Dr H McMillan MBCHb MSc MRCOG MFSRH Dip Med Ed Consultant in Obstetrics & Gynaecology CUMH/ Mercy University Hospital 4 th Year Medical Student Lecture March 2011

Amenorrhoea & PCOS

Introduction • Relevant to : • Obstetrics & Gynaecology • GP • General Medicine • Cardiology • Endocrinology • General Surgery

Overview • Basic Science • Puberty • Menstrual Cycle • Amenorrhoea • Primary • Secondary • PCOS

Puberty • Thelarche- breast development • Adrenarche- axillary +pubic hair • Menarche- start of periods

Anatomy Secondary Sexual Characteristics Pubic Hair development Tanner Stages

Physiology- Pituitary • Anterior lobe • Adenohypophysis • Secretes • Follicle Stimulating

FSH

• Luteinising

Hormone LH

• (also TSH, GH, Prolactin, ACTH, MSH)

Posterior lobe

Neurohypohysis Stores and releases Oxytocin and vasopressin

Menstrual cycle

Menstrual cycle in action

Menstrual Cycle • Day 1 is 1st day of bleeding • Days 1-4 FSH high • Signals to develop follicle in ovary • Follicle produces OESTROGEN • Oestrogen causes • Cervical mucus to be receptive to sperm • Endometrium “proliferative” • Down-regulates FSH

Menstrual Cycle • Day 14 • (if 28 day cycle) • OESTROGEN so high • Positive feedback to pituitary leads to LH surge • LH stimulates ovulation • egg released from matured follicle

Menstrual Cycle • Rest of follicle = corpus luteum (cyst) secretes PROGESTERONE • Progesterone causes • Endometrium to thicken “secretory” ready for implantation • Cervical mucus becomes hostile • FSH down-regulated • No more follicles recruited

Menstrual Cycle • If ovum not fertilized + no implantation • Corpus luteum breaks down • Oestrogen and progesterone falls • Endometrium not being maintained so sloughs off = period

Amenorrhoea • Primary • Absence of Menarche • No period by age 14 • with absence of secondary sexual characteristics • No period by age 16 • with normal secondary sexual characteristics

Primary Amenorrhoea • Differential Diagnosis- Work it out • Anatomical sieve

Hypothalamic- Pituitary axis

Pineal gland Smell See Stress

Hypothalamic- Pituitary axis

Primary Amenorrhoea • (Constitutional delay) • (Chronic systemic illness) • Chromosomal • Hypothalamic • Hypopituitarism • Congenital Adrenal Hyperplasia • Premature Ovarian failure/ Ovarian cysts/ PCOS • Uterine anomalies- absence of uterus/ vagina • Vaginal anomalies- Imperforate hymen

Primary Amenorrhoea Diagnosis -Work it out • T- Trauma • I- Infection • N-Neoplasia • C- Connective Tissue • A- Autoimmune • N –Naughty Drs (Iatrogenic) • B – Blood Disorders • E- Endocrine • D –Drugs/ Diet

Primary Amenorrhoea Trauma Infection Neoplasia (Pituitary /Ovarian Trauma) Pituitary Tumour Connective Tissue Automimmune Naughty Drs ( Iatrogenic) Uterine Vagina- Imperforate Hymen Myasthenia Gravis, Crohns , Addison’s 39% co-exist Chemotherapy Radiotherapy Blood Endocrine Drugs/ Diet Chromosomal Congenital Adrenal Hyperplasia Ovarian cyst/ PCOS Hypothalamic hypopituitarism Chemotherapy Radiotherapy Anorexia / Underweight Galactosaemia Androgen Insensitivity Swyers Turner’s Syndrome Prolactin Microadenoma Absent uterus norm ovaries Rokintansky XX 21 hydroxlylase deficiency (more 17OH progesterone) Kallman’s Syndrome (Anosmia) XY absent uterus xlinked rec XY uterus present X0 uterus present

Androgen Insensitivity

Primary Amenorhhoea -

Cause

Chromosomal Hypothalamic Hypothalmic

Investigation

Karyotype FSH, LH, Prolactin, TFTs, Oestradiol, FAI FSH, LH ,Prolactin, Growth Hormone TFTs, Oestradiol, FAI

Treatment

HRT Adoption Surgical removal of XY gonads Increase weight Decrease excess exercise HRT Growth Hormone replacement Adoption Induce menarche Induce puberty

Primary Amenorrhoea

Cause

Pituitary tumour

Investigation Treatment

MRI head (Sella Turcica) Pituitary Surgery Radiotherapy Congenital Adrenal Hyperplasia 17OH Progesterone DHEA FAI ACTH stimulation test COCP Steroids

Primary Amenorrhoea

Cause Investigation

Ovarian cysts Ultrasound Pelvis PCOS Prem Ovarian Failure FAI SHBG (FSH:LH) + FSH LH Oestradiol Uterine anomalies Absent uterus Absent vagina Imperforate Hymen MRI Pelvis Laparoscopy External examination

Treatment

Surgery – cystectomy Cons/ Medical/ Surgical HRT, Egg donation Induce puberty Surrogacy – egg collection from normal ovaries Dilators/ Surgery Surgery Incision and drainage of haematometra

Primary Amenorrhoea 1y Amen No sexual development Low FSH LH Low E2 Constitutional Chronic Illness Sexual development High FSH LH Low E2 High FSH LH Low E2 Normal FSH Lh Normal E2 45 X0 46XY 46XX 46XY Uterus present Uterus absent Uterus present Swyer syndrome gonadal dysgenesis Prem Ovarian failure Andirogen Insensitivity Gonadectomy Induce puberty HRT Induce puberty HRT Gonadectomy Induce puberty Vaginal reconstruction Oes only HRT Vaginal septum Surgery Rokitansky Kuster hauser Vaginal reconstruction

Secondary Amenorrhoea • Absence of menses after menarche • NOT Oligomenorrhoea ( infrequent menses)

Secondary Amenorrhoea • Absence of menses after a preceding Menarche • Exclude obvious causes: • Pregnancy • Menopause • Contraception • GnRha

Hypothalamic- Pituitary axis

Hypothalamic Pituitary Ovarian Axis

Secondary Amenorrhoea • Provide a brief summary of your presentation Hypothalamic Stress/ anorexia Alleviate stress Diet Pituitary tumour Hypothyroidism MRI head (Sella Turcica) TFTs Pituitary Surgery Radiotherapy Thyroid replacement Congenital Adrenal Hyperplasia Ovarian cysts PCOS Prem Ovarian Failure 17Beta Oestradiol DHEA FAI ACTH Ultrasound Pelvis COCP Cortisol/ Fludrocortisone As for PCOS Surgery – cystectomy + FAI SHBG + FSH LH Oestradiol Cons/ Medical/ Surgical HRT, Egg donation Induce puberty

PCOS

PCOS • Incidence • Genetics • Definition • Investigation • Treatment

PCOS Incidence • 7% in UK • 52% of South Asian Immigrants in UK

PCOS • Familial Inheritance • Genetic link • Probably Autosomal Dominant • Male line- Premature baldness • Cholesterol side chain cleavage (CYP11a) • Polymorphisms in INSR gene- insulin receptor function • VNTR on chromosome 11p15.5 on nearby microsattelite locus

PCOS • Definition?

PCOS Clinical definition (Old fashioned) • 1) Hyperandrogensim • Acne, hirsuite, alopecia – not virilisation • 2) Menstrual irregularity • 3) Anovulatory Infertility • Usually associated with obesity

Hypothalamic- Pituitary –Ovarian axis SHBG are the buses of the blood stream that carry androgens.

If there are fewer buses there is more free androgen free to cause symptoms

PCOS- Obese Women Obese women adipose tissue –peripheral conversion of oestrone, which increase LH secretion Insulin insensitivity- leads to hyperinsulinaemia – less SHBG, more free androgen

PCOS & Obesity Weight Loss

PCOS – Lean women Lean women with PCOS – LH hypersecretion

PCOS • Diagnostic definition – • ESHRE / ASRM /Rotterdam Criteria • 2 out of 3 criteria • 1) US features of PCOS • 2) Oligo or anovulation • 3) Clinical or biochemical hyperandrogenism • With exclusion of other aetologies

1. Ultrasound of Polycystic Ovaries (> 12 peripheral follicles 2-9mm, per ovary >10cm 3 volume) Truly a “polyfollicular ovary” Seen in 20-33% of general population

1. Ultrasound of Polycystic ovaries • “Ring of pearls”

2. Oligomenorrhoea or Anovulation

3. Clinical Hyperandrogenism Ferriman Gallwey Hirsuitism Score

Weight Loss 3. Biochemical Hyperandrogenism

PCOS - Pathophysiology Gynae presentation of a metabolic disease insulin- ovarian axis Insulin resistance (obese) LH (slim)

PCOS • Investigations • USS Pelvis • Day 21 Progesterone (Anovulatory subfertility) • Day 2-5 bloods LH:FSH ≥ 3:1ratio Free Androgen Index >5 Decreased SHBG <16 If total testosterone > 5 check other androgens

PCOS Investigations to exclude other causes 17OH Progesterone (CAH) DHEA Androstenedione Prolactin TFTs GTT/ Lipid profile D&C/ Pipelle for endometrial hyperplasia

Differential Diagnosis Menstrual Disturbance • Menstrual disturbance • Weight gain> 10% • NIDDM/ IGT • Hypothalamic • stress, over-exercise, eating disorder • Pituitary causes • Perimenopausal • Hypothyroidism

Differential Diagnosis Menstrual Disturbance • Menstrual Disturbance • Endometrial pathology • PID • Cervical disease • Ovarian disease • Endometriosis (>45y D&C) (Endocervical swabs) (Speculum) (USS pelvis)

PCOS- Menstrual Treatment • For cycle control: • Diet and Exercise (PCOS Diet) • Dianette/ cOCP (if <70kg) • Cyclical norethisterone (non-contraceptive) • Metformin • For heaviness: • Tranexamic acid +Mefenamic acid • Mirena

Differential Diagnosis of Hirsuitism • Hirsuitism • Androgen secreting tumours- rapid • CAH • Thyroid disease • Acromegaly, Cushings Syndrome • Hyperprolactinaemia • Drugs – phenytoin

PCOS-Treatment for hirsuitism • Diet and Exercise (PCOS) • COCP- Dianette • +Further cyproterone acetate for 10/7 (LFTs) • Yasmin ( Drosperinone) • Spironolactone • Metformin • Flutamide • Finasteride

PCOS Treatment for subfertility • Diet & Exercise • PCOS diet book by Colette Harris • Clomid* – Anti-oestrogen • days 2-6 of cycle • with follicle tracking • Metformin • start at 250mg od increase to max 500mg tds • GnRHa* • Laparoscopic ovarian drilling • * Risk of OHSS

PCOS Long term management • NIDDM • Yearly GTT • CVS disease • Yearly BP/ Weight • Dyslipidaemia • Yearly lipid profile • Endometrial hyperplasia • induce a regular bleed/ Mirena/ D&C • Breast cancer • due to elevated endogenous oestrogens • Breast examinations/ screening

Useful websites • www. rcog.org.uk

• www. library.nhs.uk