ADCO-FEM 35

Indications

• Prostate cancer
• Hyperandrogenism conditions such as hirsutism and acne
• Hormonal therapy for breast cancer in women
• Induction and maintenance of sexual maturation in males (specialist use only)

Dosage

Children: For children aged 12–17 years, 40 mg once daily on alternate days, adjusted according to response, with a maximum of 120 mg daily.

Adults: Initially, 250 mg every 2–3 weeks; maintenance 250 mg every 3–6 weeks. For breast cancer, 100 mg 2–3 times a week, adjusted based on clinical response.

Mechanism of action

Cyproterone acetate exerts a direct antiandrogenic effect by blocking the binding of dihydrotestosterone to its receptors in prostatic carcinoma cells. It also inhibits luteinizing hormone secretion through a negative feedback mechanism on the hypothalamo-pituitary axis, leading to reduced testicular testosterone production. Additionally, cyproterone acetate's progestogenic activity further reduces gonadotropin release, decreasing androgen levels and sexual drive.

Pharmacodynamics

As an antiandrogen, cyproterone acetate suppresses the action of androgens on target tissues by blocking androgen receptors and reducing luteinizing hormone levels, which leads to a decrease in testosterone production. This suppression results in decreased cell proliferation in androgen-dependent tissues, including prostate cancer cells.

Pharmacokinetics

Cyproterone acetate is well absorbed following oral administration, with peak plasma concentrations occurring within a few hours. It is highly protein-bound in plasma, primarily to albumin and sex hormone-binding globulin. The drug undergoes extensive hepatic metabolism, with a half-life that allows for once-daily dosing. It is primarily excreted in urine as metabolites, with minimal unchanged drug excreted.

Contra-indications

• Pregnancy
• Severe liver disease
• History of meningioma
• Thrombophilia

Adverse effects

• Diarrhea
• Mood alterations
• Increased appetite
• Arthralgia
• Breast abnormalities
• Cardiovascular disorders
• Cough
• Dysphonia
• Hypercholesterolemia
• Increased risk of infection
• Migraine
• Muscle complaints
• Fluid imbalance
• Gastrointestinal discomfort
• Hepatic function abnormalities
• Lipid metabolism changes
• Myalgia
• Fatigue
• Lassitude

Interactions

• Caution with other medications that affect liver function
• Increased risk of thrombosis when combined with other thrombotic agents

Precautions

• Monitor blood counts initially and throughout treatment
• Monitor hepatic function regularly
• Avoid in patients with a history of hepatic impairment
• Monitor adrenocortical function regularly
• Caution in patients with a history of depression

Pregnancy

Cyproterone acetate is contraindicated in pregnancy due to potential harm to the fetus.

Breast-feeding

Use with caution; consult healthcare providers for advice.

Storage

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

Formulations

• Oral tablets
• Solution for injection

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

• Hirsutism in women
• Androgen-dependent neoplasms
• Hormone therapy in transgender women
• Acne vulgaris resistant to other treatments
• Severe alopecia androgenetica

Dosage

Children: Refer to the BNF for Children for age-appropriate dosage recommendations.

Adults: Refer to the BNF for specific dosage guidelines based on the condition being treated.

Mechanism of action

Cyproterone acetate works by blocking the action of androgens at the androgen receptor level, leading to a reduction in the effects of testosterone and other androgens. It also has progestogenic activity, which contributes to its overall effectiveness in hormonal regulation.

Pharmacodynamics

Cyproterone exhibits antiandrogenic and progestogenic properties. By inhibiting the androgen receptor, it reduces the stimulation of androgen-dependent tissues, which can result in decreased sebaceous gland activity and hair growth. Its progestogenic effects can lead to alterations in menstrual cycle regulation and endometrial activity.

Pharmacokinetics

After oral administration, cyproterone is well-absorbed and undergoes extensive hepatic metabolism. The drug has a half-life of approximately 30 to 40 hours, allowing for once-daily dosing in most cases. It is mainly excreted in the urine as metabolites, with only a small percentage eliminated unchanged.

Contra-indications

• Hypersensitivity to cyproterone or any of its components
• Pregnancy
• Active liver disease
• Severe hepatic impairment
• Hormone-sensitive malignancies

Adverse effects

• Headache
• Nausea
• Fatigue
• Weight gain
• Depression
• Gastrointestinal disturbances
• Menstrual irregularities
• Liver function abnormalities

Interactions

• Antiepileptics (carbamazepine, eslicarbazepine, fosphenytoin, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide, topiramate) - may decrease efficacy
• Modafinil - may decrease efficacy
• Rifamycins - may decrease efficacy
• St John's Wort - may decrease efficacy
• Bosentan - may decrease efficacy
• Ritonavir - may decrease efficacy

Precautions

• Monitor liver function regularly during treatment
• Use with caution in patients with a history of depression
• Consider risk of thromboembolic events
• Assess for potential interactions with other medications

Pregnancy

Cyproterone is contraindicated in pregnancy due to potential harm to the fetus.

Breast-feeding

Due to potential adverse effects on the breastfed infant, cyproterone should be used with caution during breastfeeding.

Storage

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

Formulations

• Tablets
• Oral solution

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

The direct antiandrogenic effect of cyproterone is blockage of the binding of dihydrotestosterone to the specific receptors in the prostatic carcinoma cell. In addition, cyproterone exerts a negative feed-back on the hypothalamo-pituitary axis, by inhibiting the secretion of luteinizing hormone resulting in diminished production of testicular testosterone. Prostatic carcinoma and its metastases are in general androgen-dependent. Cyproterone acetate exerts a direct anti-androgen action on the tumor and its metastases. It also has progestogenic activity, which exerts a negative feedback effect on the hypothalamic receptors, so leading to a reduction in gonadotrophin release, and hence to diminished production of testicular androgens. Sexual drive and potency are reduced and gonadal function is inhibited. Cell proliferation and cell death appear in several systems as mutually exclusive, which raises the assumption that a same factor or secondary signal(s) might exert opposite control on the two processes. To test this assumption we investigated the time-course evolution of the S phase and apoptotic indices in rat liver during cyproterone acetate (CPA) induced hyperplasia and during the recovery of normal liver mass provoked, respectively, by cyproterone acetate (CPA) treatment and withdrawal. The levels of c-myc and c-ras transcripts were also followed in view of the indications of a positive role of these oncogenes in proliferation. The data showed that proliferation and cell death are not always mutually exclusive and that a high rate of cell death was indifferently associated with high or low c-ras expression. Our data are consistent with a role of this gene in proliferation but exclude that it plays an opposite role in controlling cell death. The antigonadotropic effect of cyproterone acetate is also exerted when administered with LHRH analogues. The initial increase of testosterone caused by this class of substances is reduced by cyproterone acetate. An occasional tendency for the prolactin levels to increase slightly has been observed under higher doses of cyproterone acetate. Dianette blocks androgen-receptors. It also reduces androgen synthesis both by negative feedback effect on the hypothalamo-pituitiary-ovarian systems and by the inhibition of androgen-synthesising enzymes. For more Mechanism of Action (Complete) data for CYPROTERONE ACETATE (8 total), please visit the HSDB record page.

Pharmacodynamics

Cyproterone is an antiandrogen. It suppresses the actions of testosterone (and its metabolite dihydrotestosterone) on tissues. It acts by blocking androgen receptors which prevents androgens from binding to them and suppresses luteinizing hormone (which in turn reduces testosterone levels).

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.