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Aetna Aetna
Clinical Policy Bulletin:
Gonadotropin-Releasing Hormone Analogs and Antagonists
Number: 0501


Policy

Leuprolide

  1. Aetna considers leuprolide (Lupron, Viadur, Eligard) medically necessary for the following indications subject to the specified limitations:

    1. Endometriosis (including adenomyosis, also known as endometriosis interna) (see Appendix).
    2. For the prevention of heavy uterine bleeding in pre-menopausal women during chemotherapy.
    3. For the treatment of members with prostate cancer (see Appendix).
    4. For the treatment of women with chronic refractory pelvic pain (see Appendix).
    5. For the treatment of women with dysfunctional uterine bleeding when other pharmacotherapies (e.g., non-steroidal anti-inflammatory drugs and estrogen-progestin contraceptives) have failed.
    6. For the treatment of men and pre-menopausal women with hormone-receptor positive breast cancer (see Appendix).
    7. For the treatment of relapsed granulosa cell tumors of the ovary (see Appendix)
    8. For the treatment of recurrent epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer.
    9. For the treatment-resistant paraphilias (see Appendix).
    10. For true (central) precocious puberty, which is defined as sexual maturation before age 8 in girls and age 10 in boys (see Appendix).
    11. For use in leuprolide stimulation test for diagnosing hypogonadism and central precocious puberty (see Appendix).
    12. Infertility (used in conjunction with urofollitropin or menotropins) to suppress luteinizing hormone (LH) production in members with documented premature LH surge, or used in “super-ovulation” regimens associated with in vitro fertilization (see Appendix).
    13. To decrease endometrial thickness prior to endometrial ablation or surgery (see Appendix).
    14. To decrease fibroid size and reduce anemia prior to fibroid surgery (see Appendix).
    15. To suppress onset of puberty in cases where the adolescent meets medical necessity criteria for growth hormone supplementation and has early onset of puberty and is not within target growth range (within 1 standard deviation of mean height for age and sex) (see Appendix).
    16. To suppress onset of puberty in transgender adolescents if they meet WPATH criteria (see Appendix).
    17. To treat severe refractory premenstrual syndrome (see Appendix).
       
  2. Aetna considers leuprolide experimental and investigational for all other indications, including any of the following conditions, because limited information has been published and further research including randomized, controlled trials is required to determine its efficacy:

    1. ACTH-dependent Cushing syndrome; or
    2. Alzheimer's disease; or
    3. Amenorrhea induction prior to bone marrow transplant; or
    4. Autoimmune progesterone dermatitis of pregnancy; or
    5. Benign prostatic hyperplasia; or
    6. Catamenial pneumothorax; or
    7. Endometrial cancer (including endometrial stromal sarcoma); or
    8. Epilepsy; or
    9. Hyperandrogenism; or
    10. Irritable bowel syndrome; or
    11. Juvenile idiopathic arthritis; or
    12. Menorrhagia (metromenorrhagia, metrorrhagia, menometrorrhagia); or 
    13. Menstrual migraines; or
    14. Myeloma; or
    15. Osteosarcoma; or
    16. Parotid gland cancer; or 
    17. Polycystic ovarian disease; or
    18. Poryhyria cutanea tarda; or
    19. Precocious pubarche alone, or pseudoprecocious puberty (gonadotropin independent precocious puberty); or
    20. Premature ovarian failure; or
    21. Preservation (suppression) of ovarian function during chemotherapy; or
    22. Preservation (suppression) of testicular function during chemotherapy; or
    23. Sickle cell anemia-associated priapism; or
    24. Stuttering; or
    25. Testicular cancer; or
    26. Uterine cancer.

Goserelin

  1. Aetna considers goserelin (Zoladex) medically necessary for any of the following indications:

    1. Hormone-receptor positive breast cancer in men and pre-menopausal women; or 
    2. Prostatic carcinoma; or 
    3. Endometrial thinning prior to endometrial ablation or hysterectomy (preoperative adjunct) (short-term (less than 6 months) use). (See also CPB 0091 - Endometrial Ablation); or 
    4. Endometriosis (including adenomyosis, also known as endometriosis interna) (see Appendix); or
    5. Dysfunctional uterine bleeding when other pharmacotherapies (e.g., non-steroidal anti-inflammatory drugs and estrogen-progestin contraceptives) have failed; or
    6. For true (central) precocious puberty, which is defined as sexual maturation before age 8 in girls and age 10 in boys (see Appendix); or
    7. Uterine fibroids (leiomyoma uteri) (preoperative adjunct to surgical treatment) (short-term (less than 6 months) use).

  2. Aetna considers goserelin experimental and investigational for preservation of ovarian or testicular function during chemotherapy, invasive ductal breast cancer, premature ovarian failure secondary to chemotherapy, and for all other indications because its effectiveness for these indications has not been established. For use of goserelin in infertility, see CPB 327 - Infertility.

Histrelin

  1. Aetna considers Vantas histrelin acetate subcutaneous implant medically necessary for treatment of members with prostate cancer (see Appendix).

  2. Aetna considers Supprelin LA histrelin acetate subcutaneous implant medically necessary for true (central) precocious puberty, which is defined as sexual maturation before age 8 in girls and age 10 in boys (see Appendix).

  3. Aetna considers histrelin acetate implants experimental and investigational for all other indications because there is insufficient evidence in the peer-reviewed literature (e.g., precocious puberty due to adrenal hyperplasia).

Triptorelin

  1. Aetna considers triptorelin (Trelstar) medically necessary for the following indications:

    1. Treatment of men with advanced prostate cancer (see Appendix)
    2. For true (central) precocious puberty, defined as sexual maturation before age 8 in girls and age 10 in boys (see Appendix).
    3. Non-atypical endometrial hyperplasia
    4. Endometriosis (including adenomyosis, also known as endometriosis interna) (see Appendix).
    5. Uterine fibroids (leiomyoma uteri) (preoperative adjunct to surgical treatment)

  2. Aetna considers triptorelin experimental and investigational for fibrocystic breast disease and all other indications because of insufficient evidence in the peer-reviewed literature (e.g., ovarian suppression in members with early breast cancer).

Degarelix

  1. Aetna considers degarelix (Firmagon) medically necessary for the treatment of adult men with prostate cancer.

  2. Aetna considers degarelix contraindicated and considered not medically necessary for persons with hypersensitivity to degarelix.

  3. Aetna considers degarelix experimental and investigational for all other indications (e.g., colon cancer) because of insufficient evidence in the peer-reviewed literature.

For gonadotropin-releasing hormone antagonists for infertility, see CPB 0327 - Infertility.

See also CPB 0345 - Implantable Hormone Pellets.



Background

Leuprolide (Lupron, Viadur, Eligard):

Leuprolide (Lupron, Viadur, Eligard) is a gonadotropin-releasing hormone (Gn-RH) analog, which may be indicated for treatment of certain conditions, which are hormonally regulated.

Leuprolide may be indicated in advanced cancer (palliative treatment) in patients who have inoperable prostate tumor, or refuse orchiectomy.  The available literature suggests combined therapy with leuprolide and an anti-androgen (e.g., megestrol, flutamide) appears to produce additive effects and to be more effective than leuprolide therapy alone in the treatment of advanced prostate cancer.  According to established guidelines, recommended dosing of leuprolide for palliative treatment of advanced prostate cancer is 1 mg given subcutaneously daily.  According to established guidelines, if patient is receiving leuprolide acetate suspension (Lupron depot) dosing is 7.5 mg IM once-monthly.

Leuprolide has been used in the treatment of true (central) precocious puberty, defined as sexual maturation less than age 8 in girls, and sexual maturation less than age 10 in boys.  The available literature suggests tumors should be ruled out by lab tests, CT, MRI, or ultrasound.  Leuprolide is not indicated for precocious pubarche alone or pseudoprecocious puberty (gonadotropin-independent precocious puberty).  According to established guidelines, recommended starting doses are: Lupron Depot Ped: 0.3 mg/kg every 4 weeks (minimum 7.5 mg), or Lupron injection: 50 mcg/kg daily.  Doses may be titrated upwards in order to achieve hormonal down-regulation.

Studies of leuprolide for endometriosis indicate that 6 months is an appropriate length for therapy.  Because of lack of safety data with long-term use, and because of concerns expressed in the available literature regarding effects on bone density, treatment after 6 months is typically not recommended.  According to established guidelines, recommended dosing of leuprolide for endometriosis is 3.75 mg as a single monthly intra-muscular (IM) injection.

Leuprolide has been studied for the treatment of uterine fibroids (leiomyoma uteri), as a pre-operative adjunct to surgical treatment.  Clinical studies have demonstrated the benefit of leuprolide in reducing vascular and surgical complications secondary to obstructive fibroid size.  In tests, GnRH agonists have effectively reduced the fibroid size, but their use was accompanied by a rapid re-growth following discontinuation.  The available literature states leuprolide therapy does not prevent or replace the eventual need for surgery.  If used as a pre-operative adjunct, the available literature states short-term treatment only is recommended (i.e., 1 to 3 months).

Leuprolide also has been shown to be an effective pre-operative adjunct to decrease endometrial thickness prior to endometrial ablation.  If used as a pre-operative adjunct, short-term treatment only (i.e., 1 to 2 months) is indicated.

Leuprolide is used in conjunction with urofollitropin or menotropins in patients with infertility.  It has been used to suppress LH production in patients with documented premature leteinizing hormone (LH) surge.  In addition, it has been used in “super-ovulation” regimens associated with in-vitro fertilization.  Treatment of infertility may be subject to limitations under some benefit plans.  Some HMO contracts, with or without a separate infertility benefit such as the Advanced Reproductive Technology (ART) Rider, specifically exclude injectable infertility drugs.

Leuprolide has been shown to be useful in the treatment of metastatic breast cancer in pre-menopausal patients whose disease has progressed or recurred despite a 3 or more months trial of tamoxifen.

Consensus guidelines from the National Comprehensive Cancer state that leuprolide may be an appropriate option for persons with stage II to IV granulosa cell tumors of the ovary that have relapsed after platinum-based chemotherapy (NCCN, 2007).  Granulosa cell tumors are frequently hormonally active and often demonstrate estrogen receptor positivity.  Thus, leuprolide been used as a method of reducing estrogen production in salvage therapy for recurrent, advanced stage granulosa cell tumors.

Leuprolide has been used as treatment for various other conditions (e.g., polycystic ovarian disease, hypermenorrhea, pre-menstrual syndrome, paraphilias, and endometrial cancer).  At this time limited information has been published to show efficacy for conditions other than those mentioned in the clinical criteria above.  Further research with randomized, controlled trials is required to determine efficacy in these other conditions.

The American Society of Clinical Oncology's recommendations on fertility preservation in cancer patients (Lee et al, 2006) stated that sperm and embryo cryo-preservation are considered standard practice.  On the other hand, the use of GnRH analogs or antagonists for testicular or ovarian suppression is considered investigational.  ASCO guidelines state: “At this time, since there is insufficient evidence regarding the safety and effectiveness of GnRH analogs and other means of ovarian suppression on female fertility preservation, women interested in ovarian suppression for this purpose are encouraged to participate in clinical trials.”  The guidelines also noted that there is insufficient evidence of the effectiveness of GnRH analogues in preventing chemotherapy-induced gonadal damage in men: “The efficacy of gonadoprotection through hormonal manipulations has only been evaluated in very small studies in cancer patients.”

In a review of the literature, Sonmezer and Oktay (2006) explained that there are a limited number of prospective studies of GnRH analogues in preventing chemotherapy-induced gonadal damage, “which are flawed because of short-term follow-up and/or because of lack of control subjects.”  The review notes that “[i]n addition to the lack of consistent support from clinical studies, there is currently no biological explanation for who GnRHa [GnRH analogues] can affect ovarian reserve.”  The authors concluded that “[i]n the absence of a prospective randomized study with sufficient power, we do not rely on ovarian suppression as an effective means of fertility preservation.”

Leuprolide has been employed as a therapeutic option for individuals with paraphilia who have failed pharamcotherapies such as cyproterone acetate (CPA), medroxyprogesterone acetate (MPA), and selective serotonin reuptake inhibitors (SSRIs).  Leuprolide is thought to decrease sexual drive in men afflicted with paraphilas by decreasing testosterone production.  Briken et al (2003) stated that in addition to psychotherapy, pharmacotherapy is an important treatment option for paraphilias, especially in sexual offenders.  They noted that research has showed that LH-releasing hormone (LHRH) agonists may offer a new treatment option for treatment of paraphilic patients.  These investigators performed a literature review on the use of LHRH agonist a new treatment option for treatment of paraphilic patients.  They found 4 case reports, 1 case-control study, 7 open uncontrolled studies, and 1 study comparing patients receiving CPA with those receiving LHRH agonist treatment in forensic hospitals.  In total, the studies reported on a sample of 118 treated patients with different forms of paraphilias  -- sadism, pedophilia, exhibitionism, voyeurism.  Nearly all of the studies used self-reports to measure the effects of medication.  Duration of follow-up was between 6 months and 7 years and revealed that there were no relapses if patients remained under treatment.  Patients previously treated with other agents like CPA, MPA, or SSRIs reported better effects when taking LHRH agonists.  The authors concluded that although there is a need for further research, LHRH agonists offer a treatment option for patients with severe paraphilia.  Furthermore, in a review on medications that may alter behaviors of sex-offenders, Scober and colleagues (2006) stated that therapeutic drugs include LHRH inhibitors (e.g., leuprolide acetate, CPA, and triptorelin), synthetic estrogens (e.g., diethylstilbestrol), and progesterones (e.g., MPA).

Leuprolide has also been tried for the treatment of seizures (Akaboshi and Takeshita, 2000) as well as Alzheimer's disease (Casadesus et al, 2006).  However, there is currently insufficient evidence to support its use for thes indications.

Available evidence on the effectiveness of leuprolide for the treatment of endometrial stromal sarcoma is limited to case reports.  Guidelines on systemic therapy for uterine sarcoma from Cancer Care Ontario included no recommendation for the use of leuprolide in uterine stromal sarcomas (Kanjeekal et al, 2004).  Furthermore, the National Cancer Institute's PDQ on uterine sarcoma (2008) did not include leuprolide or GnRH analogs as treatment options for uterine sarcoma.

Quaas and Ginsburg (2007) provided a systematic review on prevention and treatment of uterine bleeding in the setting of hematologic malignancy.  These researchers performed MEDLINE, PubMed, EMBASE and Cochrane searches with the terms uterine bleeding, uterine hemorrhage, hematologic malignancy.  All identified literature sources were included in the review.  The identified literature is largely comprised of case series and pilot studies.  No evidence-based protocols for gynecologists and hematologists are available.  The majority of the identified literature centers on menstrual suppression with GnRH agonists in hematologic malignancy, although no randomized trials could be identified.  Review of the identified literature suggests that medical prevention with GnRH agonist therapy is highly effective for prevention of uterine bleeding in hematologic malignancy.  With respect to treatment of acute uterine bleeding in the setting of hematologic malignancy, medical therapy can be used and is successful in the majority of patients, according to the identified studies.  Surgical treatment should be used expeditiously if medical treatment options fail to control acute bleeding.  Empiric prevention and treatment algorithms for the discussed clinical settings are proposed.  The authors stated that more research is necessary on the topic, with the goal to develop evidence-based guidelines for gynecology and hematology-oncology care providers.  Close cooperation between the specialties may improve morbidity and mortality associated with uterine bleeding in hematological malignancy in the future.

Hembree and colleagues (2009) formulated practice guidelines for endocrine treatment of transsexual persons.  This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence, which was low or very low.  Committees and members of the Endocrine Society, European Society of Endocrinology, European Society for Paediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, and World Professional Association for Transgender Health commented on preliminary drafts of these guidelines.  The authors concluded that transsexual persons seeking to develop the physical characteristics of the desired gender require a safe, effective hormone regimen that will (i) suppress endogenous hormone secretion determined by the person's genetic/biologic sex and (ii) maintain sex hormone levels within the normal range for the person's desired gender.  A mental health professional (MHP) must recommend endocrine treatment and participate in ongoing care throughout the endocrine transition and decision for surgical sex re-assignment.  The endocrinologist must confirm the diagnostic criteria the MHP used to make these recommendations.  Because a diagnosis of transsexualism in a prepubertal child can not be made with certainty, the authors do not recommend endocrine treatment of prepubertal children.  They recommended treating transsexual adolescents (Tanner stage 2) by suppressing puberty with GnRH analogs until age 16 years old, after which cross-sex hormones may be given.  They suggested suppressing endogenous sex hormones, maintaining physiologic levels of gender-appropriate sex hormones and monitoring for known risks in adult transsexual persons.

An UpToDate review on “Heavy or irregular uterine bleeding during chemotherapy” (Milbourne, 2013) states that “We suggest inducing amenorrhea with a GnRH agonist [e.g., leuprolide acetate] in premenopausal women at risk of chemotherapy induced thrombocytopenia

UpToDate reviews on “Treatment of locally advanced, recurrent, or metastatic endometrial cancer” (Campos and Miller, 2013) and “Overview of endometrial carcinoma” (Plaxe and Mundt, 2013) do not mention leuprolide as a therapeutic option.  Also, the 2013 NCCN’s Drugs and Biologics Compendium does not list uterine cancer as an indication of leuprolide acetate.

UpToDate reviews on “Malignant salivary gland tumors: Treatment of recurrent and metastatic disease” (Laurie, 2013) and “Salivary gland tumors: Treatment of locoregional disease” (Lydiatt and Quivey, 2013) do NOT mention the use of leuprolide as a therapeutic option.  Also, the 2013 NCCN’s Drugs and Biologics Compendium does not list parotid carcinoma as a recommended indication of leuprolide acetate.

Goserelin (Zoladex):

Goserelin (Zoladex) is a GnRH (also known as gonadorelin and LHRH) analog, which is indicated in certain conditions requiring suppression of estrogen or testosterone secretion.  At this time it is available only in a continuous-release subcutaneous implant that releases drug over a period of about 28 days.

Goserelin is approved by the Food and Drug Adminsitration (FDA) for treatment of advanced metastatic prostate cancer and advanced endometriosis.  Goserelin has also been shown to be effective for treatment or palliation of breast cancer in pre-menopausal patients.

Goserelin has been studied for the treatment of uterine fibroids.  Clinical studies have demonstrated the benefit of leuprolide in reducing vascular and surgical complications secondary to obstructive fibroid size.  In tests, GnRH agonists have effectively reduced the fibroid size, but their use was accompanied by a rapid reg-rowth following discontinuation.  Therefore, the literature states that goserelin therapy does not prevent or replace the eventual need for surgery.  If used as a pre-operative adjunct, the literature recommends short-term treatment (6 months or less).

Goserelin has been shown to be effective for the short-term (less than 6 months) pre-operative adjunct to endometrial ablation or surgery for leiomyomata uteri (uterine fibroids).

Goserelin is under investigation as a method of prevention of chemotherapy-induced gonadal damage.  In a prospective pilot study (n = 5), Franke et al (2005) explored the effects of goserelin acetate in women with Hodgkin's disease (HD) receiving chemotherapy while taking a continuous combined estrogen-progestin preparation as add-back on the prevention of premature ovarian failure (POF).  Pre-menopausal women with HD received goserelin and add-back until polychemotherapy was completed.  Every 4 weeks during treatment and thereafter, a hormonal profile (follicle-stimulating hormone (FSH), LH, 17beta-estradiol, progesterone and inhibin B) was measured until resumption of menstruation or the development of a hyper-gonadotropic state (2 x FSH greater than 30 U/l).  All patients reached pre-pubertal status during treatment.  Following cessation of goserelin therapy, 1 patient developed a hyper-gonadotropic state and 4 patients resumed menstruation.  One of those patients became pregnant and delivered a healthy son.  These investigators concluded that the effectiveness of GnRH agonist plus add-back on the prevention of POF during polychemotherapy in women with HD needs further elucidation in randomized controlled trials (RCTs).

Del Mastro et al (2006) noted that standard methods to prevent chemotherapy-induced early menopause in young, breast cancer patients are unavailable to date.  Pre-clinical data has suggested that LHRH analogs given during treatment can decrease the gonado-toxicity induced by chemotherapy.  In a phase II clinical trial, these investigators evaluated the activity of such a method in young, breast cancer patients undergoing adjuvant chemotherapy.  Pre-menopausal patients received goserelin 3.6 mg every 4 weeks before and during chemotherapy.  According to 2-stage optimal phase II Simon design, treatment was considered clinically interesting if it was able to prevent menopause in 19 out of 29 patients of the study population.  The resumption of ovarian function was defined by a resumption of menstrual activity or by a FSH value less than or equal to 40 IU/l within 12 months after the last cycle of chemotherapy.  A total of 30 patients were enrolled and 29 were evaluable.  Median age was 38 years (range of 29 to 47 years).  All but 1 patient received CEF regimen (cyclophosphamide, epirubicin, 5-fluorouracil).  Resumption of menstrual activity was observed in 21 patients (72 %; 95 % confidence interval [CI]: 52 to 87 %) and a FSH value less than or equal to 40 IU/l in 24 patients (83 %; 95 % CI: 63 to 93 %).  Menses resumption was observed in 16 out of 17 patients (94 %) with age less than 40 years and in 5 out of 12 patients (42 %) with age 40 years or over.  These researchers concluded that goserelin given before and during chemotherapy may prevent premature menopause in the majority of patients.  However, the different success rate by age indicates the need of a prospective evidence of the effectiveness of such a strategy.

In a prospective RCT, Badawy et al (2009) examined if GnRHa administration before and during combination chemotherapy for breast cancer could preserve post-treatment ovarian function in young women or not.  A total of 80 patients with unilateral adenocarcinoma of the breast and with no metastasis who had undergone modified radical mastectomy or breast-conserving surgery plus full axillary lymph node dissection were included in the study.  Patients were assigned randomly to receive combined GnRHa and chemotherapy or chemotherapy alone.  One woman in each group dropped out.  Main outcome measures included return of spontaneous menstruation and ovulation as well as hormonal changes (FSH, LH, E(2), P) during and after the course of treatment.  In the study group, 89.6 % resumed menses and 69.2 % resumed spontaneous ovulation within 3 to 8 months of termination of the GnRHa/chemotherapy co-treatment; 11.4 % experienced hyper-gonadotrophic amenorrhea and ovarian failure 8 months after treatment.  In the control group (chemotherapy without GnRHa), 33.3 % resumed menses and 25.6 % resumed normal ovarian activity.  The median FSH and LH concentrations, 6 months after completion of the GnRHa/chemotherapy cotreatment group, were significantly less than the control group.  During the GnRHa/chemotherapy co-treatment the concentrations of FSH, LH, and P decreased to almost pre-pubertal levels.  However, within 1 to 3 months after the last GnRHa injection, an increase in LH and FSH concentrations was detected, followed several weeks later in by an increase in P concentrations to within normal levels.  The authors concluded that administration of GnRHa before and during combination chemotherapy for breast cancer may preserve post-treatment ovarian function in women less than 40 years.  Moreover, they stated that long-term studies are needed.

In a systematic review, Clowse et al (2009) examined if administration of GnRHa during chemotherapy is protective of ovarian function and fertility.  These investigators searched the English-language literature (1966 to April 2007) using Medline and meeting abstracts and included studies that reported an association between GnRHa and ovarian preservation in women receiving chemotherapy.  Studies without a control group were excluded.  Ovarian preservation was defined as the resumption of menstrual cycles and a pre-menopausal FSH after chemotherapy.  Fertility was determined by a woman's ability to become pregnant.  These researchers estimated the summary relative risk (RR) and associated 95 % CI using a random-effects model.  A total of 9 studies included 366 women -- 3 studies included women with autoimmune disease receiving cyclophosphamide; 6 studies included women with hematologic malignancy receiving combination chemotherapy.  In total, 178 women were treated with GnRHa during chemotherapy, 93 % of whom maintained ovarian function.  Of the 188 women not treated with GnRHa, 48 % maintained ovarian function.  The use of a GnRHa during chemotherapy was associated with a 68 % increase in the rate of preserved ovarian function compared with women not receiving a GnRHa (summary RR = 1.68, 95 % CI: 1.34 to 2.1).  Among the GnRHa-treated women, 22 % achieved pregnancy following treatment compared with 14 % of women without GnRHa therapy (summary RR = 1.65, CI: 1.03 to 2.6).  The authors concluded that based on the available studies, GnRHa appear to improve ovarian function and the ability to achieve pregnancy following chemotherapy.  Several RCTs are underway to define the role and mechanism of GnRHa in ovarian function preservation.

Histrelin Acetate (Supprelin LA, Vantas):

Histrelin, an LH-releasing hormone (LH-RH) agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses.  Continuous administration of histrelin causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes.  These inhibitory effects result in decreased levels of LH and FSH.  In males, testosterone is reduced to castrate levels.  These decreases occur within 2 to 4 weeks after initiation of treatment.

The histrelin implant is designed to provide continuous subcutaneous release of histrelin at a rate of 50 to 60 mcg/day (Vantas) or approximately histrelin 65 mcg per day (Supprelin LA) over 12 months.

Children with central precocious puberty (neurogenic or idiopathic) have an early onset of secondary sexual characteristics (earlier than 8 years of age in females and 9 years of age in males).  They also show a significantly advanced bone age, which can result in diminished adult height attainment.  Supprelin LA was approved by the FDA for the treatment of children with central precocious puberty based on the results of a single-arm, open-label study involving 36 patients ranging in age from 4 to 11 years.  The primary endpoint of the study was hormonal suppression below pubertal levels by month 3 with continued suppression upon GnRH challenge.  All patients in the study were suppressed within the first month of treatment.

Prior to initiation of treatment, a clinical diagnosis of central precocious puberty should be confirmed by measurement of blood concentrations of total sex steroids, LH and FSH following stimulation with a GnRH analog, and assessment of bone age versus chronological age.  Baseline evaluations should include height and weight measurements, diagnostic imaging of the brain (to rule out intra-cranial tumor), pelvic/testicular/adrenal ultrasound (to rule out steroid secreting tumors), human chorionic gonadotropin levels (to rule out chorionic gonadotropin secreting tumor), and adrenal steroids to exclude congenital adrenal hyperplasia.

Vantas was approved by the FDA for the palliative treatment of advanced prostate cancer.  The FDA approval was based upon an open-label, multi-center study evaluating 138 patients with advanced prostate cancer and mean baseline serum levels of 388.3 ng/dL for testosterone and 83.6 ng/mL for prostate-specific antigen (PSA).  Patients were treated with a single histrelin acetate implant and were evaluated for at least 60 weeks.  Of the 138 patients, 37 had Jewett stage C disease, 29 had stage D disease, and 72 had an elevated or rising serum PSA after definitive therapy for localized disease.  Ninety percent of patients were 65 years of age or older.  Efficacy was determined by the number of patients who attained the criterion level of chemical castration (defined as serum testosterone 50 ng/dL or less) at week 4 and maintained this level through week 52.  The study found that all evaluable patients (n = 134) attained chemical castration after 4 weeks of treatment.  A statistically significant low mean testosterone level of less than 16 ng/dL (p < 0.0001) was achieved by week 4, and testosterone levels maintained below 20 ng/dL through week 52 of the study.  The investigators reported that all patients experienced a decrease in PSA levels after they began treatment with histrelin implant.  By week 24, 93 % of patients (n = 103) experienced a decrease in serum PSA to within normal limits.

The FDA labeling recommends that response to Vantas should be monitored by measuring serum concentrations of testosterone and PSA periodically, especially if the anticipated clinical or biochemical response to treatment has not been achieved.

Abarelix (Plenaxis):

Plenaxis (abarelix) is a GnRH antagonist approved by the FDA in November 2003.  It is indicated for the treatment of the symptoms of men with advanced prostate cancer who can not take other hormone therapies and who have refused surgical castration.  Plenaxis is marketed under a voluntary risk management program agreed to and administered by the sponsor that will restrict the use of Plenaxis to patients with advanced prostate cancer, who have no alternative therapy, because of an increased risk of serious, and potentially life-threatening, allergic reactions associated with its use.

In a phase III clinical study (n = 269), McLeod and colleagues (2001) evaluated the levels of testosterone and other hormones in men with prostate cancer treated with abarelix versus leuprolide.  The authors concluded that treatment with abarelix produced a higher percentage of patients who avoided a testosterone surge and had a more rapid time to testosterone suppression with a higher rate of medical castration 1 day after treatment and greater reductions in testosterone, LH, FSH, and dihydrotestosterone during the first 2 weeks of treatment compared with leuprolide.  The achievement and maintenance of castration was comparable between the two groups.

In another phase III clinical trial (n = 255), Trachtenberg et al (2002) reported that abarelix as monotherapy achieved medical castration significantly more rapidly than combination therapy (LHRH agonist and a non-steroidal anti-androgen) and avoided the testosterone surge characteristic of agonist therapy.  Both treatments were equally effective in reducing serum PSA, and achieving and maintaining castrate levels of testosterone.

Koch et al (2003) stated that abarelix provided a safe and effective medical alternative to surgical castration in symptomatic patients (n = 81) with advanced prostate cancer without the risk of the clinical flare associated with LHRH agonists.

In June 2006, the manufacturer of abarelix voluntarily discontinued its sale and distribution due to a significantly reduced demand for the product.  The drug was no longer be available after August 31, 2006.

Degarelix (Firmagon):

On December 29, 2008, the FDA approved degarelix, a GnRH receptor inhibitor, for the treatment of patients with advanced prostate cancer.  The effectiveness of degarelix was established in a clinical trial in which patients with prostate cancer received either degarelix or leuprolide.

In a 12-month, comparative, randomized, open-label, parallel-group phase III study, Klotz et al (2008) assessed the safety and effectiveness of degarelix versus leuprolide for achieving and maintaining testosterone suppression in a 1-year phase III trial involving patients with prostate cancer.  A total of 610 patients with adenocarcinoma of the prostate (any stage; median age of 72 years; median testosterone of 3.93 ng/ml, median PSA level of 19.0 ng/ml) were randomized and received study treatment.  Androgen-deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator's assessment.  Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (SC) for 1 month, followed by SC maintenance doses of 80 mg or 160 mg monthly, or IM leuprolide doses of 7.5 mg monthly.  Therapy was maintained for the 12-month study.  Both the intent-to-treat (ITT) and per protocol populations were analyzed.  The primary endpoint of the trial was suppression of testosterone to less than or equal to 0.5 ng/ml at all monthly measurements from day 28 to day 364, thus defining the treatment response.  This was achieved by 97.2 %, 98.3 % and 96.4 % of patients in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide groups, respectively (ITT population).  At 3 days after starting treatment, testosterone levels were less than or equal to 0.5 ng/ml in 96.1 % and 95.5 % of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively, and in none in the leuprolide group.  The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group (p < 0.001).  The hormonal side-effect profiles of the 3 treatment groups were similar to previously reported effects for androgen-deprivation therapy.  The SC degarelix injection was associated with a higher rate of injection-site reactions than with the IM leuprolide injection (40 % versus less than 1 %; p < 0.001, respectively).  There were additional differences between the degarelix and leuprolide groups for urinary tract infections (3 % versus 9 %. p < 0.01, respectively), arthralgia (4 % versus 9 %, p < 0.05, respectively) and chills (4 % versus 0 %, p < 0.01, respectively).  There were no systemic allergic reactions.  The authors concluded that degarelix was not inferior to leuprolide at maintaining low testosterone levels over a 1-year treatment period.  Degarelix induced testosterone and PSA suppression significantly faster than leuprolide; PSA suppression was also maintained throughout the study.  Degarelix represents an effective therapy for inducing and maintaining androgen deprivation for up to 1 year in patients with prostate cancer, and has a different mechanism of action from traditional GnRH agonists.  Its immediate onset of action achieves a more rapid suppression of testosterone and PSA than leuprolide.  Furthermore, there is no need for anti-androgen supplements to prevent the possibility of clinical "flare".  The findings of Klotz et al (2008) are in agreement with those of Gittelman et al (2008) as well as Van Poppel et al (2008).

In a phase 3, 1-year, multi-center, randomized, open-label study, Tombal et al (2010) compared the safety and effectiveness of degarelix at 240 mg for 1 month, and then 80 mg monthly (240/80mg); degarelix at 240 mg for 1 month, and then 160 mg monthly; and leuprolide at 7.5 mg/month.  Overall, 610 patients with histologically confirmed prostate cancer (all stages), for whom androgen deprivation therapy was indicated, were included.  The primary endpoint of this trial has been reported previously; the protocolled and exploratory subgroup analyses reported in this paper focus on degarelix at 240/80 mg (dose approved by the FDA and the European Medicine Evaluation Association for the treatment of patients with hormone-naive advanced prostate cancer).  Prostate-specific antigen progression-free survival (2 consecutive increases in PSA of 50 % compared with nadir and greater than or equal to 5 ng/ml on 2 consecutive measurements at least 2 weeks apart or death) and change in PSA were reviewed.  Effects of baseline disease stage (localized, locally advanced, and metastatic) and PSA level (less than 10, 10 to 20, greater than 20 to 50, and greater than 50 ng/ml) were analysed.  Patients receiving degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (p = 0.05).  Prostate-specific antigen recurrences occurred mainly in patients with advanced disease and exclusively in those with baseline PSA greater than 20 ng/ml.  Patients with PSA greater than 20 ng/ml had a significantly longer time to PSA recurrence with degarelix (p = 0.04).  The relatively low number of patients in each subgroup is a limitation of this study.  The authors concluded that these findings generate the hypothesis that degarelix at 240/80 mg offers improved PSA control compared with leuprolide.  Prostate-specific antigen recurrences occurred almost exclusively in patients with metastatic prostate cancer or high baseline PSA during this 1-year study.  The authors stated that further studies are needed to confirm these findings.

Ghiringhelli and colleagues (2013) noted that FSH receptor was recently found to be selectively expressed by endothelial cells on tumor-associated blood vessels in a wide range of human cancers.  In this context, these researchers hypothesized that degarelix may have anti-angiogenic effects via its capacity to block FSH production.  These investigators reported the case of a patient with metastatic colon cancer exhibiting tumor progression after failure of all conventional chemotherapeutic regimens.  The addition of degarelix to the last chemotherapeutic regimen was proposed as compassionate treatment.  Degarelix induced a rapid decrease in FSH level.  This treatment induced radiological stabilization and carcino-embryonic antigen stabilization during 1 year.  Contrast-enhanced ultrasonography demonstrated reduction of tumor vasculature.  The authors stated that this case represented the first report of an anti-tumoral effect of degarelix in metastatic colon cancer and suggested an anti-angiogenic property of this drug.  The clinical value of degarelix in the treatment of colon cancer needs to be ascertained in well-designed RCTs.

Triptorelin (Trelstar):

Trelstar, Trelstar Depot and Trelstar LA were approved by the FDA for the palliative treatment of advanced prostate cancer.  It offers an alternative treatment for prostate cancer when orchiectomy or estrogen administration is either not indicated or unacceptable to the patient.  The recommended dose of the depot version of triptorelin (Trelstar Depot) is 3.75 mg once-monthly.  The recommended dose of the long-acting version of triptorelin (Trelstar LA) is 11.25 mg every 84 days.  Trelstar received approval on March 10, 2010 under NDA 022437 for a recommended dose of a single 22.5-mg IM injection every 24 weeks.

Arriagada et al (2005) evaluated the role of ovarian suppression in patients with early breast cancer previously treated with local surgery and adjuvant chemotherapy.  A total of 926 pre-menopausal patients with completely resected breast cancer and either axillary node involvement or histological grade 2 or 3 tumors were randomized after surgery to adjuvant chemotherapy alone (control arm) or adjuvant chemotherapy plus ovarian suppression (ovarian suppression arm).  Ovarian suppression was obtained by either radiation-induced ovarian ablation or triptorelin for 3 years.  The analyses were performed with Cox models stratified by center.  Median follow-up was 9.5 years.  Mean age was 43 years.  Ninety per cent of patients had histologically proven positive axillary nodes, 63 % positive hormonal receptors and 77 % had received an anthracycline-based chemotherapy regimen.  Ovarian suppression was by radiation-induced ovarian ablation (45 % of patients) or with triptorelin (48 %).  At the time of randomization, all patients had regular menses or their FSH and estradiol levels indicated a pre-menopausal status.  The 10-year disease-free survival rates were 49 % (95 % CI: 44 % to 54 %) in both arms (p = 0.51).  The 10-year overall survival rates were 66 % (95 % CI: 61 % to 70 %) for the ovarian suppression arm and 68 % (95 % CI: 63 % to 73 %) for the control arm (p = 0.19).  There were no variations in the treatment effect according to age, hormonal receptor status or ovarian suppression modality.  However, in patients less than 40 years of age and with estrogen receptor-positive tumors, ovarian suppression significantly decreased the risk of recurrence (p = 0.01).  The authors concluded that the results of this trial, after at least 10 years of follow-up, do not favor the use of ovarian suppression after adjuvant chemotherapy.  They stated that the potential beneficial effect in younger women with hormone-dependent tumors should be further assessed.

Jannuzzo et al (2009) noted that LHRH agonists (e.g., triptorelin) reduce ovarian estrogen production in pre-menopausal women with hormone-sensitive breast cancer.  Aromatase inhibitors (e.g., exemestane) inhibit extra-ovarian production of estrogen and may further reduce circulating estrogens when combined with an LHRH agonist.  These researchers examined the effects of estrogen suppression in pre-menopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone.  Healthy pre-menopausal women were randomized to receive 3.75 mg triptorelin (T) on days 1 and 29 with 25 mg exemestane (EX) or matched placebo once-daily for 8 weeks, from day 1 to day 56.  The primary objective was to evaluate the effect of T +/- EX on estradiol (E(2)) suppression by comparing the AUC (days 36 to 57) for the 2 treatments.  Secondary objectives included evaluation of estrone (E(1)), LH, and FSH suppression; effects of EX on the T-induced gonadotrophin and estrogen flare; pharmacokinetics (PK); and safety.  A total of 28 subjects (14 in each arm) were evaluable for efficacy and PK.  Mean plasma estrogen levels (AUC (days 36 to 57)) were significantly lower for subjects who received T + EX than for subjects who received T alone (20.6 versus 54.0 pg d/ml [-62 %; p < 0.05], and 38.9 versus 198.0 pg d/ml [-80 %; p < 0.01] for E(2) and E(1), respectively).  Co-administration of EX did not affect the initial flare or subsequent suppression of LH and FSH following the first dose of T, or the PK of T.  Both treatments were well-tolerated.  The authors concluded that co-administration of T and EX resulted in greater estrogen suppression than when T was given alone.  They noted that these findings could translate into improved clinical outcomes for pre-menopausal breast cancer patients receiving LHRH agonists.

In a systematic review and meta-analysis, Bedaiwy and assocaites (2011) examined if GnRHa co-treatment with chemotherapy provides better reproductive outcomes for women at risk of POF as a side-effect of gonadotoxic chemotherapy.  Electronic and manual searches (e.g., MEDLINE, EMBASE, CENTRAL) up to January 2010 were performed to identify RCTs comparing GnRH co-treatment with chemotherapy alone in pre-menopausal women.  Main outcome measures included incidence of POF after treatment, incidence of women with resumption of ovulation, POF after an initial normal cycle, normal cycles but abnormal markers of ovarian reserve, spontaneous occurrence of pregnancy after treatment, and time to re-establishment of menstruation; data were also extracted to allow for an intention-to-treat analysis.  A total fo 28 RCTs were identified, but only 6 met the inclusion criteria.  Data were only available for the incidence of women with new onset of POF, resumption of ovulation, and occurrence of pregnancy.  The incidence of POF or resumption of ovulation both demonstrated a statistically significant difference in favor of the GnRH co-treatment.  The occurrence of spontaneous pregnancy showed no statistically significant difference between GnRH co-treatment and the control groups.  The authors concluded that evidence from RCTs suggests a potential benefit of GnRH co-treatment with chemotherapy in pre-menopausal women, with higher rates of spontaneous resumption of menses and ovulation but not improvement in pregnancy rates.  Data relating to study quality and possible bias for the majority of the outcomes in this review were not available, denoting possible selective reporting of trial data.

Del Mastro et al (2011) examined the effect of the temporary ovarian suppression obtained by administering triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.  The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase III superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008.  Patients were pre-menopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy.  Assuming a 60 % rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20 % absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin.  The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data.  Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin.  Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy.  Main outcome measure was incidence of early menopause (defined as no resumption of menstrual activity and post-menopausal levels of FSH and estradiol 1 year after the last cycle of chemotherapy).  The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar.  Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9 % in the chemotherapy-alone group and 8.9 % in the chemotherapy plus triptorelin group, an absolute difference of -17 % (95 % CI: -26 % to -7.9 %; p < 0.001).  The odds ratio for treatment-related early menopause was 0.28 (95 % CI: 0.14 to 0.59; p < 0.001).  The authors concluded that the use of triptorelin-induced temporary ovarian suppression during chemotherapy in pre-menopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause.

In an editorial that accompanied the afore-mentioned study, Rugo and Rosen (2011) noted that GnRH agonist therapy to suppress ovarian function during chemotherapy is an additional treatment that can potentially expand fertility possibilities in patients with hormone-insensitive disease.  On the other hand, they stated that the use of GnRH agonists concomitant with chemotherapy can not be recommended as a standard treatment and should be approached with caution in women with hormone-sensitive disease.

In a prospective randomized trial, Munster et al (2012) evaluated the effectiveness of triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer.  Pre-menopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (less than 35, 35 to 39, greater than 39 years), estrogen receptor status, and chemotherapy regimen.  Objectives included the resumption of menses and serial monitoring of FSH and inhibin A and B levels.  Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age of 39 years; range of 21 to 43 years); 47 patients were treated according to assigned groups with 4 cycles of adriamycin plus cyclophosphamide alone or followed by 4 cycles of paclitaxel or 6 cycles of fluorouracil, epirubicin, and cyclophosphamide.  Menstruation resumed in 19 (90 %) of 21 patients in the control group and in 23 (88 %) of 26 in the triptorelin group (p = 0.36).  Menses returned after a median of 5.8 months (range of 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range of 0 to 28 months) in the control arm (p = 0.58).  Two patients (aged 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries.  Follicle-stimulating hormone and inhibin B levels correlated with menstrual status.  The authors concluded that when stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.  Thus, these findings indicated that the use of GnRH agonists in pre-menopausal patients treated with contemporary neoadjuvant chemotherapy does not offer a benefit in preserving ovarian function compared with patients not treated with GnRH, and it should not be recommended.

Commenting on the study by Munster et al, Partridge (2012) stated that "the role of ovarian suppression through chemotherapy remains uncertain for prevention of premature menopause.  The value of this strategy is especially unclear for fertility preservation because of the lack of rigorous data from any study to show that actual fertility outcomes are improved with GnRH treatment throughout chemotherapy.  Given the current level of evidence, women who are interested in future fertility and the providers who are assisting them in these often difficult decisions should not rely on GnRH agonist treatment during chemotherapy for preservation of menstrual and ovarian function or fertility".

Appendix

Medically Necessary Indications for Leuprolide (and other GnRH agonists where indicated) Limitations
Endometriosis (including adenomyosis, also known as endometriosis interna)

If symptoms of endometriosis recur after the first course of therapy, a second treatment with a six-month course of leuprolide depot monthly and norethindrone acetate 5 mg daily may be considered. Leuprolide depot alone is not recommended for retreatment. If norethindrone acetate is contraindicated, then retreatment is not recommended. Bone density is recommended before retreatment begins to ensure that values are within normal limits. Further treatment beyond two treatments (12 months) is not medically necessary.

Up to 6 months per treatment -- because of lack of safety data with long-term use, and concerns in available peer-reviewed medical literature regarding effects on bone density.

Lupron dosages greater than 3.75 mg per month or 11.25 mg per 3 months are subject to medical necessity review.

To decrease fibroid size prior to surgery

Up to 3 months -- under accepted guidelines, does not prevent or replace the eventual need for surgery except in peri-menopausal women.

Lupron dosages greater than 3.75 mg per month or 11.25 mg per 3 months are subject to medical necessity review.

To decrease endometrial thickness prior to endometrial ablation

Up to 2 months.

Lupron dosages greater than 3.75 mg per month or 11.25 mg per 3 months are subject to medical necessity review.

For treatment of members with prostate cancer 1 mg given subcutaneously daily.  If receiving leuprolide acetate suspension (Lupron Depot), dosing is 7.5 mg IM once-monthly.
For true (central) precocious puberty
  1. Child should be clinically diagnosed with central precocious puberty (idiopathic or neurogenic), defined as sexual maturation before age 8 in girls and age 10 in boys; and
  2. Clinical diagnosis is confirmed with: a) bone age advanced one year or more beyond chronologic age; and b) pubertal response to a GnRH stimulation test; and
  3. Intracranial tumor has been ruled out by CT, MRI, or ultrasound; and
  4. Baseline laboratory investigations have been performed, including: a) height and weight; b) sex steroid levels; c) adrenal steroid level to exclude congenital adrenal hyperplasia; d) beta human chorionic gonadotropin to rule out chorionic gonadotropin-secreting tumor; and e) pelvic/adrenal/testicular ultrasound to rule out a steroid-secreting tumor.  

Lupron Depot Ped: 0.3 mg/kg every 4 weeks (minimum 7.5 mg).

Lupron injection: 50 mcg/kg daily.  It may be medically necessary to titrate dosages upwards in order to achieve hormonal down-regulation.

Discontinuation of leuprolide for central precocious puberty should be considered at age 11 for girls and age 12 for boys.

Infertility (used in conjunction with urofollitropin or menotropins) to suppress luteinizing hormone (LH) production in members with documented premature LH surge, or used in “super-ovulation” regimens associated with in-vitro fertilization Note: Treatment of infertility may be subject to specific limitations under some benefit plans.  Most HMO plans exclude injectable infertility drugs from coverage.
For treatment of breast cancer Indicated in men and pre-menopausal women with hormone-receptor positive breast cancer
To suppress onset of puberty in adolescents with early onset of puberty on growth hormone therapy Adolescent must meet medical necessity criteria for growth hormone supplementation, have early onset of puberty, and be below target growth range (within 1 standard deviation of mean height for age and sex)
For the treatment of women with chronic refractory pelvic pain Indicated where attempts at medical therapy with analgesics and oral contraceptive have been unsuccessful.
For treatment-resistant paraphilias For individuals with paraphilia who have failed pharmacotherapies including medroxyprogesterone acetate (MPA) and/or selective serotonin reuptake inhibitors (SSRIs).
For the treatment of granulosa cell tumors of the ovary Hormonal therapy for clinical relapse following initial treatment in persons with stage II to IV granulosa cell tumors
For use in leuprolide stimulation test for diagnosing hypogonadism and central precocious puberty. A pubertal response has been defined as an leutinizing hormone level after leuprolide stimulation greater than 8 IU/L.
To suppress onset of puberty in transgender adolescents

The adolescent has demonstrated a long-lasting and intense pattern of gender non-conformity or gender dysphoria (whether suppressed or expressed); and

Gender dysphoria emerged or worsened with the onset of puberty; and 

Any co-existing psychological, medical, or social problems that could interfere with treatment (e.g., that may compromise treatment adherence) have been addressed, such that the adoles­cent’s situation and functioning are stable enough to start treatment; and

The adolescent has given informed consent and, particularly when the adolescent has not reached the age of medical consent, the parents or other caretakers or guardians have con­sented to the treatment and are involved in supporting the adolescent throughout the treat­ment process.

Treatment of severe, refractory premenstrual syndrome For women who do not respond to or are unable to tolerate SSRIs and oral contraceptives

 

Medically Necessary Indications for Histrelin Acetate Implant Limitations
For true (central) precocious puberty, defined as sexual maturation before age 8 in girls and age 10 in boys, and tumor has been ruled out by lab tests, CT, MRI, or ultrasound

1 implant every 12 months.

The implant is inserted subcutaneously and provides continuous release of histrelin (65 mcg/day for Supprelin LA) for 12 months of hormonal therapy.

For treatment in members with prostate cancer

1 implant every 12 months.

The implant is inserted subcutaneously and provides continuous release of histrelin (50 to 60 mcg/day for Vantas) for 12 months of hormonal therapy.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
Lupron (suspension and implant):
Other CPT codes related to the CPB:
96372
HCPCS codes covered if selection criteria are met:
J1950 Injection, leuprolide acetate (for depot suspension), per 3.75 mg
J9155 Injection, Degarelix, 1 mg
J9217 Leuprolide acetate (for depot suspension), 7.5 mg
J9219 Leuprolide acetate implant, 65 mg
ICD-9 codes covered if selection criteria are met:
158.8 - 158.9 Malignant neoplasm of peritoneum
174.0 - 175.9 Malignant neoplasm of breast
183.0 Malignant neoplasm of ovary
183.2 Malignant neoplasm of fallopian tube
185 Malignant neoplasm of prostate
218.0 - 218.9 Uterine leiomyoma
233.0 Carcinoma in situ of breast
233.4 Carcinoma in situ of prostate
259.1 Precocious sexual development and puberty, not elsewhere classified
302.85 Gender identity disorder in adolescents or adults
617.0 - 617.9 Endometriosis
V10.3 Personal history of malignant neoplasm of breast
V10.46 Personal history of malignant neoplasm of prostate
V58.11 Encounter for antineoplastic chemotherapy [when used for the prevention of heavy uterine bleeding in pre-menopausal women during chemotherapy]
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
142.0 Malignant neoplasm of parotid gland
179 Malignant neoplasm of uterus, part unspecified
186.0 - 186.9 Malignant neoplasm of testis
203.00 - 203.02 Multiple myeloma
238.6 Neoplasm of uncertain behavior of other and unspecified sites and tissues (solitary myeloma)
256.31 - 256.39 Premature menopause [premature ovarian failure]
277.1 Disorders of porphyrin metabolism [porphyria cutanea tarda]
282.60 - 282.69 Sickle-cell disease
307.0 Adult onset fluency disorder [stuttering]
346.40 - 346.43 Menstrual migraine
512.82 Secondary spontaneous pneumothorax [catamenial pneumothorax]
564.1 Irritable bowel syndrome
600.00 - 600.01
600.20 - 600.21
Hyperplasia of prostate [benign]
607.3 Priapism
617.8 Endometriosis of other specified sites [catamenial pneumothorax]
626.2 - 627.1 Excessive, frequent or irregular menstruation
714.30 Pauciarticular juvenile rheumatoid arthritis
Other ICD-9 codes related to the CPB:
285.9 Anemia, unspecified
626.2 Excessive or frequent menstruation
626.8 Other disorder of menstruation and other abnormal bleeding from female genital tract
V58.69 Long-term (current) use of other [high-risk] medications
V86.0 Estrogen receptor positive status [ER+]
Lupron prior to endometrial ablation (see CPB 91):
ICD-9 codes covered if selection criteria are met:
626.2 Excessive or frequent menstruation
626.3 Puberty bleeding
627.0 Premenopausal menorrhagia
627.1 Postmenopausal bleeding
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
203.00 - 203.02 Multiple myeloma
238.6 Neoplasm of uncertain behavior of other and unspecified sites and tissues (solitary myeloma)
346.40 - 346.43 Menstrual migraine
626.2 Excessive or frequent menstruation
2 week Lupron kit:
HCPCS codes covered if selection criteria are met:
J9218 Leuprolide acetate, per 1 mg
Other HCPCS codes related to the CPB:
J3355 Injection, urofollitropin, 75 IU
S0122 Injection, menotropins, 75 IU
S0187 Tamoxifen citrate, oral, 10 mg
ICD-9 codes covered if selection criteria are met:
185 Malignant neoplasm of prostate
233.4 Carcinoma in situ of prostate
259.1 Precocious sexual development and puberty, not elsewhere classified
625.4 Premenstrual tension syndromes
628.0 - 628.9 Infertility, female
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
140.0 - 239.9 Neoplasms [when used for preservation of ovarian or testicular function during chemotherapy]
170.0 - 170.9 Malignant neoplasm of bone and articular cartilage [osteosarcoma]
182.0 Malignant neoplasm of corpus uteri, except isthmus
183.0 Malignant neoplasm of ovary
198.6 Secondary malignant neoplasm of ovary
203.00 - 203.02 Multiple myeloma
218.0 - 218.9 Uterine leiomyoma
238.6 Neoplasm of uncertain behavior of other and unspecified sites and tissues (solitary myeloma)
256.4 Polycystic ovaries
346.40 - 346.43 Menstrual migraine
626.2 Excessive or frequent menstruation
V58.11 - V58.12 Encounter for antineoplastic chemotherapy and immunotherapy [when used for preservation of ovarian or testicular function during chemotherapy]
Zoladex (Goserelin):
Other CPT codes related to the CPB:
96372
HCPCS codes covered if selection criteria are met:
J9202 Goserelin acetate implant, per 3.6 mg
ICD-9 codes covered if selection criteria are met:
174.0 - 175.9 Malignant neoplasm of breast
185 Malignant neoplasm of prostate
218.0 - 218.9 Uterine leiomyoma
233.0 Carcinoma in situ of breast
255.2 Adrenogenital disorders [precocious puberty due to adrenal cortical hyperfunction - see criteria]
256.0 Hyperestrogenism [precocious puberty due to ovarian dysfunction - see criteria]
259.1 Precocious sexual development and puberty, not elsewhere classified [see criteria]
233.4 Carcinoma in situ of prostate
617.0 - 617.9 Endometriosis
625.3 Dysmenorrhea
628.0 - 628.9 Infertility, female
V10.3 Personal history of malignant neoplasm of breast
V10.46 Personal history of malignant neoplasm of prostate
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
256.31 Premature menopause [premature ovarian failure secondary to chemotherapy]
Other ICD-9 codes related to the CPB:
V86.0 Estrogen receptor positive status [ER+]
Zoladex prior to endometrial ablation (see CPB 91):
ICD-9 codes covered if selection criteria are met:
626.2 Excessive or frequent menstruation
626.3 Puberty bleeding
627.0 Premenopausal menorrhagia
627.1 Postmenopausal bleeding
ICD-9 codes not covered for indications listed in the CPB:
140.0 - 239.9 Neoplasms [when used for preservation of ovarian or testicular function during chemotherapy]
V58.11 - V58.12 Encounter for antineoplastic chemotherapy and immunotherapy [when used for preservation of ovarian or testicular function during chemotherapy]
Vantas Histrelin acetate subcutaneous implant:
CPT codes covered if selection criteria are met:
11980
HCPCS codes covered if selection criteria are met:
J9225 Histrelin implant (Vantas), 50 mg
J9226 Histrelin implant (Supprelin LA), 50 mg
ICD-9 codes covered if selection criteria are met:
185 Malignant neoplasm of prostate
259.1 Precocious sexual development and puberty, not elsewhere classified
ICD-9 codes not covered for indications listed in the CPB:
255.2 Adrenogenital disorders (precocious puberty due to adrenal hyperplasia)
255.8 Other specified disorders of adrenal glands
Supprelin LA histrelin acetate subcutaneous implant:
CPT codes covered if selection criteria are met:
11980
HCPCS codes covered if selection criteria are met:
J9226 Histrelin implant (Supprelin LA), 50 mg
ICD-9 codes covered if selection criteria are met:
259.1 Precocious sexual development and puberty, not elsewhere classified
ICD-9 codes not covered for indications listed in the CPB:
255.2 Adrenogenital disorders (precocious puberty due to adrenal hyperplasia)
255.8 Other specified disorders of adrenal glands
Degarelix:
Other CPT codes related to the CPB:
96372
HCPCS codes covered if selection criteria are met:
J9155 Injection, degarelix, 1 mg
ICD-9 codes covered if selection criteria are met::
185 Malignant neoplasm of prostate
ICD-9 codes not covered for indications listed in the CPB:
153.0 - 153.9 Malignant neoplasm of colon
995.27 Other drug allergy [contraindicated and considered not medically necessary for persons with hypersensitivity to degarelix]
Triptorelin:
Other CPT codes related to the CPB :
96372
HCPCS codes covered if selection criteria are met:
J3315 Injection, triptorelin pamoate, 3.75 mg
ICD-9 codes covered if selection criteria are met:
185 Malignant neoplasm of prostate
259.1 Precocious sexual development and puberty, not elsewhere classified [true central]
617.0 - 617.9 Endometriosis
621.31 Simple endometrial hyperplasia without atypia
621.32 Complex endometrial hyperplasia without atypia
ICD-9 codes not covered for indications listed in the CPB:
174.0 - 174.9 Malignant neoplasm of breast
256.39 Other ovarian failure (ovarian suppression)
610.1 Diffuse cystic mastopathy [fibrocystic breast disease]
Other ICD-9 codes related to the CPB:
253.3 Pituitary dwarfism
625.8 - 625.9 Other and unspecified symptoms associated with female genital organs
V58.11- V58.12 Encounter for antineoplastic chemotherapy and immunotherapy
V66.0 Convalescence and palliative care following surgery
V66.1 Convalescence and palliative care following radiotherapy
V66.2 Convalescence and palliative care following chemotherapy
V66.7 Encounter for palliative care


The above policy is based on the following references:

Leuprolide

  1. Olin BR, ed. Drug Facts and Comparisons. St. Louis, MO: JB Lippincott Company; 1992.
  2. Conn MP, Crowley WF. Gonadotropin-releasing hormone and its analogues. N Engl J Med. 1991;324(2):93-103.
  3. Higham JM. The medical management of menorrhagia. Br J Hosp Med. 1991;45:19-21.
  4. Schriock ED. Practical aspects of pulsatile gonadotropin-releasing hormone administration. Am J Obstet Gynecol. 1990;163(5):1765-1770.
  5. Gompel A, Mauvais-Jarvis P. Induction of ovulation with pulsatile GnRH in hypothalamic amenorrhoea. Hum Reprod. 1988;3(4):473-477.
  6. Macdonald R. Modern treatment of menorrhagia. Br J Obstet Gynecol. 1990;97:3-7.
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  31. National Comprehensive Cancer Network (NCCN). Ovarian cancer. NCCN Clinical Practice Guidelines in Oncology v.1.2007. Jenkintown, PA: NCCN; 2007. 
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  38. Guzick DS, Huang LS, Broadman BA, et al. Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain. Fertil Steril. 2011;95(5):1568-1573.
  39. Youssef MA, Van der Veen F, Al-Inany HG, et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev. 2011;(1):CD008046.
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  41. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, et al; Endocrine Society. Endocrine treatment of transsexual persons: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2009;94(9):3132-3154.
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Precocious Puberty

  1. Brenner PE. Precocious puberty in the female. In: Reproductive Endocrinology, Infertility and Contraception. DR Mishell, VC Davajan, eds. Philadelphia, PA: FA Davis Co.; 1979.
  2. Partsch CJ, Sippell WG. Treatment of central precocious puberty. Best Pract Res Clin Endocrinol Metab. 2002;16(1):165-189.
  3. Mul D, Wit JM, Oostdijk W, et al. The effect of pubertal delay by GnRH agonist in GH-deficient children on final height. J Clin Endocrinol Metab. 2001;86(10):4655-4656.
  4. Cara JF, Kreiter ML, Rosenfield RL. Height prognosis of children with true precocious puberty and growth hormone deficiency: Effect of combination therapy with gonadotropin releasing hormone agonist and growth hormone. J Pediatr. 1992;120(5):709-715.  

Pelvic Pain

  1. ACOG Committee on Practice Bulletins -- Gynecology. ACOG Practice Bulletin No. 51. Chronic pelvic pain. Obstet Gynecol. 2004;103(3):589-605.
  2. Royal College of Obstetricians and Gynaecologists (RCOG). The initial management of chronic pelvic pain. RCOG Guideline No. 41. London, UK: RCOG; April 2005.
  3. Stones W, Cheong YC, Howard FM. Interventions for treating chronic pelvic pain in women. Cochrane Database Syst Rev. 2005;(2):CD000387.

Infertility

  1. Albuquerque LE, Saconato H, Maciel MC. Depot versus daily administration of gonadotrophin releasing hormone agonist protocols for pituitary desensitization in assisted reproduction cycles. Cochrane Database Syst Rev. 2005;(1):CD002808.
  2. Al-Inany H, Abou-Setta AM, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Database Syst Rev. 2006;(3):CD001750.
  3. Nugent D, Vandekerckhove P, Hughes E, et al. Gonadotrophin therapy for ovulation induction in subfertility associated with polycystic ovary syndrome. Cochrane Database Syst Rev. 2000;(3):CD000410.

Prostate cancer

  1. Wojciechowski NJ, Carter CA, Skoutakis VA, et al. Leuprolide: A gonadotropin-releasing hormone analog for the palliative treatment of prostate cancer. Drug Intell Clin Pharm. 1986;20:746-751.
  2. Debruyne F. Hormonal therapy of prostate cancer. Semin Urol Oncol. 2002;20(3 Suppl 1):4-9.
  3. National Institutes of Health. The management of clinically localized prostate cancer. National Institutes of Health Consensus Development Conference 1987 June 15-17. NCI Monogr. 1988;(7):1-174.
  4. Seidenfeld J, Samson DJ, Aronson N, et al. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer. Evidence Report/Technology Assessment No. 4. Prepared for the Agency for Healthcare Policy and Research (AHCPR) by the Blue Cross and Blue Shield Association Technology Evaluation Center. AHCPR Pub. No. 99-E0021. Rockville, MD: AHCPR; May 1999.
  5. 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 Intern Med, 2000;132(7):566-577.
  6. Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: An overview of the randomised trials. Lancet, 2000;355:1491-1498.
  7. Wilt T, Nair B, MacDonald R, Rutks I. Early versus deferred androgen suppression in the treatment of advanced prostatic cancer. Cochrane Database Syst Rev. 2001;(4):CD003506.
  8. Schmitt B, Bennett C, Seidenfeld J, et al. Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev. 1999;(2):CD001526.
  9. Augustovski F, Colantonio L, Pichon Riviere A. Androgen deprivation treatment (hormonal therapy) for the management of prostate cancer [summary]. Report ITB No. 30. Buenos Aires, Argentina: Institute for Clinical Effectiveness and Health Policy (IECS); 2006.
  10. German Agency of Health Technology Assessment (DAHTA) at German Institute for Medical Documentation and Information (DIMDI). Orchectomy versus medicamental therapy with RH-LH-analogs for the treatment of advanced prostatic carcinoma [abstract]. HTA Report. Cologne, Germany: German Agency of Health Technology Assessment (DAHTA) at German Institute for Medical Documentation and Information (DIMDI); 2006.

Leiomyomas

  1. Lefebvre G, Vilos G, Allaire C, et al. The management of uterine leiomyomas. SOGC Clinical Practice Guidelines. No. 128. Society of Obstetricians and Gynaecologists of Canada. J Obstet Gynaecol Can. 2003;25(5):396-405.
  2. Vollenhoven BJ. Uterine fibroids: A clinical review. Br J Obstet Gynecol. 1990;97:285-298.
  3. Friedman AJ. Treatment of leiomyomata uteri with short-term leuprolide followed by leuprolide plus estrogen-progestin hormone replacement therapy for 2 years: A pilot study. Fertil Steril. 1988;51(3):526-528.
  4. Farquhar C, Arroll B, Ekeroma A, et al. An evidence-based guideline for the management of uterine fibroids. Working Party of the New Zealand Guidelines Group. New Zealand Guidelines Group; November 1999.
  5. 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.

Breast cancer

  1. Olin BR. Drug Facts and Comparisons. St. Louis, MO: J.B. Lippincott Company; 1992.
  2. McEvoy GK, ed. Leuprolide. In: AHFS Drug Information. Bethesda, MD: American Society of Hospital Pharmacists; 1993:606-612.
  3. McGuire T. Breast cancer. In: Pharmacotherapy: A Pathophysiologic Approach. 2nd ed. J Dipiro, RL Talbert, PE Hayes, et al, eds. Norwalk, CT: Appleton & Lange; 1993:1930-1945.
  4. Dowsett M, Jacobs S, Aherne J, et al. Clinical and endocrine effects of leuprorelin acetate in pre- and postmenopausal patients with advanced breast cancer. Clin Ther. 1992;14 Suppl A:97-103.
  5. Manni A, Santen R, Harvey H, et al. Treatment of breast cancer with gonadotropin-releasing hormone. Endocr Rev. 1986;7(1):89-94.
  6. Harvey HA, Lipton A, Max DT, et al. Medical castration produced by the GNRH analogue leuprolide to treat metastatic breast cancer. J Clin Oncol. 1985;3(8):1068-1072.
  7. Sunderland MC, Osborne CK. Tamoxifen in premenopausal patients with metastatic breast cancer: A review. J Clin Oncol. 1991;9(7):1283-1297.
  8. No authors listed. Tamoxifen. In: Drug Evaluation Subscriptions. DR Bennett, ed. Chicago, IL: American Medical Association; 1993;5:5.
  9. Cuzick J, Ambroisine L, Davidson N, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: A meta-analysis of individual patient data from randomised adjuvant trials. Lancet. 2007;369:1711-1723.
  10. Goel S, Sharma R, Hamilton A, Beith J. LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane Database Syst Rev. 2009;(4):CD004562.

Endometriosis

  1. Henzl MR, Corson SL, Moghissi K, et al. Administration of nasal nafarelin as compared with oral danazol for endometriosis. N Engl J Med. 1988;318(8):485-489.
  2. Letassy NA, Thompson DF, Britton ML, et al. Nafarelin acetate: A gonadotropin-releasing hormone agonist for the treatment of endometriosis. DICP. 1990;24:1204-1209.
  3. Lemay A, Maheux R, Quesnel G, et al. LH-RH agonist treatment of endometriosis. Contr Gynec Obstet. 1987;16:247-253.
  4. Souney PF, Rossiter A. Focus on naferelin acetate: GnRH agonist for the management of endometriosis. Hosp Formul. 1990;25:1041-1054..
  5. Wheeler JM, Knittle JD, Miller JD. Depot leuprolide versus danazol in the treatment of women with symptomatic endometriosis. Am J Obstet Gynecol. 1992;167(1):283-291.
  6. Gerhard I, Schindler AE, Bruhler K, et al. Treatment of endometriosis with leuprorelin acetate dept: A German multicenter study. Clin Ther.1992;14(Suppl A):3-16.
  7. Crosignani PG, Gastaldi A, Lombardi PL, et al. Leuprorelin acetate depot versus danazol in the treatment of endometriosis: Results of an open multicenter trial. Clin Ther. 1992;14 (Suppl A):29-36.
  8. Tummon IS, Pepping ME, Binor Z, et al. A randomized, prospective comparison of endocrine changes induced with intranasal leuprolide or danazol for treatment of endometriosis. Fertil Steril. 1989;51(3):390-394.
  9. Fayez JA, Collazo LM, Vernon C. Comparison of different modalities of treatment for minimal and mild endometriosis. Am J Obstet Gynecol. 1988;159:927-932.
  10. Moghissi KS, Hull ME, Magyar DM, et al. Comparison of different treatment modalities of endometriosis in infertile women. Controversies Gyncec Obstet. 1987;16:236-240.
  11. Olive DL, Schwartz LB. Endometriosis. New Engl J Med. 1993;328(24):1759-1767.
  12. Saltiel E, Garabedian-Ruffal SM. Pharmacologic management of endometriosis. Clin Pharm. 1991;10:518-531.
  13. Olin BR. Drug Facts and Comparisons. St. Louis, MO: JB Lippincott Company; 1992.
  14. Schmidt CL. Endometriosis: A reappraisal of pathogenesis and treatment. Fertil Steril. 1985;44(2):157-173.
  15. Buckman RW. Endometriosis: Pharmacologic alternatives to surgery. J Pract Nurs. 1994;44(3):47-56.
  16. Rebar RW. The ovaries. In: Cecil Textbook of Medicine. 19th ed. JB Wyngaarden, LH Smith, JC Bennett, eds. Philadelphia, PA: WB Saunders Co.; 1992.
  17. Segraves R, Letassy NA. Gynecologic disorders. In: Applied Therapeutics. 5th ed. MA Koda-Kimble, LY Young, eds. Vancouver, BC: Applied Therapeutics, Inc.; 1992:70-77.
  18. Winkel CA, Scialli AR. Medical and surgical therapies for pain associated with endometriosis. J Womens Health Gend Based Med. 2001;10(2):137-162.
  19. Howard FM. An evidence-based medicine approach to the treatment of endometriosis-associated chronic pelvic pain: Placebo-controlled studies. J Am Assoc Gynecol Laparosc, 2000;7(4):477-488.
  20. Yap C, Furness S, Farquhar C. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev. 2004;(3):CD003678.
  21. Hughes E, Brown J, Collins JJ, et al. Ovulation suppression for endometriosis. Cochrane Database Syst Rev. 2007;(3):CD000155.

Premenstrual syndrome

  1. Hussain SY, Massil JH, Matta WH, et al. Buserelin in premenstrual syndrome. Gynecol Endocrinol. 1992;6(1):57-64.
  2. Blackstrom T, Hammarback S. Premenstrual syndrome--psychiatric or gynaecological disorder? Ann Med. 1991;23(6):625-633.
  3. Mortola JF, Girton L, Fischer U. Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/progestin. J Clin Endocrinol Metab. 1991;72(2):252A-252F.
  4. Hammarback S, Backstrom T. Induced anovulation as treatment of premenstrual tension syndrome. A double-blind cross-over study with GnRH-agonist versus placebo. Acta Obstet Gynecol Scand. 1988;67(2):159-166.
  5. Bancroft J, Boyle H, Warner P, et al. The use of an LHRH agonist, buserelin, in the long-term management of premenstrual syndromes. Clin Endocrinol (Oxf). 1987;27(2):171-182.
  6. Muse KN, Cetel NS, Futterman LA, et al. The premenstrual syndrome. Effects of 'medical ovariectomy'. N Engl J Med. 1984;311(21):1345-1349.

Paraphilia

  1. Reilly DR, Delva NJ, Hudson RW. Protocols for the use of cyproterone, medroxyprogesterone, and leuprolide in the treatment of paraphilia. Can J Psychiatry. 2000;45(6):559-563.
  2. Krueger RB, Kaplan MS. Depot-leuprolide acetate for treatment of paraphilias: A report of twelve cases. Arch Sex Behav. 2001;30(4):409-422.
  3. Briken P, Nika E, Berner W. Treatment of paraphilia with luteinizing hormone-releasing hormone agonists. J Sex Marital Ther. 2001;27(1):45-55.
  4. Briken P, Hill A, Berner W. Pharmacotherapy of paraphilias with long-acting agonists of luteinizing hormone-releasing hormone: A systematic review. J Clin Psychiatry. 2003;64(8):890-897.
  5. Saleh FM, Berlin FS. Sex hormones, neurotransmitters, and psychopharmacological treatments in men with paraphilic disorders. J Child Sex Abus. 2003;12(3-4):233-253.
  6. Schober JM, Byrne PM, Kuhn PJ. Leuprolide acetate is a familiar drug that may modify sex-offender behaviour: The urologist's role. BJU Int. 2006;97(4):684-686.

Zoladex

  1. No authors listed. Endocrine drugs: Drugs used for gynecologic indications. In: Drug Evaluations Subscription. DR Bennett, ed. Chicago, IL: American Medical Association; 1993; II/ENDO-6:11-12.
  2. No authors listed. Oncolytic drugs: Antineoplastic agents: Hormonal agents. In: Drug Evaluations Subscription. DR Bennett, ed. Chicago, IL: American Medical Association; 1993; III/ONC-5:12-15.
  3. United States Pharmacopeial Convention, Inc. (USPC). Goserelin (Systemic). In: USP Dispensing Iinformation. Volume 1 - Drug Information for the Healthcare Professional, 15th ed. Rockville, MD:,USPC; 1995:1410-1411.
  4. United States Pharmacopeial Convention, Inc. (USPC). Additional products and indications In: USP Dispensing Information. Volume 1 - Drug Information for the Healthcare Professional. 15th ed. Rockville, MD: USPC; 1995:2849.
  5. Lu PY, Ory SJ. Endometriosis: Current management. Mayo Clin Proc. 1995;70:453-463.
  6. Goldhirsch A, Wood WC, Senn HJ, et al. Meeting highlights: International consensus panel on the treatment of primary breast cancer (commentary). J Natl Cancer Inst. 1995;87(19):1441-1445.
  7. Vercellini P, Fedele L, Maggi R, et al. Gonadotropin releasing hormone agonist for chronic anovulatory uterine bleeding and severe anemia. J Reprod Med. 1993;38(2):127-129.
  8. DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia, PA: JB Lippincott Co.; 1993.
  9. United States Pharmacopeial Convention, Inc (USPC). USP Dispensing Information. Volume I -- Drug Information for the Health Care Professional. Rockville, MD: USPC; 1998.
  10. American Society of Health-System Pharmacists, Inc. American Hospital Formulary Service Drug Information 98. Bethesda, MD: American Society of Health-System Pharmacists; 1998.
  11. Medical Economics, Inc. Physicians' Desk Reference. 52nd ed. Montvale, NJ: Medical Economics; 1998.
  12. Mosby-Year Book, Inc. Mosby's GenRx: The Complete Reference for Generic and Brand Drugs, 8th ed. St. Louis, MO: Mosby; 1998.
  13. Korman LB. Treatment of prostate cancer. Clin Pharm. 1989;8:412-424.
  14. Furr BA, Woodburn JR. Luteinizing hormone-releasing hormone and its analogues: A review of biological properties and clinical uses. J Endocrinol Invest. 1988;11:535-537.
  15. Hughes E, Collins J, Vandekerckhove P. Gonadotropin releasing hormone analogue as an adjunct to gonadotropin therapy for clomiphene-resistant polycystic ovarian syndrome. Cochrane Database Syst Rev. 1996;(1):CD000097.
  16. Solomon C, Best L. Goserelin or other gonadotrophin releasing hormone (GnRH) analogues in the treatment of advanced prostate cancer. DEC Report No. 54. Southampton, UK: Wessex Institute for Health Research and Development (WIHRD), University of Southampton; 1996.
  17. Franke HR, Smit WM, Vermes I. Gonadal protection by a gonadotropin-releasing hormone agonist depot in young women with Hodgkin's disease undergoing chemotherapy. Gynecol Endocrinol. 2005;20(5):274-278.
  18. Del Mastro L, Catzeddu T, Boni L, et al. Prevention of chemotherapy-induced menopause by temporary ovarian suppression with goserelin in young, early breast cancer patients. Ann Oncol. 2006;17(1):74-78.
  19. Augustovski F, Colantonio L, Pichon Riviere A. Androgen deprivation treatment (hormonal therapy) for the management of prostate cancer [summary]. Report ITB No. 30. Buenos Aires, Argentina: Institute for Clinical Effectiveness and Health Policy (IECS); 2006.
  20. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: Prospective randomized study. Fertil Steril. 2009;91(3):694-697.
  21. Clowse ME, Behera MA, Anders CK, et al. Ovarian preservation by GnRH agonists during chemotherapy: A meta-analysis. J Womens Health (Larchmt). 2009;18(3):311-319.

Histrelin Acetate Implant (Supprelin LA, Vantas)

  1. Indevus Pharmaceuticals, Inc. Vantas (histrelin implant). Prescribing Information. PK000003 Rev 01. Lexington, MA: Indevus; June 2007. Available at: http://www.vantasimplant.com/vantaspi2.pdf. Accessed December 7, 2007.
  2. Indevus Pharmaceuticals, inc. Supprelin LA (histrelin acetate) subcutaneous implant. Full Prescribing Information. Lexington, MA: Indevus; May 2007. Available at: http://www.supprelinla.com/physicians/SupprelinLA_FPI.pdf. Accessed December 7, 2007. 
  3. Hirsch HJ, Gillis D, Strich D, et al. The histrelin implant: A novel treatment for central precocious puberty. Pediatrics. 2005;116(6):e798-e802.
  4. Schlegel PN, Kuzma P, Frick J, et al. Effective long-term androgen suppression in men with prostate cancer using a hydrogel implant with the GnRH agonist histrelin.
    Urology. 2001;58(4):578-582.
  5. Chertin B, Spitz IM, Lindenberg T, et al. An implant releasing the gonadotropin hormone-releasing hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate cancer. J Urol. 2000;163(3):838-844. 
  6. 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.
  7. Schlegel PN; Histrelin Study Group. Efficacy and safety of histrelin subdermal implant in patients with advanced prostate cancer. J Urol. 2006;175(4):1353-1358.
  8. Shore N, Cookson MS, Gittelman MC. Long-term efficacy and tolerability of once-yearly histrelin acetate subcutaneous implant in patients with advanced prostate cancer. BJU Int. 2012;109(2):226-232.

Plenaxis

  1. Cook T, Sheridan WP. Development of GnRH antagonists for prostate cancer: New approaches to treatment. Oncologist. 2000;5(2):162-168.
  2. McLeod D, Zinner N, Tomera K, et al. A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. Urology. 2001;58(5):756-761.
  3. Trachtenberg J, Gittleman M, Steidle C, et al. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol. 2002;167(4):1670-1674.
  4. Koch M, Steidle C, Brosman S, et al. An open-label study of abarelix in men with symptomatic prostate cancer at risk of treatment with LHRH agonists. Urology. 2003;62(5):877-882.
  5. Reddy GK. Abarelix (Plenaxis): A gonadotropin-releasing hormone antagonist for medical castration in patients with advanced prostate cancer. Clin Prostate Cancer. 2004;2(4):209-211.
  6. Debruyne F, Bhat G, Garnick MB. Abarelix for injectable suspension: First-in-class gonadotropin-releasing hormone antagonist for prostate cancer. Future Oncol. 2006;2(6):677-696.

Degarelix

  1. National Horizon Scanning Centre (NHSC). Degarelix depot (Firmagon) for advanced, hormone-dependent prostate cancer. Birmingham, UK: NHSC; September 2007.
  2. U.S. Food and Drug Administration (FDA). FDA approves drug for patients with advanced prostate cancer. FDA News. Rockville, MD: FDA; December 29, 2008. Available at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01935.html. Accessed May 18, 2009.
  3. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: A 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102(11):1531-1538.
  4. Gittelman M, Pommerville PJ, Persson BE, et al; Degarelix Study Group. A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America. J Urol. 2008;180(5):1986-1992.
  5. Van Poppel H, Tombal B, de la Rosette JJ, et al. Degarelix: A novel gonadotropin-releasing hormone (GnRH) receptor blocker--results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer. Eur Urol. 2008;54(4):805-813.
  6. Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010;57(5):836-842.
  7. Schröder FH, Tombal B, Miller K, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: Results from a 12-month, comparative, phase III study. BJU Int. 2010;106(2):182-187.
  8. Crawford ED, Tombal B, Miller K, et al. A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: Comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol. 2011;186(3):889-897.
  9. Ghiringhelli F, Isambert N, Ladoire S. Degarelix as a new antiangiogenic agent for metastatic colon cancer? World J Gastroenterol. 2013;19(5):769-772.

Triptorelin

  1. Arriagada R, Lê MG, Spielmann M, Mauriac L, et al. Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy. Ann Oncol. 2005;16(3):389-396.
  2. Jannuzzo MG, Di Salle E, Spinelli R, et al. Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone. Breast Cancer Res Treat. 2009;113(3):491-499.
  3. Bedaiwy MA, Abou-Setta AM, Desai N, et al. Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: A systematic review and meta-analysis. Fertil Steril. 2011;95(3):906-914.
  4. Drugs@FDA [database online]. Silver Spring, MD. US Food and Drug Administration/Center for Drug Evaluation and Research; 2010. Updated daily. Retrieved from http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
  5. 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.
  6. Rugo HS, Rosen MP. Reducing the long-term effects of chemotherapy in young women with early-stage breast cancer. JAMA. 2011;306(3):312-314.
  7. Munster PN, Moore AP, Ismail-Khan R, et al. Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol. 2012;30(5):533-538.
  8. Partridge AH. Ovarian suppression for prevention of premature menopause and infertility: Empty promise or effective therapy? J Clin Oncol. 2012;30(5):479-481.


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