4/8 Delayed Puberty: M and F Flashcards by Jennifer Cromwell

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

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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

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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.

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Physical signs of male puberty – based on Adrenarche? (3)

Pubic/axillary hair
Adult body odor
Sebaceous gland activity

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In males, what is the first sign of gonadal axis activation?

Testicular enlargement

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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

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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

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Physical signs of Adrenarche in the female (3)?

Pubic and axilary hair
Adult body odor
Sebaceous gland activity

(same as male adrenarche!)

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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…

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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

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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.

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For girls, what is the definition of delayed puberty?

Breast development after age 13

Menarche after 15.5

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For boys, what is the definition of delayed puberty?

Testicular enlargement after age 13.5

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What do we see on xray of kids/adolescents that correlates well with pubertal staging?

Bone age correlates quite well with pubertal staging

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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)

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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

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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.

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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

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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

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Rapid association: if you have a problem with the pituitary or the hypothalamus, your levels of gonadotropins will be high or low?

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LOW

Rapid association: if you have a problem with the ovary or testes, your levels of gonadotropins will be high or low?

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HIGH (no neg feedback)

What are some problems that could cause hypergonadotrophic hypogonadism?

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(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?

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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?

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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 **hyper**gonadotropic 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*

4/8 Delayed Puberty: M and F Flashcards

(49 cards)