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