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 1.15 Neurotransmitters that affect the HPG axis 1.16 Hypothalamus 1.17 Immortalized GnRH secreting neurons 1.18 Pituitary Gonadotropins 1.19 Hypothalamus and Pituitary anatomy 1.20 Pulsatile versus continuous GnRH 1.21 Control of the onset of puberty 1.22 Mini-puberty of infancy in males 1.23 Testosterone throughout the lifespan 1.24 Changes in the HPG axis during puberty 1.25 Kisspeptin and GPR54 at the Hypothalamus 1.26 Characteristics of normal puberty 1.27 Puberty terminology 1.28 Secondary sexual development 1.29 Physical effects of sex steroids 1.30 Puberty in girls 1.31 Puberty in boys 1.32 Puberty comparison: boys and girls 1.33 Abnormal puberty 1.34 Precocious puberty 1.35 Central precocious puberty 1.36 Causes of precocious puberty 1.37 Precocious puberty: Symptoms and diagnosis 1.38 A GPR54-activating mutation 1.39 Peripheral precocious puberty 1.40 McCune-Albright syndrome, a form of peripheral precocious puberty 1.41 Delayed puberty 1.42 Conclusion

[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.

[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

[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.

[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.

[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

• Testosterone is seen during the first and second trimesters of pregnancy, primarily.
• Then test is expresed during the mini puberty and begins to ramp up again during the 10-17 years (puberty).
• Test expression remains constant through most of adult life and then begins to fade in old age.
• http://books.google.com/books?id=9gvBlktAT6YC&lpg=PA1&ots=L23cN_r6NM&dq=kaefer%20m%20Mechanisms%20manifestations%20and%20management&lr&pg=PA256#v=onepage&q=testosterone&f=false

[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.

[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 G_s-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.