Sexual differentiation, HPG axis

From Iusmphysiology

  • started here on 04/04/11.


Contents

[edit] Sexual differentiation and the HPG Axis

[edit] Learning objectives

  • Prof will take exam questions from objectives.

[edit] 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

[edit] 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.

[edit] 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.

[edit] Differentiation of the internal genital ducts

  • Initially, embryos initially have a set of undifferentiated 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).
      • AMH causes involution of the Mullerian ducts and testosterone causes proliferation of the Wolffian ducts.
    • Ovaries produce no hormones embryonically.
      • A lack of hormones allows Wolffian ducts to involute and causes Mullerian ducts to proliferate.
  • 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.

[edit] 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.
    • Swyer syndrome is considered a "pure" gonadal dysgenesis because there is no chromosomal defect; that is, they have a normal karyotype.
    • Gonads are underdeveloped and are often referred to as "streaks".
  • 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.

[edit] 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
  • 1:1000 males has Klinefelter's syndrome

[edit] 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.
  • Said he won't ask specific details; just wants us to know that the pre-anatomy has bipotential.


  • One exam question from everything previous to this comment.

[edit] Gender role

  • Gender role is the gender presented by an individual to society.
    • Can be independent from anatomy and chromosomes.
  • Gender role can be expressed through name, clothing, physical appearance, family role, occupation, and behavior. 


No exam questions on this.

[edit] 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. 


No exam questions on this.


  • One exam question from everything after this comment.

[edit] 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.

clpt2008202f3.gif

[edit] 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.

http://www.uptodate.com/contents/images/ENDO/5463/HPG_axis_PI.jpg?title=HPG+axis+PI

[edit] 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.
      • This makes sense because females need to make and mature oocytes on a cycle each month.
    • Activin increases FSH production and release and systemically increases proliferation.
    • Inhibin decreases FSH production and release and systemically decreases proliferation

Image28.gif

[edit] Higher centers

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


No exam questions on this.

[edit] 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.

[edit] Hypothalamus

  • The hypothalamus releases GnRH at 70-90 minute intervals; we call this autorythmicity.
  • GnRH is a chromosome 8, 10mer peptide with a very short half-life--around 3 minutes.
  • The cells that secrete GnRH are neurons located in the arcuate nucleus of the medial basal hypothalamus (MBH).

[edit] Immortalized GnRH secreting neurons

What is the point of this slide?

[edit] Pituitary Gonadotropins

  • FSH and LH are released by gonadotrophs of the anterior pituitary.
  • FSH and LH are alpha-beta in structure; alpha is identical but beta is unique.
    • This won't be tested.
  • Gonadotrophs are stimulated (to release FSH and LH) and inhibited by GnRH and gonad hormones, respectively.

[edit] Hypothalamus and Pituitary anatomy

  • An illustration highlighting the point that gonadotropes reside in the anterior pituitary.

Antpit.jpg

[edit] Pulsatile versus continuous GnRH

  • When you override the pulsatile release of GnRH by infusing lots continuously, LH / FSH drops to low levels.
  • So we can see that it is important that GnRH must be released pulsatile to get normal release of LH / FSH.

004f.gif

[edit] Control of the onset of puberty

  • Puberty: the period of transition between juvenile state and adulthood, during which secondary sex characteristics appear and fertility is acquired.
  • We say that puberty occurs when the HPG axis matures, but we don't know the catalyst for puberty.
  • We do know that the onset of puberty is affected by many factors, including: genetics, nutrition, body weight, skeleton maturation (affects estrogen levels), altitude.
  • We suspect that psychosocial and environmental factors (like environmental estrogen exposure) also play a role in determining the onset of puberty.

[edit] Mini-puberty of infancy in males

  • In males, during the first month of life, there is a period of adult-like HPG axis activation.
    • That is, a period where testosterone levels are equal to those of adult males.
  • The function of this mini-puberty in boys is unknown.
  • There is no appreciable change in physical characteristics caused by these high levels of testosterone.

[edit] Testosterone throughout the lifespan

[edit] Changes in the HPG axis during puberty

  • During puberty, the HPG axis is "maturing".
  • Decreased sensitivity of GnRH-releasing neurons (hypothalamus) to negative feedback (from the gonad hormones) causes an increase in pulsatile GnRH release.
  • Increased sensitivity of gonadotrophs (anterior pit) to GnRH causes an increase in LH / FSH secretion.
  • Increased sensitivity of gonads to LH / FSH causes increased gonadal steroid production.


  • stopped here on 04/04/11.
  • started here on 04/05/11.


[edit] Kisspeptin and GPR54 at the Hypothalamus

  • Neurons of the hypothalamus is stimulated to release GnRH when kisspeptin binds GPR54.
    • GPR54 is a 7-transmembrane protein: bind extracellular signal and then transduce the signal via the cytoplasmic tail.
    • Kisspeptin is one of several peptides encoded by the Kiss-1 gene.
  • When GPR54-Kisspeptin signaling is interrupted, hypogonadotropic hypogonadism results from reduced LH / FSH signaling.

[edit] Characteristics of normal puberty

  • There are four aspects to a normal puberty phase.
    • Sexondary sexual characteristics develop: things that are not directly related to making babies (facial hair, breast enlargement, et cetera).
    • Somatic growth spurt occurs
    • Fertility is acquired
    • Physiological changes occur

[edit] Puberty terminology

  • Adrenarche: onset of adrenal and androgen production
    • Precedes puberty by 2-3 years
    • Occurs around 7-8 years old
  • Thelarche: onset of breast bud development
    • Estrogen causes thelarche
    • Greek / latin: thel- nipple, female
  • Pubarche: onset of pubic hair growth
    • Estrogen or testosterone causes pubarche.
  • Menarche: onset of menstral flow
    • Average age of menarche onset in the US is 12.8 years old

[edit] Secondary sexual development

  • Gonadarche: rise in gonadal sex steroids as a result of the HPG axis re-activation (recall that it was active in pre-natal development).
  • Adrenarche: rise in adrenal androgens independent of gonadal sex steroid production
  • We know that estrogens and androgens cause some of the changes seen in puberty because aberrant exposure to estrogens and androgens causes aberrant changes.

[edit] Physical effects of sex steroids

  • Estrogena 'and androgens cause growth acceleration, skeletal maturation, and genital changes.
  • Estrogens cause breast development in both boys and girls.
  • Androgens cause body hair, body odor, and also causes acne in both boys and girls.

[edit] Puberty in girls

  • Age of onset between 7.5 years to 13 years; average age of onset is 10.25.
  • The first sign of puberty is breast buds in 70% of cases.
    • Another common first sign is pubic hair.
    • A second sign of puberty usually follows within 6 months.
  • The peak growing time for women usually occurs 1.3 years before menarche.
    • Average growth during this growth period is 9 inches.
  • Menarche usually occurs 2.25 years after the onset of puberty.

[edit] Puberty in boys

  • Age of onset between 9 years to 14 years; average age of onset is 12.25.
  • The first sign of puberty in boys is testicular enlargement.
    • One can measure the testicular volume as an indicator of enlargement.
  • The peak growing time for men is usually 2 years later than in girls.
    • Boys usually gain around 11 inches during pubertal growth spurt.

[edit] Puberty comparison: boys and girls

  • Boys start and end later.
  • Girls start earlier and proceed more rapidly through puberty.

Slide1.PNG Tanner_scale-male.png 480px-Tanner_scale-female.svg.png

[edit] Abnormal puberty

  • There are lots of causes of abnormal puberty--some are normal variation and some are pathological.
  • Any junction of the HPG axis can be involved.
  • The treatment depends on the etiology.

[edit] Precocious puberty

  • Precocious puberty defined as "secondary sexual development occurring in girls before the age of 7.5 / 8 (AA, Hispanic / caucasians) or in boys before the age of 9".
  • There are 3 types of precocious puberty: normal variants, central, and peripheral.
  • Normal variants resulting in precocious puberty can occur by way of premature thelarch (recall that thel refers to breast in greek or latin) or premature adrenarche (adrenal or adrogen production).
  • Central precocious puberty arises from defects of the HPG axis.
  • Peripheral precocious puberty arises from an ectopic (non HPG) source of sex steroids.

[edit] Central precocious puberty

  • Most cases of precocious puberty are central precocious puberty (having to do with the HPG axis).
  • Central pp (precocious puberty) results in a normal sequence of events just at an earlier time; that is, it looks just like puberty but occurs earlier in the patient's life.
  • Central pp is much more common in females.
    • Central pp: females > males
  • Central pp's etiology is usually idiopathic.
    • CNS injuries can increase the risk for central pp. (Blows to the head, spinal injuries, etc.)
  • Secondary sexual development occurs gradually.
  • Somatic growth (which is a normal part of puberty) also starts early, is accelerated, and is then arrested relatively early (even for precocious puberty) and thus results in short stature.

[edit] Causes of precocious puberty

  • Recall that precocious puberty is ultimately the early release of sex hormones.
  • Tumors or hyperactivity of the pituitary or hypothalamus can cause early release of the sex hormones.
    • 60% of pp boys have an identified brain abnormality.
    • Most girls under 4 with pp have an identified brain abnormality.
    • 80% of girls with pp do not have an identified brain abnormality.


  • Pseudoprecocious puberty results from a tumor of the adrenal / testes / ovary that releases sex hormones.
    • In pseudoprecocious puberty, the gonads do not develop early (because they are not getting the required LH / FSH signaling) but the aberrant levels of sex hormones will cause secondary sexual development.

[edit] Precocious puberty: Symptoms and diagnosis

  • Male and female S&S: underarm / pubic hair growth, body odor change, acne, early growth, early arrest of growth, short stature,
  • Male S&S: facial hair growth, penis lengthening, appearance becomes masculine
  • Female S&S: menstruation, breast development
  • Recall that one difference between true and pseudo- precocious puberty is the development or lack of development in the gonads, respectively.
    • In true precocious puberty, the gonads develop because there are elevated levels of LH and FSH.
    • In pseudoprecocious puberty, the gonads do not develop because there are not elevated levels of LH and FSH.


  • Diagnostics include measuring blood hormone levels and taking x-rays of the hand and wrists for estimates of bone development.
  • CT, MRI, and ultrasound are also used to look for adrenal / hypothalamic / pituitary tumors and development of the adrenals and gonads.

[edit] A GPR54-activating mutation

  • Recall that the GPR54 receptor resides on the neurons of the hypothalamus (in the MBN) and is activated by kisspeptin.
  • This research identified a mutation in the GPR54 receptor that activated the receptor and caused central precociouis puberty.
    • Recall that turning on GPR54 increases GnRH which increases LH / FSH at the pit which causes development of the gonads.
  • Specifically, the mutation caused a decrease in receptor desensitization such that the receptor transduced an intracellular signal for a longer period of time than a wild-type receptor.
  • This decreased densensitization caused increased signaling through the GnRH releasing neurons and increases GnRH release.
  • This image shows the amount of phosphorylated ERK as a measure of pathway activation.
    • In the disease state, there is more phosphorylated (activated) ERK present.

[edit] Peripheral precocious puberty

  • Recall that peripheral precocious puberty occurs when sexual development is induced by sex steroids that do not originate from the HPG axis.
  • Peripheral precocious puberty is rare and can be heritable or not.
  • The non-HPG source of steroids can be endogenous or exogenous.
  • Peripheral precocious puberty often demonstrates heterogeneity:
    • there is often acute onset,
    • there is often linear growth acceleration that results in tall stature and advanced bone age (upon xray diagnostics on the hand and wrist),
    • there are many different classes of steroids to which children can be exposed,
    • the duration of exposure to steroids can be quite variable.

[edit] McCune-Albright syndrome, a form of peripheral precocious puberty

  • One cause of peripheral precocious puberty has been named: McCune-Albright syndrome results from an activating mutation of a G protein expressed in endocrine tissues.
  • The G protein's Gs-alpha subunit is mutated into a higher activity state causing increased cAMP.
  • Elevated cAMP from an over-active G protein causes hyperfunction of endocrine tissues.
  • McCune-Albright is characterized by a triad of symptoms: pp, cafe au lait, and fibrous bone dysplasia.
    • Large ovarian cysts are also seen in girls.
  • McCune-Albright precocious puberty is an example of a somatic mutation in a mosaic distribution. 
Why is it mosaic?  Because it mutates during development?  Yes per wikipedia

[edit] Delayed puberty

  • We consider puberty delayed if there is no female onset by 13 or male onset by 14.
    • We also consider pubertal development slower than one Tanner stage per year delayed puberty.
  • Delayed puberty can either be "normal variant" or pathologic.
    • Normal variant delayed puberty shows similar delay in both somatic growth and sexual development and often occurs with a family history of "late bloomers".
    • Pathologic delayed puberty can be congenital or acquired and may be caused by a problem at any level in the HPG axis.

[edit] Conclusion

  • The HPG axis is a highly integrated system with inhibitory and stimulatory modulators.
  • Though we don't know the trigger for puberty, we do know the predictable series of events that normally occur.
  • There are many different etiologies for abnormal puberty, many of which affect the HPG axis.


  • stopped here on 04/05/11.
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