Development Of Sexual Characteristics Research Articles

Current status of pubertal sexual characteristics development of 2 704 girls aged 6-18 years in Tongzhou District of Beijing

Objective: To understand the current status of pubertal sexual characteristics development of girls aged 6-18 years in Tongzhou District of Beijing and to compare the differences in sexual characteristics development among girls characterized as thin, normal, overweight, and obese. Methods: A cross-sectional survey was conducted among 2 844 girls aged 6-18 years in Tongzhou District of Beijing from September 2022 to July 2023. The developmental stages of breast and pubic hair were assessed on site, and menarche status was inquired. Weight and height were measured. The girls were subsequently characterized into thin, normal, overweight and obese groups. Basic information (including family and personal history) was obtained through questionnaires. Probit probability unit regression was applied to calculate the age of each Tanner stage of sexual characteristics development and the age of menarche. The χ2 test was applied to compare the counting data between two or multiple groups. Results: A total of 2 844 girls were surveyed and 2 704 girls met the inclusion criteria, resulting in a valid response rate of 95.1%. Among these girls, 1 105 (40.9%) were aged 6-9 years, 1 053 (38.9%) were aged 10-13 years, and 546 (20.2%) were aged 14-18 years. The of height-for-age Z-score (HAZ), weight-for-age Z-score (WAZ), and body mass index-for-age Z-score (BAZ) were 0.46(-0.23,1.16), 0.69(-0.16,1.67), and 0.67(-0.27,1.73) respectively. The prevalences of thin, overweight, and obesity were respectively 1.7% (45/2 704), 17.3% (467/2 704), and 19.9% (538/2 704), respectively. There were 45 girls in the thin group, 1 654 girls in the normal weight group, 1 005 girls in the overweight and obesity group. The age of Tanner stage breast 2 (B2), Tanner stage pubic hair 2 (P2), and menarche was 9.0 (95%CI 8.9-9.1), 10.5 (95%CI 10.4-10.6), and 11.4 (95%CI 11.3-1.5) years, respectively. The current status of breast and pubic hair maturity in girls with pubertal development shows that 64.6% (1 211/1 874) of these girls had breast development preceding pubic hair development, 32.4% (607/1 874) had concurrent breast and pubic hair development, and 3.0% (56/1 874) had pubic hairs development preceding breast development. The interval age between B2 and B5 was 4.7 (95%CI 4.6-4.8) years, between P2 and P5 was 4.5 (95%CI 4.4-4.6) years, and between B2 and menarche was 2.4 (95%CI 2.3-2.5) years. The ages of sexual characteristics development in overweight and obese groups were earlier than that in normal and thin groups. The ages of B2 in thin, normal, overweight, and obese groups were 10.0 (95%CI 9.5-10.6), 9.3 (95%CI 9.2-9.4), and 8.6 (95%CI 8.4-8.7) years, respectively. The age of menarche in thin, normal, overweight, and obese groups were 13.1 (95%CI 12.4-13.7), 11.6 (95%CI 11.4-11.7), and 11.1 (95%CI 11.0-11.2) years, respectively. The interval ages between B2 and B5 and between P2 and P5 was 4.5 and 4.1 years, respectively in the overweight and obese groups, and those in normal group and thin group was 4.7 and 4.5 years, 4.6 and 4.7 years, respectively. Conclusions: The ages of sexual characteristics development and menarche tend in Tongzhou District of Beijing to be earlier than that being reported of Beijing's survey 20 years ago. Girls characterized as overweight and obese not only start puberty at an earlier age than girls of normal weight, but also have a shorter developmental process.

FRI325 Pituitary Stalk Interruption Syndrome Presenting As Short Stature: A Case Report

Abstract Disclosure: S. Ravindra: None. S. Tirupati: None. Background: Pituitary stalk interruption syndrome (PSIS) is a rare congenital pituitary anatomical defect that leads to a variable degree of pituitary hormone deficiency. The classic neuroimaging findings of this condition include thin or interrupted stalk, absent or ectopic posterior pituitary, and hypoplastic anterior pituitary gland. The reported incidence of PSIS is 0.5 per 1,00,000 live births. The exact pathophysiology of this syndrome is not fully understood, but chromosomal microdeletions and perinatal asphyxia have some established roles in the literature as primary miscreants. Here we report a case of an adolescent male child who presented with complaints of short stature and absent secondary sexual characters development, diagnosed with PSIS following an MRI. Clinical Case: A 16-year-old male child was referred to the endocrinology department for the evaluation of short stature and delayed secondary sexual character development. This patient was born out of a non-consanguinous marriage and delivered at term by the vaginal route, with no other significant perinatal or family history. Psychomotor milestones were attained appropriately as per age but had poor linear growth. On examination, he had short stature - height 146cms (-2.7 SDS), weight: 53.5kg BMI: 23.5 Kg/m2 with normal vitals. Head-to-toe examination revealed immature facies, deep-seated eyes, broad nasal bridge, bilateral lipomastia, high-pitched voice, Tanner stage: A1P1, SPL:4cms, the testicular volume of 3cc bilaterally, with rest of the system-wise examinations being normal. Routine laboratory investigations (CBC, RFT, LFT, Electrolytes) were within normal limits. Bone age: 13years. The hormonal assessment showed central hypothyroidism, hypocortisolemia, and GH insufficiency, with pre-pubertal gonadotropin levels- suggestive of pan-hypopituitarism (Table 1). MRI pituitary showed anterior pituitary hypoplasia with interrupted stalk, and ectopic posterior pituitary, with no other brain anomalies which is consistent with the diagnosis of PSIS. The patient was initiated on hormone replacement therapy, currently taking hydrocortisone, growth hormone, levothyroxine, and testosterone. Conclusion: PSIS is a rare condition, that can present with various spectrum of clinical features. Signs and symptoms may not be evident in the neonatal and infancy period, therefore diagnosis is often delayed. Early diagnosis and treatment are crucial for preventing adverse effects of long-term hormonal deficiencies and improving the quality of life. Presentation: Friday, June 16, 2023

Medical care for children and adolescents with gender dysphoria and gender inconsistency in the light of current recommendations - how to implement the "primum non nocere" principle?

Gender identity is one of the essential aspects of human functioning. The diagnosis of gender dysphoria or gender incongruence applies to people who do not have any developmental defects of the genital organs or sex hormone secretion disorders, while the problem is the lack of acceptance of functioning in their own body and the desire to become a person of the opposite sex. This phenomenon is increasingly observed in children and adolescents. In recent years there has been a trend towards earlier use of puberty blockers and sex steroids in minors with gender dysphoria or gender inconsistency in order to inhibit the development of sexual characteristics in the direction of their own sex (referred to as the sex assigned at birth) and to mimic them to the opposite sex, i.e. according to their gender identification. In addition, surgical procedures are performed to remove the gonads and change the appearance of the genitals (and/or breast) in the desired direction (these procedures are allowed in adults, although there are many advocates of performing them in adolescents). Such therapies have been described as "gender-affirming", as opposed to "conversion" therapies, i.e. interventions aimed at restoring the acceptance of one's own sex. The literature emphasizes the lack of evidence regarding the effectiveness and safety of these procedures, allowing for an unequivocal recommendation of their application in children and adolescents, as well as the possible relationship between the increase in the frequency of gender identity disorders and the influence of peer groups, in particular the media creating a climate of affirmation of transsexualism (and non-binary gender identification). Therefore some countries (e.g. Sweden) have tightened their legal regulations in this area. The most serious long-term consequence of gender-affirming therapies is infertility. This paper aims to present these problems based on current medical literature. Extremely important bioethical and legal aspect of these issues will only be indicated, although they undoubtedly require special attention and separate studies.

Clinical Manifestations, Genetic Variants and Therapeutic Evaluation in Sporadic Chinese Patients with Idiopathic Hypogonadotropic Hypogonadism.

Genetic factors account for a large proportion of idiopathic hypogonadotropic hypogonadism (IHH) etiologies, although not necessarily a complete genetic basis. This study aimed to characterize the clinical presentations, genetic variants, and therapeutic outcomes of patients with sporadic IHH, which may be helpful for genetic counseling and treatment decisions. Eleven Chinese patients with IHH were retrospectively analyzed. Rare genetic variants were evaluated using whole-exome sequencing and bioinformatics analysis and were further classified according to the ACMG-AMP guidelines. The therapeutic responses of patients were further evaluated. Six heterozygous variants of SOX10, WDR11, PROKR2, CHD7 and FGF17 were detected in five Kallmann syndrome (KS) patients, whereas two heterozygous variants of CHD7 and PROKR2 were detected in two normosmic IHH (nIHH) patients. Among these variants, a novel likely pathogenic variant in the SOX10 (c.429-1G>C) was considered to cause the KS phenotype in patient 02, and two potential variants of uncertain significance (VUS) in CHD7 (c.3344G>A and c.7391A>G) possibly contributed to the KS phenotype in patient 05 and the nIHH phenotype in patient 07, which need to be confirmed by further evidence. Additionally, long-term testosterone or estradiol replacement treatment effectively improved the development of sexual characteristics in patients with IHH. Next-generation sequencing is a powerful tool for identifying the molecular etiology and early diagnosis of IHH. Efficient therapeutic outcomes strongly indicate a need for timely treatment.

Vaginal Bleeding In Prepubertal Girls-A Case Series in Malaysia

The etiology of prepubertal vaginal bleeding varies from isolated pubertal causes to malignant tumors and generates significant anxiety among girls and their caretakers. Hence, these cases require careful assessment and management. This is a report of five cases of prepubertal vaginal bleeding with various causes and were managed in a tertiary referral center in Malaysia. The first case was a 6-year-old girl who had no pubertal changes with 3 weeks’ history of bleeding. She underwent examination under anesthesia and found to have multiple vaginal polyps. Another 6-year-old girl noted to have a doughnut-shaped mass protruding from her urethral meatus. She was treated with estrogen cream and sitz baths. Another child had early breast development while pelvic ultrasound revealed a multiseptated ovarian cyst requiring a cystectomy. A 19-month-old toddler had a large intravaginal mass. She required further investigation, referral to the pediatric surgeon and oncologist for treatment of a malignant yolk sac tumor. Lastly, an 8-year-old girl was noted to have monthly vaginal spotting without any secondary sexual characteristics development. Prepubertal vaginal bleeding is abnormal thus requires prompt assessment to ascertain the cause and administer appropriate management. It is important to rule out sexual abuse and malignancy. Examination under anaesthesia and vaginoscopy is recommended when imaging modality is inconclusive. Referral to tertiary centres experienced in managing such cases ensures good outcomes. Thorough targeted history-taking and pediatric-specific gynecological examination skills are crucial to formulate accurate diagnosis and appropriate management.

Further progress of the etiology,diagnosis and treatment of peripheral precocious puberty

Peripheral precocious puberty(PPP),also known as puberty independent from hypothalamic-pituitary axis activation,is stimulated by hormones from other sources, with only partial sexual characteristics development but without mature sexual function. The secondary sexual characteristics development occurs before 7.5 years of age in girls and before 9 years of age in boys. Clinical manifestations are diverse, and PPP has varied etiology including congenital adrenal hyperplasia, McCune-Albright syndrome, ovarian cyst, adrenal tumor, ovarian tumor, testicular tumor, human chorionic gonadotropin producing tumor, familial male precocious puberty, aromatase excess syndrome, and environmental estrogen. Early identification of etiology, accurate differential diagnosis and prenatal gene screening play a significant role in the prevention, diagnosis and treatment of the disease.

A refined roadmap to decapod sexual manipulation

AbstractMany decapod crustaceans with sexual dimorphism in body size are economically significant species for fisheries and aquaculture, making monosex culture a desirable practice to increase farmers' yield and profits. It is well established that the male‐specific androgenic gland (AG) mediates masculinization in decapods by producing and secreting the insulin‐like AG hormone (IAG). However, IAG is not a sex‐determining factor; hence, iag silencing in decapods does not always lead to successful sex change. Since the establishment of monosex populations in the giant freshwater prawn Macrobrachium rosenbergii, the same AG/iag manipulation approach has been attempted in economically significant penaeid shrimps, crabs, crayfish and spiny lobsters, to no avail. There are many factors at play with species‐specific intricacies which require close examination when addressing monosex production. This review provides a refined roadmap to successful sexual manipulation in decapod crustaceans, highlighting the key caveats to be considered and critical gaps in knowledge such as the timing of iag expression compared to the development of sexual characteristics, the relationship between iag and a master regulator, as well as silencing capacity. Lastly, this review examines what the future might hold for monosex aquaculture in decapods, taking into consideration novel technologies such as gene editing.

Evolutionary differentiation of androgen receptor is responsible for sexual characteristic development in a teleost fish

Teleost fishes exhibit complex sexual characteristics in response to androgens, such as fin enlargement and courtship display. However, the molecular mechanisms underlying their evolutionary acquisition remain largely unknown. To address this question, we analyse medaka (Oryzias latipes) mutants deficient in teleost-specific androgen receptor ohnologs (ara and arb). We discovered that neither ar ohnolog was required for spermatogenesis, whilst they appear to be functionally redundant for the courtship display in males. However, both were required for reproductive success: ara for tooth enlargement and the reproductive behaviour eliciting female receptivity, arb for male-specific fin morphogenesis and sexual motivation. We further showed that differences between the two ar ohnologs in their transcription, cellular localisation of their encoded proteins, and their downstream genetic programmes could be responsible for the phenotypic diversity between the ara and arb mutants. These findings suggest that the ar ohnologs have diverged in two ways: first, through the loss of their roles in spermatogenesis and second, through gene duplication followed by functional differentiation that has likely resolved the pleiotropic roles derived from their ancestral gene. Thus, our results provide insights into how genome duplication impacts the massive diversification of sexual characteristics in the teleost lineage.

Abstract #1324294: Central Precocious Puberty in a Young Boy Associated With Bilateral Optic Pathway Glioma in Neurofibromatosis Type 1: A Case Report

Precocious puberty refers to sexual characteristic development before the normal age for its development. Neurofibromatosis type 1 is an autosomal dominant condition with a wide spectrum of clinical phenotype of which precocious puberty is common. This case report highlights the importance of recognizing this disease in patients presenting with precocious puberty and screening for optic pathway gliomas should be done and treat it to prevent the future chances of permanent blindness, neurologic disability, and gonadotropin deficiency.

OR26-5 Musashi-2 Regulatory Interactions Promote Adrenal Steroidogenesis

Abstract The adrenal gland is the site of steroid hormone synthesis. These hormones regulate many physiological processes including metabolism, blood pressure and volume, and sexual characteristic development. While signaling pathways, steroidogenic enzymes, and transcription factors have all been well characterized, little is known about the contribution of RNA-binding proteins (RBPs) in regulating steroidogenesis. We recently demonstrated that regulated RNA decay controls the timing of the steroidogenic gene expression response and identified 9 RBPs that regulate aldosterone production in an immortalized human cell line model for steroidogenesis, H295R. One of the RBPs we identified was Musashi-2 (MSI2), which is required for development of other steroidogenic tissues such as ovary and testis in mice. We found that MSI2 mRNA is enriched in human adrenal glands relative to other tissues, positively correlates in expression with mRNAs encoding steroidogenic enzymes, and abundantly expressed in H295R cells. Staining of normal human adrenal gland sections demonstrated that MSI2 protein is expressed in all three layers of the human adrenal cortex. Taken together, we hypothesized that MSI2 promotes steroidogenesis through regulating expression of target mRNAs encoding. Using the selective MSI2 inhibitor Ro-08-2750 (Ro) we found that aldosterone and cortisol production is decreased in a dosage dependent manner in H295R cells, which is consistent with siRNA knockdown of MSI2. We performed RNA-immunoprecipitation and sequencing and identified 1428 mRNA targets of MSI2 in H295R cells. A target of interest was Stearoyl-CoA Desaturase (SCD), which functions to convert saturated fatty acids to unsaturated fatty acids that promote formation of lipid droplets. Cholesterol esters in lipid droplets are a source of cholesterol used to produce all steroid hormones. Ro treatment of H295R cells resulted in a suppression of SCD mRNA and protein induction. Furthermore, inhibition of SCD with A939572 caused a dosage dependent decrease in aldosterone production. These data suggest that potentiation of stimulation dependent SCD induction is one mechanism by which MSI2 promotes steroidogenesis. It will be important to determine if and how MSI2 promotes steroidogenesis in primary human adrenal cells and mouse models. Since it is possible to deliver oligonucleotides to the adrenal cortex, disruption of MSI2-SCD mRNA regulatory interactions may open new therapeutic avenues for modulate aldosterone production. Presentation: Monday, June 13, 2022 12:00 p.m. - 12:15 p.m.

Rational design of thermophilic CYP119 for progesterone hydroxylation by in silico mutagenesis and docking screening

Steroid-based chemicals can affect the metabolism, immune functions, and development of sexual characteristics. Because of these effects, steroid derivatives are widely used in the pharmaceutical industry. Progesterone is a steroid-based hormone that mainly controls the ovulation period of women but is also a precursor molecule for the synthesis of important hormones like testosterone and cortisone. Cytochrome P450 (CYP) enzymes are important for the production of hydroxyprogesterones in the industry since they can catalyze regio- and enantioselective hydroxylation reactions. Although human CYP enzymes can catalyze hydroxyprogesterone synthesis with high selectivity, these enzymes are membrane bound, which limits their application for industrial production. CYP119 is a soluble and thermophilic enzyme from the archaea Sulfolobus acidocaldarius. Even though the native substrate of the enzyme is not known, CYP119 can catalyze styrene epoxidation, lauric acid hydroxylation, and Amplex®Red peroxidation. In this work, an in silico mutagenesis approach was used to design CYP119 mutants with high progesterone affinity. Energy scores of progesterone docking simulations were used for the design and elimination of single, double, and triple mutants of CYP119. Among designed 674 mutants, five of them match the criteria for progesterone hydroxylation. The most common mutation of these five mutants, L69G mutant was analyzed using independent molecular dynamics (MD) simulations in comparison with the wild-type (WT) enzyme. L69G CYP119, was expressed and isolated from Escherichia coli; it showed 800-fold higher affinity for progesterone compared to WT CYP119. L69G CYP119 also catalyzed progesterone hydroxylation. The novel designed enzyme L69G CYP119 is a potential versatile biocatalyst for progesterone hydroxylation that is expected to be stable under industrial production conditions.

Abstract #1182265: 46,XY 5-Alpha-Reductase Deficiency in a Phenotypic Female

5-alpha-reductase deficiency (5aRD) is a rare genetic sex disorder seen in 46, XY individuals inherited as an autosomal recessive mutation of the 5aR type 2 gene (SRD5A2) resulting in dihydrotestosterone deficiency during sexual characteristic development.

Masculinization of Adult Gambusia holbrooki: A Case of Recapitulation of Protogyny in a Gonochorist?

Simple SummaryAlthough gonochoristic fish express one sex or the other in adulthood, some adults display traits similar to those of their opposite sex, suggesting plasticity similar to hermaphrodites. To fully test this potential in the eastern mosquitofish, a gonochorist, two adult stages of females were fed 17α-Methyltestosterone incorporated feed (0–200 mg/kg diet) for 50 days. The hormone (particularly at 50 mg/kg diet) stimulated the formation of complex male copulatory structures and testicular tissue as well as upregulated expression of Anti-Müllerian Hormone gene and altered the behavior from females to males. Collectively, we infer that Gambusia holbrooki retains potential for sex reversal at adulthood, similar to what occurs naturally in hermaphroditic fish and can provide an ideal system to investigate these mechanisms in a regulated fashion.17α-Methyltestosterone (MT) is a synthetic steroid that has been widely used to masculinize many fish species when administered early during larval development, however, reports on its efficacy on adults is limited. To this end, this study investigated the efficacy of MT in the masculinization of the eastern mosquitofish (G. holbrooki) at two adult stages (maiden and repeat gravid females). The treated females were fed control or respective MT incorporated feed (0–200 mg/kg diet) for 50 days. Effects of the hormone on secondary sexual characteristics, internal gonad morphology, expression of the Anti-Müllerian Hormone (amh) gene and sexual behavior of the treated females were investigated. The results showed that MT at the dose of 50 mg/kg feed stimulated secondary sexual character development, upregulated expression of amh, formation of testicular tissue and a shift in the behavior similar to those of normal males, prominently so in treated maiden gravid females. Post-treatment, long-term observations indicated that only two masculinized females reverted back to being females and gave birth to young. Induction of masculinizing effects in most individuals suggests that the sexual phenotype of this species appears to be highly plastic with potential to sex reverse at adulthood. This in combination with its small size and short reproductive cycle could provide an ideal system to explore the mechanisms of sequential hermaphroditism in fish and contribute to genetic control of this pest fish.

Lifespan healthcare transitions among individuals with intersex traits in Canada: a mixed-methods and qualitative study

ObjectivesTo: (1) complete an integrative literature review of transition studies that focus on individuals with intersex traits; (2) conduct an environmental scan of the current resources (practice guidelines, policies and...

Precocious puberty: experience in the Pediatric Endocrinology Unit at the Children's Hospital in Rabat

Introductionla puberté précoce est définie par le développement des caractères sexuels avant l´âge de 8 ans chez la fille et de 9 ans chez le garçon. L´objectif de notre étude était de décrire le profil clinique, paraclinique et étiologique de la puberté précoce.Méthodesil s´agit d´une étude descriptive rétrospective s´étalant de 1999 à 2017 à l´unité d´endocrinologie pédiatrique à l´Hôpital d´Enfant de Rabat.Résultatsquatre-vingt-dix-neuf (99) enfants ont été inclus. L´âge moyen des filles était de 4,25 ± 2,6 ans, celui des garçons était de 3,6 ans ± 1,8. Nous avons noté une prédominance féminine dans 90% (90 filles). Les signes révélateurs chez la fille étaient dominés par le développement mammaire (77,77%). Chez le garçon, le motif de consultation le plus fréquent était la pilosité pubienne (70%). Sur le plan biologique, dans les pubertés précoces centrales, le taux moyen du pic de LH après stimulation par GnRH était élevé à 17 UI/L avec un rapport moyen pic LH/ pic FSH de 1,30. Les étiologies étaient comme suit: pubertés précoces dissociées (60,60%), pubertés précoces pathologiques (39,40%). Dans cette dernière, nous avons noté une prédominance des pseudo-pubertés précoces (58,98%). Pour la puberté précoce centrale, la forme idiopathique était l´étiologie la plus fréquente chez la fille (62,5%). Alors que chez tous les garçons, une lésion du système nerveux central était objectivée.Conclusionnotre étude confirme que la puberté précoce pathologique centrale est souvent liée à une lésion du système nerveux central chez le garçon justifiant ainsi la réalisation systématique d´une imagerie cérébrale.

Cellular Senescence in Adrenocortical Biology and Its Disorders.

Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders.

Segment number threshold determines juvenile onset of germline cluster expansion in Platynereis dumerilii.

Development of sexual characters and generation of gametes are tightly coupled with growth. Platynereis dumerilii is a marine annelid that has been used to study germline development and gametogenesis. P. dumerilii has germ cell clusters found across the body in the juvenile worms, and the clusters eventually form the gametes. Like other segmented worms, P. dumerilii grows by adding new segments at its posterior end. The number of segments reflect the growth state of the worms and therefore is a useful and measurable growth state metric to study the growth‐reproduction crosstalk. To understand how growth correlates with progression of gametogenesis, we investigated germline development across several developmental stages. We discovered a distinct transition period when worms increase the number of germline clusters at a particular segment number threshold. Additionally, we found that keeping worms short in segment number, by manipulating environmental conditions or via amputations, supported a segment number threshold requirement for germline development. Finally, we asked if these clusters in P. dumerilii play a role in regeneration (as similar free‐roaming cells are observed in Hydra and planarian regeneration) and found that the clusters were not required for regeneration in P. dumerilii, suggesting a strictly germline nature. Overall, these molecular analyses suggest a previously unidentified developmental transition dependent on the growth state of juvenile P. dumerilii leading to substantially increased germline expansion.

Congenital hypogonadotropic hypogonadism: from clinical characteristics to genetic aspects

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by a deficiency in gonadotropin-releasing hormone (GnRH). CHH is characterized by delayed puberty and/or infertility; this is because GnRH is the main component of the hypothalamic-pituitary-gonadal (HPG) axis, which is a key factor in pubertal development and reproductive function completion. However, since the development of sexual characteristics and reproduction begins in the prenatal period and is very complex and delicate, the clinical characteristics and involved genes are very diverse. In particular, the HPG axis is activated three times in a lifetime, and the symptoms and biochemical findings of CHH vary by period. In addition, related genes also vary according to the formation and activation process of the HPG axis. In this review, the clinical characteristics and treatment of CHH according to HPG axis activation and different developmental periods are reviewed, and the related genes are summarized according to their pathological mechanisms.

Patients with disorders of sex development.

Disorders of sex development (DSDs) are a genetically and clinically heterogeneous group of congenital conditions of the urogenital tract and reproductive system. Time and spatially controlled transcription factors, signal molecules, and an array of different hormones are involved in the development of sex characteristics, and variations in their pathways and actions are associated with DSD. These conditions may be caused by numerical or structural variations in sex chromosomes as well as autosomes, variations in genes involved in gonadal and/or genital development, and changes in gonadal and/or adrenal steroidogenesis. Endogenous or exogenous (maternal) and possibly endocrine disruptors may also interfere with genital development.

RNA-Binding Protein Musashi-2 Inhibits Aldosterone Production

The adrenal cortex is the site of steroid hormone synthesis. These hormones control important physiological processes like metabolism, blood pressure and volume, and sexual characteristic development. While the signaling pathways, transcription factors, and steroidogenic enzymes are well-characterized, surprisingly little is known about the contribution RNA-binding proteins (RBPs). RBPs exert post-transcriptional control by interacting with specific elements within target mRNAs. Here we focus on the RBP, Mushashi-2 (MSI2), which binds to UAG sequences in the 3’UTR of its target transcripts. MSI2 is required for development of steroidogenic tissues which is consistent with its higher mRNA levels in human ovaries and testis. MSI2 also exhibits high expression levels in human adrenal tissue and the immortalized human adrenocortical cell line (H295R). Based on the compelling MSI2 expression pattern, we set out to determine the role of MSI2 on aldosterone production. Depletion of MSI2 using siRNA led to significantly lower aldosterone levels in H295R cells stimulated with AngII. We also employed an orthogonal loss-of-function approach by co-treating cells with AngII and increasing concentrations of Ro-08-2750 (Ro), a direct and selective inhibitor of MSI2-RNA interactions. Ro inhibited aldosterone production in a dose-dependent manner at 1 µM with almost complete inhibition at 5 µM. The molecular mechanism by which MSI2 regulates target RNA translation and/or decay is unknown. Moreover, whether MSI2 acts as a repressor or activator appears to be context dependent. Our goal is to determine the precise molecular mechanism by which MSI2 promotes aldosterone production. Specifically, we will identify MSI2 targets, temporally resolved consequences of MSI2 inhibition, and protein interaction partners. This work will impact our understanding of fundamental principles of RBP-mediated regulation, as well as novel regulatory mechanisms underlying human steroid hormone synthesis. Indeed, Ro (or further optimized compounds) may represent new therapeutic avenues for adrenal disease.