Dr Miguel Debono MD MRCP PhD

Consultant Physician in Endocrinology and Acute Medicine and Honorary Senior Lecturer

May 2019

Optimal Management of Hormone Replacement in Hypopituitarism

Endocrine Society Guidelines October 2016

East Midlands Pituitary Day

Agenda

• Epidemiology of Hypopituitarism

• Individual Hormonal Deficiencies –• Monitoring and Treatment

• Hormonal Treatment Interactions

Epidemiology of Hypopituitarism

• Prevalence: 45 cases per 100000

• Incidence: 4 cases per 100000

Fernandez-Rodriquez Clinical Endo 2013 Appelman-Dijkstra JCEM 2011

Hormonal deficiency

Hypopituitarism post Stereotactic Radiosurgery

Simms-Williams et al 2019 Clinical Endo 90: 114 - 121

53% 75%

22% 30%

No

rmal

tyro

thro

ph

axis

No

rmal

axis

No

rmal

go

nad

al axis

No

rmal

go

nad

al axis

No

rmal

ad

ren

al

axis

New onset hypopituitarism 20 years after treatment

Diagnosis of Hypopituitarism

• 830am cortisol/ACTH +/-

Short Synacthen test

• TSH (only at diagnostic stage)/ T4

• FSH/LH/fasting 830 am testosterone, SHBG, oestradiol

• Prolactin (deficiency related to Sheehan’s or panhypopituitarism)

• IGF1, QOL AGHDA score, GH stimulation test

Epidemiology of Secondary AI

• Affects 150 – 280 per million inhabitants

Webb et al JCEM 1999 84: 3696 -3700

N = 234 patients88 new hormonal deficiencies in 52 patients

Post Pituitary Surgery Adrenal Insufficiency

Klose et al Clinical Endo 2005 63: 499 - 505

110

39Insufficient

71Sufficient

Preop

35

35

35

4

4

4

23

32

31

Postop

46

39

40Insufficient Sufficient Insufficient Sufficient

1 month

3 months

1 year

20% recovery of AI up to 5 years later

Munro Clinical Endo 2016

Secondary AI: Increased morbidity and mortality

• Mortality is increasedo Sherlock, JCEM 2009; 94: 4216

o Zueger, JCEM 2012; 97:1938

o Hammarstrand, EJE 2017; 177: 251

• Quality of Life is pooro Hahner, JCEM 2007; 92: 3912

o Bleicken, Clinical Endocrinology 2010; 72: 297

o Ragnarsson, EJE 2014; 171: 571

o Werumeus Buning, Neuroendoc 2016; 103:771

• Cardiovascular risk is elevatedo Filipsson, JCEM 2006; 91: 3954

o Werumeus Buning, 2016; 101: 3691

• Low Bone Mineral Densityo Ragnarsson, Clinical Endocrinology 2012; 76: 246

Monitoring Adrenal Status in Secondary AI

Pofi et al JCEM 2018; 103: 3050 - 3059

SST 30 minute cortisol >350nmol/L predicts recovery in 99%Delta cortisol >100nmol/L predicts recovery in 95%Morning cortisol >200nmol/l – good probability of recovery

N = 776 patients with reversible cause

In patients with no AI- Yearly 9am cortisol + monitor for symptoms- If > 200nmol/l and asymptomatic – repeat in 1 year- If <200nmol/l – do SST

(Yo Clinical Endo 2014)

Salivary cortisone: potential tool to assess for adrenal insufficiency – NIHR RfPB

Debono et al JCEM 2016; 101: 1469 - 1477

Thrice Daily Weight-Related HC

Total dose per day Patient Weight

(kg)

Total dose per day

(mg)

1stmorning dose

(mg)

2ndmidday dose

(mg)

3rdevening dose

(mg)

50-54 10.0 5.0 2.5 2.5

55-74 15.0 7.5 5.0 2.5

75-84 17.5 10.0 5.0 2.5

85-94 20.0 10.0 7.5 2.5

95-114 22.5 12.5 7.5 2.5

115-120 25.0 15.0 7.5 2.5

Patient Weight

(kg) (mg)

1stmorning dose

(mg)

2ndmidday dose

(mg)

3rdevening dose

(mg)

50-54 10.0 5.0 2.5 2.5

55-74 15.0 7.5 5.0 2.5

75-84 17.5 10.0 5.0 2.5

85-94 20.0 10.0 7.5 2.5

95-114 22.5 12.5 7.5 2.5

115-120 25.0 15.0 7.5 2.5

Mah et al., Clin Endo 2004,61,367-375)

• Monitoring: • Clinically • 4 hour cortisol level (Aim 150 – 350nmol/l)

0

100

200

300

400

500

600

700

800

900

1000

06 10 14 18 22 02 06

Time (24 Hour Clock)

Seru

m H

yd

roco

rtis

on

e (

nM

)

10 14 18 22 02 06

Absence of early morning (before wake-up)

exposure to cortisol

10mg

5mg

2.5mg

Current Hydrocortisone Replacement Therapy -Inadequate & Non-Circadian

Mah et al Clinical Endocrinology 2004; 61:367 - 375

Challenge: gut length and transit time

New Multiparticulate Chronocort® Formulation

Solution: multiparticulates

pH trigger coat (pH 6.8) allowing dissolution in the small bowel

Microcrystalline Bead

Hydrocortisone layer

Delayed Release Coat

Diurnal Chronocort®-006 (20mg nocte; 10mg mane) n=16 subjects

20 mg 10 mg

Geometric mean (10 – 90 th percentile)

Normative Data Chronocort®

AUC (0 – 24h) (nmol/l.h) 4697 (3560 - 6075) 5610 (4390 – 7974)

Peak cortisol (nmol/l) 594 (423 – 959) 665 (477 – 871)

Time of peak 07:52 (05:54 – 09:06) 8.5h (3.2h – 12.5h)

Whitaker et al Clinical Endocrinology 2014; 80: 554 - 561

Dual-Release HC - first once daily HC

Once dailyThrice daily

Johannsson et al., JCEM 2012; 97: 473 - 481

Immediate release

Slow release

20% lower bioavailability

Low Dose Prednisolone

Williams et al JALM 2016; 01: 152 - 161

Precipitating factors for adrenal crises

• N = 364

• 8.3 crises per 100 patient years

Precipitating factor Percentage

Gastroenteritis 23%

Fever 22%

Emotional stress 16%

Surgery 16%

Strenuous physical activity 9%

Omit glucocorticoid 4.3%

Cessation of glucocorticoid by doctor

1.7%

Cessation of glucocorticoidby patient

1.9%

Hahner et al JCEM 2015; 100: 407 - 416

Sick Day Steroid Rules • Extra steroid cover during acute illness, trauma or

surgery

• Double the normal daily steroid dose when patient has a temperature > 37.5oC

• If vomits/diarrhoea should take 20mg HC

immediately after and sip electrolyte fluids

• Severe illness (temp > 40oC or repetitive vomiting / diarrhoea) ask for medical help, administer 100mg HC im and hospital assessment

• Steroid cover is needed in surgery and labour

Central Hypothyroidism

• 50% of central hypothyroidism caused by pituitary macroadenomas

• Around 60 to 65% post pituitary surgery and after radiotherapy for brain tumours

• Low free T4 with a low, normal or slightly high TSH

• Aim T4 at upper half of range; dose 1.6 µg/kg/day

• Measure T4 before the morning dose

BM

IH

DL

TSH suff T4<13.1 T4 13 - 17 T4 >17

Low T4- High BMI- Low HDL- High TC- High TG- High WC

N=46N=54

N=54

Hypothyroidism and Cardiovascular Risk

N=54

Klose et al JCEM 2013; 98:3802 - 3810

High T4 levels- Increased vertebral fractures- Increased all-cause mortality- Increased CV events

pmol/l

Adult Growth Hormone Deficiency

• Annual incidence of 12 – 19 per million

• Assess for GH deficiency in those with high pretest probability

• Improvement in SMR on GH treatment especially in men

Pappachan et al JCEM 2015 100: 1405 - 1411

- 6 studies- 99, 000 person years follow up

GH Treatment

• Start at 0.2 – 0.4mg/day in <60y; 0.1 – 0.2mg/day in >60y

• Aim IGF1 to be slightly under the upper end of normal

• Monitor CV risk factors and QOL

• Side effects: arthralgia, myalgia, paresthesias, CTS, sleep apnoea, diabetes

Growth Hormone and Tumours

No relationship between GH treatment and cancer risk or pituitary tumour recurrence

Child et al EJE 2015 172: 779 - 790

SIRN= 8418 (treated) vs 1218Follow up 4.8 years

Growth Hormone and CV Risk Factors

Bo

dy F

at

WH

RN=43

Decrease- hsCRP- tPA- TC- VAT

Increase- HDL

Beauregard et al JCEM 2008 93: 2063 - 2071

Central Hypogonadism

• Effects 95% of patients with sellartumours and post surgery and RT

• Some related to hyperprolactinaemia

o Increase in body weight

o Decrease in lean body mass

o Abnormal lipid profile with increasing LDL and triglycerides

o Reduction in insulin sensitivity

(Levine et al Circulation 2010)

Cardiovascular Mortality and Hypogonadismin Females

N=1091 patientsN= 2383 controls

Su

rviv

al %

Age, years

Rivera et al 2009 Menopause 16: 15 - 23

HR: 0.65 HR: 1.84

Cardiovascular Mortality and Hypogonadism in Males

UntreatedN=218

TreatedN=449

Intact HPA axis

N=253

Sta

nd

ard

ise

d M

ort

ali

ty R

ati

o

Tomlinson et al Lancet 2001; 357: 425 - 431

Treatment of Hypogonadism - MenDose Monitoring

Nebido im injections(Testosterone undecanoate)

1g every 12 weeks

Trough levels

Testosterone gels(Tostran 2% or Testogel16.2mg/g)

30 – 80mg / day 4 hour levels

Restandol po capsules(TestosteroneUndecanoate)

40 – 120mg / day(twice daily)

Pre morning dose

Gonadotrophin sc injections HCG 2000Units three times / week

48 hours afterinjection

Monitoring: - Testosterone replacement: PSA and FBC at 6 weeks, 3 months, 12 months, yearly- Spermatogenesis: Testis size, sperm count and inhibin B

Treatment of Hypogonadism - FemalesFormulation Dose

Oral Oestradiol 1mg or 2mg Oestrogen only

Oral Oestradiol 1mg or 2mg with 1mg norethisterone or 10mg dydrogesterone

Sequential combined

Oral oestradiol 2mg with 1mg norethisterone or 1mg with 5mg dydrogesterone

Continuous combined

Transdermal oestradiol

0.06%gel – 2 measures Add other progesterone

Patches- 25 to 100µg twice weekly- 50micrograms with progesterone twice weekly

-oestrogen only

- Sequential or continuous combined

HRT Benefits and Risks To Remember –NICE Guidelines June 2018

• Risk for thromboembolism with transdermal formulations is similar to normal population

• When started under age 60 years are not at CV disease risk – CV risk factors should be treated

• Oral oestrogen has some risk for stroke

• HRT with oestrogen/progesterone increases risk slightly for breast cancer

• Risk for breast cancer will vary as per risk factors

Diabetes Insipidus

• Prevalence is of 7 – 10 per 100000 subjects

• Occurs in 10 to 30% of patients undergoing surgery and persists in only 2% to 7%

• Rare in non-operated pituitary adenoma

• Main causes:

o Usually craniopharyngioma or germ cell tumour

o Head trauma

o Infiltrative and inflammatory conditions

Treatment of Diabetes Insipidus

• In acute phase post-operatively use subcutaneous vasopressin on prn basis

• Decisions based on fluid input and output and biochemistry – serum osmolality/Na; urine osmolality/Na

Hormonal Interactions

• GH suppresses conversion of cortisone to cortisol therefore beware use of GH mainly in patients on cortisone

• GH reduces T4 levels and levothyroxine dose might need increasing; never assess for GH deficiency when hypothyroid

• Thyroxine enhances metabolism of glucocorticoids therefore treat AI before commencing levothyroxine

• Oestrogen raises cortisol binding globulin and thyroid binding globulins and reduces IGF1

• Glucocorticoids enhance free water secretion so AI might “hide” diabetes insipidus

Conclusion

• Morbidity and mortality is increased in hypopituitarism but hormonal replacement and careful management may increase longevity and improve QOL

• Well defined management pathways for long term follow ups are still not established

• Novel medications are in development to enable better physiological replacement and to improve compliance