Premarin vaginal cream 0.625 mg/g

Ethinyl estradiol may interfere with the metabolism of other drugs by inhibiting hepatic microsomal enzymes or by inducing hepatic drug conjugation, particularly glucuronidation. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of certain drugs containing ethinyl estradiol (e.g., oral contraceptives containing ethinyl estradiol). In addition, products containing ethinyl estradiol may induce the conjugation of other compounds.

Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with certain ethinyl estradiol-containing drug products (e.g., oral contraceptives containing ethinyl estradiol).

CYP3A4 inhibitors such as grapefruit juice may increase plasma concentrations of 17 β-estradiol and may result in side effects.

Sulfation of ethinyl estradiol has been shown to occur in the gastrointestinal (GI) wall. Therefore, drugs which act as competitive inhibitors for sulfation in the GI wall may increase ethinyl estradiol bioavailability (e.g., ascorbic acid, acetaminophen).

The results of certain endocrine and liver function tests may be affected by estrogen-containing products:

• 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;

  
  

• impaired glucose tolerance;

  
  

• increased serum triglycerides and phospholipids concentration;

  
  

• increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone (T₄), as measured bycolumn or radioimmunoassay;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.

  
  

The results of the above laboratory tests should not be considered reliable unless therapy has been discontinued for two to four weeks.

The pathologist should be informed that the patient is receiving hormone replacement therapy (HRT) when relevant specimens are submitted.

It was found that some herbal products (e.g., St. John’s wort), which are available as over-the-counter (OTC) products, might interfere with steroid metabolism, and therefore alter the efficacy and safety of estrogen/progestin products. Hot flashes and vaginal bleeding have been reported in patients taking estrogen replacement therapy (ERT) and combined estrogen plus progestin therapy (HRT) and St. John’s wort. St. John’s wort may induce hepatic microsomal enzymes, which theoretically may result in reduced efficacy of ERT and HRT.

Physicians and other health care providers should be made aware of other non-prescription products concomitantly used by the patient, including herbal and natural products, obtained from the widely spread Health Stores.

The following section contains information on drug interactions with ethinyl estradiol-containing products (specifically, oral contraceptives) that have been reported in the public literature. It is unknown whether such interactions occur with drug products containing other types of estrogens.

In vitro and in vivo studies have shown that 17 β-estradiol, one of the components of conjugated estrogens, is metabolized partially by Cytochrome P450 3A4 (CYP3A4). Therefore, strong CYP3A4 inducers such as phenobarbitol, phenytoin, carbamazepine, rifampicin and dexamethasome may reduce plasma concentrations of 17 β-estradiol. This may lead to a decreased effect and/or changes in the uterine bleeding profile. CYP3A4 inhibitors such as cimetidine, erythromycin, ketoconazole, clarithromycin, itraconazole, and ritonavir may increase plasma concentrations of 17 β-estradiol and may result in side effects.

Data from a drug-drug interaction study involving conjugated estrogens and medroxyprogesterone acetate indicate that the pharmacokinetic disposition of both drugs are not altered when the drugs are coadministered. Other clinical drug-drug interaction studies have not been conducted with conjugated estrogens.

Estrogens may diminish the effectiveness of anticoagulant, antidiabetic and antihypertensive agents.

Preparations inducing liver enzymes (e.g. barbiturates, hydantoins, carbamazepine, meprobamates, phenylbutazone or rifampicin) may interfere with the activity of orally administered estrogens.

Interactions can occur with drugs that induce microsomal enzymes which can decrease ethinyl estradiol concentrations (eg., rifampin, barbiturates, phenytoin, carbamazepine, troglitazone).

Coadministration of atorvastatin and certain ethinyl estradiol-containing drug products (e.g., oral contraceptives) increase AUC values for ethinyl estradiol by 20 percent.

Clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

Remove cap.

To Cleanse: Pull plunger out from barrel. Wash with mild soap and warm water. Do not boil.

Premarin Vaginal Cream should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma. Progestin therapy is not required as part of hormone replacement therapy in women who have had a previous hysterectomy.

Use of Premarin Vaginal Cream, alone, or in combination with a progestin, should be limited to the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary.

Premarin Vaginal Cream should be administered cyclically for short-term use only for the treatment of atrophic vaginitis, dyspareunia or kraurosis vulvae.

In patients with severe cases of atrophic vaginitis, the mucosa should first be conditioned with a short course of oral therapy—1.25 mg daily for approximately 10 days. Vaginal treatment should be instituted at the lowest effective dosage, and the requirement for estrogen therapy reassessed regularly.

In patients already receiving oral therapy, the oral dosage may be reduced taking into account the potential absorption from the vaginal medication. The degree of atrophy is directly responsible for the level of absorption and should be the guiding factor in dose adjustment.

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.

If a patient misses a dose, it should be taken as soon as possible. If it is close to the patient’s next scheduled dose, the missed dose should be skipped, and the patient should continue with her normal schedule. The patient should not take two doses at the same time.

The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible.

0.5 g to 2 g daily, intravaginally or topically depending on the severity of the condition. Administration should be cyclic (e.g., three weeks on and one week off).

Appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.

breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea; vaginal itching/discharge; dyspareunia; endometrial hyperplasia; pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion; breast swelling and tenderness, galactorrhea, breast discharge, amenorrhea, increase in size of uterine leiomyomata, vaginitis, application site reactions of vulvovaginal discomfort including burning, irritation and genital pruritus, vaginal candidiasis.

neuro-ocular lesions (e.g. retinal thrombosis, optic neuritis); visual disturbances; steepening of the corneal curvature; intolerance to contact lenses.

fatigue; changes in appetite; changes in body weight; changes in libido, aggravation of porphyria, angioedema, hypersensitivity, anaphylactic/anaphylactoid reactions, increased triglycerides.

palpitations; increase in blood pressure (see Warnings and Precautions); coronary thrombosis, pulmonary embolism, venous thrombosis, myocardial infarction.

aggravation of migraine episodes; headaches; migraines, dizziness; cerebrovascular accident/stroke.

cystitis; dysuria; sodium retention; edema.

chloasma or melasma, which may persist when drug is discontinued; erythema multiforme; erythema nodosum; haemorrhagic eruption; loss of scalp hair; hirsutism and acne, allergic reactions and rashes, generalized rash, urticaria, pigmentation of the skin, pruritus.

increased blood sugar levels; decreased glucose tolerance, precocious puberty.

musculoskeletal pain including leg pain not related to thromboembolic disease (usually transient, lasting 3-6 weeks) may occur, arthralgias, leg cramps.

gallbladder disorder; cholestatic jaundice.

isolated cases of: thrombophlebitis; thromboembolic disorders.

See Warnings and Precautions regarding potential induction of malignant neoplasia and other adverse effects similar to those observed with oral contraceptives.

The following additional adverse reactions have been reported with conjugated estrogens vaginal cream or are undesirable effects associated with ET/HT:

altered coagulation tests (see Drug Interactions, Drug-Laboratory Test Interactions).

Table 1 summarizes the treatment-emergent drug-related study events reported by greater than 2% of the patients. The number of patients with any study event is not necessarily the sum of the individual events since a patient might have reported two or more different study events. The addition of progestin to estrogen replacement therapy may contribute to breast pain. This is reflected by the greater percentage of patients with breast pain on combination therapy than on Premarin alone.

If adverse symptoms persist, the prescription of HRT should be re-considered.

mental depression; nervousness; irritability, mood disturbances, dementia.

nausea; vomiting; abdominal discomfort (cramps, pressure, pain, bloating), pancreatitis.

See above indications.

Premarin Vaginal Cream is not indicated for use in children.

Numerous reports of ingestion of large doses of estrogen products and estrogen-containing oral contraceptives by young children have not revealed acute serious ill effects.

Overdosage with estrogen may cause nausea, breast discomfort, fluid retention, bloating or vaginal bleeding in women.

There is no specific antidote and further treatment if necessary should be symptomatic.

Available epidemiological data indicate that use of estrogen with or without progestin by postmenopausal women is associated with an increased risk of developing venous thromboembolism (VTE).

In the oral estrogen plus progestin arm of the WHI trial, among 10 000 women on combined HRT over a one-year period, there were 18 more cases of venous thromboembolism, including 8 more cases of pulmonary embolism.

In the oral estrogen-alone arm of the WHI trial, among 10 000 women on estrogen therapy over a one-year period, there were 7 more cases of venous thromboembolism, although there was no statistically significant difference in the rate of pulmonary embolism.

Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index >30 kg/m²) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking.

The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. In women on HRT, attention should be given to prophylactic measures to prevent VTE following surgery. Also, patients with varicose veins should be closely supervised. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, hormone therapy should be discontinued immediately, given the risks of long-term disability or fatality.

If feasible, estrogens should be discontinued at least 4 weeks before major surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis or loss of consciousness should discontinue medication.

Patients with a previous history of classical migraine and who develop a recurrence or worsening of migraine symptoms should be reevaluated.

Women using hormone replacement therapy sometimes experience increased blood pressure. Blood pressure should be monitored with HRT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HRT may have to be discontinued.

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.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.

Particular caution is indicated in women with epilepsy, as HRT may cause an exacerbation of this condition.

Estrogens/progestins should not be used during pregnancy.

In some epidemiologic studies, use of estrogen-only products, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. The analysis of the WHI data suggested that estrogen plus progestin therapy may increase the risk of ovarian cancer. Other epidemiologic studies have not found these associations.

Of the total number of subjects in the conjugated equine estrogens in combination with medroxyprogesterone acetate substudy of the Women’s Health Initiative study (WHI), 44% (n=7320) were 65 years and over, while 6.6% (n=1095) were 75 and over. No significant differences in relative risks were observed between subjects 65 years and over compared to younger subjects. There was a higher relative risk of stroke and invasive breast cancer in women 75 and over compared to younger subjects.

The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and the Women’s Health Initiative (WHI) trial indicate that the use of estrogen plus progestin is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women. The results of the WHI trial indicate that the use of estrogen-alone and estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women.

Pre-existing uterine leiomyomata may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyomata requires discontinuation of medication and appropriate investigation.

A worsening of glucose tolerance and lipid metabolism have been observed in a significant percentage of peri- and post-menopausal patients. Therefore, diabetic patients, or those with a predisposition to diabetes, should be observed closely to detect any alterations in carbohydrate or lipid metabolism, especially in triglyceride blood levels.

Women with familial hyperlipidemias need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started.

Caution should be exercised in patients with pre-existing hypertriglyceridemia since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this population.

Women with porphyria need special surveillance.

Estrogens should be used with caution in individuals with severe hypocalcemia.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens has been reported.

Note: Preliminary studies conducted by the Health Products and Food Branch have demonstrated that PREMARIN Vaginal Cream may react with the latex rubber of certain mechanical barrier devices used for prevention of sexually transmitted diseases and pregnancy (diaphragms and condoms). In additional studies, Premarin Vaginal Cream has been shown to weaken latex condoms. The potential for Premarin Vaginal Cream to weaken and contribute to the failure of condoms, diaphragms, or cervical caps made of latex or rubber should be considered.

Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt appropriate diagnostic measures to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.

Available epidemiological data indicate that the use of combined estrogen plus progestin by postmenopausal women is associated with an increased risk of invasive breast cancer.

In the estrogen plus progestin arm of the WHI trial, among 10 000 women over a one-year period, there were:

• 8 more cases of invasive breast cancer (38 on combined HRT versus 30 on placebo).

  
  

The WHI study also reported that the invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P=0.04) and were at a more advanced stage compared with those diagnosed in the placebo group. The percentage of women with abnormal mammograms (recommendations for short-interval follow-up, a suspicious abnormality, or highly suggestive of malignancy) was significantly higher in the estrogen plus progestin group versus the placebo group. This difference appeared at year one and persisted in each year thereafter.

In the estrogen-alone arm of the WHI trial, there was no statistically significant difference in the rate of invasive breast cancer in hysterectomized women treated with conjugated equine estrogens versus women treated with placebo.

It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease (see Contraindications).

There is a need for caution in prescribing estrogens for women with known risk factors associated with the development of breast cancer, such as strong family history of breast cancer (first degree relative) or who present a breast condition with an increased risk (abnormal mammograms and/or atypical hyperplasia at breast biopsy).

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 women undergo mammography prior to the start of HRT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.

The overall benefits and possible risks of hormone replacement therapy should be fully considered and discussed with patients. It is important that the modest increased risk of being diagnosed with breast cancer after 4 years of treatment with combined estrogen plus progestin HRT (as reported in the results of the WHI trial) be discussed with the patient and weighed against its known benefits.

Instructions for regular self-examination of the breasts should be included in this counselling.

Caution is advised in patients with a history of liver and/or biliary disorders. If cholestatic jaundice develops during treatment, the treatment should be discontinued and appropriate investigations carried out.

Available epidemiological data indicate that the use of combined estrogen plus progestin in women age 65 and over may increase the risk of developing probable dementia.

The Women's Health Initiative Memory Study (WHIMS), a clinical substudy of the WHI, was designed to assess whether postmenopausal hormone replacement therapy (oral estrogen plus progestin or oral estrogen-alone) reduces the risk of dementia in women aged 65 and over (age range 65-79 years) and free of dementia at baseline.

In the estrogen plus progestin arm of the WHIMS (n=4532), women with intact uteri were treated with daily 0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA) or placebo for an average of 4.05 years. The results, when extrapolated to 10 000 women treated over a one-year period showed:

• 23 more cases of probable dementia (45 on combined HRT versus 22 on placebo).

  
  

In the estrogen-alone arm of the WHIMS (n=2947), women with prior hysterectomy were treated with daily 0.625 mg CEE or placebo for an average of 5.21 years. The results, when extrapolated to 10 000 women treated over a one-year period showed:

• 12 more cases of probable dementia (37 on estrogen-alone versus 25 on placebo), although this difference did not reach statistical significance.

  
  

When data from the estrogen plus progestin arm of the WHIMS and the estrogen-alone arm of the WHIMS were combined, as per the original WHIMS protocol, in 10 000 women over a one-year period, there were:

• 18 more cases of probable dementia (41 on estrogen plus progestin or estrogen-alone versus 23 on placebo).

Particular caution is indicated in women with hepatic hemangiomas, as HRT may cause an exacerbation of this condition.

Estrogen-only HRT increases the risk of endometrial hyperplasia/carcinoma if taken by women with intact uteri. Estrogen should be prescribed with an appropriate dosage of a progestin for women with intact uteri in order to prevent endometrial hyperplasia/carcinoma.

The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold or greater than in non-users and appears to be dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five years or more, and this risk has been shown to persist for at least 8 to15 years after ERT is discontinued.

In a subset of WHI (see Action and Clinical Pharmacology) no increased risk of endometrial cancer after an average of 5.2 years of treatment with combined estrogen plus progestin HRT compared to placebo was observed.

Endometrial hyperplasia (a possible precursor of endometrial cancer) has been reported to occur at a rate of approximately 1% or less with CEE or CEE/MPA in two large clinical trials [Health and Osteoporosis, Progestin and Estrogen (n=2153) and Menopausal Study Group (n=1385)]. In these two clinical trials two cases of endometrial cancer were reported to occur among women taking combination CEE/MPA.

Clinical surveillance of all women taking combined estrogen plus progestin HRT is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.

Addition of a progestin should be considered in women who have undergone a hysterectomy but are known to have residual endometriosis, since a few cases of malignant transformation after estrogen-only therapy have been reported.

Premarin Vaginal Cream is not indicated for use in children.

Particular caution is indicated in women with systemic lupus erythematosus, as HRT may cause an exacerbation of this condition.

Before Premarin Vaginal Cream is administered, the patient should have a complete physical examination including blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial biopsy should be done only when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests. Before starting treatment pregnancy should be excluded. Periodic check-ups and careful benefit/risk evaluations should be undertaken in women treated with ERT/HRT therapy. The first follow-up examination should be done within three to six months of initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals of at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.

Mammography examinations should be scheduled based on patient age, risk factors and prior mammogram results.

The importance of regular self-examination of the breasts should be discussed with the patient.

Estrogens may cause fluid retention.

Therefore, particular caution is indicated in cardiac, renal dysfunction, or asthma. If, in any of the above-mentioned conditions, a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits and risks of treatment should be reassessed based on the individual case.

In the Heart and Estrogen/progestin Replacement Study (HERS) of postmenopausal women with documented heart disease (n=2763, average age 66.7 years), a randomized placebo-controlled clinical trial of secondary prevention of coronary heart disease (CHD), treatment with 0.625 mg/day oral conjugated equine estrogen (CEE) plus 2.5 mg oral medroxyprogesterone acetate (MPA) demonstrated no cardiovascular benefit. Specifically, during an average follow-up of 4.1 years, treatment with CEE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the hormone-treated group than in the placebo group in year 1, but not during the subsequent years.

From the original HERS trial, 2321 women consented to participate in an open label extension of HERS known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. After 6.8 years, hormone therapy did not reduce the risk of cardiovascular events in women with CHD.

Oral HRT has been associated with an increased risk of cardiovascular events such as myocardial infarction (MI) and stroke, as well as venous thrombosis and pulmonary embolism (PE) (venous thromboembolism or VTE). Should any of these occur or be suspected, HRT should be discontinued immediately.

Risk factors for cardiovascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be managed appropriately.

In the combined estrogen plus progestin arm of the WHI trial, among 10 000 women over a one-year period, there were:

• 8 more cases of stroke (29 on combined HRT versus 21 on placebo).

  
  

• 7 more cases of CHD (37 on combined HRT versus 30 on placebo).

  
  

In the estrogen-alone arm of the WHI trial of women with prior hysterectomy, among 10 000 women over a one-year period, there were/was:

• 12 more cases of stroke (44 on estrogen-alone therapy versus 32 on placebo)

  
  

• no statistically significant difference in the rate of CHD.

Patients who are taking progestogens and have a history of depression should be observed. If the depression occurs to a serious degree, the drug should be discontinued.

Estrogen should not be used during lactation.

Patients who require thyroid hormone replacement therapy and who are also taking estrogen should have their thyroid function monitored regularly to assure that thyroid hormone levels remain in an acceptable range (see Drug-Laboratory Test Interactions).

Liver function tests should be done periodically in subjects who are suspected of having hepatic disease. For information on endocrine and liver function tests, see Monitoring and Laboratory Tests.

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Hot flushes, feelings of intense heat over the upper trunk and face, with flushing of the skin and sweating occur in approximately 80% of women as a result of the decrease in ovarian hormones. These vasomotor symptoms are seen in women whether menopause is surgically induced or spontaneous. However, hot flushes may be more severe in women who undergo surgical menopause. Hot flushes can begin before the cessation of menses.

No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

Conjugated estrogens are soluble in water and are well absorbed through the skin, mucous membranes, and the gastrointestinal tract after release from the drug formulation.

Endogenous estrogens are largely responsible for 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. Indirectly, they also contribute to the shaping of the skeleton, maintenance of tone and elasticity through the increase of collagen production in the supportive tissues of the heart, skin and urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, growth of axillary and pubic hair, and pigmentation of the nipples and genitals. Decline of ovarian estrogenic and progestogenic activity at the end of the menstrual cycle can result in menstruation, although the cessation of progesterone secretion is the most important factor in the mature ovulatory cycle. However, in the preovulatory or anovulatory cycle, estrogen is the primary determinant in the onset of menstruation.

Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 µg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Circulating estrogens modulate pituitary gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogen therapy acts to reduce elevated levels of these hormones seen in postmenopausal women.

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.

Conjugated estrogens used in therapy are soluble in water and are well absorbed through the skin, mucous membranes, and the gastrointestinal tract after release from the drug formulation. Some estrogens are excreted in bile; however, they are reabsorbed from the intestine and returned to the liver through the portal venous system. Water-soluble estrogen conjugates are strongly acidic and are ionized in body fluids, which favours excretion through the kidneys since tubular reabsorption is minimal.

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 intramuscular 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.

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 central nervous system), and conjugation with glucuronic acids (which are then rapidly excreted in the urine).

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. The results of clinical studies indicate that the addition of a progestin to an estrogen replacement regimen for more than 10 days per cycle reduces the incidence of endometrial hyperplasia and the attendant risk of adenocarcinoma in women with intact uteri. The addition of a progestin into an estrogen replacement regimen has not been shown to interfere with the efficacy of estrogen replacement therapy for its approved indications.

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 non-esterified forms.

Estrogen drug products administered by non-oral routes, while not subject to true “first-pass” metabolism, do undergo significant hepatic uptake, metabolism, and enterohepatic recycling. Metabolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; however, they are re-absorbed from the intestine and returned to the liver through the portal venous system. Water-soluble estrogen conjugates are strongly acidic and are ionized in body fluids, which favour excretion through the kidneys since tubular re-absorption is minimal.

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.

Conjugated estrogens used in therapy are soluble in water and are well absorbed through the skin, mucous membranes, and gastrointestinal tract after release from the drug formulation.

With a continuous therapy, several bleeding patterns may occur. These may range from absence of bleeding to irregular bleeding. If bleeding occurs, it is frequently light spotting or moderate bleeding.