Congential Adrenal Hyperplasia, Androgen Insensitivity, and 5alpha-reductase def

[docjohn101]

Can anyone please explain how to think through the congenital adrenal hyperplasias, androgen insensitivity syndrome, and 5alpha-reductase deficiency in terms of labs values and clinical features in terms of male and female sexual characteristics?

Thanks!

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[Phloston]

Can anyone please explain how to think through the congenital adrenal hyperplasias, androgen insensitivity syndrome, and 5alpha-reductase deficiency in terms of labs values and clinical features in terms of male and female sexual characteristics?

Thanks!

Hey, docjohn101, that's quite an extensive question-answer. FA explains that stuff in thorough detail.

Do you have a more specific question?

 

[docjohn101]

Which hormones influence the internal and external female and male sexual genitalia?

What is the exact cause in terms of hormones of ambiguous genitalia?

 

[AndyRSC]

Hormonal development in male as follows: 1) Sertoli cells form in sex cords and secrete Mullerian-inhibiting factor, which inhibits paramesonephric/Mullerian ducts. 2) Mesenchyme between cords (which becomes Leydig cells) secretes testosterone, which stimulates growth of mesonephric/Wolffian ducts; these become seminal vesicles, ejaculatory duct, epididymis, and ductus deferens (SEED). 3) Testosterone also converted to DHT, which causes development of penis, scrotum, and prostate (PPS).

In female: in absence of hormonal input, female internal and external structures develop; paramesonephric/Mullerian ducts turn into uterus, cervix (and top third of vagina) and Fallopian tubes.

On to pathology:
To make ambiguous genitalia, you typically require androgen deficiency during the 2nd-3rd month of gestation in a male, or a gestational excess of androgens in a female.

Androgen insensitivity syndrome (46,XY) - undescended testicles make the Mullerian-inhibiting factor, even though no internal or external male anatomy is present (in the absence of androgen stimulation). Breasts develop due to estrogen conversion by Sertoli cells and adipose tissue. Pt is externally female, thus this condition usually does not present with ambiguous genitalia, but recognized after failure to menstruate. Testosterone, estrogen, LH elevated (as the negative feedback is also insensitive to testosterone elevation).

In 5-alpha reductase deficiency, testosterone is not converted to DHT, thus external genitalia and prostate are not developed, resulting in ambiguous genitalia until puberty, when the surge in testosterone causes growth to pick back up. Testosterone, estrogen, LH normal; DHT low.

CAH comes in 3 (main) flavors:
21-hydroxylase - gluc: down, mineral: down (hypotension, hyperkalemia), andro: up
11-hydroxylase - gluc: up, mineral: up (excess of 11-deoxycortisol and DOC > HTN, hypokalemia), andro: up
17-hydroxylase - gluc: down, mineral: up (HTN, hypokalemia), andro: down
Recognize the type of CAH by the combination of glucocorticoid, mineralocorticoid, and androgen symptomatology. Ambiguous genitalia would, consequently, be created in a male with 17-, a female with 11-, or a female with 21-.

There are other causes. You can try glancing here:
http://en.wikipedia.org/wiki/Ambiguous_genitalia#Intersex_conditions_and_scope
Though sticking with what's in FA will probably be best for limiting material to what you'd likely see on the exam.

 

[mdeast]

Gosh these are my favorite diseases and I'm totally into the whole intersex issues. Such an amazing set of complicated diseases from an integrated medical and psychological standpoint. Great way to learn sex hormones and sex development/embryology as well.

Read First Aid- it has good explanations and just make sure you look at the charts to figure it out for yourself.

My personal crazy favorite is 5alpha-reductase deficiency, where patients can literally start to develop male external sex organs (i.e. testes descend, clitoris enlarges, may start to develop into a penis). Always wondered what the psychological associations with this must be, especially if someone wasn't aware of the condition until they hit puberty.

 

[Morsetlis]

Well, it's helpful to draw the axes out in a diagram.

My only input is to remind you of the SRY gene on the Y chromosome that leads to obliteration of the Muellerian duct... SRY accomplishes this by upregulating SOX9, a transcription factor with a DNA-binding site very similar to SRY's. SOX9 in turn upregulates fibroblast growth factor 9 (Fgf9), which is necessary for proper Sertoli cell differentiation.

So, the proper story starts with the SRY gene, and that's why you realize that all XY people have obliteration of the Muellerian duct, even if they are Androgen-Insensitive.

For Testosterone, it promotes development of internal sexual characteristics, including development of the prostate and growth of the penis (or penis-like structure).

For DHT, it promotes development of external sexual characteristics, including development of the penis and labioscrotal fold (note hypospadias in 5aR deficiency) and growth of the prostate.

 

[dextor2003]

Can someone please explain why testosterone, estrogen, and LH levels are all normal?