DIANE 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

• 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
• Hormone replacement therapy
• Management of menstrual disorders
• Treatment of acne in women
• Regulation of menstrual cycles

Dosage

Children: Refer to the BNF for Children for specific dosing information applicable to pediatric patients

Adults: The typical adult dosing for contraceptive purposes is one tablet daily, usually taken for 21 days followed by a 7-day break, during which withdrawal bleeding occurs. Refer to specific product guidelines for variations in dosing.

Mechanism of action

Ethinylestradiol works by binding to estrogen receptors in estrogen-responsive tissues, leading to a suppression of gonadotrophic hormones, which in turn inhibits ovulation. It thickens cervical mucus to impede sperm travel and alters the endometrial lining, making it less suitable for implantation. Additionally, it decreases luteinizing hormone levels, reducing endometrial vascularization, and increases sex hormone binding globulin levels.

Pharmacodynamics

As a synthetic estrogen, ethinylestradiol exhibits properties similar to endogenous estrogens, affecting various tissues in the body. It modulates the menstrual cycle by decreasing the secretion of luteinizing hormone and preventing ovulation, thus demonstrating a selective action with a long duration of effect when administered daily. The therapeutic index is wide, typically allowing for safe use at recommended doses, although there is a notable risk of thrombotic events associated with estrogen use.

Pharmacokinetics

Ethinylestradiol is well-absorbed after oral administration, undergoing first-pass metabolism in the liver, which influences its bioavailability. It has a half-life that allows for once-daily dosing, leading to stable plasma concentrations. Metabolism occurs primarily in the liver, and it is excreted in urine as metabolites. The drug's pharmacokinetic profile supports its use in contraceptive regimens, ensuring effective hormone levels are maintained throughout the dosing period.

Contra-indications

• History of thromboembolic disorders
• Severe hypertension
• Active liver disease
• Known or suspected pregnancy
• Estrogen-dependent tumors

Adverse effects

• Nausea
• Headache
• Breast tenderness
• Weight gain
• Mood changes
• Thromboembolic events

Interactions

• Antibiotics may reduce the effectiveness of ethinylestradiol
• Anticonvulsants may decrease plasma concentrations
• St. John's Wort may reduce effectiveness

Precautions

• Monitor for signs of thromboembolism
• Caution in patients with a history of migraines
• Monitor blood pressure regularly
• Consider risks versus benefits in patients with liver disease

Pregnancy

Ethinylestradiol is contraindicated during pregnancy due to potential harm to the fetus.

Breast-feeding

Use is not recommended during breastfeeding as it may reduce milk production.

Storage

Store at room temperature, away from light and moisture.

Formulations

• Tablets
• Combined oral contraceptive formulations

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

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.