PREMELLE

Indications

• Contraception
• Secondary amenorrhea
• Dysfunctional uterine bleeding
• Menstrual cycle irregularities
• Management of hot flushes in men undergoing androgen suppression therapy

Dosage

Children: For contraception by deep intramuscular injection: 150 mg every 12 weeks, first dose to be administered within the first 5 days of the menstrual cycle or within the first

Adults: For contraception by deep intramuscular injection: 150 mg every 12 weeks, first dose to be administered within the first 5 days of the menstrual cycle or within the first 5 days postpartum (delay until 6 weeks postpartum if breastfeeding). For oral use: 20 mg once daily initially for 10 weeks, evaluate effect at the end of the treatment period.

Mechanism of action

Medroxyprogesterone acetate inhibits the production of gonadotropin, preventing follicular maturation and ovulation. This action also results in the thinning of the endometrium. Additionally, MPA reduces nuclear estrogen receptors and DNA synthesis in endometrial epithelial cells and can induce p53-dependent apoptosis in certain cancer cell lines while inhibiting GABA-A receptors.

Pharmacodynamics

MPA primarily acts by inhibiting gonadotropin production and reducing estrogen receptor activity in the endometrium. The drug has a wide therapeutic window, with effective doses ranging from 5 mg orally daily to 1000 mg weekly as a depo injection. However, long-term use is associated with reduced bone density, particularly in adolescents, potentially increasing the risk of osteoporosis and fractures.

Pharmacokinetics

The half-life of oral MPA ranges from 40 to 60 hours, whereas other formulations may exhibit considerably longer half-lives. This allows for extended duration of action, making MPA suitable for long-term use. MPA's pharmacokinetic profile necessitates careful monitoring, especially in long-term treatment scenarios.

Contra-indications

• Current breast cancer (unless progestogens are being used in the management of this condition)
• History of thromboembolism
• Undiagnosed vaginal bleeding
• Acute porphyrias

Adverse effects

• Menstrual cycle irregularities
• Nausea
• Weight changes
• Ovarian cyst pain
• Skin reactions
• Hot flushes
• Mild to moderate endometriosis
• Risk of breast cancer
• Decreased glucose tolerance
• Reduced bone density

Interactions

• Potential interactions with other hormonal contraceptives
• Caution advised with estrogen HRT in patients with a history of stroke
• Caution advised with estrogen HRT in patients with a history of venous thromboembolism

Precautions

• Careful monitoring in patients with systemic lupus erythematosus with positive or unknown antiphospholipid antibodies
• Seek specialist advice for patients with a history of ischemic heart disease
• Multiple risk factors for cardiovascular disease

Pregnancy

Not known to be harmful, remove implant if pregnancy occurs.

Breast-feeding

Progestogen-only contraceptives do not affect lactation.

Storage

Store at room temperature, away from light and moisture.

Formulations

• Deep intramuscular injection: 150 mg every 12 weeks
• Subcutaneous injection: 104 mg every 13 weeks
• Oral tablets: 20 mg once daily initially for 10 weeks

Indications

• Menopausal symptoms
• Vulvar and vaginal atrophy
• Prevention of osteoporosis in postmenopausal women
• Hypoestrogenism due to hypogonadism or castration

Dosage

Children: Conjugated estrogens are not typically indicated for use in the pediatric population. Refer to specialized resources for any off-label use.

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

Mechanism of action

Conjugated estrogens exert their effects primarily through binding to estrogen receptors, leading to the activation of estrogen-responsive genes. This binding triggers a cascade of biological responses that promote the development and maintenance of female reproductive tissues, regulation of the menstrual cycle, and other systemic effects such as bone density maintenance and modulation of cholesterol levels.

Pharmacodynamics

The pharmacodynamics of conjugated estrogens involve their role in modulating gene expression within estrogen-responsive tissues. They help to alleviate symptoms associated with menopause, such as hot flashes and vaginal dryness, and play a critical role in bone health by inhibiting osteoclast activity, thus reducing bone resorption and helping to prevent osteoporosis.

Pharmacokinetics

Following oral administration, conjugated estrogens are absorbed through the gastrointestinal tract. They undergo first-pass metabolism in the liver, which can affect their bioavailability. The half-life of conjugated estrogens varies, but they generally have a half-life of several hours. They are metabolized primarily in the liver and excreted in urine. The pharmacokinetics can be influenced by factors such as age, liver function, and concurrent medications.

Contra-indications

• Known hypersensitivity to conjugated estrogens or any of the excipients
• Estrogen-dependent neoplasms, including breast cancer
• Undiagnosed abnormal genital bleeding
• Active or past venous thromboembolic disorders
• Severe liver dysfunction or disease
• Pregnancy

Adverse effects

• Nausea
• Headache
• Breast tenderness
• Abdominal cramps
• Bloating
• Mood changes
• Increased risk of thromboembolic events
• Hypertension
• Cholestatic jaundice
• Gallbladder disease

Interactions

• Anticoagulants may have altered effects
• Certain anticonvulsants may reduce efficacy of estrogen therapy
• Rifampicin and other enzyme inducers may decrease effectiveness
• St. John's Wort may decrease hormone levels

Precautions

• Monitor patients for signs of thromboembolic disorders
• Assess risk factors for cardiovascular disease
• Evaluate liver function before and during treatment
• Consider individual patient history of breast cancer or other estrogen-sensitive conditions

Pregnancy

Conjugated estrogens are contraindicated in pregnancy due to risk of fetal harm.

Breast-feeding

Conjugated estrogens may be excreted in breast milk; use with caution in breastfeeding women.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Oral tablets
• Injectable forms

Indications

• Hormone replacement therapy for menopausal symptoms
• Management of menopausal symptoms such as hot flashes and vaginal atrophy
• Treatment of hypoestrogenism
• Contraception in combination with progestins
• Management of estrogen receptor-positive breast cancer in postmenopausal women

Dosage

Children: Refer to the BNF for Children for appropriate dosing information for pediatric patients.

Adults: Refer to the BNF for specific dosing recommendations based on the formulation and clinical condition being treated.

Mechanism of action

Estrogens act by binding to estrogen receptors located on diverse tissues throughout the body. This binding modulates the secretion of pituitary gonadotropins, specifically luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. In premenopausal women, estrogens are predominantly secreted by ovarian follicles, and their levels fluctuate during the menstrual cycle. Following menopause, the decline in estrogen production leads to various symptoms which can be alleviated by estrogen replacement.

Pharmacodynamics

The pharmacodynamic effects of estrogens include the regulation of reproductive functions, enhancement of bone density, modulation of cardiovascular health, and maintenance of skin and mucosal integrity. Estrogens exert their effects through genomic pathways that alter gene expression, ultimately influencing tissue growth and function.

Pharmacokinetics

Estrogens are absorbed well from the gastrointestinal tract and undergo extensive first-pass metabolism in the liver. They have a high volume of distribution and are primarily metabolized in the liver, leading to the formation of various metabolites. Estrogens are eliminated through urine and feces, with a half-life that varies depending on the specific estrogen used. Additionally, their pharmacokinetics can be influenced by factors such as age, body weight, and the presence of liver disease.

Contra-indications

• Known or suspected pregnancy
• Active liver disease
• History of thromboembolic disorders
• Hormone-sensitive malignancies
• Undiagnosed abnormal uterine bleeding

Adverse effects

• Nausea
• Vomiting
• Breast tenderness
• Headache
• Mood changes
• Weight gain
• Increased risk of thromboembolic events

Interactions

• Anticonvulsants may reduce estrogen effectiveness
• Antibiotics may alter gut flora and affect estrogen metabolism
• Corticosteroids may have increased effects when used with estrogens

Precautions

• Monitor for signs of thromboembolic events
• Use with caution in patients with a history of depression
• Caution in patients with hypertension

Pregnancy

Estrogens are contraindicated in pregnancy due to potential risks to the fetus.

Breast-feeding

Estrogens may be excreted in breast milk and could affect milk production.

Storage

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

Formulations

• Tablets
• Transdermal patches
• Injectable forms
• Topical creams and gels

Indications

• Contraception
• Management of abnormal uterine bleeding
• Endometriosis
• Dysmenorrhea
• Hormonal replacement therapy

Dosage

Children: For paediatric dosing, refer to the BNF for Children

Adults: For contraception, the usual dosage is 150 mg administered intramuscularly every 3 months. For other indications, refer to the BNF for specific dosing guidance.

Mechanism of action

Medroxyprogesterone acts as a progestin, transforming the proliferative endometrium into a secretory one in women with adequate endogenous estrogen. It inhibits the secretion of pituitary gonadotropins, leading to prevention of follicular maturation and ovulation, and results in endometrial thinning, thereby exerting contraceptive effects. It is suggested that the drug acts at the hypothalamus, as it does not suppress the release of luteinizing hormone and follicle-stimulating hormone following administration of gonadotropin-releasing hormone.

Pharmacodynamics

Medroxyprogesterone exhibits progestational effects, inducing changes in the endometrial lining, thereby preparing it for potential implantation of an embryo. It also has mild androgenic properties and some anabolic effects, though it lacks significant estrogenic activity in humans. The drug also influences the hypothalamic-pituitary-gonadal axis by inhibiting gonadotropin release, affecting ovarian function and menstrual cycle regulation.

Pharmacokinetics

Medroxyprogesterone is absorbed following intramuscular or subcutaneous administration, with peak plasma concentrations occurring within a few days. The drug undergoes hepatic metabolism and is primarily excreted in urine. The pharmacokinetics may vary based on the route of administration, with intramuscular injections providing a longer duration of action compared to oral dosages.

Interactions

• sugammadex+medroxyprogesterone: Unknown (decreases exposure)

Pregnancy

Medroxyprogesterone is used during pregnancy for specific indications, such as to prevent premature labor or for other clinical reasons as determined by a healthcare provider. It is classified under Category X for contraceptive use, indicating that it should not be used during pregnancy due to potential risks.

Breast-feeding

Medroxyprogesterone is excreted in breast milk. Caution is advised when administering to nursing mothers, as the effects on the infant are not well established.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Mechanism of action

Medroxyprogesterone acetate (MPA) inhibits the production of gonadotropin, preventing follicular maturation and ovulation, which is responsible for it’s ability to prevent pregnancy. This action also thins the endometrium. MPA reduces nuclear estrogen receptors and DNA synthesis in epithelial cells of the endometrium. MPA can also induce p53 dependant apoptosis in certain cancer cell lines, and inhibit GABA-A receptors.

Pharmacodynamics

Medroxyprogesterone acetate (MPA) inhibits gonadotropin production, reduces nuclear estrogen receptors and DNA synthesis in epithelial cells of the endometrium, and induces p53 dependant apoptosis in cancer cell lines. MPA oral tablets have a half life of 40-60 hours and other formulations can have half lives that are considerably longer, so the duration of action is long. The therapeutic window is wide as patients may take doses ranging from 5mg orally daily to 1000mg as a depo injection weekly. Long term use of MPA is associated with a reduction in bone density and patients who taking MPA during adolescence may have lower peak bone mass than untreated patients, which can also increase the risk of osteoporosis and fractures in the future.

Mechanism of action

All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). The principal pharmacologic effects of conjugated estrogens are similar to those of other natural and synthetic estrogens. 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 estrogen therapy in women with metastatic carcinoma of the breast. /Estrogen General Statement/ Estrogens have generally favorable effects on blood cholesterol and phospholipid concentrations. Estrogens reduce LDL-cholesterol and increase HDL-cholesterol concentrations in a dose-related manner. The decrease in LDL-cholesterol concentrations

Mechanism of action

Medroxyprogesterone shares the pharmacologic actions of the progestins. In women with adequate endogenous estrogen, medroxyprogesterone transforms a proliferative endometrium into a secretory one. Medroxyprogesterone has been shown to have slight androgenic activity in animals. Anabolic effects have also been reported, but the drug apparently lacks appreciable estrogenic activity in humans. In animals, the drug exhibits pronounced adrenocorticoid activity, but a clinically important effect has not been observed in humans. Medroxyprogesterone inhibits the secretion of pituitary gonadotropins following usual IM or subcutaneous dosages (eg, 150 or 104 mg every 3 months), thus preventing follicular maturation and ovulation and resulting in endometrial thinning; these effects result in contraceptive activity. Available evidence indicates that these effects do not occur following oral administration of usual dosages (ie, 5-10 mg daily as single daily doses) of the drug. High doses of medroxyprogesterone inhibit pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and will prevent cyclic gonadotropin surges that occur during the normal menstrual cycle. It has been suggested that the drug acts at the hypothalamus since it does not suppress the release of LH and FSH following administration of gonadotropin-releasing hormone and since basal concentrations of LH and FSH remain within the low normal range when the drug is used as a contraceptive. Although the mechanism of action has not been determined, medroxyprogesterone has antineoplastic activity against some cancers (eg, endometrial carcinoma, renal carcinoma). Progestins elicit, to varying degrees, all the pharmacologic responses usually produced by progesterone: induction of secretory changes in the endometrium, increase in basal body temperature (thermogenic action), production of histologic changes in vaginal epithelium, relaxation of uterine smooth muscle, stimulation of mammary alveolar tissue growth, pituitary inhibition, and production of withdrawal bleeding in the presence of estrogen. /Progestins/ Following binding to cytoplasmic receptor protein, steroid is transported to nucleus, and complex is bound there in reactions analogous to those described... for estrogens. However, there is no apparent need for receptor alteration, as with estrogen receptor. /Progesterone/ Although medroxyprogesterone acetate (MPA) is used as an injectable contraceptive, in hormone replacement therapy (HRT) and in treatment of certain cancers, the steroid receptors and their target genes involved in the actions of MPA are not well understood. /Investigators/ show that MPA, like dexamethasone (dex), significantly represses tumour necrosis factor (TNF)-stimulated interleukin-6 (IL-6) protein production in mouse fibroblast (L929sA) cells. In addition, MPA repressed IL-6 and IL-8 promoter-reporter constructs at the transcriptional level, via interference with nuclear factor kappaB (NFkappaB) and activator protein-1 (AP-1). Furthermore, like dex, MPA does not affect NFkappaB DNA-binding activity. /The authors/ also observed significant transactivation by MPA of a glucocorticoid response element (GRE)-driven promoter-reporter construct in both L929sA and COS-1 cells. The MPA-induced nuclear translocation of the glucocorticoid receptor (GR), as well as the antagonistic effects of RU486, strongly suggest that the actions of MPA in these cells are mediated at least in part via the GR. /Investigators/ assessed the transcriptional effects of MPA as compared with those of progesterone and dihydrotestosterone (DHT) in human breast cancer cells. A new progesterone receptor-negative, androgen receptor-positive human breast cancer cell line, designated Y-AR, was engineered and characterized. Transcription assays using a synthetic promoter/reporter construct, as well as endogenous gene expression profiling comparing progesterone, MPA and DHT, were performed in cells either lacki