Hormonal Management of Endometriosis-associated Pain | Article

This chapter should be cited as follows:
Ferrero S, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.417663

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 3

Endometriosis

Volume Editors: Professsor Andrew Horne, University of Edinburgh, UK
Dr Lucy Whitaker, University of Edinburgh, UK

Chapter

Hormonal Management of Endometriosis-associated Pain

First published: November 2023

AUTHORS

Simone Ferrero

IRCCS Ospedale Policlinico San Martino, DINOGMI, University of Genova, Genova, Italy

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INTRODUCTION

Given that estrogen is the critical driver of endometriosis, manipulating its levels lies at the root of pharmacotherapy for symptomatic endometriosis. Hormonal therapies can efficaciously decrease the intensity of pain caused by endometriosis, and they can prevent the recurrence of endometriosis after surgery.¹^,² Furthermore, they can prevent the growth of ovarian endometriomas, while it is unclear if they control the progression of deep endometriosis. Hormonal therapies have no role in managing endometriosis-related infertility because these therapies are either contraceptives or, at least, interfere with conception. Although hormonal therapies may decrease the size of endometriotic lesions (such as endometriomas and deep nodules),³ they do not definitively cure the disease. Therefore, despite the improvement of pain during treatment, symptoms are expected to recur after discontinuation of therapy. Therefore, patients require chronic treatment and must be monitored during therapy to detect the progression of endometriosis in a timely manner. In addition, women desiring to conceive must discontinue the hormonal treatment, and they may experience severe pain, including deep dyspareunia, that may interfere with sexual function.

Several hormonal therapies have been used to treat endometriosis-related pain. These treatments include first-line therapies: progestins and combined estroprogestin contraceptives. In patients with symptoms persisting despite the use of first-line therapies, second-line therapies can be considered; they include injectable gonadotropin-releasing hormone analogs (GnRH-a), oral gonadotropin-releasing hormone antagonists (GnRH-ant), and aromatase inhibitors (AIs).⁴

PROGESTINS

Progestins are synthetic compounds that mimic the effects of progesterone.⁵ Several progestins have been used to treat endometriosis, and they can be administered by different routes: oral tablets, injections, subdermal implant, and intrauterine device. They have some advantages over estroprogestin combinations because they cause less thrombotic risk, and they can be administered to women with contraindications to estrogens (such as women with migraine) or who do not tolerate estrogens.

Norethindrone acetate (norethindrone acetate, NETA) is one of the most used progestins to treat endometriosis. It is generally administered at a daily dose ranging from 2.5 to 5 mg/day; ideally, the lowest dose that causes amenorrhea should be administered. A randomized controlled trial (RCT) demonstrated NETA's efficacy in treating deep endometriosis-associated pain. This open-label, parallel-group RCT compared a 12-month treatment with continuous combined oral contraceptive versus low-dose oral NETA.⁶ The study showed a substantial improvement in pain symptoms with both treatments without significant between-group differences. NETA also effectively treats symptoms caused by deep endometriosis, including lesions infiltrating the rectosigmoid and the urinary tract.⁷ It is generally well tolerated and suitable for long-term administration.⁸ A further advantage of this therapy is that it is not expensive.

Dienogest (DNG) is specifically marketed to treat endometriosis-related symptoms. Several RCTs demonstrated the efficacy of DNG in treating endometriosis-related pain.⁹^,¹⁰^,¹¹^,¹²^,¹³ It is administered at a daily dose of 2 mg/day. It may effectively treat the symptoms resistant to NETA administration.¹⁴ DNG is as efficacious as GnRH agonists in preventing postoperative recurrence of endometriosis after surgical excision of parametrial and bowel endometriosis.¹⁵ An ongoing RCT is comparing the efficacy of DNG and NETA in treating endometriosis-related pain (DINE study, NCT05476172). DNG may be particularly useful for treating patients with concomitant adenomyosis.¹⁶

Desogestrel (DSG) is used worldwide for contraception in breastfeeding women.¹⁷ It has the advantage of providing contraception to women with endometriosis requiring treatment of pain symptoms. Several studies documented its efficacy in treating endometriosis-related pain.³^,¹⁸^,¹⁹ It may occasionally cause breakthrough bleeding that may be more evident in women with adenomyosis and may impair the long-term use of the drug.

Medroxyprogesterone acetate was administered initially orally and, more recently, by subcutaneous or intramuscular injections.²⁰^,²¹^,²²^,²³^,²⁴ It is generally well tolerated and effective in the treatment of pain.

The levonorgestrel intrauterine device (LNG-IUD) is effective in treating pain caused by endometriosis²⁵ and is efficacious in treating pain and heavy menstrual bleeding caused by adenomyosis.

COMBINED ESTROPROGESTIN CONTRACEPTIVES

Combined estroprogestin contraceptives have been widely used to treat the pain caused by endometriosis. They can provide contraception to the patients and be administered orally (COCs), by a vaginal ring, or by transdermal patch.²⁶ They can be administered sequentially, preserving the cyclical vaginal bleeding or continuously causing amenorrhea. Continuous administration may be more suitable for women suffering severe dysmenorrhea, heavy menstrual bleeding, and those with persistent dysmenorrhea despite using cyclic COC.²⁷

Limited scientific evidence supports the use of COCs in the treatment of endometriosis. A Cochrane review investigated the effectiveness, safety, and cost-effectiveness of COCs in treating painful symptoms ascribed to the diagnosis of laparoscopically proven endometriosis. Five trials (612 women) met the inclusion criteria, but only three trials (404 women) provided data that were suitable for analysis.²⁸ The authors found insufficient evidence to judge the effectiveness of the COCs compared with the placebo. However, some RCTs demonstrated the efficacy of COCs in treating pain caused by endometriosis when compared with placebo,²⁹^,³⁰^,³⁰ with NETA,⁶ or with DNG.¹³^,³¹ A Japanese RCT evaluated the efficacy of a COC (ethinylestradiol 0.035 mg and norethisterone 1 mg) for patients with dysmenorrhea associated with endometriosis. One hundred patients were included in the study, and most had radiologic evidence of endometriosis rather than surgical diagnosis. The intensity of dysmenorrhea was significantly lower in patients treated with COC than in those receiving the placebo. The volume of endometrioma was significantly decreased in patients treated with COC but not in those receiving a placebo.³⁰ A recent RCT compared the efficacy of DNG with the COC (0.03 mg ethinylestradiol and 3 mg drospirenone) in treating endometriosis-associated pain. Seventy women were included in the study and treated for 24 weeks. DNG was associated with fewer side-effects and hence had a better safety and tolerability profile than COC.¹³

Combined contraceptives prevent the postoperative recurrence of endometriosis, including ovarian endometriomas.³²^,³³^,³⁴ An RCT evaluated the postoperative long-term cyclic and continuous administration of COC in preventing endometriosis-related pain recurrence. A total of 311 women were included in the study. Patients were randomly divided into three groups: a nonuser group receiving no therapy, and cyclic user group, and a continuous user group receiving low-dose, monophasic OC pills for 24 months in either cyclic or continuous administration. A significant reduction in recurrence rate and intensity of dysmenorrhea was evident in the continuous users versus the other groups at 6 months and in cyclic users versus nonusers at 18 months postoperatively. No significant differences in recurrence rate and intensity of dyspareunia and chronic pelvic pain were demonstrated among the groups. The increase of dysmenorrhea, dyspareunia, and chronic pelvic pain was significantly higher in nonusers than in the other groups.³³ An RCT evaluated the long-term cyclic and continuous administration of COCs in preventing ovarian endometrioma recurrence after laparoscopic cystectomy. There were 293 women included in the study. Patients were divided randomly into three groups: nonusers receiving no therapy and cyclic and continuous users receiving low-dose, monophasic COC for 24 months in cyclic or continuous administration. The crude recurrence rate within 24 months was significantly lower in cyclic (14.7%) and continuous users (8.2%) compared with nonusers (29%). At first observation, the mean recurrent endometrioma diameter was significantly lower in cyclic and continuous users than in nonusers. The mean diameter increase every 6 months of follow-up was reduced considerably in cyclic users and continuous users versus nonusers. No significant differences between cyclic and continuous users regarding endometrioma recurrence were demonstrated.³⁵

An RCT compared the effects of DNG and a COC in women with severe endometriosis treated by laparoscopic surgery. A total of 108 patients were included in the study. Treatment with DNG or COC was associated with improved pain after 6 months, as evidenced by significantly lower scores for pelvic pain and dyspareunia compared with a placebo. DNG and COC significantly improved postoperative quality of life compared with placebo.³⁶

GONADOTROPIN-RELEASING HORMONE ANALOGS

GnRH-a have been widely used in the past for treating endometriosis-related pain. They work by down-regulating the hypothalamic-pituitary-gonadal axis, ultimately suppressing ovulation and reducing estrogen levels. Many GnRH agonists are available that can be delivered through injection or nasal inhalation. The efficacy of GnRH-a in treating endometriosis-related pain was initially demonstrated in several RCTs comparing these drugs to placebo and danazol.⁴ Subsequently, GnRH-a became the standard comparison in RCTs for newly developed drugs (such as DNG).⁹^,¹¹^,¹² A prospective cohort study demonstrated the effectiveness of a 6-month GnRH agonist treatment for patients with symptomatic rectovaginal endometriosis.³⁷ Most patients showed a marked improvement in pain symptoms during the treatment. However, they experienced early pain recurrence after discontinuing treatment, and about 85% required further treatment within the first year of follow-up. Subsequently, GnRH-a were efficacious in treating symptoms caused by rectovaginal and urinary tract deep endometriosis.³⁸^,³⁹

The major limitation of GnRH-a is that they cause severe adverse effects related to hypoestrogenism, including hot flushes, vaginal dryness, mood and sleep disturbances, and loss of bone mineral density. Because of these adverse effects, GnRH-a are poorly tolerated in long-term use. When administered for more than 6 months, GnRH-a must be combined with add-back therapies (such as tibolone or low-dose NETA) that decrease the incidence and intensity of hypoestrogenism-related adverse effects.⁴⁰

GONADOTROPIN-RELEASING HORMONE ANTAGONISTS

Oral, nonpeptide GnRH-ant have recently been introduced in treating endometriosis associated-pain. These drugs work by competitively binding to and inhibiting the GnRH receptor from forming a functional unit. Like GnRH agonists, this causes down-regulation of the hypothalamic-pituitary-gonadal axis, creating similar downstream effects, including a hypoestrogenic state. What is unique to GnRH antagonists is that they can be used in different doses. At low doses, they allow for some estrogen production to continue, thus mitigating the adverse effects. The most investigated GnRH-ant are elagolix (ELX), relugolix (RLX) and lizagolix (LZX).

Two similar large multicenter, double-blind, randomized, placebo-controlled, phase 3 trials (Elaris Endometriosis I and II) demonstrated the efficacy of 6-month treatment with ELX at two doses (150 mg once daily and 200 mg once daily) in improving moderate or severe endometriosis-associated pain.⁴¹ Patients who received the two doses of ELX had significantly lower scores for dysmenorrhea and non-menstrual pelvic pain than those who received a placebo after 3 and 6 months of treatment. These results were supported by considerably better scores for endometriosis-associated pain on the Numeric Rating Scale at 3 months among those who received ELX than those who received a placebo. In addition, women who received the higher dose of ELX (200 mg twice daily) had significantly better results concerning the use of rescue analgesic agents at 3 and 6 months, dyspareunia at 3 months, and rescue opioid use at 3 months than did those receiving placebo. Oral ELX had hypoestrogenic effects such as reduced bone mineral density, increased lipid levels, and an increased incidence of hot flushes. Both ELX doses influenced bone mineral density, and the differences were significant compared to the placebo. However, the difference between the lower dose of ELX and the placebo was smaller than that for the higher dose. ELX is approved in the USA as a once-daily or more effective twice-daily high dose. However, because of the hypoestrogenic-induced decline in bone mineral density, the treatment duration is 24 months for the low dose (6 months in patients with moderate hepatic impairment) and 6 months for the high-dose regimen.

A phase 2 dose-ranging study assessed the efficacy and safety of three dose levels of RLX for 24 weeks compared with placebo and leuprorelin in women with endometriosis-associated pain.⁴² Oral administration of RLX improved endometriosis-associated pain in a dose-response manner and was generally well tolerated. RLX 40 mg/day demonstrated efficacy and safety comparable to leuprorelin. However, because of the dose-dependent decreases in bone mineral density and the increase in vasomotor symptoms, RLX is not suitable for long-term use. A Japanese phase 2 multicenter randomized controlled study compared the efficacy and safety of RLX (40 mg per day for 24 weeks) and leuprorelin in women with endometriosis-associated pain.⁴³ The treatment decreased the intensity of pain and the volume of endometriomas. Drug-related treatment-emergent adverse events with an incidence of >10% for both groups were hot flush, metrorrhagia, headache, and genital hemorrhage. Discontinuations caused by adverse events were 2.9% for RLX and 4.3% for leuprolide. Recently, two replicate, phase 3, multicenter, randomized, double-blind, placebo-controlled trials (SPIRIT 1 e SPIRIT 2) demonstrated that once-daily RLX combination therapy (RLX 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg) significantly improve endometriosis-associated pain and is well tolerated.⁴⁴

A multinational, parallel-group, randomized, placebo-controlled, double-blind, dose-ranging trial studied the effect of LZX in treating endometriosis-associated pain.⁴⁵ LZX was administered at 50, 75, 100, or 200 mg once daily for 24 weeks. Compared with placebo, doses ≥75 mg resulted in a more significant proportion of responders for overall pelvic pain at 12 weeks. A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Quality of life improved, and the rate of amenorrhea increased in a dose-dependent fashion.

AROMATASE INHIBITORS

Laboratory studies demonstrated the presence of aromatase P450 in the eutopic and ectopic endometrium of patients with endometriosis and its absence in the eutopic endometrium of healthy women.⁴⁶^,⁴⁷^,⁴⁸ Furthermore, the nuclear receptor SF-1, a regulator of aromatase production, is overexpressed in endometriosis.⁴⁹ The presence of aromatase in endometriotic lesions is a local source of estrogens. It may justify the higher estradiol concentration in the endometriotic tissue and the peritoneal and endometrioma fluid.⁵⁰ Moreover, aromatase P450 and the local production of estrogen have been proposed to be involved in a positive feedback loop. Estrogens induce the expression of the cyclo-oxygenase type 2 (COX-2) enzyme that elevates the prostaglandin E₂ levels, which stimulates the aromatase activity by inducing the nuclear receptor SF-1.⁴⁹^,⁵¹ Based on this biological background, third-generation AIs have been used to treat endometriosis. These drugs are available in pill form, including letrozole (2.5 mg/day) and anastrozole (1 mg/day). These drugs significantly improve endometriosis-related pain symptoms;⁵²^,⁵³^,⁵⁴ however, they do not cause the complete disappearance of endometriotic lesions, and recurrence of pain is expected after treatment discontinuation. The long-term administration of AIs is limited by the adverse effects, which are a direct consequence of estrogen level suppression. These adverse effects include hot flashes, vaginal dryness, arthralgia, and an increased risk of osteopenia, osteoporosis, and fracture. Furthermore, the administration of AIs has been associated with cardiovascular toxicity, alteration of lipid profile, fatigue, forgetfulness, and sleep disturbances. In addition, through negative feedback, AIs induce the release of gonadotropins, which stimulates the development of follicles in the ovaries that become functional cysts due to absent ovulation; therefore, in patients with endometriosis, AIs must be combined with ovarian suppressive agents (such as combined oral contraceptives, progestins, or GnRH-a). AIs are not approved for the treatment of endometriosis-related pain. Therefore, they can be administered only in the setting of scientific research to patients with symptoms persisting despite the administration of other therapies and who have contraindications to surgery.

CONCLUSION

The recent guidelines of the European Society of Human Reproduction and Embryology (ESHRE) recommend offering hormonal treatment as one of the options to reduce endometriosis-associated pain.⁵⁵ Several hormonal therapies are available for the treatment of endometriosis-related pain. These therapies effectively improve pain in most patients with endometriosis, but pain recurrence is expected after the treatment discontinuation. Therefore, therapies should be chronically administered, ideally from the diagnosis until the patient's desire to conceive or until menopause. A drug can be used in the long term only if the patients tolerate it; therefore, the efficacy in improving pain must be balanced with the incidence of adverse effects. Several variables must be considered when choosing the hormonal treatment in patients with endometriosis, such as previous experience with hormonal therapies, desire for contraception, menstrual preferences of the patient, presence of comorbidities (such as migraine or inflammatory bowel disease), way of administration (oral tables, vaginal ring, transdermal patch, or injections), presence of other gynecological disorders (such as adenomyosis of uterine fibroids). Before starting the hormonal therapy, patients must be informed that endometriosis may progress despite the use of the treatment and the improvement in pain symptoms. Therefore, patients with ovarian endometrioma and deep endometriosis must be monitored during treatment, such as by transvaginal ultrasonography.

First-line therapies, progestins, and combined oral contraceptives improve pain in many patients with endometriosis. Patients with persisting symptoms despite first-line therapies can be treated with surgery or second-line therapies. GnRH-ant are the new option for the treatment of endometriosis-associated pain. However, although RCTs demonstrated their efficacy compared with a placebo, these drugs have not yet been compared with first-line therapies regarding effectiveness and safety.

PRACTICE RECOMMENDATIONS

Hormonal therapies improve pain in many women with endometriosis, but they do not cause the disappearance of the lesions; therefore, recurrence of symptoms is expected after discontinuation of the treatment.
When choosing the hormonal treatment, the efficacy in improving pain must be balanced with the incidence of adverse effects to allow a long-term use of the drug.
Available hormonal therapies are contraceptives, or at least they interfere with conception; therefore, women wishing to conceive must interrupt the treatment and usually experience a recurrence of symptoms.
Endometriosis may progress despite hormonal therapies; therefore, during treatment, patients must be monitored by ultrasonography to detect endometriosis progression in a timely manner.
Progestins and combined oral contraceptives are first-line therapy for endometriosis-related pain. They are well tolerated and efficacious.
GnRH agonists are effective in improving endometriosis-related pain, but they cause adverse effects related to hypoestrogenism (including hot flushes, vaginal dryness, mood and sleep disturbances, and loss in bone mineral density).
GnRH antagonists are more efficacious than placebo in improving endometriosis-related pain, but they have not yet been compared with first-line therapies. The long-term administration of these drugs decreases bone mineral density.

CONFLICTS OF INTEREST

The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.

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