FEMODENE ED

Indications

• Hormonal contraception
• Menstrual cycle regulation
• Hormone replacement therapy
• Management of menopausal symptoms
• Treatment of polycystic ovary syndrome
• Endometriosis management
• Dysfunctional uterine bleeding

Dosage

Adults: The dosing of ethinylestradiol varies based on the formulation and indication. Commonly, it is administered in combination with progestins for contraception, typically as a daily oral tablet containing 20 to 35 micrograms of ethinyles

Mechanism of action

Ethinylestradiol acts as a synthetic estrogen by binding to estrogen receptors in estrogen-responsive tissues. It suppresses gonadotropic hormone secretion from the pituitary gland, leading to decreased luteinizing hormone levels. This results in reduced endometrial vascularization and prevents ovulation by inhibiting the hormonal changes necessary for ovarian follicle maturation. Additionally, it thickens cervical mucus to impede sperm movement and alters the endometrium to prevent implantation.

Pharmacodynamics

Ethinylestradiol has a long duration of action and a wide therapeutic index. It effectively decreases luteinizing hormone and gonadotropic hormone levels, thereby preventing ovulation and altering reproductive tract conditions. Patients using ethinylestradiol should be made aware of potential thrombotic risks, particularly in specific populations such as smokers and those with a history of thromboembolic disorders.

Pharmacokinetics

Ethinylestradiol is well absorbed when taken orally, with peak plasma concentrations occurring approximately 1 to 2 hours after administration. It has a high plasma protein binding rate, predominantly to sex hormone-binding globulin. The drug undergoes extensive hepatic metabolism, primarily by cytochrome P450 enzymes, and has a half-life of about 10-20 hours. Excretion is primarily via the kidneys, with metabolites being eliminated in urine.

Contra-indications

• Pregnancy
• History of thromboembolic disorders
• Active liver disease
• Severe hypertension
• Undiagnosed vaginal bleeding
• Hormone-sensitive cancers (e.g., breast cancer)
• Known hypersensitivity to ethinylestradiol or any component of the formulation

Adverse effects

• Nausea
• Headache
• Breast tenderness
• Mood changes
• Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism)
• Increased risk of certain cancers (e.g., breast and endometrial cancer)
• Hypertension
• Skin reactions (e.g., rash)

Interactions

• Antibiotics (e.g., rifampicin) may reduce effectiveness
• Anticonvulsants (e.g., phenytoin, carbamazepine) may reduce effectiveness
• St. John's Wort may reduce effectiveness
• Fostemsavir increases ethinylestradiol concentration
• Certain antiretrovirals may interact with ethinylestradiol

Precautions

• Monitor for signs of thromboembolism
• Caution in patients with a history of migraines
• Caution in patients with liver disease
• Regular breast examinations and mammograms are recommended
• Consider risks versus benefits in patients with a family history of breast cancer
• Use with caution in patients with hypertension, renal disease, asthma, epilepsy, and systemic lupus erythematosus

Pregnancy

Ethinylestradiol is contraindicated in pregnancy due to potential risks to the fetus and maternal health.

Breast-feeding

Caution is advised as ethinylestradiol may be excreted in breast milk. It is recommended to weigh the benefits of the treatment against potential risks to the nursing infant.

Storage

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

Formulations

• Tablets
• Transdermal patches
• Gels
• Sachets

Indications

• Contraception
• Regulation of menstrual cycle
• Management of endometrial disorders

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing guidelines.

Adults: Refer to the BNF for specific adult dosing guidelines. It is typically administered in combination with an estrogen in oral contraceptive formulations.

Mechanism of action

Gestodene inhibits ovulation by suppressing the mid-cycle surge of luteinizing hormone, thickening cervical mucus to impede sperm passage, and making the endometrium less receptive to implantation. It has minimal estrogenic activity and reduced androgenic effects compared to older progestins. Gestodene also binds to mineralocorticoid receptors, acting as a competitive aldosterone inhibitor.

Pharmacodynamics

Gestodene exhibits potent progestational effects, making it effective in preventing ovulation and altering the uterine environment. Its low estrogenic and androgenic activities contribute to a favorable side effect profile, with minimal impact on lipid and carbohydrate metabolism. Studies indicate a low incidence of side effects associated with both the progestin and estrogen components in combination formulations.

Pharmacokinetics

The pharmacokinetics of gestodene includes absorption following oral administration, with peak plasma concentrations typically reached within a few hours. It is highly protein-bound, primarily to albumin and sex hormone-binding globulin. The metabolism of gestodene occurs mainly in the liver, and it is eliminated via urine and feces. The half-life of gestodene permits once-daily dosing in contraceptive regimens, ensuring effective plasma levels.

Adverse effects

• Nausea
• Headache
• Breast tenderness
• Mood changes
• Weight gain
• Irregular menstrual bleeding

Interactions

• Antibiotics may reduce effectiveness of hormonal contraceptives
• Anticonvulsants may decrease plasma concentrations of gestodene
• St. John's Wort may reduce the efficacy of gestodene-containing contraceptives

Precautions

• History of thromboembolic disorders
• Uncontrolled hypertension
• Liver disease
• Diabetes with vascular involvement
• Smokers over 35 years old should be cautioned about cardiovascular risks

Pregnancy

Gestodene is contraindicated in pregnancy. It may cause harm to the fetus.

Breast-feeding

Gestodene is excreted in breast milk; caution is advised when used during breastfeeding.

Storage

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

Formulations

• Combined oral contraceptive tablets containing gestodene and ethinylestradiol

Mechanism of action

Ethinylestradiol is a synthetic estrogenic compound. Use of estrogens have a number of effects on the body including reduced bone density. Combined oral contraceptives suppress ovulation by suppressing gonadotrophic hormone, thickening cervical mucus to prevent the travel of sperm, and preventing changes in the endometrium required for implantation of a fertilized egg. Ethinylestradiol decreases luteinizing hormone, decreasing vascularity in the endometrium. It also increases sex hormone binding globulin. 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. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens. 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 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 e

Pharmacodynamics

Ethinylestradiol is a synthetic estrogen that decreases luteinizing hormone to decrease endometrial vascularization, and decreases gonadotrophic hormone to prevent ovulation. It has a long duration of action as it is taken once daily, and a wide therapeutic index as overdoses are generally not associated with serious adverse effects. Patients should be counselled regarding the risks of thrombotic events.

Mechanism of action

This estrogen-progestogen combination acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinizing hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation. Gestodene, one of three new gonane progestins, is the most potent on a per weight basis in regard to progestational effects and has little or no estrogenic effect. In in vivo animal studies, gestodene also has less androgenic activity compared with progestins found in older combination oral contraceptive formulations. It binds to mineralocorticoid receptors and consequently is a competitive aldosterone inhibitor, leading to speculation that it may be beneficial in hypertensive patients. ...In general, studies show that the incidence of side effects associated with the progestin and estrogen components tends to be low, with very little impact on lipid and carbohydrate metabolism. ... Gestodene (17 alpha-ethynyl-13 beta-ethyl-17 beta-hydroxy-4, 15-gonadien-3-one) is the most potent synthetic progestin currently available and it is widely used as a fertility regulating agent in a number of contraceptive formulations because of its high effectiveness, safety and acceptability. The observation that contraceptive synthetic progestins exert hormone-like effects other than their progestational activities, prompted us to investigate whether gestodene (GSD) administration may induce estrogenic effects, even though the GSD molecule does not interact with intracellular estrogen receptors (ER). To assess whether GSD may exert estrogenic effects through some of its neutral metabolites, a series of experimental studies were undertaken using GSD and three of its A-ring reduced metabolites. Receptor binding studies by displacement analysis confirmed that indeed GSD does not bind to the ER, whereas its 3 beta,5 alpha-tetrahydro reduced derivative (3 beta GSD) interacts with a relative high affinity with the ER. The 3 alpha,5 alpha GSD isomer (3 alpha GSD) also binds to the ER, though to a lesser extent. The ability of the A-ring reduced GSD derivatives to induce estrogenic actions was evaluated by the use of two different molecular bioassays: (a) transactivation of a yeast system co-transfected with the human ER alpha (hER alpha) gene and estrogen responsive elements fused to the beta-galactosidase reporter vector and (b) transactivation of the hER alpha-mediated transcription of the chloramphenicol acetyl transferase (CAT) reporter gene in a HeLa cells expression system. The estrogenic potency of 3 beta GSD was also assessed by its capability to induce estrogen-dependent progestin receptors (PR) in the anterior pituitary of castrated female rats. The results demonstrated that 3 beta GSD and 3 alpha GSD were able to activate, in a dose-dependent manner, the hER alpha-mediated transcription of both the beta-galactosidase and the CAT reporter genes in the yeast and HeLa cells expression systems respectively. In both assays the 3 beta derivative of GSD exhibited a significantly greater estrogenic effect than its 3 alpha isomer, while unchanged GSD and 5 alpha GSD were completely ineffective. Neither 3 beta GSD nor 3 alpha GSD exhibited estrogen synergistic actions. Interestingly, the pure steroidal anti-estrogen ICI-182,780 diminished the transactivation induced by 3 beta GSD and 3 alpha GSD in the yeast expression system. Furthermore, administration of 3 beta GSD resulted in a significant increase of estrogen-dependent PR in the anterior pituitaries of castrated rats in comparison with vehicle-treated animals. The characteristics of the 3 beta GSD-induced PR were identical to those induced by estradiol benzoate. The overall results demonstrate that 3 beta GSD and its 3 alpha isomeric alcohol specifically bind to the ER and possess a weak intrinsic estrogenic activity, whereas unmodified GSD does not. The data contribute to a better understanding of the GSD mechanism of action and a