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Endometriosis Association Of Ireland
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Hormonal Treatment of Pain

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  3. Treating Endometriosis Hormonally
  5. Hormonal Treatment of Pain
Hormonal Contraceptives

Hormonal contraceptives are widely used for contraception and generally accepted. They contain low doses of hormones (estrogen and progesterone) and can reduce pain associated with endometriosis by stopping follicular growth and hence reducing the production and concentration of estrogens. Low estrogens stop the activity of the growth of the endometrium in and outside the uterus, and thus pause endometriosis. The progesterone in the pill decreases the activity of the endometrium directly.

The side effects are limited and hormonal contraceptives are not expensive. Your doctor can prescribe different types of hormonal contraceptives:

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    The oral contraceptive pill (taken with or without a monthly pill-free week)
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    A vaginal contraceptive ring
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    A transdermal patch

Women with endometriosis are often advised to take hormonal birth control continuously (back to back packs) for three or more months. This concept is to reduce the amount of withdrawal bleeds and pain, however some women experience breakthrough spotting and bleeding.

Discuss this option and the side effects with your doctor. Your GP and Gynaecologist can prescribe this type of treatment in Ireland.

Progestagens and anti-progestagens

Progestagens can be used in different forms: orally, as a 3-monthly injection or a levonorgestrel-releasing intrauterine system. Different types of progestagens are medroxyprogesterone acetate (MPA), dienogest, cyproterone acetate or danazol. Progestagens are also used as contraceptives, but they only contain progesterone, not estrogen. Anti-progestagens (gestrinone) have a similar method of action. Progestagens are relatively inexpensive.

The different types of progestagens and anti-progestagens have different side effects. Doctors are recommended to take the side effects into account when prescribing this type of medication and discuss them with the patient. Patients are recommended to report any side effects with their doctor and discuss their options.

Progestagens / Anti Progestogens

Progestagens are a synthetic form of a natural hormone called progesterone. This treatment might be recommended for women who do not get pain relief from or who cannot take hormonal birth control that contains oestrogen (such as smokers). Progestagens can be used in different forms: orally daily, as a 3-monthly injection or a levonorgestrel-releasing intrauterine system. Different types of progestagens are medroxyprogesterone acetate (MPA), dienogest, cyproterone acetate or danazol. Anti-progestagens (gestrinone) have a similar method of action. In Ireland, Provera, Depo Provera and Cerazette are brand names of Progestagens.

The different types of progestagens and anti-progestagens have different side effects. It is important to read up on the side effects and discuss with your doctor before starting treatment.

The “Mirena” and other IUS

A levonorgestrel-releasing intrauterine system is a small device that is inserted in the uterus and releases low levels of progesterone. A levonorgestrel-releasing intrauterine system is frequently used for contraception; it has limited side effects. In women with endometriosis, the levonorgestrel-releasing intrauterine system is an option for reducing symptoms of pain associated with menstruation. The IUS can take up to 8 weeks to settle down, during this time pain and bleeding may be exacerbated. In some women the IUS can stop periods completely, reducing the pain and symptoms of endometriosis. In other women, the IUS is not well tolerated and is removed.

The ESHRE Guidelines 2013 recommended that “There is sufficient evidence on the effectiveness of progestagens and anti-progestagens, including the levonorgestrel-releasing intrauterine system, in reducing pain in women with endometriosis. The ESHRE group stresses that clinicians should look at side-effect profiles, to tailor the medical treatment and improve the quality of life of the woman.

Regarding the use of danazol for treatment of endometriosis-associated pain, the ESHRE group strongly believes that danazol should not be used if any other medical therapy is available, due to its severe side effects (acne, oedema, vaginal spotting, weight gain, muscle cramps)”

Discuss this option and the side effects with your doctor. Your GP and Gynaecologist can prescribe this type of treatment in Ireland.

GnRH agonists

GnRH agonists induce a very low estrogen level by stopping the follicular growth in the ovary completely. GnRH agonists can be taken intranasal, or through subcutaneous injection as a depot working either one or three months. Some of the most common GnRH agonists are nafarelin, leuprolide, buserelin, goserelin and triptorelin. GnRH agonists have more side effects than oral contraceptives and progestagens and are more expensive.

The side effects of GnRH agonists are related to the low level of estrogens and are comparable to the consequences of the menopausal status.

These so-called hypo-estrogenic symptoms are hot flushes and night sweats, vaginal dryness and related pain during intercourse, and influences on the mental health up to depressive feelings. In the long term GnRH agonists are associated with osteoporosis. To reduce these symptoms, clinicians are recommended to prescribe hormonal add-back therapy as soon as GnRH agonists are started. Hormonal add back means adding a combination of estrogens and progesterone (oral contraceptives).

This add back therapy takes away the side effects while the therapeutic effect is maintained. Since adolescents and young women up to the age of 23 have not reached their optimal bone density, it is advisable not to use GnRH agonists in these women.

Some of the most common GnRH agonists/antagonists are nafarelin, leuprolide, buserelin, goserelin and triptorelin. GnRH agonists/antagonists have more side effects than oral contraceptives and progestagens and are more expensive. They are prescribed on the “High Tech” drug scheme in Ireland. Discuss this option and the side effects with your doctor. Your Gynaecologist can prescribe this type of treatment in Ireland. Brand names include Decapeptyl, Zoladex, Prostap and Synarel.

GnRH agonists/antagonists are not used if you are trying to become pregnant.

GnRH agonists, with and without add-back therapy, are considered effective in the relief of endometriosis-associated pain during their us. Evidence is limited regarding dosage or duration of treatment. No specific GnRHa can be recommended over another in relieving endometriosis-associated pain.

Discuss this option and the side effects with your doctor. Your Gynaecologist can prescribe this type of treatment in Ireland.

Aromatase inhibitors

Aromatase inhibitors stop an enzyme called aromatase that is needed in the production of oestrogens in several cells of the body. The result is a very low oestrogen level. These drugs have only recently been used in endometriosis and not well studied yet. They have proven efficacy for other conditions.

Due to the side effects associated with low oestrogen (vaginal dryness, hot flushes, diminished bone mineral density), aromatase inhibitors should only be prescribed to those in severe pain after trying all other options of medical and surgical treatment. Examples of aromatase inhibitors include letrozole and anastrozole. They are prescribed in Ireland under the brand names Femara and Arimidex.

All evidence is based on studies in women with rectovaginal endometriosis or women that have ongoing severe pain despite previous surgical and medical treatment. The EHSRE recommendations state that aromatase inhibitors should only be prescribed to women after all other options for medical or surgical treatment are exhausted.

Aromatase inhibitors can be prescribed off label by your gynaecologist in Ireland if this medication is suitable for you. Discuss this option and the side effects with your doctor. Your Gynaecologist can prescribe this type of treatment in Ireland.

Non Hormonal Medications
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    Other Medications for Chronic Pain

    There are many other medications that can help control chronic pain and other symptoms. These medications may be prescribed in combination with other medications to help manage endometriosis pain.

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    Anti-depressant Medications

    Anti-depressants are used for some chronic pain, they help by changing your body's chemicals. There are 3 categories of anti-depressants: tricyclic anti-depressants (TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs). TCAs raise the level of certain neurotransmitters - chemicals messengers - while SNRIs change the re-absorption of neurotransmitters in the body. Examples include Duloxetine, Amitriptyline, Sertraline.

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    Anti-seizure Medications

    Also known as anti-convulsants or anti-epileptics, anti-seizure medications work to suppress the nerve signals going to your brain so pain messages aren't transmitted as well. Lyrica and Gabapentin are in this class.

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    Muscle Relaxants

    These medications are used to reduce aches and pains associated with muscles spasms that may be secondary to endometriosis pain. They can also be used to help with insomnia.

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    Topical Medications

    Also known as topical analgesics, topical medications, such as a lidocaine patch (Versatis) can help in some patients. In Ireland, the Versatis patches have been removed from the medical card and drugs payment scheme as they are only licenced for Post Herpetic Neuralgia (pain following shingles).

What are the side effects of hormonal treatment?

Since the aim of treatment in endometriosis-associated pain is lowering the level of estrogens, the side effects are related to a low estrogen level. Besides that, the side effects are related to the drugs used to reach that low estrogen level.

Side effects are therefore related either to low estrogens (hormonal contraception, GnRH analogues) or to progesterone (hormonal contraception, progestagens).

Some examples of side effects of hormonal treatment for pain in endometriosis are headaches, acne, weight gain, vaginal spotting, fatigue and hot flushes.

These side effects differ strongly between treatments and between patients. As a result, a certain treatment can be a good option for one woman, but the same treatment can have severe side effects in another woman. Your doctor should discuss side effects with you when prescribing hormonal treatment.

Medical treatment before or after surgery

There is some controversy on this subject. The guideline group does not recommend hormonal treatment before surgery to improve the results of the surgery. Of course, many women in pain get hormonal treatment during a waiting period before surgery. After surgery, starting with an oral contraceptive pill or using a levonorgestrel-intrauterine device may prevent recurrence of pain.

Is surgical treatment an option for relieving pain symptoms?

Surgical treatment of endometriosis focuses on the elimination of peritoneal endometriosis/endometrioma/deep endometriosis and division of adhesions.

In the past, open surgery or laparotomy was used routinely. Nowadays, laparoscopy is used frequently and preferred since it usually results in less pain, shorter hospital stay, quicker recovery and a smaller scar. However, laparotomy and laparoscopy are equally effective in treating pain symptoms in women with endometriosis.

Therefore, clinicians should consider surgical treatment (elimination of endometriotic lesions) when they see endometriotic lesions during laparoscopy for diagnosis.

If deep endometriosis is suspected, doctors are recommended to refer their patient to a centre of expertise, as these surgeries may be difficult.

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References
References

• Brown J, Crawford TJ, Datta S, Prentice A. Oral contraceptives for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2018, Issue 5. Art. No.: CD001019. DOI: 10.1002/14651858.CD001019.pub3.
• Brown J, Crawford TJ, Allen C, Hopewell S, Prentice A. Nonsteroidal anti‐inflammatory drugs for pain in women with endometriosis. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD004753. DOI: 10.1002/14651858.CD004753.pub4
• Brown J, Kives S, Akhtar M. Progestagens and anti‐progestagens for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD002122. DOI: 10.1002/14651858.CD002122.pub2.
• Brown J, Pan A, Hart RJ. Gonadotrophin‐releasing hormone analogues for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD008475. DOI: 10.1002/14651858.CD008475.pub2.
• Davis LJ, Kennedy SS, Moore J, Prentice A. Oral contraceptives for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD001019. DOI: 10.1002/14651858.CD001019.pub2.
• Dunselman, G., Vermeulen, N., Becker, C., Calhaz-Jorge, C., D'Hooghe, T., & De Bie, B. et al. (2014). ESHRE guideline: management of women with endometriosis. Human Reproduction, 29(3), 400-412. doi: 10.1093/humrep/det457
• Farquhar C, Prentice A, Singla AA, Selak V. Danazol for pelvic pain associated with endometriosis. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD000068. DOI: 10.1002/14651858.CD000068.pub2.
• Ferreira, R., Vieira, C., Rosa-e-Silva, J., Sá Rosa-e-Silva, A., Nogueira, A., & Ferriani, R. (2010). Effects of the levonorgestrel-releasing intrauterine system on cardiovascular risk markers in patients with endometriosis: a comparative study with the GnRH analogue. Contraception, 81(2), 117-122. doi: 10.1016/j.contraception.2009.08.003
• Furness S, Yap C, Farquhar C, Cheong YC. Pre and post‐operative medical therapy for endometriosis surgery. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD003678. DOI: 10.1002/14651858.CD003678.pub2.
• Gomes, M., Ferriani, R., Rosa e Silva, J., Japur de Sá Rosa e Silva, A., Vieira, C., & Cândido dos Reis, F. (2007). The levonorgestrel-releasing intrauterine system and endometriosis staging. Fertility And Sterility, 87(5), 1231-1234. doi: 10.1016/j.fertnstert.2006.11.044
• Hughes E, Brown J, Collins JJ, Farquhar C, Fedorkow DM, Vanderkerchove P. Ovulation suppression for endometriosis for women with subfertility. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD000155. DOI: 10.1002/14651858.CD000155.pub2.
• Moore, A. (2018, July 02). What's the point of paracetamol? Retrieved from https://theconversation.com/whats-the-point-of-paracetamol-66808
• Nawathe A, Patwardhan S, Yates D, et al. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG 2008; 115:818. https://doi.org/10.1111/j.1471-0528.2008.01740.x
• Petta, C., Ferriani, R., Abrao, M., Hassan, D., Rosa e Silva, J., Podgaec, S., & Bahamondes, L. (2005). Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Human Reproduction, 20(7), 1993-1998. doi: 10.1093/humrep/deh869
• Patwardhan, S., Nawathe, A., Yates, D., Harrison, G., & Khan, K. (2008). Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG: An International Journal Of Obstetrics & Gynaecology, 115(7), 818-822. doi: 10.1111/j.1471-0528.2008.01740.x

Kathleen King MSc Biomedical Science, MSc Healthcare Informatics
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