DENOPAUS 1 mg/2 mg

Indications

• Endometriosis
• Management of symptoms associated with female sex hormone-responsive conditions
• Treatment of conditions related to excessive androgen activity, such as acne and hirsutism

Dosage

Adults: The recommended adult

Mechanism of action

Dienogest acts as an agonist at the progesterone receptor (PR) with a weak affinity comparable to that of progesterone, yet it exhibits a potent progestagenic effect within the endometrium, inducing endometrial atrophy with prolonged use. It reduces endogenous oestradiol production, thereby suppressing its trophic effects on both eutopic and ectopic endometrium. Additionally, dienogest displays antagonistic activity at androgen receptors, which helps improve symptoms of androgen excess.

Pharmacodynamics

Dienogest exhibits a strong progestagenic effect that leads to endometrial atrophy after extended use. It mediates antiandrogenic effects equivalent to about one third of cyproterone acetate's potency. A dose of 2 mg can inhibit ovarian follicle growth and maintain low progesterone levels, while also directly inhibiting ovulation at a dose of 1 mg/kg. Clinical trials have demonstrated its efficacy in reducing symptoms and lesions associated with endometriosis. Dienogest does not possess antiestrogenic activity and instead induces hypoestrogenic effects by decreasing the expression of estrogen receptors.

Pharmacokinetics

Dienogest is well absorbed after oral administration. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes. The drug's half-life is approximately 9 to 10 hours, allowing for once-daily dosing. It is eliminated in urine and feces, with a significant portion being excreted as metabolites. The pharmacokinetics may be affected by co-administration with certain drugs, which can either increase or decrease its exposure.

Contra-indications

• Known hypersensitivity to dienogest or any of its components
• Active venous thromboembolism
• History of severe liver disease
• Hormone-dependent malignant tumors

Adverse effects

• Alopecia
• Breast abnormalities
• Dizziness
• Fatigue
• Gastrointestinal discomfort
• Headaches
• Nausea
• Pelvic pain
• Skin reactions
• Uterine disorders
• Vulvovaginal disorders
• Weight changes

Interactions

• Dronedarone: Unknown (increases exposure)
• Cobicistat: Unknown (increases exposure)
• Crizotinib: Unknown (increases exposure)
• Idelalisib: Unknown (increases exposure)
• Imatinib: Unknown (increases exposure)
• Letermovir: Unknown (increases exposure)
• Mitotane: Unknown (decreases exposure)
• Nilotinib: Unknown (increases exposure)
• Erythromycin: Unknown (increases exposure)
• Rifampicin: Unknown (decreases exposure)

Precautions

• Consider alternative therapies in patients with a history of thromboembolic disorders
• Monitor for signs of liver dysfunction
• Assess risk factors for hormone-dependent tumors

Pregnancy

Dienogest is contraindicated during pregnancy as it may adversely affect fetal development.

Breast-feeding

Dienogest is excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets
• Capsules

Indications

• Menopausal symptoms
• Osteoporosis prophylaxis
• Irregular menstruation
• Vulvovaginal atrophy
• Postmenopausal urogenital conditions

Dosage

Adults: The typical adult dosage of estradiol is 2 mg daily, initiated on day 1-5 of the menstrual cycle or at any time if cycles have ceased or are infrequent, taken with

Mechanism of action

Estradiol exerts its effects by binding to estrogen receptors, specifically estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), as well as the G protein-coupled estrogen receptor (GPER). This binding triggers the receptor-ligand complex to translocate to the nucleus, where it regulates gene transcription and the synthesis of specific proteins that mediate estradiol's physiological effects.

Pharmacodynamics

Estradiol acts on estrogen receptors to alleviate vasomotor symptoms such as hot flashes and urogenital symptoms including vaginal dryness. It has beneficial effects on bone density by inhibiting bone resorption and improving plasma lipid profiles. Additionally, estradiol decreases follicle-stimulating hormone (FSH) levels by suppressing its formation in the anterior pituitary gland. Notably, it may increase the risk of cardiovascular events, venous thromboembolism, and stroke, necessitating caution in high-risk populations.

Pharmacokinetics

Estradiol is rapidly absorbed when administered orally, with a bioavailability affected by first-pass metabolism in the liver. It is extensively metabolized in the liver, conjugated to form estrone and estrone sulfate, and eliminated through urine. The half-life of estradiol varies depending on the route of administration, with peak plasma concentrations occurring within 1-3 hours post-administration. Continuous use can lead to accumulation and requires careful monitoring of therapy duration and dosage adjustments.

Contra-indications

• History of thromboembolic disorders
• Known or suspected estrogen-dependent tumors
• Undiagnosed abnormal genital bleeding
• Severe liver dysfunction
• Pregnancy

Adverse effects

• Nausea
• Headaches
• Weight changes
• Breast tenderness
• Mood alterations
• Vaginal discharge
• Oedema
• Skin reactions
• Thromboembolic events
• Cerebrovascular accidents
• Endometrial hyperplasia
• Angioedema

Interactions

• Antiepileptics (carbamazepine, phenytoin, etc.) may decrease efficacy of estradiol
• Bosentan may decrease efficacy of estradiol
• Modafinil may decrease efficacy of estradiol
• Rifamycins may decrease efficacy of estradiol
• St. John's Wort may decrease efficacy of estradiol
• Ritonavir may decrease efficacy of estradiol

Precautions

• Monitor for signs of thromboembolic events
• Evaluate for endometrial hyperplasia in women with a uterus
• Consider cardiovascular risks before initiating therapy
• Assess liver function prior to use
• Use with caution in patients with a history of depression

Pregnancy

Estradiol is contraindicated in pregnancy due to potential harm to the fetus and increased risk of thromboembolic events.

Breast-feeding

Estradiol is excreted in breast milk; caution is advised when used by nursing mothers as it may affect milk production.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets (1 mg, 2 mg)
• Vaginal ring (continuous use, replaced every 3 months)

Mechanism of action

Dienogest acts as an agonist at the progesterone receptor (PR) with weak affinity that is comparable to that of progesterone but has a very potent progestagenic effect in the endometrium, causing endometrial atrophy after prolonged use. It promotes antiproliferative, immunologic and antiangiogenic effects on endometrial tissue. Dienogest reduces the level of endogenous production of oestradiol and thereby suppressing the trophic effects of oestradiol on both the eutopic and ectopic endometrium. Continous administration of dienogest results in hyperprogestogenic and moderately hypoestrogenic endocrine environment, which causes initial decidualization of endometrial tissue. It is an antagonist at androgen receptors, improve androgenic symptoms such as acne and hirsutism.

Pharmacodynamics

Dienogest exhibits a very potent progestagenic effect in the endometrium, and causes endometrial atrophy after prolonged use . It also mediates an antiandrogenic effect that is equivalent to approximately one third that of cyproterone acetate. A dose of 2 mg inhibits the growth of ovarian follicles at 10 mm and maintains the concentration of progesterone at a low level, but has a weak inhibitory effect on FSH and LH. 1mg/kg of dienogest also directly inhibits ovulation. In clinical trials composing of patients with endometriosis, dienogest therapy effectively reduced painful symptoms and endometriotic lesions associated with the disorder. Dienogest displays no antiestrogenic activity as it activate neither estrogen receptor (ER) α nor ERβ, and causes hypoestrogenic effects instead as it is shown to decrease the relative expressions of ERβ and ERα. It has no glucocorticoid or mineralocorticoid effects. In combined oral contraceptive pills (COCP) with ethinyloestradiol, dienogest conjuction therapy effectively reduces the symptoms of acne and hirsutism, as well as improving excessively heavy or prolonged menstrual bleeding.

Mechanism of action

Estrogen is found in the the breast, uterine, ovarian, skin, prostate, bone, fat, and brain tissues. The main source of estrogen in adult women during the reproductive period of life is the ovarian follicle, which secretes 70 to 500 mcg of estradiol each day. After menopause, however, the majority of endogenous estrogen is produced by transformation of androstenedione (which is secreted by the adrenal cortex) to estrone in the peripheral tissues. Both estrone and its sulphate conjugated form, estrone sulphate, represent the most abundant estrogens found in postmenopausal women. Estradiol, however, is considerably more potent than estrone and estriol at the estrogen receptor (ER). As a result, the higher estrone concentration in postmenopausal population, can cause various undesirable effects. These effects may include hot flashes, chills, vaginal dryness, mood swings, irregular menstruation, and chills, in addition to sleep problems. Estradiol workings by binding to subtypes of the estrogen receptor: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). It also exerts potent agonism of G Protein-coupled estrogen receptor (GPER), which is recognized an important regulator of this drug's rapid effects. Once the estrogen receptor has bound to its ligand, it enters the nucleus of the target cell, regulating gene transcription and formation of of messenger RNA. This mRNA makes contact with ribosomes producing specific proteins that express the effect of estradiol upon the target cell. Agonism of estrogen receptors increases pro-estrogenic effects, leading to the relief of vasomotor and urogenital symptoms of a postmenopausal or low estradiol state. Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. 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. ... 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. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. 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

Pharmacodynamics

Estradiol acts on the on the estrogen receptors to relieve vasomotor systems (such as hot flashes) and urogenital symptoms (such as vaginal dryness and dyspareunia). Estradiol has also been shown to exert favorable effects on bone density by inhibiting bone resorption. Estrogen appears to inhibit bone resorption and may have beneficial effects on the plasma lipid profile. Estrogens cause an increase in hepatic synthesis of various proteins, which include sex hormone binding globulin (SHBG), and thyroid-binding globulin (TBG). Estrogens are known to suppress the formation of follicle-stimulating hormone (FSH) in the anterior pituitary gland. **A note on hyper-coagulable state, cardiovascular health, and blood pressure** Estradiol may cause an increased risk of cardiovascular disease, DVT, and stroke, and its use should be avoided in patients at high risk of these conditions. Estrogen induces a hyper-coagulable state, which is also associated with both estrogen-containing oral contraceptive (OC) use and pregnancy. Although estrogen causes an increase in levels of plasma renin and angiotensin. Estrogen-induced increases in angiotensin, causing sodium retention, which is likely to be the mechanism causing hypertension after oral contraceptive treatment.