Gynaecology Flashcards
MOA TXA
Plasmin inhibitor
Tranexamic acid is a synthetic analog of lysine which reversibly binds to lysine receptors on plasminogen. This inhibits conversion of plasminogen into plasmin and arrests the breakdown of fibrin.
Ovarian dermoid cyst vs ovarian cystic teratoma
These terms are used interchangeably to describe germ cell tumours however they have slightly different tissue origins:
Ovarian dermoid cyst = purely ectodermal in origin, so contains dermal and epidermal elements (hence the name)
Ovarian mature cystic teratoma = tissue can arise from any of the three germ cell layers (mesoderm, endoderm and ectoderm). Normally 2 of the 3 are seen.
stratum functionalis: components
stratum compactum
stratum spongiosum
The Stratum compactum and stratum spongialis develop into the stratum functionalis during the first half of the menstrual cycle (proliferative phase)
When investigating subfertility, it is common to take a ‘mid-luteal’ phase progesterone. For a patient with a regular 28 day cycle, when would you advise a mid-luteal phase progesterone and what level would you be looking for?
A mid-luteal phase progesterone level can be taken to confirm if ovulation has taken place. For patients with a regular menstrual cycle, this is 7 days prior to the first day of expected menstruation.
A serum progesterone >30 nmol/L confirms ovulation has taken place.
Which anatomical structure is found within the infundibulopelvic ligament?
Also known as the ‘suspensory ligament’
Connects the ovary laterally to the pelvic wall
Not a true ligament as it is a fold of the peritoneum
Contains the ovarian artery, vein, nerve plexus and lymphatic vessels
Risk of malignancy index (RMI)
RMI = U x M x Ca-125
Ultrasound features (1 point for each) - BAMMS
Multilocular cysts
Solid areas
Metastases
Ascites
Bilateral lesions
Ultrasound score:
0 points = Ultrasound score 0
1 point = Ultrasound score 1
2-5 points = Ultrasound score 3
Menopausal status
Pre-menopausal = 1
Post-menopausal = 3
Ca-125 in IU/ml
NICE recommend referral to the specialist MDT for any patients who score 250 or more
Which lymphatic groups are most likely to be associated with cervical cancer metastases?
The most common sites of lymph node metastases from cervical cancer are the external iliac, internal iliac and obturator groups.
Which lymphatic groups is most likely to be associated with vaginal cancer metastases from the lower third of the vagina?
superficial inguinal group.
The Female Pelvic Floor
Funnel shaped muscular floor of the true (lesser) pelvis
Supports the abdominal/pelvic organs, opposes rises in intra-abdominal pressure and provides sphincteric action to the rectum and urethra
Composed of the levator ani and coccygeus
Two openings permit passage of the anal canal (rectal hiatus) and vagina/urethra (urogenital hiatus)
The perineal body connects the pelvic floor to the perineum and is located inferiorly
What is the predominant cell type of the luminal epithelium of the fallopian tube?
Secretory cells (most abundant)
Columnar cells
Peg cells (least abundant)
USS features of leiomyoma (fibroid)
Solid, round and well defined
Hypoechoic and heterogenous
Distortion of the outer uterine contour
Calcifications appear hyperechoic
Circumferential flow on colour doppler
Acoustic shadowing (large fibroids)
Type one and type two uterine cancers
Type 1 cancers are associated with unopposed oestrogen (endometrioid adenocarcinomas, slower growing)
Type 2 cancers are oestrogen independent and often related to genetic mutations (uterine serous carcinomas and clear cell carcinomas, faster growing). Risk factors include being postmenopausal, having a thickened uterine wall lining, and family history of ovarian, uterine, or bowel cancer.
True vs false female pelvis
True (lesser) pelvis: Inferior to the pelvic brim, contains the bladder, colon and reproductive organs
False (greater) pelvis: Superior to the pelvic brim, supports organs of the lower abdomen and the gravid uterus
Approximately what proportion of women with BRCA 1 mutation will develop ovarian cancer?
40% risk of women with BRCA 1 mutation developing ovarian cancer before the age of 70.
(15% BRCA 2)
Ovarian blood supply
Primary source is from the ovarian artery; a direct branch of the abdominal aorta
There is a smaller collateral supply from the uterine artery
The right ovarian vein drains directly into the inferior vena cava
The left ovarian vein drains into the left renal vein (in the majority)
Both the ovarian artery and vein are contained within the infundibulopelvic (IP) ligament
Incontinence management
First-line: Lifestyle changes, pelvic floor exercises, and bladder training.
Second-line: Anticholinergics (e.g., solifenacin, tolteridine, oxybutynin - avoid in frail older adults due to cognitive risks) or Beta-3 adrenergic agonist mirabegron or vaginal oestrogen for OAB; duloxetine for SUI.
Third-line: Botulinum toxin or neuromodulation (Percutaneous tibial nerve stimulation or sacral nerve stimulation) for OAB/ UUI; urethral bulking agents or surgery (Mid-urethral sling; colposuspension; fascial sling) for SUI.
Fourth-line: Surgery for refractory cases.
UUI is a symptom of OAB
Endometrial cancer testing
3% of all endometrial cancers are due to Lynch syndrome
The gene for tumour protein p53, is located on the short arm of chromosome 17
30% of EC is associated with BRCA1 mutation
Lynch syndrome screening for EC
Annual screening with TVS, hyst and/or endometrial sampling from age of 35 years after counselling
Lynch syndrome and abnormal vag bleeding to seek urgent medical attention.
Hysterectomy if family complete
Scenarios where women should have urgent investigations TVS, hyst and/or endometrial sampling
Women taking tamoxifen
Women with lynch syndrome
Postmenopausal
Scenarios where women should have pelvic exam inc spec
PMB
Unscheduled bleeding on HRT
Persisten IMB / irreg bleeding
heamaturia
PM Abnormal pv dc
Scenarios where women should have pelvic exam inc histology and 2ww
Premenopausal with persistent IMB/ irreg
Infrequent bleeding and obese/PCOS/Tamoxifen
Unsuccessful rx HMB
Staging vs Grading
Stage: size of the tumor and how far it has spread.
Grade: how abnormal cancer cells look and behave compared to normal cells.
FIGO staging: factors considered
- Tumor size (T): How far the cancer has spread into the uterus and nearby organs
- Lymph node spread (N): Whether the cancer has spread to the lymph nodes in the pelvis or around the aorta
- Distant spread (M): Whether the cancer has spread to distant lymph nodes or organs
- Histological type: The type of tumor
- Molecular classification: The molecular profile of the tumor, such as POLEmut, MMRd, p53abn, or NSMP
FIGO staging: stages
Stage I: UTERUS ONLY
Confined to the uterine corpus and/or ovary
IA: Limited to the endometrium or <50% myometrial invasion (low-grade, non-aggressive, minimal LVSI). EASY
IB: ≥50% myometrial invasion (low-grade, non-aggressive, minimal LVSI). DEEP
IC: Aggressive histology confined to the endometrium or a polyp. AGGRESSIVE
Stage II: INTO CERVIX
Invasion of cervical stroma, no extrauterine spread
IIA: Non-aggressive histology with cervical stromal invasion. NICE
IIB: Substantial LVSI (non-aggressive histology). STROMAL
IIC: Aggressive histology with myometrial invasion. AGGRESSIVE
Stage III: INVADES NEARBY
Local/regional spread
IIIA: Involvement of uterine serosa and/or adnexa. SEROSA
IIIB: Spread to vagina, parametria, or pelvic peritoneum. VAGINA
IIIC: Pelvic and/or para-aortic lymph node metastasis. LYMPH
Stage IV: FAR AWAY
Distant spread
IVA: Invasion of bladder or bowel mucosa. BLADDER
IVB: Peritoneal metastasis beyond the pelvis. PERITONEUM
IVC: Distant metastasis (e.g., lungs, liver, brain, bone). DISTANT
lymphovascular space involvement (LVSI)
Where is p53 located
short arm chromosome 17
EC Grades
Serous, clear cell and carcinosarcomas are considered high-grade by definition.
For Endometriod ECs, grade is based on the proportion of solid areas:
low grade = grade 1 (≤5%) and grade 2 (6%–50%);
high grade = grade 3 (>50%)
EC Histological types
Endometriod
Serous
Clear cell
Endometrial cancer - who and where are they managed
All discussed at MDT
FIGO STAGE 1A and LOW GRADE 1 or 2 can be managed by gynaecologist at gynaecology centre who is a member of MDT team.
For HIGH GRADE or ABOVE stage 1A should have surgery at cancer centred by a sub spec surgeon
Pelvic
lymphadenectomy determines which patients are eligible
for adjuvant radiotherapy, and it may also be therapeutic.
Tests to do in endometrial ca
CA-125 can detect unexpected metastatic disease
CT chest / CXR in all women
CT pelvis in some women
High risk histo or deep myometrial invasion of locally advanced disease - CTAP (helps plan adjuvent therapy)
Treatment for EC
Standard: TAH and BSO without vaginal cuff or parametrectomy. Overt Stage II.
Radical hyst should only be considered to obtain tumour free margins.
Hysterectomy/ salpingectomy with ovarian conservation can be considered in pre-menopausal patients with GRADE 1 ENDOMETRIOD EC, <50% invasion and no extrauterine disease on imaging
Sentinel LN biopsy for staging at time of op.
Surgical staging - SLNB and omental biopsy - disease greater than low risk
Patients unfit for surgical management
https://www.youtube.com/watch?v=D5dypTKqfa0
12 mins in
Fertility pr
Hormones produced by posterior pituitary
Oxytocin and vasopressin (antidiuretic hormone)
Hormones produced by anterior pituitary
Adrenocorticotrophic hormone (ACTH)
Thyroid-stimulating hormone (TSH)
Luteinising hormone (LH)
Follicle-stimulating hormone (FSH)
Prolactin (PRL)
Growth hormone (GH)
Melanocyte-stimulating hormone (MSH)
anatomical boundary of the female pelvic inlet
The pelvic inlet (also known as the pelvic brim) represents the boundary between the greater pelvis superiorly and lesser pelvis inferiorly.
The anatomical borders are defined as follows:
Anterior: Pubic symphysis (upper border)
Lateral: Iliopectineal line (arcuate and pectineal line combined)
Posterior: Sacral promontory, sacral alae and sacroiliac joints
perineal body
“central tendon of the perineum,” is a fibromuscular structure located in the midline of the perineum
Fibromuscular structure located at the border of the urogenital and anal triangles
Central attachment site for the pelvic floor and perineal muscles (levator ani, bulbospongiousus, superficial/deep transverse perineal, external anal sphincter and external urethral sphincter muscles)
Vaginal delivery may cause tears to the perineal body; this can be prevented by episiotomy
The Female Perineum
The most inferior structure of the pelvis with the pelvic floor sitting superiorly
Formed of the perineal body, ischiocavernosus, bulbocavernosus and transverse perineal muscles
Functions: urination, defecation, intercourse, vaginal delivery
Anatomically appears as a diamond structure divided into two triangles: the anterior urogenital and posterior anal triangles
The neurovascular supply to the perineum travels via the pudendal (Alcock’s) canal
The deep perineal nerve supplies the perineal muscles
Perineal neurovascular supply
The pudendal nerve (S2-4) descends towards the perineum and enters the pudendal canal where it divides. The perineal branch divides into the superficial and deep branches
The superficial perineal nerve supplies the skin of the posterior labia
The deep perineal nerve supplies the perineal muscles
Vascular supply is from the internal pudendal artery and vein, both of which travel with the pudendal nerve via the pudendal canal
Glycoprotein hormones
LH
FSH
HCG
TSH
AFP
EPO
It is the beta subunit which varies between LH, FSH, TSH and HCG and this is responsible for their differing functions. The alpha subunit is identical.
Vaginal blood supply
Receives blood from the uterine artery (superior aspect of the vagina) and vaginal artery (middle and inferior aspect of the vagina), both of which are branches of the internal iliac artery
Venous drainage is via the vaginal venous plexus which drains into the uterine vein
The most common sites of lymph node metastases from ovarian cancer
pelvic and para-aortic lymph node groups.
Female pelvic inlet diameters
The anteroposterior (AP) or ‘conjugate’ diameter of the pelvic inlet is the distance from the sacral promontory to the pubic symphysis.
The obstetric conjugate is a term used to describe the diameter from the sacral promontory to the closest border of the posterior aspect of the pubic symphysis. This represents the shortest anteroposterior diameter of the birth canal.
The oblique (or diagonal) diameter of the pelvic inlet is the largest.
Ovarian ca RF
Increased number of lifetime ovulations: nulliparity, early menarche, late menopause
BRCA1/BRCA2 mutations
Lynch syndrome
First childbirth after 35 years
Functional ovarian cysts: types
Follicular (the most common)
Corpus luteal
Theca luteal
Note: simple ovarian cysts <3 cm are categorised as ovarian follicles and are considered a normal finding in women during the reproductive years
Nabothion follicles
Also known as ‘inclusion cysts’
Benign, mucus containing cysts trapped within the cervical transformation zone
Occur following squamous metaplasia of columnar epithelium
Endocervical crypts become trapped underneath the new layer of squamous cells
Columnar cells within the trapped endocervical crypts continue to secrete mucus leading to cyst formation
Follicles are usually small, measuring <5mm
Larger follicles >10mm may be visible on transvaginal ultrasound
Approximately how many hours before ovulation does the LH surge begin?
36
what nerve supplies bulbocavernosus?
The deep perineal branch of the pudendal nerve
ovarian epithelial cancer 5 year survival rate on stage
1: 90%
2: 70%
3: 40%
4: 17%
Uterine cancer
Age range of average vs highest incidence
The average age at diagnosis is around 60 in the UK and the most cases of uterine cancer is seen in the 60-64 age group (see the graph).
It should be noted the incidence rate (cases per 100,000) is highest in the 70-74 age group.
The typical distribution of ectopic pregnancy
Tubal 95%
Interstitial 1-6%
Ovarian 3%
Abdominal 1%
Cervical <1%
Heterotopic <0.1%
Tubal pregnancies can be further subdivided into:
Ampullary section 70-75%
Isthmus 12%
Fimbrial 11%
Cornual and interstitial part of the tube 2-3%
Miscarriage rates
Maternal age at conception Miscarriage rate
20-24 9%
25-29 11%
30-34 15%
35-39 25%
40-44 51%
>45 93%
(20s =10%, 30s=20%, 40s=50%, >45=90%)
Ovarian cancer: protective factors
(decrease ovulatory cycles)
Oral contraceptive use
Higher Parity
Breast feeding
Hysterectomy
Tubal Ligation
Statins
SLE
Ovarian cancer: risk factors
Increasing age — peaks in 80s
Genetic factors, including:
1. Gene mutations — BRCA1(28–44%) and BRCA2 (27%).
2. Family history of ovarian cancer — about 3% of ovarian cancer cases occur in women with a family history of ovarian cancer.
3. Family history of cancer gallbladder, and urinary tract cancers.
Increased number of ovulatory cycles,
nulliparity,
early menarche,
late menopause.
Use of HRT
Medical conditions, including:
Cancer
Endometriosis
Diabetes
Lifestyle factors:
Tobacco smoking.
Being overweight or obese.
Occupational exposure to asbestos.
Endometrial cancer: Familial cancers
Lynch syndrome (also known as hereditary non-polyposis colorectal cancer) is associated with mutations in DNA mismatch repair (MMR) genes and deletions in the epithelial cellular adhesion molecule (EPCAM) gene.
Family history of colorectal, endometrial, and/or ovarian cancer is often observed.
Cowden syndrome, related to mutation in the PTEN tumour suppressor gene. Carriers have an increased risk for endometrial, breast, thyroid, colorectal, and renal cancer.
Lynch syndrome: wheres the mutation
mutations in, or near, the DNA sequence of mismatch repair (MMR) genes and deletions in the epithelial cellular adhesion molecule (EPCAM) gene.
Lynch syndrome: testing
IHC testing then MLH1 promoter testing.
If both these tests show that a person may have Lynch syndrome, genetic testing of a person’s non-tumour DNA should be done to confirm this.
Lynch syndrome: when to test
1.colorectal cancer
2. endometrial if identified RF (age at diagnosis, family history of Lynch syndrome-related cancers)
If sperm abnormal then what?
If sperm count abnormal repeat in 3 months (or asap if azoospermia or severe oligozoospermia i.e. <5 million sperm/mL detected)
Female fertility testing
When assessing a women who has failed to conceive NICE advise 2 tests be performed in ALL women:
- Chlamydia screen
- Mid luteal phase Progesterone (7 days before start of next period)
Others
FSH and LH
patients with irregular periods, anovulation or oligo-ovulation
Prolactin
those with an ovulatory disorder, galactorrhoea or a pituitary tumour.
Thyroid function testing is only advised if the patient has signs or symptoms of thyroid disease
Sex Chromonsome Karyotype Abnormalities 47 chromosomes
47 XXY Klinefelters
The extra X chromosome leads to testicular hypofunction and testosterone deficiency, which can result in small testes, infertility, and other symptoms/signs of hypogonadism (e.g., reduced facial/pubic hair, gynaecomastia). Developmental delay in childhood is common, particularly affecting speech.
47 XYY XYY Syndrome
Normal size testes. Normal phenotype
47 XXX Triple X syndrome
Normal phenotype
Breast ca risk gen pop/ BRCA 1/ BRCA 2
Gen pop 12%
BRCA 1 70%
BRCA 2 is 45%.
Ovarian Ca risk gen pop/ BRCA 1/ BRCA 2
Gen pop 1.3%
BRCA 1 is 40%
BRCA 2 is 15%
Congenital adrenal hyperplasia
Congenital Adrenal Hyperplasia (CAH) refers to a group of autosomal recessive disorders that result in deficiencies of enzymes involved in mediating the production of cortisol, aldosterone or both. These result in excessive or deficient steroid hormone production
90% of cases are due to 21-hydroxylase deficiency as a result of abnormal CYP21A genes. This results in androgen excess and mineralocorticoid deficiency.
5% of cases are due to 11-hydroxylase deficiency.
Carbon atoms on hormones
Progesterone 21
Test 19
Oest 18
C24 - Spironolactone based progestins
(so testosterone based progestins which is most of the new ones have C19)
What is the metabolise of norgestimate
Norelgestromin
What is the metabolite of desogestrel?
etonogestrel
Anti-androgenic progestins
Drosperinone
Dienogest
Generations of progestogens of note
1st generation
Norethisterone
Cyproterone acetate
Medroxyprogesterone
2nd generation
Levonorgestrel (Microgynon/ other first like COCP options)
Norgestrel
3rd generation
Desogestrel (Mercilon, Marvelon)
Gestodene (Femodette, Femodene)
Norgestimate (Cilest)
4th generation
Drosperinone (Yasmin)
Dienogest (Qlaira)
Newer progestogens = less androgenic (skin) and glucocorticoid (bloating/weight side effects of 1st/2nd generation) BUT maybe higher VTE
Why are CHC better for skin than POP
Combined hormonal contraception often reduces androgenic effects of progestogens
Via oestrogen -> reduces ovarian androgen release AND increases sex hormone binding globulin (SHBG)
SHBG binds to testosterone and renders it less active à less of its androgenic effects are felt
Mullerian Agenesis (Rokitansky-Kuster-Hauser syndrome)
Congenital malformation
Failure of the Mullerian duct to develop results in absent uterus and variable degrees of upper vaginal hypoplasia
Implicated in 15% cases primary amenorrhoea
Karyotype 46XX
Normal FSH/LH/E2 profile
Prevalence 1 in 5000
WNT 4
Inhibin
Secreted by ovaries in response to LH/FSH
Inhibition of activin (and therefore GnRH)
(Activin –> GnRH production)
What triggers ovulation
Serum oestrogen level >300nmol/L for 2-3 days, negative gonadotropin feedback switches to positive feedback –> rapid LH surge
stimulates the primary oocyte frozen at PROPHASE 1 of meiosis I, to complete first meiotic division -> 1 x secondary oocyte and 1 x polar body
Meiosis II is then also commenced following this, but freezes at METAPHASE II until fertilisation
Initial metabolite of cholesterol and is the precursor to all steroid hormones
Pregnenolone
where is progesterone produced?
LH –> theca cells –> progesterone and testosterone production
Both theca and granulosa cells can convert cholesterol to progesterone, but ONLY THECA cells express CYP-17 (encodes for 17-alpha hydroxylase and 17,20-lyase needed for androgen production), and ONLY GRANULOSA cells contain aromatase (needed for oestrogen production)
where is oestrogen produced?
FSH -> granulosa cells -> oestrogen production (via aromatisation)
Progesterone functions
-ve feedback HPO
Cervical mucus changes
– reduced vol
– less alkaline
– increased viscosity and cellularity
(all make unfav for sperm penetration)
Stimulates secretory phase of menstrual cycle - inhibits endometrial proliferation and increases endometrial secretions and maturation by promoting cell differentiation
Decrease tubal motility
Increase body temp 0.5 degrees
Downregs ER expression and SHBG production
Prevents further ovulation in pregnancy
Placental prog inhibits uterine contractions by limiting pg production
Maintains and promotes development of preg
Breast development
Causes of hmb
Polyp
Adenomyosis
Leiomyoma
Malig/hyperplasia
Coagulopathy
Ovulatory dysf
Endometrial
Iatrogenic
Not otherwise classified
Adenomyosis RF
Multiparity/miscarriage, previous D&C, previous LSCS
MRI = thickening of junctional zone between myo and endometrium to >=12mm
Endogenous causes of endometrial hyperplasia
Obesity (conversion of androstenedione -> estrone by adipocytes)
PCOS
Oestrogen producing tumours (usually granulosa cell)
Endometrial Hyperplasia without atypia
5% risk of malignant change over 20 years
Manage with progestogens – LNG IUD 1st line (continuous medroxyprogesterone 10–20 mg/day or norethisterone 10–15 mg/day)
Repeat endometrial biopsies every 6 months until persistently normalised
2 samples negative for hyperplasia changes
Consider hysterectomy if:
Progression to atypia
Persistent hyperplasia after 12 months LNG IUD use
Relapse after treatment
Hyperplasia with atypia
30% risk of malignant change
If fertility not desired/family complete recommended tx is TAH
If fertility desired careful counselling re risk
Initial trial of management with LNG IUD as above
3 (rather than 6!) monthly endometrial biopsies until persistently normalised (2)
Then monitor w biopsies every 6 months
One normal biopsy advised before trying to conceive
Once fertility no longer desired -> TAH
Endometrial/uterine carcinoma
Majority adenocarcinoma (87%)
Aged 70s (Only 15% of cases seen in pre-menopausal women, and rare at <40 years)
Risk factors – sustained/unopposed oestrogen exposure; anovulatory disorders/ prolonged amenorrhea, obesity
Multiple subtypes; best prognosis =
Endometroid endometrial carcinoma (type 1)
Type 2 endometrial carcinomas are not oestrogen driven; worse prognosis
Serous, mucinous, clear cell, squamous – many different types
Associated with endometrial atrophy and p53 tumour suppressor mutations
Psomomma bodies on histology (calcified deposits)
1 Confined to uterus 85-90%
1A < ½ myometrial invasion
1B > ½ myometrial invasion
2 Cervical stromal invasion but not beyond uterus 65%
3 Extension beyond uterus 45-60%
3A Tumour invades serosa or adnexa
3B Vaginal and/or parametrial invasion
3C1 Pelvic nodal involvement
3C2 Para aortic nodal involvement
4Distant Metastasis 15%
4A Tumor invasion bladder and/or bowel mucosa
4B Distant metastases including abdominal metastases and/or inguinal lymph nodes
Von-Willebrand disease
Effects ~1% of the population
Estimated to account for ~10% of abnormal uterine bleeding cases
Should be tested for early in those who present with menorrhagia from menarche
Hyperprolactinaemia bleeding pattern
Majority of women have amenorrhoea/ oligomenorrhoea
but when bleeding does occur it may be very heavy
Fibroid cut off for lng-iud
<3cm
LNG IUD
52mg levonorgestrel releasing device
80% reduction of menstrual blood loss by end of month 3.
Initial release rate 20mcg/24 hours –> 7mcg/24 hours by end of 8 year contraceptive licence
Tranexamic acid
Competitive inhibitor of plasminogen activation
Binding of plasminogen to fibrin -> fibrinolysis (clot breakdown)
Competitive inhibition of this process -> TXA ANTIFIBRINOLYTIC action
Prevents fibrinolysis (fibrin breakdown), stabilises clots and reduces menstrual loss
Contraindications:
Severe renal impairment
Previous or current history of DVT/PE
History of convulsions; rarely TXA can induce seizures (Binds to glycine receptors)
Fibrinolytic coagulopathies i.e. DIC
Cautious use (dose reductions) for those with mild-moderate renal impairment
Cautious use in women taking concurrent anti-coagulants (futile) or CHC (VTE risk)
Cautious use in children <15 years (lack of evidence)
Most common adverse effect is GI upset
More rarely, impaired colour vision has been reported (discontinue if so!)
Non-steroidal anti-inflammatory drugs (off-label use for hmb)
Cyclooxygenase (COX) inhibitors -> reduce prostaglandin synthesis
Prostaglandins = important in inflammatory response (uterine pain and bleeding)
Menorrhagia can be associated with increased prostaglandin levels
Less prostaglandins -> less inflammatory response -> less pain AND bleeding
Mefenamic acid 500mg TDS (also ibuprofen, naproxen)
Started on first day or pain OR bleeding -> continue for no more than 7 days
NSAIDs used in this way may reduce mean blood loss by ~30%
NOREITHESTERONE for hmb
5mg TDS 10days to STOP/ARREST bleeding
Duration of use variable as per individual practice and indication
–> Can be used for up to 6 months (licensed dosing for endometriosis)
If cycles regular may be recommended from days 19 – 26 of cycle (luteal phase) to PREVENT bleeding. Evidence = taking on D5-26 of cycle is more effective than luteal phase only. “Long-cycle” use here.
Contraindications:
Current breast cancer
Current/ previous VTE
Active/ recent IHD – angina or MI
Severe/ active liver disease
Acute porphyria or history of pemphigoid gestationis
Cautious use in:
Hypertension
Diabetes
Multiple cardiovascular disease or VTE risk factors
Previous breast cancer – consult with oncology prior to use
Liver tumours
Antiphospholipid antibodies/ diagnosed systemic lupus
Rheumatoid arthritis
Conditions that can be exacerbated by fluid retention (common side effect)
Renal impairment
Cardiac dysfunction
Epilepsy
Migraine
Asthma
Discontinue use if:
New onset migraine
Jaundice/ deterioration of LFTs
Increase in BP
Side effects include:
Menstrual irregularity (amenorrhoea, spotting/ breakthrough bleeding)
Breast tenderness
Less commonly – HTN, VTE
MEDROXYPROGESTERONE ACETATE (Provera) for hmb
Typically/traditionally 10mg PO OD for 5-10 days, starting between days 16-21 of cycle. Repeated for 3 cycles.
Increasing evidence to advocate for use on longer term/continuous basis
“Long-cycle” use as per norethisterone, for 3-4 weeks at a time.
10mg PO OD for 3 months (licensed dose regime for endometriosis)
uterine leiomyosarcoma
Rare – smooth muscle cancer
Rapid growth after menopause
Reliable diagnosis is by histology only
Limited evidence on whether these uterine malignancies are the result of new growth vs malignant transformation of pre-existing benign uterine fibroids
Gonadotropin releasing hormone analogues /agonists
GOSRELIN (Zolodex branded – 1 monthly) or LEUPRORELIN (Prostap branded – 1 monthly or 3 monthly as per dose)
Downregulation of/desensitisation to endogenous hypothalamic GnRH release AFTER initial gonadotropin (FSH/LH) inducing effects (Symptoms may worsen initially before improving with desensitisation effects in time)
- Over time leads to GnRH desensitisation
- Downregulation of pituitary FSH/LH release
- Suppression of ovarian function; less ovarian/follicular oestrogen synthesis
- Fibroid shrinkage (growth is oestrogen sensitive) and amenorrhoea
6 months OR 1 year with HRT cover
Temp menopause
HRT: CHC (if <50 years and no CIs) or tibolone
Tibolone
(branded Livial)
Synthetic steroid hormone; sex hormone metabolites
Metabolised into 3 metabolites -> 2 oestrogenic and 1 progestogenic/ androgenic
Ryeqo
combination of HRT and relugolix as one oral medication
40 mg relugolix
1 mg estradiol (hemihydrate)
0.5 mg norethisterone
Hyperprolactinaemia as a cause of abnormal vaginal bleeding
Pituitary adenomas (57% of all pituitary tumours; presents most commonly in women of reproductive age)
Anti-psychotic medication (Majority have raised prolactin, ~50% have AUB)
traditional antipsychotic drugs: haloperidol, chlorpromazine, and flupenthixol
atypical antipsychotics like risperidone and amisulpride
Stress can cause mild elevation of prolactin
Irregular menstrual bleeding (oligomenorrhoea)
Irregular if >10 days variation in cycle length
PCOS dx
Rotterdam 2/3
(1) Hyperandrogenism (clinical / biochemical)
(2) Ovulatory dysfunction –> menstrual irregularity (<9 cycles / year or >35 days between cycles)
(3) Polycystic ovarian morphology often observed on ultrasound
follicle number per ovary of 20 or more in at least one ovary.
((If using transabdominal ultrasound ovarian volume >=10ml should be used for diagnosis
Not possible to reliably assess follicle number with TA route of scanning ))
8 years post-menarche
Hyperandrogenism in PMW (e.g. hirsutitism) - new onset, severe or worsening
Consider PCOS (if LT hx of oligoammen)
androgen-secreting tumours
ovarian hyperthecosis (presence of nests of luteinized theca cells in the ovarian stroma)
Investigations to perform in people with suspected PCOS
(1) LH, FSH, prolactin and TSH
Excludes other causes of irregular periods/ amenorrhea
POI; High FSH/LH
Hypogonadotropic hypogonadism; Low FSH/LH
HYPOthyroidism; High TSH (with low T4)
HYPERprolactinaemia (normal = <500); may be normal- mildly elevated in PCOS alone, significant elevation suggestive of other pathology i.e prolactinoma, especially if concurrent symptoms of prolactin excess (galactorrhoea)
(2) LH:FSH ratio >2.5
(3) Total testosterone – may be normal or moderately elevated in PCOS
(4) Sex hormone binding globulin (required to calculate free androgen index)
Free androgen index
Free androgen index= total testosterone x100 / SHBG as per NICE
Assesses amount of physiologically active testosterone present
Normal value = <5
May be normal or elevated in PCOS
FAI >=5 is suggestive of PCOS
Note: cannot perform on people on hormonal contraception:
Inhibition of adrenal and ovarian androgen synthesis
Increased levels of SHBG
If biochemical androgen testing is required test after a period of 3 months on alternative non-hormonal contraception
Management of PCOS
If no contraindications, COC use (à supresses androgen production and improves symptoms)
Preventing prolonged amenorrhea (preventing endometrial hyperplasia)
Cyclical progesterone MPA 10mg for 14 days –> withdrawal bleed EVERY 3 MONTHS.
Mirena.
Metformin (off-label) alone or in combination with COC
Especially if BMI >25 or other metabolic risk factors (IGT)
Evidence demonstrates it acts as an effective ovulation induction agent in many PCOS patients
Some evidence has shown it also reduces the risk of miscarriage and gestational diabetes
Causes of hyperandrogenism which can cause oligo/amenorrhoea
PCOS
Simple obesity
Primary hypothyroidism (May have goitre. Other clinical features – weight gain, cold intolerance, fatigue, constipation etc)
Elevated prolactin (Galactorrhoea)
Congenital adrenal hyperplasia (most commonly due to 21-hydroxylase deficiency
Cushing’s syndrome (cortisol excess)
Androgen secreting tumour (adrenal or ovarian origins)
Acromegaly
Congenital adrenal hyperplasia
Most commonly due to 21-hydroxylase deficiency
Classical = ambiguous genitalia +/- adrenal crisis at birth
Non-classical = milder and may present later in life due to early pubertal changes (secondary to androgen excess) or absent/ irregular menses
If there are signs of virilisation (e.g. deep voice, reduced breast size, increased muscle bulk, clitoral hypertrophy), rapidly progressing hirsutism (less than 1 year between hirsutism being noticed and seeking medical advice) or high total testosterone levels (greater than 5 nmol/l or more than twice the upper limit of normal reference range), androgen-secreting tumours and late-onset/nonclassical congenital adrenal hyperplasia (CAH) should be excluded. 17-hydroxyprogesterone should be measured in the follicular phase and will be raised in CAH.
It is possible to have CAH without the testosterone being > 5 nmol/l, particularly if the woman is heterozygous for this condition. Hence measurement of 17-hydroxyprogesterone should be considered if there is a high index of suspicion, for example, specific groups such as Ashkenazi Jews or those with a family history of CAH. If 17- hydroxyprogesterone is borderline, it will have to be confirmed by an ACTH stimulation test to diagnose CAH. If there is a clinical suspicion of Cushing’s syndrome or acromegaly, this should be investigated as per local practice.2
Primary dysmenorrhoea
from onset of ovulatory cycles, typically within 6 months - 1 year of menses
If severe symptoms and/ or no response to first line treatment (NSAID/anovulatory hormonal contraception) within 3-6 months –> referral
Secondary dysmenorrhoea
due to pelvic pathology and typically presents at a later stage
Most common cause of secondary dysmenorrhoea = endometriosis
Other
Adenomyosis
Fibroids
PUD
Ectopic
CU-IUD
Risk factors for endometriosis:
Early menarche and late menopause, nulliparity and delayed childbearing (more cycles)
Family history
Vaginal outlet obstruction
White ethnic group
Late first sexual encounter
Smoking
Endometriosis and subfertility
Endometriosis has prevalence of 25-40% in infertile women, compared to <5% in fertile
Ovulation during puberty:
During early puberty LH levels insufficient to trigger ovulation and majority of cycles anovulatory
Positive feedback from increasing oestrogen release à increased LH à ovulation
By 4-5 years post-menarche the majority of cycles are ovulatory (80%+)
During anovulatory cycles the ovaries may appear multi-cystic in nature
Do NOT USS ovaries as part of PCOS work up if <8 years post-menarche or <20 y/o (if age of menarche not known)
Precocious puberty;
age
causes
Signs of secondary sexual characteristic development at <8 years in girls (<9 years in boys)
(1)GnRH dependent (complete or ‘true’)
> idiopathic (80%)
> Kisspeptin (GnRH stimulating peptide) mutation in some
>Hypothalamic hamartoma – rare cause (Triad of precocious puberty, developmental delay and gelastic (laughter) seizures)
(2)GnRH independent, for which a definitive diagnosis/ underlying cause is usually found — ovarian or adrenal disorders
> Granulosa cell tumour (and other gynae tumours)
>Adrenocortical tumours
>Congenital adrenal hyperplasia
>McCune-Albright syndrome
Granulosa cell tumour
most common type of solid tumour –> precocious puberty (if occurring prior to onset of puberty, which only ~5% do)
Produce excess oestrogens
McCune-Albright syndrome
Rare with incidence from 1: 10,000 – 1: million
Triad of endocrine disturbances:
(1) Precocious puberty,
(2) abnormal bone lesions (fibrous dysplasia)
(3) café-au-lait spots
Spontaneous mutation of GNAS1 gene in chromosome 20
Precisous puberty males vs females
boys usually GnRH independent/pathology
girls usually GnRH dependent/ ‘true’ and idiopathic or ‘constitutional’ in nature
sexual developmental delay (SDD)
No secondary sexual characteristic (typically breast bud development) and not begun menstruation by age 13
OR no increase in testicular volume to >4mls (marks onset of puberty in boys) by age 14 years
Girls with normal secondary sexual characteristic development and not begun menstruation by age 15
13, 14, 15
Primary amenorrhoea
NORMAL secondary sexual characteristics:
Imperforate hymen
Transverse vaginal septum
Uterovaginal agenesis
The second most common cause of primary amenorrhoea (after primary gonadal failure) and accounts for ~15% of presentations
» Absent vagina and functioning uterus
»Absent vagina and non-functioning uterus = MRKH
XY female: androgen insensitivity syndrome
Feminine secondary sexual characteristics due to aromatisation of testosterone to oestrogen, but without axillary hair development (androgenic process)
Presentation often due to primary amenorrhoea
primary amenorrhoea
absent secondary sexual characteristics
NORMAL STATURE
Hypogonadotrophic hypogonadism
(Low GnRH/LH/FSH – poor stimulation of gonadal sex hormone production)
Low GnRH/LH/FSH – poor stimulation of gonadal sex hormone production
(1) Congenital hypogonadotropic hypogonadism (CHH)
Rare and more common in males with 3.6:1 M:F ratio
Failure of GnRH release from hypothalamus
(2) Kallman’s syndrome
Defect in migrating neurons from olfactory placode (olfactory and GnRH releasing neurons)
CHH with reduced or absent sense of smell
Multiple associated gene mutations and patterns of inheritance
(3) Pituitary prolactinoma
Although rare in children/adolescents, prolactinoma (raised prolactin) inhibits GnRH release and may delay/ prevent puberty
(4) Acquired – weight loss/anorexia, excessive exercise
Low leptin levels
Leptin = hormone produce by adipocytes, stimulator of hypothalamic GnRH release
–> hypogonadotropic hypogonadism picture: anovulatory cycles/ delayed puberty
Minimum body weight of ~47kg required to initiate /activate puberty
Hypergonadotrophic hypogonadism (Failure of the gonads to produce adequate sex hormones despite stimulation ++ via GnRH/LH/FSH release)
(1) Gonadal agenesis
(2) Gonadal dysgenesis
» Turner mosaic (as full Turner’s syndrome typically presents with short stature)
» Other (more niche) X deletions of mosaicism
» XY Swyer syndrome or lack of Mullerian inhibition
** (3) Primary ovarian failure/ insufficiency **Most common cause of primary amenorrhoea -50% of presentations
FSH >30
XY Swyer syndrome or lack of Mullerian inhibition
Complete gonadal dysgenesis (only gonadal streak develops)
Varied genetic mutations can cause, can be new or inherited
~20% cases caused by mutations on Y chromosome sex determining regions but other chromosomes implicated, and the Y chromosome can be normal
XY genotype AFAB with unambiguous female genitalia present –> no AMH during embryological development –> Mullerian/paramesonephric duct develops and female reproductive organs/ external genitalia develop in absence of AMH but absence of gonads (dysgenetic gonadal streaks only)
Diagnosed around puberty due to lack of endogenous oestrogen or testosterone to be converted to oestrogen via aromatisation–> lack of development of secondary sexual characteristics (as opposed to those with androgen insensitivity syndrome who may have some phenotypically female secondary sexual characteristics)
Often noted to have a TALL stature
Swyers = only syndrome in which XY individuals have a female reproductive organs
Treated with HRT and removal of streak gonads to prevent gonadoblastoma (with ~20% rate of testicular malignancy if left in situ beyond 20 years)
Galactosaemia
as a rare cause of POI
Autosomal recessive defect on chromosome 9 with incidence 1:60,000 births
Metabolic disorder; lack of GALT enzyme to breakdown sugar galactose
Despite appropriate dietary management >90% of those with galactosaemia develop very early POI à amenorrhoea (can either be primary or secondary)
Primary amenorrhoea
absent secondary sexual characteristics
SHORT STATURE:
Hypogonadotrophic hypogonadism
(1)Congenital hypogonadotropic hypogonadism (CHH)
Rare and more common in males with 3.6:1 M:F ratio
Failure of GnRH release from hypothalamus
(2) Acquired (rare)
Trauma
Empty sella turcica
Tumours
Hypergonadotrophic hypogonadism
(1) Turner syndrome
(2) Other (more niche) X deletions or mosaicism
if primary amenorrhoea with absent secondary sexual characteristics –> DDx hypogonadotropic vs hypergonadotropic
Measure serum FSH
Elevated FSH (hypergonadotropic) suggestive of gonadal failure
Should have karyotyping to confirm if Y chromosome present
If present or hyperandrogenic features –> removal of gonads to prevent gonadoblastoma
If FSH low (hypogonadotropic) then karyotyping not required, but should have cranial imaging to rule out CNS tumour
Turner’s syndrome
5XO karyotype (aneuploidy)
In 10-15% of Turner’s cases = isochromosome X (incorrect chromosomal division -> 2 short arms on one X chromosome and 2 long arms on one X chromosome)
1:2500 live female births
> 99% of XO foetuses’ self-abort
Only viable monosomy in humans
» In typical XX females one copy of the X chromosome in each cell is functionally inactivated in a process called Lyonisation –> Formation of the Barr body
» Absent Barr body = diagnostic feature in Turner’s
Often present with short stature/ growth concerns around puberty, failed/delayed puberty (lack of secondary sexual characteristics) and/ or primary amenorrhea
Gonadal hypoplasia with other associated abnormalities
» Webbed neck
»Broad chest with wide spaced nipples
»Cubitus valgus (valgus deformity of the elbow -> increased carrying angle (lower arms ‘stick out’ from midline)
» Short 4th metacarpal
»Lymphoedema of the extremities in the neonate; especially feet
»Low set ears (80%)
»Low hairline
»Hypoplastic nails
»Congenital heart defects in 10-20%
»Coarctation of the aorta
»Early aortic stenosis due to bicuspid aortic valves
»ASD
»VSD
»Hypertension; idiopathic or secondary to coarctation of the aorta
Characteristic ‘streak’ gonads are seen posterior to the broad ligaments of the uterus
Fibrous tissue only
Devoid of germ cells
High incidence of concurrent horseshoe kidneys (shared embryological origin of genital and urinary tracts!)
Short stature (125-1.5m average height) with failure of pubertal growth spurt
May have specific learning difficulties but usually good overall mental development (vs Noonan’s which is strongly associated with low IQ/ intellectual disability)
Infertility (lack of gonadal tissue) but normal genitalia otherwise
Association with autoimmune conditions ; particularly thyroiditis and IBD
Normal life span
Diagnosis:
1. Raised FSH/LH and low oestrogen on hormonal profile
2. XO karyotype confirmation/ absence of Barr body = confirmatory
3. If diagnosis is made early hormone replacement can be initiated:
Human growth hormone -> improved stature
Oestrogen -> attainment of secondary sexual characteristics
Regardless of time of diagnosis hormone replacement with oestrogen/progesterone cover is recommended to protect bone density and should be continued until age of the natural menopause (51)
Rarely patients can be Turner’s mosaics
XO/XX – “pure” gonadal dysgenesis without other associations of Turner’s ie short stature
XO/XY – 50% rates of gonadal neoplasia (gonadoblastoma) -> Gonadal removal is recommended prophylactically
Noonan’s syndrome
Turner’s syndrome bodily phenotype with normal (XX) genotype
Autosomal dominant condition with sporadic occurrence
Chromosome 12
Mutations in PTPN11 gene >=50% of cases, most common cause
SOS1 = 10-15%
Some phenotypic distinctions:
»Characteristic facies
Broad forehead
Ptosis and hypertelorism (broadly spaced eyes)
Epicanthic folds and down-slanting eyes
Flat nasal bridge
> > Kyphoscoliosis
> > Right sided congenital heart disease associations (compared to left sided associations in Tuner’s)
Pulmonary artery stenosis
Tetralogy of Fallot
> > More strongly associated with learning difficulties/ low IQ
Management focuses on addressing congenital heart defects and supporting mental development/ additional needs
Variable prognosis as per severity of heart defects
Klinefelter’s 47XXY
Occurs due to failure of X chromosome separation during mitosis or meiosis processes
At least one extra X chromosome in the male –> reduced testosterone production (elevated LH + FSH)
Each additional X chromosome increases oestrogen: testosterone ratio –> more feminisation
Symptomatic with hypogonadism around puberty
Often having some gynaecomastia and broader hips
Usually associated with male infertility
Testosterone replacement therapy +/- assisted conception
Jacob’s 47 XYY
Extra Y chromosome in the male
Increased incidence of learning difficulties / developmental delays
Usually normal sexual development however is some association with male infertility
Triple X syndrome 47 XXX
Extra X chromosome in the female
Increased incidence of learning difficulties / developmental delays
Often no reproductive symptoms and fertility usually unaffected
Secondary amenorrhoea =
cessation of menses for 3 months or more in those with previously regular cycles, or 6 months or more in those with previous irregular cycles
Causes of secondary amenorrhoea that can be managed in primary care vs gynae vs end ref
GP
PCOS
Hypothyroidism
Pregnancy
Menopause (in those aged >=40 years)
Gynae
1. Suspected premature ovarian insufficiency
2. Recent history of uterine/cervical surgery or severe pelvic infection suggestive of Asherman’s syndrome (intrauterine adhesions) or cervical stenosis
3. associated infertility
Endo
1. Hyperprolactinaemia (level >1000 or >500 on 2 occaisions, includes drugs known to cause high prolactin
- Low FSH and LH levels – to exclude hypopituitarism or a pituitary tumour, though stress/ exercise /weight loss are more likely causes of FSH/LH suppression here
- Raised testosterone level not felt to be explained by diagnosis of PCOS (?androgen secreting tumour, late onset/ non-classical congenital adrenal hyperplasia or Cushing’s syndrome)
- Any other features of Cushing’s syndrome or late onset congenital adrenal hyperplasia
Asherman’s syndrome
Scar tissue/ adhesions forming web like structures in uterus.
Trauma to basal layer of uterus and failure to regenerate.
Causes
- Surgery
- Infection less common
tuberculosis
schistosomiasis
Oligomenorrhoea
generally defined as periods occurring at <21 days OR >35 days
Depends on timing from menarche:
(1) Irregular cycles are normal in the 1st year post-menarche
(2) At any time post-menarche a cycle of >90 days is considered irregular/ abnormal
(3) From 1-3 years post menarche = <21 or >45 days (greater accepted variation)
(4) 3 years post-menarche –> menopause = <21 or >35 days or <8 cycles per year
Hirsutism in adolescents causes:
(1) Idiopathic
Mild and not associated with other hyperandrogenic symptoms ie irregular periods
May have a family history of hirsutism
Cosmetic treatment +/- spironolactone (anti-androgenic action)
(2) Ovarian
PCOS = common
Ovarian secretory tumours = uncommon
(3) Adrenal – uncommon
Congenital adrenal hyperplasia (non-classical = milder and may be diagnosed later in life)
—> Early morning (fasting) 17-hydroxyprogesterone testing
Should be done 08:00 - 09:00 in absence of hormonal contraceptive use and ideally in the early follicular phase (days 1-5) of the cycle
Adrenal tumours, most commonly adenomas (benign), less commonly carcinomas
Ambiguous genitalia
(1) CAH
21-hydroxylase is the most common enzyme deficiency -> raised androgens , others 17 and 11.
(2) Females 46 XX DSD – virilised external genitalia; often a result of congenital adrenal hyperplasia
» Androgen exposure <12 weeks gestation = ‘labioscrotal fusion’ -> retention of urogenital sinus (single tract which urethra and vagina empty in to before reaching the perineum)
» Androgen exposure >12 weeks gestation = clitoromegaly
» No palpable gonads at external genitalia = suggestive of virilised female
(3) Males 46 XY DSD – under-virilised external genitalia
»5a-reductase deficiency
»Autosomal recessive mutation on chromosome 2
» Failed conversion of testosterone -> more potent dihydrotestosterone -> impaired virilisation
»Does not present clinically in females as no clinical/ developmental need for DHT
» Palpable gonads at external genitalia = suggestive of under-virilised male
Congenital anomalies of the vulva
(1) Labial fusion
Usually with clitoromegally as part of excess androgen pic
>CAH most common cause, but can be exogenous androgen intake/exposure or endogenous.
(2) Labial adhesion
Very common in pre-school children 2-6 years; low oestrogen naturally
Occurs as non-oestrogenised labia undergo ‘denudation’ (loss of epithelium) à fuse as adhesions
Usually self resolve at puberty with higher oestrogen levels
If not self resolving, use of oestrogen cream to better oestrogenise the skin à reduces recurrence following surgical division
Congenital anomalies of the hymen
Imperforate hymen
1:1000
Endoderm (from the urogenital sinus epithelium)
ddx :Transverse vaginal septum
Congenital anomalies of the vagina
Vaginal agenesis AKA Mullerian agenesis AKA MRKH
Androgen insensitivity syndrome (previously testicular feminisation syndrome)
Vaginal atresia
Transverse vaginal septum
Vertical or complete vaginal septum (septum down the length of the vagina - assoc with didelphys)
Vaginal adenosis
Vaginal agenesis
Also known as Mullerian agenesis or MRKH (Mayer Rokitansky Kuster Hauser) Syndrome
Primary ammenorrhoea (make up 15% of primary)
Absent vagina
non-functioning uterus
Vaginal agenesis in association with cervical and uterine agenesis/hypoplasia
75% have complete vaginal agenesis / 25% have a short vaginal pouch
Rare ~1:5000 female births
46 XX genotype with normal hormone profile
Confirmed on MRI
Fertility - could egg harvest, need surogate
No cervix - no smears
vaginal dilation for sex / neovagina if no vag present
OVARIES are NORMAL
2 TYPES:
Type I – reproductive anatomy differences alone
Agenesis upper 2/3 vagina along with absent cervix and absent or under-developed uterus
Type II – other associated anatomical differences (40%-50%)
Renal tract (most commonly!)
Hearing difficulties (middle ear)
Bone effects (fused or absent vertebrae)
Androgen insensitivity syndrome (previously testicular feminisation syndrome)
46XY genotype
Defective androgen receptors
Developing fetus cannot sense any androgens –> feminisation of external genitalia
A short vaginal pouch can form from the urogenital sinus
Mullerian (paramesonephric) ducts reabsorb as normal due to testicular production of AMH
Wolffian (mesonephric) ducts persist
Undescended, androgen producing testes present
Testosterone -> aromatised to oestrogen -> phenotypic females, often tall and without pubic hair due to lack of androgenic stimulation
Present with primary amenorrhoea
Testes should be removed to prevent gonadoblastoma
Vaginal adenosis
Persistence of Mullerian (paramesonephric) duct tissue (cervical/endometrial in appearance) within the lower 2/3 vagina (usually originating solely from the urogenital ridge)
Associated with in utero diethylstilboestrol (DES) exposure; discontinued 1971
Mullerian duct anomaly
incidence and classification
Congenital anomalies of the uterus
Mullerian anomalies have an incidence of between 1-3%
- Uterine agenesis / hypoplasia - primary amenorrhoea, MRKH, renal
- Unicornuate uterus (unicornis unicollis) - accounts for ~15% of uterine anomalies
REPRO IMPACT - Uterine didelphys (duplication) 7.5% uterine anomalies
REPRO IMPACT - Bicornuate uterus 2nd most common uterine anomaly type at ~25%.
- Septate uterus – the most common form of uterine anomaly accounting for ~45% of cases
- Arcuate uterus (“heart shaped”) - technically the mildest form of septate uterus as same pathogenesis
- T shaped uterus - from in utero exposure to diethylstilboestrol (DES)
Uterine agenesis / hypoplasia
Primary ammenohea
Concurrent renal anomalies in around 1/3
Associated with Mayer-Rokitansky-Kuster Hauser (MRKH) syndrome = absent upper 2/3 vagina also
Unicornuate uterus (unicornis unicollis)
15% of uterine anomalies
Poor pregnancy outcomes (most significant reproductive impact along with uterine didelphys)
Failure of one Mullerian/ paramesonephric duct to elongate, whilst the other develops normally
Predominantly tends to occur on the right – unexplained as to why this preference exists
(A) Communicating contralateral rudimentary horn; contains endometrium (10%)
(B) Non communicating contralateral rudimentary horn; contains endometrium (22%)
- Adolescent presentation with persistent ++ dysmenorrhoea
- Likely to have heamatometra
- Likely to have degree of retrograde menstruation -> endometrioma
(C) Contralateral horn present but with no endometrial cavity (33%)
(D) No contralateral horn present (35%)
Uterine didelphys (duplication)
Complete duplication of uterine horns AND cervix with no communication between them; 2 uterine bodies (each with one fallopian tube and one cervix)
FAILURE OF FUSION MULL DUCT
Result of failed Mullerian/ paramesonephric ductal fusion between 12th-16th weeks of development -> Two distinct and widely spaced uterine bodies with significant fundal cleft (compared to bicornuate – smaller fundal cleft for separation of horns only – or septate uteri – fibrous septum only no fundal cleft/division)
Poor pregnancy outcomes
Bicornuate uterus
2 distinct uterine horns which open into a single vagina
INCOMPLETE FUSION MULL DUCT
2 types:
Complete division of uterus down to external os -> 2 cervical canals within one cervical body structure (bicornuate bicollis)
Partial division of the uterus does not extend to the internal os, therefore only one cervical canal (bicornuate unicollis)
Does not usually require surgical intervention, though cervical sutures may be required for pregnancy
If recurrent pregnancy loss -> Strassman metroplasty (reconstruction of one cavity/ horn) can be done
Septate uterus
The most common form of uterine anomaly accounting for ~45% of cases
Tends to be associated with poor pregnancy outcomes; subfertility, recurrent early loss and preterm labour
Effects ~15% of all women presenting with recurrent pregnancy
AFTER FUSION
Result of complete or partial failure of resorption of the uterovaginal septum after fusion of the paramesonephric ducts
In septate uterus the septum tends to be fibrous (vs bicornuate where it tends to be muscular) and as such can be divided relatively safely and easily through hysteroscopy
May be associated with a vaginal septum (though less commonly here than in uterine didelphys)
HEADSS assessment
tool for adolescent safeguarding consultations
Home and environment
Education and employment
Activities
Drugs
Sexuality
Suicide/ depression
Cyclical adverse effects of hormonal contraception/ hrt
progesterone induced pre-menstrual disorder = cyclical symptoms in context of exogenous progesterone use (usually CHC or HRT)
progesterone only contraception adverse effects are non-cyclical in nature
PMS dx
PROSTPECTIVE symptom monitoring via symptom diary over at least 2 cycles (cannot be retrospective)
Daily Record of Severity of Problems (DRSP)
If completed symptom diary is inconclusive, GnRH analogues may be used for up to 3 months to confirm the diagnosis
5-8% of women who experience pre-menstrual symptoms meet criteria for PMSyndrome diagnosis
Lifestyle factors for PMS
Exercise, balanced diet, sleep hygiene, stress management
Supplements: Vit D, Ca and Mg, Vit B6 (pyridoxine), evening primrose (breast tenderness)
Simple analgesia for pain, including topical NSAIDs, and well-fitting bras
Other herbal remedies: chasteberry/ vitex agnus-castus or gingko bilboa
Pharmacological treatment for PMS
Primary hormonal treatment of PMS focuses on oestrogen therapy
There is no evidence of a beneficial role for progesterone only hormonal therapy in PMS management
FIRST LINE
continuous use of drosperinone-containing COC (not liscenced) - YASMIN
SSRI
ALTERNATIVES
» HRT – transdermal oestradiol + cyclical progestogen for 10-12days/cycle for endometrial protection
> > Danazol/ danocrine – androgen medication 200mg BD
> > GnRH analogues – only in severe cases where other treatment options have not been of benefit
> > Spironolactone
HRT rx for PMS
transdermal oestradiol + cyclical progestogen for 10-12days/cycle for endometrial protection
Insufficient evidence on long term effects on pre-menopausal endometrial and breast tissue
Micronized progesterone recommended as less likely to reintroduce/mimic PMS symptoms
Should be used alongside further contraceptive cover
Intrauterine or barrier methods of contraception best supported by RCOG green top guide in these cases, to minimise systemic progestogen exposure
In women with PMS, LNG-IUD can initially produce PMS-type adverse effects po
Danazol/ danocrine –
Never actually used??
significant luteal phase breast symptoms only
androgen medication 200mg BD
Effective for significant luteal phase breast symptoms only; not commonly used
Also used in benign mastalgia patients; good evidence that it helps with breast tenderness
Potential for irreversible virilising effects
Teratogenic (potential virilisation of female fetus); recommend IUC / SDI contraceptive cover
GnRH analogues in PMS
only in severe cases where other treatment options have not been of benefit
Highly effective for treatment of severe PMS
Optimise bone health: vitamin D/calcium, diet, weight bearing exercise, smoking cessation
If using for >6 months add-back HRT cover is recommended
**Continuous-combined HRT OR tibolone as per green top guidance **
If using for >2 years need annual DEXA scans to monitor BMD, and treatment should be stopped if significant decline in bone density is observed
Very rarely following a successful trial of GnRH analogue use (which mimics the effects of surgical menopause) TAHBSO may be considered as permanent/ surgical treatment for severe and refractory cases of PMS
Surgical treatment should NOT be used without a pre-surgery trial of GnRH analogues to ensure benefit, and test tolerability of HRT
Oophorectomy alone would necessitate use of progesterone component to HRT and risks reintroduction of PMS symptoms, therefore TAHBSO is recommended if surgical tx indicated
SSRI for PMS
a first line treatment option for PMS as per patient preference
Daily OR for 2 weeks throughout secretory/luteal phase approaching menses
Evidence of increased efficacy and lower adverse effects if used only in luteal phase
Common adverse effects: insomnia, low libido, fatigue and nausea
If being used continuously and wishing to stop, need gradual reduction to avoid withdrawal
SSRIs can be withdrawn prior to conception as PMS symptoms are expected to resolve during pregnancy
SSRIs in pregnancy
There is some evidence to suggest a link with SSRI use and congenital malformation
More evidence needed - not proven
DSM-V for PMDD
symptoms must follow luteal phase worsening, with at least 1 week symptom free following menses
Symptoms must include at least one mood/ anxiety symptom, and have a severe impact on social and/or occupational wellbeing
Must have 5 or more of the following (vs PMS where no symptom limit/ restriction for diagnosis):
1 or more of the following
» Mood changes
» Irritability/ anger/ conflict
» Depressed
» Anxiety
1 or more of the following (to reach total of 5)
» Decreased interest
» Difficulty conc
» Lethargy
»Change in eating
» Change in sleep
»Overwhelmed
»Out of control
» Physical symptoms
Steroid hormones produced by ovary:
Estradiol (from granulosa cells within developing follicles surrounding oocytes)
Progesterone (some production from both T»G cells)
Testosterone (from theca cells outlining developing follicles surrounding oocyes)
INHIBIN B (from granulosa cells; plays a role in negative feedback control)
INHIBIN
Glycoprotein synthesised/ secreted by granulosa cells within ovary
heterodimeric protein: inhibin A and inhibin B
Inhibin A = produced by granulosa cells of the dominant follicle and corpus luteum
» Rises at end of follicular phase (when follicle largest)
» Declines from mid-luteal phase onwards (as corpus luteum regresses)
Inhibin B = produced by granulosa cells of non-dominant follicles
» Rises during early follicular and reduces later follicular.
» Does not contribute significantly during the luteal phase (minimal follicular activity here)
Provides negative feedback at anterior pituitary -> less FSH/LH release
During menopause follicular activity decreases
- Less inhibin produced
- Less suppression of FSH
- FSH levels rise
NOTE: Sertoli cells of the testis in males produce inhibin
The Stages of Reproductive Aging Workshop (STRAW) model
gold standard for characterising the reproductive aging -> menopause
SEE SCREEN GRABS
Stage +1b is the 12 months following completion of the menopause
FSH levels are continuing to rise here and systemic symptoms are most likely to occur during this time
Menopausal symptoms of any kind can occur before periods stop however are most likely to occur in the first year following completion of the menopause
Vasomotor symptoms = most common
Menopause ages
Average age of meno = 51
Early menopause = menopause occurring between 40 – 45 years, in the absence of other causes of secondary amenorrhea
POI <40years
RF for early menopause
Growth restriction in late gestation
Low weight gain in infancy
Starvation/ poor nutrition in early childhood
Down’s syndrome
Early menarche (<11 years) and nulliparity/low parity (more cycles)
Smoking
Living at higher altitude
Social deprivation
Later menopause associations
Being breastfed
Higher childhood cognitive ability
Increased parity
POI causes
(1) Primary/ genetic
(2) Autoimmune
(3) Secondary/ Iatrogenic
Primary/ genetic causes of POI
Often occurring <30 years and with associated strong maternal family history
Karyotyping in <30 / suspect turners.
Chromosomal abnormalities: Turner’s syndrome / Down’s syndrome/ Fragile X syndrome (FMR1)
Enzyme deficiencies
Galactosaemia (auto-recessive def. of galactose-1 phosphate uridyltransferase)
More rarely:
»Cholesterol desmolase deficiency (produce minimal steroid hormones and rarely survive to adulthood)
» 17-aplha hydroxylase deficiency (form of congenital adrenal hyperplasia - hypertension, hypokalaemia and ovarian failure)
» Isolated 17-20 desmolase deficiency (-> isolated ovarian failure)
Check BRCA1
Autoimmune causes of POI
More commonly found in those with ‘AI predisposition’
Test thyroid and adrenal antibodies routinely due to frequency of association with POI
Secondary/ Iatrogenic causes of POI
Post-chemotherapy/ radiotherapy
» Likelihood depends on type of chemo, dosage of chemo and age when chemo received
» Pre-pubertal uterus –> uterine dysfunction: Higher rates of adverse pregnancy outcomes even if ovaries do not fail
Post treatment with gonadotrophin releasing hormone analogues
Post bilateral oophorectomy
»Results in immediate menopause
»Often intensely symptomatic
» HRT should be commenced immediately following
More rarely can occur following an infection ie mumps or tuberculosis
Most causes of POI following mumps infection àeventual return of normal ovarian function
Diagnosis of POI
Cessation of menses for more than 1 year before 40 years
UPT
2 x FSH > 30
4-6 weeks apart
(An FSH of <10 is well within normal, an FSH of >15 is generally considered to be elevated)
LH (HIGH)
FSH better than LH
(If LH is significantly elevated versus FSH, autoimmune oophoritis may be suspected)
Oestradiol
Usually low but variations often present espec in early disease
Testosterone
Karyotyping (if <30 years)
Rule out reversible causes
Prolactinoma (prolactin)
Thyroid disease (TSH elevated if AI hypothyroidism)
NICE do not recommend routine testing of AMH for diagnostic purposes in women with ?POI
Treatment of POI
HRT up to the average age of the naturally occurring menopause (51) at which point the need for ongoing HRT should be assessed as per symptoms
The combined contraceptive pill can be used as a HRT alternative if <50 years old
»> However HRT gives better bone protection and may provide better symptom control (greater ability to titrate oestrogen dosing)
When to measure FSH in perimenopausal / menopausal women?
Consider in:
< 40 (for dx POI)
40 - 45 years with typical symptoms
>=45 years with atypical symptoms
FSH should NOT be used in otherwise healthy women who are not using any hormonal contraceptive agents and who are aged >=45 years with typical menopausal symptoms
Pathophysiology of vasomotor symptoms in menopause
Hot flushes and night sweats
70% western women
(Japanese less)
More noticable in smoking/high bmi
Less oestrogen -> DECREASED density of 5HT(serotonin) receptors + lower serotonin activity
Less oestrogen -> INCREASED noradrenaline
—> Narrowed thermoneutral zone: Smaller changes in core temperature trigger heat dissipation mechanisms
Increase in body temperature -> vasodilation and increase HR (‘hot flush’)
Palpitations and anxiety often associated with vasomotor symptoms
Physiology Urogenital atrophy of menopause
Common, effecting ~ 50% of menopausal women
Effects the vagina, female urethra, bladder and pelvic floor; all have ER + PR present
Loss of oestrogen -> thinning of vaginal epithelium
» loss of vascularity of tissues
» loss of rugae, collagen and elasticity of tissues –> increase laxity of pelvic floor muscles predisposes to prolapse
Skin becomes pale with erythematous areas and petechial heamorrhage
Reduced vaginal and cervical secretions -> dryness
Vaginal pH also increases (less production of lactic acid) -> encourages growth of pathogens
Can cause subjective symptoms of – vaginal dryness, dyspareunia, urinary frequency and dysuria
» sex dysfunction
» exacerbate / cause recurrent UTIs
» corrected with vaginal oestrogens
Offer low dose topical/ local (vaginal) oestrogen only as first line HRT for isolated urogenital symptoms
If not effective/contraindicated then consider ospemifene (selective oestrogen receptor modulator: as per NICE menopause guideline) - CI: breast ca treatment.
Fragile X syndrome
Gene: FMR1
intellectual disability
FXS affects both males and females. However, females often have milder symptoms than males.
How is lactic acid in the vagina generated?
Oestrogen stimulated exfoliation of the vagina epithelial cells –> increased glycogen —> converted to lactic acid by lactobacilli –> acidic environment (3.5 - 4.5)
Low libido in menopause; management
- HRT
- Switch HRT
Oral oestrogens can reduce naturally circulating testosterone (via increase in SHBG)
Switching from oral to transdermal oestrogen can be helpful for sexual desire as may increase circulating testosterone levels without requiring exogenous use
- Testosterone (off lable)
Specialist use
Only if symptoms + low levels
STOP if no perceived benefit in 3-6 months
Adverse androgenic effects: Acne Hair growth Weight gain
Rare: alopecia, deepening of voice clitoral enlargement
Check levels PRIOR to rx
Monitor 6-12 months to ensure levels remain within the female physiological range (to reduce chances of side effects)
Dx of OP
Presence of fragility fracture
DEXA showing BMD -2.5 standard deviations below healthy mean (T score of less than - 2.5)
DXA T score and Z score
T score = comparison of BMD to average of young person (aged 20-29) of the same sex
Normal T score = +1 to -1
Osteopenia T score = -1 to -2.5
Osteoporosis T score = <-2.5
Z score = compared BMD to people of the same age and gender
Bone remodelling physiology
Mostly dependant on calc levels
PTH, calcitonin and vit D
PTH produced by PT in response to LOW serum calc
(stimulates osteoblasts to make RANK-L - breaks down bone)
Calcitonin produced by thyroid in response to HIGH serum calc
(inhibits bone resorption)
Vit D - calcium absorption from the gut - increased calcitonin.
Bone remodelling during osteoporotic change:
Low calcium -> PTH produced -> osteoblasts produce RANK-L -> stimulates production/ differentiation of osteoclasts
Changes to the bone in osteoporosis: Less trabeculae and thinning of cortical bone
Drug therapy known to impact BMD
PPI
SSRIs
Medroxyprogesterone acetate (long term/significant history of use in particular)
Aromatase inhibitors
Thiazolidinediones
Most anticonvulsants
Prevention and treatment of OP
FRAX should be calculated in all women aged >=65 or those aged 50-65 years with any risk factors
–> DEXA as per FRAX result
Oestrogen = first line therapy for the prevention of osteoporosis in women under 60 years i.e. reasonable to use HRT solely for this purpose
»> Women with osteopenia; don’t meet criteria for bisphosphonate treatment
»> Women with premature ovarian insufficiency –> bisphosphonates not first line here!)
HRT alongside bisphosphonates if osteoporosis confirmed in perimenopausal women; dual action
How does HRT help with OP
HRT acts as an anti-resorptive agent by reducing osteoclast number and activity
HRT may also increase new bone formation by stimulation of osteoblast activity
significant reduction in fracture risk is seen following 2 years of HRT treatment -> persists for several years upon withdrawing HRT
Starting HRT at >=60 years for the sole purpose of preventing osteoporotic # is not recommended (BMS)
Osteoclasts
what are they
what do they do
IL6
Bisphos
Responsible for bone resorption
Derived from mesenchymal cells (haematopoietic progenitors within bone marrow)
Formed by monocyte/ macrophage fusion
Multinucleate (2 -12 nuclei / osteoclast)
Form resorption bays/ “Howships lacunae” where lysosymes then act to release H + ions and dissolve inorganic matter (bone)
NB Interleukin 6 is a potent activator of osteoclast activity, and acts to promote bone reabsorption
Part of bisphosphonates mechanism -> inhibits IL-6 production -> osteoclast apoptosis
Treatment
Post menopausal with
(A) fragility fracture or DXA T-score ≤-2.5 or
(B) osteopenia and at high risk of fracture
Bisphosphonate
Plus calcium and vitamin D
Consider HRT additionally (first line if <60 years old or <10 years since menopause)
Early menopause/ POI and bone health rx
Oestrogen as a first-line treatment to prevent all types of fracture for women under 60 years of age (<10 years past menopause).
Some might change to bisphosphonate following menopause due to small breast ca risk.
When would you use HRT in women with osteopenia
Under 60 years of age (<10 years past menopause)
Bisphosphonates - cautions and contraindications
Contra-indicated in women with fertility aspirations - effects on the fetal skeleton as 1/2 life >12 years.
Use with caution in younger PM women (<65) as very long skeletal retention time.
Pharmacological management of OP
All work by inhibiting bone resorption
HRT
Bisphos
Denosumab
SERMs
PT hormone peptides (only one that DOESNT work by inhibiting bone resorption)
Romozosumab
Bone conserving doses of HRT
Oestradiol 2mg
Conjugated equine oestrogens 0.625mg
Transdermal 50mcg patch
LOWER DOSES also conserve bone mass - tailor dose to age of the woman.
Continuous use is required.
Bisphosphonates
MOA
How to take
EG Alendronate 70mg once weekly ( reduces vertebral and non-vertebral fractures by 50%), Risedronate 35mg once weekly.
chemical analogues of naturally occurring pyrophosphates (calcium crystal)
inhibit osteoclastic bone resorption:
(1) attach to hydroxyapatite binding sites on bony surfaces
(2) As osteoclasts resorb bone, the bisphosphonate embedded in the bone is released and impairs the osteoclast’s ability to continue bone resorption.
» Nitrogen containing bisphos: - inhibiting farnesyl pyrophosphate synthase - lose ruffled border - detach from bone.
» Non nitrogen bisphos - metabolised inside osteoclast cause apoptosis.
Secondary mechanisms:
(a) inhibition of IL-6 production: Reduce activity of osteoclasts and induce increased osteoclast apoptosis
SE: also interferes with normal bone healing and remodelling
» fatigue damage due to oversuppression of bone remodelling with long-term use in some individuals leading to femoral fragility fractures and also development of osteonecrosis in the jaw.
RARE (1 in 5000) but still do 5 years treatment then 2 year holiday to reduce risk.
Denosumab
monoclonal antibody to receptor activator of RANK-L, a major signal promoting osteoclast activity
Same as bisphos in terms of spine/ hip fracture reduction BUT risk of osteonecrosis of the jaw and femoral fragility fractures.
PRO: not retained in the skeleton and may be a safer option for younger women.
CON: associated with an increased risk of infections and should be avoided in patients with increased susceptibility
When stopping…
accelerated loss –> concern about an increased risk of fractures
SERMs for OP
EG Raloxifene
60mg/day, reduces fracs by 35%.
for women, after the menopause
Oestrogenic actions in certain tissues and anti-oestrogenic actions in others.
Also reduces risk of breast ca
SE: hot flushes calf cramps VTE
PT hormone peptides for OP
(only OP rx that DOESNT work by inhibiting bone resorption)
Recombinant 1-34 parathyroid hormone (teriparatide), given as a subcutaneous daily injection of 20 µg, reduces vertebral and non-vertebral fractures in postmenopausal women with osteoporosis (not hip).
Costly.
Romozosumab for OP
monoclonal antibody - binds sclerostin, a natural inhibitor of the Wnt/LRP pathway which is a major signal to osteoblasts to promote bone formation —> increase in bone formation.
Romozosumab is given by subcutaneous injection every 2 weeks for a 12 month course.
Calcium and vit D dose
ergocalciferol: 1000 units orally once daily
and
calcium: adults 51-70 years of age: 1000 mg/day orally
Exercise and OP
Benefits are mainly related to increased wellbeing, muscle strength, postural stability and a reduction of chronic pain rather than an increase of skeletal mass.
female patient starting a glucocorticoid for >= 3 months
FRAX
Consider bisphosphonate treatment in those with other risk factors/ scoring highly on FRAX
DEXA if intermediate FRAX score -> recalculate FRAX as per DEXA result -> consider bisphosphonate
What are you thinking if its a postmenopausal woman presenting with new onset or severe/ worsening hyperandrogenism (including hirsutism) ??
PCOS
Need to rule out
(1) Androgen secreting tumours (imaging of the adrenal glands and ovaries) and/or
(2) Ovarian hyperthecosis
Ovarian hyperthecosis
Hyperthecosis (HT) = ‘nests’ of luteinised theca cells in ovarian stroma –> testosterone release
Non-neoplastic
Usually bilateral ovaries effected
Gold standard for diagnosis is confirmation via histology of an ovarian sample
Ultrasound appearances of the ovaries may be normal, even in pre-menopausal women with HT
Becomes unmasked post-menopausally due to loss of follicular granulosa cells –> testosterone no longer being aromatised into oestradiol here –> more marked hyperandrogenis
Vaginal oestrogen
Vaginal tablets (Vagifem)
Creams (Ovestin or Gynest)
Gels (Blissel)
Vaginal ring (Estring – in situ for 3 months, maximum continuous use of 2 years)
Pessaries (Imvaggis)
transdermal HRT > oral HRT for women who:
History of previous VTE/ other VTE risk factors
Cardiovascular risk factors ie BMI >=30, uncontrolled hypertension or cholesterol
Concomitant enzyme inducing medications (wanting to avoid hepatic first pass metabolism)
Malabsorptive conditions of the GI tract
History of gallstones
History of migraine headache
Lactose sensitivity (most oral HRT contains lactose)
Side effects or persistent/ suboptimal symptom control with previously trialled oral regime
Types of naturally occurring oestrogens
Estradiol (E2)
Made: Granulosa cells (ovaries)
When: Reproductive years
Potency: most potent
Used in HRT: YES - PO/TD
Estrone (E1)
Made: Adrenal glands/ adipose tissue
When: Post menopause
Potency: 10 x less
Used in HRT: YES - conj equine oestrogen
Estriol (E3)
Made: Placenta
When: Pregnancy
Potency: 100x less
Used in HRT: YES - cream
Estetrol (E4)
Made: Fetal liver during pregnancy
When: Pregnancy
Potency:
Used in HRT: Not yet! (new COCP)
Oestrogens in HRT
Oral
Conjugated equine - E1
Estradiol 17 beta - E2
Estradiol valerate - E2 (prodrug)
All go through first pass metabolism and become estrone (E1) - much less potent so higher doses.
Patch/ gel/ spray
Estradiol 17 beta
Avoid first pass metabolism through liver, absorbed as estradiol - can check levels
Less effect on clotting factors - no increased VTE
More suitable for: VTE/CVD risk, enzyme inducers, malabsorption, migraine
Oestrogen only or combined oestrogen-progesterone patches
Combined patches contain either norethisterone or levonorgestrel
What progesterone to use in HRT
Medroxyprogesterone, Dydrogesterone and drosperinone are less androgenic (better SE profile)
Micronized progesterone or dydrogesterone for women with high cholesterol – triglyceride neutral
Drosperinone particularly good for women who suffer with fluid retention in progestogenic phase of cyclical HRT due to it’s aldosterone antagonistic effect
LNG-IUD results in very low systemic levels of progesterone but provides endometrial protection
» Good if having heavy withdrawal bleeds on cyclical combined HRT regime
» Good if ongoing progestogenic side effects with multiple systemic routes trialled
» Good for those who need contraception alongside HRT (dual effect)
Cyclical or “sequential” combined HRT
progesterone only taken for part of the month (10-14 days)
Allows withdrawal bleeds to occur following progesterone withdrawal
Bleeds occur towards end of progesterone containing phase
Recommended for women if it has not been >=12 months since their last menstrual bleed
A 3 monthly cyclical regime can be considered for women who have infrequent menses or who are poorly tolerant of the progestogen component of their HRT
Unscheduled vaginal bleeding is a common side effect of HRT within the first 3 months of use
» Quoted rates of 80% of women experience this in first 3 months (any type of HRT)
»If persistent/ problematic and pathology has been excluded -> change progestogen
Sequential HRT is beneficial if you are still having periods as adding in progesterone all the time at this point can lead to erratic, prolonged and, sometimes, heavy, bleeding
Continuous combined HRT
Same doses of oestrogen and progesterone taken each day
Suitable for women who are >12 months from last menses (post-menopausal)
No withdrawal bleeding should occur
May result in irregular spotting/ light bleeding for first 4-6 months of use
If bleeding becomes heavy, persists beyond 6 months or recurs following a period of amenorrhea then endometrial pathology should be excluded
If persistent and pathology excluded -> changing progestogen component often helpful
CHC for HRT?
If <50 years with no UKMEC contraindications, a combined contraceptive can be used in place of HRT
e.g. if still need contraception and dont want mirena
Cardioprotective aspect of HRT
Cardioprotective when commenced at <60 years of age / within 10 years of reaching menopause
‘Cardiovascular window of opportunity’
Oestrogen -> increased HDL and reduced LDL
HRT and colorectal ca
Reduced risk of colorectal cancer with oral combined HRT regime use (no transdermal data)
Risks of HRT
VTE
Coronary heart disease/ stroke
Ovarian ca
Endometrial ca
Breast ca
HRT and VTE risk
Oral HRT increases the risk of VTE by 2-4 x compared to baseline, greatest in 1st year of use
No increase in risk seen with use of transdermal HRT delivery
Transdermal HRT should be offered first line to women with any VTE risk factors, including women with a BMI of >=30
HRT and Coronary heart disease/ stroke risk
Oral but not transdermal oestrogen is associated with a small increase risk of stroke
» Use transdermal if additional stroke risk factors, or if age >=60 years
HRT does not increase CVD risk when started in women aged <60 years
HRT with oestrogen alone is associated with no or reduced risk of CHD
» Oestrogen increases HDL and reduces LDL in normal physiology – cardioprotective
Combined HRT is associated with little or no increase in risk of CHD
Presence of existing CVD is not a contraindication to HRT use; consider transdermal >oral
HRT and ovarian ca risk
Slight increase risk in developing serous and endometroid ovarian cancers in HRT users
HRT and endometrial ca
increases risk; minimised by progestogenic endometrial protection
HRT and breast ca
Oestrogen only = little/ no increase risk
(Low dose vaginal oestrogen = no evidence to suggest any increase in risk)
Combined HRT = increased risk during treatment if used for >1 year, which reduces upon stopping treatment (time taken to return to baseline depends on length of HRT treatment)
Risk increase from post-menopausal obesity or drinking >=2 units/ day of alcohol = greater
Use of HRT does not effect likely breast cancer outcomes (death rates)
Do not routinely offer HRT to women with a past history of breast cancer
Systemic HRT should be stopped immediately in women who are newly diagnosed with breast cancer (including removal of a Mirena coil if in-situ)
HRT in women with hx breast ca
Do not routinely offer HRT to women with a past history of breast cancer
In exceptions, case by case risk-benefit decisions may be made between menopause specialist and oncology team about the appropriateness of HRT use
Low dose vaginal oestrogens is generally acceptable (minimal systemic absorption) UNLESS using aromatase inhibitors:
» Prevent aromatase enzyme from fat tissue from producing oestrogen (Anastrozole, letrozole, exemestane).
Women who are carriers of the BRCA1 and BRCA2 gene mutation who have undergone risk-reducing surgery including BSO (therefore in surgical menopause), can receive add-back HRT and this has not been shown to diminish the risk-reducing benefit of BSO on subsequent risk of breast cancer diagnosis
Women on tamoxifen should also not use paroxetine or fluoxetine (for their vasomotor symptoms) as it can inhibit the efficacy of the tamoxifen
»Tamoxifen (raloxifene and clomiphene) = selective oestrogen receptor modulators/ SERMs
HRT and HYPOthyroidism
TSH levels should be checked 6 – 12 weeks after commencing /changing dosage of HRT
(as HRT can CAUSE Hypothyroidism)
Levothyroxine dose increase may be required, particularly if using oral HRT
Mechanism:
HRT (ostrogen) metabolism -> increased thyroxine binding globulin (hepatic synthesis)
-> Increasing binding of thyroxine to TBG (and less free thyroxine)
-> elevated TSH
-> women with hypothyroidism on treatment unable to naturally compensate
-> higher dose of levothyroxine needed to control TSH levels back to normal range
This effect is not reported with transdermal HRT (as avoids first pass metabolism -> TBG)
Transdermal HRT may be preferable route of administration if patient has existing hypothyroidism
Non hormonal management of menopause: vasomotor symptoms
For
(1) Antidepressants (SSRIs or SNRIs; makes sense when consider mechanism of vasomotor syx)
(2) Clonidine (alpha-2 adrenergic receptor agonist -> less sympathetic tone -> lowers BP + HR)
(3) Gabapentin (off-label)
+/- cognitive behavioural therapy
Tibolone
synthetic steroid hormone
Oral daily tablet, HRT alternative
Only suitable post-menopause (unless also using gonadotrophin releasing hormone analogue)
Metabolised into 3 metabolites -> 2 oestrogenic and 1 progestogenic/ androgenic
HRT review
+3 months when starting/ changing
then yearly
What contraceptives to use in HRT
All methods of progesterone only contraception are safe when used alongside cyclical HRT (unless other CI)
When can women stop contraception
1 year if aged >=50
2 years if aged <50
OR until age 55 if on hormonal contraception that could be masking presence of natural menses
Selective Estrogen Receptor Modulators (SERMs)
TAMOXIFEN
Breast ca/ reduce incidence of HR patients
Anovulatory infertility
ER Antagonist: breast
ER Agonist: endometrium, bone, lipids
Can cause hot flushes
CVD: Reduce tot chol and LDL, no change in HDL
SE: increase thickness of endo, polyps. Increase VTE.
RALOXIFENE
to prevent and treat osteoporosis PMW (not first ling)
ER agonist in bone
Inhibits bone resorption
CVD: Reduce tot chol and LDL, no change in HDL
Increase VTE.
CLOMIPHENE
Induction of ovulation
Increases GNRH release
SE: Hot flushes, 12 cycles increase ovarian ca risk, multiple gestations, ovarian cysts
NO increase VTE
Micronized progesterone (Utrogestan)
Oral progesterone not absorbed well; if micronized (oil and gelatin) -> better bioavailability
Vaginal absorption (i.e. in recurrent miscarriage) is quicker and less variable than oral (HRT)
» Oral - metabolised by liver/P450 cytochrome -> similar metabolites to ‘natural’ pathway
» Vaginal – metabolites present at lower levels due to lack of first-pass metabolism
Drug interactions – P450 enzyme inducing agents will reduce progesterone levels achieved
Generally considered to be the ‘safest’ oral progestogen
Has anti-mineralocorticoid activity -> reduces sodium reabsorption and produces diuresis
Dose dependent BP reducing effect
Mild sedative effect with oral use; recommended to take at night time
Made with soy – should not be used in soy or peanut allergy
Oestradiol
Qlaira and Zoely (COCPs), Vagifem pessaries (vaginal atrophy), HRT (oral and transdermal)
Oestradiol valerate is a pro-drug of oestradiol
Acute ingredient is 17β-estradiol, synthetic compound which is chemically and biologically identical to endogenous oestradiol (E2)
1 mg oestradiol valerate -> 0.76 mg 17ß-estradiol
Binds to and acts on oestrogen receptors (ER)
» ER(a) = endometrium, bone, breast cancer cells, ovarian stromal cells, hypothalamus (repro)
»ER(b) = kidney, brain, bone, heart, lungs, intestine, prostate, endothelium (non-repro)
Oral administration -> high levels of first pass metabolism to less potent Estrone (E1)
»Bioavailability as low as 2%
»Much higher doses needed
»Topical or transdermal application routes bypass first pass metabolism; lower doses effective
Following vaginal administration -> potent local activity but minimal systemic absorption
Transdermal application ~20X higher bioavailability rates
First pass metabolism via liver from P450 enzymes
»Dose reduction with concurrent use of P450 enzyme inducing agents
»Dose effective increased (less metabolism) with concurrent use of P450 enzyme inhibitors –> Increased rates of adverse effects
Bladder trigone vs rest of bladder: embryological origin
Embryological origin via integration of the two mesonephric ducts at the base of the bladder
for the rest of the bladder…
origins from the anterior division of the cloaca – urogenital sinus –
Bladder: arterial supply
Superior vesical branch of the internal iliac artery
Bladder: venous drainage
internal iliac veins
Bladder Lymphatic drainage
Superior -> external iliac nodes
Neck and fundus (posterior-inferior aspect) of the bladder -> internal iliac, sacral and common iliac nodes
Bladder: innervation
SNS Hypogastric nerve (T12-L2) -> relaxation of detrusor & bladder neck (retention of urine).
PNS pelvic nerve (S2 – S4) -> contraction of detrusor & relaxation internal urethral sphincter (micturition).
Somatic pudendal nerve(S2-4) – external urethral (and external anal) sphincter, vol
Visceral afferent via pelvic splanchnic nerves to reach the sc
Bladder SNS
Adrenergic (NE/NA)
Α1,β3 in bladder wall
Hypogastric nerve (T12 – L2)
Bladder PNS
Muscarinic (Ach)
M3
Pelvic nerve (S2 – S4)
Urethra epithelium
Progressive change from
stratified transitional epithelium —->
stratified squamous keratinising
Urethra female blood supply
internal pudendal arteries and vaginal arteries
internal pudendal vein and branches of vaginal vein
Female urethra: Lymph
Distal urethra = superficial inguinal nodes
Proximal urethra = internal iliac nodes
Onuf’s nucleus
S2-4 = the micturition centre/ Onuf’s nucleus
Receives afferent from stretch receptors in bladder wall
Sends efferent signals – both somatic (pudendal nerve) and autonomic (e.g. parasympathic pelvic nerve)
SUI causes and RFs
Causes
Urethral hypermobility
Intrinsicsphincter deficiency
RFs
Increasing age
Parity
Deficiency in supporting tissues (Prolapse, Hysterectomy, Menopause, CT disorders)
Smoking
Obesity
Constipation
Management of SUI
1
Supervised PMFT 3/12
Duloxetine
*Colposuspension (POP =SE)
*Autologous rectus fascial sling
*Retropubic mid-urethral mesh sling (mesh-related comps: pain/ vaginal problems, can be done w/o GA)
Intramural bulking agents
Oxford grading system
Pelvic floor contractions assessment
0 = no contraction.
1 = flicker.
2 = weak (no lift)
3 = mod. Lift of musc + elevation of post vaginal wall.
4 = good. Increased tension and a good contraction elevate the posterior vaginal wall against resistance.
5 = strong. Strong resistance is applied to the elevation of the posterior vaginal wall. The examiner’s finger is squeezed and drawn into the vagina.
Duloxetine
SNRI
Increases availability of serotonin and noradrenaline within Onuf’s nucleus – increases motor neuron activation of external urethral sphincter – increasing tone and improving continence
Metabolised in liver
Side Effects:
Dry mouth
Anxiety
Decreased appetite
Fatigue
Sexual Dysfunction
Cautions:
Hepatic impairment
Hx seizures
uncontrolled hypertension
Bleeding disorders – may increase risk PPH if taken month before delivery
UUI
Causes: overactivity of detrusor muscle.
Risk factors:
Increasing age
Neurological condition:Parkinsons, MS, DM, spinal cord injury
Dementia, Stroke
Idiopathic: often no specific cause found
Management UUI
1 Lifestyle intervention
Caffeine reduction
Modify fluid intake
Lose weight (BMI >30)
Urge or mixed
2.1 Anticholinergics
2.2 Mirabegron
+/- Desmopressin
urodynamic investigation if don’t respond to #1 and #2
3.1 Botulinum toxin type A
3.2 Percutaneous sacral nerve stimulation (PSNS)
Anticholinergics - how long to see effect
Give 4 weeks to see effect
Anticholinergics examples
Tolterodine
Non Selective muscarinic receptor antagonist M2/M3
– longer filling time and less urgency
Oxybutynin
Non Selective muscarinic receptor antagonist M1-3
Solifenacin
Competitive muscarinic, selective for M3
Side effects:
Dry mouth
Constipation
Flushing
Visual disturbance
Tachycardia
Contraindicated:
Angle closure glaucoma
Myasthenia Gravis
Urinary Retention
Pyloric Stenosis
Ulcerative Colitis
Anti cholinergic Burden – score to assess risk of multiple drugs in elderly, >3
Where are M1 M2 M3 receptors
M1 cognitive
M2 CVS
M3 bladder
Mirabegron
Selective Beta 3 adrenergic agonist
Clinical effectiveness of mirabegron similar to that of antimuscarinic drugs but has different side effect profile.
Side Effects: UTI, Headache, Dizziness, Tachycardia, GI upset
Cautions/ contraindications: Hepatic/renal impairment, Uncontrolled hypertension
Blood pressure should be measured before starting treatment and monitored regularly during treatment, especially in patients with hypertension.
Desmopressin
The use of desmopressin may be considered specifically to reduce nocturia in women with urinary incontinence or overactive bladder who find it a troublesome symptom.
Use particular caution in women with cystic fibrosis and avoid in those over 65 years with cardiovascular disease or hypertension.
Urodynamics: indications
urge-predominant mixed UI
unclear type UI
symptoms suggestive of voiding dysfunction
anterior or apical prolapse
a history of previous surgery for stress urinary incontinence
Urodynamics interpretation cystometry
Urge/ detrusor overactivity
Pabdo no rise,
SUI
Pdet no rise
Botulinum toxin type A injection - dose
100 units as the initial dose – can be increased to 200 units (if lasted for less than 6 months)
POProlapse: non surgical mx
Lifestyle modification
Weight loss (BMI > 30 kg/m2)
Minimise heavy lifting
Prevent or treat constipation
Vaginal oestrogens
PFMT 16/52
Symptomatic POP-Q stage 1 or stage 2
Pessaries
May cause new stress urinary incontinence
POProlapse: surgical mx
Vaginal hysterectomy, with or without sacrospinous fixation with sutures.
65% resolution of symptoms at 1 year
Vaginal sacrospinous hysteropexy with sutures.
Manchester repair (also called the Fothergill operation).
Sacro-hysteropexy with mesh
Colpocleisis - do not intend to have penetrative vaginal sex and who have a physical condition that may put them at increased risk of operative and postoperative complications
