Disorders of Ovulation_ACrev2022_studentcentral.pptx

Disorders of Ovulation Dr Anna Crown (Endocrinologist) Disorders of Ovulation Topics • Revision of physiology • Diagnosis of ovulation • Oligomenorrhoea and amenorrhoea • Hirsutism / acne • Polycystic ovarian syndrome • Premature ovarian failure • Congenital adrenal hyperplasia Learning Outcomes...

Disorders of Ovulation Dr Anna Crown (Endocrinologist) Disorders of Ovulation Topics • Revision of physiology • Diagnosis of ovulation • Oligomenorrhoea and amenorrhoea • Hirsutism / acne • Polycystic ovarian syndrome • Premature ovarian failure • Congenital adrenal hyperplasia Learning Outcomes • To understand the causes, investigation and management of common causes of oligomenorrhoea / secondary amenorrhoea, hirsutism and acne. GnRH: decapeptide, pulsatile Regulation of GnRH release + FSH • Ovarian follicle development • Androgens → oestrogens + LH • Ovulation • Theca cell androgen production release • GnRH neurons lack receptors for androgens, progesterone and oestrogens • + and – feedback mediated by hypothalamic KNDy neurons which express – Kisspeptin – Neurokinin B (NKB) – Dynorphin Central mediator: kisspeptin • A GnRH secretagogue: at the apex of the reproductive axis in the hypothalamus • KISS1 neurons highly responsive to oestrogen, implicated in both + and – central feedback of sex steroids on GnRH production • Metabolic influences on reproduction – mediated by leptin via the kisspeptin system – permissive effect on puberty & reproduction Kisspeptin at the apex of the reproductive axis Oestrogen can +/- Kiss neurons depending on their location within the hypothalamus and the developmental stage of the animal Diagnosis of ovulation Clinical: Take a history from the woman. regular menstruation usually 28 days (check not on hormonal contraception) mid cycle pain at ovulation vaginal discharge alters (increased mucus post ovulation) Diagnosis of ovulation Biochemistry: Day 21 progesterone blood test (7 days before start of next menstrual period) LH detection kits: urinary kits bought over the counter Transvaginal pelvic ultrasound done from Day 10, alternate days to demonstrate the developing follicle size and Corpus Luteum not Basal Body Temperature, cervical mucus change, Menstrual Patterns (terminology) Amenorrhoea - lack of a period for more than 6 months • Primary Amenorrhoea - never had a period (never went through menarche) • Secondary Amenorrhoea -has menstruated before Oligomenorrhoea - irregular periods •usually occurring more than 6 weeks apart Causes of Ovulation problems Hypothalamus (lack of GnRH) • GnRH deficiency (Kallmann’s syndrome) – may be associated with anosmia • ‘Functional’ hypothalamic amenorrhoea – weight loss/stress related/excessive exercise – anorexia nervosa/bulimia Pituitary (lack of FSH and LH) • pituitary tumours (prolactinoma/other tumours) • post pituitary surgery /radiotherapy These topics are discussed in other 203 Causes of Ovulation problems Ovary • Premature ovarian insufficiency – Chromosomal abnormalities eg Turner syndrome – Autoimmune – Iatrogenic • Surgery/chemotherapy/radiotherapy Hyperandrogenism – Polycystic ovarian syndrome: commonest cause – Congenital adrenal hyperplasia HIRSUTISM ‘Androgen-dependent’ hirsutism – Excess body hair in a male distribution NOT: – Androgen-independent hair growth • Hypertrichosis – Familial / racial hair growth Differential diagnosis of hirsutism • 95% PCOS or ‘idiopathic hirsutism’ • 1% Non-classical congenital adrenal hyperplasia (CAH) • <1% Cushing’s syndrome • <1% Adrenal / ovarian tumour Prevalence of polycystic ovarian syndrome: 10-20% women of reproductive age WHEN TO WORRY (may not be PCOS) • Sudden onset of severe symptoms • Virilisation – Frontal balding – Deepening of voice – Male-type muscle mass – Clitoromegaly • Possible Cushing’s syndrome Polycystic ovarian syndrome (PCOS) Clinical Features of PCOS Hyperandrogenism – Hirsutism, acne Chronic oligomenorrhoea / amenorrhoea – 9 periods / year – Subfertility Obesity (but 25% of women with PCOS are “lean”) ELEMENTS IN THE DIAGNOSIS OF PCOS Various phenotypes (spectrum of severity) polycystic ovaries androgen excess Adapted from: JCEM (2006) 91 786-789 oligo- / anovulation USS appearance of Polycystic Ovaries  10 subcapsular follicules 2-8 mm in diameter, arranged around a thickened ovarian stroma not all women with PCOS will have USS appearance Hormonal abnormalities in PCOS Raised baseline LH and normal FSH levels. Ratio LH:FSH 3:1 Raised androgens and free testosterone Reduced Sex Hormone Binding Globin (SHBG) Oestrogen usually normal Sex Hormone Binding Globulin E T T E • Produced by the liver • Binds testosterone and oestradiol • If testosterone bound - not converted to active component dihydrotestosterone ie not “free” • SHBG increased by oestrogens • SHBG decreased by testosterone thus releasing more free testosterone Treatments targeting neuroendocrine dysfunction in polycystic ovary syndrome (PCOS) Clinical Endocrinology, Volume: 97, Issue: 2, Pages: 156-164, First published: 08 March 2022, DOI: (10.1111/cen.14704) Garg, Patel, Abbara, Dhillo (Imperial) Genetic factors: Steve Franks’ hypothesis – Developmental origin of PCOS Journal of Endocrinology (2002) 174 1-5 Environmental factors: Potential consequences of insulin resistance in women with PCOS Lancet (2003) 361 1894-1901 PCOS and the metabolic syndrome • Insulin resistance with insulin – androgen production by ovarian theca cells – SHBG production by the liver • Multiplicative impact of BMI + PCOS – Impaired glucose tolerance • risk gestational DM and T2 DM – Dyslipidaemia – Non-alcoholic fatty liver disease • ? risk cardiovascular disease ? – No evidence of increased mortality rates Reproductive Effects of PCOS • PCOS is maybe associated with varying degrees of infertility • 15% of all causes of infertility is lack of ovulation • 80% of lack of ovulation due to PCOS • Associated with increased risk of miscarriage • Increased risk of gestational diabetes and other adverse pregnancy outcomes Endo 2022 97(2); 227-236 • Obesity & gestational weightClin gain are PCOS and Endometrial Cancer • Increased endometrial hyperplasia and cancer • Lack of progesterone on the endometrium • Endometrial cancer associated with type 2 diabetes & obesity TREATMENT OF PCOS LIFE-STYLE MODIFICATIONS • • • • High & Diet frequency exercise eating disorders – Bulimia associated with PCOS Stop smoking RESULTS: – insulin Lean women with PCOS should try resistance – [SHBG] not to gain weight – [free testo] – Improved fertility / pregnancy outcomes – Improve metabolic syndrome risk factors Combined Oral Contraceptives  Effective treatment for hyperandrogenism  Increases SHBG and thus decreases free testosterone  Decreases FSH & LH and therefore ovarian stimulation  Regulates cycle & avoids endometrial hyperplasia  BUT may be contraindicated in obese women because of the increased risk of venous thrombosis, and does Anti-androgens • With COCP / other form of secure contraception • Cyproterone Acetate (oral tablet) – inhibits binding of testosterone & 5 alpha dihydrotestosterone to androgen receptors • Spironolactone (oral tablet) Targeting insulin resistance in PCOS Metformin – insulin resistance, insulin levels,  ovarian androgen production – May help with weight loss / diabetes prevention – A good option for obese women with PCOS – May ovulation (with clomifene), safe in pregnancy (but usually discontinued if no diabetes) – Less helpful for hirsutism Hair removal Photoepilation (laser) / electrolysis etc Eflornithine cream (non-NHS) – Inhibits ornithine decarboxylase enzyme in hair follicles Fertility / ovulation • Clomifene is an option (under the supervision of a fertility clinic) – SERM (oestrogenic and anti-oestrogenic effects) • This is discussed in other 203 lectures PRIMARY OVARIAN INSUFFICIENCY Presentation: • Primary or secondary amenorrhoea – Secondary amenorrhoea may be associated with hot flushes & sweats Other terms used: • Premature ovarian failure • Premature menopause Aetiology: • Autoimmunity – May be associated with other autoimmune endocrine conditions • X chromosomal abnormalities • Turner syndrome • Fragile X associated • Genetic predisposition • Premature PREMATURE OVARIAN FAILURE Investigations: Management: •• history / Psychological support • examination HRT • LH and FSH – Continue till 52 • ? Karyotype • Monitor bone density • Consider pelvic – DEXA scan USS •• Fertility Consider – IVF with donor screening for egg other autoimmune TURNER SYNDROME • Complete / partial X monosomy in some / all cells – 50% of cases will be XO – Rest: partial absence of X or mosaicism • 1:2000 – 1:2500 live-born girls • Presentation – May be diagnosed in the neonate – May present with short stature in childhood – May present with primary / secondary amenorrhoea TURNER SYNDROME • Associated problems – Short stature • Consider GH treatment – CV system • • • • Coarctation of aorta Bicuspid aortic valve Aortic dissection Hypertension (adults) – Renal • Congenital abnormalities – – – – Metabolic syndrome Hypothyroidism Ears / hearing problems Osteoporosis (lack HRT) Not TS CONGENITAL ADRENAL HYPERPLASIA ADRENAL STEROID SYNTHESIS Congenital adrenal hyperplasia (CAH) • disorders of cortisol biosynthesis – Carrier frequency 1 : 60 – Most patients are compound heterozygotes • Different mutations on two alleles • 95% CAH cases caused by 21-hydroxylase deficiency – Cortisol deficiency – May have aldosterone deficiency – Androgen excess – Depends on degree of enzyme deficiency 21-HYDROXYLASE DEFICIENCY Defect in cortisol biosynthesis raised CRH / ACTH (lack of negative feedback) drives excess adrenal androgen production Diagnosis: high concentrations of 17-hydroxyprogesterone Can confirm with Synacthen test CAH PRESENTATION Childhood: – Salt wasting • Hypovolaemia, shock • Adulthood (mild): – Virilisation • Ambiguous genitalia in girls • Early virilisation in boys – Precocious puberty – Abnormal growth • Accelerated early • Premature fusion – Hirsutism – Oligo / amenorrhoea – Acne – Subfertility – Similar to ‘PCOS’ presentation CAH TREATMENT • Glucorticoid & mineralocorticoid replacement – Hydrocortisone & fludrocortisone – Additional salt in infancy • Glucocorticoids suppress CRH / ACTH • Supraphysiological glucocorticoid doses may be needed to suppress adrenal androgen production – Monitor [17-OH-P] / androstenedione – Monitor growth in childhood • Excess glucocorticoid treatment may inhibit growth • Surgical management for ambiguous genitalia • Non-classical CAH in adult women (mild) – Can treat as for PCOS with COCP antiandrogen QUIZ 1. To confirm ovulation… • History • Over the counter test • Blood test • Imaging test in subfertility clinic 2. Definitions • A girl who does not go through menarche • A woman whose periods stop aged 26 • A woman having 8 menstrual periods per year 3. Clinical features of PCOS Woman presents with: Medical terminology: 4. Treatment options for PCOS No prescription required: On prescription: 5. Why have her periods stopped? • Beth – 23, BMI 17 kg/m2, triathlete • Carol – 33, risperidone treatment, galactorrhoea • Amy – 17, short stature, aortic regurgitation • Marjorie – 50, hot flushes and sweats • Emma – 28, breast tenderness, nausea Thank-you! Questions?