leuprolide and norethindrone

Action and Spectrum

Actions and Spectrum: 

• leuprolide is a synthetic gonadotropin-releasing hormone (GnRH) agonist. Initially, it stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland.  
• norethindrone is a synthetic progestin that acts as a progesterone analogue. It binds to progesterone receptors and exerts its effects, which include inhibiting ovulation, thickening cervical mucus to block sperm entry, and altering the endometrial lining to prevent embryo implantation. 

Spectrum of activity: 

• Endometriosis: The combination of leuprolide and norethindrone is used to treat endometriosis, where tissue like the uterine lining grows outside the uterus, causing pain and inflammation.  
• Uterine Fibroids: leuprolide combined with norethindrone is sometimes used to manage uterine fibroids, which are non-cancerous uterine growths. By reducing estrogen and progesterone levels, this combination can shrink fibroids and relieve associated symptoms. 
• Assisted Reproductive Technologies (ART): In fertility treatments, the combined use of leuprolide and norethindrone can suppress natural ovulation and synchronize the development of multiple follicles in the ovaries. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Depression  

Hot flash  

Dermatological reaction 

Weakness 

Headache  

Pain  

Decreased HDL cholesterol 

Vaginitis 

1-10% 

Memory impairment 

Dyspepsia 

Edema 

Injection site reaction 

Leg cramps 

<1% 

Asthma 

Urinary tract infection 

Anaphylactoid reaction 

Nephrolithiasis 

Black Box Warning

Black box warning: 

None 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

• Hypersensitivity or Allergy: Individuals with known hypersensitivity or allergy to leuprolide, norethindrone, or any other components of the medications should not use this combination. 
• Undiagnosed Vaginal Bleeding: In women, undiagnosed abnormal vaginal bleeding should be evaluated before initiating treatment with leuprolide and norethindrone. Without an established diagnosis, this combination is not indicated for treating abnormal vaginal bleeding. 
• Known or Suspected Hormone-Related Cancers: The combined use of leuprolide and norethindrone is generally not recommended in individuals with known or suspected hormone-related cancers, such as breast cancer, ovarian cancer, or endometrial cancer. 

Caution: 

• Cardiovascular Risks: Both leuprolide and norethindrone can affect lipid metabolism and may be associated with an increased risk of cardiovascular events, such as heart attack or stroke.  
• Bone Density Loss: Long-term use of leuprolide and norethindrone can decrease bone mineral density, potentially increasing the risk of osteoporosis and fractures.  
• Diabetes: leuprolide and norethindrone may affect glucose metabolism and insulin sensitivity.  
• Mood Changes: Hormonal therapies, including leuprolide and norethindrone, may be associated with mood changes, such as depression, anxiety, or irritability.

Pregnancy / Lactation

Pregnancy consideration: It is contraindicated during pregnancy. 

Lactation: It is contraindicated during lactation 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

• Endometriosis and Uterine Fibroids: leuprolide downregulates GnRH receptors, decreasing estrogen and progesterone levels. norethindrone, as a progestin, complements this effect by providing additional progestin activity, further supporting the suppression of estrogen-driven endometrial growth in endometriosis and uterine fibroids. 
• ART and Fertility Treatments: In assisted reproductive technologies (ART), leuprolide is used to suppress natural ovulation, while norethindrone helps synchronize the development of multiple follicles in the ovaries, improving the success of fertility treatments. 

Pharmacodynamics:  

The overall pharmacodynamic effect of leuprolide is hormone suppression, which is clinically valuable in certain conditions, such as prostate cancer in males and hormone-related gynecological disorders in females. The pharmacodynamic effects of norethindrone are contraceptive, helping to prevent pregnancy by multiple mechanisms. 

Pharmacokinetics: 

Absorption 

leuprolide is available in various formulations, including subcutaneous injections and depot (long-acting) preparations. The subcutaneous injections are absorbed rapidly after administration, reaching therapeutic levels in the bloodstream relatively quickly. Depot formulations release leuprolide slowly over an extended period, providing a sustained therapeutic effect. norethindrone is well-absorbed after oral administration. It is available in oral contraceptive pills and other oral formulations.  

Distribution 

leuprolide is distributed within the body primarily through the bloodstream. It has a high affinity for tissues with GnRH receptors, such as the pituitary gland. norethindrone is distributed throughout the body via the bloodstream, binding to progesterone receptors in target tissues.  

Metabolism 

leuprolide is not extensively metabolized in the liver. Instead, it undergoes proteolytic degradation in various tissues, including the kidneys and plasma. norethindrone undergoes extensive first-pass metabolism in the liver, metabolizing it into various active and inactive metabolites. 

Elimination and Excretion 

The metabolites of leuprolide and any unmetabolized drug are excreted primarily through the kidneys in the urine. The metabolites of norethindrone, along with any unmetabolized drug, are excreted primarily through the kidneys in the urine and, to a lesser extent, in the feces. 

Adminstartion

Administration: 

Intramuscular administration: 

leuprolide-Use the gluteal region, the front of the thigh, or the deltoid to administer intramuscularly. If a blood vessel has unintentionally been damaged, do not use it. 

Oral administration 

norethindone-Administer the tablets orally 

Patient Information Leaflet

Patient information leaflet 

Generic Name: leuprolide and norethindrone 

Why do we use leuprolide and norethindrone? 

• Endometriosis: leuprolide is a gonadotropin-releasing hormone (GnRH) agonist that suppresses the production of estrogen and progesterone. At the same time, norethindrone is a synthetic progestin that helps regulate hormonal imbalances associated with endometriosis. 
• Uterine Fibroids: Uterine fibroids are non-cancerous growths in or around the uterus. Combining leuprolide and norethindrone can reduce fibroids’ size and alleviate symptoms such as heavy menstrual bleeding and pelvic pain. 
• Abnormal Uterine Bleeding: For women experiencing abnormal or heavy menstrual bleeding, this combination therapy can help regulate the menstrual cycle and reduce excessive bleeding. 
• Precocious Puberty: Precocious puberty is when a child’s body starts developing before the typical age. leuprolide and norethindrone may be used to delay puberty and slow down physical development in affected children. 
• Assisted Reproductive Technologies (ART): In some cases, leuprolide and norethindrone are used as controlled ovarian stimulation during assisted reproductive technologies like in vitro fertilization (IVF). This helps regulate the timing of ovulation and enhances the procedure’s success.