Cyp11a2 is essential for oocyte development and spermatogonial stem cell differentiation in zebrafish

Cytochrome P45011A1, encoded by Cyp11a1, converts cholesterol to pregnenolone (P5), the first and rate-limiting step in steroidogenesis. In zebrafish, cyp11a1 is maternally expressed and cyp11a2 is considered the ortholog of Cyp11a1 in mammals. A recent study has shown that depletion of cyp11a2 resulted in steroidogenic deficiencies and the mutants developed into males with feminized secondary sexual characteristics. Here, we independently generated cyp11a2 mutants in zebrafish and showed that the mutants can develop into males and females in the juvenile stage, but finally into infertile males with defective mating behavior in the adult stage. In the developing ovaries, the cyp11a2 mutation led to stage I oocyte apoptosis and final sex reversal, which could be partially rescued by treatment with P5 but not estradiol. In the developing testes, depletion of cyp11a2 resulted in dysfunction of Sertoli cells and lack of functional Leydig cells. Spermatogonial stem cells (SSCs) in the mutant testes underwent active self-renewal but no differentiation, resulting in a high abundance of SSCs in the testis, as revealed by immunofluorescence staining with Nanos2 antibody. The high abundance and differentiation competence of SSCs in the mutant testes were verified by a novel testicular cell transplantation (TCT) method developed in this study, by transplanting mutant testicular cells into germline-depleted wild-type (WT) fish. The transplanted mutant SSCs efficiently differentiated into functional spermatids in WT hosts. Overall, our study demonstrates the functional importance of cyp11a2 in early oogenesis and differentiation of SSCs.

Rearing of Bitterling (Rhodeus amarus) Larvae and Fry under Controlled Conditions for the Restitution of Endangered Populations

Among the several dozen European freshwater fish species, only European bitterling (Rhodeus amarus Bloch) and Rhodeus meridionalis belong to the group of ostrakophilous fish. The embryonic and larval development of the fish in this reproductive group until the time of the yolk sac resorption takes place in the gill cavity of river mussels (Anodonta sp. or Unio sp.). This paper presents the results of the European bitterling Rhodeus amarus being reared under controlled conditions. Bitterling larvae were caught together with river mussels in the natural environment and subsequently placed in a tank for behavioural observations. Bitterling larvae were seen swimming in the water within a week of placing the bivalves under controlled conditions. The bitterling larvae were 8.6 ± 0.11 mm long when they started to swim actively. The rearing was conducted in water at 20 and 26 ± 0.5 °C and lasted for 6.5 months (200 days) in both variants. Initially, the larvae were fed with live nauplii of Artemia salina and subsequently with fodder. The bitterlings in tanks with water at 26 ± 0.5 °C were 66.2 ± 3.0 mm long and weighed 3389 ± 548 mg. For comparison, bitterlings kept in water at 20 ± 0.5 °C were 64.48 ± 3.4 mm long and weighed 3242 ± 427 mg. No larval malformities or mortality were observed during the larvae and fry rearing. The bitterlings had well-developed secondary sexual characteristics and exhibited pre-spawning behaviour at the end of the rearing. This produced suitable bitterling stocking material to be used in the conservation of small or endangered populations.

New and consolidated therapeutic options for pubertal induction in hypogonadism: in-depth review of the literature

Delayed puberty (DP) defines a retardation of onset/progression of sexual maturation beyond the expected age due to either a lack/delay of the hypothalamo-pituitary-gonadal (HPG) axis activation or a gonadal failure. DP usually gives rise to concern and uncertainty in patients and their families, potentially affecting their immediate psychosocial well-being and also creating longer-term psychosexual sequelae. The most frequent form of DP in younger teenagers is self-limiting and may not need any intervention. Conversely, DP due to hypogonadism requires prompt and specific treatment that we summarize in this review. Hormone therapy primarily targets genital maturation, development of secondary sexual characteristics and the achievement of target height in line with genetic potential, but other key standards of care include body composition and bone mass. Finally, pubertal induction should promote psychosexual development and mitigate both short- and long-term impairments comprising low self-esteem, social withdrawal, depression and psychosexual difficulties. Different therapeutic options for pubertal induction have been described for both males and females but we lack the necessary larger randomized trials to define the best approaches for both sexes. We provide an in-depth and updated literature review regarding therapeutic options for inducing puberty in males and females, particularly focusing on recent therapeutic refinements that better encompass the heterogeneity of this population, and underlining key differences in therapeutic timing and goals. We also highlight persistent shortcomings in clinical practice, wherein strategies directed at “the child with delayed puberty of uncertain aetiology” risk being misapplied to older adolescents likely to have permanent hypogonadism.

Kallmann Syndrome and X-linked Ichthyosis Caused by Translocation Between Chromosomes X and Y: A Case Report

Background: Xp22.3 region is characterized by low frequency of interspersed repeats and low GC content. Several clinically important genes including ANOS1 (KAL1) reside in this region. This gene was first identified due to translocation between chromosomes X and Y in a patient with Kallmann syndrome. Case Presentation: A 20 year old male presented with complaints of delayed secondary sexual characteristics, impaired sense of smell, and poor scholastic performance. On examination, he had short stature (151 cm; <3rd centile). His sexual maturity corresponded to Tanner stage 3. Stretched penile length was 3.6 cm (<3rd centile). Right testis was undescended with low left testicular volume (12 ml). There was mild ichthyosis over abdomen and back. He had hyposmia, hoarse voice, and synkinesia. Investigations were suggestive of hypogonadotrophic hypogonadism. Karyotype revealed an extra chromosomal material on p arm of chromosome X (46,Xp+,Y). On cytogenetic microarray, deletion of 8.3 Mb on Xp22.33 region and duplication of 12.8 Mb on Yq11.22 region were identified. The breakpoint on X chromosome resulted in deletion of exons 7-14 of ANOS1 gene and complete STS, NLGN4X, ARSL (ARSE), SHOX, and VCX genes. Conclusion: Patients diagnosed with Kallmann syndrome should receive careful clinical evaluation to detect presence of a contiguous gene syndrome.

Polygenic sex determination produces modular sex polymorphism in an African cichlid fish

For many vertebrates, a single genetic locus initiates a cascade of developmental sex differences in the gonad and throughout the organism, resulting in adults with two, phenotypically distinct sexes. Species with polygenic sex determination (PSD) have multiple interacting sex determination alleles segregating within a single species, allowing for more than two genotypic sexes, and scenarios where sex genotype at a given locus can be decoupled from gonadal sex. Here we investigate the effects of PSD on secondary sexual characteristics in the cichlid fish Metriaclima mbenjii, where one female (W) and one male (Y) sex determination allele interact to produce siblings with four possible sex classes: ZZXX females, ZWXX females, ZWXY females, and ZZXY males. We find that PSD in M. mbenjii produces an interplay of sex-linkage and sex-limitation resulting in modular variation in morphological and behavioral traits. Further, the evolution or introgression of a novel sex determiner creates additional axes of phenotypic variation for varied traits, including genital morphology, craniofacial morphology, gastrointestinal morphology, and home tank behaviors. In contrast to single-locus sex determination, which broadly results in sexual dimorphism, polygenic sex determination can induce higher-order sexual polymorphism. The modularity of secondary sexual characteristics produced by PSD provides novel context for understanding the evolutionary causes and consequences of maintenance, gain, or loss of sex determination alleles in populations.

Cardiovascular Risk Associated With Gender Affirming Hormone Therapy in Transgender Population

Transgender men and women represent about 0.6 -1.1%% of the general population. Gender affirming hormone therapy (GAHT) helps ameliorate gender dysphoria and promote well-being. However, these treatments’ cardiovascular (CV) effects are difficult to evaluate due to the limited number of extensive longitudinal studies focused on CV outcomes in this population. Furthermore, these studies are mainly observational and difficult to interpret due to a variety of hormone regimens and observation periods, together with possible bias by confounding factors (comorbidities, estrogen types, smoking, alcohol abuse, HIV infection). In addition, the introduction of GAHT at increasingly earlier ages, even before the full development of the secondary sexual characteristics, could lead to long-term changes in CV risk compared to current data.This review examines the impact of GAHT in the transgender population on CV outcomes and surrogate markers of CV health. Furthermore, we review available data on changes in DNA methylation or RNA transcription induced by GAHT that may translate into changes in metabolic parameters that could increase CV risk.

Central Precocious Puberty in a Three-Year-Old Girl

Precocious puberty is defined as the onset of secondary sexual characteristics before 8 years of age in girls and 9 years in boys. Central Precocious Puberty (CPP) is caused by early activation of the hypothalamic-pituitary-gonadal axis. Laboratory test of LH, FSH, and Estradiol is recommended for monitoring suppressive effects from GnRHa therapy in the early three months and every six months. This study aimed to report a case of CPP in a 3-year and 3-month-old girl. A 3-year and 3-month-old girl went to the hospital with vaginal bleeding (menstruation), breast development, and pubic and axilla hair for 7-month-old. Physical examination found moderately ill with obesity, body weight 20 kg, height 98 cm. Tanner stage was A2M3P2, café au lait was found in the left forehead with size 7x3.5 cm. In March 2015 before GnRHa therapy, LH, FSH and Estradiol level increased with levels of 4.32 mlU/mL, 6.01 mlU/mL, and 67 pg/mL, and after 3 months of the treatment was 0.87 mlU/mL, 2.51 mlU/mL and <20 pg/mL. Pelvic ultrasonography showed suggestive precocious puberty, bone age 5-year and 9-month (Greulich and Pyle), CT-Scan of the brain showed hypothalamic tumor suspected hypothalamic hamartoma. This patient was treated with a GnRHa injection every 4 weeks. Leuprorelin is a synthetic non-peptide analogue of natural GnRH. The diagnosis was based on medical history, physical examination, laboratory, and radiological findings. The prognosis of the patient was good.

Ovarian inguinal hernia – a possibility in MURCS syndrome

Background Inguinal hernia containing ovary and fallopian tube can be found in paediatric population and is a rare finding in women of reproductive age group. Most of the cases are associated with congenital abnormalities of the female genital tract. Case presentation A 20 year old female presented with right reducible inguinal hernia, primary amenorrhea and normal secondary sexual characteristics. Clinical examination revealed scoliosis with convexity towards left side, prominence of left rib cage with Sprengel deformity and right sided heart sounds. Ultrasound of the inguinal swelling revealed right ovary within the hernial sac, Chest X-ray revealed right lung collapse and dextrocardia. Further Magnetic resonance imaging (MRI) of pelvis revealed inguinal hernia with right ovary as its content, normal left ovary and absent uterus. Computed tomography (CT) revealed complete collapse of right lung with compensatory left lung hyperinflation and absent right kidney. Karyotyping of the patient was normal, 46XX. A diagnosis of MURCS syndrome with right ovarian hernia was made. The hernia was surgically managed with repositioning of ovary and fallopian tube into the pelvis. Discussion Ovary in inguinal hernia is rare in women of reproductive age group. MRKH syndrome, a mullerian duct anomaly, is the congenital aplasia of uterus and upper two-thirds of vagina in a female with normal ovaries, fallopian tube, secondary sexual characteristics and 46XX karyotype. MURCS is a subtype of MRKH type 2 having mullerian duct agenesis with renal, cardiac, muscular & vertebral defects. General physical examination and primary investigations if yields abnormal findings; the patient must undergo an array of investigations to rule out MRKH/MURCS, or other congenital abnormality. Early diagnosis is essential to prevent its incarceration or torsion. The primary treatment of ovary in inguinal hernia is repositioning the ovary and fallopian tube back to pelvis to preserve fertility and repair of inguinal hernia. A multidisciplinary team is required to deal with various abnormalities present in a patient with MURCS.

Aromatase deficiency in an Ontario Old Order Mennonite family

Objectives Aromatase deficiency is a rare autosomal recessive disease that results in the absence of aromatase. In females it presents with ambiguous genitalia and lack of secondary sexual characteristics during puberty. Aromatase deficiency is not attributed to any specific population, but it is more commonly seen in consanguineous parents. Herein, we report the first Old Order Mennonite family with that diagnosis. Case presentation Our proband is an Old Order Mennonite female born with ambiguous genitalia who was identified to carry novel homozygous variant in the CYP19A1 gene c.1304G>A (p. Arg435His). Her older brother was later confirmed with the same genetic diagnosis. Conclusions Recognizing the cultural sensitivity, unrecognized affected cases, and late presentation of males affected with aromatase deficiency, this condition may be more prevalent than believed in that population.

Amenorrhea

Amenorrhoea is defined as absence of menstruation in women of reproductive age. Primary amenorrhoea is a failure to start menstruation by the age of 13 years without secondary sexual characteristics or by the age of 15 years with normal secondary sexual characteristics. Secondary amenorrhoea is the absence of menstruation for 6 months in a woman with normal prior menstruation. Secondary amenorrhea is more common type, with a prevalence of between 3 and 4%. This compares with a prevalence of 0.3% for those with primary amenorrhea.