Defects of Sex Steroid Synthesis and Response

Question 1

Roles of Androgens

Answer 1

• sexual differentiation
• spermatogenesis
• development of secondary sexual organs
• anabolic metabolism and gene regulation
• male-pattern behavior

Question 2

Targets for DHT

Answer 2

• those with highest 5 alpha-reductase activity
• prostate, external genitalia, genital skin
• BPH

-BPH treatment - receptor antagonist (flutamide), medical castration (potent GnRH agoist), 5 alpha reductase inhibitor (Proscar)

Question 3

Targets for Testosterone

Answer 3

• embryonic wolffian structures
• spermatogonia muscles, bone, kidney, brain

Question 4

The androgen receptor binds testosterone/DHT more strongly.

Answer 4

The androgen receptor binds testosterone/DHT more strongly.

Question 5

17 alpha Hydroxylase Defect in Males

Answer 5

• XY –> SRY –> development of testes and Leydig and Sertoli cells
• no testosterone from Leydig cells –> no Wolffian Duct development of internal or external male genitalia

-no testosterone –> no DHT –> no development of external male genitalia, default is external female genitalia

• Sertoli cells –> AMH (MIS) –> Mullerian Duct regression —> no internal female genitalia
• no XX –> no ovaries

SUMMARY:

• no ovaries
• testes, but no internal or external male genitalia
• external female genitalia
• No pubertal T surge to allow “gender conversion”
• Lack of androgens —> hypogonadism
• Adrenal effects —> no cortisol; overproduction of 11-deoxycorticosterone [DOC] = uncontrolled mineralocorticoid effect

Question 6

17 alpha Hydroxylase Defect in Females

Answer 6

• XX –> no SRY –> ovarian development
• no AMH (MIS) –> Mullerian Ducts —> internal female genitalia
• no testosterone –> Wolffian Duct regression
• no testosterone –> no DHT –> external female genitalia
• XX cannot make E2 – sexual infantilism; primary amenorrhea
• Lack of estrogen —> hypogonadism
• Adrenal effects –> no cortisol; overproduction of 11-deoxycorticosterone [DOC] = uncontrolled mineralocorticoid effect

Question 7

5 alpha Reductase Deficiency in Males

Answer 7

• XY –> SRY –> development of testes and Leydig and Sertoli cells
• Leydig cells –> testosterone –> Wolffian Duct development —> internal male genitalia

-no 5 alpha reductase –> no DHT –> no external male genitalia

•Sertoli cells–> AMH (MIS) –> Mullerian Duct regression

SUMMARY:

• testes
• internal male genitalia
• no internal female genitalia
• no external male genitalia
• external female genitalia
• Extent of abnormality depends on severity of defect

-may be distinctly female ambiguous: neither clearly male nor female predominantly male: micropenis and hypospadias

•“Gender conversion” at puberty due to T binding to all androgen receptors –> some development of penis and scrotum

Question 8

5 alpha Reductase Deficiency in Females

Answer 8

•increased T:DHT ratio and estrogen:DHT

• decreased body hair
• no acne
• delayed menses onset

Question 9

Androgen Insensitivity Syndrome

Answer 9

• XY –> SRY –> development of testes
• Sertoli cells –> AMH (MIS) –> degeneration of Mullerian Ducts
• Leydig cells –> testosterone, but receptors are insensitive –> no development of Wolffian Duct –> no internal male genitalia

-testosterone –> DHT, but receptors are insensitive –> no external male genitalia, defaults toexternal female genitalia

SUMMARY:

• no internal female genitalia
• external female genitalai
• testes
• no internal male genitalia
• no adrenal effects
• no external male genitalia