Adolescent Gynae Flashcards
Embryology
XY
From intermediate mesoderm → forms urogenital ridge → gonads, ductal system and primordial germ cells → SRY gene from gonads → testes determining factor → testes form → release testosterone (Leydig cells) + AMH (Sertoli cells) → Mullerian duct regresses and Wolffian duct remains → testosterone converts to DHT (dihydrotestosterone) via 5 alpha reductase → epididymis + vas deferens + seminal vesicles + common ejaculatory duct
XX
From intermediate mesoderm → forms urogenital ridge → gonads, ductal system and primordial germ cells → No SRY gene from gonads → No testes determining factor → no testosterone or AMH → Mullerian duct remains and Wolffian duct regresses → uterus + cervix + fallopian tube + upper ⅔ vagina
Yolk sac → primordial germ cells → sperm or oocytes -→ if oocytes, follicular cells -→ release oestrogen
Hindgut → cloaca → anal canal + urogenital sinus -→ urogenital sinus → external genitalia + bladder/urethra
Primary amenorrhea
Definition = no menses before 13 without secondary sexual characteristics or no menses before 15 with secondary sexual characteristics
Assess with TA ultrasound and serum FSH, E2, TSH, b-HCG
Causes:
- Physiological delay of puberty
- High FSH → Turner’s (45XO) or Swyer’s syndrome (46XY) or POI
- No uterus, normal FSH, normal testosterone → Mullerian agenesis (e.g. MRKH)
- No uterus, normal FSH, high testosterone → AIS
- Normal breast development + accumulated blood in uterus or vagina → outflow tract obstruction (imperforate hymen)
- Normal FSH + normal breast development → PCOS, hyperprolactinaemia, thyroid disease
- Low FSH/LH + no breast development → hypothalamic disorder (GnRH deficiency, constitutional delay, anorexia)
- Transverse vaginal septum
- Pituitary tumours
- CAH
- Cushing’s
- CNS defects
Hx:
- Other secondary sexual characteristics (breast development, pubic hair, growth spurt)
- FHx
- Medical Hx, medications
- Cyclic pelvic pain
- Symptoms of hyperandrogenism, galactorrhoea, visual field defect, polyuria/polydipsia
- Stress/weight loss
Ex:
- Height, weight, growth
- Signs of hyperandrogenism
- Signs of turner’s (short stature, webbed neck, widely spaced nipples)
- Genital exam (pubic hair, clitoris size, hymen, presence of cervix)
Ix:
- FSH, hCG, prolactin, oestrogen
- Oestrogen
- Karyotype
- Pelvic US
Mx:
- Treat symptoms - surgery (remove septum, gonadectomy)
- Achieve fertility
- Prevent complications (e.g. oestrogen to prevent CVD/osteoporosis)
High FSH/LH, low oestrodiol, could be hyperthalamic hypogonadism where there is impaired response of the gonads to the gonadotrophins FSH and LH and in turn lack of sex steroid production. Can be congenital (Turner’s, Klinefelters, Swyer’s) or acquired (ovarian torsion, premature ovarian failure, chemotherapy, radiation, infections, toxins)
Vaginal agenesis = absence of lower vagina, or failure of fusion if urogenital sinus and mullerian duct causing transvaginal septum; normal secondary sexual characteristics, cyclical pain, mucocolpos or haematocolpos, normal external genitalia except low vaginal agenesis. Treat by resection with end to end anastomoses or dilators pre-operatively.
Imperforate hymen = vaginal lumen and urogenital sinus separated by hymenal membrane which usually ruptures prior to birth and a thin mucous membrane persists. Same presentation as vaginal agenesis. Needs surgery to suture vaginal epithelium to hymenal membrane to remain patent.
Mullerian agenesis = absence of vagina with variable uterine development. Also called Mayer-Rokitansky-Koster-Hauser syndrome (MRKH). Presents with normal secondary sexual characteristics, amenorrhea and blind ending vaginal pouch. Can treat with vaginal dilators or McIndoe vaginoplasty (skin graft from buttocks). Can also have renal abnormalities.
Androgen insensitivity syndrome = complete or partial. 46XY. X linked recessive with defect in androgen receptor. Testes produce testosterone and AMH (AMH causes regression of mullerian structures), but no receptors to testosterone so get external genitalia female with short vagina and sparse pubic/axillary hair and internal male genitalia (undescended testes), normal breast development. Normal oestrogen (testosterone aromisation to oestrogen). Presents with primary amenorrhea, mild adrenarche and thelarche. On investigation, there are no mullerian structures, high serum testosterone (for female but is normal level for male), XY Karyotype. Treat with topical oestrogen, vaginal dilators or vaginoplasty, surgical removal of testes (usually undescended), oestrogen replacement (complete because testes removed and no conversion to oestrogen); androgens (partial with male identity). Complications include low bone density (due to low oestrogen), CVD risk, psych issues, infertility.
Turner syndrome = 45XO. Oocytes and follicles undergo apoptosis in utero -> no ovaries but external genitalia/mullerian structures develop normally -> ovaries replaced with fibroid tissue (streak ovaries). Presents with short stature, webbed neck, widely spaced nipples, cardiac anomalies, horseshoe kidney, oesteoporsis, normal adrenarche but no thelarche or menarche. Antenatally, can have cystic hygroma, hydrops, renal anomalies. Treat with oestrogen from 11-12yrs and progesterone to protect endometrial lining. Complications of low bone density, CVD, infertility.
Primary ovarian insufficiency = clinical menopause before age 40. Amenorrhea >4months or elevated FSH on 2 occasions. Caused by idiopathic, chemo/radio, mumps/CMV, fragile X. Presents with amenorrhea, vasomotor symptoms of menopause, infertility. Ix show high FSH, low oestrogen, low testosterone, normal karyotype 46XX, test for Fragile X, pelvic US. Treat with HRT until age 50. Complications are psych, subfertility, CVD, osteoporosis.
Swyer’s syndrome = 46XY with gene defect on Y chromosome means testes don’t form and get fibroid streak gonads. No AMH or testosterone so Mullerian organs and external female genitalia develop. No thelarche or menarche. High FSH and LH (pituitary trying to stimulate gonad), no ovaries on pelvic US and uterus present with karyotype XY. Treat with oestrogen and progesterone and remove streak gonads (can get gonadal tumours otherwise). Can have IVF for fertility with donated egg. Complications of osteoporosis or CVD.
Kallman syndrome/idiopathic hypogonadotropic hypogonadism = GnRH deficiency, can have associated renal abnormalities or hearing loss or cleft lip. Very low FSH/LH/oestrogen. Treat with oestrogen and progesterone.
Functional hypothalamic amenorrhea = secondary amenorrhea, abnormal GnRH. Low oestrogen and day 21 progesterone. Causes are weight loss, excessive exercise, stress, nutritional deficiency.
Resources:
- Uptodate
- No RCOG or RANZCOG resources available
- https://www.amboss.com/us/knowledge/Disorders_of_sex_development
Precocious puberty
Puberty before age 8, menarche before age 10
Determined by tanner staging, 1:5000
Central (idiopathic, CNS lesion, hypothyroidism) - gonadotropin-dependent
- With increased LH and FSH
- Timing and order of changes are normal
- Do brain MRI, pelvic US and bone studies
- Treat underlying cause with surgery or thyroxine or GnRH agonist to slow pubertal development and suppress HPO axis (may get vaginal bleeding initially due to withdrawal of progesterone)
Peripheral (functional follicular ovarian cysts, ovarian tumours - granulosa cell, sertoli-leydig, gonadoblastoma, exogenous hormones, CAH, McCune Albright syndrome) - gonadotropin independent
- Timing and order of changes are abnormal
- Low FSH and LH → suppressed by excessive peripheral oestrogen production
- Do pelvic US, adrenal US, cortisol, 17-OH, DHEAS, tumour markers LDH/HCG/AFP, LH/FSH
- Treat with surgical removal, chemo, SERM or aromatase inhibitors for McCune albright, corticosteroids for CAH
Test with GnRH agonist:
- If LH rises → central
- If LH normal → peripheral
Tanner stages of development
1 = no glandular tissue and no hair 2 = breast bud firms and sparse hair along labia 3 = breast elevation and courser public hair 4 = areolar mould and adult hair does not spread to thigh 5 = adult contour and adult hair spreads to thigh
Normal ages/sequence of puberty:
8 - Adrenarche
11 - Breast development (thelarche)
11 - Pubic hair
12 - Peak growth velocity
13 - Menarche
Müllerian duct formation
Müllerian duct and wolffian duct present in everyone → if Y chromosome present then produces SRY protein → forms testes → leydig cells in testes produce testosterone and sertoli cells produce AMH → Müllerian duct or paramesonephric duct regresses and Wolffian duct or mesonephric duct remains to form male reproductive tract.
No AMH → regression of Wolffian duct and Müllerian duct remains → differentiation of Müllerian duct occurs → paramesonephric arise from invaginations of coelomic epithelium → vertical fusion of paramesonephric ducts of which fused cranial end becomes uterus → unfused cranial end becomes Fallopian tube → caudal end becomes upper third of vagina → midline septum reabsorbs at 20wks → rest of round/ovarian ligament form
Müllerian duct anomalies
Class 1: uterine hypoplasia
- MRKH - absent uterus
- symptoms of primary amenorrhoea, normal external genitalia, short vagina, renal or skeletal abnormalities, normal secondary sexual characteristics due to normal ovaries
- treat with vaginal dilators or surgery to create vaginal passage
Class 2: unicornuate uterus
- communicating or non-communicating
- asymmetric lateral fusion defect, one cavity normal and the other duct (non communicating horn) is poorly developed
- symptoms of cyclic pain, obstetric complications especially retained placenta or adherent placenta, high association with renal abnormalities
- if pregnancy is in abnormal horn, recommend termination due to high risk of rupture
- surgery to remove non communicating horn (risk of ectopic pregnancy in that horn)
Class 3: uterus didelphys (double uterus)
- Müllerian ducts don’t fuse giving rise to 2 uterus and 2 cervix
- 75% have vaginal septum
- diagnose on ultrasound and spec showing 2 cervix rather than on MRI
- symptoms of cyclical pain due to buildup of blood in obstructed hemivagina or primary amenorrhoea with bilateral obstruction
- surgery to resect wall of obstructed vagina and create single vaginal vault
- Usually does not affect ability to conceive but may increase risk of miscarriage
Class 4: bicornuate uterus
- partial fusion of ducts creating indent in fundus
- can diagnose on HSG rather than MRI
- associated with miscarriage, preterm birth, cervical insufficiency, malpresentation
- surgery (laparotomy) to unite uterus only if poor pregnancy outcomes
Class 5: septate or subseptate uterus
- normal fundus, incomplete resorption of midline septum between 2 Müllerian ducts
- most common uterine anomaly
- higher risk of obstetric complications
- MRI best for diagnosis
- surgery to respect septum hysteroscopically
Class 6: Arcuate uterus
- slight midline septum with some cavity indentation
- similar outcomes to normal uterus shape
Class 7: T shaped uterus due to exposure to DES in fetal life
Symptoms of mullerian anomalies:
- pelvic pain, endometriosis, menstrual abnormalities, obstetric complications
Remember, renal system made closely with paramesonephric ducts so associated renal anomalies (20-30% of women have both) - usually ipsilateral to side of anomaly
Also ovaries developed separately from mullerian system so usually normal in mullerian anomalies
Obstetric complications:
- Miscarriage, recurrent miscarriage, IUGR, PPROM, malpresentation, APH, PPH, cervical insufficiency, PIH, preterm labour, retained placenta (trapped in narrow uterine horn), uterine rupture, caesarean section
Symptoms:
- Asymptomatic
- Primary amenorrhoea
- Haematometra (blood in uterus)
- Haematocolpos (blood in vagina)
- Cyclical or non-cyclical pain
- AUB - didelphys
- Dysmenorrhoea - non-communicating obstructed horn
- Dyspareunia - transverse or longitudinal vaginal septum
- Recurrent miscarriage/subfertility
- Genital tract infection
- Obstetric complications
Ix:
- HSG (hysterosalpingography), hysteroscopy, ultrasound (pelvic + renal)
- MRI to clarify complex anomalies or unable to tolerate HSG
- Laparoscopy/hysteroscopy
- Usually normal karyotype
Congenital adrenal hyperplasia
Deficiency in 21-hydroxylase enzyme -> reduces cortisol and increases androgens -> increases ACTH -> adrenal hyperplasia
Autosomal recessive
XX with virilisation
Signs of ambiguous genitalia, clitoral enlargement, scrotal appearance of labia, irregular menses, early puberty, facial hair
Salt losing - low Na, high K, acidosis, hypoglycaemia
Needs immediate treatment and lifelong treatment with hydrocortisone
Disorders of sex development
DSD: genitals that do not appear typically male or female or discordant with chromosomal sex
- Most common cause is classical CAH (21 hydroxylase deficiency)
- Need to assess urgently for CAH in any baby with atypical genitalia
Normal development:
- SRY gene → Y chromosome causes gonads to differentiate into testes → testes produce testosterone and AMH → regression of mullerian structures
Hx + Ex:
- Pregnancy Hx - exposure to androgen
- Primary amenorrhoea
- FHx - AIS, consanguinity (for recessive disorders)
- External genital exam - palpate for nonpalpable testes, microphallus, hypospadias, clitoromegaly, posterior labial fusion or palpable gonads in labioscrotal folds
- Dysmorphic features
Ix:
- 17-OHP → elevated in CAH with 21 hydroxylase deficiency
- Electrolytes → for CAH - low Na, high K, metabolic acidosis
- FSH, LH, testosterone, AMH
- FISH for Y chromosome
- Karyotype
- Pelvic/abdominal US - for gonads/uterus/vagina
- ACTH stimulation test
- Chromosomal microarray
Steps:
- Evaluate sex chromosomes - FISH for Y chromosome, karypotype
- Pelvic US - for uterus/ovaries
- Measure adrenal steroids - 17-OHP (high in CAH); ACTH stimulation test (definitive test for CAH - give synacthen and no increase in cortisol in CAH as no 21 hydroxylase)
- Measure gonadal hormones - AMH, FSH, LH, testosterone, DHT, hCG stimulation test (give hCG and will call rise in androgen levels; detects defect in testosterone synthesis; no change in high levels of testosterone in AIS)
Causes:
- Virilisation of XX female = CAH with 21 hydroxylase deficiency; exposure to in utero androgens; placental aromatase deficiency
- Under masculinisation of XY male = AIS, less common CAH; 5alpha reductase deficiency
- Ovotesticular DSD - testicular and ovarian tissue found simultaneously in same or opposite gonads
Treatment:
- Gonadectomy - if assigned female sex, risk of malignancy
- Feminising genital surgery - up to 6months, to allow passage of menstrual blood and allow penetrative sex and reduce clitoris size
- CAH - hydrocortisone
- If CAH and pregnant, take dexamethasone before 9wks to reduce virilisation of female babies then screen with CVS
DSD/primary amenorrhoea question
2015 February SAQ
Question 12 - Disorders of sexual differentiation / Primary amenorrhoea
A 15 year old girl presents with primary amenorrhoea. On examination, secondary sexual characteristics are absent. Her referring GP has test results which show her follicle stimulating hormone is 42 IU/L (normal <10 IU/L) and her oestradiol is 20 pmol/L (normal >150 pmol/L).
a. Interpret her clinical information to:
i) Name her condition. (1 mark)
Primary ovarian insufficiency
ii) List 6 possible causes of this condition. (6 marks) Turner’s syndrome
Swyer syndrome
Testicular regression syndrome
AMH receptor defect
Androgen insensitivity syndrome
Congenital adrenal hyperplasia
5 alpha reductase deficiency
History of chemotherapy or radiotherapy to gonads
Her karyotype result is 46XY. Pelvic imaging reveals a normal pre-pubertal uterus and streak ovaries.
b. Discuss the principles of management. (5 marks)
Swyer’s syndrome
- Need to confirm diagnosis with FISH and test Y chromosome function
- Testosterone levels
- Explain to girl initially and parents if she allows, that she has this condition where chromosomes are male however due to lack of functioning Y chromosome, has female internal organs
- Emotional support
- Social work, psychologist, GP
- Need for surgery to remove streak ovaries due to risk of malignancy (gonadoblastoma) and are not functioning
- Treatment is oestrogen and progesterone (to protect uterine lining) – essential for preventing menopause symptoms, CVD risk and osteoporosis risk
- Refer to Paediatrician specialising in this area for regular follow up
- *c. List her options for fertility in the future. (3 marks)**
- IVF with oocyte donation
- Surrogacy with IVF and oocyte donation
- Adoption
- Accept childlessness
Mullerian abnormality question
July 2017 Question 8 – Mullerian abnormalities
a. Outline the normal embryological development of the fallopian tubes, uterus, cervix and vagina. (5 marks)
- All develop from intermediate mesoderm - gonadal ridge
- Invagination of mesoderm → formation of paramesonephric (Mullerian) ducts by 5-6/40
- In absence of AMH – Mullerian ducts persist
- Ducts fuse to form fallopian tubes, broad ligament and uterovaginal canal
- Uterovaginal canal gives rise to uterus, cervix and upper ⅔ of vagina
- Septum from fused walls disappears and migrate to meet urogenital sinus – occurs by 12/40
- This later fuses with urogenital sinus that forms lower ⅓ of vagina (and urethra and bladder)
- By 20/40 – ring-like constriction marks position of cervix on uterus
b. A 19 year old girl presents with progressively worsening dysmenorrhoea despite 6 months of cyclic oral contraceptive pill. Further investigations including a pelvic ultrasound and MRI scan showed a right unicornuate uterus with a left, non-communicating rudimentary horn.
(i) Name and justify one (1) further important investigation you should organise for her. (2 marks) Renal US – high incidence (40%) of associated renal abnormalities with unicornuate uterus
(ii) Identify and justify the surgical procedure/s you would discuss with her to manage her presenting symptom. (4 marks) A table may be used to set out your answer.
Excision of obstructed rudimentary horn (laparoscopy or laparotomy)
- Helps prevent haematometra with functional endometrial shedding in obstructed horn causing her cyclical dysmenorrhea – symptomatic relief
- Also reduces risk of endometriosis with retrograde menstruation
- May aid pregnancy outcomes as pregnancy unable to form in rudimentary horn
Diagnostic laparoscopy +/- excision of endometriosis
- Higher risk of endometriosis given obstructed rudimentary horn – retrograde menstruation - Excision and ideally menstrual suppression post-op may help with dysmenorrhea
c. Identify four (4) pregnancy complications associated with this type of congenital malformation and explain a postulated aetiological mechanism for each. Provide a different aetiology for each complication you identify. (4 marks) A table may be used to set out your answer.
Cornual pregnancy → rupture
- Occurs with intraperitoneal passage of sperm from contralateral tube → rudimentary horn Implantation – cornual pregnancy, unable to sustain and can rupture around 20/40 – excision indicated
Malpresentation
- Asymmetric small uterine cavity doesn’t allow enough space for fetus to turn cephalic higher rates of breech
Caesarean delivery
- Greater incidence of malpresentation results in higher need for LSCS
Preterm birth
- Small uterine cavity or cervical incompetence
Fetal growth restriction
- Possibly due to abnormal vascularisation of small uterine cavity with resultant uteroplacental insufficiency
Recurrent miscarriage
- Abnormal implantation or placentation or cervical incompetence
PPH/adherent placenta
- Possibly placenta becomes partially trapped in accessory horn
Pregnancy induced hypertension
- Likely related to co-existent congenital renal abnormalities
