Predictors of reproductive and non-reproductive outcomes of gonadotropin mediated pubertal induction in male patients with congenital hypogonadotropic hypogonadism (CHH).

PURPOSE: To investigate predictors of testicular response and non-reproductive outcomes (height, body proportions) after gonadotropin-induced puberty in congenital hypogonadotropic hypogonadism (CHH). DESIGN: A retrospective analysis of the puberty induction in CHH male patients, undergoing an off-label administration of combined gonadotropin (FSH and hCG). METHODS: Clinical and hormonal evaluations before and during gonadotropin stimulation in 19 CHH patients genotyped by Targeted Next Generation Sequencing for CHH genes; 16 patients underwent also semen analysis after gonadotropins. RESULTS: A lesser increase in testicular volume after 24 months of induction was significantly associated with: (I) cryptorchidism; (II) a positive genetic background; (III) a complete form of CHH. We found no significant correlation with the cumulative dose of hCG administered in 24 months. We found no association with the results of semen analyses, probably due to the low numerosity. Measures of body disproportion (eunuchoid habitus and difference between adult and target height: deltaSDSth), were significantly related to the: (I) age at the beginning of puberty induction; (II) duration of growth during the induction; (III) initial bone age. The duration of growth during induction was associated with previous testosterone priming and to partial forms of CHH. CONCLUSIONS: This study shows that a strong genetic background and cryptorchidism, as indicators of a complete GnRH deficiency since intrauterine life, are negative predictors of testicular response to gonadotropin stimulation in CHH. Body disproportion is associated with a delay in treatment and duration of growth during the induction, which is apparently inversely related to previous androgenization.

Evaluation of the abdominopelvic region using MRI in patients with primary amenorrhea.

Background This study aimed to evaluate the imaging findings of patients who underwent an abdominal and pelvic magnetic resonance imaging (MRI) due to primary amenorrhea. Methods The pelvic and abdominal images of 34 female patients (mean age 15.61 years, range 14-19 years) were retrospectively analyzed by a single radiologist blinded to the clinical and laboratory data of the patients (other than primary amenorrhea) to evaluate the etiology of primary amenorrhea. The anatomy and anomalies of the internal genital organs and other accompanying abdominopelvic anomalies were investigated. Results Gonadal dysgenesis was present in 14 patients (41.17%) and Müllerian duct anomalies (MDAs) were present in 20 (58.83%) (Mayer-Rokitansky-Kuster-Hauser [MRKH] syndrome in 13 [65%], distal vaginal obstruction [DVO] findings in five [25%], and obstructed hemivagina and ipsilateral renal anomaly [OHVIRA] syndrome in two [10%]). Seven patients with MRKH (53.84%) were of type 1 and six (46.15%) were of type 2. A total of eight additional anomalies (vertebral and renal) were detected, six in MRKH and two in OHVIRA syndrome cases. Endometrioma and hematosalpinx were observed in one of the five patients with DVO (5%). Conclusions Primary amenorrhea is a common symptom that affects both the physical and psychosocial status of individuals. Determination of the underlying etiology is the first step in planning treatment. The evaluation of internal genital organ anomalies involved in the etiology is important for sexual function and fertility. MRI is a non-invasive imaging modality that should be preferred in these cases as it provides detailed data about the anatomy and anomalies of internal genital organs due to its high soft tissue contrast resolution.

Evaluation of the testis function of mice exposed in utero and during lactation to Pfaffia glomerata (Brazilian ginseng).

Pfaffia glomerata (Spreng.) Pedersen, popularly known as "Brazilian ginseng," is used as medicinal plant in Brazil to treat inflammatory diseases in general. Previous studies showed that its extract increases the nitric oxide (NO) levels. Knowing that NO downregulates steroidogenesis and that alterations in the action/production of androgens during perinatal life could alter testis development, the present studies sought to investigate the reproductive toxicity of Pfaffia glomerata on male mice exposed to hydroalcoholic extract in utero and during lactation. The present study shows that P. glomerata extract does not alter body weight, tubular diameter and testis function in male mice. Although a reduction in the testis weight was observed in the animals that received the highest dose directly in early post-natal life, our findings show clearly that P. glomerata may not act as an endocrine disruptor, and it is not an "antiandrogenic" compound that could lead to testicular dysgenesis syndrome.

Actualización en el manejo del síndrome de Turner en niñas y adolescentes: revisión de la literatura e Incorporación de recomendaciones de las nuevas guías clínicas / Update on the management of Turner syndrome in girls and adolescents: review of the literature and incorporation of recommendations of the new clinical guidelines

Turner syndrome (TS) is a common disorder (1/2.000 women) that affects multiple organs at different stages of life and needs a multidisciplinary approach. It can be present in women of all ethnicities and is caused by a monosomy of the X chromosome that causes a haploinsufficiency of certain genes. Its main features consist of specific but variables physical characteristics, congenital heart defects, renal anomalies, middle and inner ear diseases, skeletal alterations, and from the endocrinological point of view, short stature and ovarian insufficiency. Given the comorbidities associated with TS, it has been estimated that they have an increased risk of mortality (up to 3 times more) and a reduction in life expectancy of approximately 13 years. Depending on the genotype, the abnormalities can become very subtle, in these cases the diagnosis is late, when the adolescent consults, for example, for primary amenorrhea or an adult woman for infertility. Once the diagnosis is confirmed by a karyotype, these patients must remain in pediatric control in a continuous way to investigate associated pathologies in a timely manner, with periodic evaluations by specialists, such as otolaryngologists, cardiologists, neurologists and endocrinologists, among others. Numerous advances in the care of these patients gave rise to new guidelines published in 2017. In this article we will comment on the main conditions associated with TS and its specific etiology, we will mention what is relevant regarding the genotype-phenotype relationship in this syndrome and we will discuss the fundamental aspects of the control of the TS patient, with emphasis on the treatment of short stature and ovarian insufficiency, as well as the cardiovascular aspects and those related to fertility.

El Síndrome de Turner (ST) es una patología frecuente (1/2.000 mujeres) que afecta múltiples órganos en distintas etapas de la vida y necesita un enfoque multidisciplinario. Se produce por una monosomía del cromosoma X que provoca una haploinsuficiencia de determinados genes. Sus características principales consisten en un fenotipo característico pero variable, con presencia de cardiopatías congénitas, anomalías renales, enfermedades del oído medio e interno, alteraciones esqueléticas, y del punto de vista endocrinológico, talla baja e insuficiencia ovárica. Dadas las comorbilidades asociadas al ST, principalmente cardiovasculares (CV), presentan mayor mortalidad con respecto a la población general (hasta 3 veces más). Dependiendo del genotipo, las anomalías pueden llegar a ser muy sutiles, realizándose en estos casos el diagnóstico en forma tardía, cuando la adolescente consulte, por ejemplo, por amenorrea primaria o una mujer adulta por infertilidad. Una vez confirmado el diagnóstico mediante un cariotipo, estas pacientes deben permanecer en control endocrinológico pediátrico en forma continua hasta la transición hacia adultos, con el fin de pesquisar patologías asociadas en forma oportuna. Por ello requieren evaluaciones periódicas por especialistas, tales como otorrinolaringólogos, cardiólogos, neuropsiquiatras, entre otros. Numerosos avances en el cuidado de estas pacientes, dieron origen a nuevas guías publicadas el 2017. En este artículo comentaremos sobre las principales condiciones asociadas al ST y su etiología específica, mencionaremos lo relevante respecto a la relación genotipo-fenotipo en este síndrome y discutiremos los aspectos fundamentales del control de la paciente con ST, haciendo énfasis en el tratamiento de la talla baja y la insuficiencia ovárica, así como los aspectos CV y los relacionados a fertilidad.

Is testicular dysgenesis syndrome a genetic, endocrine, or environmental disease, or an unexplained reproductive disorder?

Progressive increases in the incidence of male reproductive disorders inclusive of hypospadias, cryptorchidism, poor semen quality, and testicular germ cell cancer (TGCC) have been observed in recent times. The central hypothesis of this study asserted that these disorders may all collectively signify testicular dysgenesis syndrome (TDS). This review aimed to provide evidence verifying the reality of TDS based on four key aspects: environmental endocrine-disrupting chemicals (EDCs), genetic factors, intrauterine growth disorders and lifestyle factors. Although TDS might result from genetic polymorphisms or aberration, recent evidence has highlighted links indicating the conditions associations to both environmental and lifestyle factors due to the rapid temporal changes in the clinical symptoms observed over recent decades. Based on our review of genetic and environmental factors, a key observation of our study suggested that there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. At present, current research has yet to elucidate the mechanisms of TDS, in addition to the lack of genuine consideration of a variety of potentially key factors and TDS mechanisms. In conclusion, our study revealed that environmental exposures owing to modern lifestyles are primary factors involved in the associated trends of the syndrome, which are capable of affecting the adult endocrine system via direct means or through epigenetic mechanisms.

Stochastic anomaly of methylome but persistent SRY hypermethylation in disorder of sex development in canine somatic cell nuclear transfer.

Somatic cell nuclear transfer (SCNT) provides an excellent model for studying epigenomic reprogramming during mammalian development. We mapped the whole genome and whole methylome for potential anomalies of mutations or epimutations in SCNT-generated dogs with XY chromosomal sex but complete gonadal dysgenesis, which is classified as 78, XY disorder of sex development (DSD). Whole genome sequencing revealed no potential genomic variations that could explain the pathogenesis of DSD. However, extensive but stochastic anomalies of genome-wide DNA methylation were discovered in these SCNT DSD dogs. Persistent abnormal hypermethylation of the SRY gene was observed together with its down-regulated mRNA and protein expression. Failure of SRY expression due to hypermethylation was further correlated with silencing of a serial of testis determining genes, including SOX9, SF1, SOX8, AMH and DMRT1 in an early embryonic development stage at E34 in the XY(DSD) gonad, and high activation of the female specific genes, including FOXL2, RSPO1, CYP19A1, WNT4, ERα and ERß, after one postnatal year in the ovotestis. Our results demonstrate that incomplete demethylation on the SRY gene is the driving cause of XY(DSD) in these XY DSD dogs, indicating a central role of epigenetic regulation in sex determination.

Dilated cardiomyopathy and ovarian dysgenesis in a patient with Malouf syndrome: a case report.

Malouf syndrome is a rare congenital disorder involving the heart, genitalia, skin and skeletal characteristics. In the present study, we report on the sporadic case of a young female with dilated cardiomyopathy, hypergonadotropic hypogonadism, a small chin, bilateral blepharoptosis, marfanoid elongated fingers and hypothyroidism. Malouf syndrome may be caused by heterozygous mutations in the lamin A/C (LMNA) gene. Genetic analyses and autopsy were performed. In spite of the patient's features, sequence analysis of the coding region of the LMNA gene including exon-intron boundaries identified only one benign polymorphism: homozygous silent variant 1698C>T (H566). There is a possibility that the sequence analysis may have not detected intronic mutations or mutations in portions of the 5'- and 3'-untranslated regions, which would confirm the clinical diagnosis.

Gonadal dysgenesis due to isochromosome formation of long arm of X chromosome.

Isochromosome involving the long arm of X chromosome is a rare structural rearrangement of the X chromosome, leading to Gonadal dysgenesis. These patients present as phenotypic females with amenorrhea and growth failure. Often other associated features like endocrine abnormalities and skeletal deformities are found. They are chromatin positive cases and are only diagnosed by karyotyping. Hashimoto's thyroiditis is a rare association with isochromosome X.

[Klinefelter's syndrome and Turner's syndrome. For a better management]. / Syndrome de Klinefelter et syndrome de Turner : pour une meilleure prise en charge.

Klinefelter's syndrome (KS) affects one in 600 men and Turner's syndrome (TS), one in 2500 women. These 2 diseases are the most sex chromosome disorders characterized by one extra X in the SK male (47XXY) and the loss of an X in the girls with ST (45 X). Their common characteristic is the gonadal dysgenesis, which is the main cause of male or female infertility. Called "the forgotten syndrome", KS is under-diagnosed because apart from the large size, there are no dysmorphic features, along with a great ignorance of cognitive and language disorders in children. There are often comorbidities that lead to diagnosis such as autoimmune diseases or metabolic syndrome. TS is often diagnosed by the short stature. Management of Turner's girls has profoundly changed with Growth hormone therapy. There is an international consensus for a better management of associated diseases such as ORL, cardiac, renal, hepatic, autoimmune and metabolic diseases. Prenatal diagnosis allows early detection and management of cognitive deficiencies and of associated diseases.

Environmental factors and testicular function.

Over the last decades there has been a dramatic increase in the incidence of some diseases associated with the male reproductive system, including poor semen quality, testicular cancer and congenital developmental abnormalities such as cryptorchidism and hypospadias, malformations of the urethra and scrotum respectively. Based on these observations one recurring theme is the concern that certain environmental chemicals and lifestyle related factors may play a role. Early fetal life is a particularly critical time period, when the endocrine system is established and organs are developing. Although available data does not yet allow recommending, evidence based, prophylactic and/or therapeutic measures to eliminate or reduce the possible negative impact of environment/lifestyle on the male reproductive capacity, it is prudent to limit exposures of people to hormonally active chemicals.

What is new in cryptorchidism and hypospadias--a critical review on the testicular dysgenesis hypothesis.

It has been hypothesized that poor semen quality, testis cancer, undescended testis, and hypospadias are symptoms of one underlying entity--the testicular dysgenesis syndrome--leading to increasing male fertility impairment. Though testicular cancer has increased in many Western countries during the past 40 years, hypospadias rates have not changed with certainty over the same period. Also, recent studies demonstrate that sperm output may have declined in certain areas of Europe but is probably not declining across the globe as indicated by American studies. However, at the same time, there is increasing recognition of male infertility related to obesity and smoking. There is no certain evidence that the rates of undescended testes have been increasing with time during the last 50 years. In more than 95% of the cases, hypospadias is not associated with cryptorchidism, suggesting major differences in pathogenesis. Placental abnormality may occasionally cause both cryptorchidism and hypospadias, as it is also the case in many other congenital malformations. The findings of early orchidopexy lowering the risk of both infertility and testicular cancer suggest that the abnormal location exposes the cryptorchid testis to infertility and malignant transformation, rather than there being a primary abnormality. Statistically, 5% of testicular cancers only are caused by cryptorchidism. These data point to the complexity of pathogenic and epidemiologic features of each component and the difficulties in ascribing them to a single unifying process, such as testicular dysgenesis syndrome, particularly when so little is known of the actual mechanisms of disease.

[Dynamics of gonadal dysgenesis frequency in Drosophila melanogaster under controlled conditions of chronic radiation exposure].

Two Drosophila melanogaster strains (Canton-S and ri-lines) for 20 generations were in the controlled terms of chronic irradiation with 3-dose rate (1,2 x 10(-8); 0,3 x 10(-8); 0,12 x 10(-8) Gy/c). The dynamics of hybrid dysgenesis frequency was explored for each generation of F1 descendants from Canton-S and ri-lines crossing. The gradual change of dose response of hybrid dispense depending on duration of irradiation of ancestors and dose rate was shown. The complex dynamics of hybrid dysgenesis frequency depending on irradiation duration of ancestors and dose rate was detected. The cumulative effect of the prolonged irradiation shows up as adaptation at the lowest dose rate and as exhaustion at the highest dose rate. Question comes into discussion about the features of transitional process and including of protective and adaptive reactions hierarchy at the conditions of radiation factor chronic action.

[Testicular dysgenesis syndrome: an update].

Researches on the testicular dysgenesis syndrome (TDS) have flourished in the recent decade, and a widely accepted view on its pathogenesis is that environmental endocrine disrupting chemicals (EDCs) act on Leydig cells and/or testicular Sertoli cells, resulting in abnormal development of the testis and leading to the symptoms of TDS. Molecular biological studies suggest a correlation of TDS etiology with insulin-like factor 3 (INSL-3), androgen receptor (AR), P27kip, WT-1 and Müllerian inhibiting substance (MIS). This review focuses on the progress in current researches on the etiology and mechanism of TDS.

Androgen action in the masculinization programming window and development of male reproductive organs.

We have shown previously that deficient androgen action within a masculinization programming window (MPW; e15.5-e18.5 in rats) is important in the origin of male reproductive disorders and in programming male reproductive organ size, but that androgen action postnatally may be important to achieve this size. To further investigate importance of the MPW, we used two rat models, in which foetal androgen production or action was impaired during the MPW by exposing in utero to either di(n-butyl) phthalate (DBP) or to flutamide. Reduced anogenital distance (AGD) was used as a monitor of androgen production/action during the MPW. Offspring were evaluated in early puberty (Pnd25) to establish if reproductive organ size was altered. The testes, penis, ventral prostate (VP) and seminal vesicles (SV) were weighed and penis length measured. Both DBP and flutamide exposure in the MPW significantly reduced penis, VP and SV size along with AGD at Pnd25; AGD and organ size were highly correlated. In DBP-, but not flutamide-, exposed animals, testis weight was also reduced and correlated with AGD. Intratesticular testosterone was also measured in control and DBP-exposed males during (e17.5) or after (e21.5) the MPW and related to AGD at e21.5. To evaluate the importance of postnatal androgen action in reproductive organ growth, the effect of combinations of prenatal and postnatal maternal treatments on AGD and penis size at Pnd25 was evaluated. In prenatally DBP-exposed animals, further postnatal exposure to either DBP or flutamide significantly reduced AGD and penis size in comparison with prenatal DBP exposure alone. In comparison, rats exposed postnatally to testosterone propionate after prenatal vehicle-exposure showed considerable increase in these parameters vs. controls. In conclusion, we show that the size of all male reproductive organs is programmed by androgen exposure in the MPW, but that growth towards this size is dependent on androgen action postnatally.

Testicular dysgenesis syndrome and Leydig cell function.

Fertility among human beings appear to be on the decline in many Western countries, and part of the explanation may be decreasing male fecundity. A hypothesis has been put forward that decreasing semen quality may be associated with a testicular dysgenesis syndrome (TDS), a spectrum of disorders originating in early foetal life. TDS comprises various aspects of impaired gonadal development and function, including testicular cancer. A growing body of evidence, including animal models and research in human beings, points to lifestyle factors and endocrine disrupters as risk factors for TDS. We present our view of the emerging role of Leydig cell dysfunction with subsequent decreased testosterone levels in the pathogenesis of TDS.

[Increased risk of testicular dysgenesis?]. / Økt forekomst av utviklingsfeil i testiklene?

The latest figures from the Cancer Registry of Norway show that Norway has the highest incidence rate of testicular cancer in the world. They also show that the incidence rate continues to increase, as it has for the last decades in the western world. The reasons for this increase, which might also be true for urogenital abnormalities in men and reduced sperm quality, are uncertain. Data suggest, however, that these anomalies originate in foetal life, and that contributing factors are genetic, pregnancy-related and environmental. The potential importance of environmental factors must be taken seriously, and the authorities must take action to strengthen the research in this area.