Continuing Education Activity

Leuprolide is a medication used in the management and treatment of prostate cancer, endometriosis, uterine fibroids, precocious puberty, and other sex hormone-related conditions. It is in the GnRH agonist class of medications. This activity reviews the indications, mechanism of action, contraindications, monitoring protocols, and other vital factors pertinent for members of an interprofessional team managing the care of patients with prostate cancer and other sex hormone-related disorders.

Objectives:

• Describe the mechanism of leuprolide.
• Identify the most common adverse reactions associated with leuprolide therapy.
• Summarize management considerations for patients on leuprolide therapy.
• Explain the importance of collaboration and communication amongst the interprofessional team to ensure the appropriate selection of candidates for leuprolide therapy.

Indications

Leuprolide is an FDA-approved gonadotropin-releasing hormone (GnRH) agonist used for the management of endometriosis, uterine leiomyomata (also known as uterine fibroids), treatment of central precocious puberty in children, and advanced prostate cancer. Off-label uses include management of breast cancer, hormone therapy for male to female transgender patients, premenopausal ovarian suppression, and management of paraphilia and hypersexuality.[1][2][3]

In patients with endometriosis receiving this medication, the goal is to reduce endometriotic lesions and improve pelvic pain/tenderness, dysmenorrhoea, and dyspareunia.[2] It can be used as an initial form of management but is only usable for a maximum duration of 6 months. It is administered either as a monotherapy or in combination with norethindrone acetate to reduce bone mineral density loss. If symptoms recur, the combination method is an option as a single retreatment course for an additional six months.[2] 

In advanced prostate cancer, leuprolide is used as a palliative treatment to help reduce comorbidities and improve quality of life. Leuprolide lowers testosterone levels, which in turn minimizes the stimulatory effect it normally has on androgen-sensitive prostate cancer cells, therefore causing them to undergo apoptosis.[4]  

For uterine leiomyomata, leuprolide is effective in multiple ways. Preoperatively it can be used along with iron to treat anemia, reduce fibroid volume, and ultimately reduce bleeding during surgery. Even if the patient isn’t undergoing surgery, leuprolide can be used to reduce fibroid size and improve symptoms related to the fibroids.[5]

In treating children with central precocious puberty with leuprolide, the goal is to slow down the progression of the secondary sex characteristics until an age when they are appropriate. If left untreated, these patients typically have diminished adult height. With the use of leuprolide, the predicted adult height increases because it slows down the closing of the growth plates. Leuprolide discontinuation should merit consideration when at the appropriate time for puberty.[6]  

Mechanism of Action

Leuprolide acetate is a GnRH receptor agonist, also called a GnRH analog. Initially, the administration of leuprolide causes stimulation of pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which leads to an increase in steroidogenesis in ovaries and testes; thus resulting in increased estrogen in females and increased testosterone and dihydrotestosterone in males.[7] With continuous administration, the levels of gonadotropins and gonadal steroids fall. Ultimately, continuous use of leuprolide decreases levels of testosterone in males and estrogen in females by inhibiting LH and FSH production.[2]

Administration

Leuprolide acetate is administrable through an intramuscular or subcutaneous injection.[2] The patient can receive injections in 1, 3, 4, or 6-month increments, and the length of time determines the specific dosage in between each injection.[3][8][9] For instance, having an injection once every six months will require a higher dose of medication compared to the injection once a month. Dosages should not be combined because there are different release characteristics.

Adverse Effects

Adverse reactions are reported to be different in children versus adults. Typically leuprolide is well tolerated in children, but the most common complaint is local pain at the injection site, which occurs in 10% of cases. Other common reactions include weight change, mood changes, skin rash, acne vulgaris, seborrhea, vaginal discharge, vaginal hemorrhage, and vaginitis. Reports also exist of anaphylactic reactions.[10] In adults, the most common adverse reactions are injection site pain, flushing, hot flashes, headaches, and migraines. Other reported adverse effects include alopecia, nausea, vomiting, diarrhea, GI upset, fatigue, edema, insomnia, upper respiratory infection, fever, nasal congestion, altered mood, weight gain, vaginitis, testicular atrophy, weakness, dizziness, hyperlipidemia, hyperglycemia, impotence, decreased libido, dermatological changes, and arthropathy. Reduced fertility has been noted but typically reverses with the cessation of the drug. There are also reports of amenorrhea in women.[2][9][11][12]

Contraindications

Contraindications to leuprolide therapy include hypersensitivity to leuprolide or any other gonadotropin-releasing hormone agonists.[13] This medication should not be used in women who are or may become pregnant. A negative pregnancy test is necessary before starting the medication. Although this drug typically inhibits ovulation and stops menstruation, pregnancy can occur and therefore patients should be placed on a nonhormonal contraceptive while on leuprolide therapy. Also, it should not be used in women who are breastfeeding, and it is contraindicated in those who have undiagnosed vaginal bleeding. Caution should be taken in giving leuprolide to patients with risk factors for bone loss and decreased bone density, as well as patients with heart failure or preexisting heart disease.[14] Finally, leuprolide is not a therapeutic choice in postmenopausal women. 

Monitoring

Monitoring parameters vary depending on the condition receiving therapy with leuprolide. For all uses, bone mineral density and psychiatric symptoms require monitoring. Risk factors for bone loss include osteoporosis or a strong family history of it, chronic medication use that can decrease bone density such as anticonvulsants or corticosteroids, and chronic tobacco and alcohol use. Caution is necessary when treating these patients with leuprolide. Mood changes such as emotional lability, aggression, irritability, anger, and impatience are all possible in patients on leuprolide therapy; thus, the development or worsening of these symptoms is essential to monitor. Use leuprolide with caution in patients diagnosed with depression.[15] 

When using this drug to manage women with endometriosis, pregnancy must initially be ruled out with a negative pregnancy test. Endometrial pain can become exacerbated at first with therapy, but the clinician should monitor the pain throughout the use of leuprolide. 

For the treatment of precocious puberty in children, LH and FSH blood serum levels must be monitored, and height and bone age should be measured every 6 to 12 months. Testosterone levels in males and estradiol levels in females should get checked as well, and tanner staging is essential to monitor before, during, and after treatment.[6] 

Pediatric females using leuprolide may experience menses or spotting during the first two months of treatment, but medical staff should follow patients to check for continued bleeding after two months.[6] 

For the treatment of prostate cancer, providers should monitor FSH and LH levels, serum testosterone levels, and prostate-specific antigen levels. Fatigue, weakness, and urinary tract obstruction all merit vigilance during the initial treatment. Screening for diabetes should take place before starting therapy, as leuprolide can worsen glycemic control. Blood glucose and HbA1c should get periodically measured throughout therapeutic use. Electrocardiograms and electrolyte levels should be monitored occasionally, as well.[16] 

Toxicity

Leuprolide might cause fetal harm when given to a pregnant woman. In clinical trials, there has not been any reported overdose with leuprolide. Studies of increased doses of leuprolide show that patients tolerate the drug well.[12][17] However, practitioners should avoid using dosage forms of leuprolide that contain benzyl alcohol in neonates. "Gasping syndrome" is fatal toxicity that can occur in neonates, and it has correlated with large amounts of benzyl alcohol. This gasping syndrome includes CNS dysfunction, respiratory distress, metabolic acidosis, and hypotension.[18] 

Enhancing Healthcare Team Outcomes

Sex-hormone related disorders present with more than just the physiological findings to treat. For instance, precocious puberty not only shows as physical changes but also has mental effects on a child and how they are perceived in the world. Therefore, an interprofessional team of healthcare providers is necessary to treat these patients. These interprofessional teams should include physicians, nurses, pharmacists, psychologists, and others. The same applies to an interprofessional team that will treat patients with advanced prostate cancer. When the clinician or specialist initiates leuprolide therapy, a pharmacist should perform drug interaction checking and verify the dosage. Nursing can counsel the patient regarding dosing and administration, as well as potential adverse events that will require them to contact the prescriber's office. Pharmacists and nurses need to notify the clinicians if they have any concerns about the patient's therapy, as this type of interprofessional interaction will improve patient outcomes. [Level 5]

There will be many different specialties that need to communicate effectively and bring about better results for the patient. With the many different uses of leuprolide, physicians, nurses, and pharmacists must have a good understanding of the clinical applications and side effects of the drug. Also, a team of interprofessional researchers found that leuprolide is helpful in IVF treatments. The study gave one group leuprolide and gonadotropins and compared it to a control group that only received gonadotropins. It found that pregnancy rates increased in the experimental group.[19] [Level 3] With increased interprofessional knowledge and communication about leuprolide, research may uncover more therapeutic uses for the drug.