Weight gain in menopause: systematic review of adverse events in women treated with black cohosh

Figures & data

Table 1. Number of cases of weight gain from the spontaneous reporting system for the time period 2005–2020.

Characteristics	Total
Substance
Cimicifuga racemosa	18
Cimicifuga racemosa and Hypericum perforatum	12
Qualification
Pharmacist	24
Physician	2
Other health-care professional	2
Other	2
Age at adverse event occurrence (years)
40–49	6
50–59	7
>60	1
Unknown	16
Duration of therapy (weeks)
24	1
12	2
8	2
4	3
2	1
1	2
Unknown	19
Daily dose
2 × 1 tablet	1
4 × 2 tablets	2
Unknown	27
Outcome as per reporter
Not recovered/not resolved	1
Recovered/resolved	6
Unknown	23
Changes in medication
Dose not changed	1
Dose reduced	1
Drug withdrawn	9
Drug withdrawn due to adverse event	2
Unknown	17
Causality assessment by the reporter
Not related	2
Not reported	21
Possible	2
Suspected	1
Unassessable/unclassifiable	3
Unlikely/remote	1

Table provides characteristics of the suspected drug, qualification of the reporters, age of patients, treatment details, the outcome and causality assessment of the adverse event as per reporter.

Table 2. Overview of weight gain in randomized controlled trials (RCTs).

Study	Design	Extract	Total	CR	Control	Duration	Results
Pkhaladze et al., 2020 [38]	Double-blind placebo-controlled study	eCR	198	148	50	12 weeks	No cases of weight gain were observed in either group
Mehrpooya et al., 2018 [39]	Double-blind reference-controlled study	eCR	80	40	40	8 weeks	None reported
Tanmahasamut et al., 2015 [40]	Double-blind placebo-controlled study	eCR	54	27	27	12 weeks	Adverse events were well tolerated and self-limited, requiring neither treatment nor study termination
Zhang et al., 2015 [41]	Reference-controlled study	iCR	98	49	49	12 weeks	None reported
Jiang et al., 2015 [42]	Double-blind placebo-controlled study	iCR	48	24	24	6 months	Safety measures did not yield any adverse event assigned to CR
Chen et al., 2014 [43]	Double-blind reference-controlled study	iCR	116	56	60	12 weeks	None reported
Mohammad-Alizadeh-Charandabi et al., 2013 [44]	Double-blind placebo-controlled study	eCR	84	42	42	4–8 weeks	No side-effects were reported in either group
Chen 2013 [25]	Reference-controlled study	iCR	120	60	60	12 weeks	Weight gain was common in the CR group when compared with Livial group; the difference had no statistical significance
Huang 2013 [45]	Reference-controlled study	iCR	172	86	86	12 weeks	None reported
Huang et al., 2013 [46]	Reference-controlled study	iCR	120	60	60	8 weeks	No significant changes existed in tested parameters before and after treatment
Schellenberg et al., 2012 [47]	Double-blind placebo-controlled study	eCR	180	120	60	12 weeks	As regards safety, no serious adverse events and 21 non-serious adverse events occurred in 20 patients. Weight gain was not reported in any of the groups
Sun et al., 2012 [48]	Double-blind reference-controlled study	iCR	70	40	30	12 weeks	There were no adverse effects during treatment
Hong et al., 2012 [49]	Double-blind placebo-controlled study	eCR	100	50	50	12 weeks	No significant change in weight between both groups
Li et al., 2011 [50]	Double-blind placebo-controlled study	iCR	89	45	44	12 weeks	None reported
Bebenek et al., 2010 [51]	Reference-controlled study	eCR	128	42	86	10 weeks	Total and abdominal body fat did not significantly change in the exercise groups. Accordingly, no differences concerning changes in these parameters were observed between the groups. Lean body mass significantly increased in the exercise groups (1.2%) whereas only slightly positive changes were determined in the exercise and CR supplementation. However, no between-group differences were assessed for lean body mass
Geller et al., 2009 [52]	Double-blind placebo-controlled study	eCR	89	21	68	12 months	There were no significant differences between groups reported for any other side-effects
Amsterdam et al., 2009 [53]	Double-blind placebo-controlled study	Unknown	28	15	13	12 weeks	None reported
Oktem et al., 2007 [54]	Reference-controlled study	eCR	120	60	60	6 months	No cases of weight gain were observed in either group
Chung et al., 2007 [27]	Double-blind placebo-controlled study	eCR	77	42	35	12 weeks	One patient reported 2-kg weight gain, but the authors did not specify whether the case occurred in the treatment or placebo group
Wuttke et al., 2006 and 2003 [55,56]	Double-blind placebo-controlled study	eCR	62	20	42	12 weeks	Incidence of non-serious adverse events of mild to moderate severity was comparable in the treatment groups. No cases of weight gain occurred
Newton et al., 2006 [57]	Double-blind placebo-controlled study	eCR	351	80	271	12 months	There were no statistically significant differences among any of the four groups and the placebo group in the number of women with adverse events
Bai et al., 2006 [24]	Double-blind reference-controlled study	iCR	244	122	122	12 weeks	One possible drug-related adverse event, weight increase, occurred in the tibolone group during treatment. The intra-group comparison of mean body weight demonstrates a clinically irrelevant increase at week 12 as compared to baseline and week 4 (p < 0.01). The inter-group comparison shows that body weight in the tibolone group at week 12 was significantly higher than in the iCR group (p = 0.027)
Uebelhack et al., 2006 [58]	Double-blind placebo-controlled study	iCR	301	151	150	16 weeks	With regard to age, body height, body weight and body mass index, no significant mean group difference was observed
Osmers et al., 2005 [26]	Double-blind placebo-controlled study	iCR	286	153	133	12 weeks	This study found a median increase of the body weight of +0.7 kg in the placebo group during the 3 months, reflecting the spontaneous change of this parameter over time during the menopausal transition. This is in contrast to +0.3 kg in the CR group. Moreover, the change in body weight ranged from −7.1 kg to 12.0 kg with the maximum increase in the placebo group. There was no case of an adverse drug reaction ‘weight increase’ reported. Thus, in this study CR did not cause an increase in body weight
Frei-Kleiner et al., 2005 [59]	Double-blind placebo-controlled study	eCR	122	81	41	12 weeks	There were no differences between the CR group and the placebo group regarding adverse events or other safety assessments. Intensity and frequency − 17/83 patients (20%) in the CR group and 10/44 patients (23%) in the placebo group – of adverse events were comparable in the two groups
Nappi et al., 2005 [60]	Reference-controlled study	iCR	64	32	32	12 weeks	None reported
Lee et al., 2002 [61]	Double-blind placebo-controlled study	Unknown	74	32	42	12 weeks	None reported
Liske et al., 2002 [62]	Double-blind reference-controlled study	iCR	152	76	76	12–24 weeks	None reported
Lehmann-Willenbrock and Riedel, 1988 [63]	Reference-controlled study	iCR	60	15	45	6 months	None reported
Stoll, 1987 [23]	Double-blind placebo-controlled study	iCR	80	30	50	12 weeks	Two patients from the placebo group terminated the study because of severe headaches and weight gain. One woman in the estrogen group complained about weight gain. In the CR group, three patients experienced minor weight gain. However, they continued the treatment. The causality with CR was assessed as ‘unlikely’ by the investigator
Warnecke, 1985 [64]	Reference-controlled study	eCR	60	20	40	14 weeks	None reported

CR, Cimicifuga racemosa; eCR, ethanolic Cimicifuga racemosa extract; iCR, isopropanolic Cimicifuga racemosa extract.

Table 3. Causality assessment regarding weight gain for identified cases (n) from different sources of reporting.

Causality assessment	Source and number of cases (n)
	Spontaneous reporting	Literature case reports	RCT
			CR	Control group
Certain	0	0	0	0
Probable	0	0	0	0
Possible/suspected	3	0	0	1
Unlikely	1	1	3	3
Unrelated	2	0	0	0
Unassessable	3	0	0	0
Not reported/not available	21	0	0	0

CR, Cimicifuga racemosa; RCT, randomized controlled trial.

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