Sexual Differentiation and Puberty Flashcards
Define puberty
Puberty describes the physiological, morphological, and behavioural changes as the gonads switch from infantile to adult forms
What are the definitive signs of puberty in boy and girls
Girls = menarche - first menstrual bleeding Boys = first ejaculation - often nocturnal
Describe the adolescent growth spurt
- Time of minimum growth velocity = the age of take off
- Peak height velocity (PHV)
- Time of decreased growth velocity and cessation of growth at the epiphyseal fusion
- Boys commence growth spurt two years later than girls
What is the height gain for girls and boys form the adolescent growth spurt?
Boys = 28cm Girls = 25cm
What are the secondary sexual characteristics of boys?
What are they caused by?
Testicular androgens
- -> eternal genitalia and pubic hair growth
- -> enlargement of larynx and laryngeal muscles –> voice deepening
What are the secondary sexual characteristics of girls?
What are they caused by?
Ovarian oestrogen
–> regulate the growth of breast and female genitalia
Ovarian and adrenal androgens
–> control public and axillary hair
Sequence of events is related to specific staging criteria: for example…
- breast developement
- pubic hair development
- external genetalia development in boys
Describe the tanner stages in boys
Stage 1 = prepubertal, no pubic hair, testicular length <2.5cm, tesituclar volume <3.0ml
Stage 2 = sparse growth of slightly curly pubic hair, mainly base of penis, testies >3.0ml (>2.5cm length), scrotum thinning and reddening
Stage 3 = Thicker, curler hair spread to mons pubis, growth of penis in width and length, further growth of testis
Stage 4 = adult-type hair, not yet spread to medial surface of thighs, penis father enlarged, testes larger, darker scrotal skin colour
Stage 5 = adult-type hair spread to medial surface of thighs, genitalia adult size and shape
Describe the tanner stages in girls
Stage 1 = prepubertal, no pubic hair, elevation of papilla only
Stage 2 = sparse growth of long, straight or slightly curly, minimally pigmented hair, mainly on labia. breast bud noted, enlargement of areola, with no separation of contours
Stage 3 = Darker, coarser hair spreading over mons pubis, further enlargement of breast and areola, with no separation of contours
Stage 4 = thick adult type hair, not yet spread to medial surface of thighs, projection of areola and papilla to form secondary mound above level of breast
Stage 5 = hair adult-type and distributed in classic inverse triangle, adult contour breast with projection of papilla only
When does puberty start in boys and girls?
Boys
- testivular volume of 4 between 10 and 14
Girls
- breast stage 2 between 9.2 and 13.2
What 5 things do you need for normal puberty?
- normal chromosomes, XX or XY
- normal hypothalamus
- normal pituitary
- normal end-organ function, ovaries or testes
- normal responsiveness of tissues to hormones
Describe the hormonal changes at puberty
- Physical changes controlled by gonadal and adrenal sex steroids regulated by the gonadotrophons, LH and FSH
- Marked by circadian rhythm of FSH and LH secretion
- Sleep-augmented LH secretion - pulse like
- Later puberty LH daytime pulses also
Describe the relationship between Kisspeptin, GPR54 and puberty
- Kisspeptin, the product of the gene Kiss1, os a ligand for the GPCR GPR54 which is expressed in hypothalamic GnRH neurones
- Loss of function mutations GPR53 cause failure to progress through puberty in man, due to hypogonadotrophic hypogonadism
- Kisspeptin-GPR54 is essential for the inititation of gonadotrophon secretion at puberty
Describe the hypothalamic maturation hypothesis
- GnRH pulse generator
- puberty only requires increase in hypothalamic GnRH
- emphasis the direct link CNS and pituitary and hypothalamic GnRH neurones
- supporting evidence from the rhesus macaque
New factors: Kisspeptin, GPR54, TAC3, TACR3
Define precocious puberty
- onset of secondary sexual characteristics before 8yrs in girls and 9yrs in boys
- menarche before 9yrs may lead to short stature
Define delayed puberty
- absence of secondary sexual characteristics by 13yrs in girls and 14yrs in boys
- delayed puberty leads to reduced peak bone mass and osteoporosis
What are the differences between precocious and precocious pseudopuberty?
Precocious
- GnRH dependent
- a central problem with the HPG axis
- all stages in right order but earlier than normal
Precocious pseudopuberty
- GnRh independent
- secreting tumours in gonads, brain, lover, retroperitoneum, mediastinum
What diagnostic tests are used to differentiate between precocious and precocious pseudopuberty?
GnRH (LHRH) stimulation test True precocious puberty - LH:FSH ratio >1 - stimulation in pubertal range Precocious pseudopuberty - LH:FSH ratio <1 - stimulation in prepubertal range or suppression - exogenous androgens decrease LH and FSH due to negative feedback
What are the possible causes of true precocious puberty?
Idiopathic CNS tumours - optic glioma associate with FD1 - hypothalamic astrocytoma CNS disorders - developmental abnormalities, hypothalamus,ic harmartoma - encepahalities, brain abscess - hydrocephalus, myelomeningocoele, arachnoid cyst - vascular lesion - cranial irradiation Secondary central precocious puberty Psychosocial i.e. adoption from abroad
What are the possible causes of precocious pseudopuberty?
Increased androgen androgen secretion - congenital adrenal hyperplasia - virilising neoplasm - leydig cell adenoma - familial male precocious puberty - testotoxicosis Gonadotrophin secreting tumours - chorioepithliomas, germinoma, teratoma - hepatoma, choriocarcinoma McCune-Albright Syndrome Ovarian cyst Oestrogen secreting neoplasm Iatrogenic or exogenous sex hormones
Describe sex determination in utero
- Migration of primordial germs cells from dorsal endoderm to urogenital ridge by 6-8 weeks gestation (biopotential gonad)
- Development of indifferent gonad of urogenital ridge
- Presence of SRY gene –> testes differentiated by week 9
- Absence of SRY gene –> ovaries present by 11-12 weeks
What is the difference between sex determination and sex differentiation?
Chromosomal sex =presence or absence of testis-determining genes
—> sex determination
Gonadal sex = gonadal steroids and peptides (T, DHT, AMH)
–> sex differentiation
Phenotypic Sex
What are the major events in sex determination and sex differentiation in males?
- urogenital ridge
- bipotential gonad
- 46XY +SRY
- testis
- Sertoli cells –> AMH –> Mullerian regression
- Leydig cells –> T and DHT –> male sex differentiation
What genes on the Y chromosome are responsible for male sex development?
SOX9
WT1
SF1
What enzyme converts testosterone to DHT?
5alpha reductase 2
What cells and their associated hormones are responsible for Mullerian regression and Wolffian development
Mullerian regression
- Sertoli cells –> AMH
Wolffian development
- Leydig cells –> T –> DHT –> virilisation
Describe the development of the external genitalia
- common genital tubercle at 8 weeks, with lateral urethral folds, labioscrotal swellings
- tubercle becomes gland penis in male, clitoris in female
- urethral folds become corpus spongiosum enclosing urethra in males and labia minora in female
- labioscrotal folds duse to form scrotum and ventral penis or labio majora
Describe the sex steroid synthesis pathway
see lecture
What are the new nomenclature for the following disorders of sex development?
- Intersex
- Male pseudohermaphrodite
- Female pseudohermaphrodite
- True hermaphrodite
- XX male or XX sex reversal
- complete sex reversal
- Intersex = disorder of sex development (DSD)
- Male pseudohermaphrodite = 46, XY DSD
- Female pseudohermaphrodite = 46, XX DSD
- True hermaphrodite = ovotesticular DSD
- XX male or XX sex reversal = 46, XX testicular DSD
- complete sex reversal = 46, XY complete gonadal dysgenesis
What are the Prader stages?
Stages I –> V
I = normal female
V = normal male
Describes stages of virilisation
Describe the layers of the adrenal cortex and what they produce
Zona glomerulosa = salt, aldosterone
Zona fasciculata = sugar, cortisol
Zona reticularis = sex, DHEA
Describe the HPA axis in congenital adrenal hyperplasia
- Mutation in CYP21A2
- No negative feedback, XS CRH, XS ACTH
- Cortisol cannot be produced as defective CYP21A2
- Therefore XS androgen produced
Which enzyme is deficient in CAH?
What 3 hormonal stages does it result in?
21-hydroxylase deficiency
Mineralcorticoid deficiency
Glucocorticoid deficiency
Sex hormone excess
What hormonal/physical states results from 17alpha hydroxylase deficiency?
Mineralocorticod excess (glucocorticoid deficiency) Sex hormone deficicieny --> undervirilised male
Describe the disorder resulting from 5alpha reductase type 2 deficiency
Karyotype = 46, XY Inheritance = autosomal recessive Genitalia = usually ambiguous with small, hypospadic phallus, blind vaginal pouch Wolffian duct derivatives = normal Mullerian duct derivates = absent Gonads = normal testes Habitus = decreased facial and body hair, no temporal hair recession, prostate no palpable --> virilise at puberty
What is the cause of androgen insensitivity syndrome?
What is the clinical and biochemical phenotype?
Mutations = in androgen receptors Xq11-12 –> AR does not respond to androgens
Clinical and biochemical phenotype
- very high testosterone and DHT
- internal genitalia male (due to AMH production)
- external genitalia and external appearance female
- gender identity female –> diagnosis usually because of primary amenorrhoea
What factors are taken into account when determining the sex of a child?
- underlying diagnosis
- likely gender identity
- appearance of genitalia
- options for urological and sexual function
- probable need for hormone replacement
- potential for fertility
- tumour risk
- consideration within the context of the views of the family and social and cultural circumstances
Which conditions lead to assumed female assignment/
Which conditions are not straightforward?
Female assumed - 46XX DSD due to CAH early diagnosis - 46XY due to CAIS Not stragithforward - mixed gonadal dysgenesis - ovotesticular DSD - partial gonadal dysgenesis - severe PAIS - androgen biosynthetic defects
