Development Flashcards
What is thelarche?
Onset of female breast development
What is pubarche?
Appearance of sexual hair
What is adrenarche?
Onset of androgen-dependent body changes such as growth of axiliary and pubic hair
Whati s the definition of delayed pubertal development in girls?
Absence of breast development by age 13 Or No menarche by age of 16 or 3 years after breast development
What is the age of pubertal development in girls?
8-12
What hormonal changes lead to the onset of puberty?
Pulsatile secretion of GnRH begins Pulsatile secretion of LH and FSH from anterior pituitary HPO axis is activated Sexual maturation
What criteria forms the diagnosis of primary amenorrhea?
The absence of menses at age 16 in the presence of normal growth and secondary sexual characteristics If by age 13, menses has not occurred and the onset of puberty, such as breast development is absent, a work up for primary amenorrhoea should be considered
What are the top three causes of primary amenorrhoea?
Gonadal dysgenesis (46%) - 45 XO, 46XX (POI), 46XY GD Mullerian agenesis (15%) - MKRH Physiological delay of puberty (14%) - Constitutional, chronic systemic illness, acute illness
What is the incidence of ambiguous genitalia?
1:4000
What are three conditions that can cause ambiguous genitalia in an infant with a normal female karyotype?
Congenital adrenal hyperplasia Exposure in utero to increased maternal androgens Placental aromatase deficiency
What are five causes of ambiguous genitalia in an infant with a normal male karyotype?
Partial gonadal dysgenesis Complete androgen insensitivity syndrome Partial androgen insensitivity syndrome Defect in testosterone biosynthesis 5-alpha reductase deficiency
What is the Prader Staging System and the Stages
Staging system for degree of sexual ambiguity 1. Isolated clitoromegaly 2. Narrow vestibule with separate urethral and vaginal opening 3. Single urogenital sinus / labia majora partially fused 4. Microbe is 5. Isolated crypto-orchidism
Almost half of the newborns with ambiguous genitalia suffer with ___ and are at risk of ______________________
CAH Salt-losing crisis Hypoglycaemia and electrolyte disturbances should be assessed and treated urgently Lifelong steroid treatment will be required
What is the incidence of congenital adrenal hyperplasia?
1:10,000
What is the pathophysiology of Congenital adrenal hyperplasia?
Enzyme deficiency in the corticosteroid production pathway 21-hydroxylase (90%), followed in frequency by 11-beta-hydroxylase Production of cortisol is decreased ACTH is increased as a result of negative feedback This leads to hyperplasia of the adrenal gland Increased levels of 17-OHP are shunted towards the production of androgens
How is congenital adrenal hyperplasia diagnosed?
Raised serum levels 17-OHP (17-hydroxyprogesterone) In equivocal cases, the levels of cortisol and 17-OHP are measured 30 and 60 minutes after the administration of synthetic ACTH (Synacthen test)
What are the anatomical abnormalities seen in Congenital Adrenal Hyperplasia?
Varying degrees of virilisation Clitoral enlargement, scrotal appearance of the labia majora, single urogenital sinus Vagina can join the posterior wall of the urethra at varying levels
What is the incidence of partial and complete androgen insensitivity?
1:40-60,000 births CAIS > PAIS
How is Partial and complete androgen insensitivity syndrome inherited?
X-linked inheritance in 2/3 of cases
What is the pathophysiology of Partial and complete androgen insensitivity?
Normal testicular production of androgens Abnormal androgen receptors Virilisation of external genitalia is incomplete or absent because it is dependent on androgen receptor activity As the testes produce AMH, Mullerian structures regress The Fallopian tubes, uterus and upper 2/3 of the vagina are absent
What is the presentation of CAIS?
- Normal female appearance: normal breast development - Primary amenorrhoea (commonest presentation) - Scant or absent pubic / axillary hair - Blind vaginal pouch, UNambiguous labia and clitoris.
What is the presentation of PAIS?
Varying degrees of virilisation, ranging from defects in spermatogenesis and isolated hypospadias to ambiguous genitalia During puberty, some degree of virilisation occurs (as opposed to CAIS)
How is PAIS/ CAIS diagnosed? What investigations should you do in a work-up for CAIS and PAIS?
- Karyotype: 46XY - Testosterone level: normal adult male level - LH level: normal - Inhibin B level: mid-normal male range; related to uninhibited Sertoli cell function. - USS or MRI pelvis: to locate testes - hCG stimulation test (in the presence of ambiguous genitalia or normal female external genitalia): normal rise of testosterone
What is the management of CAIS / PAIS?
Disclosure of XY karyotype Psychological support Info: unable to menstruate or carry a pregnancy Hormone replacement therapy: oestrogen Vaginal dilatation to allow for intercourse Consideration of gonadectomy - ideally pre-pubertal in PAIS to avoid virilisation
What is the incidence of 5alpha reductase deficiency?
Unknown Geographical variation reported Increases with consanguinity
What is the pathophysiology of 5-alpha reductase deficiency
Deficiency in the enzyme that Converts testosterone to Di hydro testosterone DHT is a potent androgen that is required for fetal genital virilisation
How does 5-alpha reductase deficiency present?
Female or ambiguous genitalia at birth Virilisation during puberty
How is 5-alpha reductase deficiency diagnosed?
Normal basal and HCG stimulated testosterone Decreased DHT (Dihydrotestosterone) Measurement of 5-alpha reductase activity in genital skin fibroblasts
What is the prevalence of uterine anomalies?
0.5% - 6% (Oxford Training in O&G Book)
Uterine anomalies are the result of abnormal development of the…
Müllerian ducts during embryogenesis
What is the ASRM Classification of uterine anomalies
- Segmental hypoplasia or agenesis involving the vagina, cervix, uterus or tubes 2. Unilateral hypoplasia or agenesis 3 and 4. Failure of fusion of Müllerian ducts 5. Non-resorption of the midline septum 6. Arcuate uterus 7. Anomalies relating to in utero diethylstilboestrol (DES) exposure
What is the definition of MRKH?
Mayer-Rokitansky-Koster-Hauser syndrome Absent or rudimentary uterus or bilateral rudimentary horns on either side of the pelvic wall
What is the incidence of MRKH?
1:4000-6000
How does MRKH present?
Normal development of secondary sexual characteristics (indicating normal ovarian function) Primary amenorrhoea Short vagina Associated with renal and skeletal anomalies
What is the definition of puberty?
The period between childhood and adulthood when reproductive and sexual development and maturation occurs
Thelarche precedes menarche by how long?
An average of 2-3 years
What is the definition of precocious puberty?
Onset of pubertal development before the age of 8 (girls) Or 9 (boys) Female 5: male 1 (more common in females)
What is the classic triad of findings in McCune Albright syndrome?
Cafe au last skin lesions Polyostotic fibrous dysplasia Gonadotrophin-independent precocious puberty
What proportion of precious puberty is caused by central causes vs peripheral causes
Central = 80% Peripheral = 20%
What are central causes of precocious puberty?
Majority idiopathic 75% Brain tumours CNS malformations
What are peripheral causes of precocious puberty?
Pseudo puberty is always pathological Hormone-producing ovarian tumours Exogenous administration of oestrogen McCune Albright Syndrome: mutation of the G protein gene, leads to its continuous activation despite the absence of a hormonal stimulation
What investigations are useful in precocious puberty?
- LH and FSH (serum gonadotrophin levels) - suppressed with peripheral causes and elevated with central causes 2. Brain imaging - in cases of central causes, to detect a lesion 3. Pelvic and abdominal imaging - to detect ovarian or adrenal tumours
What is the treatment of precocious puberty?
Normally done by an Endocrinologist Slow growth velocity and avoid early skeletal maturation If produced by a lesion, surgical resection can be attempted Pubertal development can be suppressed with GnRH analogues - which lead to downregulation of pituitary GnRH receptors and suppression of gonadotrophin production (LH and FSH)
What is the incidence of Turner Syndrome
1:2500 female live births
What are antenatal USS features of Turner Syndrome
Cystic hygroma Non-immune hydrops Fetal is Fetal growth restriction
How does Turner Syndrome present
Short stature Gonadal failure, POI. Occurring in most cases before the onset of puberty but in 1/3 of patients, after menarche Widely spaced nipples Short and webbed neck, low hairline Lymphoedema Cardiac anomaly: coarctation of the aorta Renal anomaly: horseshoe kidney Endocrine: hypothyroidism, insulin resistance
What is the management of Turner Syndrome?
Administration of growth hormone to improve adult height Induction of puberty Long-term hormone replacement Childbearing possible with ovum donation
What are the genetics of Swyer syndrome?
46XY Mutation in SRY gene in 10%
Swywer syndrome:
What is the pathophysiology of Swyer syndrome?
- 46XY with complete gonadal dysgenesis / failure of testicular development.
- Caused by mutation on SRY gene leading to failure of the indifferent gonad to differentiate into a testis.
- No testosterone production leading to:
- Failure for Wolffian ducts to develop.
- No DHT and failure to virilise external genitalia; normal female external genitalia.
- No AMH production leading to persistance of Müllerian ducts and presence of uterus, tubes, cervix and upper vagina.
What is the presentation of Swyer syndrome?
- Absence of pubertal development:
- Absence of breast development
- Primary amenorrhoea
- Sparse pubic hair
- Female external genitalia
- Presence of uterus, fallopian tubes, cervix, vagina
- Tall stature
- 30% risk of developing gonadal malignancy.
What investigations are appropriate for Swyer syndrome?
- FSH and LH levels: elevated
- Karyotype
- Pelvic imaging: uterus, tubes, no ovaries
- Assessment for mutation in SRY gene
What is the management of Swyer syndrome?
- Induction of puberty
- Gonadectomy as risk of malignancy
- Long-term HRT
- Childbearing is possible with ovum donation and HRT.
What are the genetics of Kallman’s syndrome?
X-linked disorder owing to a mutation to the Kal-1 gene
What is the pathophysiology of Kallman’s syndrome?
Dysgenesis of the olfactory bulbs and abnormal development of GnRH neutrons, which also originate from the nasal region during embryogenesis
What are the clinical features of Kallman syndrome?
Delayed puberty Anosmia or hyposmia Commonly there are associated midline structural defects and mental retardation
What are the two broad categories of causes of delayed puberty
Central = Hypogonadotrophic hypogonadism Peripheral = Hypergonadotrophic hypogonadism
How does delayed puberty due to hypogonadotrophic (central) hypogonadism present? What is the pathophysiology of this?
Constitutional delay, often following a familial pattern No pituitary of hypothalamic stimulation of the gonad Low FSH
How does delayed puberty due to hypergonadotrophic (peripheral) hypogonadism present? What is the pathophysiology of this?
Abnormal gonadal development Non-functioning gonad with high FSH
What are the differential diagnoses for hypogonadotrophic hypogonadism?
Chronic illness - diabetes, chronic renal failure, CF Anorexia nervosa Excessive exercise Kallman’s syndrome Hydrocephalus or CNS tumours Pituitary adenomas (usually prolactinomas) Panhypopituitarism
What are the differential diagnoses for hypergonadotrophic hypogonadism?
Turner Syndrome Swyer syndrome Premature ovarian failure Following chemotherapy or radiotherapy Galactosaemia Autoimmune Infections
What is the management of delayed puberty?
Pubertal induction Small dose of COCP, slowly increased If central / hypogonadotrophic: can be induced by pulsatile gonadotrophins Long term HRT
What is premature adrenarche? What is the clinical presentation? What is the cause?
- Appearance of pubic or axillary hair <8 years in girls without other signs of virilisation and without a major advance in bone age. - Rare genetic defect in DHEA sulfation
List the primary and secondary causes/aetiology of hyperandrogenism in women:
Primary adrenal causes: - Premature adrenarche - Adrenal tumours Secondary (ACTH-dependent) causes: - Congenital adrenal hyperplasia: 21-hydroxylase deficiency leading to defective conversion of 17-OH progesterone to 11-deoxycortisol. - Cortisone reductase deficiency - Primary familiar or sporadic glucocorticoid resistance syndrome.
Describe the main production pathway of androgens in women:
- Occurs in adrenal glands. - Androgens are by products of cortisol production and influenced by ACTH. - Primary andrenal androgen products are DHEA and DHEA sulfate. They are converted into androstenedione and then testosterone (and oestrogen) in adrenals and peripheral tissues.
You are investigating a woman for hyperandrogenism: What investigations would you perform? How might the androgen panel results suggest an origin of the hyperandrogenism?
Androgen panel: DHEA, DHEA sulfate, testosterone levels. - High levels of DHEA and DHEA sulfate suggest andrenal origin. - High levels of testosterone (>200) suggest either adrenal or ovarian origin. CT/MRI adrenal: look for tumours.
What hormone plays a permissive role in the development of puberty>
Lepton Metabolic hormone produced by adipose tissue in response to fat deposition
Thelarche precedes menarche by…
2-3 years Initially, GnRH, LH and FSH are only produced nocturnally and lead to a moderate rise in circulating oestrogen levels GnRH, LH and FSH have to be circulating all day for ovulation and the menstrual cycle to become established
