Análogos de la hormona liberadora de gonadotrofina para el dolor asociado con endometriosis
Editorial note
See https://doi.org//10.1002/14651858.CD014788.pub2 for a more recent review that covers this topic and has superseded this review.
Resumen
Antecedentes
La endometriosis es una enfermedad ginecológica común caracterizada por la presencia de tejido endometrial fuera de la cavidad uterina (sin incluir la adenomiosis), que frecuentemente se presenta con dolor. Los análogos de la hormona liberadora de gonadotropina (GnRH) constituyen una intervención que se ha ofrecido para el alivio del dolor en las mujeres premenopáusicas. Los análogos de la GnRH pueden ser administrados de manera intranasal, con una inyección subcutánea o intramuscular. Se piensa que provocan un descenso regulado de la hipófisis e inducen un estado hipogonadal hipogonadotrófico.
Objetivos
Determinar la eficacia y la seguridad de los análogos de la GnRH para el tratamiento de los síntomas dolorosos asociados con la endometriosis.
Métodos de búsqueda
Se realizaron búsquedas electrónicas en el registro especializado del Grupo Cochrane de Trastornos Menstruales y Subfertilidad (Cochrane Menstrual Disorders and Subfertility Group), CENTRAL, MEDLINE, EMBASE, PSYCInfo y CINAHL en abril 2010 para identificar ensayos controlados aleatorios pertinentes (ECA).
Criterios de selección
Se incluyeron ensayos controlados con asignación al azar sobre los análogos de la GnRH como tratamiento para el dolor asociado con la endometriosis versus ningún tratamiento, placebo, danazol, progesterona intrauterina u otros análogos de la GnRH. Se excluyeron ensayos que utilizaron un tratamiento auxiliar, anticonceptivos orales, cirugía, análogos de la GnRH o tratamientos complementarios.
Obtención y análisis de los datos
La evaluación de la calidad y la obtención de los datos se realizó de manera independiente por dos revisores. La medida de resultado primaria fue el alivio del dolor. Se utilizó el riesgo relativo como medida de efecto para los datos dicotómicos. Para los datos continuos, se utilizaron diferencias de medias o diferencias de medias estandarizadas.
Resultados principales
Se incluyeron 41 ensayos (n=4935 mujeres). Las pruebas indicaron que los análogos de la GnRH fueron más efectivos en el alivio de los síntomas que ningún tratamiento o placebo. No hubo diferencias estadísticamente significativas entre los análogos de la GnRH y el danazol para el tratamiento de la dismenorrea CR 0,98 (IC del 95%: 0,92 a 1,04; P = 0,53). Este resultado equivale a tres mujeres menos por 1000 (IC del 95%: 12 a 6) con alivio sintomático del dolor en el grupo de GnRHa. Se informaron más eventos adversos en el grupo de los análogos de la GnRH. Hubo un beneficio en la resolución general de los análogos de la GnRH CR 1,10 (IC del 95%: 1,01 a 1,21; P = 0,03) en comparación con el danazol. No hubo una diferencia estadísticamente significativa en el dolor general entre los análogos de la GnRH y el levonorgestrel (DME ‐0,25; IC del 95%: ‐0,60 a 0,10; P = 0,46). Las pruebas sobre la dosis o la duración óptima del tratamiento para los análogos de la GnRH fueron limitadas. Ninguna vía de administración mostró ser superior a otra.
Conclusiones de los autores
Los análogos de la GnRH demostraron ser más efectivos en el alivio del dolor asociado con la endometriosis que ningún tratamiento o placebo. No hubo pruebas de una diferencia en el alivio del dolor entre los análogos de la GnRH y el danazol, aunque se informaron más eventos adversos en los grupos de análogos de la GnRH. No hubo pruebas de una diferencia en el alivio del dolor entre los análogos de la GnRH y el levonorgestrel, y ningún estudio comparó los análogos de la GnRH con los analgésicos.
PICOs
Resumen en términos sencillos
Análogos de la hormona liberadora de gonadotrofina para el dolor asociado con endometriosis
La endometriosis es una enfermedad común que afecta a mujeres en edad fértil y se debe generalmente a la presencia de tejido endometrial fuera del útero. Los síntomas habituales incluyen dolor e infertilidad. Los análogos de la GnRH son un grupo de fármacos utilizados con frecuencia para tratar la endometriosis, ya que reducen los niveles hormonales. La presente revisión halló pruebas para sugerir que el tratamiento con un análogo de la GnRH mejoró el alivio de los síntomas en comparación con ningún tratamiento o placebo. No hubo pruebas de una diferencia estadísticamente significativa en comparación con el danazol y la progesterona intrauterina. Sin embargo, hubo más efectos secundarios en el grupo del análogo de la GnRH que en el grupo del danazol. No hay pruebas suficientes para manifestar claramente si las dosis mayores o menores del análogo de la GnRH son mejores, o qué duración del tratamiento es mejor.
Conclusiones de los autores
Summary of findings
| GnRHas compared to no treatment for pain associated with endometriosis | ||||||
| Population: women with pain associated with endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| No treatment | GnRHas | |||||
| Relief of painful symptoms ‐ Dysmenorrhoea | 188 per 1000 | 737 per 1000 | RR 3.93 | 35 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 No blinding | ||||||
| GnRHas compared to Placebo for pain associated with endometriosis | ||||||
| Population: women with pain associated with endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | GnRHas | |||||
| Relief of painful symptoms ‐ pelvic tenderness | 160 per 1000 | 667 per 1000 (259 to 1709) | RR 4.17 (1.62 to 10.68) | 49 (1 study) | ⊕⊕⊝⊝ | |
| Pain score ‐ Overall at 4 weeks | The mean overall pain score at 4 weeks was 2.9 points higher in the intervention group (2.11 to 3.69 higher) on a 0‐12 scale | 120 | ⊕⊕⊝⊝ | Endometriosis Symptom Severity Score (ESSS), range 0‐12 points | ||
| *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Evidence based on a single trial, with inadequate explanation of allocation concealment and blinding | ||||||
| GnRHas compared to Danazol for women with pain due to endometriosis | ||||||
| Population: women with pain due to endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Danazol | GnRHas | |||||
| Relief of painful symptoms ‐ Dysmenorrhoea | 825 per 1000 | 809 per 1000 | RR 0.98 | 666 | ⊕⊝⊝⊝ | |
| Overall resolution ‐ Overall resolution/improvement | 596 per 1000 | 655 per 1000 | RR 1.1 | 1046 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Randomisation was inadequately reported in five of the seven trials. Four of the trials failed to described allocation concealment adequately. There was no blinding in two trials and blinding was unclear in two trials. | ||||||
| GnRHas compared to intra‐ uterine progestogen device for pain associated with endometriosis | ||||||
| Population: women with pain associated with endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Intra‐ uterine progestagen device | GnRHas | |||||
| Relief of painful symptoms ‐ Overall | The mean relief of painful symptoms ‐ overall in the intervention groups was | 129 | ⊕⊕⊕⊝ | Standardised mean difference ‐0.25 (‐0.6 to 0.1), indicating no clinically meaningful difference in pain score between the groups | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Two of the three trials were open label and one trial did not provide adequate explanation of allocation concealment | ||||||
Antecedentes
Descripción de la afección
La endometriosis se caracteriza por la presencia de tejido endometrial fuera de la cavidad uterina. Es una enfermedad ginecológica común que afecta a la mujer en su edad reproductiva y que, en general, se considera un trastorno estrógeno dependiente. La mayoría de las observaciones que apoyan esta teoría incluyen la mejoría de la endometriosis preexistente tras la menopausia quirúrgica o natural (Kitawaki 2002), y el crecimiento de tejido endometrial en los animales bajo tratamiento estrogénico (Bruner‐Tran 2002). Mientras que la endometriosis se asocia con la esterilidad (ocasionalmente la causa de la enfermedad) (Prentice 1996), el síntoma más frecuente es el dolor (Barlow 1993). Este dolor puede tomar la forma de dismenorrea (dolor cíclico asociado con la menstruación), dispareunia (dolor durante o después de las relaciones sexuales), dolor pélvico o abdominal. La paciente también puede presentarse con síntomas cíclicos relacionados con endometriosis en sitios fuera de la pelvis.
La patogenia precisa (forma de desarrollo) de la endometriosis aún es incierta, pero es evidente que surge por la diseminación y el establecimiento subsiguiente de depósitos del endometrio en lugares ectópicos (Haney 1991; McLaren 1996). Se supone que la presencia de estos depósitos ectópicos provoca los síntomas asociados con esta enfermedad.
Descripción de la intervención
Los análogos de la hormona liberadora de gonadotropina (GnRH) son una familia de compuestos que difieren de la hormona liberadora de gonadotropina (GnRH) natural, una hormona con diez aminoácidos (decapéptido), por modificaciones en las posiciones seis y diez del decapéptido (Shaw 1991). Se pueden administrar de manera intranasal (IN), por inyección subcutánea (SC) o intramuscular (IM). Algunos de los análogos de la GnRH más frecuentes son: la buserelina, la goserelina, la leuprorelina, la leuprolida, la nafarelina y la triptorelina.
Otros tratamientos comunes para la endometriosis son el uso de analgésicos, danazol, progestágenos (Prentice 2000) que a su vez incluyen sistemas intrauterinos, anticonceptivos orales combinados (Davis 2007), levonorgestrel y tratamientos quirúrgicos (Jacobson 2009).
De qué manera podría funcionar la intervención
El tratamiento farmacológico no analgésico de la endometriosis tiene como objetivo suprimir los depósitos de endometrio ectópico mediante inducción de atrofia del endometrio ectópico dependiente de hormonas (que deja inactivo al tejido endometrial). Se recomienda la inducción de una pseudomenopausia como tratamiento farmacológico de la endometriosis, dado que la misma rara vez se observa en mujeres hipoestrogénicas (con bajos niveles de estrógenos) posmenopáusicas. El uso de los análogos de la GnRH lleva a un descenso regulado (desconexión) de la hipófisis y a la inducción de un estado hipogonadal hipogonadotrófico (bajos niveles de hormonas femeninas debido a la falta de estimulación del ovario) cuando estos son administrados de manera no pulsátil (la hipófisis es estimulada normalmente mediante pulsos de la GnRH natural y todos los análogos actúan sobre ésta a un nivel constante).
Por qué es importante realizar esta revisión
No se conoce cuál es la prevalencia de la endometriosis en la población general, pero se estima que afecta a cerca del 7% de las mujeres en edad reproductiva (Haney 1991). El costo de la endometriosis es alto, tanto en términos económicos como psicosociales (Mathias 1996). La carga económica anual de la endometriosis en los EE.UU. se estima aproximadamente en 22 mil millones de dólares, una suma considerablemente mayor que la de la enfermedad de Crohn (865 millones) o la de la migraña (de 13 a 17 mil millones) (Simoens, 2007). Además, los síntomas asociados con la endometriosis tienen una repercusión negativa sobre el bienestar físico, mental y social (Kennedy 2005).
El tratamiento disponible depende de los recursos existentes, pero también de las preferencias de cada mujer y ginecólogo. Esto se refiere de manera particular a sus decisiones con respecto a la conservación de la fertilidad o las necesidades de anticoncepción. Otros factores incluyen edad, grado de los síntomas y preferencias personales.
La presente revisión evalúa el papel de los análogos de la GnRH para el alivio sintomático del dolor en mujeres con endometriosis.
Objetivos
Determinar la eficacia y la seguridad de los análogos de la GnRH para el tratamiento de los síntomas dolorosos asociados con la endometriosis.
Métodos
Criterios de inclusión de estudios para esta revisión
Tipos de estudios
Se incluyeron sólo ensayos controlados aleatorios (ECA) que comparan el uso de los análogos de la GnRH para el tratamiento de la endometriosis sintomática. Los ensayos cruzados fueron incluidos en la revisión siempre que los datos antes y después del cruzamiento estuvieran disponibles; sólo los datos del primer brazo se utilizaron para el análisis.
Tipos de participantes
Se incluyeron mujeres premenopáusicas con síntomas atribuidos a la endometriosis. El diagnóstico clínico de la endometriosis tuvo que realizarse mediante visualización directa (laparoscopia). Los estudios se incluyeron independientemente de la duración de los síntomas. Los síntomas considerados fueron: dolor cíclico asociado (dismenorrea) o no con la menstruación; dispareunia intensa (dolor durante o después del coito); dolor abdominal bajo o dolor pelviano no relacionado con el ciclo menstrual; dolor con las deposiciones, y otros síntomas dolorosos atribuidos a la endometriosis estudiados en otros ensayos.
Se consideraron los estudios en cualquier escenario (atención primaria o secundaria).
Exclusiones:
-
Mujeres con enfermedad asintomática o esterilidad como único motivo de consulta existente.
-
Endometriosis autoinformada
-
Ensayos en donde se administró el análogo de la GnRH como tratamiento complementario a las participantes posquirúrgicas
Tipos de intervenciones
Se incluyeron ensayos aleatorios que informan las siguientes comparaciones:
-
Ensayos que comparan los análogos de la GnRH versus ningún tratamiento para el alivio de los síntomas dolorosos asociados con la endometriosis y los efectos adversos relacionados
-
Ensayos que comparan los análogos de la GnRH versus el placebo para el alivio de los síntomas dolorosos asociados con la endometriosis y los efectos adversos relacionados
-
Ensayos que comparan los análogos de la GnRH versus los analgésicos para el alivio de los síntomas dolorosos asociados con la endometriosis y los efectos adversos relacionados
-
Ensayos que comparan los análogos de la GnRH versus el danazol para el alivio de los síntomas dolorosos asociados con la endometriosis y los efectos adversos relacionados
-
Ensayos que comparan los análogos de la GnRH versus la progesterona intrauterina para el alivio de los síntomas dolorosos asociados con la endometriosis y los efectos adversos relacionados
-
Ensayos que comparan diferentes dosis de los análogos de la GnRH para el alivio de los síntomas dolorosos asociados con la endometriosis y los efectos adversos relacionados
-
Ensayos que comparan diferentes períodos de duración del tratamiento de los análogos de la GnRH para el alivio de los síntomas dolorosos asociados con la endometriosis y los efectos adversos relacionados
-
Ensayos que comparan diferentes vías de administración de los análogos de la GnRH para el alivio de los síntomas dolorosos asociados con la endometriosis y los efectos adversos relacionados
-
Ensayos que comparan diferentes regímenes de tratamiento de los análogos de la GnRH para aliviar los síntomas dolorosos asociados con la endometriosis y los efectos adversos relacionados
Exclusiones:
-
Ensayos que comparan los análogos de la GnRH versus los análogos de la GnRH en combinación con un tratamiento auxiliar, ya que se realizará otra revisión sobre este tema
-
Ensayos que comparan los análogos de la GnRH con los anticonceptivos orales combinados (Davis 2007), los progestágenos orales o inyectables (Prentice 2000) o los tratamientos quirúrgicos (Jacobson 2009), ya que se tratan en otras revisiones.
-
Ensayos que comparan a los análogos de la GnRH con los antagonistas de los análogos de la GnRH, ya que ese es el título registrado de una revisión que realizará el Grupo de Trastornos Menstruales y Subfertilidad de la Colaboración Cochrane (Menstrual Disorders and Subfertility Group).
-
Ensayos que comparan los análogos de la GnRH con la medicina alternativa y complementaria
Tipos de medida de resultado
Resultados primarios
-
Alivio del dolor definido al usar ambas medidas cuantitativas como las escalas analógicas visuales o los resultados categóricos al final del tratamiento y cuando sea posible dentro de los tres, seis, nueve, doce y veinticuatro meses de seguimiento.
Resultados secundarios
-
Efectos adversos (p.ej., sofocos, insomnio, reducción de la libido, sequedad vaginal y cefaleas), tanto los que se producen durante el tratamiento (a corto plazo) como los que se prolongan más allá del período de tratamiento (a largo plazo)
-
Resolución de la endometriosis definida por un cambio en la puntuación revisada por la American Fertility Society (AFS) y evaluada a través de una segunda laparoscopia (mayor puntuación significa mayor intensidad)
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Calidad de vida y otros factores que afectan la calidad de vida
-
Uso adicional de analgésicos
La relación entre el costo y la efectividad no fue un resultado de esta revisión.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies;Characteristics of studies awaiting classification
Results of the search
762 records were identified using the search strategy. After initial screening 124 full‐text records were retrieved for more in‐depth analysis. 43 randomised controlled trials were included in the meta‐analysis, 82 studies were excluded. Two studies (Chan 1993; Chen 2009) are currently awaiting classification. These studies are not included in the meta‐analysis.
Included studies
Forty‐two randomised controlled trials met our eligibility criteria and were included in this review (Adamson 1994; Agarwal 1997; AN Zoladex 1996; Audebert 1997; Bergqvist 1997; Bergqvist 1998; Burry 1992; Chang 1996; Cheng 2005; Cirkel 1995; Claesson 1989; Dawood 1990; Dlugi 1990; Dmowski 1989a; Fedele 1989; Fedele 1993;Ferreira 2010; Fraser 1991; Gomes 2007; Henzl 1988; Henzl 1990a; Hornstein 1995; Jelley 1986; Lemay 1988; Matta 1988; Miller 1990; Miller 2000; Minaguchi 1986; Moghissi 1987; NEET 1992; Odukoya 1995; Palagiano 1994; Petta 2005; Rock 1993; Rolland 1990; Shaw 1986; Shaw 1990; Shaw 1992; Skrzypulec 2004; Tummon 1989; Wheeler 1992; ). See Characteristics of included studies for description.
Five trials were included in two comparisons. Adamson 1994, Henzl 1988 and Moghissi 1987 compared varying dosage of GnRHa in addition to a comparison with danazol, while Dawood 1990 and Dmowski 1989a compared varying route of administration of GnRHa in addition to its comparison with danazol.
Excluded studies
Of the 83 studies that were excluded,
22 studies did not have relief of pain as an outcome (Acien 1989a; Bergquist 1990a;Burry 1989a; Calvo 2000a; de Sa Rosa e Silva 2006a; Donnez 1989a; el‐Roeiy 1988a; Fedele 1993b; Franssen 1992a; Maouris 1989; Maouris 1991a; Matalliotakis 2000a; Matalliotakis 2004a;Ochs 1993;Rotondi 2002a; Roux 1995; Surrey 1993; Tapanainen 1993; Valimaki 1989a; Vieira 2007a; Wright 1995a; Yee 1986),
19 studies did not make comparisons with GnRHas that fitted our 'Types of Interventions' protocol, see Types of interventions for detail. Choktanasiri 2001a; Cooke 1989;Crosignani 1996a; Dmowski 1989; Donnez 2004; Franke 2000; Kiesel 1989; Kiilholma 1995; Luciano 2004; Magini 1993; Newton 1996; Surrey 1995; Surrey 2002; Tahara 2000; Taskin 1997; Toomey 2003; Vercellini 1994; Warnock 1998; Zupi 2005),
five studies looked at the outcome in post‐surgical participants (Adiyono 2006; Harada 2000; Ling 1999; Vercellini 2009; Ylikorkala 1995),
endometriosis was not the main condition discussed in four studies (Fraser 1996; Shaw 2001; Sorensen 1997; Sowter 1997)
Risk of bias in included studies
Details on the quality of each individual study are described in the table 'Characteristics of included studies' where the individual quality criteria were rated for each study.
Authors have been contacted for more information when required.
See Figure 1 for 'risk of bias' table and Figure 2 for 'risk of bias' graph.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
In nine trials method of allocation concealment was adequately described (Audebert 1997; Cheng 2005; Gomes 2007; Hornstein 1995; Jelley 1986; Odukoya 1995; Petta 2005; Shaw 1992; Skrzypulec 2004).
Blinding
Twenty trials had adequate blinding where the participants and investigators were blinded by the use of an identical placebo (Adamson 1994; Agarwal 1997; Bergqvist 1997; Bergqvist 1998;Chang 1996; Cheng 2005; Dlugi 1990; Fraser 1991; Henzl 1988; Hornstein 1995;Lemay 1988;Miller 1990; Moghissi 1987; NEET 1992; Petta 2005; Rolland 1990; Shaw 1990; Skrzypulec 2004; Wheeler 1992; Wheeler 1993). 11 trials were open‐trials where there were no blinding (Audebert 1997; Dawood 1990; Dmowski 1989a; Fedele 1993;Ferreira 2010; Gomes 2007; Jelley 1986; Matta 1988; Palagiano 1994; Rock 1993; Shaw 1992). The remaining trials had unclear information or no details on blinding.
Incomplete outcome data
Only one trial did not have adequate reporting of attrition (Chang 1996). No trials lost more than 20% of the original sample during follow up.
Selective reporting
All of the included trials (n=42) reported on their stated primary outcomes and had no additional outcomes that were not stated in their methods section.
Other potential sources of bias
All studies reported baseline equality between groups with respect to age and stage of endometriosis.
Effects of interventions
See: Summary of findings 1 GnRHas compared to No treatment for pain associated with endometriosis; Summary of findings 2 GnRHas compared to Placebo for pain associated with endometriosis; Summary of findings 3 GnRHas compared to Danazol for women with pain due to endometriosis; Summary of findings 4 GnRHas compared to intra‐ uterine progestogen device for pain associated with endometriosis
1. GnRHas versus no treatment
There was only one study which compared GnRHas with no treatment (Fedele 1993) for the outcome of relief of painful symptoms (dysmenorrhoea) . The evidence suggested a statistically significant benefit for GnRHa compared with no treatment for the relief of the pain of dysmenorrhoea associated with endometriosis RR 3.93 (95% CI 1.37 to 11.28, P=0.01). No data were reported on adverse effects.
2. GnRHas versus placebo
Five studies were identified which compared GnRHas with placebo (Bergqvist 1998, Dlugi 1990, Miller 1990, Miller 2000, Skrzypulec 2004). Only Bergqvist 1998 and Miller 2000 provided usable data.
Bergqvist 1998 demonstrated that there was a statistically significant benefit in favour of GnRHas for the relief of pelvic tenderness RR 4.17 (95% CI 1.62 to 10.68, P=0.003) but no statistically significant differences between groups for dyspareunia (RR 1.16; 95%CI 0.57 to 2.34) or defecation pressure (RR 11.44; 95%CI 0.67 to 196.30). GnRHas appeared to be associated with greater incidence of sleep disturbances (20/24) compared with placebo (9/25), RR 2.31 (95% CI 1.33 to 4.02, P=0.003).
Miller 2000 evaluated pain, using the Endometriosis Symptom Severity Score (ESSS) during the stimulatory phase of GnRHa therapy and found evidence which suggested a significant increase in ESSS with GnRHa therapy compared to placebo with a MD 2.90 (95% CI 2.11 to 3.69, P<0.001).
3. GnRHas versus analgesics
No studies comparing GnRHas and analgesics were identified
4. GnRHas versus danazol
Twenty seven studies compared a GnRHa with danazol (Adamson 1994, AN Zoladex 1996, Audebert 1997, Burry 1992, Chang 1996, Cheng 2005, Cirkel 1995, Claesson 1989, Dawood 1990, Dmowski 1989a, Fedele 1989, Fraser 1991, Henzl 1988, Henzl 1990a, Jelley 1986, Matta 1988, Moghissi 1987, NEET 1992, Odukoya 1995, Palagiano 1994, Rock 1993, Rolland 1990, Shaw 1990, Shaw 1992, Tummon 1989, Wheeler 1992, Wheeler 1993).
Dichotomous data indicated no evidence of a statistically significant difference between groups for the effectiveness of pain relief in dysmenorrhoea (Adamson 1994;Cirkel 1995; Fedele 1989;Matta 1988;NEET 1992; Palagiano 1994; Wheeler 1992) RR 0.98 (95% CI 0.92 to 1.04, P=0.53); dyspareunia (Adamson 1994; Cirkel 1995; Fedele 1989; Jelley 1986; Matta 1988; NEET 1992; Palagiano 1994) RR 1.02 (95% CI 0.93 to 1.12, P=0.69); pelvic pain (Adamson 1994; Cirkel 1995; Fedele 1989; Matta 1988; NEET 1992; Palagiano 1994; Wheeler 1992) RR 0.96 (95% CI 0.86 to 1.07, P=0.47); induration (Cirkel 1995; NEET 1992) RR 1.10 (95% CI 0.94 to 1.29, P=0.23) and pelvic tenderness (Cheng 2005; NEET 1992; Wheeler 1992) RR 0.98 (95% CI 0.88 to 1.09, P=0.70). Refer to Figure 3. Continuous data from four studies (Cheng 2005; Dmowski 1989a; Tummon 1989; Fraser 1991) also indicated no statistically significant differences between GnRHas and danazol. Refer to Figure 4
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.1 Relief of painful symptoms.
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.3 Relief of painful symptoms.
Overall resolution was reported in nine studies ( AN Zoladex 1996; Audebert 1997; Burry 1992; Claesson 1989; Henzl 1988; NEET 1992; Palagiano 1994; Rolland 1990; Shaw 1990) the evidence suggested a benefit in resolution in those groups receiving GnRHas RR1.10 (95% CI 1.01 to 1.21, P=0.03). Refer to Figure 5.
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.2 Overall resolution.
The outcome of improved Retrospective American Fertility Society (rAFS) score was compared by four studies (Burry 1992, Henzl 1988, Matta 1988, Rock 1993). This score measures the incidence, extent and severity of endometriosis. There was no evidence to suggest any statistically significant differences between GnRHas (248/488) compared with danazol (109/244), RR 1.14 (95% CI 0.98 to 1.32, P=0.08). The rAFS score at approximately 24 weeks follow up was recorded by ten studies [Cheng 2005, Cirkel 1995, Claesson 1989, Dmowski 1989a, Fedele 1989, Fraser 1991, Henzl 1990a, NEET 1992, Shaw 1992, Tummon 1989]. They found no evidence of a statistically significant difference between groups, SMD ‐0.01 (95% CI ‐0.12 to 0.15, P=0.85).
There were 39 different side effects reported by 19 studies (AN Zoladex 1996, Audebert 1997, Burry 1992, Chang 1996, Cheng 2005, Cirkel 1995, Dawood 1990, Dmowski 1989a, Fedele 1989, Fraser 1991, Henzl 1988, Jelley 1986, Matta 1988, NEET 1992, Palagiano 1994, Rock 1993, Rolland 1990, Shaw 1992, Wheeler 1993).
Five of the most commonly reported side effects were vaginal dryness, hot flushes, headaches, weight gain and acne. Side effects were more frequently reported in groups receiving GnRHas than those receiving danazol. Vaginal dryness was compared in 16 studies, the evidence suggested a significant between GnRHas (444/1266) and danazol (146/802), RR 1.96 (95% CI 1.68 to 2.30, P<0.00001). Nineteen studies looked at hot flushes and found a significant difference between GnRHas (1410/1646) and danazol (537/991), RR 1.55 (95% CI 1.47 to 1.65, P<0.00001), however heterogeneity is high at I²=73%. Headaches were compared in 16 studies and a statistically significant benefit was found in favour of GnRHas (380/1303) compared to danazol (173/799), RR 1.40 (95% CI 1.22 to 1.61, P<0.00001). Weight gain was reported in 12 studies that found evidence to suggest a statistically significant increase in danazol (206/675) compared to GnRHas (60/1088) RR 0.20 (95% CI 0.16 to 0.26, P<0.00001), heterogeneity was high at I²= 78%. Acne was reported by 13 studies and evidence suggested a statistically significant increase in danazol (202/747) compared to GnRHas (198/1218) RR 0.55 (95% CI 0.47 to 0.65), heterogeneity high at I²=75%. Refer to Figure 6.
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.6 Side effects.
5. GnRHas versus intra‐uterine progestogen (LNG‐IUS)
Three studies were included that compared GnRHas with LNG IUS(Ferreira 2010; Gomes 2007, Petta 2005).
There was no evidence of a statistically significant difference in overall pain score between GnRHas and LNG IUS SMD ‐0.25 favouring GnRHas (95% CI ‐0.60 to 0.10, P=0.46). One study (Gomes 2007) also looked at the rAFS score and appeared to have found no statistically significant difference between GnRHas and LNG IUS SMD 9.50 favouring LNG IUS (95% CI ‐10.77 to 29.7, P=0.36).
6. GnRHa versus GnRHa (varying dosage)
Six studies were identified that compared varying doses of GnRHas:
Bergqvist 1997 compared 200mcg vs 400mcg nafarelin daily.
Adamson 1994, Henzl 1988 and Moghissi 1987 compared 400mcg vs 800mcg nafarelin daily.
Minaguchi 1986 compared 300mcg vs 600mcg daily, 300mcg vs 900mcg buserelin daily as well as 600mcg vs 900mcg daily which Shaw 1986 also compared.
Three studies (Adamson 1994, Henzl 1988, Minaguchi 1986) compared the relief of painful symptoms.The evidence suggested there was no statistically significant differences between the two groups for any outcome (Refer to Figure 7).
Forest plot of comparison: 6 GnRHa versus GnRHa (Varying Dosage), outcome: 6.3 relief of painful symptoms.
One study (Henzl 1988) reported on improvement in rAFS score during a 6 months follow up after treatment and found evidence of a significant difference between low (6/73) and high (14/70) groups, RR 0.41 (95% CI 0.17 to 1.01, P=0.05). Refer to Figure 8
Forest plot of comparison: 6 GnRHa versus GnRHa (Varying Dosage), outcome: 6.2 rAFS score (400mcg vs 800mcg).
One study Bergqvist 1997) looked at the side effects (hot flushes, sleep disturbances, rhinitis and upper respiratory tract infections) between 200 micrograms daily of GnRHa compared with 400 micrograms daily. The study did not find any evidence to suggest there was any significance in any of the side effects: hot flushes 7/12 for both groups, RR 1.0 (95% CI 0.51 to 1.97); sleep disturbances 9/12 for both groups, RR 1.0 (95% CI 0.63 to 1.59); rhinitis 2/12 200mcg/d versus 5/12 400mcg/d, RR 0.40 (95% CI 0.10 to 1.67) and URTI 1/12 200mcg/d versus 5/12 400mcgd, RR 0.20 (95% CI 0.03 to 1.47).
7. GnRHa versus GnRHa (varying length of treatment)
Hornstein 1995 was the only study to look at relief of painful symptoms for varying length of treatment of GnRHas. The author examined the effect of relief of dysmenorrhoea, dyspareunia, pelvic pain, pelvic tenderness and pelvic induration. Refer to Figure 9. The only outcome to show a statistically significant difference was dyspareunia MD ‐0.98 (95%CI ‐1.29 to ‐0.66; P<0.00001) in favour of a shorter duration.
Forest plot of comparison: 7 GnRHa versus GnRHa (Length of Treatment), outcome: 7.1 Relief of Painful Symptoms (3months vs 6months) at 6 months follow up.
8. GnRHa versus GnRHa (varying routes of administration)
Four studies were included that compared varying routes of administration of GnRHa.
Agarwal 1997 compared intra‐nasal (IN) vs intramuscular (IM) depot while Dawood 1990, Dmowski 1989a and Lemay 1988 all compared IN vs subcutaneous (SC) daily.
There was no evidence of a statistically significant difference between IN and IM depot for the relief of painful symptoms associated with endometriosis. The same study had no evidence to suggest there was a statistically significant difference between the episodes of hot flushes experienced in the IN (95/98) or IM depot (93/93) group RR 0.97 (95% CI 0.93 to 1.01, P=0.14).
In the comparison between IN and SC for the relief of painful symptoms associated with endometriosis, there was no evidence to suggest a statistically significant difference for the effectiveness of pain relief between the groups (Lemay 1988) for pelvic pain (RR 1.0; 95%CI 0.53 to 1.87), dyspareunia (RR 1.0; 95%CI 0.57 to 1.75), dysmenorrhoea (RR 1.22; 95%CI 0.75 to 2.06), pelvic tenderness (RR 1.55, 95%CI 0.69 to 3.27), pelvic induration (RR 0.86, 95%CI 0.47 to 1.55). There was also no evidence for a statistically significant difference in the rAFS score between groups MD 9.00 (95% CI ‐5.93 to 23.93, P=0.24). There was no evidence to suggest any statistically significant differences in adverse effects experienced between the two groups. Hot flushes were encountered in 5/7 IN and 5/6 SC, RR 0.86 (95% CI 0.48 to 1.55, P=0.62); vaginal dryness in 2/7 IN and 2/6 SC, RR 0.86 (95% CI 0.17 to 4.37, P=0.85); headaches in 2/7 IN and 1/6 SC, RR 1.71 (95% CI 0.20 to 14.55, P=0.62) and decreased libido in 1/7 IN and 1/6 SC, RR 0.86 (95% CI 0.07 to 10.96, P=0.91).
Discusión
Resumen de los resultados principales
Los análogos de la GnRH parecen ser más efectivos para el alivio del dolor asociado con la endometriosis (sensibilidad al tacto en la pelvis y la ESSS) que ningún tratamiento o placebo. No hubo pruebas de una diferencia en el alivio del dolor entre los análogos de la GnRH y el danazol (dismenorrea, dispareunia, dolor pélvico, induración pélvica, sensibilidad al tacto en la pelvis), aunque se informaron más eventos adversos en los grupos del análogo de la GnRH. No hubo pruebas de una diferencia en el alivio del dolor general entre los análogos de la GnRH y el levonorgestrel, y ningún estudio comparó los análogos de la GnRH con los analgésicos.
Cabe señalar que el costo del danazol es en general menor que el de los análogos de la GnRH, pero anecdóticamente el uso del danazol ha disminuido con el transcurso del tiempo, ya que provoca un efecto secundario irreversible: el cambio de la voz (Matabese 2009).
No existen pruebas suficientes para establecer conclusiones con respecto a los beneficios de las dosis variables o la duración del tratamiento. La vía de administración no parece ser un factor importante en la obtención de beneficios.
Compleción y aplicabilidad general de las pruebas
A pesar de que se intentó establecer contacto con los autores, quedan aún algunos datos que no pueden ser incluidos en el análisis. Los revisores han intentado obtener todo el material relevante publicado y no publicado con respecto a los objetivos de la revisión. Un asunto de interés es el método de informe del dolor en los ensayos. Algunos ensayos informan dolor general, mientras que otros proporcionan detalles sobre la endometriosis específica asociada con el dolor que incluye dismenorrea, dispareunia, dolor pélvico, induración pélvica y sensibilidad al tacto en la pelvis. Puede haber algún escepticismo al generalizar el alivio del dolor y la inquietud, cuando los ensayos no informan todas las subcategorías del dolor.
Calidad de la evidencia
Ésta era una revisión sistemática de 41 ensayos que incluían a 4742 mujeres. La calidad general de los estudios es razonable. Los estudios anteriores carecen de claridad en la asignación al azar y la ocultación de la asignación, y con frecuencia, fue difícil establecer contacto con los autores.
Sesgos potenciales en el proceso de revisión
La obtención de datos adicionales de otros autores ha resultado difícil debido a la antigüedad de algunos de los estudios. Los datos brutos estaban frecuentemente extraviados o no disponibles. Una fuente de sesgo fue la inconsistencia en el informe de los eventos adversos.
Acuerdos y desacuerdos con otros estudios o revisiones
El tema de otra revisión registrada Cochrane es el uso de un tratamiento auxiliar para aliviar los síntomas, y el riesgo de desmineralización ósea con los análogos de la GnRH se trata en la revisión realizada por Sagsveen 2003.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.1 Relief of painful symptoms.
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.3 Relief of painful symptoms.
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.2 Overall resolution.
Forest plot of comparison: 4 GnRHas versus danazol, outcome: 4.6 Side effects.
Forest plot of comparison: 6 GnRHa versus GnRHa (Varying Dosage), outcome: 6.3 relief of painful symptoms.
Forest plot of comparison: 6 GnRHa versus GnRHa (Varying Dosage), outcome: 6.2 rAFS score (400mcg vs 800mcg).
Forest plot of comparison: 7 GnRHa versus GnRHa (Length of Treatment), outcome: 7.1 Relief of Painful Symptoms (3months vs 6months) at 6 months follow up.
Comparison 1: GnRHas versus no treatment, Outcome 1: Relief of painful symptoms
Comparison 2: GnRHas versus placebo, Outcome 1: Relief of painful symptoms
Comparison 2: GnRHas versus placebo, Outcome 2: Side effects
Comparison 2: GnRHas versus placebo, Outcome 3: Pain score
Comparison 3: GnRHas versus danazol, Outcome 1: Relief of painful symptoms
Comparison 3: GnRHas versus danazol, Outcome 2: Overall resolution
Comparison 3: GnRHas versus danazol, Outcome 3: Relief of painful symptoms
Comparison 3: GnRHas versus danazol, Outcome 4: rAFS
Comparison 3: GnRHas versus danazol, Outcome 5: Improved rAFS score
Comparison 3: GnRHas versus danazol, Outcome 6: Side effects
Comparison 4: GnRHas versus intra‐ uterine progestagen device, Outcome 1: Relief of painful symptoms
Comparison 4: GnRHas versus intra‐ uterine progestagen device, Outcome 2: rAFS/ASRM score
Comparison 5: GnRHa versus GnRHa (Varying Dosage), Outcome 1: Side effects
Comparison 5: GnRHa versus GnRHa (Varying Dosage), Outcome 2: rAFS score (400mcg vs 800mcg)
Comparison 5: GnRHa versus GnRHa (Varying Dosage), Outcome 3: relief of painful symptoms
Comparison 6: GnRHa versus GnRHa (Length of Treatment), Outcome 1: Relief of Painful Symptoms (3months vs 6months) at 6 months follow up
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 1: Side effects (IN vs SC)
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 2: rAFS score (IN vs SC)
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 3: Relief of painful symptoms (IN versus IMdepot)
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 4: Side effects (IN versus IMdepot)
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 5: Improvement in symptoms (IN versus IMdepot)
Comparison 7: GnRHa versus GnRHa (Route of Administration), Outcome 6: Relief of painful symptoms (IN versus SC)
| GnRHas compared to no treatment for pain associated with endometriosis | ||||||
| Population: women with pain associated with endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| No treatment | GnRHas | |||||
| Relief of painful symptoms ‐ Dysmenorrhoea | 188 per 1000 | 737 per 1000 | RR 3.93 | 35 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 No blinding | ||||||
| GnRHas compared to Placebo for pain associated with endometriosis | ||||||
| Population: women with pain associated with endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | GnRHas | |||||
| Relief of painful symptoms ‐ pelvic tenderness | 160 per 1000 | 667 per 1000 (259 to 1709) | RR 4.17 (1.62 to 10.68) | 49 (1 study) | ⊕⊕⊝⊝ | |
| Pain score ‐ Overall at 4 weeks | The mean overall pain score at 4 weeks was 2.9 points higher in the intervention group (2.11 to 3.69 higher) on a 0‐12 scale | 120 | ⊕⊕⊝⊝ | Endometriosis Symptom Severity Score (ESSS), range 0‐12 points | ||
| *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Evidence based on a single trial, with inadequate explanation of allocation concealment and blinding | ||||||
| GnRHas compared to Danazol for women with pain due to endometriosis | ||||||
| Population: women with pain due to endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Danazol | GnRHas | |||||
| Relief of painful symptoms ‐ Dysmenorrhoea | 825 per 1000 | 809 per 1000 | RR 0.98 | 666 | ⊕⊝⊝⊝ | |
| Overall resolution ‐ Overall resolution/improvement | 596 per 1000 | 655 per 1000 | RR 1.1 | 1046 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Randomisation was inadequately reported in five of the seven trials. Four of the trials failed to described allocation concealment adequately. There was no blinding in two trials and blinding was unclear in two trials. | ||||||
| GnRHas compared to intra‐ uterine progestogen device for pain associated with endometriosis | ||||||
| Population: women with pain associated with endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Intra‐ uterine progestagen device | GnRHas | |||||
| Relief of painful symptoms ‐ Overall | The mean relief of painful symptoms ‐ overall in the intervention groups was | 129 | ⊕⊕⊕⊝ | Standardised mean difference ‐0.25 (‐0.6 to 0.1), indicating no clinically meaningful difference in pain score between the groups | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Two of the three trials were open label and one trial did not provide adequate explanation of allocation concealment | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Relief of painful symptoms Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Dysmenorrhoea | 1 | 35 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.93 [1.37, 11.28] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Relief of painful symptoms Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1.1 pelvic tenderness | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.17 [1.62, 10.68] |
| 2.1.2 Dyspareunia | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.16 [0.57, 2.34] |
| 2.1.3 Defecation pain/pressure | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 11.44 [0.67, 196.30] |
| 2.2 Side effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.2.1 Hot flushes/flashes | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.62 [0.87, 3.02] |
| 2.2.2 Sleep disturbances | 1 | 49 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.31 [1.33, 4.02] |
| 2.3 Pain score Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.3.1 Overall at 4 weeks | 1 | 120 | Mean Difference (IV, Fixed, 95% CI) | 2.90 [2.11, 3.69] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Relief of painful symptoms Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1.1 Dysmenorrhoea | 7 | 666 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.92, 1.04] |
| 3.1.2 Dyspareunia | 7 | 431 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.93, 1.12] |
| 3.1.3 Pelvic pain | 7 | 647 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.86, 1.07] |
| 3.1.4 Induration | 2 | 116 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.94, 1.29] |
| 3.1.5 Pelvic tenderness | 3 | 404 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.88, 1.09] |
| 3.2 Overall resolution Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.2.1 Overall resolution/improvement | 9 | 1046 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [1.01, 1.21] |
| 3.3 Relief of painful symptoms Show forest plot | 4 | Std. Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.3.1 Overall 90 days | 1 | 59 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.13 [‐0.64, 0.38] |
| 3.3.2 Overall 180 days | 3 | 103 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.30, 0.50] |
| 3.3.3 Dsypareunia | 1 | 49 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.19 [‐0.41, 0.79] |
| 3.3.4 Pelvic pain | 1 | 49 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐0.60, 0.60] |
| 3.3.5 Pelvic tenderness | 1 | 49 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.19 [‐0.79, 0.41] |
| 3.3.6 Pelvic induration | 1 | 49 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐0.60, 0.60] |
| 3.4 rAFS Show forest plot | 10 | 1012 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.01 [‐0.13, 0.12] |
| 3.4.1 change at 180 days | 1 | 59 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.30 [‐0.81, 0.21] |
| 3.4.2 24 weeks | 9 | 953 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.12, 0.15] |
| 3.5 Improved rAFS score Show forest plot | 4 | 732 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.98, 1.32] |
| 3.6 Side effects Show forest plot | 18 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.6.1 vaginal dryness/vaginitis | 15 | 1798 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.04 [1.72, 2.42] |
| 3.6.2 Hot flushes/flashes | 18 | 2367 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.55 [1.46, 1.65] |
| 3.6.3 Headaches | 15 | 1832 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [1.21, 1.64] |
| 3.6.4 Infections and flu like symptoms | 1 | 71 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.60 [1.31, 9.88] |
| 3.6.5 Muscle cramps/myalgia | 10 | 1537 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.06, 0.18] |
| 3.6.6 Sleep disturbance | 6 | 679 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.87 [1.46, 2.39] |
| 3.6.7 Skin rash | 3 | 324 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.10 [0.02, 0.51] |
| 3.6.8 Gastrointestinal | 4 | 363 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.26, 1.05] |
| 3.6.9 Weight gain | 11 | 1493 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.16 [0.11, 0.21] |
| 3.6.10 Acne | 12 | 1695 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.42, 0.58] |
| 3.6.11 Breast atrophy/changes | 7 | 1035 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.47, 0.76] |
| 3.6.12 Emotional lability/altered mood | 3 | 534 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.60, 1.61] |
| 3.6.13 Oedema/fluid retention | 5 | 626 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.10 [0.05, 0.20] |
| 3.6.14 Asthenia | 5 | 781 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.23, 0.58] |
| 3.6.15 Bleeding | 3 | 161 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.12, 0.48] |
| 3.6.16 Depression | 5 | 513 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.38, 0.99] |
| 3.6.17 Leukorrhoea | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.23, 4.71] |
| 3.6.18 chest pain | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.23 [0.39, 134.16] |
| 3.6.19 Generalised spasm | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.08 [0.00, 1.35] |
| 3.6.20 pharyngitis | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.74] |
| 3.6.21 Voice alteration | 2 | 114 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.16 [0.02, 1.27] |
| 3.6.22 vulvovaginal disorder | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.01, 2.74] |
| 3.6.23 Hirsutism | 6 | 866 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.11, 0.39] |
| 3.6.24 Seborrhoea | 6 | 835 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.33, 0.53] |
| 3.6.25 Alopecia | 2 | 365 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.02, 0.53] |
| 3.6.26 Altered libido | 9 | 1620 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.88, 1.24] |
| 3.6.27 Sweating | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.28 [0.03, 2.51] |
| 3.6.28 Breast tenderness | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.04, 4.33] |
| 3.6.29 Fatigue | 2 | 84 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.40, 1.26] |
| 3.6.30 Arthralgia | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 17.61 [1.08, 286.40] |
| 3.6.31 Hunger | 1 | 55 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.05 [0.00, 0.81] |
| 3.6.32 Nervousness | 2 | 504 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.20, 1.02] |
| 3.6.33 Irritability | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.74 [1.67, 13.45] |
| 3.6.34 Clitoromegaly | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.14 [0.01, 2.59] |
| 3.6.35 Appetite increase | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.09 [0.01, 1.54] |
| 3.6.36 Fatigue/malaise | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.19 [0.06, 0.61] |
| 3.6.37 Dizziness | 1 | 67 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.24 [0.03, 2.06] |
| 3.6.38 Nausea | 2 | 374 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.31, 0.80] |
| 3.6.39 Breast pain | 1 | 307 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.05 [0.66, 38.91] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Relief of painful symptoms Show forest plot | 3 | Std. Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.1.1 Overall | 3 | 129 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.25 [‐0.60, 0.10] |
| 4.2 rAFS/ASRM score Show forest plot | 1 | 18 | Mean Difference (IV, Fixed, 95% CI) | 9.50 [‐10.77, 29.77] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Side effects Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1.1 Sleep disturbance Nafareline 200mcg versus 400mcg | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.63, 1.59] |
| 5.1.2 Rhinitis Nafareline 200mcg versus 400 mcg | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.40 [0.10, 1.67] |
| 5.1.3 Upper respiratory tract infection Nafareline 200mcg versus 400 mcg | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.20 [0.03, 1.47] |
| 5.1.4 Hot flushes/flashes Nafareline 200mcg versus 400 mcg | 1 | 24 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.51, 1.97] |
| 5.2 rAFS score (400mcg vs 800mcg) Show forest plot | 1 | 143 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.17, 1.01] |
| 5.3 relief of painful symptoms Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.3.1 Dsymenorrhoea Nafarelin 400mcg versus 800mcg | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.53, 1.66] |
| 5.3.2 Dyspareunia | 1 | 57 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.79, 1.68] |
| 5.3.3 Pelvic pain | 1 | 77 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.67, 1.74] |
| 5.3.4 Overall Nafarelin 400mcg versus 800mcg | 1 | 143 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.78, 1.14] |
| 5.3.5 Overall buserelin 300mcg vs 900 mcg | 1 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [0.94, 2.35] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Relief of Painful Symptoms (3months vs 6months) at 6 months follow up Show forest plot | 1 | Std. Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 6.1.1 Dysmenorrhoea | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.02 [‐0.31, 0.27] |
| 6.1.2 Dyspareunia | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.98 [‐1.29, ‐0.66] |
| 6.1.3 Pelvic pain | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.14 [‐0.15, 0.44] |
| 6.1.4 Pelvic tenderness | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.14 [‐0.43, 0.15] |
| 6.1.5 Pelvic induration | 1 | 179 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.11 [‐0.40, 0.18] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 7.1 Side effects (IN vs SC) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1.1 Hot flushes/flashes | 1 | 13 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.48, 1.55] |
| 7.1.2 Vaginal dryness | 1 | 13 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.17, 4.37] |
| 7.1.3 Decreased libido | 1 | 13 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.07, 10.96] |
| 7.1.4 Headaches | 1 | 13 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.71 [0.20, 14.55] |
| 7.2 rAFS score (IN vs SC) Show forest plot | 1 | 19 | Mean Difference (IV, Fixed, 95% CI) | 9.00 [‐5.93, 23.93] |
| 7.3 Relief of painful symptoms (IN versus IMdepot) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.3.1 Dysmenorrhea | 1 | 192 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.82, 1.08] |
| 7.3.2 Dyspareunia | 1 | 166 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.85, 1.43] |
| 7.3.3 Pelvic pain | 1 | 192 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.78, 1.40] |
| 7.3.4 Tenderness | 1 | 192 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.67, 1.09] |
| 7.3.5 Induration | 1 | 190 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.78, 1.06] |
| 7.4 Side effects (IN versus IMdepot) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.4.1 Hot flushes/flashes | 1 | 191 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.93, 1.01] |
| 7.5 Improvement in symptoms (IN versus IMdepot) Show forest plot | 1 | 100 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.58, 3.30] |
| 7.6 Relief of painful symptoms (IN versus SC) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.6.1 Pelvic pain | 1 | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.53, 1.87] |
| 7.6.2 Dyspareunia | 1 | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.57, 1.75] |
| 7.6.3 Dysmenorrhoea | 1 | 10 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.73, 2.06] |
| 7.6.4 Pelvic tenderness | 1 | 10 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.50 [0.69, 3.27] |
| 7.6.5 Pelvic induration | 1 | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.47, 1.55] |
