{"paper_id":"3963cdba-648b-4de2-860c-58e189065a09","body_text":"Endometriosis is a chronic, often disabling disease characterized by endometrial tissue outside of the uterine cavity  1 ,  2 . Patients suffer from pelvic pain, dysmenorrhea, and infertility as a result of endometriosis  1 ,  2 . Endometriosis occurs in the reproductive‐aged population, often presenting in adolescence and persisting through menopause  1 ,  2 .\nCurrent treatments for pain caused by endometriosis are suboptimal and consist of NSAIDs and hormonal modalities  3 ,  4 ,  5 ,  6 ,  7 ,  8 ,  9 . Endometriosis is thought to be hormone‐responsive and similar to eutopic endometrium. Estrogens drive the growth of endometriosis, while progestins cause differentiation, decidualization, and prevent proliferation. Hormonal treatments aim to decrease the effect of estrogen through pseudopregnancy or pseudomenopause. Unfortunately, endometriosis is often resistant to progestin therapy and progestin therapy often fails. Endometriosis may express aromatase, thereby generating high local estrogen concentrations and negating the effects of ovarian suppression.\nContinuous combination oral contraceptives are typically the first‐line treatment, but have a high failure rate and frequent side effects including gastrointestinal discomfort and breakthrough bleeding  4 ,  6 ,  7 . Treatment with progestins alone also has a high failure rate and can cause unpleasant side effects such as bloating, breast tenderness, irregular bleeding, and mood changes  4 ,  6 . Gonadotropin‐releasing hormone (GnRH) agonists are a more effective treatment of endometriosis and result in pseudomenopausal symptoms which can be debilitating, especially in a young woman  8 ,  9 . Chronic use can also lead to osteopenia, necessitating hormonal add‐back therapy with progestins, which can then lead to other problems including breast tenderness and abnormal bleeding  10 .\nThis case series demonstrates the use of bazedoxifene with conjugated estrogens (BZA/CE) with leuprolide for the treatment of endometriosis in reproductive‐aged women. While BZA/CE was used as “add‐back” hormone therapy concomitantly with a GnRH agonist, there is likely an independent treatment effect of BZA on endometriosis.\n\nA 21‐year‐old G0 was referred to Reproductive Endocrinology for treatment of endometriosis. She reported constant pelvic pain, worse with menses, and dyspareunia. Oral contraception pills did not relieve her symptoms. She had a history of surgical resection of endometriosis and was placed on leuprolide postoperatively. She was unhappy with the menopausal side effects of leuprolide and did not continue therapy. She had also tried progestin therapy in the past but had severe mood disturbances. Her pain continued to be a major problem in her life and sought alternative treatment.\nThe patient's past medical history included hypothyroidism and fibromyalgia. In addition to the laparoscopy for endometriosis, she had a thyroidectomy for a multinodular goiter. She was taking levothyroxine, amitriptyline, and NSAIDs. Physical examination and pelvic ultrasound were unremarkable other than tenderness in the rectovaginal septum; abdomen was nontender, and ultrasound revealed normal ovaries with no evidence of endometriosis.\nInitial treatment was leuprolide with conjugated estrogen plus medroxyprogesterone add‐back therapy. She had an initial flare in her endometriosis pain after her first leuprolide injection (3.75 mg), as well as bothersome irregular uterine bleeding that continued for 6 weeks. Her pain never decreased to an acceptable level. At this point, conjugated estrogen/medroxyprogesterone was discontinued, and she was started on bazedoxifene with conjugated estrogens and was given a 3‐month course of leuprolide (11.25 mg). Within 1 month, her bleeding stopped and her pain subsided. Toward the end of the three‐month course, her pain flared again, and she was switched back to monthly leuprolide dosing. Endometrial stripe measurement on transvaginal ultrasound at that time was 4 mm. The patient is satisfied with her treatment and has had continued relief for more than 6 months without any unwanted side effects.\nA 26‐year‐old woman with long history of pelvic pain and bleeding presented with severe dysmenorrhea and abnormal uterine bleeding. She had tried OCPs at age 17, but the pain continued. She underwent two laparoscopies, the first showing psammoma bodies and the second, which was performed by a gynecologic oncologist, diagnosed endosalpingiosis. Postoperatively, she was administered depo‐medroxyprogesterone; however, she bled continuously. She subsequently received leuprolide (11.25 mg) with continued bleeding and severe pain.\nShe was given a combination of 11.5 mg leuprolide (three‐month duration) and bazedoxifene with conjugated estrogens, and the bleeding stopped. She has had recurrent episodes of pain toward the end of the duration of the leuprolide injections, but this was avoided with 2.5‐month dosing intervals instead of usual 3 months. She is now completely asymptomatic. After more than 2 years on this regimen, she reports no hot flashes and no bleeding and is attending graduate school.\nA 26‐year‐old woman with PCOS was diagnosed with endometriosis by diagnostic laparoscopy. She did not receive adequate pain relief from the surgery and was referred for further management. After failing conventional management with oral contraceptive pills, she was offered leuprolide plus bazedoxifene with conjugated estrogens, which she accepted. She has had complete pain relief and no bleeding for more than 5 months and is hoping to continue on this long term, citing no unwanted side effects.\n\nWhile there is clear evidence that endometriosis is an estrogen‐dependent disease, there has been a dearth of methods available to alter estrogen levels effectively to control endometriosis symptoms without unwanted side effects. Oral contraceptive pills have a high long‐term failure rate  4 ,  6 ,  7 . GnRH agonists cause vasomotor symptoms, vaginal dryness, and bone loss  8 ,  9 ,  10 . Progestins, used for primary treatment or for “add‐back” therapy, cause often unacceptable side effects such as weight gain, breast tenderness, and mood changes  4 ,  6 . The ideal medical treatment for endometriosis has yet to be identified.\nSelective estrogen receptor modulators (SERMs) have variable tissue‐specific agonist or antagonist activity. They are used for the treatment of breast cancer and osteoporosis due to the antagonistic effects on the breast and skeletal systems  11 . Some SERMs display antagonistic effects on the endometrium, preventing endometrial proliferation  11 . For this reason, they have been considered for suppression of endometriosis. Unfortunately, the opposite was seen in a randomized trial using raloxifene; subjects assigned to daily raloxifene treatment had more pain than those assigned to placebo  12 .\nBazedoxifene (BZA) is a new‐generation SERM that has been approved in combination with conjugated estrogens (CE) for the treatment of menopausal vasomotor symptoms  13 . The usual dosing is one tablet daily, containing 0.45 mg of CE and 20 mg of BZA. Bazedoxifene in combination with conjugated estrogens has the potential to inhibit endogenous estrogen's stimulatory effect on endometriosis, while having favorable effects on the skeletal system and central nervous system, blocking estrogen effects on the endometrium, and avoiding endometrial hyperplasia  14 ,  15 ,  16 . It also avoids use of other available agents for add‐back such as progestins, improving the safety and side effect profile.\nThe combination of BZA with CE does not affect the endometrium of menopausal women when compared to placebo  15 ,  16 . This ability to counteract the stimulatory effect of CE in the endometrium suggests that BZA is also a potential candidate to effectively treat endometriosis. The addition of estrogens to BZA may further inhibit endometriosis through feedback inhibition and decreased ovarian stimulation in a premenopausal woman.\nBazedoxifene alone has a protective effect on the skeletal system, maintaining bone mass in postmenopausal women  17 ,  18 ,  19 ,  20  and decreasing vertebral fractures over up to 7 years of use  14 . In combination with CE, treatment similarly led to increased bone density compared to placebo  21 . BZA/CE decreases vaginal atrophy, improving maturation index and reducing vaginal symptoms  22 . BZA/CE also has been shown to have an acceptable cardiovascular safety profile, with rates of coronary heart disease and stroke comparable to placebo in a meta‐analysis of postmenopausal women taking BZA with CE for up to 2 years  23  as well as improved lipid profiles  24 . Further, BZA/CE did not induce breast tenderness or increase mammographic density as is seen with menopausal hormone therapy, suggesting a neutral or potential beneficial effect on the breast  25 . Finally, BZA/CE has a high amenorrhea rate, avoiding the common occurrence of break through bleeding frequently seen upon initiation of hormone therapy.\nIn a mouse model, BZA alone or in combination with CE inhibits growth of surgically transplanted intraperitoneal endometrial lesions, reducing many of the lesions to fibrosis or scar  26 ,  27 . In these models, endometriosis lesions are sutured onto the pelvic sidewall or peritoneal surface. The mice continue to cycle while on treatment, and there is no effect on ovarian weight or cyst formation  26 ,  27 . Endometrial hyperplasia does not occur, and uterine weights decrease on treatment when compared to controls  26 ,  27 . Furthermore, treatment with BZA, alone or in combination with CE, results in decreased estrogen receptor expression  26 ,  27 , while treatment with CE alone causes increased expression  27 . BZA/CE also decreases stem cell recruitment by endometriosis lesions in this model, restoring normal stem cell engraftment of the uterine endometrium  28 .\nThe cases presented here demonstrate the safe and effective use of BZA/CE in premenopausal women with endometriosis after medically induced menopause. An additional five patients with endometriosis, ages ranging from 16 to early thirties, were referred to our centers after failing multiple treatment regimens. Each was treated with leuprolide and bazedoxifene with conjugated estrogens, and all had excellent pain relief. All were referred back to their local physician, and therefore, further details about these patients were unavailable.\nThe use of CE reduces vasomotor symptoms and bone loss associated with GnRH agonists, while the BZA inhibits the stimulatory effect on the endometrium and endometriosis, avoiding exacerbation of symptoms. The use of a progestin add‐back is avoided, eliminating the associated side effects and improving patient satisfaction and compliance. The addition of CE decreases FSH production and ovarian stimulation through negative feedback and prevents vasomotor symptoms that are typically experienced with use of SERMs alone. While the use of BZA/CE alone (without GnRH agonists) should theoretically improve endometriosis symptoms, this therapeutic approach has not been investigated in human subjects.\nFuture directions should include human trials evaluating the use of BZA/CE with and without GnRH agonists for the management of endometriosis. If use of BZA/CE alone is effective, it could eliminate the initial stimulation of endometriosis and symptom flare often experienced by patients treated with GnRH agonists, as well as the concern about long‐term use of leuprolide or newer orally active GnRH agonists in young women. Large comparative trials are needed to assess the safety of long‐term use of BZA/CE. The ability to suppress endometriosis while maintaining bone health and inhibiting endometrial growth without a progestin makes BZA/CE an ideal agent for the treatment of endometriosis.\n\nNone declared.\n\nAH: wrote the manuscript, performed background research, and involved in direct patient management as a Fellow. BL: supplied patient information, obtained informed consent, edited the manuscript, and performed direct patient management. VF: supplied patient information, obtained informed consent, and edited the manuscript. HST: supplied patient information, obtained informed consent, edited the manuscript, and performed direct patient management.","source_license":"CC0","license_restricted":false}