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Updates on Endocrinology (part 2) ACMA Biennial Conference 28/6/2014 Pui Ling Chan FRACP Endocrinologist MacMurray Specialist Centre 5 MacMurray Road, Remuera Outline Pituitary ACMA CME 16/3/2014 • Hypopituitarism Thyroid PCOS Diabetes Osteoporosis Reproductive • Testosterone replacement • Menopause management The pituitary – Master gland Hypopituitarism – causes Pituitary tumours Isolated pituitary hormone deficiency Parapituitary tumours – craniopharyngioma, meningioma, secondary deposits (breast, lung) etc 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 ImmunoDeficiency) 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) 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 (90120mins) 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 T T 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 postmenopause 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 & estrogenprogestin 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 Diagnosis is often delayed therefore patients frequently accumulate long-term, disease-associated morbidities for extended time before 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) 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 Treatment modalities To lower GH & IGF-1 Surgical resection of pituitary tumour To minimize tumour compressive symptoms Medical therapy 1. Somatostatin analogues (Octerotide/Sandostatin LAR) 2. GH receptor antagonist (Pegvisomat) 3. Dopamine agnist (Cabergoline) Radiation therapy To replace pituitary hormone deficiencies