Appeal type: Medical necessity
Decision: Upheld

Diagnosis: Right pelvic mass, dysmenorrhea and pelvic pain
Treatment: Lupron Depot
The insurer denied the request for Lupron Depot
The denial is upheld.

The patient is an adolescent female.  She underwent a laparoscopy for a right pelvic mass, dysmenorrhea and pelvic pain.  A Mullerian anomaly with a non-communicating uterine horn was found. Colonic implants of endometriosis were noted.  A right salpingectomy and excision of endometrial implants was performed.  The patient was placed on norethindrone hormonal suppression.  Elagolix treatment was recommended and ordered.  GnRH (gonadotropin-releasing hormone) agonist treatment prior to referral for robotic surgical removal of the uterine horn is recommended by her gynecologist.

No, the requested Lupron Depot is not medically necessary.

Endometriosis is a chronic, estrogen-dependent, inflammatory condition that is characterized by the implantation of endometrial-like tissue outside the uterus and affects 6 to 10% of women of reproductive age.  Endometriosis symptoms include dysmenorrhea, non-menstrual pelvic pain, and dyspareunia, as well as the less common symptoms of pain at ovulation, constipation, and painful urination.  Endometriosis-associated pain can decrease the patient's quality of life and result in substantial economic burden.  Dyspareunia can have profound inter-personal and psychological consequences.

Endometriosis has multifactorial causes, including retrograde menstruation, genetic and environmental factors, alteration of the immune system, and ectopic differentiation of mesenchymal stem cells.  Estrogen plays a necessary role in the pathophysiology of endometriosis, since it promotes the implantation of endometrial tissue in the peritoneum, has proliferative and antiapoptotic effects in endometrial cells, and stimulates local and systemic inflammation.  On the basis of the "estrogen threshold hypothesis," complete estrogen suppression may not be needed to control endometriosis-associated pain, and estrogen may be adjusted to a level that is adequate to control pain but minimizes hypoestrogenic effects.

First-line therapies for endometriosis-related pain include nonsteroidal anti-inflammatory drugs (NSAIDs) and progestin-containing oral contraceptives.  Second-line therapies involve injectable depot formulations of gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate.  Although the injectable agents are effective and reduce estrogen levels to postmenopausal levels, they are associated with side effects (such as, progressive bone loss and severe vasomotor symptoms), which limit their use to 6 months without hormone-replacement therapy.  Androgenic agents such as danazol are associated with acne, hirsutism, and changes in lipid profiles.  Surgical ablation or excision of lesions can be effective; however, symptoms often recur within 12 months, and more radical surgery (hysterectomy or oophorectomy) is a last resort.  Pain management usually requires repeated courses of medical therapies or multiple surgical treatments until menopause.

Gonadotropin-releasing hormone agonist treatment for endometriosis has been studied more extensively than other medical treatment regimens.  Gonadotropin-releasing hormone agonists are modified forms of GnRH (gonadotropin-releasing hormone) that bind to receptors in the pituitary but have a longer half-life than native GnRH (gonadotropin-releasing hormone) and thereby result in down-regulation of the pituitary-ovarian axis and hypoestrogenism.  The likely mechanism of action for relief of endometriosis pain involves the induction of amenorrhea and progressive endometrial atrophy.

Gonadotropin-releasing hormone agonists can be administered by a calibrated nasal spray twice daily (nafarelin acetate), by injection of either a short-acting formulation daily, or by injection of a depot formulation every 13 months as in this patient. Side effects relate primarily to the induced hypoestrogenic state and include hot flushes, vaginal dryness, decreased libido, mood swings, headache, and bone mineral depletion.

The American Society for Reproductive Medicine, in its Practice Committee Opinion, states, "Both medical and surgical treatments for pain associated with endometriosis are effective...Patients with endometriosis who have pain refractory to conservative surgical therapy and suppressive hormonal therapy often benefit from at least 6 months of GnRH [gonadotropin-releasing hormone] agonist therapy with add-back medicine.  Limited data exist regarding the long-term effects of GnRH [gonadotropin-releasing hormone] agonist therapy on bone mineralization in adolescent patients.  Leuprolide has been used in younger adolescents for the treatment of precocious puberty, obstructive anomalies, and for the care of transgender patients and those undergoing therapies for cancer.  Patients treated with GnRH [gonadotropinreleasing hormone] agonists should begin add-back hormone therapy at the initiation of treatment to prevent bone loss and avoid the onset of menopausal symptoms.  In a 2017 trial in adolescents, addback therapy using a combination of conjugated equine estrogen (0.625 mg [milligrams]) and norethindrone acetate (5 mg [milligrams]) daily was superior to norethindrone acetate alone when comparing quality of life outcomes and preservation of bone density.  Dual-energy X-ray absorptiometry scanning is not needed before initiation of therapy, during GnRH [gonadotropinreleasing hormone] agonist treatment of less than 12 months in duration, or after treatment.  Obstetrician-gynecologists should counsel patients on adequate dietary calcium and vitamin D intake and the benefits of weight-bearing exercise during GnRH [gonadotropin-releasing hormone] agonist therapy. After leuprolide is discontinued, patients should begin continuous hormone suppression therapy."

Elagolix is an oral, nonpeptide GnRH [gonadotropin-releasing hormone] antagonist. A phase 1 study showed that elagolix (at a dose of 200 mg [milligrams] twice daily) led to nearly full estrogen suppression.  Proof-of-concept phase 2 studies of elagolix showed efficacy in controlling both dysmenorrhea and non-menstrual pelvic pain, with an acceptable safety profile at a dose (once-daily 150 mg [milligrams]) that produces partial estrogen suppression.  Two similar multicenter, double-blind, randomized, placebo-controlled, phase 3 trials (Elaris Endometriosis I and II [EM-I and EMII]) of 6-month treatment with elagolix at two doses in women with moderate or severe endometriosis-associated pain have been published in peer review. Both higher and lower doses of elagolix were effective in improving dysmenorrhea and non-menstrual pelvic pain during a 6-month period in women with endometriosis-associated pain.  Elagolix is approved by the FDA (United States Food and Drug Administration) for the management of moderate to severe pain associated with endometriosis.

The medical records document that the patient is already on medical treatment for endometriosis.  Elagolix was also recommended and ordered. Therefore, there is no indication within the standard of care for medical treatment in addition to current medical treatment.  Therefore, the requested Lupron Depot is not medically necessary.