Action And Clinical Pharmacology: Estrogen drug products act by regulating the transcription of a limited number of genes. They may act directly at the cell’s surface via non “estrogen receptor” mechanism or directly with the estrogen receptor inside the cell. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in the wall of blood vessels, in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women.
Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, they cause growth and development of the uterus, fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat. Estrogens are intricately involved with other hormones, especially progesterone, in the processes of the ovulatory menstrual cycle and pregnancy, and affect the release of pituitary gonadotropins. They also contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, and pigmentation of the nipples and genitals.
Estrogens occur naturally in several forms. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 g of estradiol daily, depending on the phase of the menstrual cycle. This is converted primarily to estrone, which circulates in roughly equal proportion to estradiol, and to small amounts of estriol. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone – especially in its sulfate ester form – is the most abundant circulating estrogen in postmenopausal women. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than estrone or estriol at the receptor.
Conjugated estrogens used in therapy are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. However, Premarin contains a modified-release formulation of conjugated estrogens that slowly releases estrogens over several hours.
Estrogens used in therapy are also well absorbed through the skin and mucous membranes. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single i.m. injection of estradiol valerate or estradiol cypionate is absorbed over several weeks.
Administered estrogens and their esters are handled within the body essentially the same way as the endogenous hormones. Metabolic conversion of estrogens occurs primarily in the liver (first pass effect), but also at local target tissue sites. Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms which are continually interconverted, especially between estrone and estradiol and between esterified and nonesterified forms. Although naturally occurring estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin, only unbound estrogens enter target tissue cells. A significant proportion of the circulating estrogen exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogenic species. A certain proportion of the estrogen is excreted into the bile, then reabsorbed from the intestine and returned to the liver through the portal venous system. During this enterohepatic recirculation, estrogens are desulfated and resulfated and undergo degradation through conversion to less active estrogens (estriol and other estrogens), oxidation to nonestrogenic substances (catecholestrogens, which interact with catecholamine metabolism, especially in the CNS), and conjugation with glucuronic acids (which are then rapidly excreted in the urine).
When given orally, naturally occurring estrogens and their esters are extensively metabolized (first pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogenic species. This results in limited oral potency. By contrast, synthetic estrogens, such as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly in the liver and other tissues, which results in their high intrinsic potency. Estrogen drug products administered by nonoral routes while not subject to true “first-pass” metabolism, do undergo significant hepatic uptake, metabolism, and enterohepatic recycling.
Indications And Clinical Uses: The relief of menopausal and postmenopausal symptoms occurring in naturally or surgically induced estrogen deficiency states including vulvar and vaginal atrophy.
The prevention and treatment of osteoporosis in naturally occurring or surgically induced estrogen-deficiency states. This is in addition to other important therapeutic measures such as adequate diet and regular exercise. In postmenopausal women already diagnosed as having osteoporosis and vertebral fractures, treatment with conjugated estrogens may prevent further loss of bone mass. Even when started as late as 6 years after menopause, estrogen prevents further loss of bone mass for as long as the treatment is continued. When estrogen therapy is discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal period.
Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
Vulvar atrophy (with or without pruritus).
In patients with an intact uterus, conjugated estrogens should always be supplemented by administration of a progestin whose role is to prevent endometrial hyperplasia.
Contra-Indications: In patients with any of the following conditions: personal history of known or suspected estrogen-dependent neoplasia such as breast or endometrial cancer; undiagnosed abnormal vaginal bleeding; known or suspected pregnancy; active hepatic dysfunction or disease, especially of the obstructive type; active thrombophlebitis, thrombosis, or thromboembolic disorders; endometrial hyperplasia.
Premarin tablets should not be used in patients hypersensitive to their ingredients.
Manufacturers’ Warnings In Clinical States: There is evidence from several studies that estrogens, unopposed by progestins increase the risk of carcinoma of the endometrium in humans. The incidence of endometrial hyperplasia is reported to be lowered with coadministration of a progestin (see Dosage).
In some studies, women on estrogen replacement therapy, given alone or in combination with a progestin, have been reported to have an increased risk of thrombophlebitis, and/or thromboembolic disease. The physician should be aware of the possibility of thrombotic disorders (including thrombophlebitis, retinal thrombosis, cerebral embolism, and pulmonary embolism) during estrogen replacement therapy and alert to their earliest manifestations. Should any of these occur or be suspected, estrogen replacement therapy should be discontinued immediately. Patients who have risk factors for thrombotic disorders should be kept under careful observation.
Breast cancer is a multifactorial disease, which increases in frequency with age. Much of the etiology of breast cancer is unknown. Some published epidemiological studies have documented an association between a modest increase in the risk of developing breast cancer and the use of hormone replacement therapy in menopause when given for periods exceeding 10 years. Information is still lacking to show whether the risks of combination estrogen-progestin therapy differ from those of estrogen used alone. There is a need for caution in prescribing estrogens for women with a strong family history of breast cancer or who present breast nodules, fibrocystic disease of the breast, or abnormal mammograms. Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full-term pregnancy and at menopause should also be evaluated. It is recommended that a mammography be performed before starting treatment and repeated at regular intervals in patients at high risk for breast cancer.
Precautions: Before conjugated estrogens are administered, the patient should have a complete physical examination including blood pressure determination. (There is no evidence that elevation of blood pressure may occur with use of estrogens in the menopause). Breasts and pelvic organs should be examined and a Papanicolaou smear should be taken.
The first follow-up examination should be done within 6 months of initiation of treatment. Thereafter, examinations should be made once a year and should include those procedures outlined above. Patients should be encouraged to practice frequent self-examination of the breasts.
If unexpected or abnormal vaginal bleeding occurs during therapy, diagnostic aspiration biopsy or curettage should be performed to rule out the possibility of uterine malignancy.
Diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate metabolism.
When liver or endocrine function tests are indicated, or surgical procedures are performed, the laboratory should be advised of the patient’s therapy before specimens are forwarded.
Estrogen may cause sodium and water retention. Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy, or asthma.
Pre-existing uterine leiomyomata may increase in size during estrogen use.
In patients with familial defects of lipoprotein metabolism, estrogen therapy may be associated with massive elevations of plasma triglycerides leading to pancreatitis and other complications.
A 2- to 4-fold increase in the risk of surgically confirmed gallbladder disease has been reported in postmenopausal women receiving oral estrogens.
Because the prolonged use of estrogens influences the metabolism of calcium and phosphorus, estrogens should be used with caution in patients with metabolic and malignant bone diseases associated with hypercalcemia and in patients with renal insufficiency.
Pregnancy: Estrogen therapy during pregnancy is associated with an increased risk of fetal congenital reproductive-tract disorders. In females there is an increased risk of vaginal adenosis, squamous cell dysplasia of the cervix, and cancer later in life; in the male, of urogenital abnormalities. Although some of these changes are benign, it is not known whether they are precursors of malignancy.
If feasible, estrogens should be discontinued at least 4 weeks before surgery or during periods of prolonged immobilization since they may be associated with an increased risk of thromboembolism.
Drug Interactions: Estrogens may diminish the effectiveness of anticoagulants, antidiabetic and antihypertensive agents. Preparations affecting liver enzymes (e.g., barbiturates, hydantoins, carbamazepine, meprobamate, phenylbutazone or rifampin) may interfere with the activity of orally administered estrogens.
Laboratory Tests: Certain endocrine and liver function tests may be affected by estrogen-containing products: Increased sulfobromophthalein retention. Increased prothrombin time and partial thromboplastin time; increased levels of fibrinogen and fibrinogen activity; increased coagulation factors VII, VIII, IX, X; increased norepinephrine-induced platelet aggregability; decreased antithrombin III. Increased thyroxin-binding globulin (TBG), leading to increased circulating total thyroid hormone (T1) as measured by T4 levels determined either by column or radioimmunoassay; free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids respectively; free or biologically active hormone concentrations are unchanged. Reduced response to the metyrapone test. Reduced serum folate concentration. Increased serum triglyceride and phospholipid concentration, increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels. Impaired glucose tolerance.
The interpretation of the above laboratory tests should take into consideration whether or not the woman has taken estrogen therapy. The pathologist should be informed that the patient is receiving estrogen therapy when relevant specimens are submitted.
Adverse Reactions: The most serious adverse reactions associated with the use of estrogens and progestogens are indicated under Warnings and Precautions.
The following additional adverse reactions have been reported with estrogen therapy: Cardiovascular: venous thromboembolism; pulmonary thromboembolism.
Genitourinary: changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding, spotting; increase in size of uterine leiomyomata; vaginal candidiasis; change in amount of cervical secretion.
Breasts: tenderness, enlargement.
Gastrointestinal: nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis.
Skin: chloasma or melasma that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism.
Eyes: steepening of corneal curvature; intolerance to contact lenses.
CNS: headache, migraine, dizziness; mental depression; chorea.
Miscellaneous: increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; changes in libido.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing oral contraceptives by young children.
Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females. All of the ingested drug should be removed by gastric lavage and symptomatic treatment given.
Dosage And Administration: Administration: Conjugated estrogens therapy may be given continuously with no interruption in therapy, or in cyclical regimens (regimens such as 25 days on drug followed by 5 days off drug) as is medically appropriate on an individualized basis.
Continuous, noncyclic therapy may be indicated in hysterectomized women or in cases where the signs and symptoms of estrogen deficiency become problematic during the treatment-free interval. In women with an intact uterus, a progestin should be coadministered for a minimum of 10, but preferably at least 12 to 14 days per cycle to avoid overstimulation of the endometrium. In addition, progestin should be administered to minimize the occurrence of endometrial hyperplasia. Unexpected or abnormal vaginal bleeding in such patients requires institution of prompt diagnostic measures, such as endometrial biopsy or curettage to rule out the possibility of uterine malignancy. Since progestins are administered to reduce the risk of hyperplastic changes of the endometrium, patients without a uterus do not require a progestin for this purpose.
Usual Dosage Range: Menopausal Symptoms: 0.625 to 1.25 mg daily, cyclically or continuously as is medically required. Adjust dosage upward or downward according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level providing effective control.
Osteoporosis (loss of bone mass): 0.625 mg daily.
Hypoestrogenism Due To: A. Female Hypogonadism: 0.3 mg to 0.625 mg daily, administered cyclically (e.g., 3 weeks on and 1 week off) or continuously as required. Doses are adjusted depending on the severity of symptoms and responsiveness of the endometrium.
B. Female Castration or Primary Ovarian Failure: 1.25 mg daily, cyclically or continuously as required. Adjust dosage upward or downward according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level that will provide effective control.
Atrophic Vaginitis: 0.3 mg to 1.25 mg daily depending upon the tissue response of the individual patient. Administer cyclically or continuously as required.
Vulvar Atrophy: 0.3 mg to 1.25 mg daily depending upon the tissue response of the individual patient. Administer cyclically or continuously as required.
Availability And Storage: 0.3 mg: Each green, oval, sugar-coated tablet imprinted with “Premarin” contains: conjugated estrogens CDS 0.3 mg. Nonmedicinal ingredients: calcium phosphate tribasic, calcium sulfate anhydrous, carnauba wax, D&C Yellow No. 10, edible ink, FD&C Blue No. 1, FD&C Yellow No. 6, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polysorbate 60, polyvinylpyrrolidone, propylparaben, shellac, sodium benzoate, sucrose, sucrose syrup and titanium dioxide.
Energy: 4.19 kJ (1.0 kcal)/0.3 mg. Sodium:
0.625 mg: Each maroon, oval, sugar-coated tablet imprinted with “Premarin” contains: conjugated estrogens CDS 0.625 mg. Nonmedicinal ingredients: calcium phosphate tribasic, calcium sulfate anhydrous, carnauba wax, edible ink, FD&C Blue No. 2, FD&C Red No. 3, FD&C Yellow No. 6, glyceryl monooleate, gum acacia, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, polysorbate 60, propylparaben, shellac, sodium benzoate, sucrose, sucrose syrup and titanium dioxide. Energy: 4.19 kJ (1.0 kcal)/0.625 mg. Sodium:
0.9 mg: Each pink, oval, sugar-coated tablet imprinted with “Premarin” contains: conjugated estrogens CDS 0.9 mg. Nonmedicinal ingredients: calcium phosphate tribasic, calcium sulfate anhydrous, carnauba wax, edible ink, FD&C Blue No. 2, FD&C Red No. 3, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, polysorbate 60, propylparaben, shellac, sucrose and titanium dioxide. Energy: 4.19 kJ (1.0 kcal)/0.9 mg. Sodium:
1.25 mg: Each yellow, oval, sugar-coated tablet imprinted with “Premarin” contains: conjugated estrogens CDS 1.25 mg. Nonmedicinal ingredients: calcium phosphate tribasic, calcium sulfate anhydrous, carnauba wax, D&C Yellow No. 10, edible ink, FD&C Yellow No. 6, glyceryl monooleate, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, polysorbate 60, propylparaben, shellac, sucrose and titanium dioxide. Energy: 4.19 kJ (1.0 kcal)/1.25 mg. Sodium:
PREMARIN® TABLETS Wyeth-Ayerst Conjugated Estrogens Estrogenic Hormones