CONTRAINDICATIONS

Estrogen & Estrogen/Progestin combinations are contraindicated in patients with any of the following disorders:

C

Active hepatic dysfunction or disease, especially of the obstructive type.

C

Personal history of known or suspected estrogen-progestin-dependent neoplasia such as breast or endometrial cancer.

C

Endometrial hyperplasia.

C

Undiagnosed abnormal genital bleeding.

C

Known or suspected pregnancy.

C

Active or past history of arterial thomboembolic disease (e.g., stroke, myocardial infarction, coronary heart disease).

C

Classical migraine

C

Active or past history of confirmed venous thromboembolism (such as deep venous thrombosis or pulmonary embolism) or active thrombophlebitis.

C

Partial or complete loss of vision due to ophthalmic vascular disease.

C

Known or suspected hypersensitivity to any component of the product.

WARNINGS

See Boxed Warnings

at the front page.

CARDIOVASCULAR DISORDERS

Available epidemiological data indicate that use of estrogen with or without progestin is associated with an increased risk of stroke, and coronary heart disease. The WHI trial results concluded that there are more risks than benefits among women using combined Hormone Replacement Therapy (HRT), consisting of 0.625mg conjugated equine estrogens plus 2.5mg medroxyprogesterone acetate, compared to the group using placebo. In 10,000 women on this combined HRT over one year period, there were seven more cases of coronary heart disease (37 on combined HRT versus 30 on placebo per 10,000 person years) and eight more cases of strokes (29 vs 21 per 10,000 person-years). 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 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, 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.

BREAST CANCER

Current epidemiological data indicate that the use of combined HRT is associated with an increased risk of invasive breast cancer. The WHI trial results concluded that there are more risks than benefits among women using combined HRT (0.625mg conjugated equine estrogens/2.5mg medroxyprogesterone acetate), compared to the group using placebo. In 10,000 women on combined HRT over one year period, there were eight more cases of invasive breast cancer (38 on combined HRT versus 30 on placebo per 10,000 person-years). The WHI study 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 WHI trial also reported that 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. It is recommended that estrogens not be given to women with existing breast cancer or those with a previous history of the disease. 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 HRT (as reported in the results of 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.

VENOUS THROMBOEMBOLISM

Recent epidemiological data indicate that use of estrogen with or without progestin is associated with an increased risk of developing venous thromboembolism (VTE). The WHI trial results concluded that there are more risks than benefits among women using combined HRT (0.625mg conjugated equine estrogens/2.5mg medroxyprogesterone acetate), compared to the group using placebo. In 10,000 women on combined HRT over a period of one year, there were eighteen more cases of total blood clots in the lungs and legs (34 on combined HRT versus 16 on placebo per 10,000 person-years). 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) and severe obesity (body mass index > 30 kg/m2). The risk of VTE also increases with age and smoking. The risk of VTE may be temporarily increased with prolonged immobilization, major elective surgery or posttraumatic surgery, or major trauma (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). 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.

ENDOMETRIAL HYPERPLASIA & ENDOMETRIAL CARCINOMA

Estrogen-only HRT increases the risk of endometrial hyperplasia (if taken by women with intact uteri).

GALLBLADDER DISEASES

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

DEMENTIA

Current epidemiological evidence indicates that the use of combined HRT is associated with significantly increased risk of developing probable dementia. The Women's Health Initiative Memory Study, a clinical substudy of the WHI, followed 4532 post-menopausal women age 65 and over and free of dementia at baseline. There was a reported two-fold increase in the relative risk of developing probable dementia after an average follow-up of 4.05 years in the group treated with daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone versus those treated with placebo (hazard ratio [HR] 2.05, 95% confidence interval [CI], 1.21-3.48). This increased risk would result in an additional 23 cases of dementia per 10 000 women per year (45 vs 22 per 10 000 person-years; P=.01).

PRECAUTIONS

Before OGEN (estropipate, USP) is administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial biopsy should be done when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests. The first follow-up examination should be done within 3-6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals at least once a year and should include at least those procedures outlined above.

It is important that patients are encouraged to practice frequent self-examination of the breasts

.

Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt diagnostic measures like hysteroscopy, endometrial biopsy or curettage to rule out the possibility of uterine malignancy and the treatment should be re-evaluated. Pre-existing uterine leiomyoma may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyoma requires discontinuation of medication. Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use. Caution is advised in patients with a history of estrogen-related jaundice and pruritus. If cholestatic jaundice develops during treatment, the treatment should be discontinued and appropriate investigations carried out. Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness should discontinue medication. 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. Women using hormonal replacement therapy (HRT) 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 therapy may have to be discontinued. Estrogens may cause fluid retention. Therefore, particular caution is indicated in cardiac or renal dysfunction, epilepsy or asthma. Treatment should be stopped if there is an increase in epileptic seizures. 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. 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. 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 hypertriglyceridemia or porphyria need special surveillance. Lipid- lowering measures are recommended additionally, before treatment is started. 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 the section under Laboratory Tests. Estrogen administration in lactating women has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of women receiving OGEN. The use of OGEN in lactating women is not recommended.

Drug Interactions

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. 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.

1. The metabolism of ethinyl estradiol is increased by rifampin and anticonvulsants such as phenobarbital, phenytoin and carbamazepine. Coadministration of troglitazone and certain ethinyl estradiol containing drug products (e.g., oral contraceptives containing ethinyl estradiol) reduce the plasma concentrations of ethinyl estradiol by 30 percent.

Ascorbic acid and acetaminophen may increase AUC and/or plasma concentrations of ethinyl estradiol. Coadministration of atorvastatin and certain ethinyl estradiol containing drug products (e.g., oral contraceptives containing ethinyl estradiol) 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. Drug products containing ethinyl estradiol may inhibit the metabolism of other compounds. 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, these drugs containing ethinyl estradiol may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clorfibric acid have been noted when these drugs were administered with certain ethinyl estradiol containing drug products (e.g., oral contraceptives containing ethinyl estradiol). It was found that some herbal products (e.g St. John's wort) which are available as OTC products might affect metabolism, and therefore, efficacy and safety of estrogen/progestin products. Physicians and other health care providers should be aware of other non-prescription products concomitantly used by the patient, including herbal and natural products, obtained from the widely spread Health Stores.

Laboratory Tests

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

C

increased sulfobromophthalein retention;

C

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.

C increased thyroxine-binding globulin (TBG), leading to increased circulating total thyroid hormone (T4) as measured by column or radioimmunoassay; free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered;

C

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.

C

reduced response to the METOPIRONE test;

C

impaired glucose tolerance

C

reduced serum folate concentration;

C

increased serum triglycerides and phospholipids concentration

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 HRT therapy when relevant specimens are submitted.

WARNINGS

The Women's Health Initiative (WHI) study results indicated increased risk of myocardial infarction (heart attack) stroke, invasive breast cancer, pulmonary emboli (blood clots in the lungs) and deep venous thrombosis (blood clots in the leg veins) in postmenopausal women during 5 years of treatment with combined 0.625 mg conjugated equine estrogens and 2.5 mg medroxyprogesterone acetate compared to those receiving placebo tablets (sugar tablets). Therefore, the following should be highly considered: C OGEN should not be prescribed for primary or secondary prevention of heart disease. C OGEN should be prescribed at the lowest effective dose for the approved indications/use(s). C OGEN should be prescribed for the shortest period of time possible for the approved indications/use(s).

What is OGEN?

OGEN is a medicine that contains a manufactured estrogen hormone that is similar to the estrogen produced by a woman's ovaries. OGEN is used to treat menopausal or and postmenopausal symptoms. Each OGEN tablet contains an active ingredient, estropipate USP, an estrogen substance, in the following amounts: 0.625 mg, 1.25 mg or 2.5 mg. Your doctor should give OGEN to you with an appropriate dose of a progestin hormone (medroxyprogesterone acetate, 2.5 mg) if you have an intact uterus/womb. Taking estrogen and progestin together may help lower the risk of developing endometrial hyperplasia (overgrowth of the uterus lining) and may also help reduce the risk of cancer of the uterus. Treatment with OGEN should be done under a doctor's supervision with regular follow-up visits at least once a year so that any side effects associated with long-term use will be identified. The usual daily dose of OGEN is 0.625 mg to 2.5 mg. The dose of OGEN should be adjusted by your doctor depending on how well it works for you.

Who should not take OGEN?

You should not take estrogen if you have or have had any of the following conditions:

C

Certain cancers including cancer of the breast, cancer of uterus or of the endometrium (lining of the uterus)

C

Endometrial hyperplasia (overgrowth of the uterus lining)

C

Abnormal blood clotting

C Stroke or heart attack C Migraine headaches C Heart disease

C

Liver disease

C

Gallbladder disease

C

Unusual vaginal bleeding

C

Pregnancy and breast feeding

C

Partial or complete loss of vision due to disease of the vessels in the eye

C

Known or suspected allergy to OGEN or to any of its ingredients

What are the possible risks of taking OGEN?

C

Heart disease.

There is evidence that taking estrogen with or without progestin may increase the risk of heart disease, stroke or heart attack.

C

Breast cancer.

Studies show that estrogen use may increase the risk of breast cancer.

Women, especially those with known risk factors for breast cancer, such as strong family history of the disease (mother or sister), unusual breast condition(s) or abnormal mammograms, should discuss the use of estrogens with their doctor. Regular breast examinations by a health professional and monthly self-examination are recommended.

C

Cancer of the uterus.

Estrogens increase the risk of developing endometrial hyperplasia (overgrowth of the uterus lining) that may lead to cancer of the lining of the uterus (endometrial cancer). The risk of developing cancer of the uterus gets higher the longer you use estrogens and the larger doses used. Because of this risk,

it is important to take the lowest dose that works and to take it only as long as it is needed.

Using progestin together with estrogen may reduce the higher risk of cancer of the uterus related to estrogen use. If the uterus has been removed (total hysterectomy), there is no danger of developing cancer of the uterus.

C

Abnormal blood clotting.

Taking estrogens may cause changes in your blood clotting system. These changes allow the blood to clot more easily, possibly allowing clots to form in your bloodstream. Risk factors for abnormal clotting are a personal or family history, severe obesity, increased age and smoking. The risk of abnormal blood clotting

may be temporarily increased by prolonged immobilization following a major operation or major trauma (accident). You should discuss risk factors for blood clots with your doctor. If blood clots do form in your bloodstream, they can cut off the blood supply to vital organs, causing serious problems. These problems may include a stroke (by cutting off blood to the brain), a heart attack (by cutting off blood to the heart), a pulmonary embolus (by cutting off blood to the lungs), or other problems. Any of these conditions may cause death or serious long-term disability.

C

Gallbladder disease.

Women who use estrogens after menopause are more likely to develop gallbladder disease needing surgery than women who do not use estrogens.

C

Dementia.

Women who use estrogen in combination with progestin may be at higher risk of developing probable mental deterioration.

What are possible side effects with estrogens?

The following side effects are less common but serious:

C

Breast cancer

C

Cancer of the uterus

C

Stroke

C

Heart attack

C

Blood clots

C

Gallbladder disease

The following are some of the warning signs of serious side effects:

C

Breast lumps

C

Unusual vaginal bleeding

C

Dizziness and faintness

C Changes in speech C Severe headaches C Chest pain

C

Shortness of breath

C Pains in the legs C Changes in vision C Vomiting Call you doctor immediately if you get any of these warning signs, or any other unusual symptom that concerns you. Common side effects include:

C

Irregular vaginal bleeding or spotting

C

Headache

C

Breast pain

C

Water retention, bloating

C

Stomach/abdominal cramps, bloating

C

Nausea and vomiting

C

Worsening of varicose veins

C

Changes in appetite, body weight, and libido

Other side effects are:

C

High blood pressure

C

Liver problems

C

High blood sugar

C

Fluid retention

C

Enlargement of benign tumors in the uterus (fibroids)

C

Depression, irritability

C

Vaginal yeast infections

C

Acne, spotty darkening of the skin

C

Hair loss

These are not all the possible side effects with OGEN. For more information, talk to your doctor or pharmacist.

How should OGEN be taken?

C

Take OGEN as directed by your doctor or pharmacist.

C

You and your doctor should discuss regularly, about every 3 to 6 months, whether you still need to take OGEN for your symptoms.

C

The usual daily dose of OGEN is 0.625 mg to 2.5 mg. The dose of OGEN should be adjusted by your doctor depending on how well it works for you.

Some medications can interfere with the action of estrogens and estrogens can interfere with the effects of other medications. When you are using OGEN it is important to let your doctor know if you are taking any other medications, including prescription medications, over-the-counter medications, vitamins and herbal products.

What are the symptoms and treatment of over dosage?

Overdose with estrogen may cause nausea, breast discomfort, fluid retention bloating or vaginal bleeding in women. In case of overdose, call your doctor, hospital or poison control center immediately.

What are the ingredients in OGEN?

Each OGEN tablet contains an active ingredient, estropipate USP, an estrogen substance, in the following amounts: 0.625 mg, 1.25 mg or 2.5 mg. OGEN is also made up of the following inactive ingredients: lactose monohydrate and/or lactose anhydrous, magnesium stearate, potassium phosphate dibasic, tromethamine, hydroxypropyl cellulose, sodium starch glycolate, microcrystalline cellulose, colloidal silicon dioxide, hydrogenated vegetable oil wax, purified water, alcohol. OGEN .625 also contains: FD&C Yellow No. 10 and FD&C Yellow No. 6. OGEN 1.25 also contains: FD&C Yellow No. 6. OGEN 2.5 also contains: FD&C Blue No. 2.

How is OGEN supplied?

OGEN .625 is supplied as a yellow-coloured, oval tablet. OGEN 1.25 is supplied as a peach-coloured, oval tablet. OGEN 2.5 is supplied as a blue-coloured, oval tablet.

How should OGEN be stored?

OGEN should be stored at room temperature, between 15-30 degC.

REFERENCES

1. Royal College of General Practitioners. Oral contraception and thrombo-embolic disease. J Coll Gen Pract 1967; 13:267-279.

2. Inman WHW, Vessey MP. Investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of childbearing age. Br Med J 1968; 2:193-199.

3. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease: a further report. Br Med J 1969; 2:651-657.

4. Sartwell PR, Masi AT, Arthes FG, Greene GR, Smith HE. Thromboembolism and oral contraceptives: an epidemiological case-control study. Am J Epidemiol 1969; 90:365- 380.

5. Inman WHW, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steriodal content of oral contraceptives. Br Med J 1970; 2:203-209.

6. Herbst et al. Adenocarcinoma of the vagina. N Eng J Med 1971; 284:878-881.

7. Lozman H, Barlow AL, Levitt DG. Piperazine estrone sulfate and conjugated estrogens equine in the treatment of the menopausal syndrome. South M J 1971; 64(9):1143-1149.

8. Cooper W, Marnie M, Daw E. A clinical trial of piperazine oestrone sulfate (Harmogen) in the treatment of menopausal symptoms. Curr Med Res Opin 1974; 2:260-263.

9. Aylward M, Holly F, Parker RJ. An evaluation of clinical response to piperazine oestrone ("Harmogen") in menopausal patients. Curr Med Res Opin 1974; 2:417-423.

10. Daw E. Duration of effect of treatment of menopausal symptoms by oestrogen fraction. Curr Med Res Opin 1975; 3:22-25.

11. Daw E. Recent concepts in the treatment of menopausal symptoms. Practitioner 1975; 215:501-507.

12 Aylward M, Maddock J, Lewis PA, Rees PL. Oestrogen replacement therapy and blood clotting. Curr Med Res Opin 1977; 4:83-100.

1. Anderson ABM, Sklovsky E, Sayers L, Steele PA, Turnbull AC. Comparison of serum oestrogen concentrations in post-menopausal women taking oestrone sulphate and oestradiol. Br Med J 1978; 1:140-142.

2. Antunes CMF, Stolley PD, Rosenshein NB, Davies JL, Tonascia JA, Brown C, Burnett

L, Rutledge A, Pokempner M, Garcia R. Endometrial cancer and estrogen use. N Eng J Med 1979; 300(1):9-13. Wren BG, Routledge DA. Blood pressure changes oestrogens in climacteric women. Med J Aust 1981; (Nov):528-531. Wren BG, Routledge DA. The effect of type and dose of oestrogen on the blood pressure of post-menopausal women. Maturitas 1983; 5:135-142. Wren BG, Brown LB, Routledge DA. Differential clinical response to oestrogens after menopause. Med J Aust 1982; 2:329-332. Padwick ML, Pyrse-Davies J, Whitehead MI. A simple method of determining the optimal dosage of progestin in postmenopausal women receiving estrogens. N Eng J Med 1986; 315:930-934. Harris ST, Genant HK, Baylink DJ, Gallagher JC, Karp SK, McConnell AM, Green EM, Stoll RW. The effects of estrone (Ogen) on spinal bone density of postmenopausal women. Arch Intern Med 1991; 151:1980-1984. Prince RL, Smith M, Dick IM, Price RI, Webb PG, Henderson K, Harris MM. Prevention of Postmenopausal osteoporosis. A comparative study of exercise, calcium supplementation, and hormone-replacement therapy. N Eng J Med 1991; 325:1189- 1195. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative Randomized Controlled Trial. JAMA 2002; 228(3):321- 333. Hulley S, Grady D, Bush T, et al for the Heart and Estrogen-progestin Replacement study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280(7):605-613. Grady S, Herringtion D, Bittner V, et al for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/progestin replacement study follow-up (HERS II). JAMA 2002; 288(I):49- 57. Chlebowski RT, Hendrix SL, Langer RD, et al. The Women's Health Initiative randomized trial. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 2003; 289(24):3243-3253. Shumaker SA, Legault, C, Rapp SR, et al. The Women's Health Initiative Memory Study: A randomized controlled trial. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. JAMA 2003; 289(20:2651-2662.