REGULON

Indications

• Contraception
• Uterine fibroids

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: 75 micrograms daily, taken continuously at the same time each day starting on day 1 of the menstrual cycle. If the dose is delayed by more than 12 hours, the missed dose should not be taken, and the next dose should be taken at the normal time.

Mechanism of action

Desogestrel enters cells passively and selectively binds to progesterone receptors, producing an effect akin to a transcription factor, which modifies mRNA synthesis. Its active metabolite, etonogestrel, exhibits high progestational activity with minimal androgenicity. The primary contraceptive mechanism is the inhibition of ovulation, supplemented by changes in cervical mucus and endometrial alterations that reduce implantation likelihood.

Pharmacodynamics

Desogestrel affects reproductive hormones by modifying luteinizing hormone and follicle-stimulating hormone levels, leading to delayed menstruation and increased cervical mucus viscosity. It also influences metabolic processes, including insulin secretion and fat deposition. The primary therapeutic effect results from ovulation inhibition, confirmed by clinical trials showing a high efficacy rate compared to other progestogen-only contraceptives.

Pharmacokinetics

Following oral administration, desogestrel is rapidly absorbed and metabolized into etonogestrel, which is the active form. It has a half-life that allows for once-daily dosing. The pharmacokinetics might be altered by concomitant medications, particularly those affecting liver enzymes, leading to potential changes in efficacy.

Contra-indications

• Acute porphyrias
• Current breast cancer
• Hypersensitivity or allergy to peanuts or soya

Adverse effects

• Dizziness
• Breast tenderness
• Nausea
• Abdominal pain
• Changes in menstrual bleeding
• Headache
• Acne
• Weight gain

Interactions

• Antiepileptics (carbamazepine, eslicarbazepine, fosphenytoin, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide, topiramate) - may decrease efficacy
• Lamotrigine - may increase exposure
• Berotralstat - may decrease efficacy
• Lumacaftor - may decrease efficacy
• Modafinil - may decrease efficacy
• Rifamycins - may decrease efficacy
• St John's wort - may decrease efficacy
• Sugammadex - may decrease exposure

Precautions

• Caution in patients with cardiac dysfunction
• Monitor closely in patients with diabetes
• Consider risks in women with a history of venous thromboembolism

Pregnancy

Not known to be harmful.

Breast-feeding

Progestogen-only contraceptives do not affect lactation.

Storage

Store in a cool, dry place below 30°C, protect from light.

Formulations

• Desogestrel 75 micrograms tablet

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)

Indications

• Contraception
• Regulation of menstrual cycles
• Management of polycystic ovary syndrome
• Management of endometriosis

Dosage

Children: Refer to the BNF for Children for appropriate pediatric dosing recommendations.

Adults: Refer to the BNF for specific dosing guidelines, as doses may vary based on formulation and indication.

Mechanism of action

Ethinyl estradiol exerts its effects by binding to estrogen receptors in target tissues, leading to changes in gene expression. This action promotes the development of secondary sexual characteristics and regulates the menstrual cycle. It also inhibits ovulation by suppressing gonadotropin release from the pituitary gland, thereby reducing follicular maturation and ovum release.

Pharmacodynamics

Ethinyl estradiol influences the reproductive system by stabilizing the endometrial lining, making it less conducive to implantation. It also affects the cervical mucus, making it thicker and less penetrable to sperm. The pharmacodynamic effects are dose-dependent, contributing to contraceptive efficacy and menstrual regulation.

Pharmacokinetics

Ethinyl estradiol is well-absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1 to 2 hours after oral administration. It undergoes extensive first-pass metabolism in the liver, resulting in a bioavailability of approximately 40-60%. The drug is primarily metabolized by cytochrome P450 enzymes, particularly CYP3A4, and has a half-life of about 13 to 27 hours. Ethinyl estradiol is excreted mainly in urine and feces.

Interactions

• fostemsavir + ethinylestradiol from a combined hormonal contraceptive: Moderate (increases concentration)

Pregnancy

Ethinyl estradiol is generally not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

Ethinyl estradiol may pass into breast milk; caution is advised.

Storage

Store at room temperature, away from light and moisture.

Mechanism of action

Desogestrel enters the cell passively and acts by binding selectively to the progesterone receptor and generating low androgenic activity. Its binding produces an effect like a transcription factor and thus, it produces modifications in the mRNA synthesis. The active metabolite of desogestrel, [etonogestrel], presents a combination of high progestational activity with minimal intrinsic androgenicity. Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus, which increase the difficulty of sperm entry into the uterus, and changes in the endometrium which reduce the likelihood of implantation. Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity. The relevance of this latter finding in humans is unknown. In contrast to traditional progestogen-only pills, the contraceptive effect of Cerazette is achieved primarily by inhibition of ovulation. Other effects include increased viscosity of the cervical mucus. Recent studies have demonstrated that desogestrel activates the estrogen receptor-alpha at an activity of about 50% of that of 17beta-estradiol but activates the estrogen receptor-beta at an activity of only 20%. Desogestrel and/or its metabolite 3-keto-desogestrel (etonogestrel) were strongly progestogenic (approximately twofold over progesterone), weakly or not androgenic in animal studies in vivo and in-vitro binding assays and weakly or not active on the glucocorticoid receptor. The active metabolite of desogestrel, 3-ketodesogestrel, strongly bound to and activated progesterone receptor-A and, to a slightly lesser extent, progesterone receptor-B Improvement in oral contraceptive formulations was originally achieved through dose reduction of the estrogen and progestogen components. Recently, further improvement was achieved by increasing the selectivity of contraceptive progestins. The ratio between the affinity for the progesterone receptor and the affinity for the androgen receptor is an indicator of progesterone (or androgen) selectivity of a progestin. This ratio (selectivity index) reflects the relative amount of androgenic or progestational effect at a given dose. Relative selectivity can be characterized with in vitro receptor-binding studies and animal pharmacologic experiments. In comparison with levonorgestrel, desogestrel displays markedly lower androgenicity and slightly increased relative progestational activity. In receptor-binding experiments and animal pharmacologic studies, 3-keto-desogestrel, the active metabolite of desogestrel, shows the highest selectivity index. The favorable effect of desogestrel-containing oral contraceptives on lipoprotein metabolism and preexisting androgen-dependent skin disorders and the absence of adverse effects on blood pressure and body weight are attributed to the increased progestin selectivity of desogestrel. For more Mechanism of Action (Complete) data for DESOGESTREL (6 total), please visit the HSDB record page.

Pharmacodynamics

The effects of desogestrel are divided on reproductive including modification of luteinizing hormone and follicle stimulating hormone, declines on the onset of menstruation, and increases the viscosity of the vaginal fluid; and on metabolic that includes increase insulin secretion and resistance, increased lipase activity, and increased fat deposition. The effect of desogestrel on the lipids has been studied extensively and the results are contradictory. Desogestrel main therapeutic effect due to its mechanism of action is known to be related to the inhibition of the ovulation in 97% of the cycles. This effect was proven in clinical trials in non-breastfeeding women from which the Pearl failure rate was reported to be of 0.17 per 100 women-years. This result indicated that desogestrel is more efficient when compared to other progestogen-only pills. All the therapeutic effect is produced by a transformation of the endometrium followed by an inhibition of the ovulation due to the suppression of other hormones. Desogestrel has been widely confirmed to be related to an increase in the risk of venous thromboembolism due to the driven increased in blood coagulation factors, leading to a pronounced prothrombotic state. However, the effects of desogestrel are known to not impact significantly the level of total cholesterol remaining in the range of change of 10% which allows it to be a molecule that presents a favorable lipid profile.

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.