The Pharmacological Actions and uses of

Leuprolide (Lupron)®

By

Professor Kamal Eldin Hussein ElTahir

 College of Pharmacy,

King Saud University,

Riyadh 11451 P.O. Box 2457

Kingdom of Saudi Arabia

INTRODUCTION

Release of Gonadotropins:

In adults, the hypothalamus releases in a pulastile fashion a

decapeptide known as

Gonadorelin (Gn RH)

Pro – His – Try – Ser – Tyr – Gly – Leu – Arg – Pro – Gly –

NH2

Action: Releases FSH and LH in sequential manner.

Release during the menstrual cycle

The major functions of FSH:

(1) Stimulation of Growth and development of an ovarian follicle

(2) Stimulation of spermatogenesis

(3) Release of oestrogen

The major functions of LH:

(1) Release of the ovum

(2)Stimulation of progesterone synthesis

(3) Stimulation of testosterone

Release of Oestradiol and progesterone .

Major Functions of Oestradiol

1-Sensitization of the pituitary to the action of Gonadorelin

just before ovulation

2- Inhibition of Gonadorelin release during the luteal phase

3-Enlargement of the Breast .

4-Facilitation of implantation ……. + others.

1- Inhibition of Gonadorelin Release during the luteal pahse

2-Facilitation of the implantation .

3-Maintenance of pregnancy .

Major functions of progesterone

These are synthetic peptides with certain D- aminoacid

Substitution at position 6 in the natural Gonadorelin that

is Normally occupied by L-GLy.

These D- aminoacids may be Try, Leu, Ser …..etc.

This chemical change imparts to the peptide resistance

to enzymes degradation and a longer half-life instead

of the normal gonadorelin t ½ of 6 minutes.

Gonadorelins Analogs

Leuprolide [ Lupron]

This is one of the first analogs introduced. Its

chemical structure is :

5 - Oxo – Pro – His – Try – Ser – Tyr – D – Leu – L - Leu – Arg –

N – ethyl Prolinamide Acetate.

The t ½ of the non – depot product is = 3 h.

1-Initial activation of natural Gonadorelin pituitary Receptors to

stimulate release of FSH and LH. This may continue for one week

2- Then, depletion of FSH and LH from the Pituitary

No Development of ovarian follicle

No synthesis and release of oestrogen,

progesterone and Testosterone

No spermatogenesis

No ovulation.

3-Decrease in Gonadorelin Receptors and sensitivity in the Pituitary

i.e Down regulation

4- Decrease of FSH and LH Receptors in the ovaries and testes.

(All are Reversible)

Major Actions of [Lupron]

Lupron Depot 3.75mg (I.M.) Injection (Monthly)

Lupron Depot – 3Month 11.25mg (I.M.) Injection

Lupron Depot – 3Month 22.5mg

Lupron Depot – 4Month 30mg

Lupron Depot – 12 Month 65mg [Viadur]

Luporn Depot – Ped (I.M.) Inj. (Monthly)

Lupron Depot 7.5mg.

Leuprolide [ Lupron

]Pharmaceutical forms

Major uses of Lupron Treatment of

1) Endometriosis

2) Leiomyomata (Fibroids)

3) Polycystic ovarian Disease

4) Prostate Cancer

5) Precocious Puberty

6) Breast Cancer

7) Hirsutism

8) Contraception in females.

Other uses

(1) Induction of ovulation and in

vitro fertilization

(2) Treatment of male infertility

(3) Treatment of cryptorchidism

(4) Treatment of Delayed puberty

Endometriosis

Definition of Endometriosis:

It is an abnormal growth of endometrial cells. The cells can penetrate the myometrium and reach outside the uterus into the abdominal cavity. The organs affectedare: ovaries, fallopian tube, rectum, bladder .

The endometrial implants outside the uterus respond to the hormonal

Changes during the menstrual cycle as the endometrium does.

The Implants swell and shad blood into the abdominal cavity.

The implants stimulate scars and formation of Cysts that block the fallobian tubes and ovaries.

No ovulation.

Consequences

Possible Causes

• (1) Retrograde bleeding during menstruation. Some endometrial cells pass with the menstrual blood

via the fallobian tubes into the abdomen. They implant and grow. • (2)High incidence of vaginal and uterine Infections • (3) Oestrogen-induced cellular changes • (4)Genetical birth abnormalities. Some endometrial

sells may develop outside the uterus during foetal development.

Stages of Endometriosis

Stage Description of Endometriosis

• I Minimal / superficial

• II Mild with filmy adhesions

• III Extensive with dense adhesions

•  IV Very Extensive with dense adhesions

Symptoms of EndometriosisCyclic Symptoms with menstruation

• 1)    Painful menstruation with heavy flow and clottings.

• 2)    Painful Defection.• 3)    Painful Intercourse.• 4)    Infertility.• 5)    Nausea / Vomiting /Dizziness.• 6)    Low backache.• 7)    Insomnia + Fever.

Diagnosis Via

• 1)    Ultrasonography.

• 2)    Laproscopy.

• 3)    Detection of a Pelvic Organs Antigen known as CA-125 in high concentration.

Treatment of Endometriosis

• 1) Suppression of Menstruation and induction of endometrial atrophy via:

• a) Lupron Depot 3.75mg IM inj every month for + Norethindrone 5mg/day for 6 months.

• or Lupron depot – 3months 11.25mg• every 3month (To be repeated once) +

Norethindone 5mg/day for 6 months.• 2)Danazol 400mg 2× daily for 6-9 months. It is

an androgen !! It inhibits FSH + LH.

1)  Mdroxyprogesterone Suspension(Depo–provera) 150 mg every 3 months.

It inhibits gonadorelin.

2)  Surgical Removal of the endometrial implants in cases of advanced endometriosis.

3)  Laser Obliteration.

4)  Hysterecttomy.

Uterine Leiomyomas or Uterine Fibroid

• These are round – pinkish fibroid benign tumors found in the connective tissue and muscles of the uterine walls at various sites. They are composed of smooth muscles and fibrous tissue.

• They may be submucosal, intrestitail (within the walls of the uterus or subserosal. Their growth depends upon oestrogrns presence. Not present at menopause.

• The submucosal fibroids may project into the uterine cavity. They may cause infertility or re-current abortions. The interstitial ones may also prevent pregnancy.

• Rupture of the exophytic fibroids i.e. the subserosal one outside the uterus leads to intraperitoneal haemorrhages and hypovolemic shock.

Symptoms of Fibroids

• 1)    Heavy menstrual bleeding.• 2)    Post intercourse bleedings.• 3)    Bleedings between menstrual cycles.• 4)    Repeated abortions.• 5)    Low backache.• 6)    Anemia.• 7)    Infertility.

Causes of Fibroids

• No definite causes is reported.

• May be due to exposure to certain chemicals!!.

• They depend mainly on oestrogens for their growth

Diagnosis of Fibroids

• Via use of :• 1)    Ultrasonography.• 2)    Hysteroscopy (using a telescope via the

vagina and the uterus).• 3)    Laparoscopy (via a small incision into the

abdomen).• 4)    Hysterosalpinography (Injection of a dye

into the uterus and fallobian tube followed by X-ray procedure).

Treatment of Fibroids

• 1)  Induce a hypoestrogenic state to promote atrophy of the fibroids via use of :

(I.M.) Luprom Depot 3.75 mg / month for 3 months + Oral Ferrous sulphate 30 mg Fe / Day.

 • Or : Lupron Depot – 3 months 11.25 mg every

3 months (I.M. Injection) + Ferrous sulphate daily. + Analgesics.

• 2) Surgical Myomectomy to remove the fibroids from their location via use of

Laporoscopy.

• 3) Surgical Hysterectomy (removal of the uterus).

• (Severe psychological harm!!).

• Uterine Artery embolisation to prevent supply of fubroids with blood.

Polycystic Ovarian Disease Stein – Leventhal Syndrome

• Polycystic Ovarian Disease is an ovarian Disease Characterized by presence of > 8 fluid filled sacs (Cysts) in one ovary.

Symptoms of PCOD

• 1)    Hirsutism.• 2)    Absence of ovulation – (amenorrhea) (Infertility)• 3)    Dysfunctional uterine Bleeding.• 4)    Decreased Breast Size.• 5)    Obesity.• 6)    Acne.

Homonal Disturbances in PCOD

• 1)    High Release of LH.

• 2)    Excessive Testosterone Production by the ovaries.

• 3)    Low levels of Progesterone + FSH.

• 4)    High Ratio of Androstendione / oestradiol.

• 5)    Excessive Insulin Release.

• Desensitization of Insulin Receptors.

A rom atase

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Diseases Associated with PCOV

• 1) Diabetes mellitus.

• 2) Hypertension

Diagnosis of PCOS

• 1)    Pelvic Ultrasonography.

• 2)    Presence of high level of:

• Testosterone, Insulin, LH, Androstendione high ratio of LH/FSH (3:1) and Androstendione / Oestradiol

Treatment of PCOS

• Suppress the Release of LH and Testosterone• 1)  Lupron Depot 3.75mg I.M. Inj. / month for

6 months.• Or Lupron Depot 3-month 11.25 mg (I.M.

Inj.) every 3 months.• 2)  Norethindrone : 5-20 mg / day for 10-14

days every month.• 3)  Oral Contraceptive + Flutamide 250mg 2×

daily for 10 days.

4- Ovarian Cauterissation via:

Laser Vaporization (Laparoscopically)

[But excessive adhesions around the ovary].

5- Surgical Removal of the Ovary.

Problems Associated with prostate

• 1- Prostate Hypertrophy

This is a Benign Disease. It is enlargement of the gland leading to obstruction of urine flow

2-Prostate Cancer

It is an Adenocarcinoma

i.e.Carcinoma (malignant tumor of a glandular tissue 5% may be sarcomas (Tumor in the connective tissue).

Predisposing Factors of prostate Cancer

1. Genetical Factors.

2. Exposure to certain chemicals. e.g. Arsenic, Diethylstilbesterol, Cigarette smoke, Cadmium

3. Exposure to Radiations, e.g. Sun, X-rays.

4. High fat diets

• 5- Increase in Testosterone Synthesis.

• 6- Super sensitivity of prostate Testosterone receptors.

• 7- Increase in the activity of the enzyme 5-α Reductase [Gene Mutation]

• Testoterone 5-α Reductase→ 5-α Dihyrotestosterone.

Growth and Differentiation of the Prostate and its Cancer depends

upon Dihydrotesterone

Grades of Prostate Cancer

• Depends upon cell Differentiation i.e. Differentiated cells of the tumor are similar to the normal prostate cells.

Grades [Gleason Scale]

Grade Description

2                   Tumor cells are well Differentiated

(Slow Growth)

4-6 Intermediate Differentiation

8-10 Poor Differentiation (rapid growth).]

Types of Prostate CancerWhitemore Classification [American Urologic system]

Class Description

A1 Focal in gland

A2 Diffuse in gland

B1 One small nodule in one lobe of gland

B2 Diffuse big nodules in the whole gland

Class Description

C1 No Involvement of Seminal vesicles

C2 Involvement of Seminal vesicles

D1 Spread to Ureter (Obstruction)

D2 Spread to Bones or soft tissues

TNM Classification of Prostate Cancer i.e. Tumor – Nodes – Metastases(Spreading)

Class Description

T1 Tumor within the prostate capsule

T2 Tumor extended to the prostate capsule

T3 Invasion of Seminal vesicles

T4 Spreading to other near structures

Nodes – Classification Class Description

N1 One Node is affected

N2 > 1 node is affected

N3 Free Space between gland and Pelvis

N4 Involvement of Regional Lymph nodes

Metastases Classification

Class Description

M1 Spread of Tumor to bones,Urinary bladder, Urethra, Pelvis via Blood or Lymph

Symptoms in Case of Stages C + D

• 1)   Dysuria

Difficult painful Urination

(Intermittent urinary stream)

• 2)   Increase in Urinary frequency.

• 3)   Pain in Bones.

• 4)   Hematuria or Blood in Semen.

5) Fracture of Bones e.g. spine, pelvis, ribs…..etc.

Diagnosis of Prostate Cancer

• 1)   Transrectal Ultrasonography.• 2)   Transrectal Biopsy to obtain a prostate specimen.

3) Detection of high level of the prostate specific glycoprotein Antigen > 6.5 ng / ml (use Immunoassays).

• N.B. Not highly specific for prostate Cancer but also indicates BP Hypertrophy and acute prostatitis.4) Increase in Plasma alkaline Phosphatase (Indicates involvement of Bones)

Treatment of Advanced Prostate Cancer

Inhibition of LH and Testosterone Release.• 1)   Lupron Depot 7.5mg / mont.

May be combined with Flutamide 250mg 2-3× daily.

• 2)   5-α Reductase Inhibitors e.g. Finastride.• 3)   Cyclophosphamide [Endoxan] (Poor Response)• 4)   Radiation for stages A-C.

Prostatectomy ( But → Impotence)

Responses to various Therapies of Prostate Cancer

Treatment % Effectiveness

Lupron Depot 70-90

Cyclophosphamide (& other chemotherapies)

10-45

Radiations 75-80

Anti-androgens (e.g. flutamide)

varaiable

Precocious Puberty

• Precocious puberty is early sexual maturity in children before ages of 8-9 years, due to excessive sex hormones release. Its signs are:

• In Boys Appearance of facial and pubic hairDeepening of voiceEnlargement of the penis and testes

Acne.

In Girls :

Development and Enlargement of Breast

Appearance of Pubic and axillary hair.

Onset of Menstruation.

Acne.

Problems Associated with PP

• 1)   Psychological Disturbances.

• 2)  Premature Closure of the epiphyseal plates of the long bones.

:. Rapid ending of skeleton growth.

:. Short Children.

• 3)   Below normal uterus size.

Types of precocious Puberty

• 1-Central involving the Hypothalamus, Pituitary and gonadal axis due to tumors or head injuries.

2-Peripheral due to tumors in the Gonads.

Diagnosis of PP

• High level of Testosterone in boys

• High levels of Oestradial and progesterone in girls

Treatment of Central type

• 1)   Lupron (Leuprolide) Subcutaneously in a dose of 20-50µg / Kg / day for 1 year.

• 2)    Flutamide in Boys.

• 3)    Medoxyprogesterone in girls.

Breast CancerBreast Cancer

• Predisposing Factors: • 1- Mutation in gene BRCAI in chromosome

17q 12-21.• 2-  Oestrogen use by post menopausal women.• 3-  Intake of heterocyclic amines present in grilled

or fried meat.• 4-  Upper body obesity (↑ in free oestrogen).• 5-  Alcohol intake. • 6-  Exposure to Radiation.

Signs of Breast Cancer:

• 1-  Presence of a solitary, hard, non-mobile painless lump.

• 2-  There may be nipple discharge. It is stimulated by circulating oestrogens.

Diagnosis: Via

• 1-      Mammography

• 2-      Breast ultrasonography

 

• 3-      Needle Breast Biopsy

Stages of Breast CancerStages of Breast Cancer

Stage Description of tumor 

I Small localized primary

II Small primary (with involvement of a lymph node)

III Large tumor with involvement of various lymph nodes.

IV Breast tumor with spreading metastases to skin, bone, liver, lungs…etc

Treatment of Breast Cancer:

• 1-  For stages, I, II and III, Partial – segmental or total Mastectomy alone or plus Radiation.

• 2- Or Single or combined chemotherapy with cyclophosphamide, methotrexate and / or 5- flurouracil (but bone marrow depression).

• 3- Tamoxifen [Nolvadex] 20 mg/day orally for up to 5 years. It blocks oestrogen receptors in the breast.(Vaginal Bleeding + Hot flashes + hypercalcaemia)

• 4- For stage IV, Lupron 7.5mg per day S.c. injection for 28 days to suppress ovarian oestrogen synthesis plus Tamoxifen.

• 5- Paclitaxel [Taxol] 175 mg/m2 every 21 days. (But vertigo + tachycardia + ↓ of Respiration).

Side effects of LupronSide effects of Lupron

• Headache, Hot flashes, sweating,• Decrease in libido, erection dysfunction,• Decrease in Bone density,• Nervousness, depression, insomnia,• Decrease in Breast size,• Increase in blood cholesterol and triglycerides,• Slight increase in the hepatic enzyme,• Serum Glutamate Pyruvate Transaminase

• All These side effects are reversible.

• Pituitary function is restored 3 months following the end of the duration of the last dose

• Use during pregnancy: • It is labeled as category (X. (Definite foetal risk).

• Metabolism: • Via enzymatic Degradation to di, tri-and

pentapeptides• Protein Binding: 43 – 49%• Effective Plasma Concentration: 0.2 – 0.3 ng/ml.