Noristerat

Indications

• Hypogonadism in males
• Delayed puberty in boys
• Testosterone replacement therapy
• Breast cancer in women (specific cases)
• Muscle wasting conditions

Dosage

Children: Refer to BNF for Children for specific dosing information. Dosing is typically based on age and clinical condition.

Adults: Refer to BNF for specific dosing information. Generally, doses are individualized based on clinical response and testosterone levels.

Mechanism of action

Testosterone enanthate exerts its effects by binding to androgen receptors in various tissues, leading to the activation of anabolic processes. This interaction stimulates protein synthesis, promotes muscle growth, and enhances the development of male sexual characteristics. The drug also influences the hypothalamic-pituitary-gonadal axis, resulting in increased endogenous testosterone production after cessation of treatment.

Pharmacodynamics

The pharmacodynamics of testosterone enanthate involve its conversion to dihydrotestosterone (DHT) and estradiol (E2) through the action of 5-alpha reductase and aromatase, respectively. These metabolites mediate various physiological effects, including the promotion of erythropoiesis, enhancement of libido, and the development of male secondary sexual traits such as facial hair and deepened voice. Testosterone enanthate also exhibits a dose-dependent effect on muscle mass and strength.

Pharmacokinetics

Testosterone enanthate has a half-life of approximately 4.5 days when administered via intramuscular injection, providing a prolonged release of testosterone into the bloodstream. It is primarily metabolized in the liver and excreted in urine as conjugated metabolites. The absorption rate can vary based on the site of injection, with peak plasma levels typically occurring 24 to 36 hours post-injection. Steady-state concentrations are achieved after multiple doses.

Contra-indications

• Hypersensitivity to enantate or any of its components
• Severe liver dysfunction
• Active or suspected prostate cancer
• Pregnancy
• Breastfeeding

Adverse effects

• Injection site reactions (pain, swelling, redness)
• Mood swings
• Acne
• Weight gain
• Fluid retention
• Increased risk of thromboembolic events
• Gynecomastia
• Changes in libido

Interactions

• Anticoagulants (increased risk of bleeding)
• Corticosteroids (may enhance the adverse effects)
• Insulin and oral hypoglycemics (may require dosage adjustments)
• Other hormone-based therapies (can lead to additive effects)

Precautions

• Monitor for signs of thromboembolic events
• Regular check-ups for prostate health in men
• Use cautiously in patients with cardiovascular disease
• Monitor glucose levels in diabetic patients

Pregnancy

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

Breast-feeding

Not recommended during breastfeeding due to potential effects on the infant.

Storage

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

Formulations

• Injection solution (e.g., 25 mg/mL, 50 mg/mL)

Indications

• Dysfunctional uterine bleeding
• Menorrhagia
• Dysmenorrhoea
• Premenstrual syndrome
• Hormonal treatment in endometriosis
• Contraception

Dosage

Children: Refer to the BNF for

Adults: 5 mg 2–3 times a day, depending on the condition being treated, with specific dosing schedules based on the menstrual cycle for conditions such as dysfunctional uterine bleeding and dysmenorrhoea.

Mechanism of action

Norethisterone binds to progesterone receptors in target cells including those in the reproductive tract, breast, pituitary, hypothalamus, skeletal tissue, and central nervous system. This binding leads to changes in target gene expression. It increases cervical mucus viscosity, impeding sperm transport, and alters the endometrium to prevent implantation by causing atrophy, irregular secretion, and suppressed proliferation. Additionally, it exerts negative feedback on the hypothalamus and anterior pituitary, suppressing the release of FSH and LH, which prevents ovulation and follicular development.

Pharmacodynamics

Norethisterone is a potent synthetic progestin that acts similarly to endogenous progesterone. It modifies cervical and endometrial functions, inhibiting pituitary hormones involved in follicular maturation and ovulation. It is particularly effective in hormone replacement therapy to mitigate the risk of endometrial hyperplasia in postmenopausal women receiving estrogen therapy. There is a small increased risk of breast cancer associated with its use, necessitating regular breast examinations.

Pharmacokinetics

Norethisterone is well absorbed after oral administration, with a bioavailability influenced by first-pass metabolism. It is metabolized in the liver and has a half-life that allows for once or twice daily dosing in most applications. Its metabolites are primarily excreted in urine. The pharmacokinetics can vary based on individual patient factors, including hepatic function.

Contra-indications

• Current or suspected breast cancer
• Acute porphyrias
• Severe arterial disease
• Undiagnosed vaginal bleeding
• Severe hepatic impairment
• History of chloasma gravidarum
• Idiopathic jaundice during pregnancy
• Conditions that may worsen with fluid retention

Adverse effects

• Breast abnormalities
• Alopecia
• Anxiety
• Asthenic conditions
• Depression
• Gastrointestinal discomfort
• Gastrointestinal disorders
• Headaches
• Hot flushes
• Libido loss
• Mood alterations
• Nausea
• Ovarian cyst pain
• Skin reactions
• Sleep disorders
• Vomiting
• Vulvovaginal disorders
• Weight changes
• Anemia
• Appetite increase
• Broken nails
• Constipation
• Diarrhea
• Dry eye
• Dyspnoea
• Genital discharge
• Dandruff

Interactions

• Ulipristal may decrease the efficacy of norethisterone
• Antiepileptics (e.g., carbamazepine, phenytoin) may decrease the efficacy of norethisterone
• Bosentan may decrease the efficacy of norethisterone
• Ritonavir may decrease the efficacy of norethisterone
• Lumacaftor may decrease the efficacy of norethisterone
• Modafinil may decrease the efficacy of norethisterone
• Rifamycins may decrease the efficacy of norethisterone
• St. John's Wort may decrease the efficacy of norethisterone

Precautions

• Monitor patients with diabetes closely, as progestogens can decrease glucose tolerance
• Use with caution in patients with a history of depression
• Caution in patients at risk of venous thromboembolism
• Discontinue treatment during prolonged immobilization
• Consider potential risks in patients with a history of gestational diabetes or ectopic pregnancy

Pregnancy

Avoid use during pregnancy due to potential risks to the fetus.

Mechanism of action

On a molecular level, progestins like norethisterone exert their effects on target cells via binding to progesterone receptors that result in downstream changes to target genes. Target cells are found in the reproductive tract, breast, pituitary, hypothalamus, skeletal tissue, and central nervous system. Contraceptive efficacy is derived mainly from changes to the cervical mucus, wherein norethisterone increases the cell content and viscosity of the mucous to impede sperm transport and migration. Norethisterone also induces a variety of changes to the endometrium - including atrophy, irregular secretion, and suppressed proliferation - that make it inhospitable for implantation. Working via a negative feedback loop, norethisterone also acts on both the hypothalamus and anterior pituitary to suppress the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. Suppression of these hormones prevents follicular development, ovulation, and corpus luteum development. When used as a component of hormone replacement therapy in menopausal women, norethisterone’s value is mainly in suppressing the growth of the endometrium. As estrogen stimulates endometrial growth, the unopposed use of estrogen in postmenopausal women with an intact uterus can lead to endometrial hyperplasia which can increase the risk of endometrial cancer. The addition of a progestin to a hormone replacement therapy in this population protects against this endometrial hyperplasia and, therefore, lowers the risk associated with the use of hormone replacement therapies. Norethisterone, along with other progestins and endogenous progesterone, has a low affinity for other steroid receptors, such as the androgen receptor and glucocorticoid receptor. While affinity and agonistic activity at these receptors is minimal, it is thought that androgen receptor agonism is responsible for some of the adverse effects observed with progestin use (e.g. acne, serum lipid changes). Norethindrone shares the actions of progestins. Although the exact mechanism of action of progestin-only oral contraceptives is not known, norethindrone, when administered in usual contraceptive doses, appears to act principally by altering cervical mucus so that sperm migration into the uterus is inhibited. Progestational changes in the endometrium also occur which may inhibit implantation of the fertilized ovum in the uterus. In addition, continuous administration of low doses of norethindrone alters the rate of ovum transport by changing motility and secretion in fallopian tubes. Norethindrone prevents pregnancy even in the presence of ovulation. Norethindrone suppresses ovulation and causes ovarian and endometrial atrophy at high doses; the drug does not consistently suppress ovulation when administered in a continuous low-dose regimen. In low doses, norethindrone causes variable suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Norethindrone has mild androgenic activity. At low doses, norethindrone also has some estrogenic activity. Norethindrone shares the pharmacologic actions of the progestins. In women with adequate endogenous estrogen, norethindrone transforms a proliferative endometrium into a secretory one. Norethindrone has been shown to have some estrogenic, androgenic, and anabolic activity. The drug inhibits the secretion of pituitary gonadotropins at usual dosages and thus prevents follicular maturation and ovulation. Progestins enter target cells by passive diffusion and bind to cytosolic (soluble) receptors that are loosely bound in the nucleus. The steroid receptor complex initiates transcription, resulting in an increase in protein synthesis. /Progestins/ Progestins are capable of affecting serum concentrations of other hormones, particularly estrogen. Estrogenic effects are modified by the progestins, either by reducing the availability or stability of the hormone receptor complex or by turning off specific

Pharmacodynamics

Norethisterone is a synthetic oral progestin used for contraception or to treat other hormone-related conditions such as menopausal symptoms and endometriosis. As a synthetic progestin, norethisterone acts similarly to endogenous progesterone but with a much higher potency - it acts at the pelvic level to alter cervical and endometrial function, as well as via the inhibition of pituitary hormones that play a role in follicular maturation and ovulation. A small increase in the risk of developing breast cancer has been observed in patients using combined oral contraceptives, with some evidence also implicating progestin-only pills - patients starting hormonal contraception should be advised of this risk and should employ routine breast self-examinations to check for evidence of any developing masses.