Estropipate is an estrogen that is used as a replacement hormone therapy in post-menopausal women.

Estropipate Uses:

• Hypoestrogenism, female:

  • Used to treat hypoestrogenism brought on by castration, hypogonadism, or primary ovarian failure.

• Osteoporosis prevention:

  • For the purpose of preventing osteoporosis after menopause.
  • Restrictions on use: Only prescribed to women who are at high risk for developing postmenopausal osteoporosis; try using non-estrogen drugs instead.

• Vasomotor symptoms associated with menopause:

  • Used to treat mild to severe vasomotor symptoms brought on by menopause.

• Vulval and vaginal atrophy associated with menopause:

  • Used to treat menopausal symptoms of vulval and vaginal atrophy that range from mild to severe.
  • Limitations of use: Topical vaginal treatments should be taken into consideration when used only to treat vulvar and vaginal atrophy.

Note:

• The term "genitourinary syndrome of menopause" (GSM) has been approved as a new word for vulvovaginal atrophy by both the North American
• Menopause Society and the International Society for the Study of Women's Sexual Health.
• All genital and urinary signs and symptoms brought on by a decline in oestrogen related to menopause are referred to as GSM.

Estropipate Dose in Adults

Female:

• General dosing guidelines:
  • Hormone therapy should be frequently assessed for each patient to determine the best dose, duration, and method of administration depending on treatment objectives, risk factors, and general health.
  • For postmenopausal women with uteruses, combined estrogen/progestin therapy is recommended to lower the risk of endometrial cancer.
  • In general, people who have had hysterectomies do not require a progestin; however, if endometriosis has a history, one can be required.

Estropipate Dose in the treatment of Hypoestrogenism (female) due to castration or primary ovarian failure:

• Oral: 1.5 to 9 mg each day for the first 3 weeks of a theoretical cycle, followed by a rest period of 8 to 10 days.
• Adjust the dose based upon the patient's response and maintain at the lowest effective dose.

Estropipate Dose in the treatment of Hypoestrogenism (female) due to hypogonadism:

• Oral: For the first three weeks of a hypothesised cycle, take 1.5 to 9 mg per day. Then, take 8 to 10 days off.
• If bleeding has not started by the end of the rest period, repeat.
• Depending on how receptive the endometrium is, a different length of therapy may be needed to induce the withdrawal bleeding.
• Give an oral progestin in addition to oestrogen during the third week of the cycle if desired withdrawal bleeding does not develop.
• Maintaining the lowest effective dose while adjusting the dose in response to the patient's response.

Estropipate Dose in the prevention of Osteoporosis:

• Oral: 25 days of a 31-day cycle at 0.75 mg daily

Estropipate Dose in the treatment of Vasomotor symptoms associated with menopause:

• Oral: 0.75 to 6 mg in a day.
• If menstrual bleeding has not occurred for 2 or more months, cyclic administration can be initiated at any time.
• On the fifth day of bleeding if the patient has menstruated, begin cyclic administration.

Estropipate Dose in the treatment of Vulvar and vaginal atrophy associated with menopause:

• Oral: 0.75 to 6 mg in a day; administer cyclically.

Use in Children:

Not indicated in children.

Estropipate Pregnancy Risk Category: X

• Pregnant women should not use it.
• When used in combination with hormonal contraceptives, estrogen and progestin have not been shown to cause teratogenic side effects.

Estropipate use during breastfeeding:

• Estrogens, which are found in breastmilk, have been found to lower the quantity and quality of human milk.
• Manufacturer recommends caution when administering estropipate breastfeeding women.

Estropipate Dose in Kidney Disease:

The manufacturer's labeling doesn't provide any dosage adjustment (has not been studied).

Estropipate Dose in Liver disease:

Its use is contraindicated with hepatic dysfunction or disease.

Side effects of Estropipate:

• Cardiovascular:

  • Edema
  • Venous Thromboembolism
  • Hypertension
  • Pulmonary Thromboembolism

• Central Nervous System:

  • Chorea
  • Migraine
  • Depression
  • Dizziness
  • Headache

• Dermatologic:

  • Erythema Nodosum
  • Loss Of Scalp Hair
  • Chloasma
  • Erythema Multiforme

• Endocrine & Metabolic:

  • Change In Libido
  • Exacerbation Of Porphyria
  • Hirsutism
  • Hypercalcemia
  • Weight Gain
  • Weight Loss
  • Impaired Glucose Tolerance
  • Increased HDL Cholesterol
  • Decreased LDL Cholesterol
  • Increased Serum Triglycerides
  • Increased T4
  • Increased Thyroxine Binding Globulin
  • Menstrual Disease (Alterations In Frequency And Flow Of Menses)
  • Phospholipidemia

• Gastrointestinal:

  • Abdominal Cramps
  • Gallbladder Disease
  • Nausea
  • Pancreatitis
  • Bloating
  • Carbohydrate Intolerance
  • Cholecystitis
  • Cholelithiasis
  • Vomiting

• Genitourinary:

  • Breast Hypertrophy
  • Breast Tenderness
  • Vulvovaginal Candidiasis

• Hematologic & Oncologic:

  • Change In Platelet Count (Increase)
  • Decreased Antifactor Xa
  • Decreased Antithrombin III Plasma Level
  • Endometrial Carcinoma
  • Hemorrhagic Eruption
  • Increased Clotting Factor VII
  • Increased Clotting Factor VIII
  • Increased Clotting Factor IX
  • Increased Clotting Factor X
  • Increased Platelet Aggregation
  • Increased Serum Fibrinogen
  • Prolonged Prothrombin Time
  • Uterine Fibroids (Increased Size)

• Hepatic:

  • Cholestatic Jaundice

• Ophthalmic:

  • Change In Corneal Curvature (Steepening)
  • Contact Lens Intolerance

Contraindications to Estropipate:

• Hypersensitivity to estrogens and any component of the formula
• Undiagnosed abnormal Genital Bleeding;
• DVT or PE (current and/or historical of);
• Active or past history of arterial embombolic disease (eg. stroke, MI)
• Breast cancer (known, suspected or history of);
• Estrogen-dependent tumor (known and suspected);
• Hepatic impairment or disease
• pregnancy.

Warnings and precautions

• Breast cancer: [US Boxed Warn]

  • According to data from the Women's Health Initiative (WHI), invasive breast cancer is more likely to occur in postmenopausal women who use conjugated estrogens (CE) and medroxyprogesterone (MPA).
  • Observational studies show that this risk reduces with discontinuation of medication.
  • Hormone replacement therapy may result in increased breast density. It has been observed that using oestrogen alone or in combination increases the likelihood of abnormal mammography findings that call for additional assessment.
  • According to the WHI trial, women who underwent hysterectomy with CE did not have a higher risk of developing breast cancer.
  • Due to their oestrogen or progestin levels, length of therapy, route of administration, unique patient features, and the timing of therapy commencement, postmenopausal women undergoing hormone therapy may be more at risk for breast cancer.
  • When oestrogen is used, patients who have bone metastases or breast cancer may develop severe hypercalcemia. If this occurs, stop taking oestrogen.

• Dementia: [US Boxed Warning]

  • Using estrogens alone or in combination with progestin is not recommended for preventing dementia.
  • According to the Women's Health Initiative Memory Study (WHIMS), women over 65 who took CE alone or in combination had a higher risk of developing dementia.
  • Although the WHI memory tests involved older women, it is unknown if the results can be generalised to postmenopausal younger women.
  • For the treatment or prevention of cognitive decline or dementia at any age, hormone therapy is not advised.

• Endometrial Cancer: [US Boxed Warn]

  • When oestrogen is not countered, endometrial cancer is more likely to develop in females.
  • To lower the risk of endometrial Hyperplasia, a precursor to endometrial cancer, a progestin may be added to oestrogen therapy.
  • It is crucial to carry out the proper diagnostic procedures, including endometrial sampling, if required, in order to rule out cancer in women who have undetected irregular vaginal blood flow.
  • Endometrial cancer is a combination of dose and duration. It's most common in patients who have been on therapy for more than five years.
  • In comparison to synthetic estrogens with identical oestrogen dosages, there is no evidence to imply that natural estrogens have a different risk profile.
  • If modest doses of a progestin are being given locally to treat vaginal atrophy, they shouldn't be used. However, there aren't enough long-term (>1 year) evidence to back up this suggestion.

• Endometriosis:

  • Estrogens may exacerbate endometriosis.
  • Women with endometrium after hysterectomy should consider adding a progestin.
  • Post-hysterectomy with estrogen therapy unopposed has led to malignant transformation of the remaining endometrial implants.

• Heir to thrombophilia

  • Women who have inherited thrombophilias (eg protein C or S deficiencies) might be at greater risk for venous embolism.

• The Lipid Effects

  • In women who already have hypertriglyceridemia, triglycerides may also rise; if pancreatitis develops, stop taking the medication.
  • Higher HDL cholesterol and decreased LDL cholesterol are two lipid effects of oestrogen chemicals that are frequently linked.

• Ovarian cancer:.

  • An association may exist, but the risk of developing a serious condition is unlikely. The duration of therapy can also influence the likelihood of developing a severe reaction.
  • The information available regarding the use of estrogen/progestin therapy or menopausal estrogen and the risk of developing ovarian cancer is not consistent

• Retinal vascular embolism:

  • Estrogens can cause retinal vessel thrombosis. Stop taking them if you have migraines, diplopias, vision loss, proptosis or any other visual disturbances.
  • You should discontinue the treatment if you find retinal vascular or papilledema.

• Asthma

  • Patients with asthma should exercise caution as it can worsen the condition.

• Carbohydrate intolerance:

  • Before starting therapy, you should consider the age, cardiovascular, as well as metabolic risk factors of patients with diabetes.
  • Patients with diabetes may experience impaired glucose tolerance.

• Cardiovascular disease: [US-Boxed Warning]

  • To prevent heart disease, estrogens should not be combined with or without progestin.
  • According to data from the Women's Health Initiative research, CE increases the risk of deep vein thrombosis and stroke. In postmenopausal females aged 50 to 79, there has also been a reported rise in DVT, stroke, and pulmonary emboli (PE).
  • Obesity, smoking, diabetes mellitus, hypertension, hypercholesterolemia, SLE, and history of venous thromboembolism are additional risk factors (VTE).
  • When treating vasomotor symptoms of menopause in patients at high risk of thrombotic events, transdermal administration is preferable.
  • You should manage your risk factors well. If you suspect that adverse cardiovascular events may occur, stop using the medication immediately.

• Fluid retention can lead to more severe diseases

  • Patients with fluid retention-related diseases, such as cardiac or renal dysfunction, should be cautious.

• Epilepsy:

  • Epilepsy can be aggravated if you are careful.

• Gallbladder disease

  • Postmenopausal estrogen use may increase the risk of gallbladder diseases that require surgery.

• Hepatic dysfunction

  • It is not recommended for use in the presence of hepatic impairments or diseases.
  • Stop using if jaundice appears or if there are any acute or long-term hepatic problems.
  • Less likely are patients with hepatic impairment to be able to metabolise estrogens.
  • If you have a history of cholestatic jaundice brought on by oestrogen use or pregnancy, proceed with caution.

• Hepatic hemomangiomas

  • Patients with hepatic hemomangiomas should be cautious; it may worsen the condition.

• Hypocalcemia:

  • Patients with severe hypocalcemia should be cautious.

• Migraine

  • Migraine can be aggravated by taking care.

• Porphyria

  • Patients with porphyria should be cautious as it can worsen the condition.

• SLE:

  • Patients with SLE should be cautious; it may worsen the condition.

Estropipate: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Breast cancer and CVD.
• Age-appropriate breast and pelvic 
• blood pressure
• Serum triglycerides (2 weeks after commencing therapy in those with baseline level greater than 200 mg/dL)
• TSH; unplanned bleeding lasting longer than 6 months for endometrial pathology (earlier in patients who are diabetic, obese, or have a history of endometrial malignancy) (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement).

Menopausal symptoms:

• Efficacy starts 1 to 3 months after initiating therapy, and thereafter as needed, every 6 to 12 months.
• At the very least once a year, the length of the treatment should be assessed.

Note:

• Management of vasomotor symptoms or GSM does not benefit from monitoring FSH and serum oestrogen levels.
• Measurement of bone density for osteoporosis prevention

How to administer?

It may be taken without regard to meals.

Mechanism of action of Estropipate:

• Estropipate can be made from naturally occurring estrone.
• Estrogens are important for the growth and upkeep of the female reproductive system as well as the development of secondary sexual traits.
• The primary intracellular human oestrogen, estradiol, is more powerful at the receptor level than estrone or estriol.
• Additionally, it is the main oestrogen released prior to menopause.
• After menopause, males have easier access to estrone and estrone-sulfate than females do.
• Through a negative feedback mechanism, estrogens regulate the pituitary secretion hormone gonadotropins and luteinizing hormone.
• High levels of these hormones are decreased with oestrogen replacement therapy.
• Estropipate is made from crystal estrone that has been purified and then solubilized with sulphate. Utilizing piperazine, it is stabilised.

Absorption:

• Absorbed well.

Distribution:

• High quantities in the sex hormone target organs, widely scattered.

Protein binding:

• Bound to albumin and sex hormone-binding globulin.

Metabolism:

• Estrogens also undergo enterohepatic recirculation by conjugation in the liver, followed by excretion of sulphate and glucuronide conjugates into the bile, then hydrolysis in the intestine and oestrogen reabsorption. Hepatic; partial metabolism via CYP3A4 enzymes; estradiol is reversibly converted to estrone and estriol;
• The main type identified in postmenopausal women is sulphate conjugates.

Excretion:

• Primarily urine (as estradiol, estrone, estriol and their glucuronide and sulfate conjugates).

International Brand Names of Estropipate:

• Ortho-Est 0.625
• Esgen
• Genoral
• Harmogen
• Ortho-Est 1.25
• Ogen

Estropipate Brand Names in Pakistan:

There is no brand available in Pakistan.