Sexual differentiation, HPG axis
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Revision as of 01:18, 5 April 2011 by 75.207.236.188 (Talk)
- 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
- Estradiol and progesterone go on to affect target cells.
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.