MALE REPRODUCTIVE SYSTEM Summer School Berlin Disorders of Sexual Development Corrie Brown

To understand abnormal development Disorders of Sexual Development (DSD), you have to know the normal (DSD) development (formerly INTERSEX; formerly hermaphrodite/pseudohermaphrodite)

Exercise #1

• Find a friend or two, and discuss the events that lead to development of gonads and To understand abnormal development tubular genitalia (DSD), you have to know the normal development

THEREFORE, A QUICK REVIEW…..

Introduction to Sex What makes sex?

• Fertilization • Chromosomal • Gonadal • Phenotypic

1 MALE REPRODUCTIVE SYSTEM Summer School Berlin Disorders of Sexual Development Corrie Brown

Sry gene acts on Sox9 gene, and SOX9 protein goes to work on the undifferentiated gonad, making it MALE SOX9 NO SOX9

CHROMOSOMAL SEX

GONADAL SEX

DSD

If the gonads If the gonads are testes…. are ovaries….

PHENOTYPIC SEX

Where can it go wrong?

EVERY DSD is due to a problem • Chromosomal abnormalities – Failure of separation of sex chromosomes at meiosis at one of the three levels. • So what are the possibilities for the offspring, in terms of genotype? • Gonadal abnormalities If you understand the cascade, – Failure of effective signal to primordial genital ridge • So what are the all the possibilities for the offspring’s gonads? you have a better chance of • Phenotypic abnormalities – The message didn’t get through to ensure development of defining what went wrong where. mesonephric vs. paramesonephric duct work • So how might the animal appear, inside, or outside, in terms of tubular and external genitalia?

2 MALE REPRODUCTIVE SYSTEM Summer School Berlin Disorders of Sexual Development Corrie Brown

Chromosomal Abnormalities What do the X and Y chromosomes do?

• Either mom or dad spewed a gamete that had • Y is UBER‐important undergone incomplete meiosis – Sry (transient expression) tells Sox9 gene to START PUMPING SOX9 – XO – SOX9 promotes differentiation into Sertoli cells – YO (NOT…. Incompatible with life) – SOX9 inhibits the female promoters (Wnt4, Foxl2) – XXX • X works best if Y is NOT present (X prefers the – XXY DEFAULT mode) – XYY – X makes Wnt4 and Foxl2 that promote ovarian development

XO XXY • The most common of the genotype • “Klinefelter’s syndrome in humans DSDs • They are males but everything is hypoplastic; the Y • You need TWO X’s to make all the exerts its influence making the animal male, but Wnt4 and Foxl2 needed there is enough X to keep it from the Full Monty. • So… ovaries are hypoplastic; tract • Reported in dogs is rudimentary • Over‐represented in male tortoise‐shell cats

XXX XYY • Only documented in humans • Only documented in humans – Approximately 1 in 1,000 male births – Approximately 1 in 1,000 female births – Taller than average – Taller than average – Subject of intense debates – Usually no deficits – At the most, MAY be at increased risk for – If clinical (10% of affected), poor muscle tone, antisocial or criminal behavior delayed language learning, learning disabilities

3 MALE REPRODUCTIVE SYSTEM Summer School Berlin Disorders of Sexual Development Corrie Brown

YO XX Sex Reversal • Don’t survive even to the stage of recognition • Sry gets translocated to a new chromosome of pregnancy

Associated with gene for polling

Gonadal Abnormalities Testicular Hypoplasia

• Dependent on the genotype – With a Y chromosome, gonad makes Sertoli cells and interstitial cells – Without a Y chromosome, gonad proceeds in female direction – With an X chromosome (and especially with TWO X chromosomes), ovary becomes more completely developed

Cryptorchid Tubular Abnormalities • Tubular (includes external genitalia) develop from either the mesonephric (MALE) or the paramesonephric (FEMALE) embryonic structures. – With testosterone  mesonephric ducts become epididymis and vas deferens – With dihydrotestosterone  urethra, penis, scrotum develop – Without support of mesonephric development, this side fades away – Paramesonephric duct develops in the female direction UNLESS there is Mullerian Inhibitory Substance present (made by Sertoli cells)

4 MALE REPRODUCTIVE SYSTEM Summer School Berlin Disorders of Sexual Development Corrie Brown

What can go wrong with the tubules? Testicular Feminization (aka androgen insensitivity) • No androgens • Phenotypically appear female • No androgen receptors • Sterile • No Mullerian duct inhibitory substance • Could be one of three problems: formed – No androgen production • Female fetus exposed to androgens – Conversion of testosterone to DHT – Androgen receptor defects

Androgen insensitivity PERSISTENT MULLERIAN DUCT SYNDROME (aka testicular feminization) (PMDS) • Tissues are insensitive to Mullerian Inhibitory Substance (MIS) • Look male, have testes, but also have something that looks like a uterus! • May be infertile • Often cryptorchid

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