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

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

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

Androgen Insensitivity

Primary Amenorhhoea - Cause Investigation Treatment Chromosomal Karyotype HRT Adoption Surgical removal of XY gonads Hypothalamic FSH, LH, Prolactin, TFTs, Oestradiol, FAI Increase weight Decrease excess exercise Hypothalmic FSH, LH ,Prolactin, Growth Hormone Growth Hormone replacement Induce menarche Induce puberty

Primary Amenorrhoea Cause Investigation Treatment Pituitary tumour MRI head (Sella Turcica) Pituitary Surgery Radiotherapy Congenital Adrenal Hyperplasia 17OH Progesterone DHEA FAI ACTH stimulation test COCP Steroids

Primary Amenorrhoea Cause Investigation Treatment Ovarian cysts PCOS Prem Ovarian Failure Ultrasound Pelvis FAI SHBG (FSH:LH) + FSH LH Oestradiol Surgery – cystectomy Cons/ Medical/ Surgical HRT, Egg donation Induce puberty Uterine anomalies Absent uterus Absent vagina MRI Pelvis Laparoscopy Surrogacy – egg collection from normal ovaries Dilators/ Surgery Imperforate Hymen External examination Surgery- Incision and drainage of haematometra

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

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 Cause Investigation Treatment Hypothalamic Stress/ anorexia Alleviate stress Diet Pituitary tumour MRI head (Sella Turcica) Pituitary Surgery Radiotherapy Hypothyroidism TFTs Thyroid replacement Congenital Adrenal Hyperplasia 17Beta Oestradiol DHEA FAI ACTH COCP Cortisol/ Fludrocortisone As for PCOS Ovarian cysts PCOS Prem Ovarian Failure Ultrasound Pelvis + FAI SHBG + FSH LH Oestradiol Surgery – cystectomy 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 >10cm3 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

3. Biochemical Hyperandrogenism Weight Loss

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 Weight gain> 10% NIDDM/ IGT Hypothalamic stress, over-exercise, eating disorder Pituitary causes Perimenopausal Hypothyroidism

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

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 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