4/8 Delayed Puberty: M and F Flashcards
Overall, what is the level of activity of the HPO axis over various life stages? (fetal, infancy, childhood, puberty, adulthood)?
Fetal life: Onset of FSH/LH secretion and subsequent lowered levels
Infancy: early increase then gradual decline
Childhood: very low activity
Puberty: Re-activation; increased secr of GnRH, FSH, LH; gonadal response
Adulthood: Episodic GnRH, FSH, LH release; negative & pos feedback control
Map out the hormonal control of puberty. what are the main hormones involved? what are the main organs/glands involved?
Hormones: GnRH, FSH/LH, Sex hormones (Test, Est).
Also Leptin from adipocytes.
Glands: Hypothal, Pituitary, Ovaries/Testes, Fat tissue
At puberty, what determines the onset of hormonal secretion?
We know that it is stimulatory CNS influences that start puberty (these stimulatory influences overwhelm the inhibition that has predominated throughout childhood); details not well understood.
Physical signs of male puberty – based on Adrenarche? (3)
- Pubic/axillary hair
- Adult body odor
- Sebaceous gland activity
In males, what is the first sign of gonadal axis activation?
Testicular enlargement
Aside from signs of Adrenarche (adult-pattern body hair, body odor, sebaceous gland activity), what are physical signs of puberty in males?
- Testicular enlargement (initial sign of gonadal axis activation)
- Prostatic enlargement
- Penile enlargement
- Thinning of scrotum
- Accelerated growth
- Skeletal maturation
Review: Tanner states of male genitalia?
Stage 1 - preadolescent
Stage 2 - Enlargement of testes and scrotum (testes 2.7 cm or 4 cc). Thinning and reddening of scrotum
Stage 3 - Enlargement of penis, mainly in length
Stage 4 - Further enlargement of penis in length and breadth; development of the glans
Stage 5 - Adult size and shape
Physical signs of Adrenarche in the female (3)?
- Pubic and axilary hair
- Adult body odor
- Sebaceous gland activity
(same as male adrenarche!)
Aside from adrenarche-related changes, first sign of puberty in female?
Ovarian and uterine enlargement
(first sign, but not most obvious sign…)
Jen – I have thelarche as the first sign of puberty in females…
Physical signs of female puberty that are not related to Adrenarche?
- Ovarian and uterine enlargement
- Breast development
- Maturation of vaginal mucosa
- Vaginal discharge
- Accelerated growth
- Skeletal maturation
Review: Tanner stages of pubic hair in girls?
Stage 1 - no pubic hair
Stage 2 - Sparse growth of long, slightly pigmented, straight downy hair
Stage 3 - Hair is darker, coarser, curlier, and spreads over the pubis
Stage 4 - Hair is adult in type but less in quantity
Stage 5 - Hair is adult in type and quantity, in an inverted triangle.
For girls, what is the definition of delayed puberty?
Breast development after age 13
Menarche after 15.5
For boys, what is the definition of delayed puberty?
Testicular enlargement after age 13.5
What do we see on xray of kids/adolescents that correlates well with pubertal staging?
Bone age correlates quite well with pubertal staging
Define constitutional delay
Is it more common in females or males?
Kids who go through puberty, but are at least 2.5 SD delayed from the mean.
True “late bloomers” with no identifiable etiology
Diagnosis of exclusion.
More common in males (see bar graphs)
Define Hypogonadotrophic hypogonadism
(aka SECONDARY or CENTRAL hypogonadism)
Cause of delayed puberty due to hypothalamic or pituitary defect
–> yields low levels of GnRH or FSH/LH secretion.
Various types: permanent v functional
Very generally, what could cause permanent hypogonadotrophic hypogonadism?
(This type of pubertal delay is due to hypothalamic or pituitary defect -> prevents normal GnRH or FSH/LH secretion)
Could be a tumor that destroyed the pituitary gland.
What could cause functional hypogonadotrophic hypogonadism? (three categories)
(This type of pubertal delay is due to hypothalamic or pituitary defect -> prevents normal GnRH or FSH/LH secretion)
Stressors: Exercise, weight loss, chronic illness, anorexia nervosa, bulimia
Endocrine disorders (prevent normal axis maturation: Hypothyroidism, Cushing’s
Systemic Illness: IBD, Celiac Dz
Define hypergonadotrophic hypogonadism
(aka PRIMARY or PERIPHERAL hypogonadism)
Cause of delayed puberty due to failure of ovaries or testes
–> yields high levels of GnRH or FSH/LH secretion
–>because no negative feedback from estrogen/testosterone
Rapid association: if you have a problem with the pituitary or the hypothalamus, your levels of gonadotropins will be high or low?
LOW
Rapid association: if you have a problem with the ovary or testes, your levels of gonadotropins will be high or low?
HIGH (no neg feedback)
What are some problems that could cause hypergonadotrophic hypogonadism?
(Remember this is primary or peripheral hypogonadism)
- Turner’s Syndrome/Klinefelter’s (sex chromosome disorders)
- Gonadal dysgenesis (failure to form)
- Chemo or Radiation therapy
- Autoimmune destruction (can have anti-ovarian antibodies)
- Torsion
Hypergonadotrophic hypogonadism: More common in boys or girls?
What about Permanent Hypogonadotrophic hypogonadism?
Functional hypogonadotriphic hypogonadism?
Hypergonadotrophic hypogonadism: girls
Hypogonadotrophic hypogonadism (permanent): girls
Hypogonadotriphic hypogonadism (functional): equal
(remember that constitutional delay of unknown etiology is more common in boys)
Is hypergonadotrophic hypogonadism more common in girls or boys?
More common in girls
If a 15 yo girl presents with absent breast and absent pubic hair development, is it more likely that her HPG axis has a problem? or her adrenal axis? or both?
Most likely to be a problem with both axes (both HPG and HPA)
Pubic hair derives from which axis? does it depend on the other axis?
Pubic hair is primarily from the HPA axis and should appear independent of the HPG axis
The absence of pubic hair (along with the absence of other secondary sexual development) indicates what?
It is a very significant finding: suggests that both HPG and HPA axes are aberrant.
Likely to be:
-hypopitutarism
-Enzyme problem high in the pathway (ie 17-hydroxylase deficiency) preventing production of androgens and estrogens)
Specifically, what could cause hypogonadotropic hypogonadism? (3-4 items)
- Mutations in genes involved in GnRH production, secretion, migration, transport, or receptors
- Hypothalamic-pituitary tumors
- Hypopituitarism
- Idiopathic (this category gets smaller as we learn more)
How would a prolactin-secreting pituitary adenoma cause hypogonadotropic hypogonadism?
Prolactin suppresses gonadotropin release –> can delay puberty
What are some hypothalamic disorders causing hypogonadism?
- Neoplasm
- CNS Radiation
- Genetic defects: Kallman’s syndrome, DAX-1, Leptin or Leptin receptor problems
A woman, age 26, presents with idiopathic hypogonadotropic hypogonadism. She has no boobs at all but pubic hair. If she wanted to get pregnant, what could we give her?
Pulsatile GnRH to allow ovulation and become pregnant.
(in this particular case, she had no response to GnRH and was found to have a mutation in the GnRH receptor gene. But that treatment would have worked for other causes of her problem)
What are the characteristics of Kallman’s Syndrome?
- Anosmia (bad sense of smell)
- Hypogonadotropism
- Associated with renal agenesis, mid-facial cleft, oculomotor dysfunction
Kallman’s Syndrome: what genes should we be aware of that cause this syndrome?
KAL-1
FGFR 1
What does KAL-1 do?
Responsible for Kallmann Syndrome
Encodes “anosmin-1” which facilitates migration of neurons to olfactory bulb. KAL-1 also helps neural cells which produce GnRH migrate to hypothalamus.
What does FGFR1 do?
(Fibroblast Growth Factor Receptor 1)
Responsible for Kallman Syndrome
Involved in pubertal development
Adrenal hypoplasia congenita: what protein is responsible?
What does it do?
DAX-1 protein
orphan nuclear receptor that appears to effect gonadotropin secretion at both the pituitary and the hypothalamus
Adrenal hypoplasia congenita: what is it?
Adrenal insufficiency in childhood
Patients cannot form adrenal glands -> cannot make adrenal steroids. Will die of adrenal insufficiency if not treated early in life.
What will happen in the case of leptin deficiency, in terms of obesity? gonads?
Severe obesity
hypogonadotropism
What will happen in the case of leptin receptor deficiency, in terms of obesity? gonads?
Severe obesity
hypogonadotropism
Elevated levels of circulating leptin
What are some pituitary causes of hypogonadism?
-Neoplasm (craniopharyngioma)
-Inherited defects:
GnRH receptor mutation, PROP1 mutation, FSH beta, LH beta (??)
describe a craniopharyngioma. what structure is it derived from? along with pituitary dysfunction, what other problems commonly occur?
common childhood tumor
derived from Rathke’s pouch
Supersellar/intrasellar location frequently results in optic chiasm compression along with pituitary dysfunction
What is PROP1?
A PROP1 mutation will result in deficiencies of what hormones?
PROP1 is a transcription factor involved in pituitary development.
Mutation –> deficiencies in GH, Prolactin, TSH, LH, FSH
Klinefelter Syndrome: what is the karyotype?
What does it lead to in terms of gonadal development?
It’s a type of hypo- or _hyper-_gonadotropic hypogonadism?
Klinefelter: 47XXY
(relatively frequent: 1/500 births)
–> premature gonadal failure/insufficiency –> loss of follicles or germ cells
A type of hypergonadotropic hypogonadism
Klinefelter’s Syndrome: what are the classic physical features?
- Tall stature (lack of fusion of epiphyses)
- Eunichoid body habitus
- Gonadal failure of varied severity: hallmark = small testicles
- Gynecomastia
Turner Syndrome: karyotype?
Which axis is problematic: the HPA or HPG axis?
45X
Caused by loss of X chromosomal material – the missing X is maternal 80% of the time. It’s a paternal error of meiosis I and II and post-fertilization errors of mitosis. (??)
HPA axis is fine: no problems with adrenarche. HPG axis doesn’t function properly.
Turner syndrome: physical characteristics?
Other issues?
Physical appearance: webbed neck, nail hypoplasia, shirt 4th metacarpal, multiple pigmented nevi, cubitus valgas.
Other issues:
Cardiovascular problems - coarctation of aorta, predisposition for dilation, dissection and rupture of ascending aorta
Renal - Horseshoe kidney (remember ductal systems dev together)
Endocrine problems - hypothyroid, diabetes, celiac, other autoimmune dz
What is this a picture of?
What syndrome is it characteristic of?
Can patients with this syndrome have children?
Ovarian streak (the one on the right of the pic is the streak)
Characteristic of Turner’s syndrome.
20% of Turners patients have enough follicles remaining for estrogen production and onset of puberty. 5% have enough follicles to menstruate. 1% will have spontaneous pregnancies.
46 XY gonadal dysgenesis: what is it?
what are the physical characteristics?
what is the impact on gonads/sex characteristics?
46XY gonadal dysgenesis: defect at earliest stage of testicular development. 15% have an SRY mutation.
ovarian streak gonads, mullerian internal ductal system, normal female external genitalia. spontaneous puberty does not occur. Risk of cancer in streak gonads.
Taller than predicted.
Treatment is hormone therapy.
XY Androgen insensitivity: what is the problem?
Physical characteristics?
Sexual development/characteristics?
Problem = abnormal androgen receptor.
Mullerian structures regress because testes make MIF.
Aromatization of androgens leads to external feminization
Breast development (because testosterone is aromatized to estrogen). Normal female habitus incl external genitalia.
No pubic hair. Amenorrhea due to blind pouch vagina. Presence of testes, but usually removed to to cancer risk.
Jamie Lee Curtis and Gisele Bundchen said to have this
