Pharmacology + Puberty Flashcards
Tacrolimus side effects
Calcineurin inhibitor
HTN
T2DM
Hypomagnesemia
Nephrotoxicity
Tremor
Alopecia
Hyperlipidemia less common than cyslosporin
Seizures
Cyclosporine side effects
Calcineurin inhibitor
Hirsutism
Gingival hyperplasia
Nephrotoxicity
HTN
Parasthesia
Hyperlipidemia
Hypomagnesemia
Mycophenolate side effects
gastrointestinal ( nausea, diarrhoea) and haematological side effects
a. Most can be treated with dose reduction and/or brief discontinuation
Enteric-coated mycophenolic acid reduces upper GI side effects
carbimazole side effects
agranulocytosis
neutropenia
liver failure
myalgia/arthralgia
Carbimazole MOA
inhibits of iodination of tyrosine
may have some action on peroxidase
doesnt affect the uptake of iodine by thyroid gland
thyroid storm
life threatening
precipitated by surgery, trauma, infection
severe thyrotoxicosis
tachycardia, CCF arrythmia
fever
trumor agitation
delerium
psychosis
neonatal graves
1-5% of neonates born to mums with graves disease
develop hyperthyroidism (transient) due to TRAB antibodies crossing placenta
—> tachycardia, goitre, advanced bona age, poor growth, craniosynestosis
sick euthyroid
normal- ish TSH with low T3 (ESPECIALLY) and T4, but elevated rT3
T4 can sometimes be high, but T3 always low in sick euthyroid
TSH has a short half life, T4 has a a long half life, so TSH recovers first, and T4/T3 recover later
is radioiodine useful for eye disease in graves?
no, contraindicated in eye disease
treatment thyroid eye disease
doesnt respond to normal graves treatment and may get worse with carbimazole
treat mild disease with eye drops, mod disease with steroids, radiation and surgery
monoclonal antibody- teprotumumab
and stop smoking!
Gonadarche
pulsatile release of GnRH from the hypothalamus–> activation of the gonads by secretion of pituitary hormones (LH/ FSH)
Girls: breast develomment (first sign puberty), menarche
Boys: increased testicular volume >4ml , muscularity, deepening voice, body hair
Adrenarche
Release of adrenocortical androgens (DHEA/ DHEAS) due to maturation of zona reticularis
1. Results in development of pubic/axillary hair, oiliness of hair/skin, acne, body odour
2. Can occur BEFORE OR AFTER gonadarche (but gonadarche starts first in 70%)
iii. Though temporally correlated, gonadarche and adrenarche are physiologically distinct events. Individuals with defects in the hypothalamic-pituitary-gonadal axis can still undergo adrenarche. Individuals with no adrenal function can achieve gonadarche
Thelarche
breast development, primarily due to the action of estradiol from the ovarie
Pubarche
Specifically refers to the appearance of pubic hair due to adrenal androgens
ie the phenotypic result of adrenarche
Normal progress through puberty
Age:
Girls: average age 11, range 8-13 yo
Boys: average age 12, range 9-14 yo
Girls = Gonadarche (thelarche) –> adrenarche/pubarche –> growth peak –> menarche
Boys = Gonadarche (increased testicular volume) –> adrenarche/ pubarche –> growth speak –> sperm in urine
Girls Pubarche onset 2-6 months after breast development Menarche 2 years post thelarche Peak height velocity occurs 0.5 years before menarche - Peak rate = 8.5 cm/year However growth spurt starts at the onset of puberty ie at same time or soon after beginning breast development
Boys
Pubarche occurs ~6 months after testicular enlargement
Spermarche 2 years post pubarche
Facial hair 3 years post pubarche
Pubertal growth spurt starts 2 years later – additional two years of pre-pubertal growth (rate of 3-8cm per year) Usually age 13-14 years
-Peak rate = 9.5-10cm/year
Actions of oestrogen
B-estradiol most potent
ii. Functions
1. Stimulates development of genitalia, breast, female fat distribution
2. Stimulates epiphyseal closure
3. Stimulates GH growth spurt
Growth of follicle, endometrial proliferation
iii. Role in menstrual cycle:
1. Stimulates upregulation of oestrogen, LH, progesterone receptors
2. Initially provides negative inhibition of FSH/ LH
At set point, feedback changes to +ve LH feedback = LH surge stimulating ovulation
Testosterone
i. Made by Leydig cells
ii. Synthesized via 5-alpha reductase into dihydrotestosterone in target tissues
iii. Functions
1. Descent of testes (in utero)
2. Differentiation of epididymis, vas, seminal vesicles
3. Deepening of voice
4. Closure of epiphyseal plates (less action than estrogen )
5. Libido
6. ↑ basal metabolic rate
iv. Regulation
1. High in fetus due to placental hCG + fetal pituitary stimulation
2. Persists until 10 weeks of life, then decreases
3. Increases again in puberty
DHT
DHT is essential for the development of the male sex characteristics before birth, particularly the formation of the external genitalia. In the adult, DHT is needed to develop and maintain male gender characteristics, such as facial hair, deep voice, and muscle growth.
In males, about 70% of DHT is derived from the conversion of testosterone by 5α–Reductase in the prostate, testes, hair follicles, and adrenal glands.
DHT has approximately 3 times greater affinity for androgen receptors than testosterone and has 15-30 times greater affinity than adrenal androgens.
Action gonadotropins
n males
1. FSH Sertoli cells spermatogenesis
2. LH Leydig cells testosterone
iii. In females
1. 1. FSH follicular stimulation and growth. Stimulates granulosa cells to synthesize aromatase, which converts androgen produced by thecal cells to estradiol
LH Surge causes release of oocyte from follicle + stimulates the formation of corpus luteum which produces progesterone
Theca cells of ovary
Site of production of progesterone –> 17 a OH progesterne –> androstenedione and testosterone (which are metabolised by aromatase to produce estradiol)
Stimulated by LH
Granulosa cells
Stimulated by FSH
Produce aromatase which converts androgens produced by theca cells into estradiol
Produce progesterone from cholesterol
Also secrete inhibins which act on the anterior pituitary and reduce FSH secretion
Estrogen feedback to brain
normally exhibit negative feedback
shifts to positive feedback mid cycle—> LH surge and FSH –> ovulation
Why is 17 a hydroxyprogesterone measured instead of progesterone
progesterone binds to albumin with low affinity so has a very short half life ~5 min so unable to measure
Role of progesterone
breast development
suppresses milk production
reduced endometrial growth
increased secretions and increased thicness of mucosal secretions
Ovarian cycle
Follicular + luteal phases
Follicular: development of mature graafian follicle and secondary oocyte
estrogen gradually increases, causing + feedback and LH/FSH peak, while progesterone remains low throughout
–> ovulation, formation of corpus luteum (CL)
Luteal: CL = residucal theca and granulosa cells of follicle; synthesise and secrete estrogen and progesterone t maintain the feralised oocyte
If fertalisation doesnt occur (ie no HCG produced), the CL regresses and forms corpus albicans (non functional scar like structure)–> occurs 10-12 days after ovulation in absence of HCG
Endometrial cycle
precocious puberty definition
< 8 years in girls, <9 years in boys
central: gonadotropin dependant
peripheral: gonadotropin independant
–> incomplete, atypically sequenced or rapid pubertal progression
what is peripheral precocious puberty caused by
iii. Caused by excess secretions of
1. Sex hormones (estrogens or androgens) from the gonads
2. Exogenous sources of sex steroids
3. Ectopic production of gonadotropin from a germ cell tumour (eg. hCG)
iv. Not true puberty as hypothalamic-pituitary-gonadal axis is not activated
Examples: CAH, androgen secreting tumor, McCune Albright syndrome, severe hypothyroidism (ovarian stimulation secondary to high TSH which mimics FSH)
investigations in precocious puberty
Central: increased pulsatile GNRH–> increased LH and FSH –> increased estradiol and testosterone
increased LH and FSH with GNRH stimulation test
Peripheral: no GNRH pulse –> low LH and FSH, elevated estradiol and testosterone
- HCG in boys to exclude hcg secreting germ tumor
TFTs
Cholesterol
DHEAS, 17OH (CAH)
Abdo/pelvis USS
Xray for bone age
Management precocious puberty
Lucrin (GNRH agonist if central
tanner stage 2-3 breast development may regress, if >3, tends to remain
Menses ceases
pubic hair stays the same
aim to slow prior to epiphyseal fusion, as risk short stature with premature growth spurt
peripheral- treat cause
ca consider lucrin to prevent secondary central precocious puberty
Causes central precocious puberty
GnRH dependent
KEY = due to early activation of the hypothalamic-pituitary-gonadal axis
More common in girls
Idiopathic in 80-90% of girls and only 25-60% of boys
75% of boys have CNS abnormality
a. Idiopathic (80%) i. Almost all idiopathic cases are girls b. Organic brain lesions c. Hypothalamic hamartoma (Most common CNS cause of precocious puberty) d. Brain tumours (glioma, intracranial germ cell tumor (usually pineal)) hydrocephalus, severe head trauma e. Hypothyroidism prolonged and untreated f. Acquired CNS insults i. CNS irradiation – commonly associated with GH deficiency ii. Hydrocephalus, subarachnoid cysts, CP, tuberous sclerosis g. NF type --> optic glioma interrupt HPG axis h. Previous excess sex steroid exposure eg. CAH
clinical manifestations central precocious puberty
a. All components of puberty normal but early
b. Girls = early development of breasts, early menstrual cycles
c. Boys = early development of testes, early spermatogenesis
d. Both
i. Height, weight and osseous maturation are advanced early closure of epiphyses
1. Without treatment 1/3 girls and most boys = <5th centile height as adults
Ix in central precocious puberty
a. Key = elevated basal LH and/or stimulated LH concentration post GnRH
b. Sex hormone concentrations – usually appropriate for the stage of puberty
c. GnRH stimulation test (GnRH administered) or GnRH agonist (leuprolide) – helpful diagnostic test
d. Pelvis USS = may show enlarged ovaries, enlarged fundus and the whole uterus
e. X-ray bone age = advanced bone age
f. MRI = CNS pathology, may show physiological enlargement of pituitary (normal in puberty)
Peripheral precocious puberty cause
a. Caused by excess secretion of sex hormones (estrogens and/or androgens) derived from
i. Gonads
ii. Adrenal glands
iii. Exogenous sources
b. Low or suppressed gonadotropin concentrations with elevated sex hormone levels ie no activation of HPA axis
c. Pubertal status needs to be monitored for 6/12 after treatment as treatment of peripheral precocity can trigger central precious puberty
Girls: ovarian cysts (may be secondary to McCune Albright Syndrome), ovarian tumors
Boys: Leydig cell tumors, hcg secreting tumors (eg hepatoblastoma0
Both: exogenous hormones, adrenal tumors, CAH, hypothyroidism pituitary gonatrotrophin secreting tumors, McCune Albright syndrome
Triad of McCune Albright Syndrome
- Peripheral precocious puberty
2. Irregular café-au-lait skin pigmentation
3. Fibrous dysplasia of bone
Hyperthyroidism
GH excess–> gigantism/acromegaly
Cushings syndrome
Renal phosphate wasting –> hypophosphatemic rickets
Treatment options for peripheral precocious puberty in girls
Letrezole = aromatase inhibitor
Tamoxifn- anti estrogen
CAH- glucocorticoids
Treatment options for peripheral precocious puberty in boys
Letrzole
Tamoxien
anti androgens- spirnolactone, flutamide
CAH- glucocorticoids
defining test for peripheral precocious puberty
SUPPRESSED FSH and LH
elevated oestrogen/testosterone
No response to GNRH stimulation
Defining tests for central precocious puberty
Elevated FSH AND LH
Response to GNRH >6
Premature thelarche
Usually occurs <age 2 years
transient and isolated early breast development
doesnt develop beyond stage 3
no other signs of puberty
BONE AGE NOT significantly INCREASED, no increased growth velocity
usually persists for 2-5 years; menarche occurs at expected age
Only need ix if progressive sexual development, accelerated bone maturation, or increased height velocity
May have slightly elevated FSH and FSH response to GNRH, but LH and oestradiol are in the prepubertal range
Premature adrenarche
Driven by adrenal androgens
Normal growth velocity
No enlargement of testes/penis or breasts/ovaries/clitoris
Normal or slightly advanced bone age
Diagnosis requires biochemical demonstration of serum steroid pattern DHEAS >40
More common in girls than boys
Girls will have slightly increased risk of developing PCOS and metabolic syndrome
Tend to have linear growth rate and bone age that are above average, but still within normal range
Ix: 17 hydrohyprogesterone: normal excludes non classical CAH
Mod elevattion suggests CAH, need to confirm with ACTH
Very elevated- diagnostic of non classical CAH
Serum DHEAS
Bone age - Increased. 30% hav bone age more than 2 years above chronological age
a. Slowly progressive condition that requires no therapy b. Monitor to assess height velocity and watch for signs of rapid progression or breast development indicating central precocious puberty
idiopathic premature pubarche
Premature pubarche but no biochemical evidence of adrenarche
Bone age + DEHAS and androgens = normal
premature menarche
· Isolated vaginal bleeding in a girl with no other puberty, with normal growth, normal bone age, and no evidence of infection or foreign body
· MUCH less frequent than premature thelarche or premature adrenarche
· Diagnosis of exclusion – need to exclude vulvovaginitis, FB, sexual abuse, urethral prolapse, sarcoma botryoides
· Majority of girls with idiopathic premature menarche only have 1-3 episodes of bleeding
· Puberty usually occurs at normal time, menstrual cycles are normal
· Investigations
o Gonadotropins – low
o Estradiol – occasionally elevated due to ovarian estrogen secretion associated with ovarian follicular cysts \
USS pelvis: prepubertal uterus and ovaries
Classification delayed puberty
Girls: Absence of breast development by 13 years
Boys: Failure of testicular enlargement to 4ml by 14 years
· Constitutional
· Functional hypogonadism (eg. Chronic disease, nutritional inadequacy, excessive exercise)
· Primary hypogonadism – testicular or ovarian pathology
Secondary hypogonadism – hypothalamic pituitary disturbance/GnRH deficiency
Primary hypogonadism - causes
Primary hypogonadism = ↑ FSH and LH
i. Congenital
1. Chromosomal abnormalities = Turner (females), Klinefelter (males)
2. Disorders of sex development
3. Gonadal dysgenesis
ii. Acquired
1. Autoimmune
2. Post-infectious (mumps, orchitis, coxachie virus – in males)
3. Following trauma or surgery
4. Following chemotherapy or radiotherapy
Secondary hypogonadism
(hyogonadotropic hypogonadism) = ↓/normal FSH and LH
Congenital:
Isolated GnRH deficiency = idiopathic hypogonadotropic hypogonadism
a. Without anosmia or With anosmia (Kallman syndrome)
b. Caused by a variety of genetic mutations
c. Associated with adrenal hypoplasia, midline defects (cleft lip/palate), hearing loss, renal agenesis, skeletal anomalies
- GnRH deficiency associated with mental retardation/obesity
a. Prader-Willi syndrome - Combined pituitary hormone deficiency
- Congenital brain malformation causing GnRH or gonadotropin deficiencies (often associated with craniofacial abnormalities)
ii. Acquired
1. Tumours = benign, craniopharyngioma, any other CNS tumour
2. ‘Functional’ gonadotropin deficiency
a. Constitutional delay of growth and puberty
b. Chronic systemic illness eg. celiac disease
c. Acute illness
d. Malnutrition
e. Hypothyroidism, hyperprolactinaemia, diabetes mellitus, Cushing’s disease
f. Anorexia nervosa
Exam in delayed puberty
iv. Is pubertal development totally absent, or did it start then stall? Any early signs of puberty that then regressed?
v. Is there a normal sense of smell
b. Examination
i. Growth, height, weight, HC, height velocity, arm span>height (Kallaman syndrome- arm span often >5cm greater than height)
ii. Dysmorphism/midline defects
iii. Olfaction (Kallman’s syndrome)
iv. Neurological
v. Signs of chronic disease/endocrinopathy
vi. Tanner staging – puberty
vii. Bilateral cryptorchidism, micropenis, anosmia, synkinesia- Kallman syndrome
viii. Delayed cognitive development, obesity +/- dysmorphic features – genetic syndromes eg Prader Willis
Investigations in delayed puberty
a. Bone age
b. Basic bloods – FBE, UEC, ESR,CRP, LFT
c. Endocrine tests
i. LH, FSH, estradiol and testosterone
1. Random (unstimulated) measurements of LH and FSH together with estradiol (girls) or early morning testosterone (boys) – distinguishes between primary and secondary hypogonadism
2. ↑ LH + FSH indicates primary hypogonadism
3. ↓or normal serum LH/FSH with low levels of testoerone or estradiol indicates constitutional delay or isolated GnRH deficiency
ii. GnRH stimulation test – not recommended
d. Prolactin – detect hyperprolactinaemia
e. IGF-1 – excludes growth hormone deficiency as cause of delayed puberty
f. TFTs – excludes hypothyroidism as cause of delayed puberty
g. Coeliac bloods- functional delayed puberty
h. Ultrasound – to detect underlying structural abnormality
i. Additional tests
i. Primary hypogonadism
1. Karyotype to establish diagnosis of Klinefelter/Turners
2. Girls have Turners until proven otherwise- always do karyotype
ii. Secondary hypogonadism
1. Head MRI – assess for hypothalamic or pituitary disease
2. Anosmia – olfactory function test
3. If GnRH deficiency strongly suspected – genetic testing
4. Serum inhibin B (boys)- marker of Sertoli cell function
Inhibin B
produced by the sertoli cells of prepubertal testes
can be used as marker sertoli cell function
Inhibin is secreted also by granulosa cells and has a role in regulating the pituitary secretion of FSH. Therefore, inhibin is a potential marker for ovarian function and follicular content.
HCG stimulation test
Human chorionic gonadotropin (HCG) stimulation test is a reliable dynamic test for the evaluation of testicular function during childhood. A single dose of HCG injection at dose of 100 iu/kg is able to produce a progressive but modest rise in testosterone level for 72 to 120 hours in presence of a viable testicular Leydig cells.
Treatment delayed puberty
Boys >14 yrs and girls >12 yrs who show few or no signs of puberty
i. Females = estradiol
ii. Males= testosterone
iii. Cryptorchidism- surgical mx
bone age in constitutional delayed puberty
delayed bone age
reproductive potential in turners syndrome
a. Spontaneous pubertal onset 30-40%
i. Those with inhibin B are most likely to have spontaneous puberty
ii. Continuing ovarian function most likely with AMH hormone levels
b. Spontaneous menses 4%
Fertile spontaneously 1%
Endocrine management of Turners
a. Sex hormones
i. Should NOT wait - start treatment with HRT around the age of 12 years
ii. General management when complete pubertal progress is needed
1. Use estradiol (non ethinyl radical estradiol) – slowly increase dose over 2-3 years
2. Add progesterone at the end of this time
iii. ALWAYS use continuous estrogen to prevent bone loss
iv. Avoid use of contraceptive pill (as this induces hypertension – high lifetime risk in Turner syndrome)
b. Growth hormone
i. Growth hormone + estrogen gives best height outcome
When is the best time to test if concerns re hpa axis
Mini puberty (8-12 weeks of age) as relatively high LH FSH oestrogen/testosterone
Later in childhood the hpa axis is suppressed so may not show a response to stimulation
Pointless to test hormone levels in childhood as they will be very low in everyone
Is Mcune Albright syndrome a somatic or germ line mutation
Somatic
That’s why mutations may not be picked up on blood tests (may only be in certain organs)
Wide range of phenotype
Hormone levels in hypogonadotropic hypogonadism
All sex hormones low and no rise in LH/FSH with stimulation test
eg craniopharyngioma, pituitary adenoma, prolactinoma, septooptic dysplasia
Impact high dose vs low dose craniospinal irradiation
low dose- precocious puberty
high dose- delayed puberty
GH most impacted
ACTH second most impacted
Hypergonadotropic hypogonadism
High LH, FSH
Low testosterone/oestradiol despite stimulation of gonads by pituitary
eg Kleinfelters, Turners, trauma, chemotherapy (eg cyclophosphamide)radiation to gonads, cryptorchidism
Prolactinoma
40% of all pituitary tumors
Delayed puberty
hypogonadism
ammenorrhoea
infertility
galactorrhoea
bone loss
*macroadenomas more common in kids
**hyperprolactinemia interrupts pulsatile secretion of GnRH, inhibits release of LH and FSH and directly impairs gonadal steroidogenesis
what endocrine disorders are girls with Turners syndrome more at risk for
IBD
Hashimotos
Graves
Coeliac
Hypothyroidism
delayed puberty (only 30% will have spontaneous puberty, only 2-5% spontaneous menses, thus most have secondary ovarian failure soon after starting puberty)
premature ovarian failure/ovarian dysgenesis
infertility
Short stature –> need GH
Osteoporosis due to gonadal failure
Rx: GH
Ostrogen at 11-12 years (transdermal) and progesterone after 2 years of oestrogen treatment
up to 90% have progressive SN hearing loss
Infantile presentation of Klinfelter syndrome
Micropenis
Hypospadias
Cryptorchidism
However most will have no features in the post natal period
what would FSH, LH show in premature thelarche
Elevated FSH
Low LH
treatment in Klinfelters
60% will enter puberty spontaneously
Consider testosterone
treat cryptorchidism
Vit D, calcium - for bone health
Avoid high LH levels as this can reduce bone strength
Comorbidities associate d with Klinfelters
Hypothyroidism
metabolic syndrome
diabetes
obesity
Breast cancer
Osteoporosis , fractures
Epilepsy
Depression/anxiety
