‘A woman and now a man’: The legitimation of sex-assignment surgery in the United States (1849–1886)

Throughout much of recorded history, societies that assigned rights and duties based on sex were confounded by people with unclear sex. For the sake of maintaining social and legal order in those contexts, legal systems assigned these people to what they figured was the ‘most dominant’ sex. Then, in mid-19th century United States, a new classification mechanism emerged: sex-assignment surgery, which was imagined by some surgeons to ‘fix’ one’s physical and legal sex status permanently. Other surgeons, however, fiercely opposed the new practice. This article traces the controversy around sex-assignment surgery through three high-profile cases published in US medical journals from 1849 to 1886. Its central argument is that the more general effort to transform surgery into a scientific field helped legitimate the practice of sex-assignment surgery. Although such surgery was subject to intense moral criticism because it was thought to breach the laws of men and nature, over time, these concerns were abandoned or transformed into technical or professional disagreements. In a secondary argument, which helps explain that transformation, this article shows that surgeons gradually became comfortable occupying the epistemic role of sex-classifiers and even sex-makers. That is, whereas sex classification was traditionally a legal task, the new ability to surgically construct one’s genitals engendered the notion that sex could be determined and fixed in the clinic in a legally binding manner. Accordingly, I suggest that surgery became an epistemic act of fact-making. This evolution of the consensus around sex-assignment surgery also provides an early origin story for the idea of sex as plastic and malleable by surgeons, thus offering another aspect to the history of plastic sex.

Effect of the spatial–temporal specific theca cell Cyp17 overexpression on the reproductive phenotype of the novel TC17 mouse

Background In the ovarian follicle, the Theca Cells (TCs) have two main functions: preserving morphological integrity and, importantly, secreting steroid androgen hormones. TCs express the essential enzyme 17α-hydroxylase/17,20-desmolase (CYP17), which permits the conversion of pregnenolone and progesterone into androgens. Dysregulation of CYP17 enzyme activity due to an intrinsic ovarian defect is hypothesized to be a cause of hyperandrogenism in women. Androgen excess is observed in women with polycystic ovary syndrome (PCOS) resulting from excess endogenous androgen production, and in transgender males undergoing exogenous testosterone therapy after female sex assignment at birth. However, the molecular and morphological effects of Cyp17 overexpression and androgen excess on folliculogenesis is unknown. Methods In this work, seeking a comprehensive profiling of the local outcomes of the androgen excess in the ovary, we generated a transgenic mouse model (TC17) with doxycycline (Dox)-induced Cyp17 overexpression in a local and temporal manner. TC17 mice were obtained by a combination of the Tet-dependent expression system and the Cre/LoxP gene control system. Results Ovaries of Dox-treated TC17 mice overexpressed Cyp17 specifically in TCs, inducing high testosterone levels. Surprisingly, TC17 ovarian morphology resembled the human ovarian features of testosterone-treated transgender men (partially impaired folliculogenesis, hypertrophic or luteinized stromal cells, atretic follicles, and collapsed clusters). We additionally assessed TC17 fertility denoting a perturbation of the normal reproductive functions (e.g., low pregnancy rate and numbers of pups per litter). Finally, RNAseq analysis permitted us to identify dysregulated genes (Lhcgr, Fshr, Runx1) and pathways (Extra Cellular Matrix and Steroid Synthesis). Conclusions Our novel mouse model is a versatile tool to provide innovative insights into study the effects of Cyp17 overexpression and hyperandrogenism in the ovary.

Pubertal development in 46,XY patients with NR5A1 mutations

Purpose Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age. Methods We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition. Results Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty. Conclusion Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.

A Nationwide Study of the Prevalence and Initial Management of Atypical Genitalia in the Newborn in Scotland

Provision of optimum healthcare for infants with atypical genitalia requires a clear understanding of the occurrence of this condition. The objective of this study was to determine the prevalence of atypical genitalia and its initial management. A prospective, electronic survey of clinicians within managed clinical networks in Scotland was undertaken between 2013 and 2019. Notification from clinicians was sought for term neonates requiring specialist input for atypical genitalia. Additional information was also sought from the 4 regional genetics laboratories that provided details for neonates who had an urgent karyotype performed for atypical genitalia or sex determination. In total, the study identified 171 term infants who required some investigation for atypical genitalia in the neonatal period, providing a birth prevalence of 1:1,881 term births. Of the 171 infants, 97 (57%) had specialist input over the first 3 months of life, providing a birth prevalence of 1:3,318 term births that received specialist input for atypical genitalia. A total of 92 of these 97 cases had complete 3-month follow-up data, 62 (67%) presented within 24 h of birth, and age at presentation ranged from birth to 28 days. Age at sex assignment ranged from birth to 14 days, and in 63 cases (68%), sex assignment occurred at birth. Thus, the birth prevalence of a case of atypical genitalia where sex assignment was reported to be delayed beyond birth was estimated at 1:11,097 births. In 1 case sex was re-assigned at 3 months. Atypical genitalia requiring specialist input within the first month of life are rare in term newborns, and in only a third of these cases, sex assignment is delayed beyond birth. This study provides new clinical benchmarks for comparing and improving the delivery of care in centres that manage these conditions.

The Worldwide Landscape of Variants in the Androgen Receptor Gene Related to Androgen Insensitivity Syndrome: An Integrative Analysis

Androgen Insensitivity Syndrome (AIS) is an X-linked genetic disease and it is the most common cause of 46,XY DSD. It is divided into 3 phenotypes: complete (CAIS), partial (PAIS), and mild (MAIS). To analyse the landscape of AR variants in AIS we collected all AR variants reported among AIS in the literature (Pubmed, EMBASE, Medline) and websites (ensemble, HGMD, ClinVar). They were analyzed according to phenotype, exon location, domain, amino acid (aa) conservation, sex assignment, external genitalia virilization (EMS score), molecular and functional studies. Conservation analysis of the AR were performed using CONSURF plataform. To test our hypothesis that non-synonymous AR variants could also impact on splicing, we used both ESEfinder and Human Splicing Finder 3.1. We founded 901 individuals with AIS: CAIS = 565 (62.7%); PAIS = 282 (31.3%); and MAIS = 54 (6%). They had 465 different AR variants: CAIS = 290 (62.3%); PAIS = 135 (29.1%); and MAIS = 40 (8.6%). Among MAIS and PAIS, most variants were at LDB domain (22 out 40 = 55% and 84 out 135 = 62.2%, respectively) whereas they were at NTD domain among CAIS (129 out 290 = 44.5%). Most were missense (81%). However, small indels (11%), nonsense (3%), splicing sites (4%) and large deletions (1%) were all reported. Non-synonymous AR variants accounting for 60%, 96%, and 100% of CAIS, PAIS, and MAIS, respectively. Synonymous AR variants were rarely found (n=3). In 81% only the AR sequencing was performed. The remaining was detected by WES (18%) or WGS (1%). Deep intronic variant was detected in PAIS (n=1) while variants in the 5’UTR of the AR gene in both PAIS and CAIS (n=2). Most AR variants were located at conserved aa (78%), but AR variants at non-conserved aa were more frequently indels (p<.01). Functional studies were found in 38%, mostly showing reduced AR expression. Among PAIS, 48% (n=134) were assigned as male at birth. The median EMS was 5 (95% CI, 5-7) in those assigned as male while it was 3.2 (95% CI, 2-6) in those assigned as female (p<.01). The median of EMS score was lower in variants at NTD domain (2.8, 95% CI, 0-7). We identified 34 AR variants causing more than one AIS phenotype (mostly CAIS and PAIS) and 6 AR variants causing all of three AIS phenotypes. In silico analysis suggests potential to disrupt normal AR splicing in 18 (53%) by creating new acceptor or donor splicing sites (n=11) or exonic splicing signals (n=7). More severe AR variants are related to CAIS. Most AR variants were reported only based on AR sequencing. Therefore, the functional pathogenicity of these variants remains unclear. Further studies including WGS could help to expand the molecular diagnosis of AIS. There is phenotype variability in AIS. So, sex assignment of patients with PAIS cannot be based on a specific identified AR gene mutation. There is potential to alter splicing among non-synonymous AR variants, which could be an explanation for phenotype variability in AIS.

Effects of Pre and Post-Natal Androgen Exposure on Psychosexual Aspects and Gender Change in Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Introduction: Congenital Adrenal Hyperplasia (CAH) is defined as a group of autosomal recessive disorders characterized by a deficiency of the enzyme required to synthesize cortisol by the adrenal cortex. Defects in the 21-hydroxylase enzyme make up 90% of CAH. These defects impaired cortisol synthesis leading to an ACTH increase resulting in androgen excess in both salt-wasting (SW) or simple virilizing (SV) forms. As androgens play a role in the human psychosexual development favoring male psychosexuality, this study was designed to evaluate the impact of androgen exposure on the psychosexuality of individuals with CAH due 21-hydroxylase deficiency. Methods: This retrospective cohort includes 46,XX individuals (115 female-assigned; 8 male-assigned) with a molecular diagnosis of CAH due to CYP21A2 pathogenic variants in homozygous or compounds heterozygous state. External genitalia virilization was scored using Prader scale. Phenotype, time at diagnosis, sex assignment, and gender change were assessed. The gender role at childhood was assessed through the playmates and toys profile at childhood. Gender identity was assessed by a projective psychological test (HTP). Sexual orientation was assessed by self-report sexual identity. Compliance of glucocorticoid replacement was assessed by adequate testosterone and androstenedione serum levels for age. Results: CAH was diagnosed at the neonatal time in 73% (n=78). Fifth-nine (51%) had the SW form and 49% (n=56) had the SV form. While all cases of SW were diagnosed at the neonatal time (0.12 ± 0.14 months), the mean age at diagnosis among SV was 6.03 ± 8.45 years (p=<.001). The median of Prader score was 3 in both forms. Male sex assignment was associated with more virilized external genitalia (p=.002). Gender change occurred in 6 cases (female to male), all with SV form. The prader score was higher among those who changed gender (p=.01). All of those who changed their gender had poor treatment compliance. A total of 13% (n=15) of all groups defined themselves as homosexual. There was a strong association between male toys and preference for male playmates in childhood with homosexuality and male gender identity in adulthood with both gender change from female to male and homosexuality. Conclusion: Prenatal androgen exposure favors male psychosexuality in 46,XX CAH individuals as observed by the association between highest Prader scores and all assessed psychosexual outcomes. This influence is also substantiated by post-natal androgen exposure as observed by compliance issues and late diagnosis among those who changed from female to male gender.

Paternalism in DSD Management: A Real and Present Threat

In 1965, a botched circumcision left Bruce Reimer, a healthy, 8-month old XY male, with a disfigured penis. At the recommendation of Dr. John Money and physicians at Johns Hopkins, the infant was reassigned to female sex and underwent an orchiectomy and vaginoplasty. The family renamed the child “Brenda.” Unaware of her history, Brenda struggled with significant gender identity, psychological, and behavioral issues throughout her childhood and adolescence. When made aware of this history, she transitioned to male gender and assumed the name “David.” After years of psychological distress, David Reimer committed suicide in 2004. Despite the myriad lessons gleaned from this tragic story, medical and surgical management of children with atypical genitalia still remains often misguided, as providers continue to assume paternalistic roles in determining sex assignment and surgical interventions. A fifteen year old XY male with Robinow Syndrome presented for evaluation of hypogonadism and urinary incontinence. At birth, the patient was discovered to have a micropenis and perineal hypospadias and was diagnosed with hypogonadotropic hypogonadism. At the recommendation of the medical team, the infant underwent bilateral orchiectomy at eight months of age followed by urethroplasty and vaginoplasty at six years of age. The child was then given a female sex assignment. At twelve years of age, the child felt discordant from the sex of rearing and wished to be identified as male—his natal, genetic sex. He transitioned to male gender and began testosterone injections. He had history of recurrent UTIs and severe incontinence requiring diaper use. He strongly desired neophallus and urethral reconstruction for improved quality of life. The patient endorsed prior depression and desires to self-harm. He had significant concerns regarding his gender presentation and transition. He shared his difficulties in continuing in the same school system with peers who knew him as a female prior to transition and was concerned about peers knowing his medical history. In the years since the famous David Reimer case, the medical system has made tremendous strides in recognizing the need for patient autonomy and shared decision-making in patients with Differences of Sex Development and genital atypia. However, the paternalistic history of this field continues to leave its indelible mark more than 20 years since David Reimer’s case made headlines, as physicians continue to recommend definitive sex assignments and surgical interventions. As with the David Reimer case, the bodily integrity of this XY infant was altered in a permanent fashion with inadequate education of his family and little to no credence given to the autonomy of the child himself. We, as physicians, cannot continue to paternalistically apply John Money’s concept of gender neutrality and rigidly mandate sex assignments and early surgical interventions.

Disorders/Differences of Sex Development Presenting in the Newborn With 46,XY Karyotype

Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions, resulting in discordance between an individual's sex chromosomes, gonads, and/or anatomic sex. The management of a newborn with suspected 46,XY DSD remains challenging. Newborns with 46,XY DSD may present with several phenotypes ranging from babies with atypical genitalia or girls with inguinal herniae to boys with micropenis and cryptorchidism. A mismatch between prenatal karyotype and female phenotype is an increasing reason for presentation. Gender assignment should be avoided prior to expert evaluation and possibly until molecular diagnosis. The classic diagnostic approach is time and cost-consuming. Today, a different approach may be considered. The first line of investigations must exclude rare life-threatening diseases related to salt wasting crises. Then, the new genetic tests should be performed, yielding increased diagnostic performance. Focused imaging or endocrine studies should be performed on the basis of genetic results in order to reduce repeated and invasive investigations for a small baby. The challenge for health professionals will lie in integrating specific genetic information with better defined clinical and endocrine phenotypes and in terms of long-term evolution. Such advances will permit optimization of counseling of parents and sex assignment. In this regard, society has significantly changed its attitude to the acceptance and expansion beyond strict binary male and female sexes, at least in some countries or cultures. These management advances should result in better personalized care and better long-term quality of life of babies born with 46,XY DSD.

The challenges of androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic syndrome that occurs as result of an androgen receptor mutation; it affects the normal masculinization process in chromosomal male patients. More than 900 androgen receptor mutations that can lead to AIS have been identified. The complete androgen insensitivity is characterized by a total lack of response to androgens, usually in patients with 46XY karyotype but with feminine phenotype. Primary amenorrhoea and inguinal swellings in female patients are the main signs that could raise suspicion for this syndrome. Patients with partial androgen insensitivity have ambiguous genitalia at birth and gynecomastia during puberty, whereas those with mild androgen insensitivity present a normal male phenotype but altered spermatogenesis during adulthood and pubertal gynecomastia. The diagnosis of AIS often proves to be a challenge; its management is complex and requires a multidisciplinary approach to meet decision-making challenges in sex assignment, fertility and timing of gonadectomy, psychological outcomes and genetic counselling.