Transcript Updates on Endocrinology 2014 ACMA Biennial Conference

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