PRINCIPALES OF HORMONE

REPLACEMENT THERAPY
E & M module

Professor Priyadarshani Galappatthy

Professor of Pharmacology
 OBJECTIVES
• WHAT IS HORMONE REPLACEMENT THERAPY?
• DIFFERENCE BETWEEN PHARMACOTHERAPY WITH
HORMONES AND HORMONE REPLACEMENT THERAPY
WITH EXAMPLES
• EXPLAIN THE GENERAL PRINCIPLES OF HRT
• CONDITIONS WHERE HRT IS USED AND SOME
PRACTICAL POINTS
 HRT
• HRT= HORMONE REPLACEMENT THERAPY
• OFTEN TERM ‘HRT’ IS USED TO IMPLY POST
MENOPAUSAL HORMONE REPLACEMENT THERAPY (
WHICH IS ONE OF THE HRTS)
• IN THIS LECTURE HRT WILL BROADLY REFER TO
REPLACING ESSENTIAL HORMONES IN DEFICIENCY
SITUATIONS.
 HORMONE REPLACEMENT THERAPY

• HORMONE REPLACEMENT THERAPY IS

REPLACING THE MISSING HORMONE OR
HORMONES IN A WAY TO MATCH THE
PHYSIOLOGICAL SECRETION AS MUCH AS
POSSIBLE, IN CONDITIONS WHERE
HORMONE DEFICIENCY PERSISTS.
PHARMACOTHERAPY WITH HORMONES
• USED TO SUPPRESS ANOTHER HORMONE OR
PROCESS WITH HIGHER THAN PHYSIOLOGICAL
LEVEL OF THE HORMONES.(HIGHER DOSE USED)
• OFTEN NO DEFICIENCY OF THE HORMONE.
• NEEDS MORE CLOSE MONITORING AS PRONE TO
MORE SIDE EFFECTS
NAME THE SITUATIONS OF PHYSIOLOGICAL
HORMONE REPLACEMENT
• THYROXINE 200 MCG GIVEN IN A 50 KG FEMALE
PATIENT WITH PAPILLARY THYROID CARCINOMA
• HYDROCORTISONE 20 MG DAILY GIVEN FOR A
PATIENT WITH HYPOPITUITARISM
• DEXAMETHASONE 4 MG GIVEN TO A PATIENT WITH
CEREBRAL ODOEMA
• OESTROGEN AND PROGESTERONE GIVEN FOR
CONTRACEPTION
 REPLACEMENT DOSES VS
PHARMACOLOGICAL DOSES
PREDNISOLONE
• REPLACEMENT DOSE 5-7.5 MG/DAY
• ANTI-INFLAMMATORY DOSE 30-60 MG/DAY
THYROXINE
• REPLACEMENT DOSE-75-100 MCG/D
• TSH SUPPRESSION IN THYROID MALIGNANCY-200-
300MCG/D
 HRT
• IN GENERAL, ENDOCRINOLOGY HAS BEEN
EXTREMELY SUCCESSFUL IN THE TREATMENT OF
DISEASES CAUSED BY ENDOCRINE INSUFFICIENCIES.
• PREVIOUSLY LETHAL DISEASES SUCH AS ADRENAL
INSUFFICIENCY, TYPE 1 (INSULIN-DEPENDENT)
DIABETES MELLITUS AND HYPOTHYROIDISM, HAVE
BEEN SUCCESSFULLY TREATED FOR MANY DECADES.
 ADVANTAGES OF HRT

• REPLACE THE EXACT HORMONE WHICH IS

MISSING OR THE DOWNSTREAM
HORMONE WHICH IT REGULATES
• DRAMATIC RESPONSE TO THERAPY
• LIFE SAVING
• IMPROVES QUALITY OF LIFE
• LOW COST (SOME EXCEPTIONS)
TYPE 1 DIABETES
Addison’s disease
ADDISON’S DISEASE
 WHAT ARE THE ENDOCRINE
CONDITIONS WHERE HRT IS USED?
• HYPOTHYROIDISM
• TYPE 1 DIABETES
• ADDISON’S DISEASE
• HYPOGONADISM IN MEN AND WOMEN
• GH DEFICIENCY
• HYPOPITUITARISM
• VITAMIN D DEFICIENCY
• HYPOPARATHYROIDISM
• DIABETES INSIPIDUS
 HORMONE REPLACEMENT VS.
HORMONE SUPPRESSION
• CORTISOL DEFICIENCY CORTISOL EXCESS
 IS ENDOCRINE TREATMENT MORE EFFECTIVE
FOR REPLACING OR SUPPRESSING
HORMONES?
• ADDISON’S DISEASE -
• CUSHING’S DISEASE

• TYPE 1 DIABETES
• INSULINOMA

• HYPOTHYROIDISM
• HYPERTHYROIDISM

• GH DEFICIENCY
• ACROMEGALY
 PRINCIPLES OF HRT

• REPLACE EXACT MISSING HORMONE OR

• WHEN MULTIPLE HORMONES ARE MISSING
REPLACING LOWEST EFFECTOR HORMONE DOWN
THE AXIS
• EVEN WHEN STABLE, MAY NEED DOSE ADJUSTMENT
TO MEET EXCESS DEMANDS WHICH MAY OCCUR
TIME TO TIME
 PRINCIPLES OF HRT

• HORMONE DEFICIENCY Replacement hormone

• TRH DEFICIENCY Levothyroxine

• TSH DEFICIENCY
Levothyroxine

Levothyroxine
• THYROXINE DEFICIENCY
 Condition Missing Hormone Replacement Therapy

Hypothyroidism

Hypoparathyroidism

Addison’s disease

Type- 1 Diabetes

GH deficiency

Vitamin D defficincy

Diabetes Insipidus

Hypopitiutarism
 Condition Missing Hormone Replacement
Therapy
Hypothyroidism T4 and T3

Hypoparathyroidism PTH

Addison’s disease Cortisol,Aldosterone

Type- 1 Diabetes Insulin

GH deficiency GH

Vitamin D defficincy Vitamin D

Diabetes Insipidus ADH

Hypopitiutarism ACTH cortisol

TSH T4/T3
LH/FSH Testo/Oestro
ADH GH
 Condition Missing Hormone Replacement Therapy

Hypothyroidism T4 and T3 Levothyroxine

Liothyronine ?

Hypoparathyroidism PTH Calcium/Activated Vit D (PTH)

Addison’s disease Cortisol, Hydrocortisone

Aldosterone Fludrocortisone

Type- 1 Diabetes Insulin Insulin

GH deficiency GH GH

Vitamin D deficiency Vitamin D Vitamin D

Diabetes Insipidus ADH Vassopressin/Desmopressin

Hypopitiutarism ACTH Hydrocortisone

TSH Levothyroxine
LH/FSH Testo/Oes+ proges
ADH Vassopressin/Desmo
GH GH
 PRINCIPLES OF HRT
• NEEDS MONITORING AND FOLLOW-UP TO SEE
OVER REPLACEMENT OR UNDER REPLACEMENT
WILL NOT OCCUR
SIDE EFFECTS OF EXCESS HRT
• THYROXINE-SYMPTOMS OF HYPERTHYROIDISM
• INSULIN- HYPOGLYCAEMIA
• HYDROCORTISONE- IATROGENIC CUSHING’S
SYNDROME
 TASK

DISCUSS THE PHYSIOLOGICAL PATTERNS OF

HORMONE SECRETION OF
• CORTISOL
• GH
• INSULIN
 TRY TO MATCH THE BODY’S NATURAL RHYTHM OF
HORMONE SECRETION

• CORTISOL SECRETION

• HOW SHOULD BE HYROCORTISONE GIVEN TO MATCH THIS?

GH SECRETION
TRY TO MATCH THE BODY’S NATURAL RHYTHM
OF HORMONE SECRETION

HOW SHOULD INSULIN BE GIVEN IN TYPE 1 DM?

 CONSIDER THE INFLUENCE OF OTHER HORMONES
WHEN MULTIPLE HORMONES ARE GIVEN

• ALWAYS NEEDS TO BE CONSIDERED.

• SOME HORMONES MAY INCREASE METABOLISM OF
OTHERS
• E.G- THYROXINE INCREASE METABOLISM OF CORTISOL
• SOME HORMONES MAY INCREASE THE RESISTANCE TO
OTHER HORMONES.
• HIGHER DOSES OF GH NEEDED WHEN OESTROGEN
REPLACEMENT IS STARTED.
EFFECT ON COMORBID CONDITIONS ON
HRT
COMORBID CONDITIONS SHOULD BE TAKEN INTO
CONSIDERATION BEFORE HORMONE REPLACEMENT
• THYROXINE REPLACEMENT IN IHD
• OESTROGEN REPLACEMENT -HISTORY OF BREAST
CANCER
• TESTOSTERONE REPLACEMENT –HISTORY OF PROSTATE
CANCER
 HYPOTHYROIDISM
• REPLACEMENT WITH LEVOTHYROXINE (T4)
• DOSE CALCULATED ON BODY WEIGHT
• BUT OTHER FACTORS MAY INFLUENCE
• MONITORING NEEDED
• ONCE STABLE, LESS FREQUENT MONITORING.
• ADVERSE EFFECTS ARE RARE WITH PROPER DOSE.
• BODY SECRETE T4 (80%) AND T3 (20%)
• NO ROLE OF T3 REPLACEMENT AT PRESENT
• EVEN WHEN STABLE NEED DOSE ADJUSTMENTS TO MEET
EXCESS DEMANDS- PREGNANCY
 GROWTH HORMONE DEFICIENCY & GH
REPLACEMENT
• MAINLY IN CHILDREN WITH SHORT STATURE
• ADULT GH DEFICIENCY MAY BE LINKED TO EFFECTS ON
ANABOLISM, LIPOLYSIS, AND CARBOHYDRATE
METABOLISM.
• ADULT GH DEFICIENCY PATIENTS OFTEN COMPLAIN OF
DIMINISHED STRENGTH AND EXERCISE CAPACITY AND LOW
QUALITY OF LIFE THAT MAY IMPROVE WITH GH THERAPY
• COST IS THE MAJOR BARRIER IN ADULT GH REPLACEMENT
 CORTISOL REPLACEMENT
• CORTISOL IS ESSENTIAL FOR LIFE --ADRENAL CRISIS
• BOTH IN PRIMARY (ADDISON DISEASE) AND
SECONDARY HYPOCORTISOLISM
• EXCESS REPLACEMENT -IATROGENIC CUSHING’S
• HYDROCORTISONE IS THE STEROID PREPARATION OF
CHOICE
• ADDITIONAL MINERALOCORTICOID REPLACEMENT
NEEDED ONLY IN PRIMARY ADRENAL FAILURE.
• TIMING?
• WHEN TO INCREASE THE DOSE?
 CORTISOL REPLACEMENT
HOW TO ADJUST THE DOSE
• PATIENT SYMPTOMS
• PRESENCE OF ANY ADVERSE EFFECTS
• INVESTIGATIONS- CORTISOL DAY CURVE ,TSH
 TESTOSTERONE REPLACEMENT

• WHAT IS THE INDICATION?

• CAN WE USE TESTOSTERONE
REPLACEMENT TO TREAT
INFERTILITY IN MALES ?
 TESTOSTERONE REPLACEMENT
• HYPOGONADISM IN MEN LEADS TO LOW ENERGY
LEVEL, LOSS OF LIBIDO, LOSS OF SECONDARY SEXUAL
CHARACTERISTICS, DECREASE SEXUAL FUNCTION,
OSTEOPENIA, REDUCE MUSCLE MASS AND STRENGTH
AND REDISTRIBUTION OF BODY FAT
• THERAPY DOES NOT CONFER FERTILITY OR STIMULATE
TESTICULAR GROWTH
• IF FERTILITY IS DESIRED AND IF IT IS SECONDARY
HYPOGONADISM FSH AND LH IS USED
 TESTOSTERONE REPLACEMENT
• TESTOSTERONE GIVEN AS
• DEEP IM INJECTIONS-TESTOSTERONE ENANTHATE INJECTION
250 MG EVERY 3-4 WEEKS/
• 3 MONTHLY TESTOSTERONE INJECTIONS ARE AVAILABLE
• TESTOSTERONE GEL AND TRANSDERMAL PATCHES AVAILABLE
(MORE PHYSIOLOGICAL)
• ORAL TESTOSTERONE –VARIABLE ABSORPTION/SE
 TESTOSTERONE REPLACEMENT

• MONITORING-
• TESTOSTERONE TROUGH LEVELS-
BEFORE NEXT INJECTION
• HAEMATOCRIT
• PSA LEVELS (ELDERLY)
 OESTROGEN REPLACEMENT
• PRIMARY AND SECONDARY HYPOGONADISM IN
FEMALES CAN BE TREATED WITH OESTROGEN.
• OESTROGEN SHOULD ALWAYS BE COMBINED WITH
PROGESTERONE IN A WOMEN WITH INTACT UTERUS.
• OESTROGEN PROGESTERONE THERAPY CAN’T RESTORE
FERTILITY
• IF SECONDARY HYPOGONADISM FERTILITY CAN BE
RESTORED WITH GONADOTROPHIN (FSH/LH)
REPLACEMENT OR PULSATILE GNRH THERAPY
 OESTROGEN REPLACEMENT

• LESSER RISK IF PHYSIOLOGICAL PATTERN IS

FOLLOWED.
• LOW RISK OF HRT RELATED SIDE EFFECTS IN
PREMATURE OVARIAN FAILURE GROUP
COMPARED TO POST MENOPAUSAL GROUP
 TYPES OF POST-MENOPAUSAL HRT

1.OESTROGEN ALONE

2.OESTROGEN + PROGESTERONE

3.OTHER (SERM, TIBOLONE)

 DRUGS USED IN PM-HRT
Tibolone-
• SYNTHETIC STEROID, TISSUE SPECIFIC HRT
• BINDS TO PROGESTERONE & ANDROGEN RECEPTORS
• ADDITION OF PROGESTERONE NOT REQUIRED

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS)

E.G. RALOXIFENE
• EITHER OESTROGEN RECEPTOR AGONISTS OR
ANTAGONISTS IN A TISSUE-SELECTIVE MANNER
• NO RISK OF BREAST AND ENDOMETRIAL CA
• INCREASES BONE MINERAL DENSITY
• NOT EFFECTIVE FOR VASOMOTOR SYMPTOMS
 DRUGS USED IN PM-HRT
1) Oestrogens-
• ORAL: -
• CONJUGATED EQUINE OESTROGEN,OESTRADIOL
VALERATE,ETHNYL OESTRADIOL
• TRANSDERMAL (OESTRADIOL): -
• PATCHES: TWICE WEEKLY.
• GEL
• SUB CUTANEOUS IMPLANT (OESTRADIOL)
• 6 MONTHLY.
• VAGINAL: CREAM/RING
• COMPARE THE ADVANTAGES AND
DISADVANTAGES OF DIFFERENT
OESTRAGEN DOSAGE FORMS
 DRUGS USED IN PM-HRT
2) Progestins:
— ORAL ROUTE –.
— MEDROXY PROGESTERONE ACETATE: 10MG/DAY.
— NORETHISTERONE ACETATE : 0.7 – 2.5 MG/ DAY.
— NORGESTROL: 150 MG /DAY.
— MICRONISED PROGESTERONE: 200 MG /DAY.
— DYDROGESTERONE: 20 MG / DAY.
— HORMONE RELEASING INTRA UTERINE SYSTEM –.
— LEVONORGESTREL: 20 MCG / DAY.
— VAGINAL - NATURAL PROGESTERONE GEL / PESSARY.
— TRANSDERMAL - SEQUENTIAL / CONTINUOUS PATCH.
 HOW IS PM-HRT GIVEN?
Continuous Estrogen
Uterus
Estrogen
No tablet break
No bleeding as no uterus

CONTINUOUS SEQUENTIAL HRT

Estrogen
Progestogen
Day 14 Sequential therapy without tablet break
Uterus Regular bleeding at end of cycle

Continuous Combined HRT

Estrogen
Progestogen
Day 14 Combined therapy without tablet break
No bleeding at end of cycle

De Villiers TJ et al. Climacteric 2013;16:316–337.

.
 ADVERSE EFFECTS OF PM-HRT
• BLEEDING PROBLEMS: HEAVY / PROLONGED BLEEDING ON
SEQUENTIAL THERAPY –
• NAUSEA, VOMITING
• BLOATING, WEIGHT GAIN ,FLUID RETENTION
• MOOD SWINGS (ASSOCIATED WITH USE OF RELATIVELY
ANDROGENIC PROGESTOGENS) FATIGUE, DEPRESSION,
IRRITABILITY, ANXIETY, AND FORGETFULNESS
• BREAST TENDERNESS
• PROMOTE OESTROGEN DEPENDANT CANCERS
• VENOUS THROMBOEMBOLISM
 POST MENOPAUSAL HRT
RECENT ADVICE AFTER WHI STUDY
• POSSIBLE BENEFITS
• PREVENTION OF OSTEOPOROSIS
• FRACTURE RISK
• RELIEF OF MENOPAUSAL SYMPTOMS
• REDUCED COLORECTAL CANCER RISK
• POSSIBLE RISKS/PROBLEMS
ENDOMETRIAL CA IF UNOPPOSED OESTROGEN THERAPY GIVEN
WITHOUT CYCLICAL PROGESTERONE – DATA
• INCREASED RISK OF BREAST CA AND THUS ANNUAL SCREENING
NEEDED
• INCREASED RISK OF VENOUS THROMBOSIS
• CYCLICAL BLEEDING WHEN COMBINED WITH PROGESTOGENS
• INCREASED RISK OF CHOLECYSTITIS
CONTRAINDICATIONS OF CONVENTIONAL HRT
• A HISTORY OF BREAST CANCER
• A HISTORY OF ENDOMETRIAL CANCER
• SEVERE ACTIVE LIVER DISEASE
• HYPERTRIGLYCERIDEMIA
• THROMBOEMBOLIC DISORDERS
• UNDIAGNOSED VAGINAL BLEEDING
• ENDOMETRIOSIS
• FIBROIDS
 ADH DEFICIENCY
• DI IS THE CLINICAL PRESENTATION
DESMOPRESSIN
n DESMOPRESSIN: IV, IM,SC, ORAL, INTRANASAL
• ANALOG OF VASOPRESSIN
n ACT THROUGH V2 RECEPTOR INCREASE WATER
PERMEABILITY AND REABSORPTION IN THE
COLLECTING TUBULES
• MONITORING IS NEEDED AS WATER INTOXICATION MAY
OCCUR.
 HYPOPITUITARISM

• COMMONLY DUE TO A TUMOUR, TRAUMA, RADIATION OF

SURGERY
• MULTIPLE HORMONES MAY BE MISSING
• EFFECT OF EACH HORMONE ON OTHER SHOULD BE
CONSIDERED.
• FOR OPTIMAL RESULTS ALL MISSING HORMONES SHOULD
BE REPLACED
• MONITORING IS NEEDED TO EXCLUDE UNDER/OVER
REPLACEMENT
 HYPOPARATHYROIDSM
• PRIMARY TREATMENT IS BY CORRECTING THE
HYPOCALCEMIA BY ADMINISTERING CALCIUM AND
ACTIVATED VITAMIN D IN DIVIDED DOSES.
• TREATMENT TARGETED -SERUM CALCIUM LEVEL IN
THE LOWER PART OR SLIGHTLY BELOW THE LOWER
LIMIT OF THE REFERENCE RANGE
• RECOMBINANT HUMAN PARATHYROID HORMONE
(RHPTH[1-84],) IS COMMERCIALLY AVAILABLE IN
SOME COUNTRIES
 SUMMARY
• HRT HAS BEEN EXTREMELY SUCCESSFUL IN THE TREATING
HORMONE DEFICIENCY STATES
• MINIMUM SIDE EFFECTS WHEN CORRECTLY USED
• FOR OPTIMAL REPLACEMENT TRY TO MATCH NATURAL
SECRETION OF THE MISSING HORMONE
• MARKED IMPROVEMENT IN QOL, METABOLIC
PARAMETERS
• SHOULD CONSIDER EFFECTS OF OTHER HORMONES
WHEN MULTIPLE HORMONES ARE USED TOGETHER
 THANK YOU

• ANY QUESTIONS?