Intestinal delta-6-desaturase activity determines host range for Toxoplasma sexual reproduction.

Many eukaryotic microbes have complex life cycles that include both sexual and asexual phases with strict species specificity. Whereas the asexual cycle of the protistan parasite Toxoplasma gondii can occur in any warm-blooded mammal, the sexual cycle is restricted to the feline intestine. The molecular determinants that identify cats as the definitive host for T. gondii are unknown. Here, we defined the mechanism of species specificity for T. gondii sexual development and break the species barrier to allow the sexual cycle to occur in mice. We determined that T. gondii sexual development occurs when cultured feline intestinal epithelial cells are supplemented with linoleic acid. Felines are the only mammals that lack delta-6-desaturase activity in their intestines, which is required for linoleic acid metabolism, resulting in systemic excess of linoleic acid. We found that inhibition of murine delta-6-desaturase and supplementation of their diet with linoleic acid allowed T. gondii sexual development in mice. This mechanism of species specificity is the first defined for a parasite sexual cycle. This work highlights how host diet and metabolism shape coevolution with microbes. The key to unlocking the species boundaries for other eukaryotic microbes may also rely on the lipid composition of their environments as we see increasing evidence for the importance of host lipid metabolism during parasitic lifecycles. Pregnant women are advised against handling cat litter, as maternal infection with T. gondii can be transmitted to the fetus with potentially lethal outcomes. Knowing the molecular components that create a conducive environment for T. gondii sexual reproduction will allow for development of therapeutics that prevent shedding of T. gondii parasites. Finally, given the current reliance on companion animals to study T. gondii sexual development, this work will allow the T. gondii field to use of alternative models in future studies.

Similarity in transgender and cisgender children's gender development.

Gender is one of the central categories organizing children's social world. Clear patterns of gender development have been well-documented among cisgender children (i.e., children who identify as a gender that is typically associated with their sex assigned at birth). We present a comprehensive study of gender development (e.g., gender identity and gender expression) in a cohort of 3- to 12-y-old transgender children (n = 317) who, in early childhood, are identifying and living as a gender different from their assigned sex. Four primary findings emerged. First, transgender children strongly identify as members of their current gender group and show gender-typed preferences and behaviors that are strongly associated with their current gender, not the gender typically associated with their sex assigned at birth. Second, transgender children's gender identity (i.e., the gender they feel they are) and gender-typed preferences generally did not differ from 2 comparison groups: cisgender siblings (n = 189) and cisgender controls (n = 316). Third, transgender and cisgender children's patterns of gender development showed coherence across measures. Finally, we observed minimal or no differences in gender identity or preferences as a function of how long transgender children had lived as their current gender. Our findings suggest that early sex assignment and parental rearing based on that sex assignment do not always define how a child identifies or expresses gender later.

Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development.

Disorders/differences of sex development (DSD) comprise a group of congenital disorders that affect the genitourinary tract and usually involve the endocrine and reproductive system. The aim of this work was to identify genetic variants responsible for disorders of human urogenital development in a cohort of Egyptian patients. This three-year study included 225 patients with various DSD forms, referred to the genetic DSD and endocrinology clinic, National Research Centre, Egypt. The patients underwent thorough clinical examination, hormonal and imaging studies, detailed cytogenetic and fluorescence in situ hybridization analysis, and molecular sequencing of genes known to commonly cause DSD including AR, SRD5A2, 17BHSD3, NR5A1, SRY, and WT1. Whole exome sequencing (WES) was carried out for 18 selected patients. The study revealed a high rate of sex chromosomal DSD (33%) with a wide array of cytogenetic abnormalities. Sanger sequencing identified pathogenic variants in 33.7% of 46,XY patients, while the detection rate of WES reached 66.7%. Our patients showed a different mutational profile compared with that reported in other populations with a predominance of heritable DSD causes. WES identified rare and novel pathogenic variants in NR5A1, WT1, HHAT, CYP19A1, AMH, AMHR2, and FANCA and in the X-linked genes ARX and KDM6A. In addition, digenic inheritance was observed in two of our patients and was suggested to be a cause of the phenotypic variability observed in DSD.

Adolescent Sexual Development and Peer Groups: Reciprocal Associations and Shared Genetic and Environmental Influences.

Peer groups influence the emergence of sexual behaviors in adolescence, but many details regarding the mechanisms underlying these effects have yet to be described. We examined the phenotypic, genetic, and environmental links between both antisocial and prosocial peer characteristics, and several sexual behaviors from middle childhood to late adolescence (ages 11, 14, and 17 years) using a longitudinal twin sample (N = 3762). Antisocial peers predicted greater engagement in both normative (e.g., dating) and non-normative (e.g., early sexual intercourse) sexual behaviors, while prosocial peers were associated with a lower likelihood of engaging in non-normative sexual behaviors. Reciprocal effects were also observed such that early sexual experiences were associated with a more antisocial and less prosocial peer groups later in adolescence. Behavioral genetic models indicated that most of the overlap between peer group characteristics and sexual behavior was due to shared environmental influences. That is, some features of the adolescent environment exert a press toward (or against) antisocial peers and sexual behaviors. Together, the results extend the existing literature by highlighting the ways through which peer affiliations are related to sexual development in adolescence.

Systematic Review: Puberty suppression with GnRH analogues in adolescents with gender incongruity.

CONTEXT: Gender incongruence is defined as disharmony between assigned gender and gender identity. Several interventions are liable in this case including genital affirming surgery among other surgical interventions such as harmonization, and also the use of gonadotropin-releasing hormone agonists (GnRHa) for gonadal shielding. This aids in preventing the development of secondary sexual characteristics related to the genetic sex. OBJECTIVE: Systematically review the treatment of gender incongruity with GnRHa analogues. DATA SOURCES: The data source of this research is from Pubmed-Medline and Embase. STUDY SELECTION: Articles published between 2009 and 2019 which studied transgender adolescents treated with GnRHa were carefully selected. DATA EXTRACTION: Were extracted: design, sample size, study context, targeted subjects of intervention, outcome measures, and results. RESULTS: Eleven studies were included. The use of GnRHa seems to be well tolerated by the studied population. When started in pubertal transition, it was associated with a more distinct resemblance to body shape than to the affirmed sex. In addition to preventing the irreversible phenotypic changes that occur in cross-hormonal therapy, the use of GnRHa can equally contribute to the mental health of these adolescents. LIMITATION: There are few consistent studies on the use of GnRHa for gender incongruence. CONCLUSION: As the population of transgender children and adolescents grows, they acquire knowledge and greater access to the various forms and stages of treatment for sex reassignment. The medical community needs to be adequately prepared to better serve this population and offer the safest resources available.

At the Intersection of Microbiota and Circadian Clock: Are Sexual Dimorphism and Growth Hormones the Missing Link to Pathology?: Circadian Clock and Microbiota: Potential Egffect on Growth Hormone and Sexual Development.

Reciprocal interactions between the host circadian clock and the microbiota are evidenced by recent literature. Interestingly, dysregulation of either the circadian clock or microbiota is associated with common human pathologies such as obesity, type 2 diabetes, or neurological disorders. However, it is unclear to what extent a perturbation of pathways regulated by both the circadian clock and microbiota is involved in the development of these disorders. It is speculated that these perturbations are associated with impaired growth hormone (GH) secretion and sexual development. The GH axis is a broadly neglected pathway and could be the main converging point for the interaction of both circadian clock and microbiota. Here, the links between the circadian clock and microbiota are reviewed. Finally, the effects of chronodisruption and dysbiosis on physiology and pathology are discussed and it is speculated whether a common deregulation of the GH pathway could mediates those effects.

Multiplexed CRISPR/Cas9-mediated knockout of 19 Fanconi anemia pathway genes in zebrafish revealed their roles in growth, sexual development and fertility.

Fanconi Anemia (FA) is a genomic instability syndrome resulting in aplastic anemia, developmental abnormalities, and predisposition to hematological and other solid organ malignancies. Mutations in genes that encode proteins of the FA pathway fail to orchestrate the repair of DNA damage caused by DNA interstrand crosslinks. Zebrafish harbor homologs for nearly all known FA genes. We used multiplexed CRISPR/Cas9-mediated mutagenesis to generate loss-of-function mutants for 17 FA genes: fanca, fancb, fancc, fancd1/brca2, fancd2, fance, fancf, fancg, fanci, fancj/brip1, fancl, fancm, fancn/palb2, fanco/rad51c, fancp/slx4, fancq/ercc4, fanct/ube2t, and two genes encoding FA-associated proteins: faap100 and faap24. We selected two indel mutations predicted to cause premature truncations for all but two of the genes, and a total of 36 mutant lines were generated for 19 genes. Generating two independent mutant lines for each gene was important to validate their phenotypic consequences. RT-PCR from homozygous mutant fish confirmed the presence of transcripts with indels in all genes. Interestingly, 4 of the indel mutations led to aberrant splicing, which may produce a different protein than predicted from the genomic sequence. Analysis of RNA is thus critical in proper evaluation of the consequences of the mutations introduced in zebrafish genome. We used fluorescent reporter assay, and western blots to confirm loss-of-function for several mutants. Additionally, we developed a DEB treatment assay by evaluating morphological changes in embryos and confirmed that homozygous mutants from all the FA genes that could be tested (11/17), displayed hypersensitivity and thus were indeed null alleles. Our multiplexing strategy helped us to evaluate 11 multiple gene knockout combinations without additional breeding. Homozygous zebrafish for all 19 single and 11 multi-gene knockouts were adult viable, indicating FA genes in zebrafish are generally not essential for early development. None of the mutant fish displayed gross developmental abnormalities except for fancp-/- fish, which were significantly smaller in length than their wildtype clutch mates. Complete female-to-male sex reversal was observed in knockouts for 12/17 FA genes, while partial sex reversal was seen for the other five gene knockouts. All adult females were fertile, and among the adult males, all were fertile except for the fancd1 mutants and one of the fancj mutants. We report here generation and characterization of zebrafish knockout mutants for 17 FA disease-causing genes, providing an integral resource for understanding the pathophysiology associated with the disrupted FA pathway.

Physical interactions facilitate sex change in the protogynous orange-spotted grouper, Epinephelus coioides.

Sex change in teleost fishes is commonly regulated by social factors. In species that exhibit protogynous sex change, such as the orange-spotted grouper Epinephelus coioides, when the dominant males are removed from the social group, the most dominant female initiates sex change. The aim of this study was to determine the regulatory mechanisms of socially controlled sex change in E. coioides. We investigated the seasonal variation in social behaviours and sex change throughout the reproductive cycle of E. coioides, and defined the behaviour pattern of this fish during the establishment of a dominance hierarchy. The social behaviours and sex change in this fish were affected by season, and only occurred during the prebreeding season and breeding season. Therefore, a series of sensory isolation experiments was conducted during the breeding season to determine the role of physical, visual and olfactory cues in mediating socially controlled sex change. The results demonstrated that physical interactions between individuals in the social groups were crucial for the initiation and completion of sex change, whereas visual and olfactory cues alone were insufficient in stimulating sex change in dominant females. In addition, we propose that the steroid hormones 11-ketotestosterone and cortisol are involved in regulating the initiation of socially controlled sex change.

People with Differences of Sexual Development: Can We Do Better?

This article discusses how careproviders of all types can help people with differences of sexual development (DSD): people with ambiguous genitalia, who used to be referred to as intersexed. Careproviders may be in a unique position to benefit these people by offering to discuss difficult issues that concern them, even when the discussions are brief. Specific interventions include learning about people with DSD, whether through the literature or in the clinic; treating them with optimal respect; raising difficult topics such as sex, fertility, and social stigma; encouraging them and helping them to meet others with DSD; and sharing the strengths that we can see that they have. We have come far, but have a long way to go.

Plasmodium sexual differentiation: how to make a female.

Sexual development is integral to the transmission of Plasmodium parasites between vertebrates and mosquitos. Recent years have seen great advances in understanding the gene expression that underlies commitment of asexual parasites to differentiate into sexual gametocyte stages, then how they mature and form gametes once inside a mosquito. Less well understood is how parasites differentially control development to become males or females. Plasmodium parasites are haploid at the time of sexual differentiation, but a clonal haploid line can produce both male and female gametocytes, so they presumably lack the sex-determining alleles present in some other eukaryotes. Though the molecular switch to initiate male or female development remains hidden, recent studies reveal regulatory proteins needed for the sex-specific maturation of male and female gametocytes. Yuda and collaborators report the characterization of a transcription factor necessary for female gametocyte maturation. With renewed attention on malaria elimination, sex has been an increasing focus because transmission-blocking strategies are likely to be an important component of elimination efforts.

Urogenital Abnormalities in Adenosine Deaminase Deficiency.

BACKGROUND: Improved survival in ADA-SCID patients is revealing new aspects of the systemic disorder. Although increasing numbers of reports describe the systemic manifestations of adenosine deaminase deficiency, currently there are no studies in the literature evaluating genital development and pubertal progress in these patients. METHODS: We collected retrospective data on urogenital system and pubertal development of 86 ADA-SCID patients followed in the period 2000-2017 at the Great Ormond Street Hospital (UK) and 5 centers in Italy. In particular, we recorded clinical history and visits, and routine blood tests and ultrasound scans were performed as part of patients' follow-up. RESULTS AND DISCUSSION: We found a higher frequency of congenital and acquired undescended testes compared with healthy children (congenital, 22% in our sample, 0.5-4% described in healthy children; acquired, 16% in our sample, 1-3% in healthy children), mostly requiring orchidopexy. No urogenital abnormalities were noted in females. Spontaneous pubertal development occurred in the majority of female and male patients with a few cases of precocious or delayed puberty; no patient presented high FSH values. Neither ADA-SCID nor treatment performed (PEG-ADA, BMT, or GT) affected pubertal development or gonadic function. CONCLUSION: In summary, this report describes a high prevalence of cryptorchidism in a cohort of male ADA-SCID patients which could represent an additional systemic manifestation of ADA-SCID. Considering the impact urogenital and pubertal abnormalities can have on patients' quality of life, we feel it is essential to include urogenital evaluation in ADA-SCID patients to detect any abnormalities, initiate early treatment, and prevent long-term complications.

Prepubertal Vulvovaginitis.

Vulvovaginitis is a common gynecologic complaint in prepubertal girls. It typically presents with complaints of vulvovaginal itching, burning, irritation, discharge, or skin changes. Prepubertal females have anatomic, physiological, and behavioral factors that most often contribute to the development of symptoms. Careful attention to history and associated complaints will direct evaluation, diagnosis, and treatment. Most cases are nonspecific in origin and treatment includes counseling to patients and parents on hygiene and voiding techniques. Antibiotic treatment for specific pathogens may be indicated. Other less common causes include foreign bodies and lichen sclerosus.

Molecular Aspects of Sex Development in Mammals: New Insight for Practice.

Disorders (or differences) of sex development (DSD) are congenital conditions characterized by atypical development of genetic, gonadal or phenotypic sex [...].

Disrupting assembly of the inner membrane complex blocks Plasmodium falciparum sexual stage development.

Transmission of malaria parasites relies on the formation of a specialized blood form called the gametocyte. Gametocytes of the human pathogen, Plasmodium falciparum, adopt a crescent shape. Their dramatic morphogenesis is driven by the assembly of a network of microtubules and an underpinning inner membrane complex (IMC). Using super-resolution optical and electron microscopies we define the ultrastructure of the IMC at different stages of gametocyte development. We characterize two new proteins of the gametocyte IMC, called PhIL1 and PIP1. Genetic disruption of PhIL1 or PIP1 ablates elongation and prevents formation of transmission-ready mature gametocytes. The maturation defect is accompanied by failure to form an enveloping IMC and a marked swelling of the digestive vacuole, suggesting PhIL1 and PIP1 are required for correct membrane trafficking. Using immunoprecipitation and mass spectrometry we reveal that PhIL1 interacts with known and new components of the gametocyte IMC.

Voice dissatisfaction in individuals with a disorder of sex development.

OBJECTIVE: Changes of sex hormone levels in disorders of sex development (DSD) can affect the body, including the vocal folds, during and after foetal development. The voice is a gender characteristic that may also be affected. There is a lack of knowledge on voice alteration in DSD. To explore this in different forms of DSD, we describe the prevalence of voice alterations and investigate patient satisfaction with voice. DESIGN: The study is part of dsd-LIFE, a multicentre cross-sectional clinical evaluation project assessing the long-term outcomes of surgical, hormonal and psychological interventions in individuals with DSD. PATIENTS: The study included 1040 individuals with different forms of DSD, that is Turner and Klinefelter syndromes, different degrees of gonadal dysgenesis and 46 XY DSD. Participants were recruited through patient advocacy groups and health care. MEASUREMENTS: Satisfaction with voice, Adam's apple, if patient's self-identified gender was mistaken on the phone leading to distress. RESULTS: A vast majority of the participants with DSD (between 58.3% to 82% in various groups) were not satisfied with their voice, and approximately 15% (n = 147) were mistaken on the phone in accordance with self-identified gender. For 102 participants, this caused distress. CONCLUSIONS: We have identified that voice problems are a cause of distress in all forms of DSD. This result needs to be confirmed and compared with controls. We recommend that evaluation of the voice should be included in future international guidelines for management of DSD.

Predicting Early-Childhood Gender Transitions.

Increasing numbers of gender-nonconforming children are socially transitioning-changing pronouns to live as their identified genders. We studied a cohort of gender-nonconforming children ( n = 85) and contacted them again approximately 2 years later. When recontacted, 36 of the children had socially transitioned. We found that stronger cross-sex identification and preferences expressed by gender-nonconforming children at initial testing predicted whether they later socially transitioned. We then compared the gender-nonconforming children with groups of transitioned transgender children ( n = 84) and gender-conforming controls ( n = 85). Children from our longitudinal cohort who would later transition were highly similar to transgender children (children who had already socially transitioned) and to control children of the gender to which they would eventually transition. Gender-nonconforming children who would not go on to transition were different from these groups. These results suggest that (a) social transitions may be predictable from gender identification and preferences and (b) gender identification and preferences may not meaningfully differ before and after social transitions.

Ovarian hormones, age and pubertal development and their association with days of headache onset in girls with migraine: An observational cohort study.

Background Fifty-three percent of adolescent girls report headaches at the onset of menses, suggesting fluctuations of ovarian hormones trigger migraine during puberty. Aims To determine if urinary metabolites of estrogen and progesterone are associated with days of headache onset (HO) or severity in girls with migraine. Methods This was a pilot study and included 34 girls with migraine balanced across three age strata (pre-pubertal (8-11), pubertal (12-15), and post-pubertal (16-17) years of age). They collected daily urine samples and recorded the occurrence and severity of headache in a daily diary. Urine samples were assayed for estrone glucuronide (E1G) and pregnandiol glucuronide (PdG) and the daily change was calculated (ΔE1G, ΔPdG). Pubertal development was assessed by age, pubertal development score (PDS), and menstrual cycle variance. The primary outcome measures were HO days and headache severity. Generalized linear mixed models were used, and included the hormonal variables and three different representations of pubertal development as covariates. Results Models of HO days demonstrate a significant age*PdG interaction (OR 0.85 [95% CI 0.75, 0.97]) for a 1 standard deviation increase in PdG and three-year increase in age. A separate model showed a significant PDS*PdG interaction (OR -0.85 [95% CI; 0.76, 0.95]). ΔPDG was associated with headache severity in unadjusted models ( p < 0.017). Conclusion Age and pubertal development could moderate the effect of ovarian hormones on days of headache onset in girls with migraine.

Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study.

BACKGROUND: Information on the psychosexual outcome of individuals with disorders of sex development (DSDs) and intersex conditions is of great importance for sex assignment at birth of newborns with DSD. AIM: To assess gender change and gender dysphoria in a large sample of individuals with different DSDs. METHODS: A cross-sectional study was conducted in 14 European centers with 1,040 participants (717 female-identifying and 311 male-identifying persons and 12 persons identifying with another gender) with different forms of DSD. The cohort (mean age = 32.36 years, SD = 13.57) was divided into 6 major subgroups: women with 45,X DSD and variants (Turner syndrome; n = 325), men with 47,XXY DSD and variants (Klinefelter syndrome; n = 219), women with XY DSD without androgen effects (n = 107) and with androgen effects (n = 63), men with XY DSD (n = 87), and women with 46,XX congenital adrenal hyperplasia (n = 221). Data on psychosexual outcome were gathered by medical interviews and questionnaires. OUTCOMES: Gender change and gender dysphoria. RESULTS: Although gender changes were reported by 5% of participants, only in 1% (3% if those with Klinefelter and Turner syndromes-conditions in which gender issues are not prominent-are excluded) did the gender change take place after puberty and was likely initiated by the patient. 39 participants (4%) reported gender variance: between male and female, a gender other than male or female, or gender queer, alternating gender roles, or a gender expression that differed from the reported gender. This group had lower self-esteem and more anxiety and depression than the other participants. CLINICAL IMPLICATIONS: Clinicians should be aware of and sensitive to the possibility that their patients with DSD not only might have transgender feelings and a desire to change gender, but also identify as different from male or female. The complexity of their feelings might require counseling for some patients. STRENGTHS AND LIMITATIONS: The study is unique in the large number of participants from many different clinics, with sizable numbers in most subgroups, and in the large number of aspects that were measured. However, the very broadness of the study made it impossible to focus in detail on gender issues. Also, there is a need for instruments specifically measuring gender dysphoria in individuals with DSD that take non-binary genders into account. CONCLUSION: To make appropriate gender care possible for people with DSD, the gender-normative and gender-variant development of children with DSD should be studied in longitudinal studies. Kreukels BPC, Köhler B, Nordenström A, et al. Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study. J Sex Med 2018;15:777-785.

Mental Health and Disorders of Sex Development/Intersex Conditions in Iranian Culture: Congenital Adrenal Hyperplasia, 5-α Reductase Deficiency-Type 2, and Complete Androgen Insensitivity Syndrome.

Sixty-one patients (22 patients with congenital adrenal hyperplasia [CAH] with a mean age of 14.86 years [range, 5-23], 20 patients with 5-α reductase deficiency type 2 [5α-RD-2] with a mean age of 19.5 years [range, 5-29], and 19 patients with complete androgen insensitivity syndrome [CAIS] with a mean age of 18.26 years [range, 5-28]) were evaluated using the Kiddie Schedule for Affective Disorders and Schizophrenia, the Structured Clinical Interview for DSM-IV Axis I, Axis II, and the Global Assessment Functioning Scale. All participants were female-assigned at birth. Ten patients (16.4%) transitioned to the male gender. Overall, 68% of patients had one or more lifetime Axis I disorders, including 63.6% of the CAH participants, 90% of 5α-RD-2 participants, and 52.6% of the CAIS participants. The most commonly observed were affective disorders (27.9%), gender identity disorder (27.9%), and anxiety (16.4%). Our study demonstrates that mental health of Iranian patients with DSD is at risk. This might be due to the fact that patients with DSD conditions are mostly treated medically and their mental health is often superficially addressed in developing countries such as Iran, at least in the past. We argue that it is important to pay attention to the mental health issues of patients with DSD and focus on specific issues, which may vary cross-culturally.

From Genes to Behavior Through Sex Hormones and Socialization: The Example of Gender Development.

Irving Gottesman is known primarily for his work in psychopathology, but he also had a long-standing interest in understanding psychological development generally (typical and atypical). Through his mentorship, he also influenced work in gender development. Characteristics related to sex and gender are ideally suited to study the interplay of genes and environment across development. We discuss how gender development is influenced by gonadal hormones present during early life, but not in a simple way. We describe some of the challenges and opportunities to extend our understanding of the complexity of gender development. Throughout, we consider the kinds of questions Gottesman would likely have asked and emphasize his influence on our work.