Introduction
Valestra Tablet 2 mg (also known as E2V) is a pro-drug ester of Estradiol, a naturally occurring hormone that circulates endogenously within the human body. Estradiol is the most potent form of all mammalian estrogenic steroids and acts as the major female sex hormone. As a pro-drug of estradiol, estradiol acetate therefore has the same downstream effects within the body through binding to the Estrogen Receptor (ER) including ERα and ERβ subtypes, which are located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain.
Estradiol is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%). First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter systemic circulation and exert its estrogenic effects . Esterification of estradiol aims to improves absorption and bioavailability after oral administration (such as with Estradiol valerate) or to sustain release from depot intramuscular injections (such as with Estradiol Cypionate) through improved lipophilicity. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol. Ester pro-drugs of estradiol are therefore considered to be bioidentical forms of estrogen .
Estradiol valerate is commercially available as an intramuscular injection as the product Delestrogen and is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. However, 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 . 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. Because of the difference in potency between estradiol and estrone, menopause (and a change in primary hormone from estradiol to estrone) is associated with a number of symptoms associated with this reduction in potency and in estrogenic effects. These include hot flashes, vaginal dryness, mood changes, irregular menses, chills, and sleeping problems. Administration of synthetic and bioidentical forms of estrogen, such as estradiol valerate, has shown to improve these menopausal symptoms.
Uses
Estradiol valerate is an estradiol prodrug used to treat some effects of menopause, hypoestrogenism, androgen dependant carcinoma of the prostate, and in combination products for endometriosis and contraception.
Estradiol valerate is commercially available as an intramuscular injection as the product Delestrogen and is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
Estradiol valerate is also available in combination with Dienogest as the commercially available product Natazia used for the prevention of pregnancy and for the treatment of heavy menstrual bleeding.
Associated Conditions
Pharmacodynamics
Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects .
Mechanism of Action
Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.
Increases in the down-stream effects of ER binding reverses some of the symptoms of menopause, which are primarily caused by a loss of estrogenic activity.
Absorption
IM Injection: 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 .
Natazia: After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve [AUC(0–24h)] was 1301 pg·h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen.
Route of Elimination
Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.
Food Interactions
- Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of estradiol valerate.
- Exercise caution with St. John's Wort. This herb induces the CYP3A4 metabolism of estradiol valerate. Therefore it may reduce the serum concentration and effectiveness of estradiol valerate.
Dosage
For initiation and continuation of treatment of menopausal symptoms, the lowest effective dose for the shortest duration should be used. Treatment to control menopausal symptoms should be initiated with Valestra Tablet 2 mg 1 mg tablet. If considered necessary, Valestra Tablet 2 mg 2 mg should be used. Once treatment is established the lowest effective does necessary for relief of symptoms should be used.
In women with an intact uterus, a progestogen should be added to Valestra Tablet 2 mg 1 mg for at least 12-14 days each month/28 day cycle. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.
How to start Valestra Tablet 2 mg 1 mg: If the woman has an intact uterus and is still menstruating, a combination regimen with Valest and a progestogen, commencing with the oestrogen phase, should begin on the first day of bleeding. If the menstrual periods are very infrequent or if amenorrhoea is established, she may start at any time provided, if appropriate, pregnancy has been excluded.
In women transferring from a continuous combined HRT product, treatment with Valestra Tablet 2 mg may be started on any day. In women transferring from cyclic or continuous sequential HRT regimens the woman should complete the cycle and then change to without a break in therapy.
Missed or lost tablets: If the woman forgets to take a tablet at the usual time, she may take it within the following 12 hours. If the woman is more than 12 hours late the forgotten tablet should not be taken and the remaining tablets taken at the usual time on the right days. A missed dose may lead to breakthrough bleeding or spotting.
Pediatric population: Not recommended for children
Method of administration: The tablets can be taken with or without food. The tablets should be swallowed whole with a glass of water or milk. The tablets should be taken at the same time each day.
