. 2020 Oct 17;22(1):125–133. doi: 10.1007/s11154-020-09599-w

Table 2.

Overview of the articles published on mortality and growth hormone replacement therapy

Reference and country	Etiology	Study population (no.) and mean age*	Controls	Follow-up duration†	Conclusions
Svensson et al. (2004) [20] Sweden	Hypopituitarism including 4% craniopharyngioma and 5% extrapituitary tumor; Acromegaly + CD excluded	289 (F 103, M 186) 47.6 yr	General population	5 yr	All-cause mortality SMR: 0.84 (95% CI 0.36–1.66) W: 0 (95% CI 0.36–1.62), M: 1.11 (95% CI 0.48–2.20); CV mortality SMR: 0.27 (95% CI 0.03–0.99) W: 0 (95% 0–3.15), M: 0.33 (95% CI 0.04–1.18); CVA mortality SMR: 1.95 (95% CI 0.78–4.02) W: 1.22 (95% CI 0.02–6.80), M: 2.17 (95% CI 0.79–4.71); Malignancy mortality SMR: 0.88 (95% 0.35–1.80) W: 0.34 (95% CI 0.01–1.92), M: 1.17 (95% CI 0.43–2.56)
van Bunderen et al. (2011) [18] The Netherlands	Hypopituitarism including 11% craniopharyngioma, 9% extrapituitary tumor, and 10% acromegaly + CD	2229 (F 1069, M 1160) 42.6 yr	Untreated GHD (n = 109); General population	5.7 yr	All-cause mortality HR, untreated vs. treated: 1.89 (95% CI 0.86–4.13); All-cause mortality SMR: 1.27 (95% CI 1.04–1.56) W: 1.66 (95% CI 1.23–2.23), M: 1.06 (95% CI 0.81–1.40); CV mortality SMR: 1.35 (95% CI 0.95–1.94) W: 2.52 (95% CI 1.57–4.06), M: 0.84 (95% CI 0.49–1.45); Malignancy mortality SMR: 0.86 (95% CI 0.60–1.25) W: 1.12 (95% CI 0.66–1.88), M: 0.70 (95% CI 0.42–1.19)
Gaillard et al. (2012) [24] International (KIMS)	Hypopituitarism including 11% craniopharyngioma, 8% extrapituitary tumor, and 8% acromegaly + CD	13,983 (F 7174, M 6809) 43.8 yr	General population	4.9 yr	All-cause mortality SMR: 1.13 (95% CI 1.04–1.24) W: 1.56 (95% CI 1.36–1.78), M: 0.94 (95% CI 0.84–1.06); CV mortality SMR: 0.83 (95% CI 0.63–1.08); CVA mortality SM: 1.88 (95% CI 1.44–2.41); Malignancy mortality SMR: 0.88 (95% CI 0.74–1.03)
Burman et al. (2013) [25] Sweden (from KIMS)	Hypopituitarism including 11% craniopharyngioma, 10% extrapituitary tumor, and 7% acromegaly + CD; 99.7% GHRT use	1286 (F 612, M 674) 44.8 yr	General population	9.6 yr	All-cause mortality SMR: 1.42 (95% CI 1.18–1.70) W: 1.63 (95% CI 1.18–2.18), M: 1.33 (95% CI 1.05–1.66); CV mortality SMR: 1.21 (95% CI 0.81–1.74); CVA mortality SMR: 1.82 (95% CI 0.91–3.26); Malignancy mortality SMR: 0.92 (95% CI 0.61–1.34)
Hartman et al. (2013) [22] USA (HypoCCS)	Hypopituitarism including 11% craniopharyngioma	1988 (F 44%, M 56%) 46 yr	Untreated GHD (n = 442); General population	2.3 yr	All-cause mortality: 1.66% vs. GHD 2.49%; Malignancy mortality: 1.61% vs. GHD 2.71%; All-cause mortality SMR: 0.86 (95% CI 0.59–1.21)
Stochholm et al. (2014) [19] Denmark	Hypopituitarism including unknown number of craniopharyngioma, extrapituitary tumor, and acromegaly + CD	133 (F 72, M 61) 32 yr	Untreated GHD (n = 143); General population	15 yr	All-cause mortality HR: 1.78 (95% CI 0.84–3.77) vs. general population; All-cause mortality HR: 0.34 (95% CI 0.15–0.77) vs. untreated; Malignancy mortality HR: 3.45 (95% CI 1.09–10.93) vs. general population
Tritos et al. (2014) [26] International (KIMS)	GHD after acromegaly	164 (F 101, M 63 52.9 yr	NFPA (n = 2467); General population	5 yr	All-cause mortality SMR: 1.32 (95% CI 0.70–2.25) for acromegaly GHD vs. 0.58 (95% CI 0.48–0.70) for NFPA (P = 0.04); CV mortality SMR: 2.89 (95% CI 1.16–5.92) for acromegaly GHD vs. 0.68 (95% CI 0.48–0.94) for NFPA (P = 0.0004); CVA mortality SMR: 1.60 (95% CI 0.05–7.95) for acromegaly GHD 0.96 (95% CI 0.53–1.60) for NFPA (NS)
Olsson et al. (2017) [17] Sweden	NFPA	207 (F 62, M 145) 56.3 year	Untreated (n = 219) 11% (n = 25) tested for GHD, of which 100% GHD; General population	12 yr	A cox-model revealed a decreasing mortality with the years of GHRT (HR 0.94 [95% CI 0.91–0.98, P = 0.0063]) and an increasing mortality with age at start in the study (HR 1.10 [95% CI 1.08-1,12, P < 0.0001]). Other factors, such as treatment with radiotherapy, BMI, gender and different replacement therapies, did not have a significant effect. All-cause mortality SMR: 0.65 (95% CI 0.44–0.94) (P = 0.009 vs. untreated); W 0.71 (95% CI 0.31–1.41), M 0.63 (95% CI 0.39–0.97); Malignancy mortality SMR: 0.29 (95% CI 0.08–0.73)

Reference and country

Etiology

Study population (no.) and mean age*

Controls

Follow-up duration†

Conclusions

Svensson et al. (2004) [20] Sweden

Hypopituitarism including 4% craniopharyngioma and 5% extrapituitary tumor;

Acromegaly + CD excluded

289

(F 103, M 186)

47.6 yr

General population

5 yr

All-cause mortality SMR: 0.84 (95% CI 0.36–1.66)

W: 0 (95% CI 0.36–1.62), M: 1.11 (95% CI 0.48–2.20);

CV mortality SMR: 0.27 (95% CI 0.03–0.99)

W: 0 (95% 0–3.15), M: 0.33 (95% CI 0.04–1.18);

CVA mortality SMR: 1.95 (95% CI 0.78–4.02)

W: 1.22 (95% CI 0.02–6.80), M: 2.17 (95% CI 0.79–4.71);

Malignancy mortality SMR: 0.88 (95% 0.35–1.80)

W: 0.34 (95% CI 0.01–1.92), M: 1.17 (95% CI 0.43–2.56)

van Bunderen et al. (2011) [18] The Netherlands

Hypopituitarism including 11% craniopharyngioma, 9% extrapituitary tumor, and 10% acromegaly + CD

2229

(F 1069, M 1160)

42.6 yr

Untreated GHD (n = 109);

General population

5.7 yr

All-cause mortality HR, untreated vs. treated: 1.89 (95% CI 0.86–4.13);

All-cause mortality SMR: 1.27 (95% CI 1.04–1.56)

W: 1.66 (95% CI 1.23–2.23), M: 1.06 (95% CI 0.81–1.40);

CV mortality SMR: 1.35 (95% CI 0.95–1.94)

W: 2.52 (95% CI 1.57–4.06), M: 0.84 (95% CI 0.49–1.45);

Malignancy mortality SMR: 0.86 (95% CI 0.60–1.25)

W: 1.12 (95% CI 0.66–1.88), M: 0.70 (95% CI 0.42–1.19)

Gaillard et al. (2012) [24]

International (KIMS)

Hypopituitarism including 11% craniopharyngioma, 8% extrapituitary tumor, and 8% acromegaly + CD

13,983

(F 7174, M 6809)

43.8 yr

General population

4.9 yr

All-cause mortality SMR: 1.13 (95% CI 1.04–1.24)

W: 1.56 (95% CI 1.36–1.78), M: 0.94 (95% CI 0.84–1.06);

CV mortality SMR: 0.83 (95% CI 0.63–1.08);

CVA mortality SM: 1.88 (95% CI 1.44–2.41);

Malignancy mortality SMR: 0.88 (95% CI 0.74–1.03)

Burman et al. (2013) [25]

Sweden (from KIMS)

Hypopituitarism including 11% craniopharyngioma, 10% extrapituitary tumor, and 7% acromegaly + CD;

99.7% GHRT use

1286

(F 612, M 674)

44.8 yr

General population

9.6 yr

All-cause mortality SMR: 1.42 (95% CI 1.18–1.70)

W: 1.63 (95% CI 1.18–2.18), M: 1.33 (95% CI 1.05–1.66);

CV mortality SMR: 1.21 (95% CI 0.81–1.74);

CVA mortality SMR: 1.82 (95% CI 0.91–3.26);

Malignancy mortality SMR: 0.92 (95% CI 0.61–1.34)

Hartman et al. (2013) [22]

USA (HypoCCS)

Hypopituitarism including 11% craniopharyngioma

1988

(F 44%, M 56%)

46 yr

Untreated GHD (n = 442);

General population

2.3 yr

All-cause mortality: 1.66% vs. GHD 2.49%;

Malignancy mortality: 1.61% vs. GHD 2.71%;

All-cause mortality SMR: 0.86 (95% CI 0.59–1.21)

Stochholm et al. (2014) [19]

Denmark

Hypopituitarism including unknown number of craniopharyngioma, extrapituitary tumor, and acromegaly + CD

133

(F 72, M 61)

32 yr

Untreated GHD (n = 143);

General population

15 yr

All-cause mortality HR: 1.78 (95% CI 0.84–3.77) vs. general population;

All-cause mortality HR: 0.34 (95% CI 0.15–0.77) vs. untreated;

Malignancy mortality HR: 3.45 (95% CI 1.09–10.93) vs. general population

Tritos et al. (2014) [26]

International (KIMS)

GHD after acromegaly

164

(F 101, M 63

52.9 yr

NFPA (n = 2467);

General population

5 yr

All-cause mortality SMR: 1.32 (95% CI 0.70–2.25) for acromegaly GHD vs. 0.58 (95% CI 0.48–0.70) for NFPA (P = 0.04);

CV mortality SMR: 2.89 (95% CI 1.16–5.92) for acromegaly GHD vs. 0.68 (95% CI 0.48–0.94) for NFPA (P = 0.0004);

CVA mortality SMR: 1.60 (95% CI 0.05–7.95) for acromegaly GHD 0.96 (95% CI 0.53–1.60) for NFPA (NS)

Olsson et al. (2017) [17] Sweden

NFPA

207

(F 62, M 145)

56.3 year

Untreated (n = 219) 11% (n = 25) tested for GHD, of which 100% GHD;

General population

12 yr

A cox-model revealed a decreasing mortality with the years of GHRT (HR 0.94 [95% CI 0.91–0.98, P = 0.0063]) and an increasing mortality with age at start in the study (HR 1.10 [95% CI 1.08-1,12, P < 0.0001]). Other factors, such as treatment with radiotherapy, BMI, gender and different replacement therapies, did not have a significant effect.

All-cause mortality SMR: 0.65 (95% CI 0.44–0.94) (P = 0.009 vs. untreated);

W 0.71 (95% CI 0.31–1.41), M 0.63 (95% CI 0.39–0.97);

Malignancy mortality SMR: 0.29 (95% CI 0.08–0.73)

*Mean age given for total population or by sex

†Mean or median

CD: Cushing’s disease; CI: confidence interval; CV: cardiovascular; CVA; cerebrovascular accident, GHD; growth hormone deficiency; GHRT; growth hormone replacement therapy; HR; hazard ratio; HypoCCS: Hypopituitary Control and Complication Study; KIMS: Pfizer International Metabolic Database; M: men; NFPA, non-functioning pituitary adenoma; NS: not statistically significant, ND: no data; SMR: standardized mortality ratio; W: women; yr, year