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Hormonal Medications

Just as discussed with pain medications, hormonal medications may help alleviate the symptoms of endometriosis. They work for some and not others. Your provider should tailor your treatment to fit your needs and desires. Here are some points to consider:

  • Hormonal treatments, while they can relieve symptoms, do not get rid of the disease itself. They are “suppressive rather than curative” (Falcone & Flyckt, 2018). Symptoms often return rapidly once medications are stopped. Taking any medication for an extended amount of time can have significant effects on your body. It is important that you educate yourself about what medications you decide to take and understand both the short-term and long-term effects on your body when discussing with your provider.
  • In addition, hormonal medication may not stop the progression of disease- this is particularly important where the ureters and/or bowel are involved (Barra et al., 2018; Ferrero et al., 2011; Millochau et al., 2016).
  • Endometriosis lesions are different from normal endometrium (the lining of the uterus), therefore endometriosis responds differently to hormones than the endometrium. Some people’s endometriosis does not respond to progestin therapy (Guo, 2009). Many hormonal treatments aim at decreasing estrogen, as estrogen signals endometriosis lesions to increase in size, volume, height, and proliferation (see “In-depth on Endo“). However, long-term low estrogenic state can cause substantial side effects that you should discuss with your provider (see “Effects of long term low estrogen”.

Hormonal medications treat symptoms of other conditions such as menorrhagia (heavy menstrual periods), dysmenorrhea (painful menstrual periods), and adenomyosis. When discussing treatment plans with your provider, it is important to understand what other conditions you have that may benefit from hormonal medications. It is also important that your provider respect your priorities and preferences. Everyone will respond differently to hormonal treatments. Some may tolerate it well while others cannot. Some may find relief and others may find it worsens their symptoms or find the side effects may be intolerable. One size does not fit all!

1. Combined hormonal contraceptives: This is often where many providers will start when a patient complains of endometriosis symptoms. Combined hormonal contraceptives contain estrogen and progestin. They include birth control pills, patches or vaginal rings. Sometimes, providers recommend taking these medications continuously so that you do not have a period at all. This might help eliminate painful periods. 

“Nine randomized controlled trials and nine observational studies met the inclusion criteria. The quality of data was low: only two of the nine randomized trials were placebo controlled, and most trials were not blinded. The CHC agents were reported to significantly reduce dysmenorrhea, pelvic pain, and dyspareunia from baseline in most studies; continuous administration seemed to be more useful than cyclic administration. The effectiveness of CHC agents for pain reduction was similar to or less than that of oral progestins and GnRH agonists. Conclusions: The available literature suggests that CHC treatment is effective for relief of endometriosis-related dysmenorrhea, pelvic pain, and dyspareunia; however, the supportive data are of low quality. Furthermore, insufficient data exist to reach conclusions about the overall superiority of any given CHC therapy, and the relative benefit in comparison to other approaches. Additional high-quality studies are needed to clarify the role of CHC agents and other treatments in women with endometriosis-related pain.”

  • Grandi, G., Barra, F., Ferrero, S., Sileo, F. G., Bertucci, E., Napolitano, A., & Facchinetti, F. (2019). Hormonal contraception in women with endometriosis: a systematic review. The European Journal of Contraception & Reproductive Health Care, 24(1), 61-70.  Retrieved from https://www.tandfonline.com/doi/abs/10.1080/13625187.2018.1550576   

“A search of the Medline/PubMed and Embase databases was performed to identify all published English language studies on hormonal contraceptive therapies (combined hormonal contraceptives [CHCs], combined oral contraceptives [COCs], progestin-only pills [POPs] and progestin-only contraceptives [POCs]) in women with a validated endometriosis diagnosis, in comparison with placebo, comparator therapies or other hormonal therapies. Main outcome measures were endometriosis-related pain (dysmenorrhoea, pelvic pain and dyspareunia), quality of life (QoL) and postoperative rate of disease recurrence during treatment. Results: CHC and POC treatments were associated with clinically significant reductions in dysmenorrhoea, often accompanied by reductions in non-cyclical pelvic pain and dyspareunia and an improvement in QoL. Only two COC preparations (ethinylestradiol [EE]/norethisterone acetate [NETA] and a flexible EE/drospirenone regimen) demonstrated significantly increased efficacy compared with placebo. Only three studies found that the postoperative use of COCs (EE/NETA, EE/desogestrel and EE/gestodene) reduced the risk of disease recurrence. There was no evidence that POCs reduced the risk of disease recurrence. Conclusions: CHCs and POCs are effective for the relief of endometriosis-related dysmenorrhoea, pelvic pain and dyspareunia, and improve QoL. Some COCs decreased the risk of disease recurrence after conservative surgery, but POCs did not. There is insufficient evidence, however, to reach definitive conclusions about the overall superiority of any particular hormonal contraceptive.”

“For decades, combined estrogen-progestin oral contraceptive pills (OCPs) have been the first-line treatment for menstrual and pelvic pain associated with endometriosis without any clinical evidence of efficacy. Initial relief provided by OCPs is likely a result of improvement in primary dysmenorrhea. Biologic data and limited clinical evidence support a potential adverse effect of long-term use of OCPs on the progression of endometriosis.” 

2. Progestins (including progestin-only contraception): Progestins come in a variety of forms, including pills , injections, implants, or as an intrauterine device (IUD), such as levonorgestrel IUD (Mirena®Skyla®,), contraceptive implant (Nexplanon® ), contraceptive injection (Depo-Provera®) or progestin pill (Camila®). Progestins taken continuously, like combined hormonal contraception, may temporarily stop menstrual periods. This can be useful for other related conditions such as adenomyosis. However, studies have indicated that endometriosis lesions may not respond to progestins due to altered progesterone receptors.

“Progestins, synthetic progestational agents, have been used in the management of symptomatic endometriosis both as primary therapy and as an adjunct to surgical time. A variety of oral agents have been employed in this regard and investigators have demonstrated differing degrees of benefit. The lack of a standardized instrument to evaluate painful symptoms makes comparative analysis more difficult. Concern about efficacy and side effect has pushed the research on the development of new well-tolerated drugs and to develop new administration routes to minimize general side effects.”

  • Flores, V. A., Vanhie, A., Dang, T., & Taylor, H. S. (2018). Progesterone receptor status predicts response to progestin therapy in endometriosis. The Journal of Clinical Endocrinology & Metabolism, 103(12), 4561-4568. Retrieved from https://academic.oup.com/jcem/article/103/12/4561/5139742 

“Although serum levels of progesterone in women with endometriosis are similar to those of women without the disease, endometriotic lesions (ectopic endometrium) do not respond appropriately to progesterone (10, 11). The inappropriate response to progesterone (i.e., progesterone resistance) in endometriotic lesions explains the impaired efficacy of progestin-based therapies for endometriosis management (8, 12). Endometriotic lesions have altered expression of the progesterone receptor (PR) (12, 13). Specifically, it has been postulated that progesterone resistance is mediated by lower levels of PR (8, 14). Low PR may explain why progestin-containing agents [including combined oral contraceptives (OCs)] are associated with treatment failure in some patients (8, 14).”

“Progestogens most commonly used for the treatment of endometriosis include medroxyprogesterone acetate (MPA) and 19-nortestosterone derivatives (e.g., levonorgestrel, norethindrone acetate, and dienogest). As with OCs, their proposed mechanism of action involves decidualization and subsequent atrophy of endometrial tissue. Another more recently proposed mechanism involves progestogen-induced suppression of matrix metalloproteinases, a class of enzymes important in the growth and implantation of ectopic endometrium (60). Inhibition of angiogenesis has also been proposed as a mechanism to explain the effectiveness of progestins in the treatment of endometriosis (64). In observational studies involving treatment with MPA, dydrogesterone, or norethindrone acetate, pain has been reduced by 70%–100% (65). A meta-analysis of four randomized, controlled trials comparing MPA to danazol alone, danazol and combined OCs, or a GnRH-a (goserelin acetate) concluded that MPA was as effective as the other treatments (odds ratio [OR] 1.1; 95% CI 0.4–3.1) (65). Randomized studies concluded that dienogest was significantly better than placebo and as effective as the GnRH-a buserelin, LA, or triptorelin in reducing pain symptoms with diminished side effects of hot flushes and bone mineral density loss (66). The levonorgestrel-releasing intrauterine system (LNG-IUS) represents another approach to the medical treatment of endometriosis. A randomized, controlled trial comparing the LNG-IUS to expectant management after laparoscopic surgical treatment for symptomatic endometriosis found that the LNG-IUS was more effective than no treatment in reducing symptoms of dysmenorrhea (67). Other studies have demonstrated improved symptoms associated with rectovaginal endometriosis (68) and a significant decrease in the extent of disease observed at second-look laparoscopy after 6 months of treatment with the LNG-IUS (69). Relief of endometriosis pain with the LNG-IUS is similar to GnRH-a (52, 70).”

3. Gonadotropin-releasing hormone (Gn-RH) agonists and antagonists: These medications significantly lower estrogen levels and can halt menstruation, creating a medically induced menopause. The medications block the production of ovarian-stimulating hormones. This often causes side effects similar to menopause, such as hot flashes, vaginal dryness and bone loss. This bone loss may not be reversible. Due to this, recommended use is limited to a 6 month course of treatment, with no more 12 months total use (such as 2 six-month courses of treatment). Medications are available by injection, pill, or nasal spray and include Orilissa®, Lupron®, Synarel®, Zoladex®.

  • American College of Obstetricians and Gynecologists. (2010). Practice bulletin no. 114: management of endometriosis. Obstet Gynecol, 116(1), 223-236. doi: 10.1097/AOG.0b013e3181e8b073

“However, a Cochrane review found little to no difference between GnRH agonist and other medical treatments for endometriosis, suggesting again that this regimen is not recommended as a primary treatment approach.”

“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 that bind to receptors in the pituitary but have a longer half-life than native GnRH 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 (60). 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 (LA, goserelin acetate) every 1–3 months. Side effects relate primarily to the induced hypoestrogenic state and include hot flushes, vaginal dryness, decreased libido, mood swings, headache, and bone mineral depletion (75). A Cochrane analysis found that GnRH-a were more effective than placebo for endometriosis pain relief but were similar to the LNG-IUS and danazol (52). A long-term follow-up study of patients treated with a GnRH-a alone for 6 months revealed a 53% recurrence of disease/symptoms 2 years after treatment (28). To reduce negative effects of E deprivation (e.g., bone loss, hot flushes) and allow for longer treatment periods, ‘‘add-back’’ therapy with norethindrone acetate or a combination of E and progestogen has been advocated. This treatment regimen decreases bone loss seen with GnRH-a alone and also reduces the severity of hypoestrogenic side effects associated with GnRH-a treatment. The underlying theory of add-back treatment is the ‘‘E threshold hypothesis,’’ which holds that the amount of E and/or progestogen necessary to prevent hot flushes, bone loss, and other hypoestrogenic symptoms and side effects is less than that which would stimulate endometriosis (76). Although norethindrone acetate is the only hormone approved by the US Food and Drug Administration for add-back therapy, other combinations of low-dose E and progestogens also have been shown to be effective in decreasing hypoestrogenic side effects and maintaining bone density, and not adversely affecting the extent of pain relief achieved with GnRH-a treatment (52, 77). The add-back therapy should be started at the same time as the agonist rather than delaying until a period of hypoestrogenism has occurred. This approach has been shown to decrease bone loss and improve vasomotor symptoms and compliance (78).”

“GnRH-a is commonly used for symptomatic treatment and prevention of endometriosis with good clinical efficacy. However, the side effects of GnRH-a (such as hot flashes, night sweats, dizziness, fatigue, vaginal dryness, loss of libido, mood changes and bone pain) limit its long-term use [7,8]. According to the report by Sagsveen et al. [9], the bone mineral density (BMD) of lumbar vertebra decreased by 3.2% after a 6-month usage of GnRH-a and by 6.3% after a 12-month usage. The treatment course of GnRH-a is limited to 6 months because of the side effect of bone loss [10].”

“From a national healthcare perspective, laparoscopic conservative surgery for endometriosis is more cost-effective than Elagolix for the primary treatment of moderate to severe pain from endometriosis that has been refractory to standard medical care.”

  • Vercellini, P., Viganò, P., Barbara, G., Buggio, L., & Somigliana, E. (2019). Elagolix for endometriosis: all that glitters is not gold. Human Reproduction, 34(2), 193-199. Retrieved from https://academic.oup.com/humrep/article/34/2/193/5245999

“Elagolix, an orally active non-peptidic GnRH antagonist, has been approved by the Food and Drug Administration for the management of moderate to severe pain associated with endometriosis. As the degree of ovarian suppression obtained with elagolix is dose-dependent, pain relief may be achieved by modulating the level of hypo-oestrogenism while limiting side effects. Elagolix may thus be considered a novelty in terms of its endocrine and pharmacological properties but not for its impact on the pathogenic mechanisms of endometriosis, as the target of this new drug is, yet again, alteration of the hormonal milieu. Given the oestrogen-dependent nature of endometriosis, a reduction of side effects may imply a proportionate decrease in pain relief. Furthermore, if low elagolix doses are used, ovulation is not consistently inhibited, and patients should use non-hormonal contraceptive systems and perform serial urine pregnancy tests to rule out unplanned conception during periods of treatment-induced amenorrhoea. If high elagolix doses are used to control severe pain for long periods of time, add-back therapies should be added, similar to that prescribed when using GnRH agonists. To date, the efficacy of elagolix has only been demonstrated in placebo-controlled explanatory trials. Pragmatic trials comparing elagolix with low-dose hormonal contraceptives and progestogens should be planned to verify the magnitude of the incremental benefit, if any, of this GnRH antagonist over currently used standard treatments. The price of elagolix may impact on patient adherence and, hence, on clinical effectiveness. In the USA, the manufacturer AbbVie Inc. priced elagolix (OrilissaTM) at around $10 000 a year, i.e. $845 per month. When faced with unaffordable treatments, some patients may choose to forego care. If national healthcare systems are funded by the tax payer, the approval and the use of a new costly drug to treat a chronic condition, such as endometriosis, means that some finite financial resources will be diverted from other areas, or that similar patients will not receive the same level of care. Thus, defining the overall ‘value’ of a new drug for endometriosis also has ethical implications, and trade-offs between health outcomes and costs should be carefully weighed up.”

  • Leyland, N., Estes, S. J., Lessey, B. A., Advincula, A. P., & Taylor, H. S. (2020). A Clinician’s Guide to the Treatment of Endometriosis with Elagolix. Journal of Women’s Health. Retrieved from https://www.liebertpub.com/doi/full/10.1089/jwh.2019.8096

“Elagolix is the first orally administered FDA-approved treatment option for endometriosis-associated pain in more than 10 years. Unlike GnRH agonists, which induce a hypoestrogenic state through complete suppression of the hypothalamic-pituitary-ovarian axis, GnRH antagonists such as elagolix partially suppress estradiol, thereby lessening hypoestrogenic side effects (e.g., hot flush, vaginal dryness, reduced BMD, and lipid changes), while maintaining therapeutic efficacy….In clinical trials, elagolix has been shown to reduce pelvic pain (including dysmenorrhea, NMPP, and dyspareunia), improve quality of life, and decrease the need for rescue analgesics in women with endometriosis-associated pain.22–26 These improvements were maintained during 12 months of treatment….Given the mechanism of action for elagolix, the study did not include women with a history of nonresponse to GnRH agonists or antagonists, depot medroxyprogesterone acetate, or aromatase inhibitors.26 Patients with a history of osteoporosis or other metabolic bone disease were also excluded. Screening dual-energy X-ray absorption scans for BMD of the lumbar spine, femoral neck, or total hip could not be 1.5 or more standard deviations below normal (i.e., Z score ≤ −1.5)….The pivotal elagolix clinical trials were predominantly white (88%), which limits the ability to draw conclusions for other racial groups due to the small sample size…. Elagolix is not recommended for patients with a history of nonresponse to GnRH agonists or antagonists, and is contraindicated in women who are pregnant, have known osteoporosis, or have severe hepatic impairment. Elagolix should not be used concomitantly with strong organic anion-transporting polypeptide 1B1 inhibitors (e.g., cyclosporine and gemfibrozil)….Consistent with the mechanism of action, hypoestrogenic effects are among the most common adverse events reported during elagolix clinical trials. As this was an anticipated effect, special attention was given to the occurrence of vasomotor symptoms and to changes in BMD, lipids, and endometrial thickness….Dose- and duration-dependent decreases in BMD have been observed in elagolix clinical trials. The magnitude of decrease was generally modest.23–27 After 6 months of treatment in phase 3 studies, mean percentage changes in lumbar spine BMD were −0.3% to −0.7% with elagolix 150 mg once daily and −2.5% to −2.6% with elagolix 200 mg twice daily.27 Follow-up assessments in a long-term extension study revealed partial recovery of BMD at 6 and 12 months post-treatment,27 although the influence of these BMD changes on bone health and fracture risk over time is currently not known….Other common mild adverse events that occurred during elagolix clinical trials included headache, insomnia, mood swings, night sweats, and arthralgia.26 Patients should be made aware that elagolix may decrease menstrual bleeding or cause amenorrhea, thereby obscuring early recognition of pregnancy. Depression and mood changes, particularly if these include suicidal ideation, warrant further investigation, with assessment of the benefits and risks of continuing treatment and referral to a mental health professional, as appropriate.”

4. Aromatase inhibitors: These medications also decrease the amount of estrogen in your body. Bone loss is a significant side effect of this class of medications as well and should be discussed with your provider.

“In several studies involving small numbers of patients, aromatase inhibitors have been shown to be effective for the treatment of endometriosis and pelvic pain in premenopausal and postmenopausal women (79, 80)….Endometriotic tissue, unlike disease-free endometrium, exhibits a high level of aromatase activity that may result in increased local concentrations of E that may favor growth of endometriosis (20, 79). This observation may help to explain the presence of endometriosis in postmenopausal women and the persistence of disease symptoms in some patients receiving GnRH-a treatment. A randomized trial of women on goserelin treated with anastrozole or placebo reported no difference in symptom scores during treatment, but the anastrozole group had a lower recurrence rate as well as a longer time to symptom recurrence (81). However, anastrozole increased bone loss compared with goserelin alone (81). In premenopausal women aromatase inhibitors lead to an increase in FSH levels and subsequent follicular development and therefore must be used in combination with additional agents (progestogens, combined OCs, or GnRH-a) to down-regulate the ovaries. The combination of an aromatase inhibitor with a combined OC may improve endometriosis pain while suppressing follicle development and preserving bone mineral density (79).”

“Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body’s oestrogen is produced outside the ovaries after menopause…. Aromatase activity is absent in normal human endometrium and is increased in endometriosis [9]. It was demonstrated that extrauterine endometrial tissue is a source of oestrogens. Moreover, oestrogens stimulate synthesis of PGE2, which is a potent inducer of aromatase activity in endometrium….Long-term use of aromatase inhibitors is associated with increased risk of osteoporosis and bone fractures [18, 30]. The incidence of fractures was 2-11% in women receiving aromatase inhibitors as adjuvant therapy for breast cancer [34, 35]. The incidence of bone fractures was 11% (n = 3092) in the anastrozole group and 7.7% (n = 3094) in the tamoxifen group after five years of treatment. The incidence of bone fractures was 9.3% among patients receiving letrozole and 6.5% in those treated with tamoxifen after five years of treatment. After six months of treatment with exemestane, BMD decreased by 2.6% (n = 78) at the lumbar spine. The ASCO (American Society of Clinical Oncologists) guidelines recommend BMD testing once a year to all patients receiving aromatase inhibitors as adjuvant therapy for breast cancer, and treatment with bisphosphonates for those with BMD T-scores ≤ –2.5 [36]. After six months, combination treatment with anastrozole and goserelin was associated with a greater decrease in BMD than was goserelin alone. This effect was maintained after discontinuation of treatment.” 

5. Danazol: Although not used much anymore, danazol has been used in endometriosis. Its main side effects stem from its hyperandrogenic effects, such as acne, weight gain, and deepening of the voice. 

“Danazol is an oral androgenic agent that induces amenorrhoea through suppression of the hypothalamic-pituitary-ovarian (HPO) axis, accompanied by increased serum androgen concentrations and low serum estrogen levels (Rotondi et al., 2002; Valle et al., 2003). Multiple studies have demonstrated the efficacy of danazol in reducing endometriosis-associated pain symptoms (Telimaa et al., 1987a,b; Fraser et al., 1991; Crosignani et al., 1992; Cirkel et al., 1995; Chang and Ng, 1996; The Australian/New Zealand ZOLADEX Study Group, 1996)….However, danazol was poorly tolerated, and 18.5% of patients treated with this agent withdrew during the study due to adverse events compared with 5.5% of patients receiving a GnRH analogue (P < 0.05) (Rotondi et al., 2002). In fact, poor tolerability represents the major drawback of danazol as a treatment for endometriosis: this agent has both androgenic and anabolic properties, leading to side effects, such as weight gain, edema, myalgia, acne, oily skin and hirsutism (Biberoglu and Behrman, 1981; Rotondi et al., 2002). These concerns limit treatment duration to 6 months, and the use of this agent has been in decline in recent years (Valle et al., 2003). Danazol should not be used in women with liver disease or hyperlipidemia, and women receiving danazol therapy also must use effective contraception during the entire course of treatment (Valle et al., 2003).”

References

Barra, F., Scala, C., Biscaldi, E., Vellone, V. G., Ceccaroni, M., Terrone, C., & Ferrero, S. (2018). Ureteral endometriosis: a systematic review of epidemiology, pathogenesis, diagnosis, treatment, risk of malignant transformation and fertility. Human reproduction update, 24(6), 710-730. https://academic.oup.com/humupd/article/24/6/710/5085039?login=true

Falcone, T., & Flyckt, R. (2018). Clinical management of endometriosis. Obstetrics & Gynecology, 131(3), 557-571. Retrieved from https://journals.lww.com/greenjournal/Abstract/2018/03000/Clinical_Management_of_Endometriosis.23.aspx?context=FeaturedArticles&collectionId=4

Ferrero, S., Camerini, G., Venturini, P. L., Biscaldi, E., & Remorgida, V. (2011). Progression of bowel endometriosis during treatment with the oral contraceptive pill. Gynecological Surgery, 8(3), 311-313. Retrieved from https://link.springer.com/article/10.1007/s10397-010-0610-3

Guo, S. W. (2009). Recurrence of endometriosis and its control. Human reproduction update, 15(4), 441-461. Retrieved from http://humupd.oxfordjournals.org/content/15/4/441.full

Millochau, J. C., Abo, C., Darwish, B., Huet, E., Dietrich, G., & Roman, H. (2016). Continuous amenorrhea may be insufficient to stop the progression of colorectal endometriosis. Journal of minimally invasive gynecology, 23(5), 839-842. Retrieved from https://www.jmig.org/article/S1553-4650(16)30047-4/abstract?fbclid=IwAR2Q7o1kJtfNNgMd0Q4_5K0BDe9_DjH1QOUTxTLK2HpgiFVgws5NT9xVdwo

Saeid Gholami

Dr. Saeid Gholami is a medical doctor and the founder of iCareBetter. As a physician, he saw many patients with endometriosis who were suffering. And his patients had to deal with many unanswered questions, misleading information, and the lack of access to qualified experts. For that reason and to combat this issue, he built iCareBetter to optimize how patients and doctors connect.

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