Sexual differentiation, HPG axis

From Iusmphysiology

Revision as of 13:42, 5 April 2011

• 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.

Hypothalamus

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

Immortalized GnRH secreting neurons

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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.
• Gonadotrophs are stimulated (to release FSH and LH) and inhibited by GnRH and gonad hormones, respectively.

Hypothalamus and Pituitary anatomy

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Pulsatile versus continuous GnRH

• LH and FSH show a characteristic switch from pulsatile release to continuous release of the course of months.

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, altitude.
• We suspect that psychosocial and environmental factors also play a role in determining the onset of puberty.

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.

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

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.

Kisspepti and GPR54 at the Hypothalamus

• Neurons of the hypothalamus is stimulated to release GnRH when kisspeptin binds GPR54.
  • GPR54 is a 7-transmembrane protein.
  • Kisspeptin is one of several peptides encoded by the Kiss-1 gene.
• When GPR54-Kisspeptin signaling is interupted, hypogonadism results from reduced gonadotropism (that is, reduced LH / FSH).

Characteristics of normal puberty

• There are four aspects to a normal puberty phase.
  • Sexondary sexual characteristics develop
  • Somatic growth spurt occurs
  • Fertility is acquired
  • Physiological changes occur

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

Secondary sexual development

• Gonadarche: rise in gonadal sex steroids as a result of the HPG axis activation
• 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.

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

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.

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.

Puberty comparison: boys and girls

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

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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.

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.

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.

*There is some incongruity in secondary sexual development and somatic growth.
**While secondary sexual development occurs along a similar time frame as normal puberty, somatic growth is relatively accelerated but arrests early.
**Therefore, central pp can result in early growth yet short stature.

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.

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.

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.

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.

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?  Because it is only expressed in endocrine tissues?

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.

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 04/04/11.