Norethisterone - Mechanism of Action, Uses, Contraindications, and Side Effects

Introduction:

Progesterone is a female sex hormone that regulates the menstrual cycle, fertility, pregnancy, and the development of embryos inside the uterus. They are classified under endogenous (produced by the body) steroids. Other than its role in the reproductive system, progesterone also has various other functions like breast development, skin health, sexual drive, nervous system regulation, and brain function.

The synthetic form of progesterone is called progestin, which has wide medical use to support reproduction in females and treat various gynecological disorders.

What Is Norethisterone?

Norethisterone comes under the class of progestin medications that are mainly used as components of birth control pills (contraception), hormonal therapy for menstrual and menopausal problems, and other disorders related to reproductive organs. They are formulated as low-dose and high-dose slabs and can be used alone or with estrogen (another female sex hormone). The route of administration is an oral tablet or muscular injection. Norethisterone is listed as an essential medicine advocated by the World Health Organization (WHO).

Norethisterone was one of the first derived Progestins in 1951. Later, it was established as a medicine and used either on its own or in combination with estrogen for contraception.

Norethisterone is known by the name Norethindrone.

How Does Norethisterone Act in the Body?

Norethisterone is commercially available in the form of Norethisterone acetate, which, when consumed, is readily and completely deacetylated to Norethisterone.

• Norethisterone has a higher affinity to the progesterone receptors and readily binds to them. Progesterone receptors are found in the cells of female reproductive organs, exocrine glands in the breast, hypothalamus, and the pituitary gland.

• Norethisterone works by restricting the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus.

• Norethisterone also has a weak affinity to androgen and estrogen receptors. Thus having more progestogenic activity and fewer androgenic and estrogenic activities.

The average bioavailability of Norethisterone taken as an oral tablet is about 64 percent. Micronization (breaking into fine molecules) of particles can increase bioavailability due to more intestinal absorption and less intestinal metabolism. The majority of Norethisterone is metabolized in the liver. More than 97 percent of Norethisterone circulates in the blood and is bound to plasma proteins. Norethisterone is excreted mainly through urine and a little in feces.

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What Are the Uses of Norethisterone?

Norethisterone is prescribed at different doses and schedules depending on the condition. For example, at a low dose, the drug can be used for menstrual-related issues like frequent periods, heavy bleeding, abnormal uterine bleeding, and premenstrual symptoms. At high doses, the drug has benefits for breast cancer. Some of the detailed applications of Norethisterone are,

• Contraception: Hormonal contraceptive pills are available as combined oral contraceptive pills or progesterone-only pills.

• Control Endometriosis Symptoms: Endometriosis is a medical condition where the cells of the uterine lining grow outside the uterus. Norethisterone inhibits ovulation and induces endometrial proliferation, thus reducing endometriosis symptoms. This tablet is started with a low dosage and is gradually increased. The physician may advise having the tablet daily and continuously without a break until advised to stop.

• Regulate Menstrual Cycle: Irregular periods are mainly due to hormonal imbalances. Norethisterone can normalize the menstrual cycle and regulate menopause. They are used to treat amenorrhea (absence of periods) and abnormal uterine bleeding without any underlying pathology like uterine fibroids or cancer. It is generally advised to take the tablet post-ovulation continuously for ten days before the next menstrual cycle.

• Post-menopause Complications: Norethisterone can be used as a hormonal replacement in the management of osteoporosis (brittle bones), temperature dysregulation, hot flashes, and night sweats after attaining menopause.

When Is Norethisterone Contraindicated?

• Overdose of Norethisterone can cause small vein occlusion in the liver. Hence, they are contraindicated in patients with liver disease, liver cancer, and bone marrow transplantation.

• Allergic to the active ingredient.

• Breast cancer.

• Clotting disorders.

• Pregnant women or those who are trying to get pregnant.

• Breastfeeding mothers.

Discuss with the physician about the medical history, especially if one has diabetes, hypertension, heart diseases, liver disorders, depression, epilepsy, migraine, kidney disease, tumors, and asthma. Inform them about the past and current medications (especially antibiotics, anticoagulants, antivirals, and anti-epileptic drugs). Also, tell them about smoking and alcohol usage. According to these data, the dosage of the medication is altered.

Is Norethisterone Effective?

Norethisterone tablets can delay periods when taken three days before the expected date, but they are not contraceptives. When taken continuously, they help regulate the menstrual cycle under guidance. They are highly effective in treating hormonal imbalances.

How Does Norethisterone Interact With Other Drugs?

Norethisterone is rapidly metabolized by the enzyme cytochrome P450 enzyme, which is predominantly present in the liver cells. Certain drugs can induce the activity of cytochrome P450, thereby eliminating Norethisterone quickly and reducing its efficacy. They include antiepileptic drugs (Phenytoin, Carbamazepine, Topiramate), antibiotics (Ampicillin, Tetracycline, Rifampicin), and antivirals (Ritonavir, Nelfinavir).

Herbal formulations containing St. John's wort will also increase the clearance of Norethisterone from the body.

What Are the Side Effects of Norethisterone?

Some common side effects of Norethisterone are:

• Menstrual disturbances (irregular menstrual cycle).

• Irregular menstrual flow.

• Spotting and breakthrough bleeding.

• Prolonged bleeding.

• Weight gain.

• Nausea.

• Vomiting.

• Bloating.

• Sleep disturbances.

• Acne.

• Skin discoloration.

• Abnormal liver function.

As Norethisterone does few activities related to androgen and estrogen, it can also produce side effects like hirsutism, voice change, and breast enlargement.

What Happens If Norethisterone Is Missed or Overdosed?

The general recommendation is to have this medicine at the same time daily. If a dose is missed, take it immediately once one remembers. If the time is close to the next dosage, ignore the missed dose and take the next one at the regular time. Do not stop the tablet until advised by the physician.

Studies have not reported any severe side effects from the excess or overdose of Norethisterone, even in the pediatric population. The manifestations will be an extended form of adverse effects like vomiting, abdominal bloating, and menstrual irregularities. However, seek medical help if one suspects an overdose of Norethisterone.

Conclusion:

Norethisterone is a prescription medicine and is sold under different brand names, but each of them is formulated for a specific use. Some are developed only to be used for contraception, and others may be indicated for endometriosis. Hence, all brands of Norethisterone do not contain the same usage property.

Always follow the prescription as instructed by the physician for the exact brand, dosage, and form to get the maximum benefit from the drug.