257 Form

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Pharmacy Medical Policy Growth Hormone and Insulin-like Growth Factor Table of Contents Authorization Information Coverage Criteria
Appendix Policy History
References Endnotes Policy Number: 257 BCBSA Reference Number: 5.01.06 Related Policies • N/A

Prior Authorization Information

Policy ☒ Prior Authorization ☐ Step Therapy ☒ Quality Care Dosing ☐ Administrative Reviewing Department Pharmacy Operations: Tel: 1-800-366-7778 Fax: 1-800-583-6289 To request for coverage: Providers may call, fax, or mail the attached form (Formulary Exception/Prior Authorization form) to the address below.
Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043
Tel: 1-800-366-7778 Fax: 1-800-583-6289

Individual Consideration for the atypical patient: Policy for requests that do not meet clinical criteria of this policy, see section labeled Individual Consideration
Policy Last Updated 1/2026 Pharmacy (Rx) or Medical (MED) benefit coverage ☒ Rx ☐ MED Policy applies to Commercial members with BCBSMA formulary:
• Managed Care (HMO/POS) • PPO/EPO
• Indemnity
• MEDEX with Rx plans • Managed Blue for Seniors Policy does NOT apply to: • Medicare Advantage
Provider Documentation Requirements: Documentation from the provider to support a reason preventing trial of formulary alternative(s) must include the name and strength of alternatives tried and failed (if alternatives were tried, including dates if available) and specifics regarding the treatment failure. Documentation to support clinical basis preventing switch to formulary alternative should also provide specifics around clinical reason. We may also use prescription claims records to establish prior use of formulary alternatives or to show if step therapy criteria has been met. We will require the provider to share additional information when prescription claims data is either not available or the medication fill history fails to establish use of preferred formulary medications or that step therapy criteria has been met. Other documentation requirements, if any, are outlined in prior authorization criteria.
See Appendix for additional information.

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This is a comprehensive policy covering prior authorization requirements for Growth Hormones and Insulin-like Growth Factors. Please refer to the chart below for the formulary status/requirements of the medications affected by this policy: Drug Formulary Status (BCBSMA Commercial Plan) Requirement Additional Considerations Formulary, Preferred

SPBO - Pharmacy benefit coverage only Egrifta (tesamorelin) Covered, PA

PA Required. See below for criteria.

Supporting Documentation Required Genotropin (somatropin) Genotropin Miniquick (somatropin) Increlex (mecasermin) Norditropin (somatropin) Serostim (somatropin) Serostim LQ (somatropin) Skytrofa (lonapegsomatropin-tcgd) Sogroya (somapacitan) Non-Formulary, Non-Preferred Humatrope (somatropin) NFNC, PA Meet PA criteria AND trial and failure of two covered formulary alternatives Ngenla (Somatrogon) Nutropin Depot (somatropin) Nutropin (somatropin) Nutropin AQ (somatropin) Omnitrope (somatropin) Saizen (somatropin) Saizenprep (somatropin) Zomacton (somatropin) PA – Prior Authorization; NFNC – Non-formulary, Non-Covered; SPBO – Specialty Pharmacy access Approval Length: 12 months, unless otherwise specified in Clinical Guideline Coverage Criteria

Clinical Coverage Criteria: Growth Hormones Egrifta
Egrifta may be covered and considered MEDICALLY NECESSARY and covered when ALL of the below criteria are met:

1. Documented HIV infection AND
2. Used for the reduction of excess abdominal fat due to lipodystrophy due to antiretroviral therapy Serostim
   Serostim may be covered and considered MEDICALLY NECESSARY and covered when ALL of the below criteria are met:
3. Documented HIV infection AND

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2. Wasting or cachexia to increase lean body mass and body weight, and improve physical endurance Norditropin, Genotropin, Genotropin Miniquick
   Initial Criteria Norditropin and Genotropin may be covered and considered MEDICALLY NECESSARY for Any of the following indications:
3. Children with proven growth hormone deficiency (GHD)
4. Children with growth failure due to Prader-Willi syndrome, who do not have the following contraindications: history of upper airway obstruction or sleep apnea or severe respiratory impairment
5. Children with height below the 3rd percentile for chronologic age with chronic renal insufficiency
6. Children with Turner syndrome
7. Children and young adults with short stature due to Noonan syndrome
8. Children with short stature due to SHOX (short stature homeobox-containing gene) deficiency
9. Promotion of wound healing in patients with 3rd-degree burns
10. Prevention of growth delay in children with severe burns
11. Patients with HIV/AIDS wasting syndrome who meet all the following: a. Weight loss of at least 10% from baseline weight or BMI<20 kg/m2 b. Wasting syndrome rather than malnutrition, mental illness, endocrine disease, or other causes for weight loss c. Concomitant anti-viral therapy for the duration of treatment
12. Patients with short bowel syndrome receiving specialized nutritional support in conjunction with optimal management of short bowel syndrome
13. Adults with proven growth hormone deficiency (GHD)* Continuation Criteria (For Pediatric Patients, age < 18 Years) Norditropin and Genotropin may be covered for continuation when ALL of the criteria below are met:
14. Open epiphyses (as determined within the last year by radiographic evidence) AND
15. No evidence of active neoplasm AND
16. Growth velocity > 2cm/year AND
17. Absence of significant side effects AND
18. Compliance with therapy AND *Proven adult GHD Defined as: • An abnormal response to TWO provocative stimulation tests, such as L-dopa, clonidine, glucagon, arginine, growth hormone‒releasing hormone (GH-RH), or insulin; OR • An abnormal response to ONE provocative stimulation test in patients with defined central nervous system pathology, history of irradiation, multiple pituitary hormone deficiency, or a genetic defect; OR • Low IGF-I concentration in patients with complete hypopituitarism

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6. NOT used in combination with another somatropin agent (such as Serostim, Zorbtive or any other product covered by this policy) AND
7. For Nutropin Depot: Trial and failure or treatment-limiting adverse effects of formulary endogenous growth hormone (GH) products Norditropin or Genotropin Humatrope, Nutropin or Nutropin AQ, Nutropin Depot, Omnitrope, Saizen, Saizenprep®, and Zomacton ® Humatrope, Nutropin, Omnitrope, Saizen, Saizenprep, and Zomacton may be covered and considered MEDICALLY NECESSARY only after treatment failure with, limiting side effects of, or contraindication to at least TWO formulary alternatives (see drug chart).
   Clinical Coverage Criteria: Long-Acting Growth Hormones Skytrofa
   Skytrofa may be considered MEDICALLY NECESSARY for the treatment of growth failure due to inadequate secretion of endogenous growth hormone when ALL of the following criteria met:
8. Age is greater than or equal to 1 years of age,
   AND
9. The child’s weight is at least 11.5 kg (are 25.3 Lbs.) AND
10. Epiphyses are confirmed to still be open AND

11. Proven growth hormone deficiency

    Skytrofa may be considered MEDICALLY NECESSARY for replacement of endogenous growth hormone in Growth Hormone Deficiency (GHD) when ALL of the following criteria met:

12. Patient is 18 years old and older AND
13. Proven growth hormone deficiency* Sogryoa
    Sogroya may be considered MEDICALLY NECESSARY and covered when ALL of the following criteria
    met:
14. Age is greater than or equal to 1 years of age AND
15. The child’s weight is at least 11.5 kg (are 25.3 Lbs.) AND
16. Epiphyses are confirmed to still be open *Proven adult GHD Defined as: • An abnormal response to TWO provocative stimulation tests, such as L-dopa, clonidine, glucagon, arginine, growth hormone‒releasing hormone (GH-RH), or insulin; OR • An abnormal response to ONE provocative stimulation test in patients with defined central nervous system pathology, history of irradiation, multiple pituitary hormone deficiency, or a genetic defect; OR • Low IGF-I concentration in patients with complete hypopituitarism

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AND

4. Proven growth hormone deficiency Ngenla
   Ngenla may be considered MEDICALLY NECESSARY and covered when ALL of the following criteria
   met:
5. Age is greater than or equal to 1 years of age AND
6. The child’s weight is at least 11.5 kg (are25.3 Lbs.) AND
7. Epiphyses are confirmed to still be open AND
8. Proven growth hormone deficiency AND

9. Trial and failure or treatment-limiting adverse effects of formulary endogenous growth hormone (GH) products two Formulary Growth Hormone products (Norditropin, Genotropin, Skytrofa, or Sogroya).

   Clinical Coverage Criteria: Insulin-Like Growth Factors Increlex
   Increlex may be considered MEDICALLY NECESSARY and covered when ALL of the following criteria are met:

10. Documented diagnosis of growth failure in children with severe primary insulin-like growth factor-1 (IGF-1) deficiency (primary IGFD) OR with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH AND
11. Height standard deviation score less than or equal to -3 for age and sex AND
12. Basal IGF-1 standard deviation score less than or equal to -3 for age and sex AND

13. Normal or elevated growth hormone (defined as stimulated serum GH peak level of greater than 10 ng/ml or basal (unstimulated) serum GH level greater than 5ng/ml).

    BCBSMA does NOT cover Insulin-like Growth Factor for secondary forms of IGF-1 deficiency including (but not limited to):23

14. GH Deficiency
15. Malnutrition
16. Hypothyroidism

17. Chronic treatment with pharmacologic doses of anti-inflammatory steroids.

    Non-Covered Indications for Growth Hormone The following indications approved by the Food and Drug Administration are considered NOT MEDICALLY NECESSARY and therefore not covered:

18. Pediatric patients born small for gestational age who fail to show catch-up growth by age 2 years
19. Children with height standard deviation score of -2.25 or below without documented growth hormone deficiency (Idiopathic short stature). Other Non-Covered Indications:

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1. Children with familial short stature11 (ie, lower than expected height percentiles based on parents’ height)
2. Growth hormone insensitivity (Laron Syndrome)5
3. Children with constitutional growth delay22
4. Children with growth failure caused by glucocorticoids22
5. Children who are not growth hormone deficient but have short stature associated with chronic disease11
6. Children with functioning renal transplants
7. Children with chromosomal and genetic disorders11 including Russell Silver syndrome21. (Use in (Turner’s, Noonan and Prader Willi Syndromes )11 and SHOX (short stature homeobox-containing gene) deficiency is covered as above.)
8. Enhancement of body mass or strength for professional, recreational or social reasons22, with or without anabolic steroids
9. To counteract acute or chronic catabolic illness except for AIDS (e.g., surgery outcomes, trauma, cancer, chronic hemodialysis) in both adult and pediatric patients22
10. Altered body habitus or lipodystrophy such as buffalo hump associated with antiviral therapy in HIV-infected patients22 OTHER THAN abdominal lipodystrophy (see Egrifta, above)
11. Treatment of precocious puberty22 in conjunction with GnRH (gonadotropin releasing hormone) analogs
12. Treatment of obesity22
13. Treatment of cystic fibrosis22
14. Treatment of idiopathic dilated cardiomyopathy22
15. Treatment of juvenile idiopathic arthritis.22
16. Treatment of congestive heart failure (CHF).10
17. Adults with age-related GH deficiency (AR-GHD), who have neither organic causes nor childhood origin of growth hormone deficiency.17
    Investigational Indications The following indications are considered INVESTIGATIONAL and NOT covered:
18. Treatment of altered body habitus (e.g., buffalo hump) associated with antiviral therapy in HIV- infected patients
19. Constitutional delay (lower than expected height percentiles compared with target height percentiles and delayed skeletal maturation when growth velocities and rates of bone age advancement are normal)
20. Treatment of children with “genetic potential” (ie, lower than expected height percentiles based on parents’ height)
21. In conjunction with gonadotropin-releasing hormone analogues as a treatment of precocious puberty
22. Growth hormone therapy in older adults without proven deficiency
23. Treatment of cystic fibrosis
24. Anabolic therapy (except for AIDS) provided to counteract acute or chronic catabolic illness (eg, surgery outcomes, trauma, cancer, chronic hemodialysis, chronic infectious disease) producing catabolic (protein wasting) changes in both adult and pediatric patients
25. Anabolic therapy to enhance body mass or strength for professional, recreational, or social reasons
26. Glucocorticoid-induced growth failure
27. Short stature due to Down syndrome
28. Treatment of obesity
29. Treatment of idiopathic dilated cardiomyopathy
30. Treatment of juvenile idiopathic or juvenile chronic arthritis. Other Information

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Blue Cross Blue Shield of Massachusetts (BCBSMA*) members (other than Medex®; Blue MedicareRx, Medicare Advantage plans that include prescription drug coverage) will be required to fill their prescriptions for the above medications at one of the providers in our retail specialty pharmacy network.

Appendix Formulary Status For non-covered medications, in addition to the prior authorization criteria, the member must also have had a previous treatment failure with, or contraindication to, at least two covered formulary alternatives when available. See section on individual consideration for more information if you require an exception to any of these criteria requirements for an atypical patient. Member cost share consideration A higher non-preferred cost share may be applied if an exception request is approved for coverage of a non-preferred or a non-formulary/non-covered drug. Criteria Documentation Provider must submit supporting documentation (e.g., chart notes, lab results or other clinical information) to show that the member has met all approval criteria. Forms To request prior authorization using the Massachusetts Standard Form for Medication Prior Authorization Requests (eForm), click the link below: https://www.bluecrossma.org/medical- policies/sites/g/files/csphws2091/files/acquiadam- assets/023%20E%20Form%20medication%20prior%20auth%20instruction%20prn.pdf OR Print and fax, Massachusetts Standard Form for Medication Prior Authorization Requests #434 Individual Consideration (for Atypical Patients) Our medical policies are written for most people with a given condition. Each policy is based on peer reviewed clinical evidence. We also take into consideration the needs of atypical patient populations and diagnoses.
If the coverage criteria outlined is unlikely to be clinically effective for the prescribed purpose, the health care provider may request an exception to cover the requested medication based on an individual’s unique clinical circumstances. This is also referred to as “individual consideration” or an “exception request.”
Some reasons why you may need us to make an exception include: therapeutic contraindications; history of adverse effects; expected to be ineffective or likely to cause harm (physical, mental, or adverse reaction).
To facilitate a thorough and prompt review of an exception request, we encourage the provider to include additional supporting clinical documentation with their request. This may include: • Clinical notes or supporting clinical statements; • The name and strength of formulary alternatives tried and failed (if alternatives were tried) and specifics regarding the treatment failure, if applicable; • Clinical literature from reputable peer reviewed journals; • References from nationally recognized and approved drug compendia such as American Hospital Formulary Service® Drug Information (AHFS-DI), Lexi-Drug, Clinical Pharmacology, Micromedex or Drugdex®; and • References from consensus documents and/or nationally sanctioned guidelines Providers may call, fax or mail relevant clinical information, including clinical references for individual patient consideration, to: Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043 Phone: 1-800-366-7778 Fax: 1-800-583-6289

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Samples Requests based exclusively on the use of samples will not meet coverage criteria for exception. Additional clinical information demonstrating medical necessity of the desired medication must be submitted by the requesting prescriber for review. Specialty Blue Cross Blue Shield of Massachusetts (BCBSMA*) members (other than Medex®; Blue MedicareRx, Medicare Advantage plans that include prescription drug coverage) obtaining the medication from the Pharmacy benefit instead of the Medical benefit will be required to fill their prescriptions for medications listed as specialty at one of the providers in our retail specialty pharmacy network, see link below: Link to Specialty Pharmacy List

Policy History

Date Action 1/2026 Moved Humatrope to Non-Formulary, Non-Covered. Removed Zorbtive as it has been discontinued by the manufacturer. Updated formatting. 10/2025 Moved Norditropin to Preferred status. Updated Prior Authorization box. Removed step requirement for Skytrofa and Sogroya. Added new indication for Skytrofa. 2/2025 Updated to change and add both Sogroya ® and Skysona ™ to preferred. 1/2025 Updated to move Nutropin from Preferred Specialty Brand to Non-Formulary, Non- Covered (NFNC) and to move Genotropin from Non-Formulary, Non-Covered (NFNC) to Preferred Specialty Brand. 7/2024 Updated to move Ngenla ® and Sogroya ® to Non-Formulary Non-Covered in the policy. 12/2023 Reformatted Policy. 9/2023 Updated to add Sogroya ® to the policy and updated IC to align with 118E MGL § 51A. 7/2023 Updated to add Saizenprep ® to the policy and remove Tev-Tropin ® and Zorbtive ® due to market withdrawal. 2/2022 Updated policy to include Skytrofa ™ to the policy. 12/2021 BCBSA National medical policy review. No changes to policy statements. New references added. 12/2020 BCBSA National medical policy review. No changes to policy statements. New references added. 10/2020 Clarified coding information 10/2019 Clarified coding information. 1/2019 Clarified coding information. 8/2018 Clarified coding information. 5/2018 Clarify criteria with Association language. 10/2017 Updated to change Walgreens Specialty Name. 7/2017 Updated to add AllCare to Pharmacy Specialty list. 6/2017 Updated address for Pharmacy Operations. 4/2017 Clarified criteria for Omnitrope®. 1/2016 New references added from BCBSA National medical policy. 10/2015 Updated to included revised language for Pharmacy only medications. 7/2015 Added Zomacton® To the policy. 12/2014 New references added from BCBSA National medical policy. 7/2014 Updated to include ICD-10 and to add Coverage for Egrifta™. 2/2014 Removal of Curascript from specialty pharmacy section. 1/2014 Updated ExpressPAth Language and removed Blue Value. 4/2012 Updated 4/2012 to update specialty pharmacy contact information. 11/2011-4/2012 Medical policy ICD 10 remediation: Formatting, editing and coding updates.
No changes to policy statements.
1/2012 Updated to include medical necessity criteria requirement to have treatment failure or contraindication to formulary products.
5/2011 Reviewed - Medical Policy Group - Pediatrics and Endocrinology.

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No changes to policy statements. 5/2011 Updated to include new FDA approved medication Egrifta™.
5/2010 Reviewed - Medical Policy Group - Pediatrics and Endocrinology. No changes to policy statements. 2/2010 Reviewed - Medical Policy Group - Psychiatry and Ophthalmology. No changes to policy statements. 2/2010 Updated to reflect formulary changes and update Specialty Pharmacy information for Walgreens Specialty Pharmacy.
10/2009 Updated to reflect UM requirements and to remove Medicare Part D criteria from policy.
5/2009 Reviewed - Medical Policy Group - Pediatrics and Endocrinology. No changes to policy statements. 2/2009 Reviewed - Medical Policy Group - Psychiatry and Ophthalmology. No changes to policy statements. 5/2008 Reviewed - Medical Policy Group - Pediatrics and Endocrinology. No changes to policy statements. 2/2008 Reviewed - Medical Policy Group - Psychiatry and Ophthalmology. No changes to policy statements. 5/2007 Reviewed - Medical Policy Group - Pediatrics and Endocrinology. No changes to policy statements. 2/2007 Reviewed - Medical Policy Group - Psychiatry and Ophthalmology. No changes to policy statements. 10/1989 New policy, effective 10/1989, describing covered and non-covered indications.

References

1. Lo JC, Mulligan K, Tai VW, et al. "Buffalo hump" in men with HIV-1 infection. Lancet. Mar 21 1998; 351(9106): 867-70. PMID 9525364
2. Strasburger CJ, Vanuga P, Payer J, et al. MOD-4023, a long-acting carboxy-terminal peptide- modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults. Eur J Endocrinol. Mar 2017; 176(3): 283-294. PMID 27932411
3. Luo X, Hou L, Liang L, et al. Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies. Eur J Endocrinol. Aug 2017; 177(2): 195-205. PMID 28566441
4. Hoybye C, Pfeiffer AF, Ferone D, et al. A phase 2 trial of long-acting TransCon growth hormone in adult GH deficiency. Endocr Connect. Apr 2017; 6(3): 129-138. PMID 28196799
5. Blethen SL, Allen DB, Graves D, et al. Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience. J Clin Endocrinol Metab. May 1996; 81(5): 1704-10. PMID 8626820
6. Critical evaluation of the safety of recombinant human growth hormone administration: statement from the Growth Hormone Research Society. J Clin Endocrinol Metab. May 2001; 86(5): 1868-70. PMID 11344173
7. Hoybye C, Beck-Peccoz P, Murray RD, et al. Safety and effectiveness of replacement with biosimilar growth hormone in adults with growth hormone deficiency: results from an international, post- marketing surveillance study (PATRO Adults). Pituitary. Aug 2021; 24(4): 622-629. PMID 33742320
8. Beck-Peccoz P, Hoybye C, Murray RD, et al. Malignancy risk in adults with growth hormone deficiency undergoing long-term treatment with biosimilar somatropin (Omnitrope (R) ): data from the PATRO Adults study. Ther Adv Endocrinol Metab. 2020; 11: 2042018820943377. PMID 32973992
9. Thomas-Teinturier C, Oliver-Petit I, Pacquement H, et al. Influence of growth hormone therapy on the occurrence of a second neoplasm in survivors of childhood cancer. Eur J Endocrinol. Oct 2020; 183(4): 471-480. PMID 32738133
10. Swerdlow AJ, Cooke R, Beckers D, et al. Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study. J Clin Endocrinol Metab. May 01 2017; 102(5): 1661-1672. PMID 28187225
11. Carel JC, Ecosse E, Landier F, et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. J Clin Endocrinol Metab. Feb 2012; 97(2): 416-25. PMID 22238382
12. Poidvin A, Touze E, Ecosse E, et al. Growth hormone treatment for childhood short stature and risk of stroke in early adulthood. Neurology. Aug 26 2014; 83(9): 780-6. PMID 25122206

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13. Tidblad A, Bottai M, Kieler H, et al. Association of Childhood Growth Hormone Treatment With Long- term Cardiovascular Morbidity. JAMA Pediatr. Feb 01 2021; 175(2): e205199. PMID 33346824
14. Pfizer. Highlights of Prescribing Information: Genotropin (somatropin [rDNA origin] for injection). 2019; http://labeling.pfizer.com/ShowLabeling.aspx?id=577. Accessed August 15, 2021.
15. Eli Lilly. Highlights of Prescribing Information: Humatrope (somatropin [rDNA ORIGIN] for injection, for Subcutaneous Use). 2019; http://pi.lilly.com/us/humatrope-pi.pdf. Accessed August 15, 2021.
16. Root AW, Kemp SF, Rundle AC, et al. Effect of long-term recombinant growth hormone therapy in children--the National Cooperative Growth Study, USA, 1985-1994. J Pediatr Endocrinol Metab. 1998; 11(3): 403-12. PMID 11517956
17. Reiter EO, Price DA, Wilton P, et al. Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. J Clin Endocrinol Metab. Jun 2006; 91(6): 2047-54. PMID 16537676
18. Beauregard C, Utz AL, Schaub AE, et al. Growth hormone decreases visceral fat and improves cardiovascular risk markers in women with hypopituitarism: a randomized, placebo-controlled study. J Clin Endocrinol Metab. Jun 2008; 93(6): 2063-71. PMID 18381581
19. Widdowson WM, Gibney J. The effect of growth hormone replacement on exercise capacity in patients with GH deficiency: a metaanalysis. J Clin Endocrinol Metab. Nov 2008; 93(11): 4413-7. PMID 18697875
20. Widdowson WM, Gibney J. The effect of growth hormone (GH) replacement on muscle strength in patients with GH-deficiency: a meta-analysis. Clin Endocrinol (Oxf). Jun 2010; 72(6): 787-92. PMID 19769614
21. Xue P, Wang Y, Yang J, et al. Effects of growth hormone replacement therapy on bone mineral density in growth hormone deficient adults: a meta-analysis. Int J Endocrinol. 2013; 2013: 216107. PMID 23690770
22. Barake M, Klibanski A, Tritos NA. Effects of recombinant human growth hormone therapy on bone mineral density in adults with growth hormone deficiency: a meta-analysis. J Clin Endocrinol Metab. Mar 2014; 99(3): 852-60. PMID 24423364
23. Hoffman AR, Kuntze JE, Baptista J, et al. Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab. May 2004; 89(5): 2048-56. PMID 15126520
24. Maison P, Chanson P. Cardiac effects of growth hormone in adults with growth hormone deficiency: a meta-analysis. Circulation. Nov 25 2003; 108(21): 2648-52. PMID 14623813
25. Sesmilo G, Biller BM, Llevadot J, et al. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intern Med. Jul 18 2000; 133(2): 111-22. PMID 10896637
26. Gotherstrom G, Svensson J, Koranyi J, et al. A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices. J Clin Endocrinol Metab. Oct 2001; 86(10): 4657-65. PMID 11600522
27. Ishii H, Shimatsu A, Nishinaga H, et al. Assessment of quality of life on 4-year growth hormone therapy in Japanese patients with adult growth hormone deficiency: A post-marketing, multicenter, observational study. Growth Horm IGF Res. Oct 2017; 36: 36-43. PMID 28923784
28. Frixou M, Vlek D, Lucas-Herald AK, et al. The use of growth hormone therapy in adults with Prader- Willi syndrome: A systematic review. Clin Endocrinol (Oxf). Apr 2021; 94(4): 645-655. PMID 33296095
29. Luo Y, Zheng Z, Yang Y, et al. Effects of growth hormone on cognitive, motor, and behavioral development in Prader-Willi syndrome children: a meta-analysis of randomized controlled trials. Endocrine. Feb 2021; 71(2): 321-330. PMID 33222122
30. Passone CGB, Franco RR, Ito SS, et al. Growth hormone treatment in Prader-Willi syndrome patients: systematic review and meta-analysis. BMJ Paediatr Open. 2020; 4(1): e000630. PMID 32411831
31. Kuppens RJ, Bakker NE, Siemensma EP, et al. Beneficial Effects of GH in Young Adults With Prader- Willi Syndrome: A 2-Year Crossover Trial. J Clin Endocrinol Metab. Nov 2016; 101(11): 4110-4116. PMID 27552545
32. Craig ME, Cowell CT, Larsson P, et al. Growth hormone treatment and adverse events in Prader-Willi syndrome: data from KIGS (the Pfizer International Growth Database). Clin Endocrinol (Oxf). Aug 2006; 65(2): 178-85. PMID 16886957
33. Van Vliet G, Deal CL, Crock PA, et al. Sudden death in growth hormone-treated children with Prader- Willi syndrome. J Pediatr. Jan 2004; 144(1): 129-31. PMID 14722532

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34. Grugni G, Livieri C, Corrias A, et al. Death during GH therapy in children with Prader-Willi syndrome: description of two new cases. J Endocrinol Invest. Jun 2005; 28(6): 554-7. PMID 16117198
35. Wu Y, Cheng W, Yang XD, et al. Growth hormone improves growth in pediatric renal transplant recipients--a systemic review and meta-analysis of randomized controlled trials. Pediatr Nephrol. Jan 2013; 28(1): 129-33. PMID 22660958
36. Hodson EM, Willis NS, Craig JC. Growth hormone for children with chronic kidney disease. Cochrane Database Syst Rev. Feb 15 2012; (2): CD003264. PMID 22336787
37. Hokken-Koelega AC, Stijnen T, de Muinck Keizer-Schrama SM, et al. Placebo-controlled, double- blind, cross-over trial of growth hormone treatment in prepubertal children with chronic renal failure. Lancet. Sep 07 1991; 338(8767): 585-90. PMID 1715501
38. Hokken-Koelega A, Mulder P, De Jong R, et al. Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency. Pediatr Nephrol. Jul 2000; 14(7): 701-
39. PMID 10912546
40. Li P, Cheng F, Xiu L. Height outcome of the recombinant human growth hormone treatment in Turner syndrome: a meta-analysis. Endocr Connect. Apr 2018; 7(4): 573-583. PMID 29581156
41. Baxter L, Bryant J, Cave CB, et al. Recombinant growth hormone for children and adolescents with Turner syndrome. Cochrane Database Syst Rev. Jan 24 2007; (1): CD003887. PMID 17253498
42. Juloski J, Dumancic J, Scepan I, et al. Growth hormone positive effects on craniofacial complex in Turner syndrome. Arch Oral Biol. Nov 2016; 71: 10-15. PMID 27372203
43. Giacomozzi C, Deodati A, Shaikh MG, et al. The impact of growth hormone therapy on adult height in noonan syndrome: a systematic review. Horm Res Paediatr. 2015; 83(3): 167-76. PMID 25721697
44. MacFarlane CE, Brown DC, Johnston LB, et al. Growth hormone therapy and growth in children with Noonan's syndrome: results of 3 years' follow-up. J Clin Endocrinol Metab. May 2001; 86(5): 1953-6. PMID 11344190
45. Takeda A, Cooper K, Bird A, et al. Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation. Health Technol Assess. Sep 2010; 14(42): 1-209, iii-iv. PMID 20849734
46. Blum WF, Crowe BJ, Quigley CA, et al. Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: Two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. Jan 2007; 92(1): 219-28. PMID 17047016
47. Benabbad I, Rosilio M, Child CJ, et al. Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial. Horm Res Paediatr. 2017; 87(1): 42-50. PMID 28002818
48. Child CJ, Zimmermann AG, Chrousos GP, et al. Safety Outcomes During Pediatric GH Therapy: Final Results From the Prospective GeNeSIS Observational Program. J Clin Endocrinol Metab. Feb 01 2019; 104(2): 379-389. PMID 30219920
49. Breederveld RS, Tuinebreijer WE. Recombinant human growth hormone for treating burns and donor sites. Cochrane Database Syst Rev. Dec 12 2012; 12: CD008990. PMID 23235668
50. Knox J, Demling R, Wilmore D, et al. Increased survival after major thermal injury: the effect of growth hormone therapy in adults. J Trauma. Sep 1995; 39(3): 526-30; discussion 530-2. PMID 7473919
51. Singh KP, Prasad R, Chari PS, et al. Effect of growth hormone therapy in burn patients on conservative treatment. Burns. Dec 1998; 24(8): 733-8. PMID 9915674
52. Losada F, Garcia-Luna PP, Gomez-Cia T, et al. Effects of human recombinant growth hormone on donor-site healing in burned adults. World J Surg. Jan 2002; 26(1): 2-8. PMID 11898025
53. Hart DW, Herndon DN, Klein G, et al. Attenuation of posttraumatic muscle catabolism and osteopenia by long-term growth hormone therapy. Ann Surg. Jun 2001; 233(6): 827-34. PMID 11371741
54. Aili Low JF, Barrow RE, Mittendorfer B, et al. The effect of short-term growth hormone treatment on growth and energy expenditure in burned children. Burns. Aug 2001; 27(5): 447-52. PMID 11451596
55. Moyle GJ, Schoelles K, Fahrbach K, et al. Efficacy of selected treatments of HIV wasting: a systematic review and meta-analysis. J Acquir Immune Defic Syndr. Dec 01 2004; 37 Suppl 5: S262-
56. PMID 15722869
57. Evans WJ, Kotler DP, Staszewski S, et al. Effect of recombinant human growth hormone on exercise capacity in patients with HIV-associated wasting on HAART. AIDS Read. Jun 2005; 15(6): 301-3, 306-8, 310, 314. PMID 15962453
58. Wales PW, Nasr A, de Silva N, et al. Human growth hormone and glutamine for patients with short bowel syndrome. Cochrane Database Syst Rev. Jun 16 2010; (6): CD006321. PMID 20556765

12

57. Scolapio JS. Effect of growth hormone, glutamine, and diet on body composition in short bowel syndrome: a randomized, controlled study. JPEN J Parenter Enteral Nutr. Nov-Dec 1999; 23(6): 309- 12; discussion 312-3. PMID 10574477
58. Seguy D, Vahedi K, Kapel N, et al. Low-dose growth hormone in adult home parenteral nutrition- dependent short bowel syndrome patients: a positive study. Gastroenterology. Feb 2003; 124(2): 293-302. PMID 12557135
59. Szkudlarek J, Jeppesen PB, Mortensen PB. Effect of high dose growth hormone with glutamine and no change in diet on intestinal absorption in short bowel patients: a randomised, double blind, crossover, placebo controlled study. Gut. Aug 2000; 47(2): 199-205. PMID 10896910
60. Maiorana A, Cianfarani S. Impact of growth hormone therapy on adult height of children born small for gestational age. Pediatrics. Sep 2009; 124(3): e519-31. PMID 19706577
61. Lindboe JB, Langkilde A, Eugen-Olsen J, et al. Low-dose growth hormone therapy reduces inflammation in HIV-infected patients: a randomized placebo-controlled study. Infect Dis (Lond). Nov- Dec 2016; 48(11-12): 829-37. PMID 27417288
62. Wanke C, Gerrior J, Kantaros J, et al. Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV. AIDS. Oct 22 1999; 13(15): 2099-103. PMID 10546863
63. Bryant J, Baxter L, Cave CB, et al. Recombinant growth hormone for idiopathic short stature in children and adolescents. Cochrane Database Syst Rev. Jul 18 2007; (3): CD004440. PMID 17636758
64. Deodati A, Cianfarani S. Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review. BMJ. Mar 11 2011; 342: c7157. PMID 21398350
65. Paltoglou G, Dimitropoulos I, Kourlaba G, et al. The effect of treatment with recombinant human growth hormone (rhGH) on linear growth and adult height in children with idiopathic short stature (ISS): a systematic review and meta-analysis. J Pediatr Endocrinol Metab. Dec 16 2020; 33(12): 1577-1588. PMID 33035189
66. Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. Genentech Collaborative Study Group. J Pediatr. Nov 1989; 115(5 Pt 1): 713-9. PMID 2681637
67. Ackland FM, Jones J, Buckler JM, et al. Growth hormone treatment in non-growth hormone-deficient children: effects of stopping treatment. Acta Paediatr Scand Suppl. 1990; 366: 32-7. PMID 2206005
68. Cowell CT. Effects of growth hormone in short, slowly growing children without growth hormone deficiency. Australasian Paediatric Endocrine Group. Acta Paediatr Scand Suppl. 1990; 366: 29-30; discussion 31. PMID 2206004
69. Leschek EW, Rose SR, Yanovski JA, et al. Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. Jul 2004; 89(7): 3140-8. PMID 15240584
70. McCaughey ES, Mulligan J, Voss LD, et al. Growth and metabolic consequences of growth hormone treatment in prepubertal short normal children. Arch Dis Child. Sep 1994; 71(3): 201-6. PMID 7979491
71. Barton JS, Gardineri HM, Cullen S, et al. The growth and cardiovascular effects of high dose growth hormone therapy in idiopathic short stature. Clin Endocrinol (Oxf). Jun 1995; 42(6): 619-26. PMID 7634503
72. Soliman AT, abdul Khadir MM. Growth parameters and predictors of growth in short children with and without growth hormone (GH) deficiency treated with human GH: a randomized controlled study. J Trop Pediatr. Oct 1996; 42(5): 281-6. PMID 8936959
73. Kamp GA, Waelkens JJ, de Muinck Keizer-Schrama SM, et al. High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature. Arch Dis Child. Sep 2002; 87(3): 215-20. PMID 12193430
74. Volta C, Bernasconi S, Tondi P, et al. Combined treatment with growth hormone and luteinizing hormone releasing hormone-analogue (LHRHa) of pubertal children with familial short stature. J Endocrinol Invest. Nov 1993; 16(10): 763-7. PMID 8144848
75. McCaughey ES, Mulligan J, Voss LD, et al. Randomised trial of growth hormone in short normal girls. Lancet. Mar 28 1998; 351(9107): 940-4. PMID 9734940
76. Albertsson-Wikland K, Aronson AS, Gustafsson J, et al. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. J Clin Endocrinol Metab. Nov 2008; 93(11): 4342-50. PMID 18728172
77. Hindmarsh PC, Brook CG. Effect of growth hormone on short normal children. Br Med J (Clin Res Ed). Sep 05 1987; 295(6598): 573-7. PMID 3117236

13

78. Wit JM, Rietveld DH, Drop SL, et al. A controlled trial of methionyl growth hormone therapy in prepubertal children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group. Acta Paediatr Scand. May 1989; 78(3): 426-35. PMID 2662700
79. Volta C, Ghizzoni L, Muto G, et al. Effectiveness of growth-promoting therapies. Comparison among growth hormone, clonidine, and levodopa. Am J Dis Child. Feb 1991; 145(2): 168-71. PMID 1994682
80. Lanes R. Effects of two years of growth hormone treatment in short, slowly growing non-growth hormone deficient children. J Pediatr Endocrinol Metab. Jul-Sep 1995; 8(3): 167-71. PMID 8521190
81. Tao S, Li G, Wang Q, et al. Efficacy and Safety of Human Growth Hormone in Idiopathic Short Stature. Indian J Pediatr. Jul 2015; 82(7): 625-8. PMID 25893526
82. Zadik Z, Mira U, Landau H. Final height after growth hormone therapy in peripubertal boys with a subnormal integrated concentration of growth hormone. Horm Res. 1992; 37(4-5): 150-5. PMID 1490656
83. Wit JM, Boersma B, de Muinck Keizer-Schrama SM, et al. Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group. Clin Endocrinol (Oxf). Apr 1995; 42(4): 365-
84. PMID 7750190
85. Hindmarsh PC, Brook CG. Final height of short normal children treated with growth hormone. Lancet. Jul 06 1996; 348(9019): 13-6. PMID 8691923
86. Buchlis JG, Irizarry L, Crotzer BC, et al. Comparison of final heights of growth hormone-treated vs. untreated children with idiopathic growth failure. J Clin Endocrinol Metab. Apr 1998; 83(4): 1075-9. PMID 9543120
87. Lopez-Siguero JP, Garcia-Garcia E, Carralero I, et al. Adult height in children with idiopathic short stature treated with growth hormone. J Pediatr Endocrinol Metab. Nov-Dec 2000; 13(9): 1595-602. PMID 11154155
88. Coutant R, Rouleau S, Despert F, et al. Growth and adult height in GH-treated children with nonacquired GH deficiency and idiopathic short stature: the influence of pituitary magnetic resonance imaging findings. J Clin Endocrinol Metab. Oct 2001; 86(10): 4649-54. PMID 11600520
89. Wit JM, Rekers-Mombarg LT. Final height gain by GH therapy in children with idiopathic short stature is dose dependent. J Clin Endocrinol Metab. Feb 2002; 87(2): 604-11. PMID 11836292
90. van Gool SA, Kamp GA, Odink RJ, et al. High-dose GH treatment limited to the prepubertal period in young children with idiopathic short stature does not increase adult height. Eur J Endocrinol. Apr 2010; 162(4): 653-60. PMID 20110402
91. Lopez-Siguero JP, Martinez-Aedo MJ, Moreno-Molina JA. Final height after growth hormone therapy in children with idiopathic short stature and a subnormal growth rate. Acta Pediatr. 1996;85:113-57.
92. Shemesh-Iron M, Lazar L, Lebenthal Y, et al. Growth hormone therapy and short stature-related distress: A randomized placebo-controlled trial. Clin Endocrinol (Oxf). May 2019; 90(5): 690-701. PMID 30721549
93. Ross JL, Sandberg DE, Rose SR, et al. Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. J Clin Endocrinol Metab. Oct 2004; 89(10): 4873-8. PMID 15472178
94. Theunissen NC, Kamp GA, Koopman HM, et al. Quality of life and self-esteem in children treated for idiopathic short stature. J Pediatr. May 2002; 140(5): 507-15. PMID 12032514
95. Downie AB, Mulligan J, McCaughey ES, et al. Psychological response to growth hormone treatment in short normal children. Arch Dis Child. Jul 1996; 75(1): 32-5. PMID 8813867
96. Liu S, Liu Q, Cheng X, et al. Effects and safety of combination therapy with gonadotropin-releasing hormone analogue and growth hormone in girls with idiopathic central precocious puberty: a meta- analysis. J Endocrinol Invest. Oct 2016; 39(10): 1167-78. PMID 27225286
97. Tuvemo T, Gustafsson J, Proos LA. Growth hormone treatment during suppression of early puberty in adopted girls. Swedish Growth Hormone Advisory Group. Acta Paediatr. Sep 1999; 88(9): 928-32. PMID 10519330
98. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Recombinent Human Growth Hormone (GH) Therapy in Adults with Age-Related GH Deficiency. TEC Assessment. 2001;Tab 11. PMID
99. Thaker V, Haagensen AL, Carter B, et al. Recombinant growth hormone therapy for cystic fibrosis in children and young adults. Cochrane Database Syst Rev. Jun 05 2013; (6): CD008901. PMID 23737090
100. Thaker V, Carter B, Putman M. Recombinant growth hormone therapy for cystic fibrosis in children and young adults. Cochrane Database Syst Rev. Dec 17 2018; 12: CD008901. PMID 30557452

14

100. Phung OJ, Coleman CI, Baker EL, et al. Recombinant human growth hormone in the treatment of patients with cystic fibrosis. Pediatrics. Nov 2010; 126(5): e1211-26. PMID 20921071
101. Stalvey MS, Anbar RD, Konstan MW, et al. A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis. Pediatr Pulmonol. Mar 2012; 47(3): 252-63. PMID 21905270
102. Raman S, Grimberg A, Waguespack SG, et al. Risk of Neoplasia in Pediatric Patients Receiving Growth Hormone Therapy--A Report From the Pediatric Endocrine Society Drug and Therapeutics Committee. J Clin Endocrinol Metab. Jun 2015; 100(6): 2192-203. PMID 25839904
103. Grimberg A, Allen DB. Growth hormone treatment for growth hormone deficiency and idiopathic short stature: new guidelines shaped by the presence and absence of evidence. Curr Opin Pediatr. Aug 2017; 29(4): 466-471. PMID 28525404
104. Grimberg A, DiVall SA, Polychronakos C, et al. Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency. Horm Res Paediatr. 2016; 86(6): 361-397. PMID 27884013
105. Gravholt CH, Andersen NH, Conway GS, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. Sep 2017; 177(3): G1-G70. PMID 28705803
106. Fleseriu M, Hashim IA, Karavitaki N, et al. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. Nov 2016; 101(11): 3888-
107. PMID 27736313
108. Sklar CA, Antal Z, Chemaitilly W, et al. Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. Aug 01 2018; 103(8): 2761-2784. PMID 29982476
109. National Institute for Health and Care Excellence (NICE). Human growth hormone (somatropin) for growth failure in children [TA188]. 2010; https://www.nice.org.uk/guidance/ta188. Accessed August 16, 2021.
110. Yuen KCJ, Biller BMK, Radovick S, et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF GROWTH HORMONE DEFICIENCY IN ADULTS AND PATIENTS TRANSITIONING FROM PEDIATRIC TO ADULT CARE. Endocr Pract. Nov 2019; 25(11): 1191-
111. PMID 31760824
112. Cohen P, Rogol AD, Deal CL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab. Nov 2008; 93(11): 4210-7. PMID 18782877
113. Deal CL, Tony M, Hoybye C, et al. GrowthHormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab. Jun 2013; 98(6): E1072-87. PMID 23543664
114. Allen DB, Backeljauw P, Bidlingmaier M, et al. GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults. Eur J Endocrinol. Feb 2016; 174(2): P1-9. PMID 26563978
115. Collett-Solberg PF, Ambler G, Backeljauw PF, et al. Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective. Horm Res Paediatr. 2019; 92(1): 1-14. PMID 31514194
116. Kaplowitz P, Bloch C, Sills IN, et al. Evaluation and Referral of Children With Signs of Early Puberty. Pediatrics. Jan 2016; 137(1). PMID 26668298
117. Skytrofa ™ [package insert]. Princeton, NJ: Ascendis Pharma Endocrinology, Inc.: 10/2022
118. Sogroya ® [package insert]. Plainsboro, NJ: Novo Nordisk Inc.: 4/2023