The Effectiveness of Herbal Medicines on Cyclic Mastalgia: A Systematic Review on Meta-analysis

Mirzaee, Firoozeh; Fakari, Farzaneh Rashidi; Babakhanian, Masoudeh; Roozbeh, Nasibeh; Ghazanfarpour, Masumeh

doi:10.1055/s-0042-1755456

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Revista Brasileira de Ginecologia e Obstetrícia

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Sumário

Review Article • Rev Bras Ginecol Obstet 44 (10) • 2022 • https://doi.org/10.1055/s-0042-1755456 copy

The Effectiveness of Herbal Medicines on Cyclic Mastalgia: A Systematic Review on Meta-analysis

A eficácia dos medicamentos fitoterápicos na mastalgia cíclica: Uma revisão sistemática em metanálise

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective

Different drugs are used to treat mastalgia, such as danazol and bromocriptine, and both are associated with side effects, due to which most of women and healthcare providers are interested in herbal medicines. Therefore we aim to study the effectiveness of phytoestrogens on the severity of cyclic mastalgia.

Methods

To carry out the present study, English electronic resources such as the Cochrane Library, ISI Web of Science, Scopus, and PubMed were used systematically and with no time limitation up to February 10, 2020.

Results

In total, 20 studies were included in the present meta-analysis. The results of the meta-analysis showed that herbal medicines versus the control group (standard mean difference [SMD] = - 0.585; 95% confidence interval [CI]: - 0.728–- 0.44; heterogeneity; p = 0.02; I2 = 42%), herbal medicines versus the B group (SMD = - 0.59; 95%CI: - 0.75–- 0.44; heterogeneity; p = 0.03; I2 = 42%), and its subgroups, such as phytoestrogen (SMD = - 0.691; 95%CI: - 0.82–- 0.55; heterogeneity; p = 0.669; I2 = 0%), Vitex-agnus-castus (SMD = - 0.642; 95%CI: - 0.84–- 0.44; p < 0.001; p = 203; I2 = 32%), flaxseed (SMD = - 0.63; 95%CI: - 0.901–- 0.367; p = 0.871; I2 = 0%), and evening primrose (SMD= - 0.485; 95%CI:- 0.84–- 0.12; p = 0.008; heterogeneity; p = 0.06; I2 = 56%] may have effective and helpful effects on improving cyclic breast mastalgia. Also, chamomile, isoflavone, cinnamon, and nigella sativa significantly reduced mastalgia symptoms.

Conclusion

Herbal medicines and their subgroups may have effective and helpful effects on improving cyclic breast mastalgia. The findings of our meta-analysis must be done cautiously because low methodological quality in some evaluated studies of this systematic review.

Keywords
mastodynia; phytoestrogens; systematic review; herbal medicine

Author (year)	Type of clinical trial	Age (years old)	Outcome	Intervention (dose and duration of treatment)	Comparison (dose and duration of treatment)	Duration of follow-up	Intensity of mastalgia	Assessment tools	Inclusion criteria	Results
Vaziri et al. (2014)¹⁶16 Vaziri F, Zamani Lari M, Samsami Dehaghani A, Salehi M, Sadeghpour H, Akbarzadeh M, et al. Comparing the effects of dietary flaxseed and omega-3 Fatty acids supplement on cyclical mastalgia in Iranian women: a randomized clinical trial. Int J Family Med. 2014;2014:174532. Doi: 10.1155/2014/174532 https://doi.org/10.1155/2014/174532...	Single-blind	20–45	Treatment of mastalgia	180 g of flaxseed for 2 cycles	Omega 3 fatty acids (180 mg of eicosapentaenoic acid and 120 mg of docosahexaenoic acid)	3 months	Cyclicmastalgia	Visual analog scale	181	Flaxseed was more effective in reducing mastalgia
Sekhavat et al. (2009)¹⁸18 Sekhavat L, Zare Tarzejani T, Kholase Zadeh P. The effect of vitex agnus-castus on mastalgia in women. Iran South Med J. 2009;11(02):147–152	Double-blind	18–40	Treatment of mastalgia	60 drops of Vitagnus daily	Placebo	3 months	Cyclic or noncyclic mastalgia	Visual analog scale	117	Vitagnus reduced mastalgia more than placebo.
Saghafi et al. (2018)¹⁵15 Saghafi N, Rhkhshandeh H, Pourmoghadam N, Pourali L, Ghazanfarpour M, Behrooznia A, et al. Effectiveness of Matricaria chamo-milla (chamomile) extract on pain control of cyclic mastalgia: a double-blind randomised controlled trial. J Obstet Gynaecol. 2018;38(01):81–84. Doi: 10.1080/01443615.2017.1322045 https://doi.org/10.1080/01443615.2017.13...	Double-blind	> 18	Treatment of mastalgia	5 drops of chamomile 3 times a day for 2 consecutive months	Placebo(distilled water)	2 months	Cyclicmastalgia	Visual analog scale	55	Chamomile reduced mild to moderate mastalgia.
Rajaby Gharaiy et al. (2017)¹³13 Gharaiy NR, Shahnazi M, Kia PY, Javadzadeh Y. The effect of cinnamon on cyclical breast pain. Iran Red Crescent Med J. 2017;19(06):e26442	Double-blind	18–40	Treatment of mastalgia	400 mg of cinnamon 3 times a day	Placebo	2 months	Cyclic mastalgia	Cardiff checklist	74	Cinnamon can be effective in reducing the severity of mastalgia in women.
Mirmolaei et al. (2017)¹⁴14 Mirmolaei ST, Olfatbakhsh A, Falah Huseini H, Kazemnezhad Leyli E, Sotoodeh Moridiani A. The effect of Nigella Sativa syrup on the relief of cyclic mastalgia: a triple-blind randomized clinical trial. J Hayat. 2017;23(01):33–43	Triple-blind	15–49	Treatment of mastalgia	10 ml (2 tablespoons) of Nigella sativa syrup	Placebo(paraffin oil syrup)	2 months	Cyclic mastalgia	McGill questionnaire and visual analog scale	72	Nigella sativa syrup reduced pain intensity compared with placebo.
Jahdi et al. (2019)¹⁹19 Jahdi F, Tolouei R, Neisani Samani L, Hashemian M, Haghani H, Mojab F, et al. Effect of evening primrose oil and vitamin b6 on pain control of cyclic mastalgia associated with fibrocystic breast changes: a triple-blind randomized controlled trial. Shiraz E Med J. 2019;20(05):e81243. Doi: 10.5812/semj.81243 https://doi.org/10.5812/semj.81243...	Triple-blind	18–50	Treatment of mastalgia	1000 mg evening primrose every 12 hours, 50 mg vitamin B6 every 12 hours,	Placebo	1, 2, and 3 months	Cyclic mastalgia	Visual analog scale	94	B6 and evening primrose have the same therapeutic effects in the treatment of cyclical mastalgia
Alvandipour et al. (2011)⁹9 Alvandipour M, Tayebi P, Alizadeh Navaie R, Khodabakhshi H. Comparison between effect of evening primrose oil and vitamin E in treatment of cyclic mastalgia. JBUMS. 2011;13(02):7–11	Double-blind	–	Treatment of mastalgia	Evening primrose 2 g/day and vitamin E 400 mg/day	Placebo	After 1 month and 6 months	Cyclic mastalgia	McGill questionnaire	100 women with cyclic mastalgia	Evening primrose and vitamin E had a similar effect in the treatment of mastalgia
Gateley et al. (1992)²⁰20 Gateley CA, Miers M, Mansel RE, Hughes LE. Drug treatments for mastalgia: 17 years experience in the Cardiff Mastalgia Clinic. J R Soc Med. 1992;85(01):12–15	Clinical trial	> 17	Treatment of mastalgia	Danazol 200 mg daily/bromocriptine 1.25 mg daily	Evening primrose oil, 3 g/day	2 months	Cyclicmastalgia	Cardiff checklist	478 women with cyclic mastalgia	Danazol was more effective in reducing the severity of mastalgia in women than bromocriptine and evening primrose oil.
Blommers et al. (2002)²¹21 Blommers J, de Lange-De Klerk ES, Kuik DJ, Bezemer PD, Meijer S. Evening primrose oil and fish oil for severe chronic mastalgia: a randomized, double-blind, controlled trial. Am J Obstet Gynecol. 2002;187(05):1389–1394. Doi: 10.1067/mob.2002.127377a https://doi.org/10.1067/mob.2002.127377a...	Double-blind clinical trial	−	Treatment of mastalgia	3 g of evening primrose oil and control oil	3 g of fish oil and control oil	3 and 6 months	Cyclic or noncyclic mastalgia	Clinical examinations	120 women with cyclicmastalgia	Both groups showed a similar reduction in pain.
Aydin et al. (2012)²²22 Aydin I, Baltaci D, Turkyilmaz S, Oncu M. Comparison of vitex agnus castus with meloxicam and placebo in treatment of patients with cyclical mastalgia. Duzce Med J. 2012;14(01):1–5	Prospective clinical trial	19–54	Treatment of mastalgia	Group 1 = vitex agnus castus and group 2 = meloxicam	Placebo	3months	Cyclic mastalgia	Visual analog scale	108 women with cyclicmastalgia for at least 5 days in 1 cycle with normal and high prolactin	Vitex-agnus-castus was more effective in reducing mastalgia than meloxicam and placebo.
Jaafarnejad et al. (2017)²³23 Jaafarnejad F, Adibmoghaddam E, Emami SA, Saki A. Compare the effect of flaxseed, evening primrose oil and Vitamin E on duration of periodic breast pain. J Educ Health Promot. 2017;6:85. Doi: 10.4103/jehp.jehp_83_16 https://doi.org/10.4103/jehp.jehp_83_16...	Quasiexperimental clinical trial	18–45	Treatment of mastalgia	Group 1 = flaxseed, group 2 = 1000-mg capsules of evening primrose oil daily	Vitamin E group, 400-IU capsules	1–2 months	Cyclic mastalgia	Researcher-made checklist	Women with cyclicmastalgia	Flaxseed, evening primrose oil, and vitamin E reduced the duration of mastalgia, but this decrease was significant only inin the flaxseed group.
Ingram et al. (2002)²⁴24 Ingram DM, Hickling C, West L, Mahe LJ, Dunbar PM. A double-blind randomized controlled trial of isoflavones in the treatment of cyclical mastalgia. Breast. 2002;11(02):170–174. Doi: 10.1054/brst.2001.0353 https://doi.org/10.1054/brst.2001.0353...	Double-blind	>18	Treatment of mastalgia	Isoflavones, 80 and 40 mg daily	Placebo	2 months	Cyclic mastalgia	Breast pain checklist	12 women with cyclicmastalgia	Isoflavones could be effective as complementary therapy in the treatment of mastalgia.
Mirghafourvand et al. (2016)²2 Mirghafourvand M, Mohammad-Alizadeh-Charandabi S, Ahmadpour P, Javadzadeh Y. Effects of Vitex agnus and Flaxseed on cyclic mastalgia: A randomized controlled trial. Complement Ther Med. 2016;24:90–95. Doi: 10.1016/j.ctim.2015.12.009 https://doi.org/10.1016/j.ctim.2015.12.0...	Double-blind	18–45	Treatment of mastalgia	Group 1 = 25 g flaxseed powder and group 2 = 3.2–8.8 mg of Vitagnus daily	Placebo	2 months	Cyclic mastalgia	Cardiff checklist	159 women with cyclical mastalgia	Flaxseed and Vitagnus were effective in reducing mastalgia in the short term.
Kiliç et al. (2016)²⁵25 Kiliç MÖ, Şen M, Içen D. The comparison of evening primrose oil, fructus agni casti and reassurance in the treatment of mastalgia. Int J Surg Med.. 2016;2(02):83–88	Prospective clinical study	> 18	Treatment of mastalgia	Group 1 = evening primrose oil and group 2= fructus agni casti/reassurance	Placebo	3 months	Cyclic or noncyclic mastalgia	Cardiff checklist	128 women with cyclicmastalgia	Fructus agni casti was more effective in reducing mastalgia than evening primrose and placebo.
Ataollahi et al. (2015)²⁶26 Ataollahi M, Akbari SA, Mojab F, Alavi Majd H. The effect of wheat germ extract on premenstrual syndrome symptoms. Iran J Pharm Res. 2015;14(01):159–166	Triple-blind	–	Treatment of the symptoms of premenstrual syndrome	400 g wheat germ 3 times a day from the 16th day of the cycle until the next 5 periods	Placebo	2 months	Cyclic mastalgia	Daily Symptom Record	84 women with premenstrual syndrome	Wheat germ was effective in treating mastalgia
Ghazanfarpour et al. (2011)²⁷27 Ghazanfarpour M, Kaviani M, Asadi N, Ghaffarpasand F, Ziyadlou S, Tabatabaee HR, et al. Hypericum perforatum for the treatment of premenstrual syndrome. Int J Gynaecol Obstet. 2011;113(01):84–85. Doi: 10.1016/j.ijgo.2010.11.007 https://doi.org/10.1016/j.ijgo.2010.11.0...	Double-blind	31	Treatment of the symptoms of premenstrual syndrome	Hypericum perforatum (1360-μg hypericin tablets per day)	Placebo	2 months	Undermine	Premenstrual syndrome questionnaire	170	Hypericum perforatum was more effectiveness than placebo
Pruthi et al. (2010) ²⁸28 Pruthi S, Wahner-Roedler DL, Torkelson CJ, Cha SS, Thicke LS, Hazelton JH, et al. Vitamin E and evening primrose oil for management of cyclical mastalgia: a randomized pilot study. Altern Med Rev. 2010;15(01):59–67	Double-blind	> 18	Treatment of mastalgia	3 g of evening primrose	Placebo	6 months	Mastalgia	McGill questionnaire	85 women > 18 years old who develop mastalgia for at least 2 cycles 2 weeks before menstruation	Evening primrose and vitamin E, either alone or in combination, had a similar effect in the treatment of mastalgia
Masumi et al. (2017)²⁹29 Masoumi Z, Khalili A, Delforooz A, Faradmal J, Shayan A. [Comparison the effect of evening primrose oil and vitamin E on premenstrual syndrome]. CMJA. 2017;7(02):1931–1943Persian.	Double-blind	> 18 years	–	1000 mg of evening primrose daily	400 mg of vitamin E daily	60 days	Undermine	Premenstrual Symptoms Screening Tool	70 women with moderate to severe menstrual syndrome	Evening primrose caused a greater decrease in the treatment of premenstrual syndrome symptoms than vitamin E.
Pakgohar et al. (2005)³⁰30 Pakgohar M, Ahmadi M, Salehi Surmaghi M, Mehran A, Akhondzadeh S. Effect of Hypericum perforatum L. for treatment of premenstrual syndrome. Faslnamah-i Giyahan-i Daruyi. 2005;4(15):33–42	Double-blind	–	Treatment of premenstrual syndrome	60 drops of Hypiran daily 7 days before menstruation for 2 cycles	Placebo (60 drops daily 7 days before menstruation in 2 cycles)	2 months	Undermine	Daily Symptom Record	70 students with at least 5 symptoms of premenstrual syndrome	Hypiran was more effective than placebo in treating the symptoms of premenstrual syndrome, including mastalgia.
Mirmolaei et al. (2017)¹⁴14 Mirmolaei ST, Olfatbakhsh A, Falah Huseini H, Kazemnezhad Leyli E, Sotoodeh Moridiani A. The effect of Nigella Sativa syrup on the relief of cyclic mastalgia: a triple-blind randomized clinical trial. J Hayat. 2017;23(01):33–43	Triple-blind	15–49	Treatment of mastalgia	Daily Vitagnus (8 cc)	Placebo (Oral paraffin)	3 months	Cyclic mastalgia	McGill questionnaire and visual analog scale	67 women aged 15 to 49 years old with a visual analog scale score > 4	Vitagnus was more effective in reducing mastalgia than placebo.

Authors	Blinding			Randomization			Account of all patients
Authors	Mentions randomization	Method: appropriate	Method: inappropriate	Mention srandomization	Method: appropriate	Method: inappropriate	Account of all patients
Vaziri et al. (2014)¹⁶16 Vaziri F, Zamani Lari M, Samsami Dehaghani A, Salehi M, Sadeghpour H, Akbarzadeh M, et al. Comparing the effects of dietary flaxseed and omega-3 Fatty acids supplement on cyclical mastalgia in Iranian women: a randomized clinical trial. Int J Family Med. 2014;2014:174532. Doi: 10.1155/2014/174532 https://doi.org/10.1155/2014/174532...	+	+	−	−	−	−	+
Sekhavat et al. (2009)¹⁸18 Sekhavat L, Zare Tarzejani T, Kholase Zadeh P. The effect of vitex agnus-castus on mastalgia in women. Iran South Med J. 2009;11(02):147–152	+	+	−	+	+	−	+
Saghafi et al. (2018)¹⁵15 Saghafi N, Rhkhshandeh H, Pourmoghadam N, Pourali L, Ghazanfarpour M, Behrooznia A, et al. Effectiveness of Matricaria chamo-milla (chamomile) extract on pain control of cyclic mastalgia: a double-blind randomised controlled trial. J Obstet Gynaecol. 2018;38(01):81–84. Doi: 10.1080/01443615.2017.1322045 https://doi.org/10.1080/01443615.2017.13...	+	+	−	+	+	−	+
Rajaby Gharaiy et al. (2017)¹³13 Gharaiy NR, Shahnazi M, Kia PY, Javadzadeh Y. The effect of cinnamon on cyclical breast pain. Iran Red Crescent Med J. 2017;19(06):e26442	+	+	−	+	+	−	+
Mirmolaei et al. (2017)¹⁴14 Mirmolaei ST, Olfatbakhsh A, Falah Huseini H, Kazemnezhad Leyli E, Sotoodeh Moridiani A. The effect of Nigella Sativa syrup on the relief of cyclic mastalgia: a triple-blind randomized clinical trial. J Hayat. 2017;23(01):33–43	+	+	−	+	+	−	+
Jahdi et al. (2019)¹⁹19 Jahdi F, Tolouei R, Neisani Samani L, Hashemian M, Haghani H, Mojab F, et al. Effect of evening primrose oil and vitamin b6 on pain control of cyclic mastalgia associated with fibrocystic breast changes: a triple-blind randomized controlled trial. Shiraz E Med J. 2019;20(05):e81243. Doi: 10.5812/semj.81243 https://doi.org/10.5812/semj.81243...	+	+	−	+	+	−	+
Alvandipour et al. (2011)⁹9 Alvandipour M, Tayebi P, Alizadeh Navaie R, Khodabakhshi H. Comparison between effect of evening primrose oil and vitamin E in treatment of cyclic mastalgia. JBUMS. 2011;13(02):7–11	+	+	−	−	−	−	+
Gateley et al. (1992)²⁰20 Gateley CA, Miers M, Mansel RE, Hughes LE. Drug treatments for mastalgia: 17 years experience in the Cardiff Mastalgia Clinic. J R Soc Med. 1992;85(01):12–15	+	+	−	+	+	−	−
Aydin et al. (2012)²²22 Aydin I, Baltaci D, Turkyilmaz S, Oncu M. Comparison of vitex agnus castus with meloxicam and placebo in treatment of patients with cyclical mastalgia. Duzce Med J. 2012;14(01):1–5	−	−	−	−	−	−	−
Blommers et al. (2002)²¹21 Blommers J, de Lange-De Klerk ES, Kuik DJ, Bezemer PD, Meijer S. Evening primrose oil and fish oil for severe chronic mastalgia: a randomized, double-blind, controlled trial. Am J Obstet Gynecol. 2002;187(05):1389–1394. Doi: 10.1067/mob.2002.127377a https://doi.org/10.1067/mob.2002.127377a...	+	+	−	+	−	+	+
Jaafarnejad et al. (2017)²³23 Jaafarnejad F, Adibmoghaddam E, Emami SA, Saki A. Compare the effect of flaxseed, evening primrose oil and Vitamin E on duration of periodic breast pain. J Educ Health Promot. 2017;6:85. Doi: 10.4103/jehp.jehp_83_16 https://doi.org/10.4103/jehp.jehp_83_16...	+	−	−	−	−	−	+
Ingram et al. (2002)²⁴24 Ingram DM, Hickling C, West L, Mahe LJ, Dunbar PM. A double-blind randomized controlled trial of isoflavones in the treatment of cyclical mastalgia. Breast. 2002;11(02):170–174. Doi: 10.1054/brst.2001.0353 https://doi.org/10.1054/brst.2001.0353...	−	+	+	+	+	−	+
Mirghafourvand et al. (2016)²2 Mirghafourvand M, Mohammad-Alizadeh-Charandabi S, Ahmadpour P, Javadzadeh Y. Effects of Vitex agnus and Flaxseed on cyclic mastalgia: A randomized controlled trial. Complement Ther Med. 2016;24:90–95. Doi: 10.1016/j.ctim.2015.12.009 https://doi.org/10.1016/j.ctim.2015.12.0...	+	+	−	+	+	−	+
Kiliç et al. (2016)²⁵25 Kiliç MÖ, Şen M, Içen D. The comparison of evening primrose oil, fructus agni casti and reassurance in the treatment of mastalgia. Int J Surg Med.. 2016;2(02):83–88	+	−	−	−	−	−	−
Ataollahi et al. (2015)²⁶26 Ataollahi M, Akbari SA, Mojab F, Alavi Majd H. The effect of wheat germ extract on premenstrual syndrome symptoms. Iran J Pharm Res. 2015;14(01):159–166	+	+	−	+	−	−	−
Ghazanfarpour et al. (2011)²⁷27 Ghazanfarpour M, Kaviani M, Asadi N, Ghaffarpasand F, Ziyadlou S, Tabatabaee HR, et al. Hypericum perforatum for the treatment of premenstrual syndrome. Int J Gynaecol Obstet. 2011;113(01):84–85. Doi: 10.1016/j.ijgo.2010.11.007 https://doi.org/10.1016/j.ijgo.2010.11.0...	+	+	−	+	+	−	+
Pruthi et al. (2010)²⁸28 Pruthi S, Wahner-Roedler DL, Torkelson CJ, Cha SS, Thicke LS, Hazelton JH, et al. Vitamin E and evening primrose oil for management of cyclical mastalgia: a randomized pilot study. Altern Med Rev. 2010;15(01):59–67	+	+	−	+	+	−	+
Masumi et al. (2017)²⁹29 Masoumi Z, Khalili A, Delforooz A, Faradmal J, Shayan A. [Comparison the effect of evening primrose oil and vitamin E on premenstrual syndrome]. CMJA. 2017;7(02):1931–1943Persian.	+	+	−	+	+	−	+
Pakgohar et al. (2005)³⁰30 Pakgohar M, Ahmadi M, Salehi Surmaghi M, Mehran A, Akhondzadeh S. Effect of Hypericum perforatum L. for treatment of premenstrual syndrome. Faslnamah-i Giyahan-i Daruyi. 2005;4(15):33–42	+	+	−	+	+	−	+
Mirmolaei et al. (2016)¹⁰10 Mirmolaei S, Olfatbakhsh A, Fallahhosseini H, Kazemnejad E, Sotodeh A. The effect of vitagnus on cyclic breast pain in women of reproductive age. JBUMS. 2016;18(09):7–13	+	+	−	+	+	−	+

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[1] Address for correspondence Masumeh Ghazanfarpour, PhD Department of Midwifery, Nursing Research Center, Kerman University of Medical Sciences Kerman Iran (e-mail: masumeh.ghazanfarpour@yahoo.com).