NORCOLUT

Indications

• Contraception
• Menopausal symptoms
• Endometriosis
• Hormone replacement therapy

Dosage

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

Adults: Refer to the BNF for specific dosing information based on indication and patient characteristics.

Mechanism of action

Norethisterone binds to progesterone receptors in target cells located in the reproductive tract, breast, pituitary, hypothalamus, skeletal tissue, and central nervous system. This binding results in changes to target genes, leading to increased viscosity of cervical mucus, making it difficult for sperm to reach the egg. It also induces endometrial atrophy and suppresses the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), preventing ovulation and corpus luteum development. In hormone replacement therapy, it protects against endometrial hyperplasia caused by unopposed estrogen.

Pharmacodynamics

Norethisterone exhibits similar actions to natural progesterone but is more potent. It modifies the endometrium and cervical mucus, enhancing contraceptive efficacy while addressing conditions like endometriosis and menopausal symptoms. The use of norethisterone may be associated with a slight increase in breast cancer risk, necessitating regular self-examinations.

Pharmacokinetics

Norethisterone is well-absorbed following oral administration, with peak plasma concentrations generally reached within 1-3 hours. It undergoes hepatic metabolism, primarily via the cytochrome P450 system, and is excreted in urine as metabolites. The elimination half-life is approximately 6-8 hours, though this may vary based on individual metabolism.

Contra-indications

• Pregnancy
• Known or suspected breast cancer
• Severe liver disease
• Undiagnosed vaginal bleeding
• History of thromboembolic disorders

Adverse effects

• Nausea
• Headache
• Breast tenderness
• Weight gain
• Mood changes
• Acne
• Irregular menstrual bleeding
• Increased risk of thromboembolic events

Interactions

• Anticonvulsants (e.g., phenytoin, carbamazepine) may decrease norethisterone efficacy
• Rifampicin may decrease contraceptive effectiveness
• Certain antibiotics may affect norethisterone metabolism

Precautions

• Monitor for signs of thromboembolic disorders
• Use with caution in patients with a history of depression
• Regular breast examinations are recommended
• May need dose adjustment in liver impairment

Pregnancy

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

Breast-feeding

Norethisterone may be used during breastfeeding, but caution is advised as it can pass into breast milk.

Storage

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

Formulations

• Tablets

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.