Delayed and precocious puberty Flashcards
What in particular should be done when assessing the karyotype in Turner’s?
Examination of at least 20 cells
Because of the likelihood of Mosaicism
How should pubertal induction be done in delayed puberty due to hypergonadotrophic hypogonadism?
Always commence oestrogen alone for induction of puberty - timing/duration depends on age
If identified in childhood:
- start age 10 year
- Low dose 6.25mcg transdermal oestradiol patches
- Initially at night time
- Dose increased at 6 monthly intervals
- Progesterone introduced after 2-3 years
If identified in adolescence (most cases):
- Start low dose transdermal estradiol 12.5 mcg
- Commence progesterone after 6-12 months, or if breakthrough bleeding starts
- Progesterone usually given as medoxyprogesterone or micronised progesterone for 14 days in luteal phase
- Can be transitioned to COCP for long term MHT treatment until age of menopause
What is the definition of delayed pubertal development in girls?
Absence of secondary sexual characteristics by age 13
(or 14 in boys)
What is the definition and presentation of precocious puberty?
Onset of pubertal development before the age of 8 (girls) or 9 (boys)
Presentation:
Girls - breast buds and pubic hair growth <8yo OR menarche <9yo
Boys - testicular volume >4ml and pubic hair growth <9yo
What is the classic triad of findings in McCune Albright syndrome?
Skin: Cafe au lait skin lesions
Bone: Fibrous dysplasia of bones. Normal bone tissue replaced by fibrous tissue- results in weakening, lytic lesions. Fractures and skeletal abnormalities etc.
Endocrine: Gonadotrophin-independent precocious puberty (often around age 5) due to oestrogen released from ovary in high amounts. Can also have hyperthyroidism, cushing’s, acromegaly, hyperprolactinemia
What proportion of precocious puberty is caused by central causes vs peripheral causes
Central = 80% Peripheral = 20%
What are central / gonadotrophin dependent causes of precocious puberty?
- Majority idiopathic 75%
- Intracranial causes
- Brain tumours (either direct or indirect effect on GnRH)
- Congenital CNS malformations (arachnoid cysts, myelomeningocele, hydrocephalus)
- CNS injury (trauma / infection / bleed / post irradiation)
- Paraneoplastic syndromes
- germ cell tumours secreting HCG (gonads, liver, brain, mediastinum)
- hepatoblastoma
- germ cell tumours secreting HCG (gonads, liver, brain, mediastinum)
What are peripheral / gonadotrophin independent causes of precocious puberty?
Any cause of elevated oestrogen or androgens from a peripheral source - The HPG axis is not activated
- Benign follicular ovarian cysts are commonest cause.
- Hormone-producing ovarian tumours (granulosa cell tumours, sertoli-leydig cell tumours)
- McCune Albright Syndrome: mutation of the GNAS1 gene. Classic triad is follicular ovarian cysts and precocious puberty, cafe au lait spots, fibrous dysplasia of bones.
- Exogenous administration of oestrogen
- Adrenal causes:
- CAH is commonest cause of androgen excess in boys and girls.
- Adrenal tumours (DHEAS +++)
- Severe longstanding hypothyroidism
Additional causes in boys:
Testosterone secreting tumours of the testis
Paraneoplastic germ cell tumours secreing HCG - stimulate LH receptors on testes.
What investigations are useful in precocious puberty?
Investigation should be undertaken by a paediatric endocrinologist - not usually gynaecologist.
From O&G Magazine (2017) and TOG 2012:
- A careful history and examination are essential
- A growth assessment should include height, height velocity, weight and body proportions - plotted on age specific growth charts
Bloods:
- Serum LH and FSH levels (baseline)
- GnRH (LHRH) stimulation test (LH and FSH) (performed as a day case, with a stimulated LH >5IU/L being considered abnormal (sensitivity >98%, specificity 100%)).
- Estradiol/testosterone levels
- Adrenal steroids, e.g. 17 OH progesterone, DHEAS and androstenedione (raised in CAH and adrenal tumours)
- Adrenocorticotrophic hormone stimulation test (to identify steroid synthesis defects, e.g. CAH)
- Free thyroxine and TSH
- Serum prolactin levels (may be raised in chronic hypothyroidism, McCune–Albright syndrome or prolactinomas or point towards pituitary stalk compression)
- Urinary steroid profile (to identify and quantify excess adrenal androgens)
Imaging
- Left wrist X-ray for bone age
- Pelvic ultrasound (size, shape of uterus, endometrial thickness and ovarian morphology)
- Cranial magnetic resonance imaging/computed tomography (CT) for central causes
- CT adrenals (adrenal masses) if adrenal causes
- Skeletal survey/bone scan (McCune–Albright syndrome)
What is the treatment of precocious puberty?
Ususally under care of paediatric endocrinologist
Main aim is to slow growth trajectory and bone age
Not all children need treatment i.e. if close to normal age of puberty and no underlying pathology identified, adult height may be unaffected
Central / gonadotrophin-dependent cause:
- GnRH analogues (leupoprelin or goserelin) to supress GnRH secretion from hypothalamus and thus reduce FSH/LH release
- 3-6 monthly height and tanner stage assessment
- Annual bone age X-ray assessment
- Treatment withdrawn at age 10-11 to allow normal puberty to progress at the correct time
Peripheral Gondaotrophin-independent cause:
Treat underlying cause (i.e. surgical excision of ovarian tumours/cysts)
McCune Albright - Vitamin D, bisphosphonates, some evidence for estrogen supression with aromatase inhibitors (letrozole) and SERM (tamoxifen) - but safety concerns
What is the prevalence of Turner Syndrome
1:2500 female live births
What are antenatal USS features of Turner Syndrome
Increased nuchal thickness/translucency
Cystic hygroma
Cardiac anomalies - bicuspid aortic valve, coarctation of the aorta
Renal anomalies - horseshoe kidney, pelvic kidney
Non-immune fetal hydrops
Fetal growth restriction
Short limbs
How does Turner Syndrome present
Heterogenous due to possible mosaicism 45XO/45XX - usually milder phenotype than pure 45XO
Classic triad:
- infertility (95%)
- Delayed puberty or primary amennorrhea (Premature ovarian failure +/- streak gonads)
- Short stature
Other features:
Facial features: sloping eyes, high palate, low set ears, strabismus
Broad/’shield’ chest with Widely spaced nipples
Short and webbed neck
Short 4th metacarpal
Lymphoedema
Cardiac anomaly: coarctation of the aorta, bicuspid aortic valve
Renal anomaly: horseshoe kidney, pelvic kidney
Endocrine: hypothyroidism, insulin resistance
What is the management of Turner Syndrome?
Genetic councelling
Psychosocial support
Administration of growth hormone to improve adult height
Induction of puberty
Lifelong MHT with oestrogen and progesterone
IVF with donor egg when fertility required
In cases with Y chromosome mosaicism and gonadal dysgenesis, the streak ovaries thould be removed due to increased risk of gonadoblastoma and malignant change
Management of associated endocrine abnormalities (hypothyroidism, insulin resistance)
Management of cardiac or renal abnormalities (bicuspid aortic value, coarctation of aorta, horseshoe kidney etc)
What are the genetics of Kallman’s syndrome?
Most cases are sporadic, without prior family history.
X-linked disorder owing to a mutation to the KAL-1 gene.
Can also be inhertied in austosomal dominant and autosomal recessive by a variety of other mutations.
What is the pathophysiology of Kallman’s syndrome?
Most cases are X-linked inheritance of mutation of Kal-1 gene (can also by AD and AR of different mutations)
Dysgenesis of the olfactory bulbs, causing anosmia
GnRH releasing neurons which originate from the nasal region during embryogenesis are unable to migrate to their position in the hypothalamus due to abnormal development of the olfactory neurones
GnRH deficiency causes hypogonadotrophic-hypogonadism
What are the clinical features of Kallman syndrome?
More commonly affects males, but can affect females
- Anosmia or hyposmia
- Small or undescended testis
- micropenis
- Delayed puberty
- Infertility
- Reduced libido, erectile dysfunction
- Commonly there are associated midline structural defects - cleft lip/palate, missing teeth
- Sensorineural hearing loss
- Renal agenesis
Females may also present with:
- Delayed puberty - absent breast development
- Primary amennorrhea
What are the two broad categories of causes of delayed puberty
Central = Hypogonadotrophic hypogonadism
Peripheral = Hypergonadotrophic hypogonadism / premature gonadal failure
How does delayed puberty due to hypogonadotrophic (central) hypogonadism present? What is the pathophysiology of this?
Abscence of the pubertal growth spurt and development of secondary sexual characteristics by 13 years old
Deficiency of GnRH secretion, causing reduced LH/FSH secretion and low levels of sex hormone secretion.
How does delayed puberty due to hypergonadotrophic (peripheral) hypogonadism present? What is the pathophysiology of this?
Abnormal gonadal development
Non-functioning gonad which does not secrete normal levels of sex hormone, therefore the abscence of negative feedback on the hypothalamus and anterior pituitary results in uninhibited, high levels of FSH/LH
What are the differential diagnoses for delayed puberty due to hypogonadotrophic hypogonadism?
- Constitutional delay (check FHx)
- Hypothalamic causes
- Functional - Anorexia nervosa, Excessive exercise
- Kallman’s syndrome
- craniopharyngioma
- Pituitary causes (hyperprolactinemia)
- Chronic illness - diabetes, chronic renal failure, CRF
- Pressure on pituitary stalk - Hydrocephalus, CNS tumours
- Pituitary adenomas
- empty sella syndrome
What are the differential diagnoses for delayed puberty due to peripheral / hypergonadotrophic hypogonadism?
= Premature ovarian failure
Congenital
- Turners syndrome (45XO or mosaicism)
- Klinefelters (47XXY)
- Swyer syndrome (46XY)
- Pure gonadal dysgenesis
- Fragile X premutation syndrome
Acquired
- Radiotherapy/chemotherapy/ surgical excision
- autoimmune oopheritis
- Mumps / TB oophoritis
What is the management of delayed puberty?
Hypergonadotrophic hypogonadism:
- Counselling and support
- Pubertal induction with transdermal estradiol, and later introduction of progesterone
- MHT till menopause
- IVF and donors eggs
If central / hypogonadotrophic:
- constitutional requires no intervention
- Puberty can be induced by pulsatile gonadotrophins
List the causes/aetiology of hyperandrogenism in women.
Ovarian sources:
- PCOS (commonest 70% cases)
- Krukenberg ovarian tumours (secrete HCG which acts on LH receptors of theca cells)
- Sertoli-leydig ovarian tumours
- Insulin resistance and hyperinsulinemia (insulin acts on theca cells to increase androgen secretion)
Adrenal sources:
- Congenital adrenal hyperplasia: 21-hydroxylase deficiency leading to defective conversion of 17-OH progesterone to 11-deoxycortisol (precursor cortisol), and of progesterone to 11-deoxycorticosterone (precursor aldosterone)
- Adrenal tumours
- Cushings syndrome
What are the long term implications of precocious puberty?
- Stunted growth - althrough initially children will experience accelerated growth, the advanced bone age and early ossification of the epiphyses of long bones
- Body image dysmorphia
- Emotional distres from looking different to peers
- Behavoural issues from being treated older than their cognitive age - bullying and risk taking behaviour, early sexuality
How does isolated thelarche normally present? How is it managed?
Often presents by age 3 with isolated unilateral or bilateral breast buds, but no other secondary sexual characteristics.
It is a benign self-limiting condition with no effect on growth.
No treatment required. Resolves with 1-2 years.
How does isolated adrenarche present?
How is it investigated?
And managed?
- Usual onset 6-9 yo
- Isolated pubic hair development, +/- growth spurt
IX:
- Bone age Xray left hand/wrist
- Screen for adrenal causes and CAH (17-OH progesterone, DHEA, testosterone)
Rx:
- If pathology excluded, no treatment required, and parents can be reassured growth and puberyt will occur at the normal time
- CAH = glucocorticoid (dexamethasone) +/- mineralocorticoid (fludrocortisone) replacement
What is the cause and presentation of klinefelters syndrome?
- 47XXY
- Often noticed at puberty when delayed onset of puberty due to primary gonadal failure
features:
- Delayed puberty
- Tall stature
- small testis
- infertility
- gynaecomastia
- sparse body hair
What is the incidence of precocious puberty?
1 / 5000 to 1 / 10,000
10 times more common in females
How is a GnRH stimulation test interpreted?
- A GnRH stimulation test is performed as a day case
- Prepubertal girls and isolated thelarche usually have FSH predominant response to exogenous GnRH
- Pubertal girls (and those with precocious puberty) usually have an LH predominant response to GnRH
- Stimulated LH >5IU/L is considered abnormal (sensitivity >98%, specificity 100%).
- A supressed LH and FSH is indicative of peripheral / gonadotrophin-independent precocious puberty
What should be part of the history for precocious puberty?
- Age of onset, sequence and progression of pubertal changes
- Family history: timing of onset of puberty in mother and siblings
- Neurological symptoms
- Exogenous sex steroid exposure in food, drugs or cosmetics (e.g. steroid creams, estrogen, anabolic steroids)
- Social history: history of adoption or child sexual abuse
What should be part of the examination for precocious puberty?
• Height and weight measurements plotted using age-specific growth charts
- Body mass index
- Pubertal Tanner staging
- Neurological examination
- Examination of eyes including visual fields and fundoscopy
- Skin lesions (e.g. caf ́e au lait spots)
- Abdominal examination (ovarian masses)
- Examination of external genitalia
- Signs of virilisation: clitoromegaly, deepening of voice, hirsutism
