Sexual differentiation, HPG axis

From Iusmphysiology

• started here on 04/04/11.

Contents 1 Sexual differentiation and the HPG Axis 1.1 Learning objectives 1.2 Sexual differentiation 1.3 Differentiation of the gonads 1.4 SRY and PAR on the Y chromosome 1.5 Differentiation of the internal genital ducts 1.6 Swyer syndrome 1.7 Klinefelter's syndrome 1.8 Differentiation of external genitalia 1.9 Gender role 1.10 Gender identity 1.11 Key concepts of the HPG axis 1.12 HPG axis in males 1.13 HPG axis in females 1.14 Higher centers

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