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INVITATION ARTICLES -  DRUGS IN ENDOMETRIOSIS

DRUGS IN ENDOMETRIOSIS
BY:
Dr.(Mrs). V. Suguna , MD (OBG),
Ex-Prof of OBG, Al- Ameen Med College, Vijayapur.
Was DNB teacher, Civil hospital, Vijayapur
Director, Suguna Maternity Hospital, Vijayapur, Karnataka

Medical management in Endometriosis:
A) Empirical treatment, in suspected cases of endometriosis without a definitive diagnosis, based on the symptoms, after counselling a therapeutic trial of analgesics, progestogens, OCPS, GnRHa may be given for a short term
B) Medical therapy recommended in
1) Prevention of recurrence following surgery and for long term follow up
2) If recurrence occurs
3) In patients who refuse surgery
The medical interventions are
 

*currently available and sufficient evidence to recommend usage
** currently available but insufficient evidence to recommend usage
*** product(s) in development ( basic science or phase I,II,III trails)
Source- Advances in medical management of endometriosis – N.Panay, BJOG 2008; 115: 814-817.

NSAIDs- used as first line treatment for pain.

Mechanism of action: They act by blocking prostaglandin production. They inhibit the action of cyclooxygenase (COX), an enzyme responsible for the formation of prostaglandins. NSAID are non-selective because they inhibit both COX-1 and COX-2 enzymes.

Onset of action: NSAIDs should be started at least 24hours before the onset of pain to block PG production.

Adverse effects: include gastric irritation, ulcers, nausea, vomiting, diarrhoea thus taken with food to reduce gastric side effect. Other side effects are headache, drowsiness, dizziness, dryness of mouth.

Commonly used NSAID:
Fenamate - Mefenemic acid (commonly used NSAID) 500mg once followed by 250mg 6hourly orally. ( US FDA- Category B)
Propionates - Ibuprofen 400mg 6 hourly not to exceed 1.2g per day and Naproxen 500mg followed by 250 mg 6-8hourly orally. (US FDA- Category B)
Acetates -Diclofenac 50mg 8hourly orally. (US FDA –Category –C)

Available evidences are inconclusive to show whether NSAIDs are effective in management of pain in endometriosis, or whether any individual NSAID is more effective than another.

Opioids are stronger painkillers but can be addictive, overtime they work less or higher dosages required

HORMONAL DRUGS
Suppression of ovarian function for 6 months reduces pain. Aim is to induce atrophy of ectopic endometrium, and reduce pain by reducing menstrual blood flow or by inducing amenorrhoea, also prevent the growth of new areas and scars (adhesions). Hormonal manipulation does not affect the primary biological mechanisms of the disease process; therefore medical treatment does not always provide complete pain relief. Symptoms of recurrence are common.

COCs /OCP and Depo MPA can be used long term, but Danazol and GnRH agonists are restricted for 6month because of their side effects.

COCs ( combined oral contraceptive pills) – available COCs in the market usually contain ≤ 35 mcg of ethinylestradiol or 20 mcg in low dose pills and progesterone are levonorgestrel 100-150mcg, norethisterone 500, gestodene 60mcg, desogestrel 75mcg, drosperinone 3mg, nomegestrol 1.25mg, dienogest 1-2mg.

Indication: Used for endometriosis associated pain, dyspareunia, dysmenorrhea and non-menstrual pain.

Duration of treatment: Consider the continuous use of OCP in women suffering from endometriosis for 3 months at a time. Another approach is called as ‘menstrually signalled’ take continuously until experience four days of vaginal spotting or bleeding after which has a four day pill break. Most of the available packs contain 28 days packs with 21 active and 7 inactive, thus the inactive pills are skipped. Evidence support the safety of continuous use for up to 12months

Consider using vaginal contraceptive ring (Nuva ring) delivers 120mcg of etonorgestrel and 15mcg of ethinylestradiol per day to the systemic circulation over a period of 3 week.

Consider Transdermal oestrogen/progesterone patch if the women tend to forget taking oral pills

Side effects:-
Nausea – reduce the oestrogen to low dose, or change to progesterone only pill.
Breast tenderness - reduce Oestrogen / progesterone dose or change to pill containing drosperinone .
Bloating and fluid retention, weight gain - reduce oestrogen or change progesterone to drosperinone.
Headache change dose of oestrogen/progesterone , try oestradial valerate /denogest pill.
Break through bleeding – if on 20 mcg of ethinylestradiol change to 35mcg, consider vaginal ring.

Contraindication: COCs increase the risk of venous thromboembolism, thus contraindicated in women who smoke, increase BMI, immobile patient, personal or family history of thromboembolism or thrombogenic mutations. Pills containing 50mg ethinylestradiol have higher risk. Compared with pills containing levonogestrel, those with desogestrel, gestodene and drospirenone may have a higher risk
COCs are associated with increased risk of myocardial infraction and ischemic stroke

Precautions : women with personal history of arterial disease, obesity, smoking, age over 35years, migraine with aura, diabetes and vascular complications should not use COCs.
US FDA: Category X

Progestogens
Indicated when COCs are contraindicated. Oral progestins with or without oestrogen component have been effective in the treatment of endometriosis. Derivatives of natural progesterone are C17-OH-progesterone ,or derivatives of C19-nortestosterone ( norethisterone, desogestrel, dienogest) used.

Mechanism of action: Progesterone reduces the elevated activity of metalloprotienases and growth factors in the endometriosis, inhibition of blood vessel growth and anti-inflammatory action. The peripheral oestrogen levels are minimized via negative feedback to the hypothalamic-pituitary axis reduces or eliminates pain symptoms.
Long term follow up shows recurrence rate of 50%. Long term medication required, but no data are currently available for progestin therapy lasting longer than 6-12months.

Available as
Medroxyprogestetone acetate (MPA) tab, dosage 10 -30mg a day up to 60mg per day used if necessary
Depot- MPA – IM injection. Dosage- 50mg each week or 100mg every 2 weeks, or 150mg every 2-3months
Subcutaneous implants of MPA 104mg every 3 months
MPA- US FDA: Category X
Subdermal implant of etonogestrol or depot progesterone
Norethisterone- tablet – dosage 2.3 -5mg a day. US FDA : Category X
Dienogest tablet – dosage 2mg -6mg/day.US FDA: Category X
Dydrogesterone tablet - used in patient desiring pregnancy, does not inhibit ovulation , no androgenic side effect. Dosage 10-60mg/day. US FDA: Category D
Levonorgestrel –Intra Uterine System – this device contains 52mg of Levonorgestrel, releases 20mcg per day which is slowly released into the uterus over a period of 5 years. Data show positive effect on endometriosis related pain and also deep infiltrating endometriosis. May be a good option for rectovaginal endometriosis. Pain free continuation rate of 56% in 3 year follow up study.

Side effects- Vary from progestin to progestin depending on their chemical nature and the dosage used. Reducing the dosage to minimum needed to suppress menstruation will often minimise the side effect.

Negative side effect is disturbances of lipid and carbohydrate metabolism and clotting system more seen in C-19 derivatives. Negative influences on mood swings and depression seen in C-17 derivatives. With levonorgestrel spotting, breakthrough bleeding, bloating, weight gain and headache reported. Spotting, bloating and weight gain with MPA. Acne, hot flushes, headache, breast tenderness loss of libido and fatigue with dienogest.

Cochrane review- both progestogen and antiprogestogen gestrinone are effective therapies for the treatment of painful symptoms associated with endometriosis. Continuous high dose of MPA appears effective, luteal phase dydrogesterone is no more effective than placebo.

Gestrinone ( anti progesterone)

Mechanism of action: Gestrinone is a synthetic steroidal hormone which has androgenic, anti-estrogenic and anti progestogenic properties.

Dosage: oral tab 2.5mg twice weekly, start on the first day of menstrual cycle, usually for a period of 6 months.
Administered: may be taken with or without food

Contraindication: metabolic and vascular disorders, thromboembolic disorders, marked hepatic, cardiac kidney dysfunction, undiagnosed genital bleeding, androgen dependent tumours, pregnancy and lactation

Special precautions: conditions which may be adversely affected by fluid retention, history of thrombosis, adolescents, diabetes mellitus, polycythaemia, Withdraw in the event of androgen effects. Monitor liver function during treatment

Adverse drug effect: menstrual disturbances, acne ,oily skin fluid retention, weight gain, hirsutism, voice changes, head ache, GI disturbances, altered libido, hot flushes, breast size reduction, nervousness, change in appetite, muscle cramp, depression, arthralgia, isolated case of benign intracranial tension
 

Drug interaction antiepileptic drugs, rifampicin, oral contraceptives

Lab interference increased liver enzyme
US FDA: Category X

Danazol
Antigonadotropic agent suppresses pituitary-ovarian axis, inhibiting the output of FSH and LH, resulting in regression and atrophy of normal and ectopic endometrial tissue. Has immunological effect, decreases serum Immunoglobulins, autoantibodies, CA 125 levels, increases serum C4 and inhibits IL-1 and TN-F production.

Dosage: oral 200-800mg daily in 2-4 divided doses, adjusted according to response, duration of treatment 3-6months up to 9 months if necessary

Administered: consistently either talways with or without meals.

Vaginal danazol/IUCD loaded with danazol may be an option but not available in India.

Contraindication: Undiagnosed abnormal genital bleeding, androgen dependent tumour, thromboembolic disease, h/o thrombosis, severe cardiac impairment, severe hepatic and renal impairment, pregnancy and lactation.

Special precaution with epilepsy, migraine, DM, polycythaemia, lipoprotein disorder, hepatic and renal impairment
Adverse drug effect: Significant androgen effects (acne, weight gain, hair loss, voice changes, clitoral hypertrophy), peliosis hepatis, benign hepatic adenoma, cholestasis jaundice, benign intracranial HTN.

Nervous- nervousness, emotional liability, headache
CVS- palpitation, tachycardia
RS- interstitial pneumonitis
Genitourinary- vaginal dryness and irritation
Endocrinal- menstrual disturbances
Skin- rash, Steven Johnson’s syndrome, erythema multiforme
Potential fatal – thromboembolism, thrombotic and thrombophlebitic events, including sagittal sinus thrombosis and stroke
US FDA: Category X

GnRH analogues
Produce a hypogonadotrophic-hypogonadic state by down regulation of the pituitary gland. Native GnRH is a decapeptide released from the hypothalamus in a pulsatile fashion. GnRHa is a synthetic peptide structurally analogous to the natural GnRH decapeptide, through the alteration of the amino acids at the 6 and 10 position.

• Longer half life
• Greater receptor affinity
• Greater potency
Commonly used GnRHa are Goserelin and Leuprolide
Goserilin given SC, 3.6mg monthly injection or 10.8mg 3 monthly implant

Leuprolide given IM 300µg/kg monthly ( Leuprolide depot 3.75mg), SC 900µg /kg 3 monthly ( Leuprolide depot 11.25mg)

GnRHa therapy may lead to improvement in pain associated with endometriosis in 85-100% of women, pain relief believed to persist for 6-12months after cessation of treatment.

Side effects: hypoestrogenic state, a major limitation to longer use of GnRHa. Hot flushes (80%), mood changes, insominia, depression, fatigue, vaginal dryness, urogenital atrophy, decreased libido, arthralgia, decreased skin elasticity, breakthrough bleeding. Decreased BMD at a rate of 6% loss in long term use.

Add back Hormone replacement therapy can alleviate the undesirable hypoestrogenic effects of GnRHa and protect against BMD. Also does not reduce the effect of pain relief. Add back therapy involves a low –dose Oestrogen and Progestin. Hypo oestrogenic adverse are significantly less severe in women on oestrogen-progestin add back. Danazol add back effective its adverse effect limits its use. Tibolone showed significant benefit as add back. Calcium regulating agents- Calcitonin insufficient evidence as add back.

Treatment for up to 12months with combined oestrogen-progestogen ‘add back’ appears to be effective n safe in terms of pain relief and BMD protection.
US FDA : Category X

Oral Gonadotropin Releasing Hormone Antagonist
Elagolix is the first and only oral gonadotropin releasing antagonist designed specially for endometriosis and FDA approved. Study proved significant reduction in non-menstrual pain, menstrual pain, and pain during intercourse.

Dose: 150mg once daily for 24months, 200mg twice daily for 6 months. Greater use not recommended due to dose dependent decrease in BMD

Side effects: hot flushes, night seats, headache, nausea, trouble sleeping, anxiety, joint pain, depression and mood swings.
US FDA -Category X

Aromatase inhibitors (AIs)
AIs suppress oestrogen synthesis in the ovaries and in peripheral tissue starting from the next day after dosing. They work by inhibiting the action of aromatase enzyme which converts androgens into oestrogens in the ectopic endometrial lesions and also oestrogen stimulates synthesis of PGE2 a potent inducer of aromatase activity, that triggers the virtuous cycle leasing to new ectopic endometrial tissue and AIs stop this virtuous cycle.

The most potent selective and reversible inhibitors are the third generation AIs ( Anastrozole, Letrozole ) which decrease serum 17β-estradiol by 97-99% as early a 24hours after dosing.

Dosage: Anastrozole 1mg and letrozole 2.5mg can be given daily for 12 weeks with progesterone add back therapy

Side effects: vaginal dryness, hot flushes, headache, back pain, numbness in lower extremities and arthralgia, which is primarily associated with low oestrogen levels.

Limitations of AIs: recurrence after finishing treatment, cost, serious side effects.
AIs used in associated to another hormonal treatment (OCPs, Progestogen, GnRh analogues) only in whom surgical and medical treatment failed.
US FDA -Category X.

Role of Anti angiogenic therapy ( Statins)
Inhibits the growth of endometriosis by their ability to reduce cell viability and migration, inhibiting angiogenesis and anti-inflammatory activity.

Anti angiogenic agents : Atorvastatin 20, 40mg. Simvastin 20mg, TNP-470

Adverse effect: on gonadal activities, steroidogenesis and fertility function, and uncertainties regarding impact on gonadal function may define them as an appropriate therapy in young fertile women. When symptom of endometriosis have been treated by hormones or surgery, antiangiogenic agents may be applied to eradicate residual or microscopic endometriosis.
US FDA- Category X

Selective progesterone receptor modulators (SPRMS):
Progesterone receptor ligands exhibit both progesterone agonistic and antagonistic activities. In the presence of progesterone, show weak antiprogestagenic properties, particularly in endometrium
Mifepristone 50mg daily. Asoprisnil (5mg,10mg,25mg) shown to improve pain and regression of endometriosis implants.

Side effects: headache, abdominal pain tenderness, they induce endometrial change known as progesterone receptor modulator associated endometrial changes (PAECs), the level of oestrogen maintained. BMD not effected.

SPRMs seem to be promising medical treatment in endometriosis, but more number of RCT must to assess the potential benefits.
US FDA- Category X

Anti-tumour necrosis factor-A
Infliximab- a monoclonal anti-tumour antibody. Anti-tumour necrosis factor is a non-hormonal alternative acts by modulating inflammation by TNF-α blockers. There is no enough evidence to recommend anti-tumor necrosis factor in endometriosis.

Immunomodulators
Pentoxifylline shows antiangiogenic effect on endometriotic lesions and does not inhibit ovulation, but no evidence of increase in clinical pregnancy or improvement in pain score. Little evidence to support pentoxyfylline in endometriosis.

Currently hormonal contraceptives, progestogens, anti- progestogens, GnRH agonists and aromatase inhibitors are in clinical use. There are Insufficient data supporting SERMs, SPRMs, anti angiogenic agents, immunomodulators. With no overwhelming evidence to support particular treatment over others, it is important to recognise that the decisions in any treatment plan are individual, and the women is able to make informed choices based on a good understanding of what is happening to her body.

References
1. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. (review article) Brown J,et al. Cochrane Database Syst Rev.2017
2. The efficacy, side effect and continuation rates in women with symptomatic endometriosis undergoing treatment with an intrauterine administered progesterone (levonogestrel)- a 3 year follow , Lockhat F B et al–up. Human Reprod, 20,789-93,2005 ,
3. Progestogens and anti-progestogens for pain associated with endometriosis. Cochrane Database Syst, Rev, 2 CD002122(2000). Keves S, Brown J et al
4. Aromatase inhibitors in the treatment of endometeriosis- R .Slopien . Mar.2016. Przeglad Menopauzalny=Menopause review ,Termedia Publishing.
5. An update on pathophysiology and medical management of endometriosis. Kulvinder Kochar Kaur, Gautam Allahbadia. Advances in reproductive sciences, 2016, 4, 53-73
6. Angiogenesis as a therapeutic target in endometriosis, Dusan DJOKOVIC, carlos CALHAZ-JORGE. Acta Med Port 2014, Jul-Aug ; 27 (4) 489-497.
7. Advances in the medical management of endometriosis. N Panay. BJOG2008; 115; 814-817
8. Management of women with endometriosis .ESHRE Guidelines 2013
9. Good clinical practice recommendations on endometriosis. Under the agesis of FOGSI endometriosis committee 2014-2016
10. Endometriosis: diagnosis and management. NICE Guideline Sept 2017

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