Puberty, Androgenism, and Hirsuitism Flashcards
Adrenarche normally begns at age __ in girls
Menarche normally begns at age __ in girls
Adrenarche normally begns at age 6-8 in girls
Menarche normally begns at age 12-14 in girls
Sequence of events in puberty in normal physiology
- Growth acceleration
- Thelarche (breast development, stimulated by estradiols)
- Pubarche (beginning of pubic hair growth, stimulated by androgens)
- Maximum growth rate
- Menarche
If a girl with abnormal puberty fails to undergo pubarche, the problem is likely ___.
If a girl with abnormal puberty fails to undergo thelarche, the problem is likely ___.
If a girl with abnormal puberty fails to undergo pubarche, the problem is likely failure of adrenal androgen production.
If a girl with abnormal puberty fails to undergo thelarche, the problem is likely failure of estrogen production.
Mild to moderate obesity results in __ puberty
Mild to moderate obesity results in early puberty
Puberty and depression
Pre-pubertal rates of depression are equal among boys and girls, however among age-matched boys and girls undergoing puberty, girls are disproportionately affected by pubertal depression.
Precocious puberty “line”
- Weirdly, it is different by ethnicity
- Prior to age 6 for girls of African American heritage
- Prior to age 7 for girls of European heritage
Gn-RH dependent precocious puberty etiologies
- Mostly idiopathic
- Infection/inflammation of the CNS
- Rarely a tumor of the hypothalamic-pituitray stalk
Characteristic features of McCune Albright syndrome
- Café-au-lait spots with ragged edges
- Polyostotic fibrous dysplasia (bones replaced by fibrous tissue)
- Endocrinopathies (precocious puberty, cushing syndrome, acromegaly, hyperthyroidism)
The 3 P’s of McCune-Albright syndrome
- Polyostotic fibrous dysplasia
- Pigmentation (café-au-lait spots)
- Precocious puberty.
GnRH-independent precocious puberty
-
McCune Albright Syndrome:
- Ovaries produce estrogen without FSH signaling
- Multiple bone factures
- Cafe-au-lait spots
- Estrogen-secreting tumor (granulosa cell)
- Adrenal hormone-secreting tumor
- Congenital adrenal hyperplasia
- Iatrogenic (OCP)
Rapid progression in precocious puberty is more likely to be. . .
. . . GnRH independent
Laboratory test to differentiate GnRH-dependent and -independent precocious puberty
Baseline LH is the standard. If high, GnRH dependence is already confirmed. If low, GnRH stimulation (non-pulsatile!!!) can tell you if LH is responding appropriately (inhibited) or not (elevated).
Once you determine that precocious puberty is GnRH dependent, the next step is. . .
. . . brain imaging
To visualize the pituitary
Delayed puberty categories
Most common cause of hypergonadotropic hypogonadism
Turner’s syndrome
FSH will be high. If missed at birth, these patients usually present with primary amenorrhea.
Treating hypergonadotropic hypogonadism
Usually involves supplementing the estrogen. So, basically, OCP.
Causes of hypogonadotropic hypogonadism
- Constitutional delay (most common, often familial)
- Kallman’s syndrome (hypogonadotropic hypogonadism plus poor olfactory tracts/no sense of smell)
- Anorexia (Leptin-mediated)
- Exercise (Athlete’s triad)
- Stress
- Craniopharyngioma
17-alpha-hydroxylase deficiency
Rare form of CAH that causes BOTH androgeneic effects AND mineralocorticoid effects
Specific definition of hirsuitism
- Excess terminal hair in a male pattern of distribution
- Terminal hair is dark and coarse. Develops first during puberty.
- Vellus hair is soft, downy, and fine. Present from birth.
Specific definition of virilization
- “Masculinization” of a woman
- Enlargement of clitoris
- Temporal balding
- Deepening of voice
- Involution of breasts
- Remodeling of limb-shoulder girdle
Four important forms of CAH
- Common CAH genotypes:
- 21-hydroxylase deficiency
- 11-beta-hydroxylase deficiency
- CAH plus salt wasting
- 3-beta-hydroxysteroid-dehydrogenase deficiency
- CAH plus hyperaldosteronism:
- 17-alpha-hydroxylase deficiency
Ddx for someone who develops secondary amenorrhea with hirsuitism and virilization at age 20
- PCOS
- Cushing’s syndrome
- Hyperprolactinemia
- Acromegaly
- Hypothyroidism
- Atypical CAH
-
Sertoli-Leydig tumor
- It is really important not to forget the last two because they are less common but potentially dangerous – moreso than PCOS
Ferriman-Gallway score
Score quantifying the presence of hirsuitism in 9 different locations on a female to assess for the presence of hirsuitism in that individual.
Note that ethnicity is relevant here, since different populations have different patterns of normal hair distribution (for example, women of Asian descent express no androgen receptors on their face, so they will never have hirsuitism there even when they have sky high androgens)
Eflornithine hydrochloride
- Facial cream approved for treatment of facial hirsuitism
- Inhibits the anagen phase of hair production
- Irreversible inhibitor of ornithine decarboxylase
Anti-hirsuitism medications
- Eflornithine hydrochloride (topical)
- OCP
- Spironolactone
- Finasteride
What do elevated testosterone, ACTH, cortisol, and DHEAS tell you about the source of the androgen hormones in a female patient with hirsuitism?
- Testosterone: Source is the ovary
- ACTH, cortisol, DHEAS: Source is the adrenal gland
Ovarian androgen synthesis diagram
___ express LH-R in the ovaries, which activates PKA to turn on ___.
___ express FSH-R in the ovaries, which activates PKA to turn on ___.
Theca cells express LH-R in the ovaries, which activates PKA to turn on androstenedione synthesis.
Granulosa cells express FSH-R in the ovaries, which activates PKA to turn on aromatase (conversion of androstenedione to estrone and estriol).
Adrenal gland diagram
OCP progestins that have less androgeneic properties
- Desogestrel
- Gestodene
- Norgestimate
Effects of estrogen on 5-alpha reductase
Decreases the activity of 5-alpha reductase, preventing the conversion of testosterone to dihydrotestosterone
This is why estrogen-containing OCP is so effective for treating male-pattern balding in women
Medroxyprogesterone
Decreases GnRH, resulting in decreased testosterone production
If hirsuitism is caused by adrenal hyperandrogenism, then ___ is the drug of choice.
If hirsuitism is caused by adrenal hyperandrogenism, then a glucocorticoid is the drug of choice.
Ketoconazole’s interaction with the androgen system
Inhibits steroidogenic cytochrome enzymes, resulting in decreased free testosterone and androstenedione
5-alpha reductase deficiency
- Classical presentation is a pre-pubertal female that becomes male at puberty (development of vulvar enlargement, penoid clitoris)
- Happens this way because the end effects of testosterone are mediated mostly by DHT. Prior to puberty, testosterone levels are too low to overcome the low enzyme activity. But at puberty, testosterone surge produces significant quantities of DHT, which then produce male secondary sex characteristics.
- Three sexual differentiations:
- Genetic: Male
- Gonadal: Male
- Genital: Female
Obstructive azoospermia
- Will be associated with low fructose (added from seminal vesicles)
- Most commonly congenital vas deferens absence due to cystic fibrosis
Non-classical CAH
- Presents very similarly to PCOS
- Pubertal or post-pubertal onset of hirsuitism and virilization
- Screen w/ DHEAS and 17 hydroxyprogesterone. Diagnose w/ cosyntropin stimulation w/ 17-OH PG as readout.
- Three sexual differentiations:
- Genetic: Female
- Gonadal: Female
- Genital: Female (unlike classical CAH, which would be male)
Mosaic Turner’s
Mixed phenotype.
Will have a late onset, be associated with normal stature, and may cause secondary amenorrhea.
Karyotype will be mixed 45X/46XX/47XXX.
Timing of gonadal vs genital differentiation of sex during embryonic development
Gonadal: 6 weeks EGA, SRY-dependent
Genital: 8-12 weeks EGA, testosterone and AMH-dependent
Sertoli cells vs Leydig cells
Sertoli: Produce AMH, stimulate mullerian agenesis
Leydig: Produce testosterone, stimulate wolffian differentiation
XY Gonadal agenesis
- Genetically XY, but SRY is nonfunctional or otherwise insufficient
- Testes do not develop properly or at all
- If any gonadal tissue develops, it must be removed. High risk of progression to malignancy
- Three sexual differentiations:
- Genetic: Male
- Gonadal: None/Malformed Male
- Genital: Female
Androgen insensitivity syndrome
- XY w/ androgen receptor deficiency
- No wolffian or mullerian structures, otherwise phenotypically female
- Gonadectomy recommended after puberty
- Three sexual differentiations:
- Genetic: Male
- Gonadal: Male
- Genital: Female
Mullerian agenesis
- 46XX karyotype
- Etiology unknown
- Mullerian system spontaneously regresses, but ovaries are still functional.
- Three sexual differentiations:
- Genetic: Female
- Gonadal: Female
- Genital: None/Malformed Female
Kallman syndrome
- May be 46XX or 46XY
- No GnRH neurons or sense of smell (anosmia)
- Three sexual differentiations:
- Variable, but there will be no spontaneous secondary sex characteristics apart from adrenarche and no spontaneous menarche in females
Androgen insensitivity syndrome produces a phenotypically female invidual with a karyotype of ___ and ___ testosterone.
Mullerian agenesis produces a phenotypically female invidual with a karyotype of ___ and ___ testosterone.
Androgen insensitivity syndrome produces a phenotypically female invidual with a karyotype of XY and High testosterone.
Mullerian agenesis produces a phenotypically female invidual with a karyotype of XX and Low testosterone.
Rough picture for Tanner stages
Stage 1: Prepubertal
2: Few pubic hairs (just a couple)
3: Minimal pubic hairs (still countable)
4: Sparse pubic hair (no longer countable)
5: Adult pubic hair
Order of events in female puberty
- Thelarche
- Growth spurt / peak growth velocity (1 year later)
- Adrenarche
- Menarche
McCune Albright syndrome
- Three P’s: Precocious puberty, pigmented skin lesions (cafe-au-lait), and polyostic fibrous dysplasia
- Constant production of estrogen by ovaries due to cellular signaling defect. Form of peripheral precocious puberty.
- Treat w/ letrozole (aromatase inhibitor)
First test you should order in any patient with precocious puberty
Bone age!!!!
This confirms the presence of true precocious puberty. If you can only get one test, get this one.
If we don’t intervene, epiphyseal plates will close and they will never reach adult height.
Classical CAH
- Autosomal recessive
- Genes:
- 21-hydroxylase (90% of cases)
- 11 beta hydroxylase (associated with hypertension, mineralocorticoid effects)
- 3 beta hydroxysteroid dehydrogenase
- In-utero virilization of fetus at 6-7 weeks
- If suspected in a pregnancy, give dexamethasone immediately (if prior to or at 6-7 wks). You can stop if the sex is confirmed as male. This will prevent abnormal male genital development in a genetically female fetus.
“Flow” of adrenal steroid pathway
The very first manifestation of puberty in girls
Growth acceleration
17-hydroxyprogesterone in different forms of CAH
- In 21-hydroxylase deficiency and 11-beta-hydroxylase deficiency, the most classical forms of CAH, 17-OHP is markedly elevated.
- In 3-beta-hydroxysteroid-reductase deficiency, 17-hydroxyprogesterone is extremely low, but the precursor 17-hydroxypregnenolone will be markedly elevated.
- In 17-alpha-hydroxylase deficiency, 17-hydroxyprogesterone is extremely low, but deoxycorticosterone will be markedly elevated.
Tests to order once the diagnosis of Turner’s syndrome has been established
- Turner’s patients are at increased risk of cardiac disease, vascular disease, skeletal, renal, and hepatic disease
- Echocardiography is the most important test to order to screen for cardiac abnormalities at the time of diagnosis
- LFTs should be ordered regularly as part of this patient’s annual visit
Constitutional hirsuitism
- Idiopathic
- Hirsuitism-style hair growth in the absence of high levels of circulating androgens
- Occurs more in certain ethnic groups (Mediterranean, Indian)
In a female-bodied, pre-pubertal child, clitoral size greater than ___ indicates clitoromegaly suggestive of virilization
In a female-bodied, pre-pubertal child, clitoral size greater than 1 cm indicates clitoromegaly suggestive of virilization
The most common cause of precocious puberty is ___ and it is treated with ___.
The most common cause of precocious puberty is idiopathic and it is treated with GnRH agonist (leuprolide)
Three factors vital to proper function of the endocrine system driving puberty
- Adequate body weight (input from leptin)
- Adequate sleep
- Occular exposure to sunlight
Van Wyk Grumbach syndrome
When hypothyroidism causes precocious puberty
Correcting the hypothyroidism with levothyroxine causes regression of secondary sex characteristics in these patients
So, always check a TSH in patients with precocious puberty of unknown etiology!
Telling apart gonadal dysgenesis and androgen insensitivity clinically
- Gonadal dysgenesis: No estrogen OR testosterone, thus no breast development OR virilization
- Androgen insensitivity:Breast development present (since excess testosterone is all aromatized to estrogen!)
- Both: High risk of gonads being malignant, and both will need removal of gonads
