MED2042 WEEK 5 - Hormones and Sex

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What are some IVF facts and figures?: - Since 1978, nearly 2 million babies have been born worldwide using assisted reproductive technology
- About 250 000 babies were born in Australia in 2002 with almost 2% of thse babies (1 in 50) born as a result of assisted reproductive technology
- There are now more than 50 000 children born in Australia as a result of assisted reproductive technology
- Success at Monash IVF has resulted in the birth of more than 8000 babies.
What are the causes of infertility?: Ovulation disorders - no egg
Tubal infertility - no transport
Male factor - no fertilisation
Implantation failure - no implantation
Endometriosis
Unexplained infertility
What is infertility?: Absence of conception after 1 year of regular, unprotected intercourse around the time of ovulation
How many couples experience difficulties with infertility?: 15%
Who is affected?: Male - 30%
Female - 30%
Both - 30%
Unexplained - 10%
What is the probability of conception after 3 months, after 6 months, after 9 months, after 12 months and after 24 months?: After 3 months - 30%
After 6 months - 50-60%
After 9 months - 60-70%
After 12 months - 80-90%
After 24 months - 95%
What is the effect of female age on fertility?: Age related infertility
- Reduction in fertility rate in women 35 years and over
- Dramatic reduction in fertility rate in women over the age of 40
What is the effect of body weight on fertility?: ?
Taking a history for female and male infertility.: Female
- Coital frequency
- Menstrual history
- Previous conceptions
- PGH, PSH, PMH, FH
- Med/alcohol/drugs
- Smoker

Male
- coital frequency
- previous conceptions
- undescended testes
- orchitis, STD, trauma
- PSH, PMH, FH
- alcohol, drugs, meds
- smoking, environment
What is orchitis?: Orchitis is an often very painful condition of the testicles involving inflammation, swelling and frequently infection.
Examination for female and male infertility.: Female
- BMI
- Secondary sexual characteristics
- Hirsuitism
- Galactorrhea
- Genetic manifestations
- Genital malformations

Male
- secondary sexual
- Testicular size
- Varicocele
- Vas deferens
- Genital Malformations
- Prostate disease
What is varicocele?: Varicocele is an abnormal enlargment of the veins in the scrotum draining the testicles. The testicular blood vessels originate in the abdomen and course down through the inguinal canal as part of the spermatic cord on their way to the testis. Up-ward flow of blood in the veins is ensured by small one-way valves that prevent backflow. Defective valves, or compression of the vein by a nearby structure, can cause dilatation of the veins near the testis, leading to the formation of a varicocele.
What is galactorrhea: Galactorrhea or galactorrhoea is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing. It can be due to local causes or dysregulation of certain hormones.

Lactation requires the presence of estrogen, progesterone and prolactin, and the evaluation of galactorrhea includes eliciting a history for various medications (methyldopa, opiates, some typical antipsychotics) and for behavioral causes (including licorice, stress, and breast and chest wall stimulation), as well as evaluation for pregnancy, pituitary adenomas (with overproduction of prolactin or compression of the pituitary stalk), and hypothyroidism. Overproduction of prolactin leads to cessation of menstrual periods and infertility, which may be a diagnostic clue.
What are the reasons for ealier referral for females and males in the case of infertility?: Female
- 35+ years
- oligo-amenorrhoea
- sterilisation reversal
- previous PID/STD (pelvic inflammatory disease/sexually transmitted disease)
- previous abdo surgery
- abnormal pelvic exam
- 2+ miscarriages

Male
- previous genital pathol.
- prev. urogenital. surgery
- previous STD
- Varicocoele
- Systemic illness
- abnormal genital exam
What is the diagnositc workup for infertility?: For him
- semen analysis and spabs test (preferably by fertility clinic)

For her
- Blood tests (rubella, hormones - FSH, LH, E2, TSH)
- Ultrasound
- Laparoscopy
- Hysteroscopy

For both
- BLood tests - HIV, Hep B and C
- Glood group
What is hysteroscopy?: Hysteroscopy is the inspection of the uterine cavity by endoscopy. It allows for the diagnosis of intrauterine pathology and serves as a method for surgical intervention (operative hysteroscopy).
Differential Diagnosis for infertility.: Female infertility
- Ovulation
- Endometriosis
- Tubal factors
- Implantation failure
Male infertility
- unexplained
What are some tests of unproven significance?: - Basal body temperature chart
- Postcoital test
- Sperm function tests
- Endometrial biopsy
- Serum sperm antibodies in both partners
What are the effective treatments in female infertility?: OVULATION DISORDERS
- clomiphene citrate
- human recombinant FSH
N.B. both of these have risks of multiple pregnancy and OHSS

- laparoscopic ovarian drilling for PCOS
- bromocryptine for hyperprolactinemia
- GnRH pump for hypothalamic disorders

TUBAL INFERTILITY
- prox. occlusion: retrogreade catheterization
- Distal occlusion: tubal microsurgery
- IVF + salpingectomy for hydrosalpinx

IMPLANTAION FAILURE
- Hysteroscopic resection of:
> intrauterine adhesions
> submucosal fibroids
What is OHSS: Ovarian hyperstimulation syndrome (OHSS) is a complication from some forms of fertility medication. Most cases are mild, but a small proportion is severe.
What is salpingectomy?: Salpingectomy refers to the surgical removal of a Fallopian tube. The procedure was first performed by Lawson Tait in patients with a bleeding tubal pregnancy; this procedure has since saved the lives of countless women. Other indications for a salpingectomy include infected tubes, (as in a hydrosalpinx) or as part of the surgical procedure for tubal cancer. Salpingectomy is different from a salpingostomy, a procedure where an opening is made into the tube to remove an ectopic pregnancy, but the tube itself is not removed.

Salpingectomy has been traditionally done via a laparotomy, more recently however, laparoscopic salpingectomies have become more common as part of minimally invasive surgery.

Salpingectomy is commonly done in conjunction as part of a "complete" hysterectomy - a procedure called a salpingo-oophorectomy where the uterus and both ovaries and Fallopian tubes are removed in one operation.
What are the effective treatments in male infertility?: - microsurgical vasectomy reversal
- embolisation for varicocoele with oligozoospermia
- intrauterine insemination for total motile sperm counts > 10 million
- IVF and ICSI

ICSI used to treat the majority of infertile males
Azoospermia treated by
- sperm cells obtained from epididymis (PESA)
- sperm cell attained from testis (TESA)
What is oligozoospermia?: Oligozoospermia is the medical condition of a man having fewer than 20 million sperm per mL, but still a measurable level (unlike azoospermia which is a complete lack of measurable sperm).

Severe Oligozoospermia is a special case where the count is 5 million sperm per mL and below.
What is ICSI?: Intracytoplasmic sperm injection (ICSI) is an in vitro fertilization procedure in which a single sperm is injected directly into an egg; this procedure is most commonly used to overcome male infertility problems.
What is PESA?: The Per-cutaneous Epididymal Sperm Aspiration (PESA) technique is used to determine sperm counts in the event of a possible blockage of the vas deferens. A small needle is inserted through the skin of the scrotum, to collect sperm from the epididymis where sperm are usually stored after production in the testes.
What are the effective treatments in unexplained infertility?: - Expectant management (<3 years)
- Ovarian stimulation + IUI
- IVF
What is IUI?: Intrauterine insemination
- Ovaries stimulated
- 2-3 eggs released in tube
- sperm washed and concentrated
- drop of prepared sperm inseminated in urterine cavity
What is IVF?: In Vitro fertilisation
- ovaries stimulated +++
- >10 eggs collected
- sperm washed and mixed with eggs
- 1-2 fertilised eggs transferred back into uterine cavity
What is in-vitro?: In vitro (Latin: (with)in the glass) refers to the technique of performing a given experiment in a test tube, or, generally, in a controlled environment outside a living organism. In vitro fertilization is a well-known example of this. Many experiments in cellular biology are conducted outside organisms or cells, thus, the conditions and, therefore, results may not correspond to those inside. Consequently, experimental results are often annotated with in vitro or its opposite in vivo as it applies.
Describe Sperm preparation in the lab.: In order to prepare the sperm for insemination with the eggs, the healthy, motile sperm have to be separated from the non motile and abnormal sperm.

They are then washed with culture media.
What are two ways of Insemination?: Standard insemination
- 80 000 motile sperm are added to each egg and left to fertilised in the test tube

Microinjection
- A single sperm is selected and injected directly into the cytoplasm of the egg

Microinjection (ICSI)
- Also referred to as "ICSI"
- Sucessful for treating male subfertility
> low sperm count
> poor motility
> testicular sperm (e.g. failed vasectomy reversals)
- preferred treatment for low or failed fertilisation in previous IVF cycle

Mature oocyte is stripped for ICSI
How do you tell if an egg has been fertilised normally?: Normal fertilised egg has 2 nuclei

Unfertilised egg has no nuclei

Abnormal fertilised egg has 3 nuclei
Describe embryo development form 2 cells to 8 cells.: 2-cell (day 2)
4-cell (day 2-3)
8 cell (day 3)

24 hours after fertilisation, the embryo starts to divide.
Describe extended culture (blastocyst).: Early blastocyst
Expanding blastocyst
Expanded blastocyst

The embryo divides rapidly after reaching the 8-cell stage and within the next couple of days will contain about a hundred cells, and is then called a "blastocyst"
When is an embryo transfered to the uterus?: When the embryos have grown to a suitable stage (usually 2 or 3 days after the egg collection), 1 or 2 embryos are transferred into the uterus using a catheter
What is embryo freezing?: After embryo transfer, any remaining embryos which are good quality can be frozen. The embryos are stored in liquid nitrogen at -196degreesC
What is embryo thawing?: Frozen embryos are thawed and replaced in a Frozen Embryo Tranfer (FET).

70% of embryos survive the freezing/thawing process
What situations allow the donation of eggs and embryos.: Indication for donation:
- absent ovaries
- chromosomal abnormaility - Turners syndrome
- Streak ovaries
- Premature ovarian failure (menopause)
- Inherited genetic diseases transmitted through the female
- Repeated failed IVF cycles
- Over the age of 40
- Castration following readiation and chemotherapy
What is an embryo biopsy done for?: PRE-IMPLANTATION GENETIC DIAGNOSIS
- single gene disorders e.g. cystic fibrosis, haemophilia, huntingtons
- test for genetic mutation and tansfer unaffected embryos

CHROMOSOME TESTING
- advanced maternal age
- recurrent miscarriages
- allow investigation of chromosome status
How is an embryo biopsy carried out?: - Embryos cultured by IVF to day 3 (6-8 cell stage)
- Hole drlled in shell of egg by a laser beam
- 1 or 2 cells extracted (biopsied) and tested
- Healthy/unaffected embryos chosen for embryo transfer
What are the symptoms of menopause?: The symptoms of menopause occur in a spectrum of no symptoms to symptoms including:
- hot flushes (80% women, 20% significant, 25% for more than 5 years)
- night sweats
- formications
- anxiety, irritability
- sleep disturbances
- lessened memory, concentration
- vaginal dryness, low libido
- fatigue
- muscle/joint pains
- overall diminished wellbeing
What is the impact of hormone profiles?: Perimenopausal symptoms are attributable to unstable hormone profiles (begin age 35)

Often start in perimenopause (cycles may still be regular)

Onset and duration of symptoms unpredictable.

Hormone profile changes
- falling inhibin levels
- fluctuations in FSH levels
- Estrogen maintained until late perimenopause

Unreliable to test serum hormone levles
What are the hormonal changes in life?: - During reproductive years, cyclic fluctuations estrogen & progesterone
- These hormones fluctuate increasingly as we approach menopause
- Perimenopause
- Menopause
What are treatment options for menopause?: - Education/self empowerment
- Exercise
- Diet
- Lifestyle
- HT vs HRT
- Alternative "Natural" treatment options
- Selective serotonin reuptake inhibitors (SSRIs)
What kind of education and advice is there regarding menopause?: - Daily symptoms diary
- Rapport with health professional
- Resources
> evidence based
> independent/reputable
- Warnings regarding vested interest
- Resources
> jeanhailes.org.au
> Australasian Menopause society
> Bone health for life
What is the link between nutrition and physical actitivity with menopause?: - Regular "ENDURANCE EXERCISE" helps:
> +ve effects on muscle, heart disease, bones, symptoms, stress, anxiety and wellbeing

- Nutrition
> healthy/balanced
> long-term plan
> NHMRC resources
What is the link between lifestyle, anxiety and depression?: - anxiety increased midlife/menopause
- physical symptoms distressing
- exacerbates symptoms - role of stress
- reduces tolerance of symptoms
- needs to be addressed
- depression not related to menopause per se
Describe the pendulum reaction to hormone therapy.: USA 91 000 000 on HT 2001
Enthusiasm and high expectations

USA 57 000 000 on HT 2003
Sensationalised misinterpretation

2006 - a time for rational mature evidence based approach.
What are indications for HRT?: Menopausal symptoms
- relieved by HRT (hot flushes, sweating, sleep disturbance)
- may be improved by HRT (fatigue, irritabiliy, anxiety)

Urogenital atrophy
- atrophic changes and consequences
- e.g. vaginal dryness, dyspareunia)

Prevention and treatment of osteoporosis
- Early postmenopause in women with synptoms
What is the management of symptoms of menopause?: HT
- treatment short-term (annual review)
- perimenopausal women options:
> support, education, daily symptom diary
> low dose OCP
> hormone therapy when oligomenorrheic

Early (2years) postmenopausal - cyclic hormone therapy
Later - combined continuous, consider low dose, tibolone
What is the HT dose recommendation?: Recommended starting doses of oestrogen:
- 0.5 - 1mg 17 beta-oestradiol (oral)
- 25-37.5 ug transdermal (patch) oestradiol
- 0.5mg oestradiol gel (1/2 sachet)
- 150 ug intranasal oestradiol (1 spray)
What types of progestins are there for menopause?: Progestin only if uterus intact
- low dose + drospirenone
- dydrogesterone
- norethisterone and its acetate
- medroxyprogesterone acetate
Tibolone for menopause.: Steroid hormone with complex metaolites
- estrogenic (provides symptom relief, improves BMD/ decreases fracture risk)
- androgenic (minimal virilisation, improves libido)
- Progestogenic (no need for progestins, minimal vaginal bleeding)

- breast advantages
- ? decreased thrombosis
- decrased HDL (?)
What pre-treatment assessment needs to be done for menopause?: History
- menopausal symptoms/menstural history
personal and/or family history
Osteoporotic fracture, VTE, breast cancer, CVD
PHysical examination weight and BP

Additional assessments
- Vaginal ultrasound and/or endometrial biopsy
- Mammography
- Bone mineral density based on risk

Lifestyle issues, discuss options
What is the guiding principle for hormone therapy?: Whether to use hormone therpay is an individual choice made by the woman and her doctor taking account of current knowledge regarding benefits and risks

Serious side effects rare but need to be discussed in all cases to permit an informed decision.
What is done to monitor HT treatment?: Adverse effects of HT are primarily minor
- Review wome 6-8 weeks, see x2 in first six months
> consider symptom severity
> trial withdrawal of therapy
> discuss recent literature
- indivitualise therapy
What are the adverse effects of HT?: Serious adverse effects
- cardiovascular disease/stroke/dementia
- venous thromboembolism
- breast cancer

Update on literature beyond WHI
- questions answerd by WHI
- Those not answered
- Critical windo hypothesis

- Advice simplified by consensus statements
> AMS, RANZCOG, NH&MRC
What is the duration of treatment?: - Based on the indication
- Dose and type should be re-evaluated annually
- Need determined by temparay discontinuation
- Prevention or treatment of osteoporosis
> only long-term therapy is effective
> can start with 5 years HT and move on later
What is atrophic vaginitis?: - Topical therapy most appropriate and not systemically absorbed
> no need for progestin
- 40% of women on systemic HT still have consistent complaints of vaginal dryness
- Add topical therapy rather than increasing sytemic doses.
What is the conclusion for dealing with menopausal symptoms?: - The interpersonal skill of the practitioner is the factor most consistently identified as being of value to the patient
- HT reasonable choice for women with moderate to severe symptoms - informed choice
- Complementary Rx and Bioidenticals need further research for safety and efficacy and need greater regulation.
- HT should only be prescribed when it is clearly indicated, primarily for symptom relief
- HT is the initial option for fracture risk reduction in women at significanlty increased fracture risk. HT involves some additional risk, serious but rare side-effects:
> venous thromboembolic disease
> stroke
> breast cancer
HRT continuation should be reviewed regularly.
What is the incidence of short stature?: Short stature is one of the most common problems presenting to consultant pediatricians.

Most is familial and/or pubertal delay - 80%

Other medical e.g. coelia, CRF - 10%

Idiopathic - 5%

Occasionally hormonal - 4%
+ turner's (girls) 3%
What is the endocrine origin of short stature?: Thyroid insufficiency
Growth hormone deficiency
Glucocorticoid excess
What kinds of thyroid insufficiency are there?: Congenital
- ectopic gland or agenesis
- hormone synthetic defects - very rare
Detected on newborn screen by very high TSH

Acquired
- Hashimoto's thyroiditis or autoimmune chronic lymphocytic thyroiditis.
> usually but not always have anti-thyroid antibodies (Anti-TPO)
> will have high TSH and low T4
- Colloid goitre (mostly euthyroid)
- hypopituitarism - surgery, autoimmune, tumour
What kinds of growth hormone deficiency are there?: Anything that can go wrong will go wrong!
- Congenital structural defects e.g. agenesis of corpus callosum, midline facial defects
- Acquired e.g. perinatal trauma, CNS infections, cranial irradiation etc
- tumours of hypothalamus or pituitary e.g. craniopharyngioma, glioma/astrocytoma, germinoma. Also secondary tumours e.g. lynphoma etc (GH+ other pit. hormones)
- pscyosocial deprivation
- genetic
> pituitary genes (combined hypo pit.)
> GH structural genes (low or absent GH)
> Bio-inactive GH - n or high GH low IGF-I
- GH receptor - esp consanguiity India & Brazil; failure of IGF-1 response
- Idiopathic
What kinds of glucocorticoid excess are there?: Endogenous
- Cushing's disease (ACTH excess may be seen in adolescents
- Rarely, especially if <7 years may have adrenal tumour

Exogenous
- high dose steroids for SLE (Systemic lupus erythematosus), asthma etc
What is the mature pituitary?: Functionally diverse population of specialised cells producing 6 hormones

This differentiated strucure is result of complex activation and repression of many genes encoding homeodomain transcription factors.
What are the hypothalamic Pituitary Hormones?: Hypothalamus
GHRH GnRH TRH CRH Dopamine
+ + + + -
Pituitary
GH LH FSH TSH ACTH Prolactin

Target (receptors
liver gonads thyroid adrenal breast tissue
IGF-1 TETO/E2 T3&T4 corisol
What are the dynamic patterns of hormone secretion?: Constant e.g. TSH

Diurnal e.g. ACTH

Pulsatile e.g. GH, LH, FSH
Patient results. NC was a 10 day old girl for follow up of a positive newborn screening test. TSH > 100.0 (RR 1.0-25.0) FT4 1.8 (RR 12-30) Why do we screen? What is the cause? Thyroid or pituitary? Treat: To protect newborn from treatable congenital metabolic disorders

Thyroid cause because TSH from pituitary works but FT4 is not being produced by thyroid.

Treatment is by replacement of Thyroid hormone thyroxine.
Patient results 2 GM short 6 year old girl recently migrated from Guatamala. Also psychomotor retardation, constipation & T 35.8. TSH >451.0 (RR 0.3-5.0) FT4 <1.3 (RR 9-25) Creatine kinase 1982 (RR 25-200)<: Severe hypothyroidism?
Patient 3 results 4 year old short & chubby boy with Down's syndrome. TSH 5.1 (RR 0.3-5.0) FT4 71.3 (RR 9-25) What is going on?: Rare situation and often cannot be explained.

Could this be thyroid hormone resistance?

TSH 5.1 (RR 0.3-5.0)
FT4 71.3 (RR 9-25)

FT3 3.7 (RR 3.5-6.5)

Which result is anomalous?

FT4

Repeat FT4 in another laboraty (alt. method)

FT$ 15.4 (RR 9-25)
Patient results 4 RI 14 year old boy with short stature and pubertal delay. GH 0.4 (RR 0-15) Is this result helpful?: No. GH has a pulsatile secretion.

How can we test for a deficiency?

Dynamic testing required e.g. Exercise, glucagon, insulin etc.

GH after 2.6 km on motorised treadmill over 20 min in fasting state. Heart rate 200/min.

GH
- Baseline - 0.4
- Post exercise - 59.1
- RR 0-15(post ex >15)

IGF-1
- Baseline 0.5
- RR 0.3-1.4

Conclusion? normal.
Value of IGF-1? normal.
Patient results 5 US 15 year old boy with short stature. His 3 year old brother was up to his shoulder. Several members over 6 feet. Exercise 2.4 km over 20 mins. Heart rate 180/min GH - Baseline - 0.2 - Post exercise: Conclusion?

What now?
Patient results 6 RR 14 yr old indian girl with extremely short stature. Exercise 2.1km over 20 min. Heart rate 174/min. GH - Baseline - 2.9 - Post exercise - 265.1 - Ref rance - 0-15 (post >15) IG: ?
What are some physical signs of cushing's syndrome?: Moon face with erythema and hirsutes

Thin skin and fragile blood vessels - bruising commonly reults from very minor trauma + purpura

Striae
What are biochemical complications of Cushing's?: Glucose intolerance, type 2 diabetes (NIDDM)

Electrolyte imbalance due to mineralocorticoid excess - low K+
How is cortisol excreted?: Unbound cortisol is excreted in urine.
What is the diagnosis of Cushing's sydrome?: Inappropriate cortisol roduction

ACTH dependant
- Pituitary
- Ectopic

Non ACTH dependant
- Adrenal tumours - adenoma or carcinoma
- Exogenous steroid
Describe plasma cortisol level's diurnal rhythm.: Serum
Cortisol AM 520 (240-620)
Cortisol PM 450 (100-280)
How is cortisol excretion measured?: 24 hour urinary free cortisol.
Is it possible to suppress cortisol?: Post dexamethasone (1mg at 11pm)
Cortisol AM 480 (<140 post dex)
(normal AM ref range: 240-620)

98% Cushing's fail to suppress

Failure to suppress may also be due to obesity, chronic illness, enzyme inducing drugs - phenytoin, phenobarb etc.

May need longer suppresion test to distinguish from Cushing's syndrome
Patient Results 8 Long history of steroid asthma associated with short stature. Anxious mother tended to be heavy user of oral steroids as well as inhaled fluticasone. Counselled to reduce steroid medication but concerns: Synacthen test

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