Editing Sexual differentiation, HPG axis

*started here on 04/04/11.


==Sexual differentiation and the HPG Axis==

===Learning objectives===

===Sexual differentiation===
*Genetics is determined at fertilization.
**XY = male
**XX = female
*The sperm has either an X or a Y and donates it to the X-containing ovum.


*There are many levels of sexual differentiation:
**establishing the genetic sex
**differentiation of the gonads
**differentiation of the internal reproductive organs
**differentiation of the external genitalia
**gender role
**gender identity

===Differentiation of the gonads===
*As an embryo develops, the gonads become the source of gender hormones:
**In males, the gonads become the testes and provide testosterone and dihydrotestosterone.
**In females, the gonads become the ovaries and provide estrogen.
*The gonads take their developmental cues from their genotype as to how it should develop and what hormones it should produce.
*An XY gonad has a Y chromosome with the '''Sex-determining region Y (SRY)'''.
**SRY is also called ''testis determining factor (TDF)''.
*SRY is the master switch that causes differentiation to head toward male.
*SRY encodes a transcription factor that is part of the '''high mobility group (HMG)''' family.

===SRY and PAR on the Y chromosome===
*The PAR (psudoautosomal region) of the Y chromosome is a well conserved area that allows the Y chromosome to pair with the X chromosome for cell division.
*PAR is at the very distal area of the short arm of the Y chromosome.
*SRY is located just proximal to the PAR and is considered part of the '''sex determining region'''.


*Two diseases are associated with SRY:
**SRY defects lead to XY females; '''Swyer syndrome'''.
**Translocation of the SRY region from the Y chromosome to the X chromosome yields XX males; '''XX male syndrome'''.

===Differentiation of the internal genital ducts===
*Initially, embryos initially have a set of undifferntiated gonads and both Wolffian ducts and Mullerian ducts.
*The ducts become the transporters of sperm or egg.
**Wolffian ducts mature into the epididymis and vas deferens.
**Mullerian ducts mature into the oviduct, uterus, and upper part of the vagina.
*Based on the genotype of the gonads (that is, the presence or absence of SRY), the gonads will begin to express hormones.
**Testes produce AMH (anti-Mullerian hormone), testosterone, and dht (dihydrotestosterone).
**Ovaries produce no hormones embryonically.
*The presence of hormones from the gonads determines the differentiation of the internal genitalia.


*If SRY is present:
**AMH, test, and testosterone are produced by the developing gonads
**Anti-Mullerian hormone (AMH) is responsible for degeneration of the female-associated Mullerian ducts in males
***We say that the Mullerian ducts '''involute'''; involute: "rolled inwards spirally" per [www.biology.lsu.edu/heydrjay/ThomasSay/terms.html LSU Biology]
**Gonads '''differentiate''' into testes.


*If SRY is not present:
**No hormones are produced by the developing gonads
**The Wolffian ducts atrophy.
**Gonads '''differentiate''' into ovaries.
**Note that '''female seems to be the default gender'''.

===Swyer syndrome===
*Recall that Swyer syndrome results from a '''SRY defect''' in an XY patient.
*Swyer syndrome is considered a type of hypogonadism because the expected male gonads did not develop.
*Not that though the gonads do not develop correctly in Swyer syndrome, '''the internal and external genitalia do develop normally'''.
**Note, however, that puberty does not occur normally so external genitalia do not mature through puberty.
*Patients with Swyer syndrome are often treated with estrogen and progesterone replacement therapy.

===Klinefelter's syndrome===
*Klinefelter's syndrome results from a 47 XXY genotype.
*XXY genotype results in poorly developed testicles.
*Underdeveloped testicles can result in non-masculine features and pro-feminine features:
**Non-masculine: poor beard growth, poor chest hair growth, frontal hair growth (lack of frontal balding), small testicular size
**Pro-feminine features: narrow shoulders, wide hips, breast development, female-like pubic hair growth

===Differentiation of external genitalia===
*Like gonads and ducts (internal genitalia), the external genitalia begin in a bipotent state from which they can develop into either male or female external genitalia.
*External genitalia are signaled to develop by the presence or absence of androgens--particularly DHT.
*Male external genitalia develop in the presence of DHT.
*Female external genitalia develop in the absence of DHT.
 Listen for how much anatomy we need to know.

===Gender role===
*'''Gender role is the gender presented by an individual to society'''.
*Gender role can be expressed through name, clothing, physical appearance, family role, occupation, and behavior.

===Gender identity===
*'''Gender identity is the internal conviction of one's own gender'''.
*We do not currently understand all the factors and complexity of gender identity.
*There is an interesting, intimate relationship between nature and nurture as it relates to development of role identity.
**Think prenatal androgen exposure, family beliefs, appearance of the genitalia, and medical / surgical experiences.

===Key concepts of the HPG axis===
*The HPG axis is the hypothalamus-(anterior)pituitary-gonad axis.
**Note that the HPG axis also includes some activity from the cortical regions of the brain (the ''higher-function centers of the brain'').
**Some examples of higher brain centers that affect the hypothalamus are the visual, olfactory, pineal and stress centers.
*The hypothalamus contributes to the HPG axis by releasing GnRH.
**GnRH binds to receptors on the gonadotropes of the anterior pituitary.
*The gonadotropes of the anterior pituitary contribute to the HPG axis by releasing leutinizing hormone (LH) and follicle stimulating hormone (FSH).
*The gonads contribute to the HPG axis by secreting sex steroids and peptide hormones.
**The gonads also release '''inhibin which feeds back on the anterior pituitary to reduce LH and FSH release'''.
**The gonads are also the site of germ cell production and maturation.
**Testosterone and estrogen from the gonads feed back on the anterior pituitary and the hypothalamus to reduce LH / FSH and GnRH release, respectively.

===HPG axis in males===
*In males, the hypothalamus releases GnRH to affect gonadotropes of the anterior pituitary.
*Upon GnRH signaling, gonadotropes of the anterior pituitary release LH and FSH to affect the testicles.
**LH and FSH negatively feedback on the hypothalamus, too.
*Upon LH / FSH signaling, the leydig and sertoli cells of the testicles release testosterone and inhibin.
**Testosterone triggers spermatogenesis and negatively feeds back on the anterior pit and hypothalamus.
**Inhibin inhibits the anterior pituitary.


*Note that testosterone is bound by ABP (androgen binding protein) in the blood.

===HPG axis in females===
*In females, the hypothalamus releases GnRH to affect gonadotropes of the anterior pituitary.
*Upon GnRH signaling, gonadotropes of the anterior pituitary release LH and FSH to affect the ovaries.
**'''Note that LH / FSH don't negatively feed back on the hypothalamus like they do in the male.'''
*Upon LH / FSH signaling, granulosa cells of the ovaries release estradiol, progesterone, inhibin, and activin.
**Estradiol and progesterone go on to affect target cells.
***Estradiole and progesterone have opposite feedback effects on the anterior pit and hypothalamus depending on the phase: positive feedback in the follicular phase and negative feedback in the luteal phase.
**Activin increases FSH production and release and systemically increases proliferation.
**Inhibin decreases FSH production and release and systemically decreases proliferation

===Higher centers===
*The HPG axis is affected by stress, sight, smell, and emotion.
*These emotions can generate inhibitory or stimulatory signals.

===Neurotransmitters that affect the HPG axis===
*There are LOTS of NTs that affect the HPG axis: norepinephrine, dopamine, epinephrine, acetylcholine, endorphins / opioids, neuropeptide Y, leptin, serotonin, cholecystokinin, GABA-major inhibitory NT.