updates on endocrinology (part 2) acma biennial conference 28/6/2014 pui ling chan fracp...
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Updates on Endocrinology (part 2)
ACMA Biennial Conference 28/6/2014
Pui Ling ChanFRACP
Endocrinologist
MacMurray Specialist Centre
5 MacMurray Road, Remuera
Outline
Pituitary
• Hypopituitarism
Reproductive
• Testosterone replacement
• Menopause management
ACMA CME 16/3/2014
Thyroid
PCOS
Diabetes
Osteoporosis
The pituitary – Master gland
Hypopituitarism – causes
Pituitary tumours Parapituitary tumours –
craniopharyngioma, meningioma, secondary deposits (breast, lung) etc
Radiotherapy – pituitary, cranial, nasopharyngeal
Pituitary infarction (apoplexy), Sheehan’s syndrome
Pituitary infiltration – sarcoidosis, lymphocytic hypophysitis, haemochromatosis
Empty sella
Infection – TB abscess
Trauma – head trauma, iatrogenic (neurosurgery)
Isolated pituitary hormone deficiency
GnRH deficiency (Kallman’s syndrome)
Isolated ACTH deficiency
Pit 1 gene mutation (leads to isolated GH. PRL & TSH deficiency)
DAVID syndrome (Deficit in Anterior Pituitary function and Variable Immuno-Deficiency)
Hypopituitarism - features
Potentially severe medical condition
Anterior pituitary deficit
Posterior pituitary deficit (diabetes insipidus)
Panhypopituitarism
Depending on severity of hormone deficiency & rate of development
Order of diminished hormone reserve function is usually GH>FSH>LH>TSH >ACTH
PRL deficiency is rare except in Sheehan’s
Amelioration of diabetes mellitus in hypopituitarism = Houssay phenomenon (reduction in counter regulatory hormones)
Hypopituitarism
Associated with increased all cause mortality (SMR 1.42) – respiratory & vascular diseases
Data had shown 2 commonest reasons for mortality were
(i) adrenal crisis in response to acute stress and intercurrent illness;
(ii) increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy.
JCEM 2013 Vol 98(4)
Hypopituitarism – treatment goals
Adequate & appropriate hormone replacement
Management of underlying cause(s)
Replacing the target hormone
Remains challenging
Glucocorticoid replacement therapy ACTH deficiency usually needs glucocorticoid only (not
mineralocorticoids), in contrast to patients with Addison’s disease
Hydrocortisone most commonly used – rapidly absorbed, short T1/2 (90-120mins)
Prednisone & Dexamethasone – CAH
Equivalent doses Potency
Hydrocortisone 20mg 1
Prednisone 5mg 4
Prednisolone 5mg 4
Dexamethasone 0.75mg 20-30
Hydrocortisone replacement & cortisol circadian rhythm
Monitoring of glucocorticoid replacement
Over-replacement:
Hypertension
Diabetes
Reduced bone density
Cushingoid
Under-replacement:
Non-specific symptoms e.g. lethargy, weight loss, anorexia, weakness, dizziness, postural hypotension, GI symptoms (n&v, abod pain, diarrhoea)
Can use hydrocortisone day curve
glucocorticoid replacement during acute/severe intercurrent illness
Mild disease without fever – no change in dose
Pyrexial illness – double the dose for duration of fever
Vomiting or diarrhoea – IM Hydrocortisone100mg
Severe illness/surgery – IM Hydrocortisone 50-100mg q6h (e.g. 72h for major surgery, 24h for minor surgery)
Thyroxine replacement in hypopituitarism L-thyroxine (T4)
Dose similar to treatment of primary hypothyroidism
Usually 25 to 75mcg per day
Dose of thyroxine titrated to achieve mid-normal clinically euthyroid fT4
TSH levels not useful
Beware if a woman is also on estrogen replacement as TBG levels can be increased by estrogen
Thyroxine overdosing can lead to arrhythmia, osteopenia
Thyroxine should not be initiated until adrenal reserve has been evaluated, as T4 can accelerate cortisol metabolism and exacerbate hypoadrenalism and precipitate adrenal crisis
Testosterone replacement – when to treat?
Androgen Deficiency – Signs & Symptoms Delayed sexual development
Low libido and sexual activity
Decreased spontaneous erections
Loss of body hair (axillary, pubic)
Infertility
Hot flushes, sweat
Gynaecomastia
Small testis (<5ml)
Low bone density
Low energy, motivation, mood, insomnia
Reduced muscle bulk, increased body fat, reduced physical performance
Conditions related to high prevalence of low testosterone
Sellar/pituitary mass
Drugs – opioids, glucocorticoids
HIV-associated weight loss
ESRF & haemodialysis
Moderate to severe COPD
Infertility
Osteoporosis or low trauma fracture (especially young men)
Type 2 DM and metabolic syndrome
Androgen Deficiency Syndrome – Testosterone Therapy in Men (The Endocrine society Guidelines 2013) Hypogonadism is a clinical
syndrome due to failure of testosterone production from testis
Primary hypogonadism : low T, raised FSH/LH, impaired spermatogenesis
Secondary hypogonadism: low T, low or low-normal FSH/LH, impaired spermatogenesis
Lab levels should be done at a reliable lab with accurate assay
Testosterone therapy Endocrine Society Clinical Practice Guidelines
ONLY established indication is for CLASSICAL HYPOGONADISM
Clinical signs & symptoms of androgen deficiency & abnormal lab
Goal: to restore normal level of TT formulations (NZ) Preparation Dosages
T undecanoate 40mg capsules (Andriol testocaps)
40-80mg BD (after meals)
T undecanoate 250mg/ml (Reandron) 1000mg initially, then 100mg @ 6wk, f/by 1000mg every 10-14wks
T esters 250mg/ml (Sustanon) 250mg every 3-4 wks or 50-100mg weekly
T cypionate 100mg/ml (Depo-T) 100-200mg every 2wks or 50-100mg weekly
T transdermal patches 2.5mg/day (Androderm) 2.5-5.0mg/day
Illustrative Case 1
64-yr old man with poor libido, reduced sexual function & energy level
Weight gain 10kg over last 5 years
Poor dietary habit, no exercise
No sleep apnoea
PMH: T2D x6yrs (A1c 9%); HTN, hyperlipidemia, CAD
Meds: metformin, SU, statin, ACEi, aspirin
BMI 31kg/m2, central obesity
Normal male pattern hair, testes 20mls, no gynecomastia
Loss of muscle bulk, no visual field deficit
Case 1 - investigations
Morning Testosterone levels 7.4 and 7.8 nmol/L (ref: 10-28)
SHBG 24 nmol/ (ref: 13-71)
Free testosterone 160 pmol/L (ref: 230-610)
LH 4.3 IU/L (ref:1-10); FSH 3.7 IU/L (ref: 1-10)
Prolactin, TFTs – normal
Pituitary MRI not preformed
Case 1 – does he have hypogonadism?
- how would you manage him? No evidence suggesting organic hypothalamic-pituitary-testis axis
pathology
Sexual symptoms & low T levels meet criteria for late onset hypogonadism (LOH)
Likely functional low T state
Could be reversible with lifestyle intervention & weight loss
Outcome: trial of lifestyle intervention & weight loss. After 10 months he lost 11kg, repeat T 11.1 nmol/L, A1c improved to 6.8% reported improving energy level and sexual function
T replacement in late onset hypogonadism (LOH)
Risk-benefit ratio of T for men with LOH is unknown
Most of the men with LOH have functional, non-destructive suppression of HPT axis
Non-specific symptoms
Borderline low T
Priority – diet control; weight loss; optimize co-morbidities (depression, sleep apnoea, diabetes); remove offending drugs (steroid, opioids)
Testosterone therapy - monitoring
Evaluate symptoms, adverse effects, compliance
Serum testosterone : 2-3mth after start, then 3-6mthly. Morning level. Midway between injections or towards end of cycle [Anytime for transdermal]
PSA
Haematocrit – stop T if Hct>54% (risk of VTE)
Bone density if osteoporotic/had fracture
Worsening of sleep apnoea
Cardiovascular risks
Menopause & Premature Ovarian Insufficiency
Average age of natural menopause 51yrs
3% women go through menopause prior to age 40
~25% women going through natural menopause will have severe symptoms which severely compromise their quality of life (QoL)
As life span expands, women more likely to spend 1/3 of their live post-menopause
Case 2
49yr woman presented with severe hot flushing and night sweats for 18 months. She is unable to sleep & that’s making her tired & depressed. She is a business executive and has a busy, full time job. She has BMI of 32 & T2D, which is diet-controlled
Q1: What Ix you wish to do?
Q2: Is it unusual for women to present with vasomotor sx prior to menopause & are they significant?
Q3: She is desperate for an effective tx. What would you recommend?
Q4: Are there aternatives if she refuses HRT?
Q5: Will the HRT has any effect on her diabetes?
Barriers to practice
Major publications in early part of this century changed the attitude towards HRT
Interest in menopause problems decreased significantly, but problems hadn’t changed
Generation of young physician who have no idea about problems of menopause and how to help women, should they require it
Women are often told to live with it…
Review of Menopause – Short Term Symptoms
Mood disorder
Vasomotor symptoms
Sexual problems
Musculoskeletal problems
Vulvo-vaginal atrophy
VSM : commonest sx in West, 25% of women, usually lasts 2-3yrs, some will have it persists for many years, obese, depression, sleep problems
In Eastern cultures, musculoskeletal sx more common (?cause)
Menopause – Short Term Symptoms : Diagnosis &
Management FSH assessment rarely valuable in women >45yrs
FSH rise may last up to 4 years, considerable fluctuations can occur
Treatment should start after symptoms investigations
Hormone replacement therapy (HRT) Extremely effective for VSM & mood problems
Dramatic effect on hot flushes (85% will get better!!!)
HRT should be first line tx for VSM unless clear contraindications
Lowest possible dose
Shortest possible duration
Menopause – Long Term Symptoms : Management
Osteoporosis
Cardiovascular disease
Main controversy about use of HRT is weighing the risk & benefit
Women Health Initiative (WHI) trial
Timeline in long term HRT
Meta-analysis of 25 observational studies (1976-1996) showed reduction in risk of coronary heart disease, including Nurse’s Health Study (year 2000)
Women’s Heath Initiative (JAMA 2002) – 2 large RCT in more than 161,000 healthy postmenopausal women age 50-79 found INCREASED risk of cardiovascular complications and INCREASED breast cancer risk in both estrogen-only & estrogen-progestin group
Subsequent reassessment of WHI data led to different interpretation of the data, with focus shifted to “Timing of HRT” – (a) estrogen is beneficial in early phase of atherosclerosis. (b) long duration of HRT will increase risk of breast cancer. (c) efficacy of HRT in osteoporotic fracture remains undisputed.
Hormone replacement therapy (HRT)
Combined estrogen & progestogen (no hysterectomy)
Estrogen alone (hysterectomised women) – does not increase breast cancer risk
Most studies (JAMA 2004, Lancet 2003) showed ↑ breast ca risk in combined therapy
Diabetes/HTN – not contraindicated
Hypertriglyceridemia – caution as conjugated equine estrogen can ↑TG
Alternatives to HRT Selective Estrogen Receptor Modulator (SERM)
(a) Raloxifene – beneficial to treat postmenopausal osteoporosis
(b) Tibolone - great for VSM but high stroke risk
Antidepressants – SSRIs e.g. venlafaxine, fluoxetine (interfere with tamoxifen)
Clonidine for hot flushes (UK), barely better than placebo
Gabapentin – small clinical trials, very poor side effect profile
SOY-based products beneficial
Androgen (DHEA) replacement : no proven evidence-based benefit on sexual hypofunction
Case 2
49yr woman presented with severe hot flushing and night sweats for 18 months. She is unable to sleep & that’s making her tired & depressed. She is a business executive and has a busy, full time job. She has BMI of 32 & T2D, which is diet-controlled
Q1: What Ix you wish to do?
Q2: Is it unusual for women to present with vasomotor sx prior to menopause & are they significant?
Q3: She is desperate for an effective tx. What would you recommend?
Q4: Are there aternatives if she refuses HRT?
Q5: Will the HRT has any effect on her diabetes?
Case 3
Mrs AB is 59yrs, fit & slender (BMI 23). She has no major health issues. Her mother died following osteoporotic fracture. Mrs AB has been on HRT for vasomotor sx for 5 years, and she wishes to continue. She does not drink alcohol and takes calcium & vitamin D supplement
Q1: Are there health benefits that may outweigh the risk of breast cancer for this woman?
Case 4
25yrs old lady presented with 1 year of amenorrhoea. She had normal menstrual cycle since 14yrs. She has normal BMI (24). She partakes in regular but not excessive exercise No galactorrhoea. She has very severe hot flushing & vaginal dryness which distress her. Secondary sexual characteristics were normal
Q1: What Ix is required?
Q2: How should she be managed?
Q3: Is there any possibility she might become pregnant?
Premature Ovarian Insufficiency
Menopause before 40yrs
Distressing, ↑risk of CVD & osteoporosis later in life is significant
Causes: idiopathic, surgery, cancer treatment
Assessment: FSH, Anti-Mullerian hormone (AMH)-estimate of follicular reserve
HRT & Combined OCP are helpful (↑bone density, ↓fracture, improvement in CV risk factors)
Should be treated till the age of natural menopause
Local estrogen
Fertility issue is complex – pregnancy (wanted or unwanted) may happen if POI is incomplete
Main conclusions Women should be taken seriously about their menopausal problems
Women should not be told their menopausal problems “don’t kill them” and are of “no significance”.
Women should be aware of lifestyle measure & treatment options available
HRT’s pros & cons in treating short-term & long-term symptoms
Potential of breast cancer risk vs beneficial effects on symptoms/QoL
Women with vulvo-vaginal atrophy should be offered topical estrogen
Avoid in those with DVT, premature CAD, breast cancer
HRT remains beneficial for osteoporosis
POI – use HRT till natural menopause unless strong reason not doing so
Each woman should be treated individually
THANK YOU
Acromegaly
Rare, yet insidious
Affects 40-60 per million population
Common in 40s & 50s
Men = Women
Excessive growth hormone
99% from pituitary adenoma
Acomegaly – signs & symptoms
Specific symptoms Frontal bossing, prognatism,
widened nose
Poor biting, teeth spaced out
Enlarged tongue & lip – snoring, dribbling, daytime sleepiness
Enlarged hands & feet – increased shoes size, tight rings
Other symptoms Excessive sweating
Oilier, thicker skin
Carpal Tunnel Syndrome
Menstrual problems
Hypertenison
Diabetes
Arthritis
Acromegaly – Diagnosis
Serum IGF-1 – almost invariably raised
Oral glucose tolerance test (OGTT) – failure to suppress GH to <1mU/L in response to 75g glucose (normal response will be suppressing it to undetectable level)
Random growth hormone (GH) – often not useful
Pituitary MRI
GHRH level if pituitary adenoma is not apparent (e.g. GHRH-secreting carcinoid of lung or pancreas)
Diagnosis is often delayed therefore patients frequently accumulate long-term, disease-associated morbidities for extended time before diagnosis
Beware of variability of IGF-1 levels –extreme BMI, malnutrition, anorexia, severe liver disease, oestrogen use, poory controlled DM wil lower IGF-1 production
Acromegaly – treatment
Goals of therapy To lower GH & IGF-1
To minimize tumour compressive symptoms
To replace pituitary hormone deficiencies
Treatment modalities Surgical resection of pituitary
tumour
Medical therapy
1. Somatostatin analogues (Octerotide/Sandostatin LAR)
2. GH receptor antagonist (Pegvisomat)
3. Dopamine agnist (Cabergoline)
Radiation therapy