Previous
Proposed
Intersex
Disorders of sex development
Male pseudohermaphrodite
46, XY DSD
Undervirilization of an XY male
Undermasculinization of an XY male
Female psuedohermaphrodite
46, XX DSD
Overvirilization of an XX female
Masculinization of an XX female
True hermaphrodite
Ovotesticular DSD
XX male or XX sex reversal
46, XX testicular DSD
XY sex reversal
46, XY complete gonadal dysgenesis
However, despite almost universal acceptance by clinicians, some patient groups remain uneasy with the new DSD terminology [39]. Reasons given include the application of the term “disorder” where “variation” might have been preferable and the lack of distinction in some languages between the terms sexual development and sex development. Finally, sufferers of Congenital Adrenal Hyperplasia (CAH) may regard their condition as a primarily endocrine disease rather than a disorder of sex organs. It is important that clinicians working within DSD remain sensitive to these differences in opinion.
The DSDs are broadly classified by their genetic etiologies as sex chromosome DSD, 46, XY DSD, and 46, XX DSD. Further identification of the source of the problem (for example gonad structure/function, androgen synthesis, androgen excess, receptor status) will lead to a specific diagnosis.
46, XY DSD
The most common XY DSDs involve disorders of androgen action or synthesis. In Complete Androgen Insensitivity Syndrome (CAIS), for example, binding of testosterone and dihydrotestosterone (DHT) to the androgen receptor is impaired. The testes function normally, producing testosterone and anti-mullerian hormone (AMH) therefore preventing the formation of the internal müllerian system. However, androgen-dependant tissues are unresponsive to testosterone thus producing a female phenotype.
Defects in testosterone synthesis can be due to a number of enzyme deficiencies in the pathway of testosterone production. In 5α-reductase deficiency, the enzyme that converts testosterone to its more potent form, DHT, is defective. Since DHT is needed for masculinisation of the external genitalia, patients have undervirilised or phenotypically female external genitalia. In phenotypic females with 5α-reductase deficiency, virilisation may occur at puberty as testosterone production increases.
Other 46, XY DSDs include disorders of testicular development, including complete gonadal dysgenesis (Swyer syndrome), LH receptor defects and disorders of AMH (persistent müllerian duct syndrome). Isolated hypospadias and cryptorchidism are also considered forms of XY DSD.
46, XX DSD
46, XX DSDs result from defects in ovarian development or conditions leading to excess androgen exposure, of which CAH is the most common. In the female newborn, CAH is the leading cause of virilised genitalia. Inherited in an autosomal recessive manner, more than 95 % of cases are caused by a deficiency in 21-hydroxylase in the adrenal cortex. As a result, adrenal cortisol production is blocked, leading to a shunting of steroid precursors toward adrenal androgen production. In addition to virilisation, severe deficiencies can lead to critical electrolyte abnormalities and can be life threatening.
46, XX DSDs also include gonadal dysgenesis, androgen exposure due to placental aromatase and oxidoreductase deficiencies, as well as maternal virilising tumours. Abnormalities of the müllerian ducts, including vaginal atresia and cloacal anomalies, are also considered part of the spectrum of XX DSD.
Sex Chromosome DSD
Sex chromosome DSD include mosaic karyotypes including 45, X/46, XY mixed gonadal dysgenesis, Turner (45, X) and Klinefelter (47, XXY) Syndromes and their variants.
The Importance of the Multidisciplinary Team and Psychosocial Support
Patients with a DSD should be managed by a multidisciplinary team (MDT) with experience and expertise in the management of these complex disorders [19]. Although the exact composition of the team can vary from one centre to another, ideally the team would be composed of an endocrinologist, urologist/pediatric surgeon, gynaecologist, psychologist, ethicist, and geneticist. The collaboration of a variety of health professionals can facilitate timely assessment, ensure necessary and appropriate investigations are done, and abet decisions regarding sex assignment when necessary. It is increasingly clear that ongoing psychological care is essential to self-acceptance and social adjustment. Each case should be individualized and cooperation among specialists is crucial to ensure decisions are made in line with the best interests of each patient and family. In addition, parents should be intimately involved with the team immediately and their participation in decision-making should be encouraged.
The implementation of an MDT has been shown to be effective at improving medical and mental health services for patients with DSD. In the setting of structured multidisciplinary care, significantly more patients received appropriate indicated testing. Additionally, they benefited from more frequent mental health counseling, structured education, and peer support group participation [37].
Many European DSD centres have adopted an MDT approach to DSD care in accordance with the consensus recommendations. Encouragingly, nearly all centres surveyed (95 %) reported offering psychological support services. However, nearly half of European centres had not implemented a multidisciplinary approach to DSD care, highlighting that a need for improvement remains [35].
Presentation and General Management Considerations
Patients with a DSD may come to medical attention via two main clinical presentations. Some present with ambiguous genitalia at birth. In others, a diagnosis may come to attention around the time of puberty in the form of delayed pubertal development, primary amenorrhea, or virilisation at puberty. Gynaecologists managing DSD will therefore be involved in the care of adolescents with a known DSD transitioning to adult services as well as girls and women presenting for the first time with a new diagnosis of DSD.
Management of the Neonate
At birth, any atypical genital appearance should raise the possibility of an underlying DSD. Specifically, overt genital ambiguity, virilised female genitalia (clitoromegaly, labial fusion, inguinal or labial mass), and undervirilised male genitalia (bilateral cryptorchidism, unilateral cryptorchidism with incomplete scrotal fusion or hypospadias, and perineal hypospadias) require investigation. Such abnormalities, sufficient enough to warrant further investigation, are estimated to occur in 1/4,500 births [1].
A disorder of sex development at birth raises both medical and psychosocial issues that need to be immediately addressed. First and foremost, a life-threatening condition, namely salt-wasting CAH, must be excluded. Secondly, a specific diagnosis should be investigated and, whenever possible, be identified. Lastly, a viable sex of rearing needs to be determined. It is important however that the latter is done only after proper evaluation by an experienced multidisciplinary team.
Gender assignment recommendations are clear-cut in only a minority of patients. In all cases, it is imperative that decisions be made by a fully informed family along with the MDT. At the time of gender assignment, the primary goal is to avoid an assignment that is ultimately inconsistent with gender identity, leading to gender dysphoria and psychological morbidity. Multiple factors have been identified which may play a role in adult outcomes and can be used to guide gender assignment decisions. These include psychosocial factors (social/cultural circumstances), fetal CNS androgen exposure, anatomy of the external genitalia, options for functional surgical repair, anticipated quality of sexual function, and fertility potential. Outcome studies suggest that the best predictor of adult gender identity is, in fact, the initial gender assignment [16].
Once a sex of rearing has been determined, consideration is usually given to the need and desire for surgical reconstruction of gender concordant genitalia. As will be discussed, the indications, ideal timing, and methods for surgical management remain highly debated.
Management of the Adolescent
In the adolescent with either a known or newly diagnosed DSD, general considerations may include the need for gonadectomy, vaginal assessment and treatment for menstruation and future intercourse, and hormone replacement.
The Adolescent with a New Diagnosis
A significant proportion (10–20 %) of patients with a DSD present later in childhood or young adulthood. In these cases, ambiguity of the external genitalia is not present at birth. These patients most commonly seek gynaecologic care due to absent, delayed, or incomplete puberty, virilisation at puberty, or primary amenorrhea. An initial work up for delayed puberty including physical examination, FSH level and karyotype will provide clues to the diagnosis. More specific testing such as testosterone, androstenedione, DHT, AMH levels, HCG stimulation testing, specific gene sequencing, enzyme assays, and appropriate imaging can subsequently be performed. The majority of these patients will be diagnosed with CAIS, gonadal dysgenesis (XX or XY), or other XY DSD including testosterone biosynthesis defects.
The Adolescent with a Previous Diagnosis of DSD
At adolescence, patients diagnosed with a DSD in infancy will begin to transition to adult care. Adolescence can be a difficult time for all children, however this is particularly true in the setting of a DSD. Psychosocial support is of paramount importance during this transition period. The psychologist can address issues of gender identity, adjustment and transition through puberty, sexuality, sexual behavior and relationships.
In most cases, vaginal assessment will be required. Many patients will have had feminising surgery as infants and children. In those with a uterus, such as girls with CAH, examination should assess for patency for menstruation. Examination should also note whether there is sufficient vaginal caliber for future tampon use and vaginal intercourse. Given the high rates of vaginal stenosis in this setting, a thorough examination is important. In an adolescent, particularly in those with a history of multiple genital surgeries, examination can be difficult and is often performed under general anesthesia. Vaginal dilation and surgical vaginoplasty may be required depending on the examination findings.
Management Controversies in Disorders of Sex Development
Sex Steroid Replacement in DSD
Patients with DSD may require hormone replacement either due to gonadal failure or following gonadectomy. Hormonal supplementation is required to induce development of secondary sexual characteristics, acquire normal bone mineralization, and to initiate menses at the time of puberty. The gynaecologist should work along side an experienced endocrinologist to determine if and when hormonal replacement should be initiated. In general, puberty induction and maintenance is undertaken in three phases, simulating normal pubertal development. Estrogen replacement for the induction of breast development is most commonly followed by progestin and estrogen combination replacement for the establishment of normal menses if a uterus is present. Long-term maintenance of a normal estrogen state must be obtained for bone health. The selection of doses and method of cycling depends on individual needs. A progestin should be provided in girls with a uterus secondary to the established risk of endometrial hyperplasia with unopposed estrogen stimulation. However, there is no evidence that the addition of cyclic progestin is beneficial in those without a uterus.
Feminising Genitoplasty
Despite improving surgical techniques, controversy persists surrounding surgical care of patients with DSD. In patients assigned to a female sex of rearing, debate encompasses the type, timing, and indication for feminising genitoplasty. The controversy is fueled by a lack of long-term outcome studies in patients following genitoplasty. Most commonly, feminising genitoplasty is performed in virilised girls with CAH, but may also be performed in partially virilised patients with XY DSD assigned to a female sex of rearing (i.e. partial androgen insensitivity, mixed gonadal dygenesis). Feminising genitoplasty generally includes clitoroplasty, vaginoplasty, and labioplasty as needed.
Timing
Historically, sentiment surrounding feminising surgery in DSD patients was routed in the hypothesis of ‘psychosexual neutrality’ proposed by John Money in the 1950s. Inherent in this hypothesis, early reconstructive genital surgery was thought to be imperative to the acceptance of an assigned gender. The “optimal gender policy,” as it came to be known, encouraged early corrective surgery as this was thought to help the child, as well as their parents, to facilitate gender identity and appropriate gender role behavior [30, 31].
Supporters argue that early surgical management to create gender concordant genitalia will lead to better psychosocial outcomes and avoid ridicule from peers and social withdrawal in childhood. However, there have been no studies to evaluate this hypothesis. There are currently no studies to show that early surgical feminisation improves psychosocial outcomes or gender acceptance. A study of a group of adult CAH women found no correlation between age of clitoroplasty or vaginoplasty and development of female gender identity [5].
Resistance to the paradigm of early feminising genitoplasty has arisen from accruing evidence of poor cosmetic and functional outcomes in adult women following surgery in infancy or childhood. The Intersex Society of North America has published recommendations that center on the avoidance of genital surgery unless medically necessary without the patient’s informed consent, sighting the potential consequences of genital surgery [20]. Genitoplasty appears to be associated with impaired global sexual functioning including decreased arousal, sexual desire, lubrication, orgasm, as well as increased pain with intercourse. In addition, this population is less likely to be sexually active, and shows a lower frequency of intercourse when compared to the general population [12, 17, 18, 22].
Although these results may not be solely a result of surgical manipulation, recognizing the role of multifactorial psychological components in sexual satisfaction, there does appear to be sufficient data to suggest a detrimental effect of surgical genitoplasty on sexual function. DSD patients who have not undergone surgical intervention do not have the same discrepancies as those who have, with sexual function comparable to the general population [12].
Clitoroplasty
The clitoris is an organ with a sole function of providing sexual pleasure. The possibility of a disrupted sexual response due to reduced innervation of the clitoris after surgery must be considered before clitoroplasty is performed [29]. Crouch et al. objectively demonstrated decreased clitoral sensation amongst a group of CAH patients following clitoroplasty when compared to controls. There was a linear relationship between the amount of sensitivity impairment and severity of sexual difficulties [12].
Therefore, the main objectives of modern clitoroplasty are to reduce the size of the clitoris to achieve feminine appearing external genitalia while attempting to maintain clitoral sensitivity through preservation of the dorsal neurovascular bundle. Currently, a number of clitoral reduction techniques exist but there are no comparative studies of the outcomes of each. There continues to be much debate surrounding optimal techniques. As more has been learned about the functional outcomes of clitoral surgery, historical excisional procedures have been abandoned for nerve sparing reduction procedures. It does appear that procedures that preserve dorsal nerve function offer some functional benefit over total excision [12, 33].
Vaginoplasty
Vaginoplasty is considered to reconstruct or create a vagina in cases where little or no vagina is present. This can be in the setting of a primary procedure, or in cases with a history of previous vaginal surgery. The goals of treatment include allowing penetrative intercourse, as well as improving sexual function and psychological outcomes. Similar to clitoroplasty, there are no evidence-based practice guidelines regarding the ideal timing or method of vaginoplasty.
Vaginoplasty in the Neonate with Ambiguous Genitalia
When performed in infancy for virilised genitalia, current society guidelines recommend early separation of the common urogenital sinus with vaginoplasty at the time of genitoplasty [19, 40]. There are surgical considerations to suggest an advantage to early single stage procedures. For example, if performed at the time of clitoroplasty, the phallic skin can also be used as part of the vaginal reconstruction. It has been suggested that vaginal reconstruction in the neonatal period may be facilitated by a greater degree of elasticity of the vaginal tissue due to recent exposure to placental and maternal estrogens [4]. Lastly, by separation of the vagina and urethra at the time of vaginoplasty, potential urinary complications can be avoided.
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