Recent Trends in Medical Management of Endometriosis

Abstract

Endometriosis affects about 10 percent women in the reproductive age group globally and approximately 42 million in India. Managing the patient’s pain symptoms associated with endometriosis appears to be the cornerstone in endometriosis disease management. The ideal medical treatment in endometriosis would be suppressing estradiol enough to alleviate symptoms of endometriosis but maintain sufficient levels to mitigate hypoestrogenic side effects. NSAIDs are generally prescribed for the initial management of pain symptoms in endometriosis along with hormonal agents like progestogens or combined oral contraceptive pills (COCPs). Injectable depot gonadotropin-releasing hormone (GnRH) agonists such as leuprolide acetate and letrozole are effective as second-line agents in the management of endometriosis-associated pain. Dienogest is a 19-nortestosterone derivative which has a high specificity for progesterone receptors and improves endometriosis-related symptoms and the overall quality of life. Dydrogesterone is quite effective in the treatment of endometriosis-associated pelvic pain without causing suppression of ovulation. GnRH agonists and GnRH antagonists both have been used in the treatment of endometriosis. Elagolix a first oral, non-peptide gonadotropin-releasing antagonist for the management of moderate to severe pain associated with endometriosis is successfully used. Aromatase inhibitors are used as second-line drugs in the management of endometriosis-associated pelvic pain. They prevent the conversion of steroid precursors to estrogens, both at the periphery and at the ovarian level. Tamoxifen, raloxifene and bacidoxifen have an anti-proliferative effect and regress the endometriotic implants. Mifepristone (progesterone receptor antagonist) and Ulipristal acetate (SPRM) have been used for medical management of endometriosis. LNG-IUS is emerging as a good option for patients with endometriosis who are not desirous of conception. Hormonal management is one of the effective management options in endometriosis. One has to be mindful of molecule-specific adverse effects while prescribing drugs.

Introduction

Endometriosis is a chronic debilitating inflammatory condition which is hormone dependent characterized by the presence of endometrial tissue outside the uterine cavity. It affects about 10% women in the reproductive age group globally and approximately 42 million in India [1]. According to WHO, 196 million women are affected worldwide. Patients suffering from endometriosis generally present with at least one of the three problems, chronic pelvic pain, infertility and/or an adnexal mass. The primary management of endometriosis revolves around managing patient’s pain symptoms. The endometriosis-associated pain including dysmenorrhea, non-menstrual pelvic pain (NMPP) and dyspareunia are often detrimental on the quality of life as well as productivity at the workplace. The symptoms being vague often delay the diagnosis by about 7 years [2], by which time the patient would have acquired significant burden of the disease. Managing the patient’s pain symptoms associated with endometriosis appears to be the cornerstone in endometriosis disease management.

Pathogenesis of Endometriosis

Various theories have been postulated to explain the pathological mechanism of endometriosis. According to Retrograde menstrual theory, endometrial tissue fragments through menstrual blood migrate through the fallopian tube into the peritoneal cavity and lead to the formation of endometriosis. Several other pathogenic pathways have been considered such as coelomic metaplasia, stem cells theory, immune dysregulation, embryogenetic theory and hormonal disbalance. The exact mechanism of origin and progression of disease is poorly understood.

Hormonal Dysregulation in Endometriosis [3, 4]

In the healthy endometrium, the coordination of progesterone and estrogen signaling is crucial and dependent on the phase of the menstrual cycle. This coordination plays a vital role in maintaining a normal menstrual cycle, supporting embryo implantation and facilitating the development of pregnancy. Dysregulation of these hormones, such as estrogen dominance and progesterone resistance, can lead to the development of endometriosis. The ideal hormonal treatment in endometriosis would be suppressing estradiol enough to alleviate symptoms of endometriosis, but maintain sufficient levels to mitigate hypoestrogenic side effects [4].

Medical therapy in Endometriosis

Endometriosis therapy revolves around relief of pain symptoms and improving fertility. NSAIDs are generally prescribed for the initial management of pain symptoms in endometriosis along with hormonal agents like progestogens or combined oral contraceptive pills (COCPs). Injectable depot gonadotropin-releasing hormone (GnRH) agonists such as leuprolide acetate and letrozole are effective as second-line agents in the management of endometriosis-associated pain. They lead to complete suppression of estrogen levels, to cause postmenopausal symptoms such as progressive bone loss and vasomotor side effects. The inability to titrate estradiol levels and unpredictable reversibility of treatment with GnRH agonist limit their usage to 6 months. Hormonal dysregulation in endometriosis leading to progesterone resistance limits the effectiveness of COCs and progestogens in about one-third of the patients [5]. Some newer drugs such as prostaglandin E2 receptor antagonists, resveratrol, IL-1 antagonist and dopamine receptor antagonist are also explored in the management of endometriosis. Studies have demonstrated that postsurgical medical management delays the recurrence of symptoms in endometriosis patients.

The concept of medical management is to suppress estrogen, reduce the retrograde spill, overcome the progesterone resistance, reduce the inflammation, suppress aromatase and promote anti-angiogenic and immune modulatory effects. Being a chronic disease, one should consider not only the efficacy but also the long-term safety and tolerability of the drugs used.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

This can reduce the pain due to elevated levels of PGs, ILs and cytokines. Because of their side effects and inconclusive effectiveness, NSAIDs are slowly taken away from the management of endometriosis. Still, it can be used in women with very early endometriosis for relief of pain. Fertility is not affected by NSAIDs [6].

Combined Oral Contraceptives (COCs)

Combined oral contraceptives can be used continuously for better pain control. It was used earlier as a first-line drug. Now, the disease being estrogen dependent, there is a controversy regarding the use of COCs as it contains estrogen. Women who use COCs for the treatment of dysmenorrhea may get relief from pain, but the development of deep endometriosis may be masked. There is always a high rate of recurrence once the drug is withdrawn and there is also a slightly increased risk of thromboembolism.

Progesterone [7]

It can suppress serum estrogen levels and cause decidualization and atrophy of endometrial cells, reduction of inflammation and inhibition of matrix metallo-proteinases (MMPs) and has anti-angiogenic and immune modulatory action. Commonly used progesterone preparations are dienogest, dydrogesterone, medroxyprogesterone acetate (MPA) and norethindrone.

MPA is given through the oral route up to 30 mg/day or depot preparations once in 3 months at a dose of 150 mg/mL given deep IM or 104 mg/0.65 mL given subcutaneous [8].

Progestins like dienogest have a therapeutic role in endometriosis through multiple mechanisms like modulating estrogen receptors, preventing endometrial proliferation, inhibiting inflammatory responses and promoting apoptosis of endometriotic cells. These drugs reduce the gonadotropin-releasing hormone release, leading to a decrease in FSH and LH and thus suppressing estrogen.

Dienogest is a 19-nortestosterone derivative which has a high specificity for progesterone receptors. It can be used in the dose of 2 mg/day and has a very good safety profile and efficacy. It is well tolerated and improves endometriosis-related symptoms and the overall quality of life. It has a minimal side effect like irregular bleeding which improves over a period. It can even be safely used in adolescent girls as a primary treatment of endometriosis based on symptoms even without imaging or HPE evidence. Long-term use of dienogest for the treatment of endometriomas and deep endometriosis is found to be effective in reducing the pain as well as the size of the lesion. Advantages include reduction in pain, less hypoestrogenic side effects, minimal androgenic effects and oral convenience. Disadvantages include breakthrough bleeding, impact on bone mineral density with long-term usage, progestin resistance in one-third of patients and other mild side effects. Postoperative use of dienogest reduces the incidence of recurrence and is as effective as GnRH agonist.

Dydrogesterone

Dydrogesterone is retroprogesterone which has a good immune modulatory effect by suppressing IL-1, 6 and 8. It increases the nitric oxide production and has excellent anti-inflammatory action. It is quite effective in the treatment of endometriosis-associated pelvic pain(EAPP) without causing suppression of ovulation [8]. Hence, women who are desirous of pregnancy can be started on dydrogesterone 10 mg twice daily from day 5 to 25.

LNG-IUS

LNG-IUS contains 52 mg of levonorgestrel and releases 20 µg/day [9]. There are many studies that show LNG-IUS give excellent pain relief at par with GnRH analogues, due to endometriosis, especially in patients with adenomyosis and deep endometriosis. Hence, it is emerging as a good option for patients with endometriosis who are not desirous of conception [10].

Etonogestrel Implant

This is an alternate route of progesterone delivery where subdermal implants commonly known as Implanon are used for contraception and good relief of EAPP. Side effects and efficacy are similar to injectable MPA [11].

Selective Progesterone Receptor Modulators (SPRM)

They are relatively a new class of agents which can selectively modulate the progesterone receptors. Mifepristone can act as a progesterone receptor antagonist in both ectopic and eutopic endometrium, given in the dose of 5–25 mg per day [12]. Ulipristal acetate is another selective progesterone receptor modulator (SPRM) which can be used for endometriosis. These drugs can inhibit endometrial proliferation without causing hypoestrogenism, and they also reduce bleeding [14].

Gonadotropin-Releasing Hormone (GnRH) Agonist [15]

GnRH agonists like leuprolide work by down-regulating the hypothalamic–pituitary–gonadal axis, ultimately leading to suppression of ovulation and reduction of estrogen levels, a key hormone known to suppress endometriosis, however initial flare-up effect is not good for patients. The most common adverse effect seen is bone mineral density loss and osteoporosis. Hypoestrogenic side effects such as hot flashes, night sweats, vaginal dryness, mood swings and sleep disturbances are severe in many patients, necessitating add-back therapy.

GnRH Antagonist

GnRH antagonists like elagolix, relugolix and linzagolix competitively bind to the GnRH receptors and inhibit them. They have a short half life, therefore, they allow rapid reversibility. These drugs are devoid of the initial flare seen with GnRH agonists. Studies have shown that GnRH antagonists are an important advancement in the treatment of endometriosis.

Native GnRH is released in a pulsatile manner from the hypothalamus. The frequency of GnRH pulses regulates cyclic changes in gonadotropins (LH, FSH) and estradiol concentrations during the cycle. Depot GnRH agonists initially stimulate the HPO axis, which results in a transient hormonal flare. Continued stimulation of GnRH-R consequently leads to their desensitization and profound estradiol suppression. GnRH antagonists competitively bind to GnRH-R and produce rapid and dose-dependent suppression of the HPO axis, which results in a partial estradiol suppression at lower doses to nearly full suppression at higher doses.

Elagolix

The molecule was first approved by USFDA (2018). Besides the advantage of being a competitive GnRH antagonist, elagolix allows rapid and reversible onset and offset, thus providing flexibility in modulating the hypothalamus–pituitary–gonadal axis.

In the phase 1 clinical trial experience, elagolix administered in healthy women showed dose-dependent suppression of LH, FSH and estradiol within hours of elagolix administration on day 1 of treatment and a rapid reversibility of these effects after stopping therapy. Maximum suppression at 200 mg BD and inhibition of ovulation at > 100 mg BD per day. In a study [16], assessing the safety of elagolix in terms of bone mineral density loss after 6 months of treatment, elagolix 150 mg OD compared subcutaneous DMPA showed minimal mean changes from in spine BMD at 24 weeks. In a study comparing with leuprolide for 12 weeks [17], elagolix partially suppressed estradiol (E2) concentrations (150 mg: 36.4–39.6 pg/ml; 250 mg: 22.0–26.2 pg/ml) compared with placebo, whereas leuprolide fully suppressed median E2 concentration to 3.6 − 6.4 pg/ml; in phase II trial elagolix was also found to be more cost-effective versus leuprolide acetate in the management of moderate to severe endometriosis pain over 1–2 year time horizons in the USA [18].

Two large, phase 3, global multicenter studies—ELARIS EM I (n = 872) and ELARIS EM II (n = 817) studies—demonstrated that elagolix 150 mg and 200 mg twice daily for 6 months improved dysmenorrhea and non-menstrual pelvic pain in women suffering from moderate to severe pain associated with endometriosis. Elagolix 200 mg twice daily showed exclusive efficacy for dyspareunia at 6 months of treatment. [19, 20] At 12 months following an additional 6 months of elagolix therapy, sustained improvement in endometriosis chronic pelvic pain symptoms was seen.

Almost 1 in every 4 Indian women with endometriosis experiences dyspareunia [1]. Women experiencing dyspareunia can have difficulties with achieving penetrative intercourse associated with infertility [21, 22]. Elagolix 200 mg twice daily demonstrated exclusive efficacy in reducing dyspareunia score through statistically significant reduction in dyspareunia score.

Aromatase Inhibitors

Aromatase inhibitors are used as second-line drugs in the management of endometriosis-associated pelvic pain. They prevent the conversion of steroid precursors to estrogens, both at the periphery and at the ovarian level. This is especially useful when there is failure of treatment with first-line drugs, as well as in postmenopausal women where peripheral fat is the predominant source of estrogen. Anastrozole and letrozole are third-generation aromatase inhibitors, which when used along with progestins or COCs can significantly reduce the endometriosis-associated pelvic pain and size of the lesion and improve the quality of life. The only disadvantage is that it can lead to ovarian follicular cyst and bone losses with long-term use, which can be overcome by add-back therapy [13].

Selective Estrogen Receptor Modulators (SERM)

Tamoxifen, raloxifene and bacidoxifen have an anti-proliferative effect and regress the endometriotic implants at a dose of 10 mg per kg body weight. There is always a risk of hot flushes and vascular thromboembolism [12]. Adequate human trials are still not available.

Estrogen receptor ligands like oxa-bicycloheptane sulfonate and chlorindazole are in the experimental stage for the treatment of endometriosis [23].

Anti-angiogenic drugs such as cabergoline, endostatins, anginex, rapamycin, doxycycline, PPARs (rosiglitazone) and thalidomide are found to have an effect on endometriosis [12].

They are found to lower the proliferative index, suppress neuroangiogenesis and reduce the size of the lesion giving excellent pain relief. It prevents progression, reduces recurrence and normalizes the menstrual cycle [24].

Rapamycin [25], statins [26], TNFα blockers [27], resveratrol [28], neurotrophic medications like gabapentin can be used in the effective treatment of chronic pelvic pain. Tricyclic antidepressants, preferably amitriptyline and SNRI medications, such as duloxetine, venlafaxine or desvenlafaxine can be used.

Alternate Treatment

Yoga and meditation can be used as adjuvant therapy. Acupuncture may be effective for severe dysmenorrhea. There is limited use of neuromodulators, behavioral therapy, reflexology and psychological therapy for the treatment of endometriosis-associated pelvic pain.

Conclusion

Chronic pelvic pain caused by endometriosis is a chronic and debilitating disease and the diagnosis is often delayed for many years after onset of symptoms. Hormonal management is one of the effective management options in endometriosis. Elagolix, an oral GnRH antagonist, a new molecule, provides an effective hormonal option in women suffering from endometriosis-associated pain to achieve effective reduction in pain symptoms while minimizing adverse effects. One has to be mindful of molecule-specific adverse effects while prescribing drugs.

Declarations

Conflict of interest The authors have no conflicts of interest.