Association between testosterone with type 2 diabetes in adult males, a meta-analysis and trial sequential analysis

Figures & data

Figure 1. Forest plot of the WMD of TT in patients with T2DM in cross-sectional studies.

Table 1. Characteristics of studies included in the meta-analysis.

First author, published year	Design	Nationality	Ethnicity	ED	Follow-up(years)	Age (years)	BMI	Patients number		Nos.
								T2DM	no T2DM
Rovira-Llopis (2017)	Cross-sectional study	Spain	Caucasian	NM	/	56.4	30	280	50	7
Hu (2015)	Cross-sectional study	China	Asian	NM	/	61.3	24.1	145	145	8
Bekaert (2015)	Cross-sectional study	Belgium	Caucasian	NM	/	48.5	42.7	33	24	7
Xia (2015)	Cross-sectional study	China	Asian	NM	/	75.8	23.3	35	30	7
Daka (2015)	Cross-sectional study	Sweden	Caucasian	NM	/	62.2	26.4	54	488	8
Mattack (2015)	Cross-sectional study	India	Asian	NM	/	55.45	24.5	40	40	7
Shi (2014a)	Cross-sectional study	China	Asian	Yes	/	52.39	NM	85	49	7
Shi (2014b)	Cross-sectional study	China	Asian	No	/	50.6	NM	20	86	7
Tsilidis (2014)	Cross-sectional study	Multi-countries	Caucasian	NM	/	NM	NM	37	589	7
Hayek (2014)	Cross-sectional study	Jordan	Asian	NM	/	51.3	29.4	1089	628	7
Kim (2014)	Cross-sectional study	Korea	Asian	NM	/	53.8	23.9	38	41	7
Asare-Anane (2014)	Cross-sectional study	Ghana	African	NM	/	45.9	24.7	105	105	8
Mazur (2014)	Cross-sectional study	Germany	Caucasian	NM	/	63	28.9	183	808	8
Rabijewski (2013)	Cross-sectional study	Poland	Caucasian	Yes	/	59	29.7	184	149	8
Ho (2013)	Cross-sectional study	China	Asian	NM	/	54.3	24.7	186	577	8
Fui (2013)	Cross-sectional study	Australia	Caucasian	NM	/	57.5	29.2	80	80	8
Goto (2012)	Cross-sectional study	Japan	Asian	NM	/	64.5	23.8	300	300	8
Bai (2011)	Cross-sectional study	China	Asian	NM	/	56.7	24.4	39	11	7
Biswas (2012)	Cross-sectional study	England	Caucasian	NM	/	48	28.6	115	121	8
Cao (2011)	Cross-sectional study	China	Asian	NM	/	72	25.3	129	259	8
Dhindsa (2010a)	Cross-sectional study	America	Caucasian	NM	/	63.7	23	36	275	8
Dhindsa (2010b)	Cross-sectional study	America	Caucasian	NM	/	61.7	27.4	135	687	8
Dhindsa (2010c)	Cross-sectional study	America	Caucasian	NM	/	58.9	35.2	227	489	8
Ibanez (2008)	Cross-sectional study	Spain	Caucasian	NM	/	65.7	28.8	11	9	7
Hamdan and Al-Matubsi (2008)	Cross-sectional study	Jordan	Asian	Yes	/	45	NM	38	30	7
Crawford (2007)	Cross-sectional study	America	Caucasian	NM	/	60.3	27	238	2678	8
Selvin (2007)	Cross-sectional study	America	Caucasian	NM	/	42.4	26.4	101	1312	8
Chen (2006a)	Cross-sectional study	Australia	Caucasian	NM	/	76.4	26.1	35	160	7
Corona (2006)	Cross-sectional study	Italy	Caucasian	Yes	/	50.9	26.4	199	1024	8
Achemlal (2005)	Cross-sectional study	Morocco	African	NM	/	53.4	25.4	35	35	7
Pitteloud (2005)	Cross-sectional study	Sweden	Caucasian	NM	/	60.6	26.6	21	27	7
Tong (2005)	Cross-sectional study	China	Asian	NM	/	41.1	25.4	179	128	8
Rhoden (2005)	Cross-sectional study	Brazil	African	NM	/	57.3	27	116	630	8
Corona (2004)	Cross-sectional study	Italy	Caucasian	Yes	/	56	27.5	155	872	8
Corrales (2004)	Cross-sectional study	Spain	Caucasian	NM	/	64	27.2	55	8	7
Svartberg (2004)	Cross-sectional study	Norway	Caucasian	NM	/	60.5	26.1	55	1364	8
Abate (2002)	Cross-sectional study	America	Caucasian	NM	/	50.8	27.9	33	24	7
Jang (2001)	Cross-sectional study	Korea	Asian	NM	/	54	24.7	25	64	7
Abou-Seif and Youssef (2001)	Cross-sectional study	Egypt	African	NM	/	48	NM	22	6	7
Chearskul (2000)	Cross-sectional study	Thailand	Asian	NM	/	65.7	23.5	43	39	7
Zietz (2000)	Cross-sectional study	Germany	Caucasian	NM	/	58	26.7	155	155	8
Defay (1998a)	Cross-sectional study	French	Caucasian	NM	/	46.9	29	16	16	7
Defay (1998b)	Cross-sectional study	French	African	NM	/	46.7	28.9	77	77	8
Tibblin (1996a)	Cross-sectional study	Sweden	Caucasian	NM	/	67	25.1	40	411	7
Andersson (1994)	Cross-sectional study	Sweden	Caucasian	NM	/	56.5	26.3	46	11	7
Barrett-Connor (1992)	Cross-sectional study	America	Caucasian	NM	/	72.1	26.1	44	88	7
Barrett-Connor (1990)	Cross-sectional study	America	Caucasian	NM	/	63.7	25.7	110	875	8
Semple (1988)	Cross-sectional study	Scotland	Caucasian	NM	/	52.4	26.3	15	15	7
Small (1987)	Cross-sectional study	Scotland	Caucasian	NM	/	56.2	26.4	28	15	7
Ando (1984)	Cross-sectional study	Belgium	Caucasian	NM	/	37.8	NM	39	10	7
Phillips (1984)	Cross-sectional study	America	Caucasian	NM	/	43.7	26.1	21	19	7
Daubresse (1978a)	Cross-sectional study	Belgium	Caucasian	No	/	52	NM	8	7	7
Daubresse (1978b)	Cross-sectional study	Belgium	Caucasian	Yes	/	45	NM	9	8	7
Shahwan (1978a)	Cross-sectional study	England	Caucasian	No	/	52.1	NM	20	10	7
Shahwan (1978b)	Cross-sectional study	England	Caucasian	Yes	/	52.1	NM	11	10	7
Li (2016)	Longitudinal study	Australia	Caucasian	NM	8	54.1	28	146	1486	9
Atlantis (2016)	Longitudinal study	Australia	Caucasian	NM	5	NM	NM	137	1362	8
Salminen (2015)	Longitudinal study	Finland	Caucasian	NM	9	72.4	26.5	30	400	7
Svartberg (2014)	Longitudinal study	Norway	Caucasian	NM	16	62.6	31.7	638	1786	8
Chen (2006b)	Longitudinal study	Australia	Caucasian	NM	8	NM	26	8	162	7
Laaksonen (2004)	Longitudinal study	Finland	Caucasian	NM	11	51.3	26.2	57	645	8
Stellato (2000)	Longitudinal study	America	Caucasian	NM	9	53.9	27.1	54	976	8
Haffner (1996)	Longitudinal study	America	Caucasian	NM	5	44.8	29.4	176	176	7
Tibblin (1996b)	Longitudinal study	Sweden	Caucasian	NM	13	67	25.2	35	411	7

ED: erectile dysfunction; NM: not mentioned; NOS: Newcastle-Ottawa Scale.

Table 2. Endpoints of variables in studies included in the meta-analysis.

First author, published year	Total T (nmol/L)		Free T (pmol/L)		FT detecting methods	SHBG (nmol/L)
	T2DM	No T2DM	T2DM	No T2DM		T2DM	No T2DM
Rovira-Llopis (2017)	15.3 ± 0.6	23.8 ± 1.6	NM	NM	/	NM	NM
Hu (2015)	13.5 ± 3.6	16.3 ± 4.4	NM	NM	/	38.4 ± 18.9	49.6 ± 20.6
Bekaert (2015)	7.2 ± 2.9	10.8 ± 5.1	164.1 ± 69.9	239.5 ± 109.0	Formula	24.0 ± 8.5	22.4 ± 8.2
Xia (2015)	11.8 ± 2.9	14.4 ± 3.2	NM	NM	/	NM	NM
Daka (2015)	11.7 ± 4.4	13.7 ± 4.4	210.0 ± 80.0	260.0 ± 80.0	Formula	40.2 ± 18	39.7 ± 16
Mattack (2015)	10.2 ± 9.2	18.6 ± 8.3	217.0 ± 258.0	293.0 ± 163.0	Formula	39.2 ± 31.9	62.0 ± 29.0
Shi (2014a)	11.6 ± 5.1	13.9 ± 7.6	206.0 ± 70.0	231.0 ± 90.0	NM	41.2 ± 22.2	40.4 ± 16.8
Shi (2014b)	10.5 ± 6.2	16.0 ± 5.8	182.0 ± 70.0	278.0 ± 80.0	NM	36.6 ± 17.7	43.2 ± 18.0
Tsilidis (2014)	14.1 ± 6.1	15.9 ± 6.2	244.0 ± 104.0	273.0 ± 105.0	Formula	39.6 ± 17.4	43.3 ± 18.0
Hayek (2014)	13.1 ± 5.9	17.1 ± 8.7	248.0 ± 128.0	348.0 ± 198.0	Formula	37.51 ± 15.3	35.88 ± 17.8
Kim (2014)	13.3 ± 1.1	19.6 ± 1.1	264.0 ± 17.0	306.0 ± 16.0	Formula	42.1 ± 25.7	48.8 ± 21.5
Asare-Anane (2014)	10.8 ± 5.0	15.6 ± 3.9	200.0 ± 100.0	400.0 ± 100.0	Formula	27.6 ± 2.0	27.9 ± 1.3
Mazur (2014)	13.1 ± 1.1	15.4 ± 0.4	NM	NM	/	NM	NM
Rabijewski (2013)	13.3 ± 1.7	17.1 ± 1.7	315.0 ± 80.0	382.0 ± 70.0	Formula	30.9 ± 2.0	28.7 ± 2.0
Ho (2013)	13.2 ± 4.6	15.3 ± 5.3	267.0 ± 90.0	299.0 ± 90.0	Formula	NM	NM
Fui (2013)	12.4 ± 3.4	13.6 ± 4.2	250.0 ± 71.2	229.0 ± 64.5	Formula	31.0 ± 22.2	39.0 ± 18.5
Goto (2012)	16.3 ± 5.9	18.7 ± 5.9	NM	NM	/	72.6 ± 28.3	76.7 ± 28.9
Bai (2011)	14.9 ± 3.1	16.0 ± 3.4	NM	NM	/	NM	NM
Biswas (2012)	13.7 ± 6.0	19.4 ± 5.8	250.0 ± 80.0	390.0 ± 130.0	Formula	NM	NM
Cao (2011)	13.8 ± 4.7	15.9 ± 6.1	9.8 ± 4.3	10.0 ± 3.8	ELISA	165.0 ± 96.1	176.0 ± 88.3
Dhindsa (2010a)	12.8 ± 5.2	13.5 ± 5.8	204 ± 68.0	215 ± 67.0	Formula	76.0 ± 27.8	71.4 ± 27.6
Dhindsa (2010b)	12.4 ± 4.9	13.5 ± 4.8	198 ± 68.0	211 ± 67.0	/	57.0 ± 27.8	58.8 ± 27.5
Dhindsa (2010c)	11.5 ± 4.7	12.2 ± 4.6	176.0 ± 67.0	193.0 ± 68.0	/	53.6 ± 27.5	51.8 ± 27.6
Ibanez (2008)	10.6 ± 2.9	20.3 ± 6.0	45.7 ± 15.6	54.6 ± 15.5	Radioimmunoassay	NM	NM
Hamdan and Al-Matubsi (2008)	15.6 ± 10.4	17.2 ± 10.4	NM	NM	/	NM	NM
Crawford (2007)	10.4 ± 5.1	13.7 ± 6.9	NM	NM	/	NM	NM
Selvin (2007)	14.1 ± 6.1	17.7 ± 11.6	NM	NM	/	38.9 ± 18.7	35.0 ± 27.5
Chen (2006a)	12.1 ± 4.1	14.2 ± 5.1	NM	NM	/	NM	NM
Corona (2006)	14.5 ± 6.0	16.6 ± 6.1	39.0 ± 14.9	45.0 ± 14.9	Radioimmunoassay	NM	NM
Achemlal (2005)	13.4 ± 7.2	11.7 ± 6.2	NM	NM	/	NM	NM
Pitteloud (2005)	13.1 ± 4.0	18.0 ± 6.5	NM	NM	/	NM	NM
Tong (2005)	17.1 ± 5.3	17.8 ± 5.9	NM	NM	/	23.6 ± 10.8	29.9 ± 12
Rhoden( 2005)	16.3 ± 4.9	18.2 ± 6.1	50.0 ± 30.0	60.0 ± 20.0	Radioimmunoassay	NM	NM
Corona (2004)	14.5 ± 5.8	16.6 ± 6.1	36.4 ± 14.0	44.4 ± 15.8	Radioimmunoassay	NM	NM
Corrales (2004)	15.6 ± 5.1	18.0 ± 5.2	38.1 ± 7.7	40.9 ± 14.7	Radioimmunoassay	NM	NM
Svartberg (2004)	11.2 ± 5.4	13.2 ± 5.1	NM	NM	/	43.8 ± 21.4	51.8 ± 22.0
Abate (2002)	NM	NM	49.0 ± 10.0	60.0 ± 25.0	Radioimmunoassay	19.1 ± 14.0	19.1 ± 14.0
Jang (2001)	15.5 ± 6.2	18.4 ± 5.3	NM	NM	/	48.1 ± 12.3	52.8 ± 20.8
Abou-Seif and Youssef (2001)	3.6 ± 0.8	7.6 ± 1.1	NM	NM	/	NM	NM
Chearskul (2000)	12.4 ± 5.6	16,1 ± 6.6	NM	NM	/	NM	NM
Zietz (2000)	11.8 ± 0.5	14.3 ± 0.5	NM	NM	/	NM	NM
Defay (1998a)	13.8 ± 5.1	20.5 ± 7.5	75.3 ± 31.9	109.0 ± 41.6	Radioimmunoassay	NM	NM
Defay (1998b)	16.4 ± 4.8	20.2 ± 6.7	79.1 ± 24.4	103.3 ± 39.6	Radioimmunoassay	NM	NM
Tibblin (1996a)	15.0 ± 5.5	17.3 ± 5.3	58.8 ± 16.6	69.0 ± 22.5	Radioimmunoassay	41.1 ± 24.5	51.5 ± 30.5
Andersson (1994)	16.0 ± 7.5	22.6 ± 10.6	NM	NM	/	25.0 ± 16.3	41.3 ± 19.6
Barrett-Connor (1992)	14.7 ± 5.8	17.4 ± 5.6	NM	NM	/	NM	NM
Barrett-Connor (1990)	17.0 ± 6.1	18.5 ± 6.3	NM	NM	/	28.5 ± 19.2	32.9 ± 19.3
Semple (1988)	14.2 ± 4.6	14.9 ± 4.6	NM	NM	/	NM	NM
Small (1987)	12.9 ± 5.9	17.7 ± 6.1	NM	NM	/	NM	NM
Ando (1984)	16.9 ± 5.8	20.1 ± 8.9	NM	NM	/	NM	NM
Phillips (1984)	17.7 ± 7.9	19.3 ± 5.7	NM	NM	/	NM	NM
Daubresse (1978a)	23.4 ± 2.0	28.0 ± 7.3	NM	NM	/	NM	NM
Daubresse (1978b)	15.6 ± 5.8	16.6 ± 4.7	NM	NM	/	NM	NM
Shahwan (1978a)	15.6 ± 10.7	19.0 ± 6.3	NM	NM	/	NM	NM
Shahwan (1978b)	16.3 ± 8.5	19.0 ± 6.3	NM	NM	/	NM	NM
Li(2016)	15.0 ± 5.7	17.6 ± 5.7	NM	NM	/	NM	NM
Atlantis(2016)	15.0 ± 5.9	17.7 ± 5.9	NM	NM	/	NM	NM
Salminen (2015)	15.8 ± 6.5	20.8 ± 7.6	236.5 ± 91.5	270.1 ± 91.1	Formula	38.7 ± 21.5	53.1 ± 21.1
Svartberg (2014)	11.6 ± 5.3	12.7 ± 5.0	201 ± 77	187 ± 65	Formula	43.2 ± 21.4	54.5 ± 24.6
Chen (2006b)	15.2 ± 5.9	14.1 ± 5.1	NM	NM	/	NM	NM
Laaksonen (2004)	18.0 ± 6.6	20.6 ± 6.9	NM	NM	/	NM	NM
Stellato (2000)	15.2 ± 6.6	18.4 ± 5.4	288.0 ± 17.0	347.0 ± 35.0	Centrifugal  ultrafiltration	24.4 ± 1.4	32.3 ± 0.5
Haffner (1996)	17.3 ± 5.1	18.0 ± 5.1	NM	NM	/	NM	NM
Tibblin (1996b)	13.6 ± 4.1	17.3 ± 5.3	NM	NM	/	NM	NM

FT: free testosterone; NM: not mentioned; SHBG: sex hormone binding globulin; T2DM: type 2 diabetes mellitus.

Figure 2. Forest plot of the WMD of FT in patients with T2DM in cross-sectional studies.

Figure 3. Forest plot of the WMD of SHBG in patients with T2DM in cross-sectional studies.

Table 3. Meta-analyses results.

Subgroup	Cross-sectional studies		Prospective studies
	No. of studies	Pooled OR (95%CI)	No. of studies	Pooled OR (95%CI)
TT
All studies	54	−2.98 (−3.48 to −2.47)	9	−2.35 (−3.24 to −1.46)
Ethnicity
Caucasian	34	−2.91 (−3.55 to −2.27)
Asian	15	−3.14 (−4.30 to −1.98)
African	5	−2.95 (−4.49 to −1.40)
Erectile function
ED	7	−2.57 (−3.63 to −1.52)
Non-ED	3	−5.00 (−7.42 to −2.59)
NM	44	−2.99 (−3.56 to −2.43)
FT
All studies	26	−32.82(−39.70 to −25.95)	3	−25.69 (−83.98 to 32.05)
Ethnicity
Caucasian	16	−21.69 (−28.95 to −14.43)
Asian	7	−49.60 (−79.24 to −19.95)
African	3	−75.71 (−136.99 to −14.43)
Erectile function
ED	4	−20.03 (−30.15 to −9.90)
Non-ED	1	−96.00 (−131.03 to −60.97)
NM	21	−36.42 (−47.85 to −24.99)
Detecting method
Radioimmunoassay	9	−9.40 (−12.44 to −6.37)
Formula	14	−57.68 (−80.81 to −34.55)
SHBG
All studies	25	−2.47 (−3.93 to −1.02)	3	−0.62 (−1.88 to 0.63)
Ethnicity
Caucasian	14	−1.75 (−4.19 to 0.69)
Asian	10	−5.72 (−9.78 to −1.66)
African	1	−0.30 (−0.76 to 0.16)

FT: free testosterone; NM: not mentioned; SHBG: sex hormone binding globulin; T2DM: type 2 diabetes mellitus; TT: total testosterone.