Oestrogens - Endocrinal Drug

Oestrogens

Oestrogens are hormones secreted primarily by the ovarian follicles and also by the adrenals, corpus luteum, placenta and testes, or they are synthetic steroidal and non-steroidal compounds. Oestrogens are readily absorbed through the skin and mucous membranes. Following intramuscular administra-tion of aqueous suspensions or oil solutions, absorption begins promptly and continues for several days. Natural, unconjugated oestrogens are inactivated in the gastrointestinal tract and liver following oral administration. Conjugated oestrogens, some synthetic derivatives and the non-steroidal oestrogens can be administered orally.

Oestrogens are widely distributed throughout most body tissues with the greatest concentrations in fat deposits. Steroidal oestrogens are metabolised primarily in the liver. Metabolism also occurs in the kidneys, gonads, and muscle tissues. Endogenous oestrogens appear in the urine as glucuronides and sulfates of oestradiol, oestrone, and oestriol. Diethylstilbestrol (DES) is metabolised to active intermediates such as DES semiquinone and DES quinone. The steroids and their metabo-lites are conjugated which increases their water solubility and facilitates excretion into the urine, which is the primary route of excretion.

Classification

·              Steroidal oestrogens—oestradiol, ethinyl oestradiol, poly- estradiol mestranol, quinestrol, estrone, equilin, equilenin.

·              Non-steroidal oestrogens—diethylstilbestrol, dienestrol, bisphenol A, genistein.

Uses:

·              Oral contraceptive.

·              Hormone replacement therapy (in post-menopausal women).

·              Treatment of ovarian dysgenesis (Turner’s syndrome).

Adverse Effects

·              Carcinogenicity: Oral contraceptives can increase the riskof breast cancer, (controversial). Post-menopausal women taking unopposed oestrogen or taking oestrogen combined with progestin have an increased risk of breast cancer compared with post-menopausal women taking no hormone replacement therapy. Older women (60–64 years) had the greatest increase in risk. Oestrogen (without progestins) in post-menopausal women increases the risk of endometrial carcinoma. Increased relative risk of endometrial carcinomahas been associated with prolonged continuous administra- tion of oestrogens for relief of menopausal symptoms in several retrospective case-control studies. There is a lower risk of endometrial cancer associated with use of a combined oestrogen-progestagen regimen in post-menopausal women than with unopposed oestrogens. However, long-term (5 years or more) use of combined therapy, even when the progestagen is added for more than 10 days per month, is associated with an increased risk of endometrial cancer.

·              There is increased incidence of vaginal and cervical adenocarcinoma in female offspring of mothers adminis- tered diethylstilbestrol (DES) during the first trimester of pregnancy. Maternal ingestion of DES during early preg- nancy increases the risk of vaginal adenocarcinoma and the incidence of epididymal cysts, maldescended testes, hypoplastic testes, varicocoeles, spermatozoal defects and perhaps seminoma in the exposed offspring many years later. Masculinisation of the female foetus may occur during the first trimester. Due to the potential risk to the infant, breast-feeding is not recommended when the mother is receiving hormone therapy.

·              Increased susceptibility to gall bladder disease. Oestrogen is thought to promote the formation of gallstones by increasing cholesterol saturation of bile, altering bile acid composition, and decreasing bile flow. Chronic use has also been associated with an increased risk of thromboembolic disease. Risk for thromboembolic disorders and consequent pulmonary embolism is increased by current oral contraceptive oestrogen use or post-menopausal oestrogen use, but past use of post-menopausal hormones or oral contra- ceptives does not increase risk for thromboembolic disorders.

·              Fullness and tenderness of breasts, with development of oedema. Therapeutic, chronic doses may produce decreased glucose tolerance, changes in the menstrual cycle (break- through bleeding, spotting, missed menses, amenorrhoea, changes in menstrual flow), and breast changes. Chronic exposure to oestrogenic substances often causes breast tenderness, enlargement and secretion Increased tendency to suffer migraine. The occurrence of persistent severe headaches may be a sign of impending cerebrovascular occlusion. Leg cramps.

·              Gynaecomastia.

·              Porphyria cutanea tarda, and chloasma.

·              Hypertension.

·     Older contraceptives containing high doses of oestrogens were associated with increased risk for myocardial infarc-tion.

·     Hepatotoxicity. Elevated liver function tests, cholestatic jaundice, and liver tumours have occurred in patients receiving therapeutic doses of oestrogen.

·     Contact lens intolerance and visual disturbances may occur in patients receiving oestrogens therapeutically. Contact dermatitis has been reported with oestradiol transdermal patch.

·     Hirsutism/alopecia has been reported with oestrogen therapy. 

Toxic Effects

·              Oral contraceptives taken orally in overdose usually do not produce serious toxicity. Toxicity, other than gastro- intestinal effects, is unlikely following acute exposure to oestrogens.

·              Nausea, vomiting, abdominal cramps, diarrhoea and biliary calculi may occur following an acute overdose. Oestradiol implant overdose has resulted in facial swelling, pitting oedema, and hypertension.

Treatment

·              Symptomatic and supportive measures.

·              Oestrogen blood levels are not clinically useful after overdose.

·              No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise indicated.

·              Gastric decontamination is rarely necessary. Treatment to ease gastrointestinal irritation is all that is required.

·              In chronic toxicity, discontinue medication and monitor for severe signs of toxicity and treat symptomatically.