DINOTILIS

Indications

• Vaginal atrophy associated with menopause
• Prophylaxis of recurrent urinary tract infections in postmenopausal women

Dosage

Children: Estriol is not typically indicated for pediatric use; consult the BNF for Children for further guidance.

Adults: Refer to the BNF for specific dosing guidelines. Common formulations include vaginal cream, pessaries, or tablets which should be used as directed by a healthcare professional.

Mechanism of action

Estriol exerts its effects by binding to estrogen receptors present in target cells, facilitating their entry into the nucleus where they regulate gene transcription. This process leads to the formation of messenger RNA (mRNA), which is translated into proteins that mediate estriol's effects. Estriol increases the hepatic synthesis of sex hormone binding globulin (SHBG) and thyroid-binding globulin (TBG), while also suppressing follicle-stimulating hormone (FSH) from the anterior pituitary. Its estrogenic activity helps correct the atrophic changes in the vaginal epithelium seen in estrogen-deficient states.

Pharmacodynamics

Estriol is one of the three principal estrogens in the human body, predominantly produced during pregnancy. It has been shown to alleviate symptoms of multiple sclerosis in pregnant women. Estriol's weak estrogenic properties make it particularly useful in restoring the physiological functions of estrogen-deficient tissues.

Pharmacokinetics

Estriol is absorbed and metabolized in the liver, where it undergoes biotransformation to various metabolites. It exhibits a relatively short half-life, necessitating frequent dosing in therapeutic settings. The pharmacokinetic profile can vary based on the route of administration and individual patient factors.

Contra-indications

• Active arterial thromboembolic disease (e.g. angina or myocardial infarction)
• History of breast cancer
• History of venous thromboembolism
• Oestrogen-dependent cancer
• Recent arterial thromboembolism

Adverse effects

• Abdominal pain
• Headaches
• Nausea
• Skin reactions
• Vaginal haemorrhage
• Diarrhoea
• Fluid retention
• Genital pruritus
• Increased risk of ischaemic stroke
• Insomnia
• Endometrial hyperplasia
• Weight increase
• Vulvovaginal fungal infection
• Migraine or migraine-like headaches

Interactions

• Increased risk of thrombotic events with prolonged exposure to unopposed oestrogens
• Antiphospholipid antibodies may increase the risk of thrombotic events

Precautions

• Caution in patients with a history of migraine
• Regular review of treatment necessary to assess need for continued therapy
• Increased risk of endometrial cancer with prolonged use of oestrogen
• Increased risk of ovarian cancer with long-term use of combined HRT or oestrogen-only HRT

Pregnancy

Not known to be harmful, estriol levels can indicate fetal health.

Breast-feeding

Avoid; adverse effects on lactation.

Storage

Store in a cool, dry place away from light.

Formulations

• Estradiol 10 microgram pessaries
• Estradiol 10 microgram vaginal tablets
• Estring 7.5 micrograms/24 hours vaginal delivery system
• Vagifem 10 microgram vaginal tablets

Mechanism of action

Estriol levels can be measured to give an indication of the general health of the fetus. DHEA-S is produced by the adrenal cortex of the fetus. This is converted to estriol by the placenta. If levels of "unconjugated estriol" are abnormally low in a pregnant woman, this may indicate a problem with the development of the child. The drug 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 estriol 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. ... Synthetic estriol, is chemically and biologically identical to endogenous human estriol. Estriol, a weak estrogen, is a natural metabolite of estradiol, the predominant estrogen. Estriol exerts estrogenicity by binding to estrogen receptors, present in the female genital tract. Estriol, oral or vaginal, similar to estradiol, corrects lowered proliferation and abnormal physiology in the atrophic vaginal epithelium seen in estrogen deficient states, such as after natural or surgical menopause. In contrast, the histology of the endometrium after using Gynest Cream rarely shows minor signs of proliferation in previously atrophic endometria. Estrogens have an important role in the reproductive, skeletal, cardiovascular, and central nervous systems in women, and act principally by regulating gene expression. Biologic response is initiated when estrogen binds to a ligand-binding domain of the estrogen receptor resulting in a conformational change that leads to gene transcription through specific estrogen response elements (ERE) of target gene promoters; subsequent activation or repression of the target gene is mediated through 2 distinct transactivation domains (ie, AF-1 and AF-2) of the receptor. The estrogen receptor also mediates gene transcription using different response elements (ie, AP-1) and other signal pathways. Recent advances in the molecular pharmacology of estrogen and estrogen receptors have resulted in the development of selective estrogen receptor modulators (eg, clomiphene, raloxifene, tamoxifen, toremifene), agents that bind and activate the estrogen receptor but that exhibit tissue-specific effects distinct from estrogen. Tissue-specific estrogen-agonist or -antagonist activity of these drugs appears to be related to structural differences in their estrogen receptor complex (eg, specifically the surface topography of AF-2 for raloxifene) compared with the estrogen (estradiol)-estrogen receptor complex. A second estrogen receptor also has been identified, and existence of at least 2 estrogen receptors (ER-alpha, ER-beta) may contribute to the tissue-specific activity of selective modulators. While the role of the estrogen receptor in bone, cardiovascular tissue, and the CNS continues to be studied, emerging evidence indicates that the mechanism of action of estrogen receptors in these tissues differs from the manner in which estrogen receptors function in reproductive tissue. /Estrogen General Statement/ Intracellular cytosol-binding proteins for estrogens have been identified in estrogen-responsive tissues including the female genital organs, breasts, pituitary, and hypothalamus. The estrogen-binding protein complex (ie, cytosol-binding protein and estrogen) distributes into the cell nucleus where it stimulates DNA, RNA, and protein synthesis. The presence of these receptor proteins is responsible for the palliative response to estrogen therapy in women with metastatic carcinoma of the breast. /Estrogen General Statement/ Estrogens have generally favorable effects on blood cholesterol and phospholipid concentrations. Estrogens reduce LDL-cholester

Pharmacodynamics

Estriol (also oestriol) is one of the three main estrogens produced by the human body. It is only produced in significant amounts during pregnancy as it is made by the placenta. In pregnant women with multiple sclerosis (MS), estriol reduces the disease's symptoms noticeably, according to researchers at UCLA's Geffen Medical School.