Effects of hormone replacement therapy on growth hormone secretion patterns in correlation to somatometric parameters in healthy postmenopausal women

JOURNAL OF THE CLIMACTERIC & POSTMENOPAUSE

Maturitas 22 (1995) 239-246

Effects of hormone replacement therapy on growth hormone secretion patterns in correlation to somatometric parameters in healthy postmenopausal women Beda Hartmann* a, Sylvia Kirchengastb, Alexander Albrecht”, Thomas Lamla, Diana Bikas”, Johannes Huber” aVniversiriits-Frauenklinik. Spitalgasse 23, A-1090 Vienna, Austria bInstitute for Human Biology, University of Vienna, Vienna, Austria

Received 6 April 1995;revisionreceived16August1995;accepted 23 August 1995

Objectives: The aimof the presentstudywasto investigatethe influenceof a continousestrogen,cyclic progesterone replacementtherapy on the Secretionof growth hormone(GH) and IGF I aswell asof somatometric-GHcorrelation patterns.Methodr: The studyincluded 23 healthy postmenopausal women. Of the proband group 13 randomly selected

women weretreated with orally applicated 2 mg estradiol-valerat (E2V) and 10 mg dydrogesterone for 10 months. Ten women did not receive any hormonal treatment during this time. After 10 months all probands were reexamined and their OH and IGF I secretion,aswell as their somatometric-hormonal correlation patterns, compared with those of a fertile control group. Results: It could be shown,that in postmenopausal womena IO-monthoral hormonereplacement therapy led to a significant increase of GH- and IGF I levels, however, the treated postmenopausal women did not reach the levels of the fertile controls. Those womenwho did not receive any hormonal treatment and the postmenopausal womenbeforeHRT showednearly identicalGH- and IGF I levelsaswell assomatometric-GHcorrelation patterns.Conclusions: The resultsof the presentpaperindicatea markedinfluenceof estrogens on GH and IGF

I secretion. Furthermore, hormonal replacement therapy (HRT) may influence somatometric GH correlation patterns too. Keywork Menopause;Hormone replacementtherapy; Growth hormonesecretionpatterns; Somatometricparameters;Body build

1. Introduction GH shows typically pulsatile secretion patterns with peaks at about midnight [l-3]. The amplitude and the frequency of these discrete pulses are regulated by a complex interaction of * Corresponding author.

endogeneous and exogeneous stimuli such as age, sex, body composition, physical activity and nutrition [1,4-7). Especially the influence of gonadal steroids on the GH- and IGF I-axis can be observed: Compared with men, females show higher circulating GH concentrations after activity and fasting [1,5] and generally higher 24 h integrated GH levels [6]. Furthermore, postmeno-

0378.5122@5i$O9.50 0 1995ElsevierScience IrelandLtd. All rightsreserved SSDI 0378-5122(95)00942-E

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pausal women show lower GH-concentrations and IGF I levels than premenopausal ones [6,8]. Therefore a positive correlation between estrogen levels and GHAGF I levels can be assumed 19,lo]. Several studies have shown an increase of GHand IGF I levels in postmenopausal women after application of estrogen replacement therapy [ 1 1- 151, however the route of administration, oral or transdermal, has been a major determinant of the effects of exogeneous estrogens on the GWIGF I axis [16]. Additionally most of the investigators used the synthetic estrogen, ethinyl estradiol for oral replacement therapy [ 12,13,16]. Furthermore typical correlation patterns between GH secretion and somatometric parameters could be stated for healthy males as well as for pre- and postmenopausal females [8,17,18]. It turned out that the amount of body fat correlated significantly negatively with the frequencies of the GH pulses and the amplitude of the individual bursts, however, the number of significant correlations differed markedly between pre- and postmenopausal women. Premenopausal females showed more and higher significant correlations than postmenopausal women [8]. During the post-fertile lifespan typical wellknown somatic changes occur: body weight and body mass increase, and additional fat deposits, especially at the abdominal region, are applied [19-211. As mentioned above, body fat is associated negatively with endogenous GH-concentrations. We therefore assume that the increasing amount of adipose tissue in postmenopausal women is coinduced by the decrease of GH secretion, which is related to the reduced estradiol (E2) production. We also suggest that the application of natural estrogens can interrupt the decrease of GH production and leads to GH secretion patterns comparable with those observed in fertile women. The aim of the present study was to test our hypothesis investigating the influence of oral applicated natural estrogens on the GH/ IGF I secretion patterns in healthy postmenopausal women. Since previous studies yielded [22] differential somatometric-hormonal correlation patterns for pre- and postmenopausal females, the impact of an E2V replacement therapy on the somatometric-GH correlation patterns was also tested.

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2. Subjects and methods 2.1. Subjects

The 23 probands aged between 39 and 56 years (x = 5 1.8) were examined from January to August 1992 and reexamined between December 1992 and July 1993 after giving written informed consent. All probands were postmenopausal women whose menopause had occurred spontaneously at a minimum interval of 1 year prior to the present investigation (x = 49.8). A twice determination of the sex hormone status yielded estradiol levels below 25 pg/ml and FSH levels above 40 miU/ml. All probands were healthy and had not received any hormonal replacement therapy up to the time of the first examination. After the first examination the probands were divided into two randomly selected groups: Group 1 comprised 13 women who were treated with an E2 /progesterone replacement therapy consisting of 2 mg E2V continously and 10 mg dydrogesteron for 10 days per month. Group 2 comprised 10 women who were not substituted. The probands of the two groups did not differ significantly with regard to their age at the time of investigation and to their age at menopause. After 10 months the probands were reexamined, those females who had been substituted in the pure estrogen phase. At this time one proband from group 1 left the group because of severe bleeding. The GH and IGF I levels as well as the hormonal-somatometric correlation patterns were compared with those of a group of 25 healthy women with regular cycles aged between 20 and 37 years (x = 27.6). The procedure in this group was performed during the early follicular phase (5’h to 10th day of cycle). We informed our probands regarding the aim of our examination and obtained a written consent from each subject. 2.2. Hormone assays

The postmenopausal status of the probands was confirmed by determination in duplicate of E2, FSH and LH levels. Blood samples were collected in the morning between 8.00 and 10.00 h (see Table 1). To draw up a daily profile of GH and IGF I secretion patterns the probands were admitted to the I. Universitiits-Frauenklinik for 24 h. The examinations were started at 10.00 h after the pro-

B. Hartmann et al. / Maturitas 22 (1995) 239-246

bands had a deprivation of food for more than 10 h. During the examination the probands only had less physical exercise. Blood was taken from the probands at the above mentioned time per 24 h in intervals of 2 h, i.e. 8 ml blood in each case. Thereafter the drain tube was kept passable by irrigation with physiologic sodium chloride solution. To avoid the dilution effect 5 ml blood was taken in each case and disposed before the actual blood withdrawal. Serum was separated and stored at -20° C until assayed. In order to obtain information about the secretory patterns we used the DEDECT program. Analyses of the blood samples were carried out at the central hormone labratory of the Allgemeines Krankenhaus in Vienna. All labratory tests were performed according to GLP directions. The GH levels were measured by the highly specific Double Antibody hGH-assay by Diagnostic Product corporation, with a limiting value of 0.9 rig/ml. IGF I levels were measured by 125i radioimmunassay (Serono seria assay). 17@-estradiol was measured by a solid phase 1125i radioimmunassay (Diagnostic Product corporation) with an interassay variance of 7.8%. LH and FSH were determined by an enzymimmunassay (Boehringer Mannheim Enzymun). 2.3. Somatometric traits From each proband the following somatometric parameters, especially suited for a detailed description of the amount and distribution of the subcutaneous fat tissue [23], were taken according to Knussmann [24]; Measurements: stature, chest girth, waist girth, abdominal girth, body weight, skinfold triceps, skinfold subscapular and skinfold abdominal. Furthermore, the body mass index (BMI) was computed. 2.4. Statistical evaluation Statistical evaluation of the data was carried out using the SPSSX program version. Since the results of the Kolmogoroff-Smirnov test indicated that no normal distribution could be assumed for all hormonal and somatometric variables, for the statistical analyses nearly exclusively nonparamteric procedures were applied. Mann-Whitney tests and Duncan tests were carried out in order to test group differences in hor-

241 GH

ns/ml

12

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9-

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I

10 -

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12

14

16

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fertile controls

I

i

20 22 lime(h) .’

I

I

I

I

24

2

4

6

‘.’ postmenopausal

l

6

before HR7

Fig. I. Means and standard deviations of GH levels in fertile controls and postmenpausal women before HRT.

mone values with respect to their statistical significance-. The relations between body dimensions and hormonal variables are described by partial correlation coefficients (age = constant). Partial correlations were computed in order to eliminate the influence of age on the correlation coefficients. The area under the curve (Auc) was computed by using the trapezoid rule. 3. Results 3.1. Growth hormone and IGF I - levels Means and standard deviations of the GH and IGF I levels are listed in Figs. l-4. The fertile control group showed significantly higher GH levels than the postmenopausal probands before HRT (P < 0.01). This could also be demonstrated for the IGF I levels. After 10 months of treatment nglml l2 i

I

-3 ’ IO d

12

14

postmenopausal

16

16

wth HRT

20 22 time (h) n

24

2

postmenopausal

4

6

6

wthout

HRT

Fig. 2. Means and standard deviations of GH levels in postmenpausal women without HRT and during HRT.

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Fig. 3. Means and standard deviations of IGF I levels in fertile controls and poshnenpausalwomen before HRT.

Fig. 4. Means and standard deviations of IGF I levels in postmenpausal women without HRT and during HRT.

with oral applicated natural estrogen a significant increase of GH and IGF I levels couJd be stated, however the GH concentration of treated women did not reach the level of fertile controls. Regarding the secretion patterns the GH secretion of the treated postmenopausal group resembled the secretion patterns of the fertile group. The highest secretion peak was reached at midnight, while in untreated women the highest secretion peak

occurred at 8.00 11, as in the postmenopausal women before HRT. Concerning the area under the curve (Auc) of GH and IGF I, the fertile controls surpassed the postmenopausal women before HRT group significantly (P < 0.001). After 10 months of treatment the Auc increased significantly (P < 0.001). In untreated women a slight decrease of the Auc could be observed (see Tables 1 and 2).

Table 1 Random sample parameters (means x, standard deviation S.D.) of estrogen-, LH and FSH levels, AUC of Growth hormone and IGF 1 and the somatometric variables (in mm, body weight in kg) and z-values (Mann-Whitney-tests) of Fertile and postmenopausal probands before HRT Hormone somatometfics

Fertile

Postmenopausal

(?I = 25)

(n=

SD.

X

152b&W LH (MIEfml) FSH (WE/ml) ALJC GH AUC IGF I

95.2 9.5 11.9 22.21 7.80

18.2 8.9 7.6 5.81 2.12

SD.

X

18.6 48.5 42.8 6.08 6.14

Stature Chest girth

1663.4

19.3

1620.7

looo.l

166.7

1055.8

waist

796.9 1006.5 61.9

183.1 182.5 17.6

218.0 205.1 241.8 22.1

104.5 123.4 122.5 4.0

girth

Abdominal girth Body weight Skinfolds TIicCps subscapular

Abdominal BMI Lqpd:

I

z-value

23)

16.3 7.8 6.9 2.43 2.31

-7.12'. -6.08** -7.14** -10.30*** -3.19**

866.0 1051.8 73.0

49.1 139.2 169.3 153.7 18.9

-5.21** -4.53" -5.29** -4.98** -5.332.

243.5 240.1 308.7 28.2

63.8 98.6 80.1 5.3

-6.29'; -7.11.' -6.98'. -7.02*+

AUC = Area under the curve. of sie: * P < 0.05; ** P < 0.01; l ** P < 0.001,

243

B. Hartmann et al. / Maturitas 22 (1995) 239-246

Table 2 random sample parameters (means x, standard deviation SD.) of estrogen-, LH and FSH levels, AUC of Growth hormone and IGF I and the somatometric variables (in inm, body weight in kg) and F-values (Duncan-tests) of postmenopausal women before HRT, after HRT and without HRT Hormone somatometrics

E2bvzhl) LH (ME/ml) FSH (ME/ml) AUC GH AUC IGF I Stature Chest girth Waist girth Abdom. girth Body weight Skinfolds Triceps Subscapular Abdominal BMI

Postmenopausal (n = 23)

Oral HRT (n = 12)

x

x

SD. I8.6b 48Sb 6.8b 6.08b 6.14b

16.3 7.8 6.9 2.43 2.31

no HRT (n = IO) SD.

123.4aqC 20.4=qc 17.8a,c l8.8Y 7.50a*=

SD.

X

99.8 9.8 4.3 8.21 4.27

F-value

17.2b 49.7b 44.4b 5.12b

6.04b

17.0 16.4 10.1 I.21 2.23

6.6** 5.8** 6.l** 7.3+** 5.5**

1620.7 1055.8 866.0 1051.8 73.0

49.1 139.2 169.3 153.7 18.9

1617.4 1059.1 857.8 1048.2 72.9

43.9 122.9 162.7 140.4 17.4

1622.8 1057.2 862.4 1051.1 73.3

41.8 133.5 158.9 139.2 17.9

0.5 0.8 1.1 0.4 0.6

243.5 240. I 308.7 28.2

63.8 98.6 80. I 5.3

242.2 239.1 306.7 28.1

59.7 86.8 84.2 5.1

243.9 242.2 307.2 28.2

61.4 14.3 73.6 4.9

0.5 0.7 0.5 0.4

Legend: AUC = Area under the curve. %ignificantly different from postmenopausal group before HRT. bSigniI&antly different from HRT group. cSignificantly different from group without HRT. Levels of significance: * P c 0.05; ** P < 0.01; l ** P < 0.001.

3.2. Somatometric parameters The means and standard deviations of the somatometric parameters of all proband groups are listed in Tables 1 and 2. The fertile controls surpassed the postmenopausal women in height exlusively. Regarding the body fat measures, the postmenopausal women showed significantly higher values (P c 0,Ol). After 10 months of HRT no marked changes in body build could be observed. The somatometric parameters of postmenopausal women with HRT and those of postmenopausal women without HRT did not differ markedly, 3.3. Somatometric-GH correlation patterns Regarding the direction of the correlations, the GH-somatometric correlation patterns were very similar in postmenopausal females before HRT and fertile controls. The stature correlated positively but not significantly with the Auc of GH, while those somatometric variables, which

described the amount and the distribution of the subcutaneous fat tissue and the body weight, correlated significantly negatively with the individual GH levels (see Table 3). Statistically significant correlations between somatometrics and the Auc of IGF I were not observed. 3.4. GH-estradiol correlation patterns The partial correlations between estradiol levels and the Auc of GH as well as IGF I showed significantly positive correlations for fertile controls and postmenopausal females after 10 months of HRT. Postmenopausal women without HRT exhibited no statistically significant correlations. No significant correlations were found for the Auc of IGF I and E2 in all probands (see Table 4). 4. Dismssion Typical association patterns between body build

244 Table

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3

Partial correlation (age = constant) between body dimensions and AUC of Growth hormone Somatometrics Stature Chest girth Waist girth Abdominal girth Body weight Skinfolds Triceps Subscapular Abdominal Body mass index

Fertile controls 0.10 -0.53+*

-0.61” -0.63*** -0.59**

-0.71*** -0.69***

-o&t*** -0.592'

Postmenopausal before HRT

Oral HRT 0.11

no HRT 0.10

0.12 -0.39* -0.42' -0.37+ -0.42*

-0.57** -0.59** -0.58** -0.54,

-0.42. -0.44* -0.33 -0.372

-0.432 -0.44* -0.46* -0.38*

-0.69*** -0.64*** -0.61*** -0.59**

-0.40* -0.42* -0.47* -0.40*

Legend: AUC = Area under the curve. Levels of significance: l P < 0.05; ** P < 0.01; *** P < 0.001.

and GH levels could be observed in healthy males and females [f&17,18]. The marked interaction between body build and GH secretion may be explained by the well known metabolic and growth-promoting effects of GH 125,261. According to our hypothesis the marked decrease of GH secretion after menopause which accompanies the menopausal decrease of estradiol production is, at least in part, responsible for the well-known postmenopausal weight gain and increase of adipose tissue, in particular in the abdominal region. In the present study the influence of a lo-month oral HRT on GH and IGF I secretion and the somatometric-hormonal correlation patterns was tested. As expected, it transpired that HRT leads to a significant increase of GH and IGF I levels, however the postmenopausal women after HRT did not reach the GH and IGF I levels of the fertile controls. These results are in accordance with the

findings of previous studies [ 13- 181, which describe a strong relationship between the application of estrogen replacment therapy and increasing GH secretion. Weissberger et al. [la] recently reported that oral estradiol treatment leads to a threefold increase in GH levels and to a slight reduction in IGF I, while transdermal administration elevates IGF I without changing GH concentrations. The difference to our results - we observed an increase in GH and IGF I concentrations in course of orally administered E2 - could be based on the fact that the cited study used the synthetic estrogen, ethinyl e&a&d for oral therapy while we used E2V. The influence of estrogen on GH-IGF I physiology may be due to the direct influence of estrogen on the pituitary gland or the hypothalamus [27,28]. That HRT treated postmenopausal females did not reach the GH and IGF I levels of

Table 4 Partial correlations (age = constant) between Estradiol levels and the AUC of Growth hormone and IGF 1 AUC

Fertile controls

Postmenopausal before HRT

Oral HRT

no HRT

GH IGF 1

0.52** 0.33

0.41' 0.31

oso* 0.32

0.34 0.31

Legend: AUC = Area under the curve. Levels of significance + P < 0.05; ** P c 0.01.

B. Hartmann et al. /Maturiras 22 (1995) 239-246

fertile controls may be explained by the independent effect of age on GH secretion [1,6,7,29-311. During the third, fourth and fifth decades of life a marked decline of GH secretion occurs [4,6,8]. Since during this phase of life in females a decrease of endogeneous estrogens is evident, age and estrogen levels have an independent but also an interrelated effect on GH secretion [6]. During this stage of life an increase of relative adiposity may also occur [29-311. Our postmenopausal probands also showed significantly higher body fat measures and body mass indices. In the present study it could be demonstrated that HRT treated postmenopausal females showed nearly the same correlation patterns between somatometric variables, describing the amount of body fat, and GH levels as the fertile controls. Since no statistically significant differences regarding the somatometric variables and age between the two postmenopausal proband groups could be assumed, it is concluded that estrogen levels may be coresponsible for the expression of correlations between body build and GH levels. References [I] Hartman ML, Iranmanesh A, Thorner MO, Veldhuis JD. Evaluation of pulsatile patterns of growth hormone release in humans: A brief review. Am J Hum Biol 1993; 5: 603-14. (21 Drobney EC, Amburn K, Baumann G. Circadian variation of basal plasma growth hormone in man. J Clin Endocrinol Metab 1983; 57: 524-8. 131 Lucke C, Morgner KD, Kiinkel H. Lack of fluctuation in growth hormone secretion during early sleep in early and mid menstrual cycle. J Chn Endocrinol Metab 1974; 39: 585-8. 141 Hartman ML, Pezzoli SS, Thorner MO. Diminished pulsatile growth hormone secretion associated with aging is reversed by fasting. Clin Res 1991; 39: 165A. PI Hartman ML, Veldhuis JD, Johnson ML et al. Augmented growth hormone secretory burst frequency and amplitude mediate enhanced GH secretion during a two day fast in normal men. J Clin Endocrinol Metab 1992; 14: 757-65. 161Ho KY, Evans WS, Blizzard RM et al. Effects of sex and age on the 24-h profile of growth hormone secretion in man: Importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 1987; 64: 51-8. lranmanesh A, Lizaralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and the amplitude of growth hormone secre-

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