Disorders of Sexual Development

The basic definition of sex used here is biological sex. 'Gender' has many meanings depending on the group or persuasian. It literally means 'kind' or belonging to a group. Thus it is synonomous with biological sex (reproductive anatomy), the behavioral, cultural, or psychological traits typically associated with one sex, or sexual identity, especially in relation to society or culture (see dictionary.com for a long list of explanations).

Contents

Historical perspective

Modern perspective

Introduction to DSD

Sex chromosome DSD

XX DSD

XY DSD

Historical perspective

Persons with unusual genitalia were called hermapthrodites. In Greek mythology, Hermes is the son of Zeus and the nymph Maia. He is the 'messenger of the gods' and the god of land travel, merchants, weights and measures, oratory, literature, athletics and thieves. Aprhodite is the goddess of love, beauty and sexual rapture. Aprhos means 'sea foam'. She was born when Uranus was castrated by his son Cronus, who threw the genitals into the ocean, which began to churn and foam around them. Aprodite loved many gods. Her son with Hermes was Hermaphroditus, a handsome lad who caught the eye of the nymph Salmacis. Although her overtures to Hermaphroditus were rejected, she wraped herself around him and forcable kissed him. She prays to the gods that they should never part and her wish is granted - and their bodies blend into an intersexual form. He has the body of a woman and the genitals of a man.

Modern perspective

There are many names given to animals with ambiguous or incomplete development of the genitalia. They include sexual ambiguity, intersex, hermaphroditism, sex reversal, feminizing or masculinising conditions and various combinations. It is difficult to categorize all conditions with a single definition, so I will use the term ‘'disorders of sexual development (DSD)'’ and adopt the scheme described by Hughes (2008). Meyers-Wallen (2012) subsequently published a review using this nomenclature.

Many diseases and conditions are now placed in the DSD category including cryptorchidism, hypoplasia, and segmental aplasia.

Complete characterisation of an anomaly of sexual development requires the description of the presence of sex chromosomes or genotype, the type of gonad, and the phenotype. As greater sophistication develops, there will be greater complexity in definition with identification of individual genetic, transcriptional or translational abnormalities. In domestic animals, we are often limited to observations of the gonads and phenotype.

Normal male mammals are XY and females are XX. For XY individuals, the gonads should be testes and for XX individuals, the gonads should be ovaries. Just about every combination is possible - there are XX males and XY females.

More recently, further evaluation of the gonad has changed the classification Normal (testis, ovary) gonad, hypoplastic gonad, dysplastic gonad, streak gonad and ovotestis

Introduction

According to the consensis paper by Hughes (2008), the human DSD are divided into three major groups: those with chromosomal abnormalities (the Sex chromosome DSD), those involving individuals with an XX chromosomes (XX DSD), and those with an XY chromosomes (XY DSD). This scheme is now accepted for the veterinary world.

 

Sex Chromosome DSD

Sex chromosome DSD include X_ (Turner syndrome), XXY (Kleinfelter syndrome), and various combinations where chimeras and mosaics can be XX/XY and any combinations of reduced or excessive numbers of chromosomes. There are basically 2 different types of sex chromosome DSD. Those individuals with aneuploidy, and those with chimerism and mosiacism.

Sex Chromosome DSD with Aneuploidy

Aneuploidy is an abnormal number of chromosomes, literally an-(not) ploidy (well, good). The normal number of chromosomes is haploid. Diploid is 2 equal sets of chromosomes.

The main types are X_ (monosomy X, Turner syndrome), XXX (trisomy X) and XXY (Kleinfelter syndrome). They occur because of failure of the chromosomes to come apart (nondisjunction) during meiosis (mitotic nondisjunction).

X_ individuals are female with that are infertile. They have afollicular ovaries and the female genitalia can be normal or hypoplastic.

XXX individuals are female, infertile and have underdeveloped genitalia.

XXY individuals are either male or female. Those with ovarian development are females with afollicular ovaries and abnormal female genitalia. XXY males have hypoplastic testes some have a uterus.

Chimeras and Mosaics

A chimera is a mythological creature with the head of a lion, the body of a goat and the tail of a serpent. The mythical centaur, the veterinary symbol, is a chimera. The product of mating of a donkey and horse (mule or hinny) is a chimera. The usual chimera in DSD are XX/XY chimeras which form when the cells of different zygotes fuse. A freemartin is a chimera.

Mosaics are similar but the error is the result of non-disjunction in a single zygote. Examples include XX/X_, XX/XY, XX/XXY. The phenotype is dependent on the amount of testicular tissue. Some have testes, others ovaries and some ovotestes.

XX Disorders of Sexual Development

Mammals with an XX DSD have sex chromosomes that are XX (female) but their chromosomal and gonadal type or phenotype do not agree. This was called XX sex reversal. The subgroupings of XX DSD are based on gonadal type (the type of gonad is either dygenetic, ovotestis or testis), and for those with normal ovaries, there are those with androgen excess from abnormal hormonal or receptor function, and miscellaneous conditions like vaginal atresia and uterine anomalies.

Where possible, the genetic alterations should be included in the complete definition, thus there are XX SRY+ and XX SRY- DSD.

XX DSD, normal testis

These individuals have an XX sex chromosomes, no SRY and either normal ovaries or testes. External or altered androgen and or receptor function results in virilization of the female. Also included in this grouping are the many different anomalies of the internal or external female tubular genitalia.

XX DSD, normal ovaries

These individuals have an XX sex chromosomes, no SRY and either normal ovaries or testes. External or altered androgen and or receptor function results in virilization of the female. Also included in this grouping are the many different anomalies of the internal or external female tubular genitalia.

XX DSD, hypoplastic gonad (usually testis)

These individuals have an XX genotype and gonads that are hypoplastic testes. The hypoplasia is defined as fewer seminiferous tubules without germ cells usually, and an edematous stroma.

XX DSD, Gonadal dysplasia

Gonadal dysplasia is defined as a gonal with architectural disorganization, rrregular, branched seminiferous tubules, thin irregular testicular capsule and a fibrous interstitium.

XX DSD, Streak gonad

A streak gonad is one with abundant fibroblastic interstitium, no tubules and no follicles

XX DSD, ovotestis

 

 

 

 

 

 

XY Disorders of Sexual Development

The development of gonads and the development of the duct systems and external genitalia are 3 different areas to consider. Normally, the genes activated in those destined to have male gonads result in the production of the testis determining factor. This is usually controlled by the sex determining region of the Y chromosome (SRY). There is a very complicated process involving the formation of the stroma of the gonads and interaction with the duct system. The development of the gonad drives the development or lack of the other areas. The mesonephric duct and tubules develop and the paramesonephric duct forms - these are formed from the coelomic surface by a process of invagination.

The testis produces the male hormones including testosterone. This influences external genital development - the penis, prepuce and scrotum. Mullerian inhibitory substance (MIS) inhibits the paramesonephric system, often on the side of the gonad. The mesonephric system develops.

Foetal structure
Hormone or factor
Result of failure of development or regression.
Gonadal ridge SRY aplasia, hypoplasia
Mesonephric ducts   segmental aplasia, cystic remnants including inclusion cysts, paradidymis interna and externa,
Mesonephric ductules   segmental aplasia of efferent ducts, inclusion cysts.
Paramesonephric ducts Anti Mullerian Hormone (Mullerian inhibitory substance) persistent Mullerian duct syndrome - uterine development, uterus masculinus, appendix testis
Urogenital sinus testosterone female phenotype with vulva, and or small penis.

Differentiation of cysts and cystic structures cannot be accurately done in all cases based on histology alone - one requires information on exact anatomical location. In general, paramesonephric duct remnants have the histological appearance of uterus - with glands and invaginations whereas mesonephric remnants should not.

In keeping with the subgrouping of the XX DSD, there are groupings of the XY DSD. Where possible, the SRY status should be included in the definition.

XY DSD with normal testes

These individuals have a normal XY genotype, testes but abnormal hormonal or receptor functions. They may also have other anomalies such as cryptorchidism, hypospadias, or persistent Mullerian duct syndrome.

Cryptorchidism

There are three phases of testicular descent, and failure of any of these results in retention of the testis.

Almeida et al examined the expression of AMH, AMHR, Androgen Receptor and found that the Sertoli cell profile was that of an immature cell, suggesting inhibition of maturation and communication of Sertoli cells in retained testes in horses.

Testicular hypoplasia

XY DSD, normal ovaries

 

 

 

XY DSD, hypoplastic gonad (usually testis)

These individuals have an XX genotype and gonads that are hypoplastic testes, as defined by fewer seminiferous tubules and an edematous stroma.

XY DSD, Gonadal dysplasia

Gonadal dysplasia is defined as a gonal with architectural disorganization, rrregular, branched seminiferous tubules, thin irregular testicular capsule and a fibrous interstitium.

XY DSD, Streak gonad

A streak gonad is one with abundant fibroblastic interstitium, no tubules and no follicles

XY DSD, ovotestis

 

References

Almeida J, Conley AJ, Ball BA (2012) Expression of anti-Müllerian hormone, CDKN1B, connexin 43, 1 androgen receptor and steroidogenic enzymes in the equine cryptorchid testis. Equine Vet J 2012,

Hughes IA (2008) Disorders of sex development: a new definition and classification. Best Practice & Research Clinical Endocrinology & Metabolism 22 (1): 119-134.

Lepais L, Morel Y, Mouriquand P, Gorduza D, Plotton I, Collardeau-Frachon S, Dijoud F. A novel morphological approach to gonads in disorders of sex development. Mod Pathol. 2016; 29(11): 1399-1414

Meyers-Wallen VN (2012) Gonadal and sex differeintiation abnormalities of dogs and cats. Sexual Develop 2012, 6: 46-60

Poth T, Breuer W, Walter B, Hecht W, Hermanns W (2010). Disorders of sex development in the dog - adoption of a new nomenclature and reclassification of reported cases. Anim Reprod Sc 2010 121: 197-207

 

 

 

Curious factoids about DSD

Wolbachia bacteria are blamed for inducing a predominence of female butterflies by inducing a male to female reversal to enhanse spread!