Combined treatment with GnRH analogues and add-back therapy for women with uterine fibroids

Review question

Uterine fibroids may be shrunk with gonadotropin-releasing hormone (GnRH) analogues but commonly cause hot flushes. Combining GnRHa with other drugs may decrease hot flushes (a strategy known as add-back therapy) but cause other problems such as low bone mineral density. The efficacy and safety of this approach is controversial.

Background

Uterine fibroids are benign tumours that arise from the wall of the uterus. Although they are mostly asymptomatic, women with associated symptoms may require treatment. Medical options for treating the condition are limited and, among them, a class of drugs named GnRH analogues is considered effective for decreasing the size of the tumour and for controlling symptoms such as uterine bleeding and pelvic pressure. This class of drugs, however, is limited by its adverse effects, mainly a rise in the incidence of hot flashes and reduced bone mass. Therefore, prolonged treatment is usually not recommended.

Study characteristics

In June 2014, Cochrane authors performed computer searches of the medical literature to locate all relevant studies about this subject, in any language. We found 14 eligible randomized controlled trials. We analysed their data, assessed them for the quality of their methods and precision of their results, and communicated with their authors to obtain additional information and to clarify any doubts about the information.

Key results

Quality of life

Available evidence from 110 women suggested that tibolone may have a very small to large benefit with respect to quality of life when compared with the use of GnRH analogues alone. There was no evidence that raloxifene had an effect on quality of life (data from 74 women). The effect of other add-back agents on quality of life had not been studied.

Bone mass

Evidence from 91 women suggested that raloxifene may have a moderate to large benefit for preserving bone mass when used for up to six months, while tibolone may have a small to moderate bone mass-preserving effect, based on data from 160 women. Estriol (studied in 12 women) and ipriflavone (studied in 95 women) may have had a large effect in decreasing the loss of bone mass associated with the use of GnRH analogues. The effect of medroxyprogesterone (MPA) on bone mass was uncertain.

Vasomotor symptoms

Tibolone may have had a large effect in decreasing vasomotor symptoms (data from 268 women) when compared with the use of GnRH analogues without add-back therapy. MPA may also have decreased vasomotor symptoms (840 to 137 fewer women with vasomotor symptoms per 1000 women, data from 16 women).

Adverse effects

Tibolone could lead to a greater uterine size (increased by 8 cm3 to 39 cm3, data from 365 women) and increased bleeding (data not pooled but studied in 310 patients). MPA may also have resulted in a increased uterine size (by 77 cm3 to 606 cm3, data from 32 women). Conjugated estrogens could also result in greater uterine size (data from 27 women).

Evidence regarding this subject was generally of low quality and higher quality studies are necessary for more robust conclusions to be achieved.

Quality of the evidence

Evidence ranged from very low to moderate quality and the main limitations were risk of bias in the primary studies and imprecision of the estimates. For quality of life, evidence was of low quality for both tibolone and raloxifene. For bone mass, evidence was of moderate quality for tibolone and of low quality for all the other treatments studied.

Authors' conclusions: 

There was low or moderate quality evidence that tibolone, raloxifene, estriol and ipriflavone help to preserve bone density and that MPA and tibolone may reduce vasomotor symptoms. Larger uterine volume was an adverse effect associated with some add-back therapies (MPA, tibolone and conjugated estrogens). For other comparisons, outcomes of interest were not reported or study findings were inconclusive.

Read the full abstract...
Background: 

Uterine fibroids (also known as leiomyomas) are the most common benign pelvic tumours among women. They may be asymptomatic, or may be associated with pelvic symptoms such as bleeding and pain. Medical treatment of this condition is limited and gonadotropin-releasing hormone (GnRH) analogues are the most effective agents. Long-term treatment with such agents, however, is restricted due to their adverse effects. The addition of other medications during treatment with GnRH analogues, a strategy known as add-back therapy, may limit these side effects. There is concern, however, that add-back therapy may also limit the efficacy of the GnRH analogues and that it may not be able to completely prevent their adverse effects.

Objectives: 

To assess the short-term (within 12 months) effectiveness and safety of add-back therapy for women using GnRH analogues for uterine fibroids associated with excessive uterine bleeding, pelvic pain, or urinary symptoms.

Search strategy: 

We searched electronic databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, PubMed, EMBASE, LILACS, CINAHL, PsycINFO; and electronic registries of ongoing trials including ClinicalTrials.gov, Current Controlled Trials, World Health Organization (WHO) International Clinical Trials Registry Platform. All searches were from database inception to 16 June 2014.

Selection criteria: 

Randomized controlled trials (RCTs) that included women with uterine fibroids experiencing irregular or intense uterine bleeding, cyclic or non-cyclic pelvic pain, or urinary symptoms, and that compared treatment with a GnRH analogue plus add-back therapy versus a GnRH analogue alone or combined with placebo were eligible for inclusion.

Data collection and analysis: 

Two authors independently reviewed the identified titles and abstracts for potentially eligible records. Two review authors reviewed eligible studies and independently extracted data. Two authors independently assessed the studies' risk of bias. They assessed the quality of the evidence using GRADE criteria.

Main results: 

Fourteen RCTs were included in the review. Data were extracted from 12 studies (622 women). The primary outcome was quality of life (QoL).

Add-back therapy with medroxyprogesterone (MPA): no studies reported QoL or uterine bleeding. There was no evidence of effect in relation to bone mass (standardized mean difference (SMD) 0.38, 95% confidence interval (CI) -0.62 to 1.38, 1 study, 16 women, P = 0.45, low quality evidence) and MPA was associated with a larger uterine volume (mean difference (MD) 342.19 cm3, 95% CI 77.58 to 606.80, 2 studies, 32 women, I2 = 0%, low quality evidence).

Tibolone: this was associated with a higher QoL but the estimate was imprecise and the effect could be clinically insignificant, small or large (SMD 0.47, 95% CI 0.09 to 0.85, 1 study, 110 women, P = 0.02, low quality evidence). It was also associated with a decreased loss of bone mass, which could be insignificant, small or moderate (SMD 0.36, 95% CI 0.03 to 0.7, 3 studies, 160 women, I2 = 7%, moderate quality evidence). Tibolone may, however, have been associated with larger uterine volumes (MD 23.89 cm3, 95% CI= 8.13 to 39.66, 6 studies, 365 women, I2 = 0%, moderate quality evidence) and more uterine bleeding (results were not combined but three studies demonstrated greater bleeding with tibolone while two other studies demonstrated no bleeding in either group). Four studies (268 women; not pooled owing to extreme heterogeneity) reported a large benefit on vasomotor symptoms in the tibolone group.

Raloxifene: there was no evidence of an effect on QoL (SMD 0.11, 95% CI -0.57 to 0.34, 1 study, 74 women, P = 0.62, low quality evidence), while there was a beneficial impact on bone mass (SMD 1.01, 95% CI 0.57 to 1.45, 1 study, 91 women, P < 0.00001, low quality evidence). There was no clear evidence of effect on uterine volume (MD 27.1 cm3, 95% CI -17.94 to 72.14, 1 study, 91 women, P = 0.24, low quality evidence), uterine bleeding or severity of vasomotor symptoms (MD 0.2 hot flushes/day, 95% CI -0.34 to 0.74, 1 study, 91 women, P = 0.46, low quality evidence).

Estriol: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. Add-back with estriol may have led to decreased loss of bone mass, from results of a single study (SMD 3.93, 95% CI 1.7 to 6.16, 1 study, 12 women, P = 0.0005, low quality evidence).

Ipriflavone: no studies reported QoL, uterine size or uterine bleeding. Iproflavone was associated with decreased loss of bone mass in a single study (SMD 2.71, 95% CI 2.14 to 3.27, 1 study, 95 women, P < 0.00001, low quality evidence); there was no evidence of an effect on the rate of vasomotor symptoms (RR 0.67, 95% Cl 0.44 to 1.02, 1 study, 95 women, P = 0.06, low quality evidence).

Conjugated estrogens: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. One study suggested that adding conjugated estrogens to GnRH analogues resulted in a larger decrease in uterine volume in the placebo group (MD 105.2 cm3, 95% CI 27.65 to 182.75, 1 study, 27 women, P = 0.008, very low quality evidence).

Nine of 12 studies were at high risk of bias in at least one domain, most commonly lack of blinding. All studies followed participants for a maximum of six months. This short-term follow-up is usually insufficient to observe any significant effect of the treatment on bone health (such as the occurrence of fractures), limiting the findings.

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