Corticosteroids

Glucocorticoids

Pharmacological/Physiological actions of Glucocorticoids

Hormonal Replacement Therapy:

 Hormones are administered as a supplement to meat out deficiency of hormone in the body. They are used as a substitute for naturally occurring hormones. They are used to treat disease developed due to hormone deficiency.

·         Acute adrenal insufficiency: It is also known as an adrenal crisis. It may be due to untreated Addison's disease, bleeding from the adrenal gland, the sudden stop of glucocorticoids administration. Adrenal crisis is a life-threatening situation and it requires immediate medical attention. Cortisol is administered by IV route to treat adrenal crisis

·         Primary adrenal insufficiency (Addison’s disease): Adrenal cortex dysfunction, adrenal surgery, adrenal cortex lesion causes Addison's disease. Failure to treat Addison's disease may cause the death of a patient. It is treated with hydrocortisone.

·         Secondary and tertiary adrenal insufficiency: Defect in adrenocorticotropic hormone (ACTH) production from pituitary gland inhibits release of corticoids hormone synthesis and release from the adrenal gland. This is called secondary adrenal insufficiency. The defect in the release of corticotrophin release hormone from the hypothalamus that inhibits synthesis and release of corticoids hormone from adrenal gland is called tertiary adrenal insufficiency. These can be treated with hydrocortisone.

·         Cushing’s syndrome: Hypersecretion of glucocorticoids causes Cushing’ syndrome. It is mainly due to excessive release of corticotropin from the anterior pituitary gland and adrenal tumors. Synthetic glucocorticoids administration suppresses the release of corticotropin from the anterior pituitary gland. It does not suppress the release of corticotrophin from an adrenal tumor. It does not suppress adrenal tumor release of corticotrophin hormone.

·         Congenital adrenal hyperplasia: Enzymes are used to synthesize adrenal hormones. A defect in the synthesis of any one enzyme causes congenital adrenal hyperplasia. It is treated by corticosteroid administration.

  

              NON-Endocrinal Diseases Treatment

Oral Contraceptives

Sex Hormones

SEX HORMONES

Female sex hormones

Estrogens: Estrogens are produced ovaries and in pregnant women also by the placenta. It's level declines after delivery. It is also produced in small amount by testes. Very low level of estrogens is found in postmenopausal women. There are three naturally occurring estrogens:

·        

                                    Estradiol

·                                                          Estrone and

·                                                          Estriol (E3) also spelled Oestriol.

Estradiol is most potent Estrogen. It is in highest concentration during mid menstruation cycle. The liver metabolizes Estradiol to Estrone and Estriol. Estrogens are soluble in lipid and insoluble in water. They are dissolved in water before administration. They are rapidly absorbed from intact skin, mucous membrane and GIT.

Natural estrogens, their conjugates or esterified derivatives are rapidly absorbed from intact skin, mucous membrane, GIT, and muscles (upon intramuscular injection). They are rapidly metabolized in the liver by the microsomal enzyme.

Synthetic estrogens like ethynylestradiol and mestranol are well absorbed from skin, GIT and mucous membrane. The human body converts mestranol to ethynylestradiol. They are stored in adipose tissues and released slowly. Ethynyl estradiol metabolizes slowly in the liver and peripheral tissues. Thus, synthetic estrogens have a longer duration of action than natural estrogens.  Estrogens are metabolized in the liver. Thus, in liver dysfunction Estrogens are metabolized slowly. That may increase estrogens level inside the body. That produces feminization in the male.

Mechanism of Action:  Estrogen initiates RNA synthesis. Estrogens bind to receptors. Estrogen receptor complex binds with DNA. It stabilizes RNA polymerase enzymes and other proteins. These are must to initiate RNA synthesis.

Pharmacological action: Estrogens are must for female maturation:

·         They produce following changes during puberty:

o   Breast enlargements by

§  Ductal growth,

§  Stromal developments (Connective tissue cells of any organ)

§  Adipose tissue deposition

o   Growth of axillaries  (armpit) and pubic (just above external genitals) hair

o   Pigmentation of skin surrounding nipple

o   Feminine behavior

·         Metabolic effect: They are weak anabolic (tissue building) steroid. They also retain fluids

·         Lipid profile: They increase HDL level and decrease LDL level & Cholesterol. Thus they develop low risk of coronary artery disease and myocardial infarction

·         Blood Coagulation: They decrease blood platelets adhesiveness and increases coagulation factors.

Adverse Effects: Estrogens therapy may produce following adverse effects 

·         Nausea like morning sickness in early pregnancy period

·         Breast tumor and breast tenderness.

·         Hypertension, Headache

·         Oedema

·   Endometrial carcinoma in postmenopausal women, if estrogens are administered as   hormonal replacement therapy

·     In male, they cause gynecomastia (enlarged breast in male), Suppression of libido and feminization

Estrogens consumed by women during early pregnancy may have a daughter suffering from vaginal adenocarcinoma (vaginal carcinoma begins from glandular cells. Glandular cells in vaginal mucous membrane secrete mucus continuously). Thus pregnancy due to oral contraceptives failure must be terminated. Most of the oral contraceptives have estrogens as active ingredients.

Therapeutic Uses:

         1.      Oral Contraceptives

         2.      Hormonal replacement therapy to treat

a.  Menopause: Estrogens decline or deficiency produce menopausal symptoms like flushing, sweating, atrophic vagina (inflammation in vagina due to a decrease in lubrication and shrinking & thinning of tissues). It can be treated by estrogen therapy. But estrogens cannot control psychopathological state or depression.

Estrogens are administered in the cyclic pattern. Estrogens are administered for Three weeks daily followed by one weak gap. Usually, progestin is administered along with estrogens. Progestin encounters endometrial carcinoma adverse effect of estrogens.

b.  Primary female hypogonadism (a diminished activity of ovaries): Impaired ovarian development produces estrogens deficiency.  Its treatment is started at age of 11-12 years. It stimulates changes during pregnancy. It develops secondary sex character and menstruation in a female.

c.  Senile atrophic vaginitis (Adhesion of opposite mucus membrane surfaces in the vagina. It is mainly due to vaginal infection): It occurs due to chronic female reproductive organ infection. Estrogens administration shows improvement in sanile atrophic vaginitis.

d. Dysmenorrhoea: Estrogen therapy inhibits ovulation. This helps to relief from dysmenorrhoea. Prostaglandins synthesis takes place in dysmenorrhea. Thus it can also be treated by using NSAIDs.

e.  Osteoporosis: Osteoporosis occurs due to loss of calcium and protein matrix from bones. This leads to weakening, thinning and fracture in bones. Osteoporosis occurs in menopause is called postmenopausal osteoporosis. Osteoporosis occurs in elder is called senile osteoporosis.

Estrogens therapy blocks calcium loss from bone. If estrogens therapy does not show improvement in bone condition then it should be stopped.

f.    Breast cancer: Breast removal by surgery is the first choice. Estrogen is used inoperable or metastatic case.

g.      Prostatic Cancer Treatment

h.  Hirsutism in Women: Increased production of androgens in women body produces Hirsutism. Androgen production can be blocked by corticosteroids. Estrogens therapy is recommended in corticosteroid failure.

i.   Acne: Androgen secretion produces acne in boys and girls. Estrogens are recommended to control acne in girls. It is not recommended for boys. It is usually used as topical application.

Progestins: Progestins are the synthetic analog of progestogens. Progestogens are steroid hormones that bind with progesterone receptor to activate them. Progesterone is major progestogen hormone in the body. It is also considered as natural progestin.

Progesterone is secreted by corpus luteum and placenta in the female, testes in male and adrenal cortex in both sexes. Corpus luteum secretes progesterone in the second half of menstruation cycle.

·        

          Progesterone derivatives

o   Medroxy Progesterone acetate

o   Hydroxy Progesterone caproate

o   Progesterol acetate

o   Dydrogesterone

·         

         19-Nor testosterone derivatives

o   Norethisterone

o   Norethynodrel

o   Ethynodiol Diacetate

o   Levonorgestrel

Pharmacological Actions: Progesterone promotes secretory endometrium development. Developed endometrium can accommodate embryo implantation. Corpus luteum release high amount of progesterone in the second phase of menstruation. Progesterone secretion continues if conception takes place. It maintains favorable condition to continue the pregnancy. It also reduces uterine contraction. If conception does not occurs then corpus luteum stop progesterone release. This stimulates the onset of menstruation. Both estrogens and progesterone are required for normal endometrium changes. Estrogens induce watery secretion. Progesterone induces thick viscid secretion.

Progesterone and estrogens stimulate mammary gland acini (Sac like a cavity) in the second half of pregnancy.

Progesterone has also thermogenic effect. It increases body temperature by 0.5⁰ C. Rise in temperature helps with ovulation.

Pharmacokinetics: Progesterone is absorbed by all routes. But it is orally ineffective due to rapid first-pass metabolism. If it is administered through any other route, it is rapidly metabolized in the liver. Metabolism is by conjugation i.e. glucuronide or sulfate conjugation. Thus it has a very short half-life. Metabolites are excreted by the kidney.

Therapeutic Uses: Progesterone itself is not used therapeutically due to its rapid metabolism and low bioavailability.

Synthetic analog, progestins have low first pass metabolism and low bioavailability. They are effective orally at the low dose. There are two types of synthetic progestins

    Ø  Oral contraceptives

  

   Ø  Dysmenorrhoea: NSAIDs are preferred to treat dysmenorrhoea. Estrogens are also used. Progesterone is administered with estrogens to counter adverse effects of estrogens.

   Ø  Premenstrual Symptoms or Syndrom (PMS): Irritability, weight gain, breast tenderness, headache are pathological PMS due to hormonal changes. Progestins are used to control these symptoms.

Endometriosis

   Ø  Endometriosis (Tissue lined inside the uterus – endometrium grows outside the uterus. A      
      painful condition):  It can b managed by 
      Progestins  high dose    

   Ø   Dysfunctional uterine bleeding: It is irregular bleeding. It occurs during puberty and menopause. Continuous use of estrogens causes endometrium hypoplasia. Progestin is used to stop bleeding.

   Ø  Habitual and threatened abortion: It should be used only in the female having a deficiency of progesterone during pregnancy. Otherwise, progestin has no additional benefits for pregnant women. It may increase the risk of virilization and genital deformities in women. 

   Ø Suppression of postpartum lactation

   Ø  Endometrium carcinoma treatment

Adverse effects: Progestins have weak androgenic activity. Its all adverse effects are linked to their androgenic activity. Ther use during pregnancy may develop masculinization in the female fetus.

A headache, a rise in body temperature, mood swing, breast (breast painfully overfilled with milk). Increase in LDL level that causes thrombophlebitis, pulmonary edema, weight gain, hirsutism, acne, and depression.

                                                                 Male Sex Hormones

Androgens: Androgens are the natural or synthetic steroid that acts as the hormone to regulate development and maintenance of male characteristics i.e. embryological development of primary male character and development of secondary male sex characters at puberty. They are synthesized by testes, ovary and adrenal gland. Ex. Testosterone,  Dihydrotestosterone (DHT) and androstenedione.

Testosterone: It is natural androgen, synthesized in testes, ovary, and adrenal cortex. It is essential for male sex characteristics. Testosterone produces androgenic effect due to its metabolites estradiol and dihydrotestosterone. It develops male phenotype in the embryonic stage, a secondary male character at puberty, sexual male behavior and spermatogenesis.

Pharmacological/ Physiological effects of Testosterone:

• ·         Enlargement of testes, scrotum, and penis
• ·         Growth of pubic hair, penile erection, masturbation in boys at puberty.
• ·         Growth of beard, auxiliary hair, hair on trunk and limbs.
• ·         Deepening of voice (Coarsening of voice or hoarsening of voice)
• ·         Musculature leading to weight gain and bone enlargement,
• ·         Retain nitrogen, water, sodium, potassium, chloride, phosphate etc that contribute in weight gain. These all increase height
• ·         Thick and oily skin
• ·         Prominent vein and no subcutaneous fat
• ·         Spermatogenesis

Therapeutic Uses:

·    Delay in puberty in the male is called hypogonadism. Testes failure to secrete testosterone caused hypogonadism. Treatment of hypogonadism requires testosterone administration for the longer duration.

 Post-puberty testicular failure can also be treated by testosterone therapy.

·         Breast cancer: Breast has estrogens receptors. This receptor also responds to testosterone. Thus testosterone acts as anti-estrogens. Due to this action, testosterone is used as an adjuvant to chemotherapeutic agents in the treatment of breast cancer.

Adverse effects

·         Virilising Effects in women: Virilisation is a biological process that brings about changes in the male body that differentiate male body from female body. Androgen produces most of these changes. Acne, facial hair growth, voice deepening, menstruation irregularities etc. Withdrawal of testosterone administration subsides these effects.

       Long-term use of testosterone may develop male pattern baldness, excessive body hair, muscle development, hypotrophy of clitoris.

·         Feminising effect: It occurs in male as gynecomastia. It is more prominent in male and children suffering from liver disease.

·         Oedema: Oedema does not occur at a low dose. High dose of testosterone administration may cause edema especially in the patient suffering from liver and heart disease.

             Jaundice: 2 to 5 months therapy may develop jaundice.

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