Infertility / Andrology / Endocrinology Flashcards
Normal parameters for semen assessment;
1. Semen volume
2. PH
3. Sperm Concentration
4. Total sperm number
5. Total motility
6. Vitality
7. Sperm morphology
- Greater than it equal to 1.5ml
- pH > or equal to 7.2
- > or = to 15 million sperm/ml
- 39 million sperm per ejaculate or more
- 40% or more motile or 32% with progressive motility
- 58% or more live sperm
- 4% or more normal
Azoospermia on single semen sample?
What to do if abnormalities persist?
Repeat semen sample in 3 months.
If abnormalities persist, then the male partner will need hormone profiling to look for hypogonadotrophic hypogonadism which can potentially be treated with gonadotropins.
First line management for couples with endometriosis and subfertility ?
ART in the form of IUI with Ovarian Stimulation.
Effect of cystectomy for endometriomas on ART ?
Cystectomy is associated with poorer response to stimulation and greater risk of cycle cancellation compared to no surgery (13.7% vs 0%)
Precocious Puberty
- Define
- Features
- What % is idiopathic
- Onset of pubertal development < 8 years of age
- 5-8x more common in girls than boys
- 75% is idiopathic
- NOT associated with premature menopause and reproductive life is normal
- Children are transiently tall but there is early epiphyseal fusion resulting in short stature
- Intellectual and psychological development consistent with chronological age
What are the 2 types of precocious puberty?
- GnRH Dependent - early activation of the hypothalamic - pituitary - gonadal axis
- GnRh Independent - incomplete, peripheral, precocious pseudo-puberty
Causes of GnRH dependent precocious puberty ?
- Idiopathic - 74% girls
- CNS Abnormality, include:
a) SOL - glioma, hamartoma, hydrocelpalus
b) Infection - post encephalitis, brain abscess, meningitis
c) Head Injury/ Irradiation
d) Tuberous Sclerosis and Neurofibromatosis
e) Late/Incompletely Treated CAH
Causes of GnRH independent precocious puberty?
- Topical/ systemic androgens or oestrogens
- Tumours - Ovarian (in 10% of girls with precocious puberty - granuloma, theca cell tumours), Adrenal (rare and associated with increased DHEA-S)
- Severe Hypothyroidism - TSH has LH and FSH activity
- McCune-Albright Syndrome
- CAH
McCune Alrbight Syndrome (polyostotic fibrous dysplasia)
- Gene mutation - not inherited
- 5% female precocity
- Bone cysts, pathological fractures, cafe-au-lait spots, sexual precocity
- Early production of oestrogens by the ovaries
- Fertility and adult height are normal
Testosterone is bound to?
- Sex hormone binding globulin and is metabolically inactive - 85%
- 10-15% bound to Ablumin
- 1-2% free
Free and albumin bound testosterone is metabolically active.
Testosterone is converted to the biologically active .. by ..
- Dihydrotestosterone
- 5-alpha reductase
Increased activity of this enzyme may cause manifestations of androgen excess.
List causes of hyperandrogenism
- Exogenous/Iatrogenic - testosterone, anabolic steroids, danazol
- Ovarian - PCOS, Ovarian tumours (sertoli-leydig, Krukenburg tumours)
- Adrenal tumours, Cushing’s syndrome, adult onset CAH
- Androgen excess in Pregnancy - luteoma
- Idiopathic Hirtuism
- Abnormal gonadal/ sexual development
Investigations for hyperandrogenism
- Increased testosterone = ovarian
Increased DHEAS = adrenal
**Markedly elevated testosterone should prompt investigation for virilising tumour **
- If history + exam convincing of Cushing’s Syndrome - for overnight dexamethasone suppression test
- Late onset CAH - 17 hydroxyprogesterone levels after ACTH stimulation
- Pelvic US - ovarian mass/ PCOS
- CT/MRI - adrenal tumour
- Karyotype if virilisation
- Consider serum lipids + GTT
Ovarian Hyperthecosis
Rare Disorder
Severe hyperandrogenism and insulin resistance
Postmenopausal women
Associated with large islands of luetinised theca cells throughout the ovarian stoma with increased androgen production
Peripheral oestrogen also increased - risk of endometrial hyperplasia/ carcinoma
IMPORTANT Ddx in POSTMENOPAUSAL WOMAN WITH VIRILISATION / TESTOSTERONE >5
Rotterdam Criteria for PCOS diagnosis?
2 of 3:
1. Polycystic Ovaries (>12 peripheral follicles or increased ovarian volume >10cm3)
- Oligo- or anovulation
- Clinical and or biochemical signs of hyperandrogenism
Recommended baseline screening tests when investigating PCOS?
- TFT
- Serum Prolactin
- Free Androgen Index (total testosterone/SHBG x100)
In the presence of hyperandrogenism and testosterone >5:
1. 17-hydroxyprogesterone
2. Exclude androgen secreting tumours
Prevalence of PCOS?
6-7%
Biochemical derangements in PCOS
- Raised androgens - testosterone from ovarian hyper secretion, 50% of women with PCOS will have elevated DHEAS
- Inc concentrations of free Oestradiol
- Decreased SHBG production by the liver resulting in higher free, biologically active androgens and estradiol
- Hyperprolactinaemia (20%, mild)
- LH Hypersectretion - 40% women with PCOS, thought to be associated with reduced chance of conception and increased chance of miscarriage
- Insulin resistance - 30 - 60%
Long term sequelae of PCOS?
- Insulin Resistance - 40% NIDDM by age 40
- Sleep Apnoea
- Multiple pregnancy from ovulation induction
- PIH - independent of obesity and GDM
- Endometrial cancer (5 fold) - if > 3 months between menses
- Cardiovascular Disease
Management of menstrual irregularity in PCOS?
Loss of 10% body weight alone may result in return to regular ovulation + menses.
COCP - use non androgenic progestogen (avoid norethisterone/ levonorgestrel) or cyproterone acetate
Alternatively medroxyprogesterone acetate 5-10 days every 1-3 months to induce withdrawal bleed
Metabolic Syndrome - diagnostic criteria
3/5 of the following:
1. Abdominal Obesity
2. Hypertriglyceridaemia
3. Low HDL Cholesterol
4. Hypertension
5. High Fasting Glucose
Pharmacological Methods to manage Hirtuism?
- COCP - suppressed LH production and ovarian androgen synthesis. Avoid androgenic progestogens (norethisterone/ levonorgestrel). Try cyproterone acetate. Use with contraceptive as can emasculate a male fetus.
- Medroxyprogesterone Acetate - in those COCP contraindicated
- Spironalactone - anti androgen and aldosterone effect
- Flutamide - non steroidal antiandrogen, check LFTs
- Finasteride - 5 alpha reductase inhibitor
- Ketoconazole - significant hepatotoxicity
Causes of Primary Amenorrhoea?
- Abnormal Karyotype eg Turners
- Abnormal CNS-Hypothalamic response (eg. Kallmans Syndrome, anorexia nervosa)
- Abnormal Pituitary Function (eg. Pituitary tumour, prolacinoma)
- Gonadal/ Adrenal Abnormalities (eg. late onset CAH, gonadal genesis, galactosaemia, POF)
Kallman Syndrome
X linked recessive
Delayed/absent puberty (hypogonadotrophic hypogonadism)
Impaired sense of smell
Cleft palate
1/120,000 females
Androgen Insensitivity Syndrome
- Most present after puberty
- 46 XY karyotype
- Short, blind ending vagina, absent uterus and cervix
- Testes found within abdomen, inguinal canal, labia
- Inc risk of cancer in testes - recommend gonadectomy after puberty
5 alpha reductase deficiency
- Autosomal recessive
- Poor masculinisation of external genetalia in male fetus
- Uterus, tubes and vagina absent
Primary amenorrhoea + elevated FSH + 46XX karyotype.
What further investigations are required?
U&E/ serum progesterone to exclude 17- alpha hydroxylase deficiency (RARE)
- Hypokalaemia
- Hypernatraemia
- Elevated serum Progesteroje
- Low 17 hydroxy progesterone
Need cortisol replacement + oestrogen and progesterone HRT
Primary amenorrhoea + 46XX karyotype + low FSH.
What further investigations are required?
Serum Prolactin + cranial CT scan to exclude Prolactinoma.
If normal CT/Prolactin- use oestrogen and progesterone to induce breast development and GnRH to induce ovulation when fertility required.
Clomiphene citrate ineffective.
Primary amenorrhoea + normal breast development + absent uterus.
Causes?
- Mullerian Agenesis - normal body hair with cyclical ovulating symptoms, normal female testosterone levels. Need renal scan to exclude renal tract abnormalities.
- Androgen Insensitivity - 46XY + male testosterone levels. Go addicting after puberty + oestrogen replacement
Causes of Hyper-Prolactinaemia?
- Hypothalamic - lesions which disrupt portal circulation of dopamine to pituitary. Craniophyringioma is the commonest
- Pituitary
- Prolactin secreting adenoma
- Acromegaly (25%)
- Cushings (10%)
- Empty Sella Syndrome - Drugs
- Psychotropic agents, diazepam, tricyclic antidepressants, opiates, haloperidol
- Methyldopa, propranolol
- Metoclopramide
- COCP - Primary Hypothyroidism
- Associated with increased thyrotropin releasing hormone which stimulates prolactin release
3-5% of women with hyper prolactinaemia have HypoT.
What % of pituitary tumours secrete Prolactin?
80%
Define micro adenoma vs macro adenoma
Micro-Adenoma: <10mm diameter
Macro-Adenoma: >10mm diameter
If Prolactin < 1000IU/L - investigations? possible causes?
Exclude:
1. Stress
2. Recent breast exam
3. Drug induced
Repeat test + TSH to exclude hypothyroidism.
PCOS may be associated with levels up to 2500IU/L - organise Pelvic US.
If Prolactin > 1000IU/L - investigations? possible causes?
Prolactin levels:
1. Micro adenoma
2. Macro adenoma
CT/MRI of pituitary fossa.
Macro-adenoma usually associated with Prolactin levels > 5000IU/L.
Micro adenomas usually associated with levels 1500-4000IU/L
First line medical treatment for hyper prolactinaemia secondary to pituitary adenoma?
Mechanism of action?
SE’s?
Bromocriptine
Dopamine Agnoist
Nausea, vomiting, headache, postural hypotension, constipation, dizziness, drowsiness, Raynaud’s, psychiatric phenomenon
Avoid breastfeeding!
Second linemedical treatment for hyper prolactinaemia secondary to pituitary adenoma?
Mechanism of action?
SE’s?
Cabergoline
Long acting dopamine agonist
Dispepsia, abdominal pain, nausea, breast pain, palpitations, nose bleeds, angina, depression, hot flushes
Prolacinoma and pregnancy?
Ovulation induction by which method?
Anterior pituitary enlarges in Pregnancy as a result of lactotroph hyperplasia with resultant increase in serum prolactin (10-20x)
Ovulation induction with Bromocriptine required in most Women.
Risk of symptoms in Pregnancy in women with micro-prolactinomas?
2-5%
Risk of symptoms in pregnancy in women with macro-prolactinomas?
15 - 33%
Antenatal tumour enlargement should be treated by Bromocriptine in the first instance.
Tubal damage is responsible for infertility in what % of infertile couples?
15%
Incidence of OHSS:
1. Mild
2. Moderate
3. Severe
- Mild - 33%
- Moderate - 3 - 6%
- Severe - 0.3 - 0.5%
OHSS Risk Factors?
- Previous OHSS
- High AMH
- High astral follicle count
- Multiple pregnancy
- High dose gonadotrophin
Mild OHSS
Abdominal bloating
Mild abdominal pain
Ovarian size <8cm
Moderate OHSS
Moderate abdominal pain
Nausea +/- vomiting
US evidence of ascites
Ovarian size usually 8-12cm
Severe OHSS
Clinical ascites
Oliguria
HCT > 0.45
Hyponatraemia (Na+ <135)
Hypo osmolality (<282 mOsmol/kg)
Hyperkalaemia (K+ >5mmol/l)
Albumin < 35
Ovarian size > 12cm
Critical OHSS
Tense Ascites
HCT > 0.55
WCC > 25
Oliguria/Anuria
Thromboembolism
ARDS
OHSS - indications for paracentesis?
- Severe abdominal pain and distension secondary to ascites
- SoB and respiratory compromise secondary to ascites and increased intra abdominal pressure
- Oliguria despite adequate volume replacement, secondary to increased abdominal pressure causing reduction in renal perfusion
Complications of oocyte retrieval incidence?
1. Intraperitoneal haemorrhage
2. Pelvic Infection
- Intra peritoneal haemorrhage - 0.2%
- Pelvic Infection - 0.4%
Incidence of Ectopic Pregnancy in IVF?
Heterotopic Pregnancy in IVF?
2-11%
1%
Causes of infertility:
1. Male factor
2. Female factor
3. Combined male and female factor
4. No cause
- Male - 20-30%
- Female - 20-35%
- Combined - 25-40%
- No cause - 10-20%
Most common cause of female factor infertility is ovulatory dysfunction
Optimal timing for repeat semen analysis following initial abnormal result?
3 months
if azoospermia or severe oligozoospermia, repeat sample in 2-4 weeks.
Causes of azoospermia?
- Hypothalamic-pituitary failure
- < 1% cases
- deficiency of LH and FSH, failure of spermatogenesis and testosterone production eg. Kallman Syndrome - Primary Testicular Failure eg. torsion, trauma, orchitis, chromosome disorders (Kleinfelters), idiopathic (66%)
- Obstruction of the genital tract
- < 2% of cases
- eg. congenital bilateral absence of vas deferent in CF - Anejaculation
- Retrograde Ejaculation
Definition:
1. Asthenoozospermia
2. Asthenoteratozoospermia
3. Azoospermia
- % of progressively motile sperm below the lower reference limit
- % of both progressively motile and morphologically normal spermatozoa below the lower reference limits
- No spermatozoa in the ejaculate
Varicocele:
1. Define
2. % of men with normal semen?
3. % of men with abnormal semen?
4. Management of Grade I, II, III
- Collection of dilated veins in the spermatic cord
- 11.7%
- 25.4%
Grade I: no Rx, offer semen analysis if fertility is a concern
Grade II - III asymptomatic with normal semen parameters: observe, semen analysis every 1-2 years
Grade II - III symptomatic with abnormal semen parameters: refer to Urology for surgical management
Define:
1. Oligoasthenozoospermia
- Oligoasthenoteratozoospermia
- Oligoteratozoospermia
- Total number (concentration) of spermatozoa and % of progressively motile sperm, below the lower reference limits
- Total number (concentration) os spermatozoa, % of progressively motile sperm and morphologically normal sperm below lower reference limits
- Total concentration and number of morphologically sperm below lower reference limits
Myotonic Dystrophy + fertility
1. Inheritance pattern
2. Fertility issues
- Autosomal dominant
- Most common form of myotonic dystrophy that begins in adulthood - Fertility issues:
a) Testicular Atrophy
b) Primary Hypogonadism in males
- small testes, oligo or azoospermia, impaired secondary sexual characteristics (low libido, no facial and body hair)
- Low testosterone with inc FSH and sometimes LH
- Gynaecomastia may occur
Medical treatment of infertility secondary to hypogonadotrophic hypogonadism in males?
- Self administration of FSH and HCG - stimulates spermatogenesis, 80% +ve sperm count
- Pulstatile GnRH
Medical treatment for anejaculation in males?
- Alpha agonistic drugs - ipiramine, pseudoephedrine
- Parasympatheticomimetics (more successful)
Medical treatment for retrogradee ejaculation in males?
Aims of treatment ?
Aim to increase sympathetic tone of the bladder or decrease parasympathetic tone of the bladder.
- Anticholinergics
- Antihistamines
Which of the following tests can be performed to predict ovarian response to gonadotropin stimulation in IVF?
- Antral Follicle Count measured on TVUS on D3 of cycle (>16 high response)
- AMH (<4.5 low response, > 25 high response)
**Inc AMH associated with increased risk of OHSS.
- FSH (>8.9 low response, <4 high response)
Oligo and an ovulation cause what % of female factor infertility?
21%
WHO Classification of Ovulation Disorders
Class I - hypothalamic pituitary failure (stress/anorexia/exercise)
Class II - hypothalamic pituitary dysfunction (PCOS)
Class III - ovarian failure
WHO classification of Ovulation Disorders: Class II
Hypothalamic Pituitary Failure
- Stress/ Anorexia/ Exercise
- 10% ovulatory disorders
- Low gonadotrophins, normal prolactin, low oestrogen
WHO Classification of Ovulation Disorders: Class II
Hypothalamic Pituitary Dysfunciton
- PCOS
- Gonadotrophin disorder, normal oestrogen
- 85% Ovulatory disorders
- Polycystic ovaries are present in 80-90% of women with oligomenorrhoea and 30% of women with amenorrhoea
WHO Classification of Ovulation Disorders: Class III
Ovarian Failure
- 4-5% ovarian disorders
- Hypogonadism, low oestrogen
- High gonadotrophins
Incidence of highperprolactinaemia in infertile, but ovulatory women?
3.8 - 11.5%
Tubal factor infertility accounts for what % of cases of subfertility in women?
14%
Chlamydia prophylaxis in women undergoing HSG?
Azithromycin
Doxycycline
According to FIGO, the normal menstrual cycle lasts?
24 - 38 days
Multiple pregnancy from IVF vs spontaneous conception?
1:4 vs 1:80
Embryo transfer for:
1. Women < 37 years old
2. Women age 37 - 39 years old
3. Women age 40 - 42 years old
- Age < 37
- In the first full cycle, use single embryo transfer
- In the second full IVF cycle, use single embryo transfer if 1 or more top quality embryos are available. Consider 2 embryos.
- In the third full cycle, transfer no more than 2 embryos - Age 37-39
- transfer 1 embryo on first cycle, consider double embryo transfer if no top quality embryos
- in the 3rd cycle transfer no more than 2 embryos - Age 40-42 years
- consider embryo transfer
Embryo transfer strategy based on age of egg donor!
Minimum number of motile sperm needed for IVF?
50,000 - 500,000 motile sperm
ICSI may be more suitable for men with lower numbers of motile sperm.
First line ovarian treatment for women with PCOS?
- Clomifene citrate and/or Metformin
Clomifene is taken as a single 50mg dose for 5 days early in the menstrual cycle.
If ovulation is not achieved at this dose, can be increased to up to 150mg.
If ovulation is not achieved at theses doses 100-150mg, then the term ‘clomifene resistance’ is used.
Multiple pregnancy rate associated with Clomifene?
10%
Prevalence of Chlamydia in subfertile women?
1.9%
Letrozole
1. Mechanism of action
2. Uses
- Aromatase inhibitor
Blocks the conversion of androgens to estrogens in the ovarian follicles, peripheral tissues, and in the brain. This results in:
a) fall in circulating and local estrogens
b) rise in intraovarian androgens
- First line treatment in postmenopausal women with hormone dependant advanced breast cancer.
Skin manifestations of PCOS?
- Hirtuism
- Acne
- Seborrhoea
- Alopecia
- Acanthosis Nigricans - thought to be the result of Insulin resistance
One full cycle of IVF will take approximately how long?
4-6 weeks
Which drugs are typically used to trigger ovulation?
HCG
Recombinant LH
GnRH
Mimics the LH surge which triggers ovulation.
Monitoring of stimulated IVF
Cycles. Three US scans are commonly offered, when?
- At the start of ovarian stimulation in GnRH agonist controlled cycle
- To assess at day 7-9
- To determine timing of HCG administration at days 11 - 14
Treatment of confirmed Sheehans syndrome on pituitary MRI?
COCP or HRT
ACTH: hydrocortisone or prednisolone
GH: Growth Hormone
TSH: Thyroxine
CAH - enzyme deficiency?
21 hydroxylase deficiency
resulting in a failure of conversion of 17-alpha-hydroxyprogesterone to 11-deoxycortisol;
17-hydroxyprogesterone and progesterone levels are increased with subsequent conversion to androstendione and testosterone with resulting masculinisation of the female fetus
CAH - investigations?
- Karyotype
- 17-alpha hydroxyprogesterone
- U+E - Low Na+/Cl-, High K+
- Pelvic Ultrasound - to identify uterus/ovaries/vagina
5 alpha reductase deficiency
1. Inheritance
2. Features
- Autosomal recessive
Poor masculinisation of external genitalia in male fetus
- Uterus, tubes and vagina are absent as production of Mullerian inhibitory factor is normal
- Development of Wolffian duct structures independent of 5-alpha reductase
- Child usually reared as female initially
- Virilisation occurs at puberty due to increased testicular testosterone production
- Sex of rearing dependent on the degree of masculinisation of the external genitalia
MKRH:
1. Incidence
2. What % have renal tract abnormalities?
3. What % have absent kidney?
- 1:5000 female births
- 40% renal tract abnormalities
- 12% have absent kidney
An AMH over what level is strongly consistent with diagnosis of PCOS ?
> 35
Midluteal progesterone > what confirms ovulation?
> 30
Prevalence of PCO vs PCOS
PCO - 20-33%
PCOS - 10-15%
% of women with PCOS who have:
1. Impaired glucose tolerance
2. T2DM
- 34%
- 9%
Success rate of IVF in women > 45?
<3% therefore usual recommendation is ICSI.
Life cycle of a sperm ?
3 months
AMH is a glycoprotein expressed by?
Granulosa cells
Most common cardiac defect in women with Turners?
And the second?
- Bicuspid aortic valve - 30%
- Coarctation of aorta - 12%
Both are associated with aortic dilatation.
What % of cases of Azoospermia are obstructive in nature ?
40%
Where is DHEAS produced?
Adrenal cortex.
DHEA-S -> DHEA -> androstenedione
(Precursor for testosterone and estrone).
Make and female factor infertility?
40%
What is the incidence of subfertility?
15% (1/7 couples)
