus callosum, and epilepsy of neonatal onset with ambiguous genitalia comprises the XLAG syndrome and only 15 cases have been reported in literature. Due to its rarity, the exact clinical course and outcome are not known. Exact associations of this disease are also elusive. Hereby we are reporting this extremely rare entity and we searched the English literature extensively to get consolidated knowledge regarding this entity that would help the readers. Pre-natal radiological work-up can detect these malformations, which should be followed by medical termination, counseling and karyotyping. Till date the longest survival noted was 4 years only.

The reduction in sexual behavior induced by neonatal immune stress is not related to androgen levels in male rats.

PURPOSE: It is known that various types of stress in early life increase the incidence of diabetes, myocardial infarctions, and psychiatric disorders in adulthood. We examined the mechanism by which neonatal immune stress reduces sexual behavior in adult male rats. METHODS: Male rats were randomly divided into 3 groups: the control (n = 17), postnatal day 10 lipopolysaccharide (PND10LPS) (n = 31), and PND25LPS (n = 16) groups, which received intraperitoneal injections of LPS (100 µg/kg) or saline (injection volume: ≤0.1 ml/g) on postnatal days 10 and 25. In experiment 1, male rats (age: 11 to 12 weeks) were put together with female rats in a one-to-one setting for mating, and sexual behavior (mounting, intromission, and ejaculation) was monitored for 30 minutes. The serum levels of luteinizing hormone (LH) and testosterone (T) and the hypothalamic mRNA expression levels of factors related to sexual behavior were examined. After experiment 1 finished, the remaining 37 male rats were used for experiment 2: the control group (n = 8), PND10 LPS group (n = 21) and PND25LPS group (n = 8) these rats had been given an i.p. injection of the saline during the expriment1. All of the rats were orchidectomized at 14 weeks of age. After a 3-week recovery period, a silastic tube containing crystalline T was subcutaneously implanted into the back of each rat. The rats' sexual behavior, serum hormone concentrations, and hypothalamic mRNA expression levels were assessed. RESULTS: In experiment 1, preputial separation occurred significantly later in the PND10LPS group than in the control group. The frequency of sexual behavior was significantly lower in the PND10LPS group than in the control group. The serum T concentrations of the PND10LPS and PND25LPS groups were significantly lower than that of the control group, but the serum LH concentrations of the 3 groups did not differ significantly. The hypothalamic mRNA expression levels of progesterone receptor B (PRB) and gonadotropin-releasing hormone (GnRH) were significantly lower in the PND10LPS and PND25LPS groups than in the control group, whereas the hypothalamic PRA + B mRNA expression levels of the 3 groups did not differ significantly. In experiment 2, after T supplementation the frequency of sexual behavior was significantly lower in the PND10LPS and PND25LPS groups than in the control group, although there were no significant differences in the serum T or LH concentrations or the hypothalamic PRB, PRA + B, or GnRH mRNA expression levels of the 3 groups. CONCLUSION: In male rats, immune stress in the early neonatal period delayed sexual maturation, reduced sexual behavior, suppressed the serum T concentration, and downregulated the hypothalamic mRNA expression levels of GnRH and the PR in adulthood. The delayed sexual maturation was presumed to have been caused by the reduction in the serum T concentration. However, the rats that experienced neonatal stress exhibited reduced sexual behavior irrespective of their serum T concentrations.

Efficacy of kidney-tonifying traditional Chinese medicine prescriptions in hypoplastic uterus treatment: a systematic review and meta-analysis.

AIM: To review and evaluate the efficacy of kidney-tonifying traditional Chinese medicine prescriptions (KT-TCMP) in hypoplastic uterus (HU) treatment. METHODS: We searched MEDLINE, the Cochrane Library, CNKI (China National Knowledge Infrastructure), WANFANG and VIP databases until 14 December 2013 independently with two investigators. Randomized controlled trials (RCT) involving KT-TCMP as a combined or monotherapy in the treatment of HU were reviewed and analyzed. Meta-analysis was performed by Review Manager (version 5.2). RESULTS: Nine RCT of 1745 patients were eligible for this review and meta-analysis, of which eight RCT described the primary outcome of clinical efficacy and three RCT drew the secondary outcome of uterine size. Meta-analyzed 'recovery' clinical efficacy of KT-TCMP in seven RCT was conducted which considered diethylstilbestrol therapy alone as control, as well as three RCT that meta-analyzed the effect of KT-TCMP on uterine diameter enlargement. As a result, KT-TCMP therapy had a significantly improved difference in increasing 'recovery' clinical efficacy (risk ratio, 2.34; 95% confidence interval [CI], 1.90-2.89) and enlarging the uterine diameter (standardized mean difference, 1.62; 95% CI, 1.39-1.84). One study reported adverse reactions as an important outcome and found it was safe during KT-TCMP therapy. CONCLUSION: The therapy of applying KT-TCMP as a combined or monotherapy in the treatment of HU may be more efficacious. However, these RCT were of moderate methodological quality and small sample size; thus, the results should be confirmed with more rigorously controlled further studies.

Histological intersex (ovotestis) in the European lobster Homarus gammarus and a commentary on its potential mechanistic basis.

This paper provides the first report of the intersex (ovotestis) condition in the European lobster Homarus gammarus. A single specimen (10% of males sampled) presenting the condition was discovered as part of routine sampling, from the Weymouth Bay region of the English Channel, UK. The lobster presented externally as a male, but upon histological examination was seen to contain an ovotestis, containing elements of both male and female gonadal tissue. Previtellogenic oocytes were present in several otherwise normal seminiferous tubules throughout the testis. The seminiferous tubules were also engaged in the production of apparently normal sperm lineages, and mature spermatozoa were present within the tubule lumens. In some cases, oocytes were in direct contact with mature spermatozoa within the same seminiferous tubules. The significance of this finding is placed into context with a previous observation of elevated intersexuality in the congeneric species H. americanus collected from specific sites in Canadian waters. The potential mechanism for development of intersex in lobsters, which is probably related to a disrupted signalling to the germinal component of the testis from the decapod androgenic gland, may be an effect of exposure to endocrine disrupting chemicals in the marine environment.

The interactive effect of dietary fat-soluble vitamin levels on the depression of gonadal development in growing male rats kept under disturbed daily rhythm. Investigations based on the L16(2¹5) type orthogonal array.

The purpose of this study was to clarify the effects of nutrients on the gonadal development of male rats kept under constant darkness as a model of disturbed daily rhythm. In the present study we examined fat-soluble vitamins and their interactions in this test population. Four fat-soluble vitamins (vitamin A (V.A), vitamin D (V.D), vitamin E (V.E) and vitamin K (V.K)) were selected as experimental factors, and the dietary content of these vitamins was normal (AIN-93G) or three times the normal content. Lighting conditions (constant darkness or normal lighting) were also added as a factor. Four-week-old rats (Fischer 344 strain) were kept under constant darkness or normal lighting (12-h light/dark cycle) for 4 wk. The lighting condition and V.E, and the interactions between the lighting condition and V.E and between V.A and V.D were observed to affect the testes and epididymides weights. There was an influence of the lighting condition only on the seminal vesicles and prostate weights and the serum testosterone concentration. Among the constant darkness groups (D-groups), the highest value for testes weight was observed under the normal-V.A, normal-V.D and high-V.E diet. The interaction between lighting condition and V.E showed the testes weight increased slightly in response to changing to a high-V.E diet from a normal-V.E diet under normal lighting (N-group) but was greatly increased in response to this change in the D-group. It became clear that the amount of dietary V.E necessary for the gonadal development of rats increases when rats are kept under constant darkness.

Carlos II: Del hechizo a su patología génito-urinaria / Charles II: From spell to genitourinary pathology

OBJETIVO: Tratar de desentrañar la compleja patología del último rey de la dinastía de los Austrias, Carlos II, apodado El Hechizado, dentro de la cual la urogenital fue preponderante, impidiéndole cumplir con una de las finalidades de la institución monárquica cual es la transmisión a un descendiente y produciéndole una serie de complicaciones que le llevaron al fallecimiento.MÉTODOS: Revisamos las obras en las cuales se describe la vida del Rey, haciendo hincapié en sus antecedentes consanguíneos, en las dudas sobre su sexo en el momento del nacimiento, sus procesos patológicos, la repercusión en las Cortes Europeas, pero sobre todo en sus matrimonios y en la incapacidad para generar un heredero. Resaltamos como, siguiendo el pensamiento de la sociedad española del siglo XVII, hizo pensar que se encontraba hechizado. Sobrenombre con el que pasó a la historia.RESULTADO: Deducimos que pudo presentar un hipospadias posterior que junto con la monorquia y testículo atrófico, hace pensar que presentó un estado intersexual con genitales ambiguos. Su fenotipo físico inclina más hacia un hermafroditismo verdadero y sobre todo un varón XX, que hacia un síndrome de Klinefelter que ha sido el más atribuido. Es probable su asociación con un síndrome X frágil. Monorreno congénito muy posiblemente, su muerte se debió a una insuficiencia renal crónica producida por una glomerulopatía o una nefropatía intersticial a consecuencia de una litiasis renal más infecciones del tracto urinario recidivantes.CONCLUSIONES: Fruto de una reiterada política matrimonial endogámica, feneció en 1700 la dinastía de los Habsburgo en España encarnada en Carlos II, un monarca pluripatológico que sólo se libraría de especulaciones si se efectuaran estudios cromosómicos y genéticos de sus restos presentes en el monasterio de El Escorial(AU)

OBJECTIVES: We attempt to unravel the complex condition of the last king of the Hapsburg dynasty in Spain, Charles II, called The Bewitched, in whom a genitourinary disorder was preponderant, preventing him from fulfilling one of the objectives of the monarchial institution, engendering a heir, and causing a series of complications that led to his death. METHODS: We review the works describing the life of the King, with special emphasis on his bloodline, the doubts about his sex at birth, his pathological processes, the repercussion among European Courts, but above all on his marriages and the inability to engender an heir. We also emphasize the thought of 17th century Spanish society which led to the belief that he was bewitched. The nickname he passed into history with.RESULT: It was deduced that he could have presented posterior hypospadias which, together with monorchism and atrophic testicle, led to the belief that he presen-ted an intersexual state with ambiguous genitals. The physical phenotype leans more towards true hermaphro-ditism and above all a XX male, rather than the more often attributed Klinefelter’s syndrome. This is probably also associated with a fragile X syndrome. Very possibly congenital monorenal, death was due to chronic kidney failure caused by glomerulopathy or interstitial nephro-pathy as a consequence of renal lithiasis plus recurrent infections of the urinary tract.CONCLUSIONS: As a result of a reiterated endogamic matrimonial policy, the Hapsburg dynasty died out in Spain in 1700, represented by Charles II, a pluripatho-logical king who can only be freed from speculation by chromosomal and genetic studies of his remains buried in El Escorial monaster(AU)

[The ependymal lining of the infundibular recess in males and hermaphrodites in small ruminants in scanning electron microscopy]. / Ependýmová výstelka infundibulárneho recesu samcov a hermafrodita malých prezúvavcov v riadkovacom elektrónovom mikroskope.

A scanning electron microscope was used to study the surface of the ependymal epithelium of the lower part of the third cerebral ventricle of rams, he-goats, and in one goat with a developmental sexual disorder (testicular hermaphroditism). During mating, the apical membranes of the ependymal tanycytes of the rams and billy goats were found to be covered by numerous blebs (ependymosecretion). It was only in the billy goats in the mating season (not in the rams) that individual supraependymal cells with protrusions forming "ruffled membranes" were present on the surface of the infundibular recession. Although the finding on the sexual organs of the hermaphrodite was closer to the male, the presence of the large number of supraependymal cells was rather a female trait. As suggested by the results, it is also in the males of small ruminants that the activity of the sexual organs is associated with the structure and function of the ependymal epithelium in the infundibular recess.