Esterified estrogens (Menest) is a synthetic female sex hormone that is used to relieve the symptoms associated with menopause and low female sex hormones in females such as vaginal dryness and atrophy.

Esterified estrogens Uses:

• Metastatic Breast cancer:

  • Treatment of metastatic breast cancer (palliation) in appropriately selected men and postmenopausal women.

• Hypoestrogenism (female):

  • Treatment of hypoestrogenism due to, castration, hypogonadism or primary ovarian failure

• Prostate cancer:

  • Palliative therapy of advanced prostatic carcinoma.

• Vasomotor symptoms associated with menopause:

  • Treatment of moderate to severe vasomotor symptoms associated with menopause

• Vulvar and vaginal atrophy associated with menopause:

  • Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause
  • Limitations of use: When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered
• Note:
  • The International Society for the Study of Women’s Sexual Health and The North American Menopause Society has endorsed the term genitourinary syndrome of menopause (GSM) as new terminology for vulvovaginal atrophy.
  • The term GSM encompasses all genital and urinary signs and symptoms associated with a loss of estrogen due to menopause.

Esterified estrogens (Menest) Dose in Adults

Esterified estrogens (Menest) General dosing guidelines:

• When treating symptoms of menopause, hormone therapy should be evaluated routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health.
• Combined estrogen/progestin therapy is indicated for postmenopausal persons with a uterus to decrease the risk of endometrial cancer.
• Individuals who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis.
• Adjust dose based on patient response.

Esterified estrogens (Menest) Dose in the treatment of advanced Prostate cancer:

• Oral: 1.25 to 2.5 mg thrice a day.

Esterified estrogens (Menest) Dose in the treatment of Female hypoestrogenism due to hypogonadism:

• Oral: 2.5 to 7.5 mg per day in divided doses for 20 days followed by a 10-day rest period.
• If bleeding does not occur by the end of the 10-day period, repeat the same dosing schedule; the number of courses to produce bleeding is dependent upon the responsiveness of the endometrium.
• If bleeding occurs before the end of the 10-day period, begin an estrogen-progestin cyclic regimen of 2.5 to 7.5 mg per day in divided doses for 20 days; during the last 5 days of estrogen therapy, give an oral progestin.
• If bleeding occurs before the regimen is concluded, discontinue therapy and resume on the fifth day of bleeding.

Esterified estrogens (Menest) Dose in the treatment of Female hypoestrogenism due to castration and primary ovarian failure:

• Oral: 1.25 mg per day, cyclically (3 weeks on and 1 week off).
• Adjust the dosage upward or downward, according to the severity of symptoms and patient response.
• For maintenance, adjust the dosage to the lowest level that will provide effective control.

Esterified estrogens (Menest) Dose in the treatment of Vasomotor symptoms associated with menopause:

• Oral: 1.25 mg per day administered cyclically (3 weeks on and 1 week off).
• If menstrual bleeding has not occurred for 2 months or more than 2 months, cyclic administration can be started at any time.
• If the patient is menstruating, cyclical administration is started on day 5 of the bleeding.

Esterified estrogens (Menest) Dose in the treatment of Vulvar and vaginal atrophy associated with menopause:

• Oral: 0.3 to ≥1.25 mg per day, initiate at the lowest dose, and adjust based on patient response.
• Administer cyclically (3 weeks on and 1 week off).

Esterified estrogens (Menest) Dose in the treatment of metastatic Breast cancer, (appropriately selected patients):

• Males and postmenopausal females:

  • Oral: 10 mg thrice in a day for at least 3 months

Esterified estrogens (Menest) Use in Children:

Not indicated.

Esterified estrogens Pregnancy Risk Category: X

• Use of estrogens esterified is not recommended during pregnancy.
• When used in combination with hormonal contraceptives, estrogen and progestin have not been shown to cause teratogenic side effects.

Esterified estrogens use during breastfeeding:

• Breast milk contains estrogens.
• It has been proven that estrogen can decrease the quality and quantity of human milk.
• If the medication is to be administered to a nursing woman, it is recommended that caution be taken.

Esterified estrogens (Menest) Dose in Kidney Disease:

Manufacturer's labeling doesn't provide any dosage adjustments; use with caution.

Esterified estrogens (Menest) Dose in Liver disease:

The manufacturer's labeling doesn't provide any dosage adjustments; use is contraindicated with hepatic impairment or dysfunction.

Side effects of Esterified estrogens (Menest):

• Cardiovascular:

  • Cerebrovascular Accident
  • Edema
  • Myocardial Infarction
  • Pulmonary Embolism
  • Retinal Thrombosis
  • Venous Thromboembolism
  • Hypertension
  • Local Thrombophlebitis

• Central Nervous System:

  • Chorea
  • Dementia (Exacerbation)
  • Depression
  • Dizziness
  • Exacerbation Of Epilepsy
  • Headache
  • Irritability
  • Migraine
  • Mood Disorder
  • Nervousness

• Dermatologic:

  • Chloasma
  • Erythema Multiforme
  • Erythema Nodosum
  • Pruritus
  • Loss Of Scalp Hair
  • Skin Rash
  • Urticaria

• Endocrine & Metabolic:

  • Change In Libido
  • Exacerbation Of Porphyria
  • Menstrual Disease (Alterations In Frequency And Flow Of Menstrual Patterns)
  • Premenstrual-Like Syndrome
  • Weight Gain
  • Fibrocystic Breast Changes
  • Galactorrhea
  • Hirsutism
  • Hypocalcemia
  • Weight Loss

• Gastrointestinal:

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

• Genitourinary:

  • Breakthrough Bleeding
  • Breast Hypertrophy
  • Vulvovaginal Candidiasis
  • Vaginitis
  • Breast Tenderness
  • Change In Cervical Ectropion
  • Change In Cervical Secretions
  • Cystitis-Like Syndrome
  • Dysmenorrhea
  • Endometrial Hyperplasia
  • Nipple Discharge

• Hematologic & Oncologic:

  • Endometrial Carcinoma
  • Hemorrhagic Eruption
  • Uterine Fibroids (Increased Size)
  • Malignant Neoplasm Of Breast
  • Malignant Neoplasm Of Ovary

• Hepatic:

  • Cholestatic Jaundice
  • Exacerbation Of Hepatic Hemangioma (Enlargement)

• Hypersensitivity:

  • Anaphylactoid Reaction
  • Angioedema
  • Anaphylaxis

• Neuromuscular & Skeletal:

  • Arthralgia
  • Leg Cramps

• Ophthalmic:

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

• Respiratory:

  • Exacerbation Of Asthma

Contraindications to Esterified estrogens (Menest):

• Hypersensitivity to estrogens and any component of the formula
• Undiagnosed abnormal Genital Bleeding;
• DVT or PE (current and/or historical of);
• Active or recent (within one year) arterial embombolic disease (eg stroke, MI);
• Breast carcinoma (known, suspected, or history of), except for patients being treated for metastatic disease.
• Known or suspected estrogen-dependent cancer
• Hepatic dysfunction or disease
• Pregnancy known or suspected

Warnings and precautions

• Breast cancer: [US Boxed Warn]

  • Data from the Women's Health Initiative (WHI), shows that postmenopausal women who use conjugated estrogens (CE) and medroxyprogesterone (MPA) have a higher risk of developing invasive breast cancer.
  • This risk decreases when therapy is stopped, according to observational studies.
  • Increased breast density may be linked to hormone therapy. An increase in abnormal mammogram findings that require further evaluation has been reported using estrogen alone or in combination.
  • Patients with breast cancer or bone metastases may experience severe hypercalcemia from estrogen use. If this happens, discontinue estrogen.
  • The WHI study found no evidence of an increase in breast cancer risk for women who had a hysterectomy with CE.
  • Postmenopausal women receiving hormone therapy could be at greater risk for breast cancer due to their estrogen or progestin doses, timing of therapy initiation, length of therapy, route of administration and patient characteristics.

• Dementia: [US Boxed Warning]

  • To prevent dementia, it is not a good idea to use estrogens without or with progestin.
  • The Women's Health Initiative Memory Study, (WHIMS) found that women over 65 years old who took CE or combined with MPA had a higher incidence of dementia.
  • The WHI memory studies were done on women over 65, but it is not known if the findings can be applied to younger women postmenopausal.
  • Hormone therapy is not recommended for any age in order to treat or prevent cognitive decline or dementia.

• Endometrial Cancer: [US Boxed Warn]

  • Endometrial cancer is more likely to occur in women who have an intact uterus.
  • A progestin may be added to estrogen therapy to reduce the risk of endometrial Hyperplasia, which is a precursor of endometrial carcinoma.
  • To rule out malignancy in women who have undiagnosed abnormal vaginal blood flow, it is important to perform appropriate diagnostic tests, including endometrial sampling, if necessary.
  • Endometrial cancer risk appears to be dependent on the duration and dose of treatment. It is highest for patients who have been using therapy for 5 or more years. This may continue even after discontinuation.
  • There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses.
  • A progestin should not be used if low doses are being administered locally to treat vaginal atrophy. However, there are no long-term data that support this recommendation.

• 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 thrombophilia (eg protein C or S deficiencies) might be at greater risk for venous embolism.

• The Lipid Effects

  • Patients with familial lipoprotein metabolism defects may experience an increase in glycerides.
  • Estrogen compounds have lipid effects, such as higher HDL-cholesterol or decreased LDL cholesterol.

• Ovarian cancer:

  • The information available regarding the risk of ovarian carcinoma and the use of estrogen/progestin therapy or menopausal estrogen is not consistent.
  • 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.

• Retinal vascular embolism:

  • Estrogens can cause retinal vein thrombosis.
  • Stop if you experience migraine, proptosis or diplopia or any other visual disturbances.

• Asthma

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

• Carbohydrate intolerance:

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

• Cardiovascular disease: [US-Boxed Warning]

  • To prevent heart disease, estrogens should not be combined with or without progestin.
  • Data from the Women's Health Initiative studies has shown that CE has an increased risk for stroke and deep vein thrombosis. In addition, CE has an increased risk for DVT, stroke and pulmonary emboli (PE) in postmenopausal females.
  • Males who have taken estrogens to treat prostate cancer have also experienced adverse cardiovascular events.
  • You should manage your risk factors well. If you suspect that adverse cardiovascular events may occur, stop using the medication immediately.
  • Other risk factors include hypertension, hypercholesterolemia, hypertension SLE, diabetes mellitus and obesity.
  • Transdermal administration is preferred to treat vasomotor symptoms associated with menopause in patients at high risk for developing thrombotic events.
  • Women with an active DVT, PE, or arterial thromboembolic diseases (stroke and MI) are not recommended.

• Fluid retention can lead to more severe diseases

  • Patients with fluid retention-related diseases, such as renal dysfunction or cardiac disease, 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

  • Hepatic disease is a contraindication.
  • If jaundice occurs or if there are acute or chronic hepatic disorders, discontinue use.
  • Patients with hepatic dysfunction are less likely to be able to metabolize estrogens.
  • Be cautious if you have a history of cholestatic jaundice due to previous estrogen use or pregnancy.

• 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.

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Esterified estrogens: Drug Interaction

Monitoring parameters:

Females:

• Prior to therapy, baseline risk for breast cancer and CVD.
• During therapy, age-appropriate breast, and pelvic exams;
• blood pressure;
• unscheduled bleeding lasting more than 6 months for endometrial pathology (sooner in patients who are diabetic, obese, or have a history of endometrial cancer);
• serum triglycerides (2 weeks after starting therapy in patients with a baseline level of more than 200 mg/dL);
• TSH (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement).

Menopausal symptoms:

• Efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate.
• The duration of treatment should be evaluated at least annually.

Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms or GSM. 

How to administer?

It may be administered without regard to meals. 

Mechanism of action of Esterified estrogens (Menest):

• Esterified estrogens are a combination of estrogenic substances.
• The principal component is estrone.The preparations contain between 75 percent and 85 percent sodium estrone, sulfate, and 6 percent to 15% sodium equilin sodium sulfate.
• This means that they are not >90 percent. Estrogens are responsible to the development and maintenance the female reproductive system as well as secondary sexual characteristics.
• Estradiol, the main intracellular human estrogen, is more potent that estrone or estriol at receptor level. It is also the primary estrogen secreted before menopause.
• Estrone and estrone succate are more abundant in males than they are in females after menopause.
• Through a negative feedback mechanism, estrogens regulate the pituitary secretion gonadotropins,luteinizing hormone and follicle stimulating hormone.
• Estrogen replacement decreases high levels of these hormones.

Absorption:

• Readily

Distribution:

• Widely distributed;
• high concentrations in the sex hormone target organs

Protein binding:

• Bound to sex hormone-binding globulin and albumin

Metabolism:

• Hepatic;
• partial metabolism via CYP3A4 enzymes;
• estradiol is reversibly converted to estrone and estriol;
• oral estradiol also undergoes enterohepatic recirculation by conjugation in the liver, followed by excretion of sulfate and glucuronide conjugates into the bile, then hydrolysis in the intestine and estrogen reabsorption.
• Sulfate conjugates are the primary form found in postmenopausal women.

Excretion:

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

International Brand Names of Esterified estrogens:

• Estragyn
• Menest

Esterified estrogens Brand Names in Pakistan:

There is no brand available in Pakistan.