Disorders of Ovulation

Question 1

Menstrual cycle

• Whenever you measure any of the hormones (E.g. oestrogen, progesterone, LH, FSH) you must note where within a women’s cycle you are taking the blood test.
  
  • Preovulatory surge in … and …
  • … rises and falls just before the Preovulatory surge and then have a secondary rise in the … phase of the cycle
  • Progesterone levels low in … phase of the cycle - then provided the cycle has been ovulatory and … … formed - progesterone levels peak as they are produced by this
  • Alongside the menstrual cycle there is an … cycle - with a … phase followed by the … phase

Answer 1

• Whenever you measure any of the hormones (E.g. oestrogen, progesterone, LH, FSH) you must note where within a women’s cycle you are taking the blood test.
  
  • Preovulatory surge in LH and FSH
  • Estradiol rises and falls just before the Preovulatory surge and then have a secondary rise in the luteal phase of the cycle
  • Progesterone levels low in follicular phase of the cycle - then provided the cycle has been ovulatory and corpus luteum formed - progesterone levels peak as they are produced by this
  • Alongside the menstrual cycle there is an endometrial cycle - with a proliferative phase followed by the secretory phase

Question 2

Central mediator: Kisspeptin

• A GnRH …: at the … of the reproductive axis in the …
• KISS1 neurons highly responsive to …, implicated in both + and – central feedback of sex steroids on … production
• … influences on reproduction
  
  • mediated by … via the kisspeptin system
  • … effect on puberty & reproduction

Answer 2

• 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

Question 3

Diagnosis of ovulation - Clinical

• Take a … from the women
• Regular menstruation usually … days (check not on … …)
• Mid cycle … at ovulation
• vaginal discharge alters (… muscus post ovulation)

Answer 3

• Take a history from the women
• Regular menstruation usually 28 days (check not on hormonal contraceptives)
• Mid cycle pain at ovulation
• vaginal discharge alters (increased muscus post ovulation)

Question 4

Diagnosis of ovulation - Biochemistry / Tests

• Day 21 … blood test (7 days before start of next menstrual period)
• … detection kits: urinary kits bought over the counter
• … … ultrasound done from Day …, alternate days to demonstrate the developing follicle size and Corpus …
  
  • NOT - … body temperature, cervical … change, vaginal … changes nor … biopsies

Answer 4

• Day 21 progesterone blood test (7 days before start of next menstrual period)
• LH detection kits: urinary kits bought over the counter
• Tranvaginal pelvis ultrasound done from Day 10, alternate days to demonstrate the developing follicle size and Corpus Luteum
  
  • NOT - basal body temperature, cervical mucus change, vaginal epithelium changes nore endometrial biopsies

Question 5

Define Amenorrhoea

Answer 5

Lack of a period for more than 6 months

Question 6

Define Primary Amenorrhoea

Answer 6

Never had a period (never went through menarche)

Question 7

Define Secondary Amenorrhoea

Answer 7

Has menstruated before (lack of period for >6months)

Question 8

Define Oligomenorrhoea

Answer 8

Irregular periods - usually occuring more than 6 weeks apart

Question 9

Define Polymenorrhoea

Answer 9

Periods occuring less than 3 weeks apart

Question 10

Causes of Ovulation Problems:

• … (lack of GnRH)
  
  • GnRH deficiency (… syndrome)
    
    • may be associated with …
  • ‘…’ hypothalamic amenorrhoea
    
    • weight …/… related/excessive …
    • People with … disorders e.g.
• Pituitary (lack of … and …)
  
  • pituitary tumours (…/other tumours)
  • post pituitary … /…

Answer 10

• 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

Question 11

Causes of Ovulation Problems

• Ovary
  
  • Premature ovarian …
    
    • Chromosomal abnormalities eg … syndrome
    • Autoimmune
    • Iatrogenic
      
      • Patients who have had …/…./…
• Hyperandrogenism
• • … … syndrome : commonest cause
    
    • … adrenal …

Answer 11

• Ovary
  
  • Premature ovarian insufficiency
    
    • Chromosomal abnormalities eg Turner syndrome
    • Autoimmune
    • Iatrogenic
      
      • Surgery/chemotherapy/radiotherapy
• Hyperandrogenism
  
  • Polycystic ovarian syndrome: commonest cause
  • Congenital adrenal hyperplasia

Question 12

Hirsutism

• ‘…-dependent’ hirsutism
  
  • Excess … … in a male distribution
• NOT:
  
  • –…-… hair growth
    
    • known as Hyper…
• … / … hair growth

Answer 12

• ‘Androgen-dependent’ hirsutism
  
  • Excess body hair in a male distribution
• NOT:
  
  • Androgen-independent hair growth
    
    • Hypertrichosis
• Familial / racial hair growth

Question 13

Differentiatial Diagnosis of Hirsutism

• 95% due to … or ‘… hirsutism’
• 1% Non-classical … … …(CAH)
• <1% … syndrome
• <1% Adrenal / ovarian …
  *

Answer 13

• 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:
• 5-10% women!

Question 14

Prevalence of polycystic ovarian syndrome: …-…% of women

Answer 14

5-10% women!

Question 15

When to worry about Hirsutism

• … onset of … symptoms
• V…
  
  • Frontal …
  • … of voice
  • …-type … mass
  • Clitoro…
• Possible … syndrome

Answer 15

• Sudden onset of severe symptoms
• Virilisation
  
  • Frontal balding
  • Deepening of voice
  • Male-type muscle mass
  • Clitoromegaly
• Possible Cushing’s syndrome

Question 16

Clinical Features of PCOS

• Hyper…
  
  • Causing H… and a…
• Chronic … / …
  
  • < (and including) … periods / year
  • S…
• … (but …% of women with PCOS are “lean”)

Answer 16

• Hyperandrogenism
  
  • Hirsutism, acne
• Chronic oligomenorrhoea / amenorrhoea
  
  • < (and including) 9 periods / year
  • Subfertility
• Obesity (but 25% of women with PCOS are “lean”)

Question 17

USS Appearance of Polycystic Ovaries

• > and including 10 … follicules …-…mm in diameter, arranged around a thickened ovarian stroma
  
  • Do all women with PCOS have USS appearance?

Answer 17

• > and including 10 subcapsular follicules 2-6mm in diameter, arranged around a thickened ovarian stroma
• not all women with PCOS will have USS appearance

Question 18

What is this USS showing?

Answer 18

PCOS

Question 19

Hormonal Abnormalities in PCOS

• Raised baseline … and normal … levels. Ratio is …:1
• Raised … and free …
• Reduced … (SHBG)
• … usually normal

Answer 19

• 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

Question 20

Sex hormone Binding Globulin

• Produced by the …
• Binds … and …
• If … bound - not converted to … component dihydrotestosterone ie not “…”
• SHBG increased by …
• SHBG decreased by … thus releasing more free …

Answer 20

• 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

Question 21

PCOS and the Metabolic Syndrome

• … resistance with increased …
  
  • increased … production by ovarian … cells
  • decreased … production by the liver
• Impaired … tolerance
  
  • increased risk … DM and T2 DM
• Dys…
• … dysfunction
• ? ­ risk cardiovascular disease ?

Answer 21

• Insulin resistance with insulin
  
  • increased androgen production by ovarian theca cells
  • decreased SHBG production by the liver
• Impaired glucose tolerance
  
  • risk gestational DM and T2 DM
• Dyslipidaemia
• Vascular dysfunction
• ? ­ risk cardiovascular disease ?

Question 22

Potential consequences of … resistance in women with PCOS

Answer 22

Potential consequences of insulin resistance in women with PCOS

Question 23

Reproductive Effects of PCOS

• PCOS is maybe associated with varying degrees of …
  
  • …% of all causes of infertility is lack of ovulation
    
    • …% of lack of ovulation due to PCOS
• Associated with increased …
• Increased risk of … Diabetes

Answer 23

• 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 miscarriages
• Increased risk of Gestational Diabetes

Question 24

PCOS and Endometrial Cancer

• Increased endometrial … and …
• Lack of … on the endometrium
• Endometrial cancer associated with … & …

Answer 24

• Increased endometrial hyperplasia and cancer
• Lack of progesterone on the endometrium
• Endometrial cancer associated with type 2 diabetes & obesity

Question 25

_Treatment of PCOS - Lifestyle modifications_ * Diet & exercise * Stop ... * RESULTS: * ... insulin resistance * ... [SHBG] * ... [free testo] * Improved fertility / pregnancy outcomes * Improve ... syndrome risk factors * High frequency ... disorders * ... associated with PCOS * Lean women with PCOS should ...

Answer 25

* Diet & exercise * Stop **smoking** * RESULTS: * **decreased** insulin resistance * **increased** [SHBG] * **decreased** [free testo] * Improved fertility / pregnancy outcomes * Improve **metabolic** **syndrome** risk factors * High frequency **eating** disorders * **Bulimia** associated with PCOS * Lean women with PCOS **should try not to get fat!**

Question 26

_Treatment of PCOS - Combined Oral Contraceptives_ * Increases ... and thus ... free testosterone * Decreases ... & ... and therefore ovarian stimulation * ... cycle & decreases endometrial ... * BUT may cause weight ..., venous ..., adverse effects on ... risk factors

Answer 26

* Increases **SHBG** and thus **decreases** free testosterone * Decreases **FSH** & **LH** and therefore ovarian stimulation * **Regulates** cycle & decreases endometrial **hyperplasia** * BUT may cause weight **gain**, venous **thrombosis**, adverse effects on **metabolic** risk factors

Question 27

_Anti-androgens_ * With ... / other form of ... * Cyproterone A... (oral tablet) * inhibits binding of testosterone & 5 alpha dihydrotestosterone to androgen receptors * S... (oral tablet) * anti mineralocorticoid and anti androgen properties

Answer 27

* With COCP / other form of secure contraception * Cyproterone Acetate (oral tablet) * inhibits binding of testosterone & 5 alpha dihydrotestosterone to androgen receptors * Spironolactone (oral tablet) * anti mineralocorticoid and anti androgen properties

Question 28

_Targeting Insulin Resistance in PCOS_ * Metformin (biguanide) * Decreased insulin resistance, decreased insulin levels, decreased ovarian ... production * May help with ... loss / ... prevention * May increase­ ... (with clomifene), safe in ... * Less helpful for ... & ..., but may be an option for ... PCOS women

Answer 28

* Metformin (biguanide) * Decreased insulin resistance, decreased insulin levels, decreased ovarian **androgen** production * May help with **weight loss / diabetes prevention** * May increase­ **ovulation** (with clomifene), safe in **pregnancy** * Less helpful for **hirsutism** & **oligomenorrhoea**, but may be an option for **obese** PCOS women

Question 29

_Hair removal - women with Hirsutism_ * ... (laser) / electrolysis etc * ... cream (non-NHS) * Inhibits ornithine decarboxylase enzyme in hair follicles

Answer 29

* **Photoepilation** (laser) / electrolysis etc * **Eflornithine** cream (non-NHS) * Inhibits ornithine decarboxylase enzyme in hair follicles

Question 30

... is an option for fertility/ovulation in people with PCOS

Answer 30

**Clomifene** is an option for fertility/ovulation in people with PCOS

Question 31

_Primary Ovarian Insufficiency_ * **Presentation**: * Primary or secondary ... * Secondary ... may be associated with hot flushes & sweats * **Other terms used:** * Premature ovarian ... * Premature ... * **Aetiology:** * Autoimmunity * May be associated with other autoimmune endocrine conditions * X chromosomal abnormalities * ... syndrome * ... ... associated * Genetic predisposition * Premature menopause * Iatrogenic * Surgery, radiotherapy or chemotherapy

Answer 31

* **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 menopause * Iatrogenic * Surgery, radiotherapy or chemotherapy

Question 32

_Premature Ovarian Failure: Investigations_ * history / examination * High ... and ... * ? K... * Consider pelvic ... * Consider screening for other ... endocrine disease * ... function tests, ..., ...

Answer 32

* history / examination * **High LH and FSH** * ? **Karyotype** * Consider pelvic **USS** * Consider screening for other **autoimmune** endocrine disease * **Thyroid function tests, glucose, cortisol**

Question 33

_Premature Ovarian Failure: Management_ * Management: * ... support * HRT * Continue till ± age ... * Monitor bone ... * ... scan * Fertility * ... with donor egg

Answer 33

* Management: * **Psychological** support * HRT - hormone replacement therapy * Continue till ± **52** * Monitor bone **density** * **DEXA** scan * Fertility * **IVF** with donor egg

Question 34

_Turner Syndrome_ * Complete / partial ... ... in some / all cells * ...% of cases will be ... * Rest: partial absence of X or mosaicism * How common? 1 in ... * What gender? * Presentation * May be diagnosed in the ... * May present with ... stature in childhood * May present with ... / ... ...

Answer 34

* 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**

Question 35

_Turner Syndrome - Associated Problems_ * ... stature * Consider ... treatment * CV system * ... of aorta * ... aortic valve * Aortic ... * ... (Adults) * Renal * ... abnormalities * ... syndrome * ...thyroidism * Ears/... problems * ... (lack HRT)

Answer 35

* **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)

Question 36

_Congenital Adrenal Hyperplasia_ * disorders of ... biosynthesis * Carrier frequency 1 : ... * Most patients are compound ... * Different mutations on ... alleles * ...% CAH cases caused by 21-hydroxylase deficiency * ... deficiency * May have ... deficiency * ... excess * Depends on degree of enzyme ...

Answer 36

* 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**

Question 37

_Congenital Adrenal Hyperplasia - Diagnosis_ * High concentrations of 17-... * Can confirm with ... test

Answer 37

* High concentrations of 17-**hydroxyprogesterone** * Can confirm with **Synacthen** test

Question 38

_CAH Presentation_ * CHILDHOOD * ‘Classic’ / ‘severe’ * ...-losing (2/3rd) * Non-... losing (1/3rd) * Simple vi... * ADULTHOOD * ‘Non-classic’ / ‘...’ * ‘...-onset’

Answer 38

* **CHILDHOOD** * ‘Classic’ / ‘**severe**’ * **Salt**-losing (2/3rd) * **Non-Salt** losing (1/3rd) * Simple **virilising** * **ADULTHOOD** * ‘Non-classic’ / ‘**mild**’ * ‘late-onset’

Question 39

_CAH Presentation - Childhood_ * ... wasting * H..., S... * V... * Ambiguous genitalia in ... * Early ... in boys * ... puberty * Abnormal ... * ... early * ... fusion

Answer 39

* Childhood: * **Salt wasting** * **Hypovolaemia, shock** * **Virilisation** * Ambiguous **genitalia** in girls * Early **virilisation** in boys * **Precocious** puberty * **Abnormal** **growth** * **Accelerated early** * **Premature** fusion

Question 40

_CAH Presentation - Adulthood (mild)_ * Adulthood (mild): * H... * O.. / a... * A... * S... * Similar to ‘...’ presentation

Answer 40

* Adulthood (mild): * **Hirsutism** * **Oligo / amenorrhoea** * **Acne** * **Subfertility** * **Similar to ‘PCOS’ presentation**

Question 41

_CAH Treatment_ * ... & .... replacement * Such as H... & F... * Additional ... in infancy * ... treament will suppress CRH / ACTH * Supraphysiological ... doses may be needed to suppress adrenal ... production * Monitor [17-OH-P] / androstenedione * Monitor ... in childhood * Excess ... treatment may ... growth * ... management for ambiguous genitalia * Non-classical CAH in adult women (mild) * Can treat as for ... with COCP ± anti-androgen

Answer 41

* **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 ± anti-androgen

Question 42

_Why have her Periods stopped?_ 1. Beth – 23, BMI 17 kg/m2, triathlete 2. Carol – 33, risperidone treatment, galactorrhoea 3. Amy – 17, short stature, aortic regurgitation 4. Marjorie – 50, hot flushes and sweats 5. Emma – 28, breast tenderness, nausea

Answer 42

1. Beth – 23, BMI 17 kg/m2, triathlete * **Hypothalamic amenorrhoea** 2. Carol – 33, risperidone treatment, galactorrhoea * **Hyperprolactinaemia due to medication** 3. Amy – 17, short stature, aortic regurgitation * **Turner syndrome** 4. Marjorie – 50, hot flushes and sweats * **Menopause** 5. Emma – 28, breast tenderness, nausea * **Pregnancy**

Question 43

_Treatment options for PCOS​_ ## Footnote **No prescription required:​ (3) vs On prescription: (4)**

Answer 43

1. Diet / exercise 2. Smoking cessation 3. Epilation * Prescription: 1. Combined oral contraceptive pill 1. –+/- anti-androgens 2. Metformin 3. (Eflornithine cream) 4. Clomifene - To induce ovulation

Question 44

_Clinical features of PCOS​_ ## Footnote **Woman presents with: (4) v Medical terminology: (4)**

Answer 44

1. **Unwanted hair growth in a male distribution = Hirsutism** 2. **Spots = Acne** 3. **Irregular menstrual periods = Oligomenorrhoea** 4. **Trying to conceive without success = Subfertility**

Question 45

_To confirm ovulation…_ * History * Over the counter test * Blood test * Imaging test in subfertility clinic

Answer 45

_History_ * **28 day menstrual cycle** _Over the counter test_ * **LH detection in urine** _Blood test_ * **21 day progesterone** _Imaging test in subfertility clinic_ * **Trans-vaginal USS (follicle tracking)**

Question 46

_Definitions - Disorders of Ovulation_ * A girl who does not go through menarche * ... * A woman whose periods stop aged 26 * ... * A woman having 8 menstrual periods per year * ... * A woman having menstrual periods every 3 weeks * ...

Answer 46

* A girl who does not go through menarche * **Primary amenorrhoea** * A woman whose periods stop aged 26 * **Secondary amenorrhoea** * A woman having 8 menstrual periods per year * **Oligomenorrhoea** * A woman having menstrual periods every 3 weeks * **Polymenorrhoea**