Endometriosis is a modern epidemic; it affects one in 10 women. Women present to health practitioners with a spectrum of symptoms that can affect them physically, sexually and psychosocially. Endometriosis can lead to subfertility, infertility and chronic pelvic pain. More than 73 per cent of adolescents and young adults with a history of severe and primary dysmenorrhea have endometriosis. It is estimated that 700 000 Australian women have endometriosis.

Endometriosis is characterised by endometrial-like tissue growing outside of the uterine cavity. Our current understanding of the pathophysiology of endometriosis describes dysfunction of molecular and immunological responses.¹ These alterations result in increased oestrogen synthesis and progesterone resistance, both of which drive the proliferation of endometriosis. Hormonal management aims to suppress these pathophysiological processes.

Overview of management

As diverse as the disease, women have complex and individual needs and their treatment and management should be personalised. A stepwise approach to management is well documented and involves²:

• a short trial of analgesics (paracetamol and/or NSAIDs) for first-line management of endometriosis-related pain
• hormonal treatment for women with suspected, confirmed or recurrent endometriosis. Table 1 summarises an approach to hormonal management in endometriosis
• combination of medical and surgical treatment
• neuromodulators and neuropathic pain treatments

Women need to be educated about pharmacological management in the setting of their disease. As a chronic disease, the balance of symptom management, side-effect profiles, fertility treatment and decreasing disease recurrence following surgery are all important.

Table 1. Summary of approach to hormonal management of endometriosis.

Hormonal therapy

The overarching role of hormonal therapy in endometriosis is chronic suppression of the disease process. Hormonal treatments can be used to avoid surgical intervention, as an adjunct to surgical intervention, or post-surgical intervention.³ By suppressing follicular growth and ovulation, a hypo-oestrogenic environment is created and ectopic endometrial growth is thus inhibited and when withdrawal bleeds are avoided so is the risk of recurrence following retrograde menstruation. Hormonal treatment is effective and tolerated in about 70 per cent of women. Available hormonal treatments are outlined below.

Combined oral contraceptive pill

The oral contraceptive creates a relative hypo-oestrogenic environment by inhibiting the mid-cycle peak of gonadal oestrogen production. The evidence suggests that low dose combined oral contraceptive pill (COCP) prescribed as continuous therapy is most effective as management of cyclical pelvic pain associated with endometriosis. The COCP is cheap and generally well tolerated with mild side effects. It may be contraindicated in women who smoke, are older than 35, have high blood pressure, breast cancer, high risk of cardiovascular disease or venous thromboembolism. As a hormonal therapy for endometriosis, the COCP can be used in in three ways. Firstly, for symptom management of primary dysmenorrhea that is not responsive to NSAIDs. Secondly, for the prevention of disease recurrence post-surgery. Thirdly, as ‘add back’ therapy (described below).^{4 5}

Prescribe:

• Levonorgestrel 150 μg/Ethinylestradiol 30 μg daily oral dose (4×28, PBS: $17.44)

Progestins

Progestins are synthetic progesterone-like hormones, which can be administered via multiple routes (orally, implant or IUD). Progestins can act on multiple pathways, including stopping proliferation of endometrium, altering oestrogen receptors and inhibiting growth of endometriosis lesions. Furthermore, progestins have been shown to have an anti-inflammatory and anti-angiogenic activity. Side effects of progestins include irregular bleeding, mood changes, breast tenderness and weight gain. Importantly, they have an intrinsic bone-sparing effect and can be used as ‘add-back’ therapy (see below). Progestins cannot be used in pregnancy, but can be used while breastfeeding.^{6 7}

Prescribe:

• Norethisterone acetate 5 mg daily oral dose, for up to 6 months (1×30, PBS: $33.54)
• Medroxyprogesterone acetate (depot) 150 mg intramuscular injection every 12 weeks (PBS: $25.46)
• Levonorgestrel-releasing intrauterine system 52 mg (PBS: $208)
• Dienogest 2 mg/day (available on private script as Visanne)

Gonadotropin-releasing hormones agonists

Gonadotropin-releasing hormone agonists (GnRHa) induce a hypo-oestrogenic state by blocking GnRH receptors in the pituitary. Initially, this results in a transient surge of FSH and LH, but ultimately leads to a down regulation of GnRH receptors. FSH and LH levels are subsequently reduced, leading to a ‘medical menopause’ with many undesirable side effects. The hormonal surge may briefly cause increased endometriosis symptoms while the subsequent menopausal state may lead to hot flushes, decreased libido, mood swings and decreased bone mineral density (BMD). The current recommendations are that GnRHa therapy should be combined with ‘add back’ therapy to counter the side-effect profile and to protect against osteoporosis if given for longer than six months. ‘Add back’ therapy is the concurrent prescription of a synthetic progestin as well as the consideration of bisphosphonates and/or oestrogen to combat the side effects. As hormonal therapy for endometriosis, the GnRHa can be used in a variety of ways, including as an option to avoid surgery, adjunct to surgery or to prevent recurrence post-surgery.^{8 9}

Prescribe:

• Goserelin subcutaneous implant 3.6 mg every four weeks for up to six months (PBS: $264)
• Nafarelin 200 μg intranasal twice daily (1*60 doses, PBS: $121.65)

Androgenic steroids

Androgenic steroids are synthetic hormones that inhibit ovulation by directly suppressing folliculogenesis. While androgens induce a hypo-oestrogenic state, these are less favoured due to significant and poorly tolerated androgenic side effects (hirsutism, acne) with some risk of irreversible virilisation (voice change) as well as increased metabolic risks (liver toxicity, lipid derangement).^{10 11}

Prescribe:

• Danazol 100–400 mg orally, twice daily for three–nine months (100x100mg, PBS: $49)

Newer hormonal agents

Aromatase inhibitors

While inhibition of ovulation can lead to a hypo-oestrogenic state, research has shown that aromatase is abnormally expressed in endometriotic lesions. The enzyme aromatase converts androgens into oestrogen and local production of oestrogen is thus likely even when ovulation is suppressed. Side effects include vaginal dryness, hot flushes, headache and decreased BMD. As hormonal therapy for endometriosis, aromatase inhibitors are potent new agents with a poor side-effect profile and therefore are used when other hormonal therapies have been ineffective. It is recommended that ‘add back’ therapy should be initiated when commencing aromatase inhibitors.^{12 13}

Prescribe

• Letrozole 2.5 mg daily oral dose
  (1×30, PBS: $31.12)

GnRH antagonists

GnRH antagonists induce a hypo-oestrogenic state by competitively blocking GnRH receptors in the pituitary. This results in immediate suppression of LH and FSH and does not cause an initial flare. GnRH antagonists have been showed to decrease symptoms and suppress disease progression. There is a lower degree of hypo-oestrogenism, which leads to a better side-effect profile than GnRHa. They have the potential to be better tolerated and an oral form is now clinically available but, as yet, not in Australia.^{14 15}

Other

The use of newer and novel agents have aimed to prevent the action of oestrogens on endometriosis lesions, block receptors and inhibit enzymes. The majority of these medications have only been investigated experimentally. They include selective oestrogen receptor modulators (SERMs), selective progesterone receptor modulators (SPRMs), anti-angiogenesis factors and tumour necrosis factor alpha (TNF-a) blockers.

Clinical considerations

There are a couple clinical considerations when prescribing hormonal management.

Firstly, there is limited research into the cost effectiveness of hormonal management of endometriosis.¹⁶ Preliminary models into the COCP showed increased quality adjusted life years (QALYs) and lower cost to no hormonal treatment. This is assumed to be a result of decreased visits to the GP and days away from work. Furthermore, GnRHa and dienogest have been demonstrated to be equally effective for long-term treatment of pain symptoms associated with endometriosis; however, have very different costs (in favour of GnRHa, which is available on PBS) and side-effect profile (in favour of dienogest).¹⁷

Secondly, since endometriosis is a disease most prominent during childbearing years, the main prescribing conundrum is balancing a woman’s desire for fertility with the safety and side-effect profiles of medications. The outlined hormonal treatments have no fertility benefit and are generally counterproductive as they suppress ovulation or are contraceptive in other ways. GnRHa (with add back therapy) may be used in preparation for IVF in those women with endometriosis and adenomyosis seeking fertility.

Conclusion

Overall, there are three main issues in the long-term medical management of endometriosis.¹⁸ Firstly, women experience a recurrence of symptoms following cessation of medication. Secondly, the medications have significant and sometimes intolerable side effects. Lastly, many women desire fertility. Appropriate pharmacological management has the capacity to synergistically contribute to a reduction in the impact and burden of disease at individual and population levels. New pharmacological research should focus on finding medical treatment that does not prevent or preclude pregnancy and has a favourable side-effect profile as well as being affordable.

1. T Falcone, R Flyckt. Clinical Management of Endometriosis. Obstet Gynecol. 2018;131(3):557-71.
2. GA Dunselman, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-12.
3. S Rafique, AH DeCherney. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017;60(3):485-96.
4. S Rafique, AH DeCherney. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017;60(3):485-96.
5. F Barra, G Grandi, G Tantari, et al. A comprehensive review of hormonal and biological therapies for endometriosis: latest developments. Expert Opinion of Biological Therapy. 2019;19(4):343-60.
6. S Rafique, AH DeCherney. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017;60(3):485-96.
7. F Barra, G Grandi, G Tantari, et al. A comprehensive review of hormonal and biological therapies for endometriosis: latest developments. Expert Opinion of Biological Therapy. 2019;19(4):343-60.
8. S Rafique, AH DeCherney. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017;60(3):485-96.
9. F Barra, G Grandi, G Tantari, et al. A comprehensive review of hormonal and biological therapies for endometriosis: latest developments. Expert Opinion of Biological Therapy. 2019;19(4):343-60.
10. S Rafique, AH DeCherney. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017;60(3):485-96.
11. F Barra, G Grandi, G Tantari, et al. A comprehensive review of hormonal and biological therapies for endometriosis: latest developments. Expert Opinion of Biological Therapy. 2019;19(4):343-60.
12. S Rafique, AH DeCherney. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017;60(3):485-96.
13. F Barra, G Grandi, G Tantari, et al. A comprehensive review of hormonal and biological therapies for endometriosis: latest developments. Expert Opinion of Biological Therapy. 2019;19(4):343-60.
14. S Rafique, AH DeCherney. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017;60(3):485-96.
15. F Barra, G Grandi, G Tantari, et al. A comprehensive review of hormonal and biological therapies for endometriosis: latest developments. Expert Opinion of Biological Therapy. 2019;19(4):343-60.
16. TS Grand, H Basarir, LJ Jackson. The Cost Effectiveness of Oral Contraceptives compared to ‘no hormonal treatment’ for endometriosis-related pain: an economic evaluation. PLoS ONE. 2019;14(1):e0210089.
17. F Barra, G Grandi, G Tantari, et al. A comprehensive review of hormonal and biological therapies for endometriosis: latest developments. Expert Opinion of Biological Therapy. 2019;19(4):343-60.
18. S Rafique, AH DeCherney. Medical Management of Endometriosis. Clin Obstet Gynecol. 2017;60(3):485-96.