Gonadotropin releasing hormone (GnRH) analogs are synthetic analogs of naturally occurring GnRH with greater potency than the natural hormone.  

The following agents are addressed in this document:

• Degarelix (Firmagon^®_, Ferring Pharmaceuticals Inc., Parsippany, NJ)
• Goserelin acetate (Zoladex^®_, AstraZeneca Pharmaceuticals, Wilmington, DE)
• Histrelin acetate (Vantas^®_; Supprelin^® LA 12 month implant, Endo Pharmaceuticals Solutions Inc., Chadds Ford, PA)
• Leuprolide acetate (Lupron Depot^® and Lupron Depot-Ped^®_, Abbott Laboratories,  North Chicago, Illinois; Eligard^®_, Sanofi-Aventis, Bridgewater, NJ)
• Nafarelin acetate (Synarel Nasal Spray^®_, GD Searle LLC., NY, NY)
• Triptorelin pamoate (Trelstar^®_, Trelstar LA^®_, Trelstar Depot^®_, Watson Pharma, Inc., Morristown, NJ)

Note:
This document does not address infertility treatment. Please see the following document for additional information: CG-DRUG-11 Injectable Infertility Drugs

I. Breast Cancer –Goserelin acetate or leuprolide acetate 

Medically Necessary 

Goserelin acetate or leuprolide acetate is considered medically necessary for the treatment of hormone receptor positive breast cancer in pre- or peri-menopausal women. 

Not Medically Necessary 

Goserelin acetate or leuprolide acetate is considered not medically necessary for the treatment of breast cancer when the criteria above are not met.

II. Ovarian Cancer (including fallopian tube cancer and primary peritoneal cancer)–Leuprolide acetate

Medically Necessary 

Leuprolide acetate is considered medically necessary for ovarian cancer when any of the following are met:

• Hormonal therapy for clinical relapse in individuals with stage II-IV granulosa cell tumors; or
• Hormonal therapy for treatment of epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer as a single agent for:
  1. Progressive, stable or persistent disease on primary chemotherapy; or
  2. Relapse after complete remission following primary chemotherapy; or
  3. Stage II-IV disease showing partial response to primary treatment; or
  4. Low grade or focal recurrences after a disease free interval of greater than 6 months. 

Not Medically Necessary 

Leuprolide acetate is considered not medically necessary for ovarian cancer when the criteria above are not met.

III. Prostate Cancer-Degarelix, goserelin acetate, histrelin acetate (Vantas), leuprolide acetate, or triptorelin pamoate 

Medically Necessary 

1. Degarelix, goserelin acetate, histrelin acetate (Vantas), leuprolide acetate, or triptorelin pamoate is considered medically necessary for the treatment of prostate cancer when any of the following indications are met:
   • Clinically localized disease* with intermediate (T2b to T2c cancer, Gleason score of 7, or prostate specific antigen (PSA) value of 10-20 ng/mL) or higher risk of recurrence; or
   • Locally advanced disease*; or
   • Other advanced*, recurrent, or metastatic* disease; or
   • In combination with antiandrogen (flutamide or bicalutamide) for locally confined stage T2b-T4 (stage B2-C) disease.
     
     *See definition section below for description of term
      
2. Degarelix, goserelin acetate, histrelin acetate (Vantas), leuprolide acetate or triptorelin pamoate is considered medically necessary to shrink an enlarged prostate to an acceptable size prior to brachytherapy, cryosurgery or external beam radiation therapy for the treatment of prostate cancer.

Not Medically Necessary 

Degarelix, goserelin acetate, histrelin acetate (Vantas), leuprolide acetate, or triptorelin pamoate is considered not medically necessary for treatment of prostate cancer when the criteria above are not met. 

IV. Central Precocious Puberty- Leuprolide acetate (Lupron Depot-Ped), nafarelin acetate, or histrelin acetate subcutaneous implant (Supprelin LA) 

Medically Necessary 

Leuprolide acetate (Lupron Depot-Ped), nafarelin acetate or histrelin acetate subcutaneous implant (Supprelin LA) is considered medically necessary for the treatment of children with central precocious puberty (defined as the beginning of secondary sexual characteristics before age 8 in girls and 9 in boys). 

Not Medically Necessary 

Leuprolide acetate (Lupron Depot-Ped), nafarelin acetate or Supprelin LA (histrelin acetate subcutaneous implant) is considered not medically necessary for the treatment of central precocious puberty when the criteria above are not met.

V. Gynecology Uses-Goserelin acetate, leuprolide acetate or nafarelin acetate 

Medically necessary: 

1. Goserelin acetate, leuprolide acetate or nafarelin acetate is considered medically necessary when any of the following indications are met:
   • Chronic pelvic pain (noncyclical pain lasting 6 or more months that localizes to the anatomic pelvis, anterior abdominal wall at or below the umbilicus, the lumbosacral back, or the buttocks, and is of sufficient severity to cause functional disability or lead to medical care [ACOG, 2004])-not to continue beyond 3 months if there is no symptomatic relief; or
   • Endometriosis (for goserelin acetate the 3.6 mg implant only should be used); or
   • To induce amenorrhea in women in certain populations, including menstruating women diagnosed with severe thrombocytopenia or aplastic anemia.
2. Goserelin acetate is considered medically necessary for any of the following additional indications:
   • Dysfunctional uterine bleeding; or
   • Endometrial thinning prior to endometrial ablation for dysfunctional uterine bleeding (3.6 mg implant only).
3. Leuprolide acetate is considered medically necessary for any of the following additional indications:
   • Preoperative treatment as adjunct to surgical treatment of uterine fibroids (leiomyoma uteri). May be used to reduce size of fibroids to allow for a vaginal procedure; or
   • Prior to surgical treatment (myomectomy or hysterectomy) in individuals with documented anemia.

Not Medically Necessary 

Goserelin acetate, leuprolide acetate or nafarelin acetate is considered not medically necessary for gynecological uses when the criteria above are not met.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

GnRH analogs are a group of hormonal drugs consisting of GnRH agonists and antagonists, both of which suppress pituitary hormones. GnRH agonists typically act over several days and GnRH antagonists act quickly within several hours. Affecting the pituitary gland in the brain, GnRH analogs suppress function of the ovaries and testes, blocking the production of testosterone in males and estrogen in females. Repeated administration of these drugs will cause gonadal hormone dependent tissues/organs to reduce or cease activity, such as the normal prostate gland that is dependent on testosterone for growth and function. This effect is reversible on discontinuation of the drug therapy.

Drugs classified as GnRH analogs include, but are not limited to: degarelix (Firmagon^®),goserelin acetate (Zoladex^®), histrelin acetate (Vantas^® 12 month implant; Supprelin^® LA 12 month implant), leuprolide acetate (Lupron Depot^®_, Lupron Depot-Ped^®_, Eligard^®), nafarelin acetate (Synarel Nasal Spray^®), and triptorelin pamoate (Trelstar^®_, Trelstar LA^®_, Trelstar Depot^®). There are both Food and Drug Administration (FDA) approved and non-FDA approved indications for these drugs. The non-FDA approved indications listed in this document are based on drug compendia (The National Comprehensive Cancer Network^® NCCN Drugs & Biologic Compendium^™_,DrugPoints^® Compendium, and the American Hospital Formulary Service^®) and published peer reviewed literature as detailed in CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use.

Although GnRH products may differ in specific labeled indications and dosing requirements, clinical evidence does not support differential effectiveness of one product over the other for FDA approved clinical indications. 

Breast Cancer

Breast cancer is the most common cancer diagnosed in women today with the exception of skin cancer. Suppression of ovarian function with the use of goserelin acetate or leuprolide acetate has been shown to be effective in the treatment of hormone receptor positive breast cancer in pre- or peri-menopausal women. Two clinical studies (Jonat, 2002; Jakesz, 2002) compared ovarian suppression hormones, such as GnRH analogs to conventional chemotherapeutic agents, such as a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).  Five years after the completion of one study, no difference between goserelin acetate (Zoladex) and CMF was established in the final outcome review.  Converting subjects from an estrogen receptor positive to negative state, CMF induces significantly better disease free survival and overall survival.

Ovarian Cancer 

There are several small studies in the peer reviewed published literature assessing the role of leuprolide acetate as a treatment for ovarian cancer. Fishman (1996) evaluated six women with recurrent or persistent ovarian granulosa cell tumor who were treated with monthly leuprolide acetate injections. Cessation of disease progression was noted in five subjects. The sixth subject remained disease free since her primary cytoreductive surgery while on adjuvant therapy with leuprolide acetate for 24 months. There were no major side effects noted and the treatment was well tolerated. The authors concluded that a reasonable disease progression-free interval occurred and leuprolide treatment should be considered for further trials of therapy. Balbi (2004) reported on a study in which 12 women with advanced ovarian cancer previously treated with paclitaxel were administered leuprolide on days 1, 8, and 28. Progression free survival was six months and the treatment was well tolerated. The authors noted: "the high tolerability and the results obtained with leuprolide versus platinum in second-line therapy might permit a better use of the analogs for advanced ovarian cancer."

Prostate Cancer 

Prostate cancer is the most common form of cancer, other than skin cancer, among men. Wilt and colleagues (2008) report that approximately 90% of men with prostate cancer have disease confined to the prostate gland (clinically localized disease). GnRH analogs are commonly used in the treatment of prostate cancer under specific conditions.

Men with prostate cancer are categorized according to their recurrence risk into those with clinically localized disease at low, intermediate and high risk of recurrence, or those with locally advanced disease at very high risk of recurrence, or those with metastatic disease. The 2011 NCCN Prostate Cancer Guideline includes the following additional information defining prostate cancer recurrence risk categories:

Low risk category includes men with tumors stage T1-T2a, low Gleason score (less than or equal to 6), and serum PSA level below 10.

Intermediate risk category includes men with any T2b to T2c cancer, Gleason score of 7, or PSA value of 10-20 ng/ mL. Those with multiple adverse factors may be shifted into the high risk category.

Men with prostate cancer that is clinically localized Stage T3a or Gleason score 8-10 or preoperative PSA level greater than 20 ng/mL are categorized by the NCCN Guideline Panel as high risk for recurrence after definitive therapy, and those at very high risk of recurrence have Stage T3b to T4 (locally advanced) disease.

Androgen deprivation therapy (which includes GnRH analogs) may be used to shrink the size of the prostate to an acceptable size prior to brachytherapy (NCCN Clinical Practice Guideline for Prostate Cancer, 2011). The NCCN Drugs and Biologic Compendium (2011) issued 2A recommendations for the following GnRH analogs advising that these agents may be used to shrink a large prostate to an acceptable size for brachytherapy: degarelix, goserelin acetate, histrelin acetate (Vantas), leuprolide acetate, and triptorelin pamoate. The American Academy of Urology (2008) indicates that there is evidence of benefit from hormone therapy prior to cryosurgery for downsizing purposes. The American Cancer Society (2011) reports that androgen deprivation therapy may be used before surgery or radiation to shrink the prostate cancer to make other treatments more effective. In addition, several early studies demonstrated reduction of the size of the prostate with GnRH prior to cryosurgery or external beam radiation therapy for treatment of prostate cancer. Shearer and colleagues (1992) reported a significant reduction in prostate volume achieved with GNRH (goserelin) in 20 of 22 individuals prior to external beam radiotherapy. These authors also noted that hormonal therapy allows for reduction of tumor volume and hence the size of the radiotherapy field. Wong and colleagues (1997) treated 47 cases of prostate cancer with androgen ablation (leuprolide acetate) prior to cryosurgery to shrink the gland. Wilson and colleagues (2004) report that GnRH antagonists clearly provide efficacy in downsizing the prostate and urologists are utilizing androgen deprivation therapy before surgical and radiation procedures for prostate cancer. Specialty consensus review also recommends short-term use of androgen deprivation therapy prior to brachytherapy, cryosurgery or external beam radiation therapy in men with large prostates (50 grams or more) for a period of 3-9 months prior to therapy to shrink the gland in order to make radiation or cryotherapy feasible. If the gland is too large, therapy may be inadequate.

Central Precocious Puberty:

Central precocious puberty (CPP) refers to premature activation of the hypothalamic-pituitary-gonadal axis (Eugster, 2007; Phillip, 2005). CPP is generally defined as the beginning of secondary sexual characteristics before age 8 in girls and 9 in boys. Carel and colleagues (2009) reported that GnRH analogs are standard of care for CPP. Lupron Depot-Ped (leuprolide acetate), Synarel Nasal Spray (nafarelin acetate), and Supprelin LA (histrelin acetate subcutaneous implant) are all FDA approved GnRH analogs for the treatment of CPP.

Gynecology Uses 

Guidelines from the Royal College of Obstetricians and Gynaecologists (2005) state women with cyclical pelvic pain should be offered a therapeutic trial, using the combined oral contraceptive pill or a GnRH agonist for a period of 3-6 months before having a diagnostic laparoscopy.

The American College of Obstetrics and Gynecology (ACOG) (2004; reaffirmed 2008) practice bulletin for chronic pelvic pain includes the following Level A recommendation and conclusion which is stated to be based on good and consistent scientific evidence:

• GnRH agonists are effective in relieving pelvic pain associated with endometriosis and irritable bowel syndrome, as well as in women with symptoms consistent with endometriosis who do not have endometriosis. Thus, empiric treatment with GnRH agonists without laparoscopy should be considered as an acceptable approach to treatment. 

Level B recommendations which are based on limited or inconsistent scientific evidence include the following:

• GnRH agonists should be considered as a treatment option for chronic pelvic pain because they have been shown to relieve endometriosis-associated pelvic pain.

The ACOG (2010) practice bulletin for the management of endometriosis includes the following Level A recommendations and conclusions:

• Medical suppressive therapy (includes GnRH agonists) improves pain symptoms; however, recurrence rates are high after the medication is discontinued.
• Medical suppressive therapies such as oral contraceptives (OCs) or GnRH agonists for endometriosis associated infertility are ineffective.
• When relief of pain from treatment with a GnRH agonist supports continued therapy, the addition of add-back therapy (bone sparing agents) reduces or eliminates GnRH agonist-induced bone mineral loss and provides symptomatic relief without reducing the efficacy of pain relief.

Level B recommendations include the following:

• After an appropriate pretreatment evaluation (to exclude other causes of chronic pelvic pain) and failure of initial treatment with OCs and NSAIDS empiric therapy with a 3-month course of a GnRH agonist is appropriate.

The Ling (1999) study is a small, short-term, randomized controlled trial (RCT) used for support of empiric therapy for management of chronic pelvic pain. 

The effect of GnRH analogs on fertility preservation during chemotherapy has also been investigated. Del Mastro and colleagues (2011) indicated that the use of triptorelin to induce temporary ovarian suppression during chemotherapy in premenopausal women with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause. In another study, Gerber and colleagues (2011) concluded that premenopausal women with breast cancer receiving goserelin acetate during chemotherapy did not experience statistically significantly less amenorrhea six months after end of chemotherapy compared with those receiving chemotherapy alone. Although the resumption of menses was more favorable in the triptorelin study, the actual number of live births between both groups was not significantly different. Published data regarding the efficacy of GnRH in protecting the ovaries during chemotherapy is conflicting and it unclear at this time if these agents are able preserve fertility.

Conclusion

The uses of GnRH analogs considered to be medically necessary in this document have sufficient evidence available to support them. However, there is a lack of scientific evidence found from which conclusions could be made concerning the safety and efficacy of treating various other indications, including, but not limited to: premenstrual syndrome; fertility preservation during chemotherapy, menopause or mood related disorders; cancer of the endometrium, cancer of the liver; benign prostatic hypertrophy; male castration, and to stop pubertal development in order to maximize growth for children of short stature on growth hormones.

Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure; may include chemotherapy, radiation, hormone, or biological therapy.

Advanced prostate cancer: Disease that has spread beyond the prostate to surrounding tissues or distant organs.

Androgen deprivation therapy (also known as androgen ablation or androgen suppression): Treatment to suppress or block the production or action of male hormones. This is done by having the testicles removed, by taking female sex hormones, or by taking drugs called antiandrogens or GnRH analogs.

Brachytherapy (also known as internal radiation): A type of radiation treatment used to stop the growth of cancer cells by implanting radioactive material directly into the tumor or into the surrounding tissues.

Cancer staging: The process of determining how much cancer there is in the body and where it is located; describes the extent or severity of an individual's cancer based on the extent of the original (primary) tumor and the extent of spread in the body.

Central precocious puberty: The beginning of secondary sexual characteristics before age 8 in girls and age 9 in boys.

Chronic pelvic pain: Noncyclical pain lasting 6 or more months that localizes to the anatomic pelvis, anterior abdominal wall at or below the umbilicus, the lumbosacral back, or the buttocks, and is of sufficient severity to cause functional disability or lead to medical care (ACOG, 2004).

Clinically localized prostate cancer: Cancer presumed to be confined within the prostate based on pre-treatment findings such as physical exam, imaging, and biopsy findings.

Cryosurgery (also called cryotherapy or cryosurgical ablation): Is the use of extreme cold produced by liquid nitrogen (or argon gas) to destroy abnormal tissue. Cryosurgery may be used to treat tumors on the skin (external tumors), such as basal cell carcinoma, or tumors inside the body (internal tumors), such as prostate cancer.    

External beam radiation therapy (EBRT) (also known as teletherapy): A form of therapy using radiation to stop the growth of cancer cells. A linear accelerator directs a photon or electron beam from outside the body through normal body tissue to reach the cancer and the radiation is given 5 days a week for a period of 3 to 8 weeks.

Gleason Grading System: A prostate cancer grading system based on a number range from one to five; the lower the number, the lower the grade, and the slower the cancer growth.

Gleason score: Represents the sum of the two most common Gleason grades observed by the pathologist on a specimen, the first number is the most frequent grade seen.

Locally advanced disease (prostate cancer): Cancer that has spread from where it started to nearby tissue or lymph nodes. 

Metastatic: The spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Risk of recurrence (prostate cancer):

Low risk of recurrence: Men with tumors stage T1-T2a, low Gleason score (less than or equal to 6), and serum PSA level below 10.

Intermediate risk of recurrence: Men with any T2b to T2c cancer or Gleason score of 7 or PSA value of 10-20 ng/mL.

High risk of recurrence: Men with prostate cancer that is clinically localized stage T3a or Gleason score 8-10, or PSA level greater than 20 ng/mL after definitive therapy.

Very high risk of recurrence: Men with Stage T3b to T4 (locally advanced) disease.

Peer Reviewed Publications:

1. Balbi G, Piano LD, Cardone A, Cirelli G. Second-line therapy of advanced ovarian cancer with GnRH analogs. Int J Gynecol Cancer. 2004; 14(5):799-803.
2. Carel JC. Can we increase adolescent growth? Eur J Endocrin. 2004; 151:U101-U108.
3. Carel JC. Management of short stature with GnRH agonist and co-treatment with growth hormone: a controversial issue. Mol Cell Endocrinol. 2006; 254-255:226-233.
4. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009; 123(4):e752-762.
5. Chudecka-Głaz A, Rzepka-Górska I. Favorable effects of long-term therapy with gonadoliberin analogues in three patients with advanced and recurrent ovarian cancer. Eur J Gynaecol Oncol. 2009; 30(5):589-591.
6. Del Mastro L, Boni L, Michelotti A, et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA. 2011; 306(3):269-276.
7. Donnez J, Vilos G, Gannon MJ, et al. Goserelin acetate (Zoladex) plus endometrial ablation for dysfunctional uterine bleeding: a large, randomized double-blind study. Fertil Steril. 1997; 68(1):29-36.
8. Eugster EA, Clarke W, Kletter GB, et al. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. J Clin Endocrinol Metab. 2007; 92(5):1697-1704.  
9. Fishman A, Kudelka AP, Tresukosol D, et al. Leuprolide acetate for treating refractory or persistent ovarian granulosa cell tumor. J Reprod Med. 1996; 41(6):393-396.
10. Franke HR, van de Weijer PH, Pennings TM, van der Mooren MJ. Gonadotropin-releasing hormone agonist plus "add-back" hormone replacement therapy for treatment of endometriosis: a prospective, randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000; 74(3):534-539.
11. Gerber B, von Minckwitz G, Stehle H, et al; German Breast Group Investigators. Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. J Clin Oncol. 2011; 29(17):2334-2341.
12. Jakesz R, Hausmaninger H, Kubista E, et al. Austrian Breast and Colorectal Cancer Study Group Trial 5. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol. 2002; 20(24):4621-4627.
13. Jonat W, Kaufmann M, Sauerbrei W, et al. Zoladex Early Breast Cancer Research Association Study. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol. 2002; 20(24):4628-4635.
14. Ling, FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol. 1999; 93(1):51-58.
15. Meirow D, Rabinovici J, et al. Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate. Cancer. 2006; 107(7):1634-1641.
16. Messing E, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer: results at 10 years of EST 3886. J Urol. 2003; 169: 396, A1480.
17. Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer. N Engl J Med. 1999; 341(24):1781-1788.
18. Phillip M, Lazar L. Precocious puberty: growth and genetics. Horm Res. 2005; 64 Suppl 2:56-61.
19. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma- long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005; 61(5):1285-1290.
20. Quaas AM, Ginsburg ES. Prevention and treatment of uterine bleeding in hematologic malignancy. Eur J Obstet Gynecol Reprod Biol. 2007; 134(1):3-8.
21. Roach M III, deSilvio M, Lawton C, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol. 2003; 21(10):1904-1911.
22. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer. a systematic review and meta-analysis. Ann Internal Med. 2000; 132(7):566-577.
23. Shearer RJ, Davies JH, Gelister JS, Dearnaley DP. Hormonal cytoreduction and radiotherapy for carcinoma of the prostate. Br J Urol. 1992; 69(5):521-524.
24. Thompson I, Thrasher JB, Aus G, et al; AUA Prostate Cancer Clinical Guideline Update Panel. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007; 177(6):2106-2131.
25. van Gool SA, Kamp GA, Visser-van Balen H, et al. Final height outcome after three years of growth hormone and gonadotropic-releasing hormone agonist treatment in short adolescents with relatively early puberty.  J Clin Endocrinol Metab. 2007; 92(4):1402-1408.
26. Wheeler JM, Knittle JD, Miller JD. The Lupron Endometriosis Study Group. Depot leuprolide acetate versus danazol in treatment of women with symptomatic endometriosis: a multicenter, double-blind, randomized clinical trial II. Assessment of safety. Am J Gynecol Obstet. 1993; 169(1):26-33.
27. Wilson S. Downsizing and prostate cancer. Rev Urol. 2004; 6 Suppl 7:S19-24.
28. Wilt TJ, MacDonald R, Rutks I, et al. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med. 2008; 148(6):435-448.
29. Wit JM, Visser-van Balen H, Kamp GA, Oostdijk W. Benefit of postponing normal puberty for improving final height. Eur J Endocrin. 2004; 151:S41-S45.
30. Wong WS, Chinn DO, Chinn M, et al. Cryosurgery as a treatment for prostate carcinoma: results and complications. Cancer. 1997; 79(5):963-974.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Albuquerque LE, Saconato H, Maciel MCR. Depot versus daily administration of gonadotropin releasing hormone agonist protocols for pituitary desensitization in assisted reproduction cycles. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD002808.
2. American College of Obstetrics and Gynecology Committee on Practice Bulletins -- Gynecology. ACOG Practice Bulletin No. 51. Chronic pelvic pain. Obstet Gynecol. 2004 (reaffirmed 2008); 103(3):589-605.
3. American College of Obstetrics and Gynecology Committee on Practice Bulletins -- Gynecology. ACOG Practice bulletin no. 114: management of endometriosis. Obstet Gynecol. 2010; 116(1):223-236.
4. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2011^®_. Bethesda, MD: American Society of Health-System Pharmacists^®_, 2011.
5. Babaian RJ, Donnelly B, Bahn D, et al. Best practice statement on cryosurgery for the treatment of localized prostate cancer. J Urol. 2008; 180(5):1993-2004.
6. Bayram N, van Wely M, Van der Veen F. Pulsatile gonadotropin releasing hormone for ovulation induction in subfertility associated with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No.: CD000412.
7. Degarelix Acetate. In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Last Modified: September 13, 2010. Available at: http://www.thomsonhc.com. Accessed on September 29, 2011.
8. Degarelix [Product Information], Parsippany, NJ. Ferring Pharmaceuticals Inc., February 2009. Available at: http://www.ferringusa.com/files/FIRM060%20DEGARELIX%20Glossy%20PI_L4_2.12.09.pdf. Accessed on September 29, 2011.
9. Eligard [Product Information], Bridgewater, NJ. Sanofi-aventis US, LLC; March 2011. Available at: http://products.sanofi-aventis.us/eligard/eligard_75.html. Accessed on September 29, 2011.
10. Firmagon [Product Information], Parsippany, NJ. Ferring Pharmaceuticals Inc., Available at: http://www.firmagon.us/docs/fpi-physician.pdf. Accessed on September 29, 2011.
11. Goserelin acetate Monograph. May 2010. American Hospital Formulary Service^®_. Available at: http://www.ashp.org/ahfs/. Accessed on September 29, 2011.
12. Goserelin acetate (Zoladex^®). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Last modified August 12, 2011. Available at: http://www.thomsonhc.com. Accessed on September 29, 2011.
13. Histrelin acetate Monograph. December  2010. American Hospital Formulary Service^®_. Available at: http://www.ashp.org/ahfs/. Accessed on September 30, 2011.
14. Histrelin acetate (Vantas^®_, Supprelin^®_, Supprelin^® LA). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Last modified March 11, 2011. Available at: http://www.thomsonhc.com. Accessed on September 29, 2011.
15. Lee SJ, Schover LR, Partridge A, et al. American Society of Clinical Oncology Recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006; 24(18):2917-2931.
16. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001; (2):CD000547.
17. Leuprolide acetate Monograph. May 2010. American Hospital Formulary Service^®. Available at: http://www.ashp.org/ahfs/. Accessed on September 30, 2011.
18. Leuprolide acetate (Lupron^®_, Lupron Depot^®_, Lupron Depot-Ped^®_, Eligard^®). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Last modified September 19, 2011. Available at: http://www.thomsonhc.com. Accessed on September 29, 2011.
19. Lupron Depot [Product Information], North Chicago, IL. Abbott Laboratories; June 2011. Available at:  http://www.lupron.com/prescribing-information.cfm?ref=3. Accessed on September 29, 2011.
20. Loblaw DA, Virgo KS, Nam R, et al. American Society of Clinical Oncology. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007; 25(12):1596-1605.
21. Lupron Depot-Ped [Product Information], North Chicago, IL. Abbott Laboratories; August 2011. Available at: http://www.rxabbott.com/pdf/lupronpediatric.pdf. Accessed on September 29, 2011.
22. Nafarelin acetate Monograph. May 2010. American Hospital Formulary Service^®_. Available at: http://www.ashp.org/ahfs/. Accessed on September 30, 2010.
23. Nafarelin acetate (Synarel Nasal Spray^®). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Last modified May 7, 2011. Available at: http://www.thomsonhc.com. Accessed on September 29, 2011.
24. National Comprehensive Cancer Network^®_. NCCN Drugs & Biologic Compendium^™ (electronic version). 2011. For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 29, 2011.
    • Degarelix
    • Goserelin acetate
    • Histrelin acetate
    • Leuprolide acetate
    • Triptorelin pamoate
25. National Comprehensive Cancer Network^® (NCCN). Clinical Practice Guidelines in Oncology. 2011. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 30, 2011.
    • Breast Cancer (V.2.2011). Revised March 25, 2011.
    • Ovarian Cancer (V.2.2011). Revised November 15, 2010.
    • Prostate Cancer (V.4.2011). Revised June 21, 2011.
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1. American Cancer Society. Prostate Cancer. Hormone (androgen deprivation) therapy. Last Revised: 06/17/2011. Available at: http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-treating-hormone-therapy. Accessed on October 4, 2011.

Breast Cancer
Central Precocious Puberty (CPP)
Chronic Pelvic Pain
Degarelix
Dysfunctional Uterine Bleeding
Endometrial Thinning
Eligard
Endometriosis
Firmagon
Gonadotropin Releasing Hormone (GnRH) Analogs
Goserelin Acetate
Histrelin Acetate
Leuprolide Acetate
Lupron
Lupron Depot
Lupron Depot-Ped
Nafarelin Acetate
Ovarian Cancer
Prostate Cancer
Supprelin LA
Synarel Nasal Spray
Trelstar
Trelstar Depot
Trelstar LA
Triptorelin Pamoate
Uterine Fibroids
Vantas
Zoladex

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.