Normal Sexual Maturation Research Articles

Effect of long-term temperature-controlled rearing on growth traits and sexual maturity of common carp (Cyprinus carpio)

Many economically important fish have a long sexual maturation cycle, with the first sexual maturation time exceeding four years, which poses a long-term challenge for the cultivation of excellent varieties of these fish. Gonadal development and reproductive timing of fish are closely related to changes in environmental temperature. This study used the common carp as an economic fish model and set up three aquaculture modes for a one-month old common carp population: constant temperature test group (CTTG), normal temperature control group (NTCG), and variable temperature control group (VTCG). A long-term (approximately 11 months), temperature-controlled aquaculture experiment was conducted. The results of growth traits and gonadal development tests showed that at 10 months, the body length and weight of the CTTG were significantly higher than those of the other two groups. At seven months, the gonadosomatic index (GSI) value of CTTG was also significantly higher than that of the other two groups; At 10 months, the serum estradiol (E2) concentration of CTTG was significantly higher than that of the other two groups, while the testosterone (T) levels of VTCG and CTTG were significantly higher than those of NTCG, and only the 11-ketotestosterone (11-KT) concentration of VTCG was significantly higher than that of the other two groups. Simultaneously, qPCR analysis of sex hormone regulatory genes revealed that the expression of Cyp19a1a in CTTG ovaries was significantly higher than that in NTCG and VTCG ovaries, whereas the expression of Cyp11b and Hsd11b2 in VTCG ovaries was significantly higher than that in NTCG and CTTG ovaries. At 12 months, artificial reproduction revealed that only fish from the CTTG (66.67%) successfully laid eggs and fertilized normally. The results indicate that long-term constant temperature cultivation at 28 °C starting from the juvenile stage is not only beneficial for the body growth of common carp, but also promotes their gonadal development. This may be due to the conversion of T into E2 by Cyp19a1a in the common carp, ultimately facilitating the functional development of gonadal tissue under hypothalamus-pituitary-gonadal (HPG) axis regulation, normal egg laying, and fertilization. This study reduced the normal first sexual maturation time of common carp by at least 50% and provides a reference for the rapid cultivation of excellent varieties of other economically important fishes.

The impact of leptin on sperm.

Despite its important role in numerous physiological functions, including regulation of appetite and body weight, immune function and normal sexual maturation, raised leptin levels could result in significant damaging effects on sperm. The adverse effects of leptin on the male reproductive system result from its direct actions on the reproductive organs and cells instead of the hypothalamus-pituitary-gonadal axis. Binding of leptin to the receptors in the seminiferous tubular cells of the testes increases free radical production and decreases the gene expression and activity of endogenous enzymatic antioxidants. These effects are mediated via the PI3K pathway. The resultant oxidative stress causes significant damage to the seminiferous tubular cells, germ cells and sperm DNA leading to apoptosis, increased sperm DNA fragmentation, decreased sperm count, increased fraction of sperm with abnormal morphology, and decreased seminiferous tubular height and diameter. This review summarises the evidence in the literature on the adverse effects of leptin on sperm, which could underlie the often-reported sperm abnormalities in obese hyperleptinaemic infertile males. Although leptin is necessary for normal reproductive function, its raised levels could be pathologic. There is, therefore, a need to identify the cut-off level in the serum and seminal fluid above which leptin becomes pathological for better management of leptin associated adverse effects on male reproductive function.

UPLC-QTOF/MS Metabolomics and Biochemical Assays Reveal Changes in Hepatic Nutrition and Energy Metabolism during Sexual Maturation in Female Rainbow Trout (Oncorhynchus mykiss).

Mobilization and repartition of nutrients and energy are prerequisites for the normal sexual maturity of broodstock. However, there are few studies on the mechanisms of hepatic nutrients and energy metabolism during sexual maturation in female rainbow trout (Oncorhynchus mykiss). This study investigated hepatic metabolite changes and explored the potential nutritional regulation mechanism between mature and immature female rainbow trout by combining UPLC-QTOF/MS metabolomics and biochemical assays. It was observed that hepatic biochemical assays differed considerably between the two groups, such as glucose, triglycerides, hexokinase, lipase, and aspartate aminotransferase. Liver metabolomics showed that various differential metabolites involved in amino acid and lipid metabolism markedly increased, suggesting the enhancement of lipid metabolism and amino acid anabolism in the liver provides the necessary material basis for ovarian development. Meanwhile, glycogen catabolism and glycolysis hold the key to maintaining organismal energy homeostasis with normal sexual maturation of female rainbow trout. Overall, the results from this study suggested that the liver undergoes drastic reprogramming of the metabolic profile in response to mobilization and repartition of nutrients and energy during the sexual maturation of female rainbow trout. This study further deepened the understanding of the reproductive biology of rainbow trout, and provided the theoretical basis and practical ramifications for nutritional requirements of breeding high-quality broodstock in the artificial propagation of rainbow trout.

Primary Epstein-Barr virus infection with and without infectious mononucleosis.

Infectious mononucleosis (IM) is a common adverse presentation of primary infection with Epstein-Barr virus (EBV) in adolescence and later, but is rarely recognized in early childhood where primary EBV infection commonly occurs. It is not known what triggers IM, and also not why IM risk upon primary EBV infection (IM attack rate) seemingly varies between children and adolescents. IM symptoms may be severe and persist for a long time. IM also markedly elevates the risk of Hodgkin lymphoma and multiple sclerosis for unknown reasons. The way IM occurrence depends on age and sex is incompletely described and hard to interpret etiologically, because it depends on three quantities that are not readily observable: the prevalence of EBV-naϊve persons, the hazard rate of seroconverting and the attack rate, i.e. the fraction of primary EBV infections that is accompanied by IM. We therefore aimed to provide these quantities indirectly, to obtain epidemiologically interpretable measures of the dynamics of IM occurrence to provide etiological clues. We used joint modeling of EBV prevalence and IM occurrence data to provide detailed sex- and age-specific EBV infection rates and IM attack rates and derivatives thereof for a target population of all Danes age 0-29 years in 2006-2011. We demonstrate for the first time that IM attack rates increase dramatically rather precisely in conjunction to typical ages of puberty onset. The shape of the seroconversion hazard rate for children and teenagers confirmed a priori expectations and underlined the importance of what happens at age 0-2 years. The cumulative risk of IM before age 30 years was 13.3% for males and 22.4% for females. IM is likely to become more common through delaying EBV infection in years to come. The change in attack rate at typical ages of puberty onset suggests that the immunologic response to EBV drastically changes over a relatively short age-span. We speculate that these changes are an integrated part of normal sexual maturation. Our findings may inform further etiologic research into EBV-related diseases and vaccine design. Our methodology is applicable to the epidemiological study of any infectious agent that establishes a persistent infection in the host and the sequelae thereof.

GnRH-A Key Regulator of FSH.

The hypothalamic decapeptide, GnRH, is the gatekeeper of mammalian reproductive development and function. Activation of specific, high-affinity cell surface receptors (GnRH receptors) on gonadotropes by GnRH triggers signal transduction cascades to stimulate the coordinated synthesis and secretion of the pituitary gonadotropins FSH and LH. These hormones direct gonadal steroidogenesis and gametogenesis, making their tightly regulated production and secretion essential for normal sexual maturation and reproductive health. FSH and LH are glycoprotein heterodimers comprised of a common α-subunit and a unique β-subunit (FSHβ and LHβ, respectively), which determines the biological specificity of the gonadotropins. The unique β-subunit is the rate-limiting step for the production of the mature gonadotropins. Therefore, FSH synthesis is regulated at the transcriptional level by Fshb gene expression. The overarching goal of this review is to expand our understanding of the mechanisms and pathways underlying the carefully orchestrated control of FSH synthesis and secretion by GnRH, focusing on the transcriptional regulation of the Fshb gene. Identification of these regulatory mechanisms is not only fundamental to our understanding of normal reproductive function but will also provide a context for the elucidation of the pathophysiology of reproductive disorders and infertility to lead to potential new therapeutic approaches.

Serum vitamin D levels in girls with central precocious puberty

Precocious puberty can cause several adverse effects on final growth and social behavior in girls. Recent studies showed that low serum level of vitamin D might be associated with precocious puberty. The aim of this research was to investigate the association between serum vitamin D level and central precocious puberty in girls. Girls with central precocious puberty under the age of eight were enrolled in the study. Subjects with brain tumor, inherent adrenal hyperplasia, or thyroid dysfunction were excluded from the study. Age, weight, height, serum level of vitamin D, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, free thyroxin (FT4), bone age, thyroid-stimulating hormone (TSH), and Tanner stages were determined for all the subjects. Healthy girls with no precocious puberty were considered as the control group. Finally, 58 girls (28 with central precocious puberty and 30 healthy) were included in the study. The average levels of serum vitamin D were 12.9 ± 7.8 ng/mL and 15.2±5.9 ng/mL in the case and control groups, respectively (P = 0.02). We found that 37% of girls with precocious puberty were in Tanner stage 2 and 63% in stage 3. The serum vitamin D level had considerable relationship with chronologicalbone age difference (P < 0.01). Vitamin D deficiency was more common in girls with central precocious puberty than those with normal sexual maturation. Insufficiency and deficiency of vitamin D were more common in girls who were evaluated in this study in comparison with other studies.

Kenyon Cell Subtypes/Populations in the Honeybee Mushroom Bodies: Possible Function Based on Their Gene Expression Profiles, Differentiation, Possible Evolution, and Application of Genome Editing.

Mushroom bodies (MBs), a higher-order center in the honeybee brain, comprise some subtypes/populations of interneurons termed as Kenyon cells (KCs), which are distinguished by their cell body size and location in the MBs, as well as their gene expression profiles. Although the role of MBs in learning ability has been studied extensively in the honeybee, the roles of each KC subtype and their evolution in hymenopteran insects remain mostly unknown. This mini-review describes recent progress in the analysis of gene/protein expression profiles and possible functions of KC subtypes/populations in the honeybee. Especially, the discovery of novel KC subtypes/populations, the “middle-type KCs” and “KC population expressing FoxP,” necessitated a redefinition of the KC subtype/population. Analysis of the effects of inhibiting gene function in a KC subtype-preferential manner revealed the function of the gene product as well as of the KC subtype where it is expressed. Genes expressed in a KC subtype/population-preferential manner can be used to trace the differentiation of KC subtypes during the honeybee ontogeny and the possible evolution of KC subtypes in hymenopteran insects. Current findings suggest that the three KC subtypes are unique characteristics to the aculeate hymenopteran insects. Finally, prospects regarding future application of genome editing for the study of KC subtype functions in the honeybee are described. Genes expressed in a KC subtype-preferential manner can be good candidate target genes for genome editing, because they are likely related to highly advanced brain functions and some of them are dispensable for normal development and sexual maturation in honeybees.

MKast is dispensable for normal development and sexual maturation of the male European honeybee

The European honeybee (Apis mellifera L.) exhibits various social behaviors. The molecular and neural mechanisms underlying these behaviors have long been explored, but causal relations between genes or neurons and behaviors remain to be elucidated because effective gene manipulation methods in the honeybee have not been available until recently. We recently established a basic technology to produce mutant honeybee drones using CRISPR/Cas9. Here we produced mutant drones using CRISPR/Cas9 targeting mKast, which is preferentially expressed in a certain subtype of class I Kenyon cells that comprise the mushroom bodies in the honeybee brain. By immunoblot analysis, we showed that mKast protein expression was completely lost in the mutant drone heads. In addition, during the production process of homozygous mutant workers, we demonstrated that heterozygous mutant workers could be produced by artificial insemination of wild-type queens with the sperm of mutant drones, indicating that mKast mutant drones were sexually mature. These results demonstrate that mKast is dispensable for normal development and sexual maturation in drone honeybees, and allow us to proceed with the production of homozygous mutant workers for the analysis of a particular gene by gene knockout in the future.

Growth and puberty in a prospective cohort of patients with sickle-cell anaemia: an assessment over ten years abstract

Introduction: Hereditary haemoglobinopathies are the most common group of monogenic hereditary diseases in the world. Erythrocytes in sickle form, cellular expression of polymerization of deoxygenated HbS, cause intermittent vascular obstruction, leading to tissue ischaemia and consequent chronic damage in organs and endocrine glands. Objective: The evaluation of the growth pattern and pubertal development of a group of patients with sickle-cell anaemia (SCA) from childhood to adulthood. Method: Thirty patients with SCA between the ages of 10 and 23 years were evaluated in a prospective longitudinal study at three points in time (Te1: 2005; Te2: 2010 and Te3: 2015) and compared with controls. Anthropometric, pubertal and hormonal evaluations were carried out. Age- and gender-specific Z-scores for weight, height and BMI (body mass index) were calculated according to the reference growth standards. Results: Thirty patients with SCA (mean age = 13.93 years) were evaluated at Te1 and 26 patients (mean age = 25.08 years) at Te3. The SCA group lower showed Z-scores for weight (p = 0.0002), height (p = 0.0184) and BMI (p = 0.0011) than the control group at Te1. At Te3, there was no difference in height, but weight (p = <0.0001) and BMI (p = <0.0001) were lower in the SCA group. Men showed greater weight commitment than women at the three study times (Te1: p = 0.0340, Te2: p = 0.0426 and Te3: p = 0.0387) and lower BMI in Te3 (p = 0.0155) in the SCA group. There was a significant increase in weight when comparing Te1 with Te3 (p = 0.0009) and in height when comparing Te1 with Te2 (p = 0.0292) and with Te3 (p = 0.0003) in the SCA group. There was a significant increase in weight when comparing Te1 and Te3 (p = 0.0009) and in height when comparing Te1 and Te2 (p = 0.0292) and Te3 (p = 0.0003) in the SCA group. At Te1, 14 cases and 2 controls were prepubertal. Bone age was delayed in 12 patients. Age at menarche was delayed and lower in the SCA group (mean = 15 years). Five patients had gestated, but no patient had experienced fatherhood. At Te1, TSH levels were higher (p = 0.0080) and T3 levels were lower (p = 0.0020) in the SCA group. At Te3, LH and FSH levels were higher in men with SCA (p = 0.0014; p; 0.0002). IGF-I levels were lower in cases both at Te1 (p = 0.0002) and at Te3 (p = 0.0032). Conclusions: Patients with SCA showed growth impairment and pubertal delay compared with healthy controls. However, albeit belatedly, they reached normal sexual maturation and height in adulthood. Women with SCA showed no fertility problems. The findings highlight the need to investigate the intention of paternity and fertility among men with SCA.

Mouse Models of Gonadotrope Development.

The pituitary gonadotrope is central to reproductive function. Gonadotropes develop in a systematic process dependent on signaling factors secreted from surrounding tissues and those produced within the pituitary gland itself. These signaling pathways are important for stimulating specific transcription factors that ultimately regulate the expression of genes and define gonadotrope identity. Proper gonadotrope development and ultimately gonadotrope function are essential for normal sexual maturation and fertility. Understanding the mechanisms governing differentiation programs of gonadotropes is important to improve treatment and molecular diagnoses for patients with gonadotrope abnormalities. Much of what is known about gonadotrope development has been elucidated from mouse models in which important factors contributing to gonadotrope development and function have been deleted, ectopically expressed, or modified. This chapter will focus on many of these mouse models and their contribution to our current understanding of gonadotrope development.

Study of gonadal hormones in Egyptian female children with sickle cell anemia in correlation with iron overload: Single center study

Objective/BackgroundSickle cell disease is a hereditary hemoglobinopathy characterized by abnormal hemoglobin production, hemolytic anemia, and intermittent occlusion of small blood vessels, leading to tissue ischemia, chronic organ damage, and organ dysfunction including endocrine organs. The aim of this work was to evaluate some gonadal hormones in female children with sickle cell anemia (SCA) in correlation with iron overload. MethodsThis study was conducted on 40 female children with SCA with a serum ferritin of > 1000ng/mL, who were attendants at the Hematology Unit, Pediatric Department, Tanta University, Tanta, Egypt in the period from May 2012 to April 2014. Their ages ranged from 11 years to 15years and the mean age value was 12.63±1.36 years (Group I). Forty female children with SCA of matched age with no iron overload served as a control Group (Group II). For all patients in Groups I and II the following were performed/assessed: complete blood count, hemoglobin electrophoresis, serum iron status, serum estrogen, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). ResultsThere were significantly higher serum ferritin and serum iron levels and significantly lower total iron binding capacity, FSH, LH, and estrogen levels in Group I compared with Group II (mean serum ferritin was 2635.1±918.9 in Group I vs. 292.55±107.2 in Group II with a p value of .001; mean serum iron was 196.3±55.6 in Group I vs. 120±16.57 in Group II with a p value of .001 and mean serum total iron binding capacity was 247.3±28.6 in Group I vs. 327.8.7±21.96 in Group II with a p value of .001; mean FSH level was 1.36±0.22mIU/mL in Group I vs. 2.64±0.81mIU/mL in Group II with a p value of .021; mean LH level was 0.11±0.006mIU/mL in Group I vs. 1.78±1.12mIU/mL in Group II with a p value of .003; mean estrogen level was 21.45±10.23pg/mL in Group I vs. 42.36±15.44pg/mL in Group II with a p value of 0.001) with significant negative correlation between serum gonadal hormones and serum ferritin (r=− .835 and p value of .01 for FSH and serum ferritin; r=− .597 and a p value of .01 for LH and serum ferritin; and r=− 0.624 and p value of .01 for estrogen and serum ferritin. ConclusionFemale patients with SCA with iron overload may have gonadal hormone deficiency with significant negative correlations between gonadal hormones including FSH, LH, estrogen, and serum ferritin. Recommendations include regular iron chelation for prevention of irreversible damage of the ovaries and attaining normal sexual maturation, and regular follow up for females with SCA with assessment of puberty as they are more vulnerable to develop hypogonadism and may require hormonal replacement therapy.

Meeting the Reproductive Needs of Female Adolescents With Neurodevelopmental Disabilities

The complexity of caring for female adolescents with neurodisabilities often overshadows normal biological changes. These young women may require additional or individualized support as they adapt to normal puberty and sexual maturation. Many choices are available to assist in managing menstrual problems, hygiene issues, and contraception. Special considerations regarding contraceptive methods, sexual education, and improving service accessibility are explored for clinicians.

Androgens and obesity in male adolescents.

Data on sex steroid levels and pubertal development in obese adolescent boys are scarce and contrasting. The present review summarizes the most recent results obtained with improved methodology to measure low sex steroid levels in children. Obese pubertal boys have lower serum sex hormone-binding globulin and consequently lower total testosterone levels compared to normal-weight peers. However, during pubertal development, free testosterone levels in obese adolescents are not different from controls, indicating preserved androgen exposure as is additionally suggested by similar clinical genital staging (Tanner), serum gonadotropins levels, and serum prostate-specific antigen concentrations compared to nonobese adolescents. In pre and early puberty, total testosterone levels is not decreased, notwithstanding low sex hormone-binding globulin, and free testosterone is slightly increased in obese boys. This may result from increased adrenal activity as revealed by elevated serum androstenedione and dehydroepiandrosterone sulfate. In obese adolescent boys, increased aromatization of testosterone to estradiol tends to accelerate skeletal maturation. In obese adolescent boys, free testosterone is a better index than total testosterone levels of androgen status, which is not different from nonobese controls. Increased aromatization of testosterone to estradiol underlies the dissociation between normal clinical sexual maturation and advanced skeletal maturation in the obese adolescent.

Body Mass Index and Height Growth Curves are influenced by Sexual Maturation Status in Brazil: Cross-Sectional Study

Abstract Background: To describe and analyze growth curves of body mass index (BMI) and height according to sexual maturation status in children and adolescents aged 8-14 years old in the city of Florianopolis, Santa Catarina, Brazil. Methods: Cross-sectional study conducted in 2007 with a random sample of 2,339 students from public and private elementary school. Excess weight was determined by BMI curves of the World Health Organization according to sex and age. Sexual maturation was self-assessed and classified according to Tanner stages of sexual development. Tertiles of age in each sexual maturation stage were used to classify individuals in early, normal or late sexual maturation. Growth curves of BMI and height were estimated using median values for each sex, using six degree polynomial to smooth the curve. Results : We observed different growth curves of BMI and height according to sexual maturation status for both boys and girls. Early sexual maturation is associated with increased BMI z score to boys until 11 years of age and to girls in all groups age, and with increased height z score to boys in all age groups and in girls of 9 -12.5 years of age. Late sexual maturation is associated with lower values of BMI Z score in boys between 10 to 12 years of age and slower evolution of BMI Z score in girls. Conclusion : The sexual maturation seems to affect directly the evolution of BMI and height and should be considered in the assessment of nutritional status during childhood.

Association of sexual maturation with excess body weight and height in children and adolescents

BackgroundStudies addressing the influence of early sexual maturation on the excess of body weight and height of children and adolescents are scarce. The aim of the study was to analyze the association of sexual maturation with excess body weight and height in children and adolescents.MethodsThis was a cross-sectional study performed in Florianópolis city, Brazil, in 2007, with 2339 school children, aged 8–14 years (1107 males). Selection was based on a probabilistic, cluster-stratified sampling technique. School children were classified according to the presence of excess body weight, using sex- and age-specific body mass index (BMI) cutoff points. Z-scores were calculated from height and BMI data. Sexual maturation was self-assessed according to Tanner stages of development. Subjects were ranked based on tertiles of sexual maturation (early, normal and late) for each stage of development. Poisson and linear regression models were used.ResultsCompared to the reference group (normal sexual maturation), early maturing females had higher prevalence of excess weight (adjusted prevalence ratio: 1.70; 95% CI: 1.24 to 2.33) and increased height-for-age (adjusted β: 0.37; 95% CI: 0.14 to 0.59), while late maturing females had lower prevalence of excess weight (adjusted prevalence ratio: 0.57; 95% CI: 0.37 to 0.87) and decreased height-for-age (adjusted β: −0.38; 95% CI: −0.56 to −0.20). In males, early and late sexual maturation were associated with increased (adjusted β: 0.37; 95% CI: 0.14 to 0.59) and decreased (adjusted β: −0.38; 95% CI: −0.56 to −0.20) height-for-age, respectively.ConclusionEarly sexual maturation is associated with excess body weight in females and with greater height-for-age in both sexes.

CHARGE syndrome as unusual cause of hypogonadism: endocrine and molecular evaluation

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies (CHARGE) syndrome is a genetic syndrome in which hypogonadism is a frequent feature. A causative mutation within the chromodomain helicase DNA-binding protein-7 gene, which plays an important role in the embryonic development, is present in 2/3 of affected patients. We describe the clinical, hormonal and molecular characteristics of a young man from Ecuador who was diagnosed as having CHARGE syndrome at an adult age. The patient showed several phenotypic features of the syndrome, associated with a prepubertal state and cryptorchidism; hypogonadotrophic hypogonadism with undetectable testosterone levels not responsive to hCG testing and severe osteoporosis were ascertained. Molecular evaluation of the CHD7 gene showed the novel frameshift truncating heterozygous mutation p.Tyr1046Glyfs*23 in exon 12. Magnetic resonance imaging revealed mild hypoplasia of the pituitary gland and hypoplasia of the posterior cranial fossa. Parenteral testosterone therapy led to sexual development over time and, in combination with diphophonate therapy and calcium-vitamin D supplementation, significantly improved bone mineralisation. Early proper hormonal treatment of hypogonadism in patients with complex genetic syndromes is important to achieve normal sexual maturation, improve quality of life and avoid significant comorbidities, such as osteoporosis.

The Long-Term Clinical Follow-Up and Natural History of Men with Adult-Onset Idiopathic Hypogonadotropic Hypogonadism

Adult-onset idiopathic hypogonadotropic hypogonadism (AHH) is a rare disorder characterized by an isolated failure of gonadotropin secretion occurring after an otherwise normal sexual maturation in men. This study aims to examine the etiology and long-term natural history of this disorder. Long-term follow up, including detailed clinical, biochemical, and genetic examinations, were performed and compared with those at diagnosis. Patients included 10 men with AHH [serum testosterone (T) <125 ng/dl]. Overnight neuroendocrine studies, semen fluid analyses, and genetic screening were performed (KAL1, FGFR1, PROK2, PROKR2, NELF, TAC3, TACR3, and GNRH1) over a decade of longitudinal follow up. Follow-up evaluations were conducted 10.6 +/- 5.9 yr after initial studies and revealed that the clinical characteristics and seminal fluid analyses of AHH men (body mass index, 28.8 +/- 4.1 vs. 27.0 +/- 4.3 kg/m(2); testicular volume, 18 +/- 6 vs. 19 +/- 6 ml) do not change over a decade with no spontaneous reversals. Several men exhibited some variability in their endogenous GnRH-induced LH secretory patterns, including emergence of endogenous pulsatility in three individuals. However, all remained hypogonadal (T < or =130 ng/dl). A single heterozygous DNA sequence change in PROKR2 (V317L) was identified, although this rare sequence variant did not prove to be functionally abnormal in vitro. Seven days of pulsatile GnRH therapy in this subject nearly normalized his serum T, supporting that the site of the defect is hypothalamic and not pituitary. 1) AHH in men appears to be a long-lasting condition. 2) Although minor changes in the abnormal pattern of endogenous GnRH-induced LH secretion occurred in some AHH patients, all remained frankly hypogonadal.

Reproductive Hormones and Hypothalamic-Pituitary-Ovarian Axis in Female Patients With Homozygous β-Thalassemia Major

Homozygous beta-thalassemia major (hbeta-TM) is an autosomal recessive hemoglobinopathy with prominent endocrine complications. Our aims were to evaluate reproductive hormones, hypothalamic-pituitary-ovarian axis, and fertility in female patients with hbeta-TM. One hundred forty-four female patients with hbeta-TM, aged 18 years or above were enrolled in the study. Seventy-four age-matched healthy female volunteers served as controls. Two blood samples were drawn from each subject at 20-minute intervals for the determination of the resting levels of the following hormones: luteinizing hormone, follicle-stimulating hormone, estradiol, insulin-like growth factor-1, and insulin-like growth factor binding protein-3. The hypothalamic-pituitary-ovarian axis was also assessed using the gonadotropin-releasing hormone test. Menstruation status and growth rate were also noted. Puberty was assessed in both groups by Tanner classification. The mean age of puberty in the control group and hbeta-TM patients was 10.8+/-1.2 and 16.4+/-2.2 years, respectively (P=0.01). The mean age of menarche was 11.4+/-1.3 and 16.8+/-2.1 years in control subjects and patients with thalassemia, respectively (P=0.01). Of studied subjects with hbeta-TM, 61 (42.4%) were short in stature (height below the third percentile and below -2 SD scores). The baseline and peak levels of luteinizing hormone, follicle-stimulating hormone, and estradiol after gonadotropin-releasing hormone test in thalassemic group were significantly lower than in the control group. Further interventional studies are warranted to better clarify the treatment options to attain normal puberty and sexual maturation in patients with thalassemia.

The recent genetics of hypogonadotrophic hypogonadism – novel insights and new questions

The complex organization and regulation of the human hypothalamic-pituitary-gonadal axis render it susceptible to dysfunction in the face of a variety of genetic insults, leading to different degrees of hypogonadotrophic hypogonadism (HH). Although the genetic basis of some HH was recognized more than 60 years ago the first specific pathogenic defect, in the KAL1 gene, was only identified within the last 20 years. In the past decade, the rate of genetic discovery has dramatically accelerated, with defects in more than 10 genes now associated with HH. Several themes have emerged as the genetic basis of HH has gradually been uncovered, including the association of some genes such as FGFR1, FGF8, PROK2 and PROKR2, both with HH in association with hyposmia/anosmia (Kallmann syndrome) and with normosmic HH, thus blurring the clinical distinction between ontogenic and purely functional defects in the axis. Many examples of digenic inheritance of HH have also been reported, sometimes producing variable reproductive and accessory phenotypes within a family with non-Mendelian inheritance patterns. In strictly normosmic HH, human genetics has made a particularly dramatic impact in the past 6 years through homozygosity mapping in consanguineous families, first through identification of a key role for kisspeptin in triggering GnRH release, and very recently through demonstration of a critical role for neurokinin B in normal sexual maturation. This review summarises current understanding of the genetic architecture of HH, as well as its diagnostic and mechanistic implications.

Paediatric Orphan Drugs

Rare diseases are frequently genetically determined and caused by an inborn metabolic error, thus occurring early in life and affecting normal growth, and sexual and CNS maturation. The development of a paediatric orphan medicine presents a real hurdle for pharmaceutical companies because of the nature of the patient population where little knowledge is available. In addition, clinical trials are more difficult to run, take longer and cost more. An overview of the current situation in the paediatric orphan medicines field in Europe is provided below through the identification of unmet therapeutic needs still existing in the field (TEDDY NoE work), which represents a description of the orphan drugs so far authorised in Europe and of the paediatric drugs under development (Paediatric Investigation Plan – PIP).