Paed and adolescent gynaecologist Flashcards
Hormone changes for normal puberty
Pulsatile secretion of GnRH, initially occurs at night time only, then progresses to daytime secretion
During this time levels of LH and FSH, increase in pulsatility and amplitude
Pulses then stimulate a rise in estradiol levels
Normal puberty begins:
- 8-12y in girls - 9-14y in boys
Briefly describe Tanner stages
I - pre-puberty
II - buds, few hairs
V - fully formed and adult shape pubic hair, extends to thighs
Define Precocious puberty
Incidence
Usually as the development of secondary sexual characteristics before age 8 in girls, 9 in boys
Or the onset of periods before age 9 in girls
2%
Causes of precocious puberty
CENTRAL - more common. Sequential development - growth, breasts, pubic hair, then menarche
- Idiopathic (80%)
- Destruction from tumour or SOL
- Excessive pressure e.g. hydrocephalus
- Meningitis
- Head injury
- Irradation
- Neurofibromatosis type 1
PERIPHERAL - relatively uncommon in girls, always pathological
- Granulosa cell tumour (oestrogen)
- Androgen secreting tumour - sertoli-leydig tumour
- Exogenous sex steroids
- McCune Albright syndrome
McCune Albright syndrome
Triad of fibrous dysplasia of bone (abnormal bone cysts), café au lait spots and endocrinopathies especially GnRH independent precocious pseudopuberty
Rx: suppression of gonadal steroidogenesis with aromatase inhibitors
History features for precocious puberty
Age of onset, sequence and progression of pubertal changes
FHx: pubertal onset of parents and siblings
Linear growth acceleration
Neurological symptoms
Behavioural changes
Abdominal pain or bloating
- Suggestive of ovarian tumour or cyst
Previous Hx CNS disease
History of exposure to exogenous sex steroids
- E.g. to treat severe asthma
History of trauma
Exam for precocious puberty
Height, weight BMI Skin exam - any café au lait spots Pubertal Tanner staging Neurological exam Abdominal exam Examination of external genitalia Signs of virilisation - clitoromegaly, deepening of voice, hirsutism
Ix for precocious puberty
Hormone profile - LH, FSH, E2, testosterone
Adrenal steroids
- DHEAs
- 17-OH progesterone
- Androstenedione
TFTs, free thyroxine
Prolactin
- May be raised in chronic hypothyroidism, McCune-Albright syndrome, prolactinomas, or pituitary stalk compression
Pelvic and abdominal US
Left wrist X-ray - bone age
Directed imaging
- CT/MRI brain, adrenals
Consequences of precocious puberty
Short adult stature due to premature epiphyseal closure
Psychosocial problems
- Pubertal levels of sex steroids --> adolescent behaviour - Altered self image - Girls are at increased risk of sexual abuse and early pregnancy
Treatment of precocious puberty
Goal of treatment:
- Halt or cause regression of secondary sexual characteristics
- Prevent early menarche
- Retard skeletal maturation and improve final height
- Avoid psychosocial / behavioural sequelae
Paediatric endocrinologist
Central idiopathic precocious puberty
- GnRH analogues - suppress natural GnRH production - Continue until 10-11y
3-6 monthly clinical assessment
Annual bone density assessment
Peripheral
- Surgery
- remove oestrogen exposure
Definition of delayed puberty
Absence of breast development by age 13
Or no menarche by 3y after breast development (or age 16)
Aetiology of delayed puberty
Hypogonadotropic hypogonadism
- Central defect - no pituitary or hypothalamic stimulation of the gonad and low FSH
Constitutional delay – often familial pattern
Chronic illness e.g. diabetes, CF, renal failure
Anorexia nervosa
Hydrocephalus or CNS tumours
Kallmans Syndrome
Hypergonadotropic hypogonadism No functioning gonads, high FSH Abnormal gonadal development Turner Syndrome Following Chemotherapy or Radiotherapy Galactosaemia
Genital bleeding in childhood - differentials
Vulvovaginitis Foreign body Genital trauma - Inadvertent or deliberate Neoplasm Neonatal estrogen withdrawal bleed Premature menarche or precocious puberty Urethral prolapse UTI Labial adhesions Dermopathy - Contact / allergic, dermatitis, lichen sclerosis, eczema, psoriasis Pinworms with excoriation
Vulvovaginitis
- Pathogenesis
Children lack the protection that women have
- Lack of vaginal oestrogen (skin is therefore thin and delicate)
- Lack of labial hair and fat pads
Proximity of anus
Other contributing factors can include:
- Poor perineal hygiene
- Chemical irritation due to bubble baths and detergents
Treatment of vulvovaginitis
Information (written) Reassure Improved hygiene - Wipe from front to back - Avoid soaps / bubble baths - Urinating with knees apart - Cotton underwear
Barrier creams or emollients
Children nearly always grow out of it by puberty
Probiotics
Labial adhesions / fusion
Incidence
Up to 3.3% of pre-pubertal girls
Peak incidence is in the first year of life
Never present at birth
Likely from lack of oestrogen
Treatment of labial adhesion
Reassure await resolution
Avoid traction, oestrogen, steroids
Topical oestrogen if urinary symptoms
- Short course, 6 weeks (max)
Primary vs. secondary dysmenorrhoea
Primary = menstrual pain in the absence of any organic cause, which occurs within the first three years of menarche
- often crampy
Secondary = crampy pain a/w menses due to organic disease - e.g. endo, adenomyosis, adhesive disease, outflow tract obstruction
Associated symptoms of primary dysmenorrhoea
- N/v
- Fatigue or weakness
- Changes in bowel movements
- Backache
- Headache
- Breast tenderness
- Dizziness
Significant impact on QoL
- Absenteeism, academic performance, social activities, difficultly concentrating, mood
Pathophysiology of primary dysmenorrhoea
Multifactorial
- Excess prostaglandin production –> uterine contractions
- Narrow cervix
- Retrograde menstruation
Management of primary dysmenorrhoea
Consider 3/12 course of NSAIDs prior to investigations (e.g. Ponstan / mefenamic acid 500mg TDS, day prior to period starting)
NSAIDs - ibuprofen, mefanamic acid, naproxen
- Reduces volume of menstrual flow if started at onset of bleeding and taken at appropriate dose and frequency
- Inhibit COX 1/2 enzymes –> reduced PG and thromboxane production
Cochrane 2015
- Significantly more effective than placebo in relieving pain
- Differences between NSAIDs not shown
- Adverse events with NSAIDs only slightly raised
COCP containing levonorgestrel
- Reduce menstrual flow and pain by 50%
TXA - Reduces flow, less bleeding = less pain
Progesterone oral therapy - cyclical provera
Mirena IUS
Self-care / alternative therapies
Primary amenorrhoea
definition and incidence
Primary amenorrhoea is rare - 0.3%
Defined as the absence of menses at age 16 in the presence of normal growth and secondary sexual characteristics
Or if 14y with no secondary sexual characteristics
Causes of primary amenorrhoea
ANOMALIES OF OUTFLOW TRACT - 20%, normal FSH and E2
Imperforate hymen
Transvaginal septum
Mullerian dysgenesis (MRKH syndrome)
Complete androgen insensitivity syndrome
PRIMARY OVARIAN INSUFFICIENCY - 40%, high FSH, low E2
Chromosomal abnormalities - turner, Swyer, 46 XX (pure gonadal dysgenesis)
Single gene mutation - fragile X
Autoimmune disorders
Injury - mumps, chemo
CENTRAL - 35%, low FSH and E2 Weight loss / anorexia Idiopathic hypogonadotrophic hypogonadism Tumour Hyperprolactinaemia
OTHER ENDOCRINE
PCOS
Thyroid
Investigations of primary amenorrhoea
Bloods
- HCG
- FSH, LH, oestradiol, 17-OH progesterone, prolactin, TFT, testosterone, DHEA, SHBG,
Karyotype
Abdominal / pelvic US
○ Uterus absent or abnormal –> karyotype
- 46, XY –> androgen insensitivity syndrome
- 46, XX –> Mullerian agenesis
+/- MRI
Bone age
Idiopathic hypogonadotropic hypogonadism
causing primary amenorrhoea
Genetic disorders that affect the production and/or action of GnRH, resulting in reduced serum levels of sex steroids
Have normal ovaries
In females, onset of adrenarche with absent of thelarche and menarche
- Pubertal induction for breast development and uterine growth with oestradiol
- Maintenance of normal menstrual cycle and bone health with COCP
- Pregnancy can be achieved in patients who have received and responded to treatment
Weight / exercise related
causing primary amenorrhoea
Reduced fat cells –> no leptin –> informing the hypothalamus that not well fed enough to reproduce –> reduced FSH/LH –> low oestradiol
In order to normalised pubertal development and optimise growth, calorie intake and energy expenditure should be adjusted
Estrogen therapy and current bone age assessment may be considered
Optimise vitamin D and calcium
HHEEEEADDSS
H: - Home (Family) - Housing E: - Education - Employment - Eating - Exercise A: - Activities (Friends) D: - Drugs - Depression S: - Sexuality Suicide
Disorders of sexual differentiation / development (DSD)
Patients with genital appearance that is atypical or discordant with chromosomal sex
Use terms: ‘typical male’ and ‘typical female’
Ambiguous genitalia
- incidence
- causes
1 in 4500 live births
XX KARYOTYPE
Congenital adrenal hyperplasia
- Most common cause of ambiguous genitalia
Exposure in utero to maternal androgens
Placental aromatase deficiency
- Leads to increased fetal androgen production –> virilisation of both mother and fetus
XY KARYOTYPE Partial gonadal dysgenesis Partial AIS Defect in testosterone biosynthesis 5 alpha reductase deficiency - Enzyme deficiency - usually converts testosterone to DHT (potent androgen required for fetal genital virilisation)
History for ambiguous genitalia
History of maternal drug use
- E.g. progesterones can cause virilisation, cyproterone which causes under-masculisation
Virilisation in the mother during pregnancy
- E.g. poorly controlled CAH
- Placental aromatase deficiency leads to increased fetal adrenal androgens which in turn cross the placenta virilising both mother and fetus
Family history of CAH and X linked disorders
History of consanguinity
Pathophysiology of AIS
Karyotype 46 XY
X-linked recessive condition
Defect in androgen receptor gene
- Androgen receptors in the body cannot respond to testosterone and dihydrotestosterone
Gonads = testes (regardless of complete, partial or mild)
- Produce testosterone
- Produce AMH
Complete AIS
1 in 20,000
Phenotypically female with normal breast development but sparse pubic hair
- At puberty, testosterone converts peripherally to oestrogen so secondary characteristics start to develop
Primary amenorrhoea as no uterus
After puberty:
- Serum testosterone concentrations are high-normal to slightly elevated for typical post-pubertal boys
- Estradiol levels are in the upper typical male reference range
Vaginal development is variable but vaginal hypoplasia is common
Mild AIS
External genitalia of a typical male but maybe underdeveloped
At puberty:
- Gynaecomastia and virilisation
Slightly diminished secondary sexual hair
Spermatogenesis mostly severely impaired
No gonadectomy, but surveillance recommended
Partial AIS
External genitalia are partially but not fully masculinised = ambiguous
Management of AIS
Psychological support
Sex assignment
- if partial AIS and presenting with ambiguous genitalia
Hormone replacement or supplementation
- For CAIS and PAIS who are phenotypic females
- If pubertal age - low doses of oestrogen should be begun to promote feminisation
- Adult women - give full estrogen replacement immediately
Vaginal dilators in CAIS
- high success rates 90%
Genetic counselling
- 1/3 - 1/6 that siblings carrying gene mutation
Risk of gonadal malignancy (CAIS)
- Small risk during childhood ~5%
- Increases during adulthood (~14%), therefore recommend gonadectomy in early adulthood (16-25y)
Infertility - will need donor oocyte and surrogate
Pathophysiology
of CAH
Autosomal recessive disorders
21-hydroxylase deficiency in an XX individual
- ~90-95% of CAH
- Lack of enzyme –> decrease in the level of cortisol –> increase ACTH secretion –> increase in the levels of cortisol precursors which are forced along the androgen pathway
- “Salt wasting” - severe form (occurs in 75% with classic 21 OHD). Aldosterone levels will also be low –> salt wasting, volume depletion, hypotension, reduced renal blood flow and raised renin activity
Classic CAH - 0-2% enzyme activity Nonclassic CAH (more common) - 20-50% 21-hydroxylase enzyme activity
Investigations
of CAH
Serum 17-OH progesterone - high
Low aldosterone, low cortisol, high androgens
Urea and electrolytes - abnormal in salt losing CAH - Hyponatraemia, hyperkalaemia
Management of CAH
Normal newborn care
Care for parents
Expect and manage adrenal crisis
Expect and manage electrolyte imbalance if CAH
Genital surgery - controversial, timing difficult
replace aldosterone with fludrocortisone
Replaced glucocorticoid to suppress ACTH overactivity
Pure gonadal dysgenesis definition
46XX or 46XY phenotypic females who have streak gonads and normal Mullerian structures
Genetics:
- May occur sporadically
- May be inherited as an Autosomal recessive trait or X-linked trait in XY gonadal dysgenesis
46XX gonodal dysgenesis
Typically female, often present with primary amenorrhoea, may have some breast / hair develop (from circulating androgens from the adrenals)
Average height
Underdeveloped uterus and cervix, streak / absent ovaries
Elevated FSH and no oestrogen as streak gonads produce neither steroid hormones nor inhibin
Management - through specialist
- As for primary ovarian failure
- Pubertal induction
46XY - Swyer syndrome / Complete gonadal dysgenesis
Pathogenesis
46 XY
Disorder at the start of the sex differentiation pathway
Aetiology thought to be:
- Altered SRY function due to a mutation on chromosome Y, or
- A gene on X chromosome that is necessary for SRY function
Failure of testes to develop so no testosterone or AMH produced
Clinical features of Swyer syndrome
Typical female external genitalia appearance
No breast development
Intact Mullerian structures - uterus and fallopian tubes are present
Streak gonads
Tall stature
Investigations - Raised FSH - Low E2 and progesterone - Normal female androgens USS - uterus, fallopian tubes
Management of Swyer syndrome
Need gonadal removal to avoid germ cell tumours (30%)
- Often present at puberty with gonadoblastoma
Usually proceed with pubertal induction and continue HRT to remain phenotypically female
Bone density monitoring
Psychological support
Pregnancy possible with donor oocytes
Embryology
- ovary
Primordial germ cells migrate from the gonad ridge to ~T10 level
No SRY gene –> gonads differentiate into an ovary (around week 7)
Germ cells differentiate into oogonia and enter the first meiotic division as primary oocytes, at which point development is arrested until puberty
Oocytes:
- 5 million at 20/40
- 1-2 million at birth
- 180,000 at puberty
Embryology
- internal genitalia
No SRY gene, therefore no AMH is produced and the Mullerian ducts continue to develop and the Wolffian ducts regress
Mullerian (paramesonephric) ducts develop into the fallopian tubes, uterus, cervix and upper 1/3 vagina
- starts at 6 weeks
At 8/40 - fusion of the 2 ducts to form uterus, cervix and upper vagina occurs
- tubes remain unfused
Upper vagina fused with the urogenital sinus at 12/40
Canalisation from 12/40, complete resorption by 5/12
Embryology
- external genitalia
Early in the 5th week, folds of tissue form on each side of the cloaca and meet anteriorly in the midline to form the genital tubercle
Cloaca forms from primitive hindgut, then becomes the urogenital sinus
Cloaca divided by the urorectal septum –> urogenital folds and anal folds
Genital tubercle –> clitoris
Urogenital folds (anterior cloaca) –> labia minora
Labial scrotal swellings –> labia majora
Associated abnormalities with Mullerian tract anomalies
May be associated with renal anomalies (e.g. unilateral agenesis, horseshoe kidney, pelvic kidney) in up to 40%
- Renal USS as well as part of work up
Spinal anomalies in up to 10-20%
Pregnancy complications of Mullerian tract anomalies
IUGR
- reduced intrauterine space
- Related to abnormal uterine vasculature
PTB
- Cervical incompetence has been associated
CS
- Increased malpresentation and labour dystocia
Pregnancy-associated HTN
- Attributed to coexistent congenital renal abnormalities, or abnormal uterine vasculature
Fetal malpresentation
- small uterine cavity –> inhibit fetal movement
Rupture of rudimentary horn
Subseptate / septate
- Risk of miscarriage
Causes of Mullerian tract anomalies
Most defects are likely to be related to polygenic and multifactorial causes
Three main mechanisms
Agenesis or hypoplasia
- Leads to variable uterine development and MRKH syndrome
Lateral fusion defect
- Leads to development of organs that are either symmetric or asymmetric, and non-obstructed or obstructed - e.g. bicornuate uterus, uterus didelphys
Vertical fusion defect
Leads to development of a transverse vaginal septum, segmental vaginal agenesis, and/or cervical agenesis or dysgenesis
Imperforate hymen
- incidence and treatment
1/2000
Most common outflow tract anomaly
Association with endometriosis
- consider diagnostic lap is pain continues
Excision under GA - cruciate incision and excision of flaps
Risk of vaginal stenosis - dilators post-op
Transverse vaginal septum
- cause
- management
Failed fusion and canalisation of urogenital sinus and Mullerian ducts
Normal hymenal opening visible without bulging membrane
US and MRI required to assess extent and location of septum
Consider pre-op dilation to thin septum Suppress menstruation until ready for OT If very thin, excise and anastomose May need skin or bowel graft Dilation post-op to prevent stenosis
Cervical agenesis or dysgenesis (with normally functioning uterus)
- associations
- treatment
Up to 50% will have concomitant vaginal agenesis
33% have other associated Mullerian anomalies
Traditionally - hysterectomy
Now - anastomosis of uterus or vagina - preserves fertility (theoretically)
Obstructed / non-communicating uterine horn
- presentation
- treatment
Normal menstruation and worsening dysmenorrhoea
40% renal anomaly
Remove horn laparoscopically
- Should be removed due to high rate of rupture if a pregnancy occurs in the horn
GnRH analogues pre-op to relieve symptoms
Hysteroscopic procedure to open passage
Menstrual suppression
Treatment (laparoscopic removal) is always recommended even if the horn is communicating
Septate uterus
- pathophysiology
- management
- pregnancy risks
Most common uterine anomaly
Either from defect in canalisation of the two fused mullerian ducts or from a defect in resorption of the midline septum
Increased risk spontaneous abortion, PTB, breech, abruption
Most women with septate uteri (75-80%) will have normal reproductive function
Management: resection of the septum hysteroscopically
- Some gynaecologists recommend immediate resection, others only if complications, e.g. recurrent miscarriage
- Concurrent laparoscopy to decrease risk of perforation and assess exact anomaly of uterus
Didelphys
- associations
- management
15-20% also have unilateral anomalies, e.g. obstructed hemivagina and ipsilateral renal agenesis
Septated vagina (in 75%) - may cause difficulty with sex or vaginal delivery
- can perform excision if symptomatic
removal of 1 copy not recommended as worse pregnancy outcomes
Investigations:
- Renal ultrasound - Commonly associated with renal tract abnormalities (in up to 30%)
- Need to perform cervical smears from both cervices
Fertility / chance of conceiving is usually not affected
May be at increased risk of early miscarriage or recurrent miscarriage
Resection of septum, reduces malpresentation but compromises cervical blood supply
Symptoms of longitudinal vaginal septum
Difficulty removing tampons / retained tampons
Dyspareunia
Heavy / persistent bleeding during period despite using tampon
Awareness of two vaginal passages
If an obstructive then dysmenorrhoea
- progressive pelvic pain and /or cyclical rectal pain and constipation secondary to haematocolpos
Bicornuate uterus
- management
Fundus indented >1cm, vagina and cervix generally normal
Results from partial rather than complete fusion of Mullerian ducts
Associated with cervical incompetence - recommend cervical length assessment
No evidence that procedure to join two cavities improves fertility
Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) / Rokitansky syndrome
- incidence and clinical features
1 in 5000 women
Vaginal agenesis
Normal karyotype
Variable uterine development
- Most patients have a rudimentary non-functioning uterus
- 2-7% have a uterus with functioning endometrium
Ovaries present therefore normal secondary sexual characteristics
External genitalia are normal
Vaginal dimple or small pouch
Management of Rokitansky syndrome
USS +/- MRI
Good prognosis with vaginal dilators - effective in 85%
- For vagina sufficient for intercourse
- Vaginal reconstruction surgery if not effective
Psychological support
Fertility
- Can have own genetic children using ova retrieval and ART with surrogate
In utero Diethylstilbestrol (DES) exposure
- female genital tract anomalies
Uterine anomalies
- T-shaped uterine cavity, hypoplastic cavity
Vaginal adhesions, transverse septa
Cervical anomalies - hypoplasia, pseudopolyps
Brief overview of Klinefelter syndrome
1-2.5 per 1000 boys
90% 47, XXY
10% mosaicism (47, XXY / 46XY)
High LH and FSH
Low serum free and total testosterone
Features: Tall stature Mild IQ impairment Female pubes Small balls Breasts Osteoporosis No baldness Impotence Micropenis
Turner syndrome
Features and pathophysiology
Loss of X or Y chromosome during meiosis
Unlike non-disjunctions, the incidence does not appear to rise with maternal age
~1 in 2500 female births
Can occur either in pure or mosaic forms
Short stature Gonadal dysgenesis Peripheral oedema Broad chest with wide nips Short neck Renal abnormalities (>60%) Cardiac defects in 20% Obesity and HTN
Up to 25% will enter puberty spontaneously, but only 10% will progress through puberty and only 1% will develop ovulatory cycles
- More likely in mosaicism
Management of Turner syndrome
Adolescent women with primary amenorrhoea undergo artificial induction of puberty in conjunction with specialised optimisation of growth - under paediatric endocrinologist
Uterine growth should be promoted in anticipation of potential pregnancy through oocyte donation and IVF
Pregnancy complications with turners syndrome
- PIH, PET, HELLP (20%)
- SGA (25%)
- PTB (15%)
- Life threatening conditions, aortic dissection, in 2-3%
Prepregnancy
- Examination of cardiac and general health status
- Biscuspid aortic valve and coarctation of the aorta are contraindications for IVF
- Always single embryo transfer
Antenatal management
- Aortic dissection cannot be predicted
- Aim BP <140/90
Kallmann syndrome
Hypogonadotropic hypogonadism
Congenital absence of olfactory neurons and GnRH producing neurons in the brain
May be sporadic or inherited
Females > males
Anosmia
Colour blindness
Lack of secondary sexual characteristics
Primary amenorrhoea
Urinary tract anomalies that can co-exist with Mullerian fusion anomalies
Renal agenesis / renal hypoplasia
Horseshoe kidney
Ureteric duplication of aberrant path / drainage
