Role of ovarian
steroids in the regulation of secretion of hypogonadal women
sex
thyrotropin (TSH)
Winfried G Rossmanith, Claudia St\l=a"\bler,Reiner Benz, Stefan R Bornstein and Werner A Scherbaum Departments of Obstetrics-Gynecology and Internal Medicine', University of Ulm, Ulm/D, Germany
Rossmanith WG, Stäbler C, Benz R, Bornstein SR, Scherbaum WA. Role of ovarian sex steroids in the regulation of thyrotropin (TSH) secretion of hypogonadal women. Acta Endocrinol 1992;127:131-7. ISSN 0001-5598 The exact role of ovarian sex steroids in the neuroendocrine regulation of thyrotropin (TSH) release in women can only be accurately assessed in the absence of any considerable ovarian sex steroid feedback upon the hypothalamic-pituitary unit. Consequently, the unstimulated episodic and thyrotropin\x=req-\ releasing hormone (TRH) stimulated TSH secretion was evaluated in postmenopausal women before and during sequential ovarian sex steroid replacements. Seven euthyroid women (mean age: 59.4 years) were studied initially without any sex steroid replacement (control studies), then on the last day of a 21-day course of oral estradiol-valeriate (E2) administration (2 mg daily) and finally, on the last day of a 21-day course of oral estradiol-progesterone (E2/P4) replacement (2 mg E2 and 200mg micronized P4 daily). During all study occasions, blood was sampled at 10 min intervals for 10 h, while TRH (200 \g=m\giv) was administered 8 h after initiation of blood collections. Compared to the control conditions, serum E2 and P4 concentrations markedly increased (p< 0.001) following oral E2 or E2/P4 treatments. Total triiodothyronine (T3) and thyroxine (T4) concentrations and free T3 and T4 equivalents remained unchanged during E2 and E2/P4 regimens. In the unstimulated secretory profiles, TSH was found to be episodically released, with little interindividual variability for each study condition. Since the TSH pulse attributes (pulse amplitudes, frequencies, interpulse intervals, mean TSH concentrations, by Cluster pulse algorithm) did not significantly change during E2 and E2/P4 replacements, the episodic character of TSH secretion virtually remained unchanged by sex steroid replacements. In addition, the TRH\x=req-\ stimulated TSH releases during E2 and E2/P4 replacement therapies closely resembled those during control conditions. These observations demonstrate that both the unstimulated episodic and TRH\x=req-\ stimulated TSH secretion are unaffected by ovarian sex steroid replacement in hypogonadal women. Collectively, our findings suggest that ovarian sex steroids may not be critically involved in the neuroendocrine regulation of TSH secretion in women.
Winfried D-7900
G Rossmanith, Department of Obstetrics-Gynecology, University of Ulm, Ulm/D, Germany
a general clinical impression, the prevalence of thyroid dysfunction is greater in women than in men. Such endocrine derangements are preferably encoun¬ tered in close temporal association with changes in the endogenous ovarian sex steroid environment, thereby particularly manifested during pregnancy and meno¬
As
pause (1). These clinical observations support the notion that ovarian sex steroids may be critical for the regula¬ tion of thyroid function in humans. Therefore, several
investigators have aimed
at determining a role of sex steroids in the neuroendocrine regulation of thyrotropin
(TSH) secretion. Using various experimental approaches in vivo and in vitro, numerous studies have been conducted both in animals (2-4) and in humans (5-7).
Yet, the diversity of obtained results precluded firm conclusions as to whether sex steroids critically partici¬ pate in the differential regulation of TSH release in humans. Based on the available information, contro¬ versy still exists as to the role of ovarian sex steroids for basal unstimulated and thyrotropin-releasing hormone
Prittwitzstrasse
43,
(TRH) stimulated TSH secretion in women. However, this issue should be thoroughly appraised, since the clinical impact of treatment with ovarian sex steroids or their synthetic dérivâtes on thyroid function may be decisive. A possible influence of ovarian sex steroids on the regulation of TSH secretion can be most accurately assessed when sex steroid feedback by the ovaries is virtually absent. The postmenopausal state of women would provide a physiologic condition in which women are deprived of any considerable ovarian feedback on the hypothalamic-pituitary unit (8). Their hypogonadal state may then represent a unique model to delineate the relative contribution, if any, of ovarian sex steroids in the neuroendocrine control of TSH secretion. Hence, TSH secretory profiles should be determined in the absence and presence of ovarian sex steroid feedback. We therefore studied hypogonadal (postmenopausal) women before and during ovarian sex steroid exposure, using frequent blood sampling.
132
Winfried G Rossmanith et al.
Experimental protocol Study population Seven postmenopausal women between the ages of 54 and 64 years (mean age: 59.4 years) participated in this study. All postmenopausal women were in good general health and did not suffer from any chronic disease known to interfere with the hormone secretion. The women had experienced natural cessation of their menstrual bleedings at least one year prior to this investigation. Endocrinological evaluation confirmed the hypogonadal state of postmenopause in all women studied. All women were euthyroid, as assessed by the finding of thyroxine (T4) and triiodothyronine (T5) as well as the free T4 (FT4E) and free T3 (FT3E) equivalents within the normal range of women. Subjects presenting with positive antibodies against thyroglobulin, TSH receptors or thyroid microsomes were excluded. None of the women was taking any medication known to interfere with physiological hormone release. This proto¬ col was approved by the local Ethics Committee, and informed written consent was obtained from each woman prior to the study.
Study design All
studied on three occasions. Initial conducted during the hypogonadal state of postmenopause, i.e. in the absence of any sex steroid replacement (control conditions). In addition, the women were studied on the last day of a 21 -day course of oral replacement of estradiol-valeriate (2 mg daily; Schering, Berlin, Germany). Final studies were con¬ ducted on the last day of administration of oral estrogen and progesterone (estradiol-valeriate 2 mg plus micronized progesterone 200 mg; Laboratoire Besins, Paris, France) for 21 days. Starting between 08.00 and 10.00, blood samples (3 ml) were obtained at 10 min intervals for 10 h through an iv catheter placed in a forearm vein. Eight hours after initiation of blood sampling, thyrotropin-releasing hormone (200 yg iv) was administered, while the blood sampling was continued uninterrup¬ tedly. The women were kept in recumbent positions, and were not permitted to smoke, to drink caffeinated beverages, or to sleep during the investigations. women were
investigations
were
acta endocrinologica 1992. 127
equivalents were determined by commercially available assays (Amersham, Braunschweig, Germany). An esti¬ mation of the free concentrations can be made by correcting the total hormone level of T3 or T4 using a thyroid hormone binding capacity value such as the T3
uptake.
The free thyroid index or equivalent was therefore calculated from the total T4 or T3 value and the T3 uptake (10). To establish TSH secretory profiles, serial determinations of TSH were performed in all collected samples using an ultrasensitive (0.04 ¿tlJ/1) immunoradiometric assay (Sorin, Duesseldorf, Germany). This assay has been previously characterized in detail (11). The mean intra-assay and interassay coefficients of variation (CV) were 3.2% and 4.8%, respectively, for the range of TSH concentations relevant in this study. All samples from one individual were analyzed in duplicate in
a
single assay to minimize interassay variability.
Pulse
analysis and data evaluation
identify significant fluctuations within the hormone a computerized version of the Cluster pulse algorithm developed by Veldhuis and Johnson (12) was utilized. This program searches for episodic fluctuations in hormone arrays by evaluating a group of individual To
data arrays,
values (clusters) for increases and decreases within the data series. To be considered a significant pulse or peak, hormone concentrations had to be preceded by an upstroke and followed by a downstroke. In accordance with the publishers' suggestions (12), we selected criteria for the TSH pulse determination to yield a false-positive pulse detection rate of less than 2.5%. Accordingly, a nadir cluster size of 2 and peak size of 2 together with f-statistic values of 2.1/2.1 were chosen. A quadratic equation was used in the TSH pulse deter¬ mination program to estimate the within-sample variance as a function of the hormone levels (13). Details of this calculation equation have been described
previously (14).
Since normal distribution of the data series could not be assumed, the data were transformed logarithmically. Two-way analysis of variance and Student's £-test were employed where appropriate. A p
steroids in the regulation of secretion of hypogonadal women
sex
thyrotropin (TSH)
Winfried G Rossmanith, Claudia St\l=a"\bler,Reiner Benz, Stefan R Bornstein and Werner A Scherbaum Departments of Obstetrics-Gynecology and Internal Medicine', University of Ulm, Ulm/D, Germany
Rossmanith WG, Stäbler C, Benz R, Bornstein SR, Scherbaum WA. Role of ovarian sex steroids in the regulation of thyrotropin (TSH) secretion of hypogonadal women. Acta Endocrinol 1992;127:131-7. ISSN 0001-5598 The exact role of ovarian sex steroids in the neuroendocrine regulation of thyrotropin (TSH) release in women can only be accurately assessed in the absence of any considerable ovarian sex steroid feedback upon the hypothalamic-pituitary unit. Consequently, the unstimulated episodic and thyrotropin\x=req-\ releasing hormone (TRH) stimulated TSH secretion was evaluated in postmenopausal women before and during sequential ovarian sex steroid replacements. Seven euthyroid women (mean age: 59.4 years) were studied initially without any sex steroid replacement (control studies), then on the last day of a 21-day course of oral estradiol-valeriate (E2) administration (2 mg daily) and finally, on the last day of a 21-day course of oral estradiol-progesterone (E2/P4) replacement (2 mg E2 and 200mg micronized P4 daily). During all study occasions, blood was sampled at 10 min intervals for 10 h, while TRH (200 \g=m\giv) was administered 8 h after initiation of blood collections. Compared to the control conditions, serum E2 and P4 concentrations markedly increased (p< 0.001) following oral E2 or E2/P4 treatments. Total triiodothyronine (T3) and thyroxine (T4) concentrations and free T3 and T4 equivalents remained unchanged during E2 and E2/P4 regimens. In the unstimulated secretory profiles, TSH was found to be episodically released, with little interindividual variability for each study condition. Since the TSH pulse attributes (pulse amplitudes, frequencies, interpulse intervals, mean TSH concentrations, by Cluster pulse algorithm) did not significantly change during E2 and E2/P4 replacements, the episodic character of TSH secretion virtually remained unchanged by sex steroid replacements. In addition, the TRH\x=req-\ stimulated TSH releases during E2 and E2/P4 replacement therapies closely resembled those during control conditions. These observations demonstrate that both the unstimulated episodic and TRH\x=req-\ stimulated TSH secretion are unaffected by ovarian sex steroid replacement in hypogonadal women. Collectively, our findings suggest that ovarian sex steroids may not be critically involved in the neuroendocrine regulation of TSH secretion in women.
Winfried D-7900
G Rossmanith, Department of Obstetrics-Gynecology, University of Ulm, Ulm/D, Germany
a general clinical impression, the prevalence of thyroid dysfunction is greater in women than in men. Such endocrine derangements are preferably encoun¬ tered in close temporal association with changes in the endogenous ovarian sex steroid environment, thereby particularly manifested during pregnancy and meno¬
As
pause (1). These clinical observations support the notion that ovarian sex steroids may be critical for the regula¬ tion of thyroid function in humans. Therefore, several
investigators have aimed
at determining a role of sex steroids in the neuroendocrine regulation of thyrotropin
(TSH) secretion. Using various experimental approaches in vivo and in vitro, numerous studies have been conducted both in animals (2-4) and in humans (5-7).
Yet, the diversity of obtained results precluded firm conclusions as to whether sex steroids critically partici¬ pate in the differential regulation of TSH release in humans. Based on the available information, contro¬ versy still exists as to the role of ovarian sex steroids for basal unstimulated and thyrotropin-releasing hormone
Prittwitzstrasse
43,
(TRH) stimulated TSH secretion in women. However, this issue should be thoroughly appraised, since the clinical impact of treatment with ovarian sex steroids or their synthetic dérivâtes on thyroid function may be decisive. A possible influence of ovarian sex steroids on the regulation of TSH secretion can be most accurately assessed when sex steroid feedback by the ovaries is virtually absent. The postmenopausal state of women would provide a physiologic condition in which women are deprived of any considerable ovarian feedback on the hypothalamic-pituitary unit (8). Their hypogonadal state may then represent a unique model to delineate the relative contribution, if any, of ovarian sex steroids in the neuroendocrine control of TSH secretion. Hence, TSH secretory profiles should be determined in the absence and presence of ovarian sex steroid feedback. We therefore studied hypogonadal (postmenopausal) women before and during ovarian sex steroid exposure, using frequent blood sampling.
132
Winfried G Rossmanith et al.
Experimental protocol Study population Seven postmenopausal women between the ages of 54 and 64 years (mean age: 59.4 years) participated in this study. All postmenopausal women were in good general health and did not suffer from any chronic disease known to interfere with the hormone secretion. The women had experienced natural cessation of their menstrual bleedings at least one year prior to this investigation. Endocrinological evaluation confirmed the hypogonadal state of postmenopause in all women studied. All women were euthyroid, as assessed by the finding of thyroxine (T4) and triiodothyronine (T5) as well as the free T4 (FT4E) and free T3 (FT3E) equivalents within the normal range of women. Subjects presenting with positive antibodies against thyroglobulin, TSH receptors or thyroid microsomes were excluded. None of the women was taking any medication known to interfere with physiological hormone release. This proto¬ col was approved by the local Ethics Committee, and informed written consent was obtained from each woman prior to the study.
Study design All
studied on three occasions. Initial conducted during the hypogonadal state of postmenopause, i.e. in the absence of any sex steroid replacement (control conditions). In addition, the women were studied on the last day of a 21 -day course of oral replacement of estradiol-valeriate (2 mg daily; Schering, Berlin, Germany). Final studies were con¬ ducted on the last day of administration of oral estrogen and progesterone (estradiol-valeriate 2 mg plus micronized progesterone 200 mg; Laboratoire Besins, Paris, France) for 21 days. Starting between 08.00 and 10.00, blood samples (3 ml) were obtained at 10 min intervals for 10 h through an iv catheter placed in a forearm vein. Eight hours after initiation of blood sampling, thyrotropin-releasing hormone (200 yg iv) was administered, while the blood sampling was continued uninterrup¬ tedly. The women were kept in recumbent positions, and were not permitted to smoke, to drink caffeinated beverages, or to sleep during the investigations. women were
investigations
were
acta endocrinologica 1992. 127
equivalents were determined by commercially available assays (Amersham, Braunschweig, Germany). An esti¬ mation of the free concentrations can be made by correcting the total hormone level of T3 or T4 using a thyroid hormone binding capacity value such as the T3
uptake.
The free thyroid index or equivalent was therefore calculated from the total T4 or T3 value and the T3 uptake (10). To establish TSH secretory profiles, serial determinations of TSH were performed in all collected samples using an ultrasensitive (0.04 ¿tlJ/1) immunoradiometric assay (Sorin, Duesseldorf, Germany). This assay has been previously characterized in detail (11). The mean intra-assay and interassay coefficients of variation (CV) were 3.2% and 4.8%, respectively, for the range of TSH concentations relevant in this study. All samples from one individual were analyzed in duplicate in
a
single assay to minimize interassay variability.
Pulse
analysis and data evaluation
identify significant fluctuations within the hormone a computerized version of the Cluster pulse algorithm developed by Veldhuis and Johnson (12) was utilized. This program searches for episodic fluctuations in hormone arrays by evaluating a group of individual To
data arrays,
values (clusters) for increases and decreases within the data series. To be considered a significant pulse or peak, hormone concentrations had to be preceded by an upstroke and followed by a downstroke. In accordance with the publishers' suggestions (12), we selected criteria for the TSH pulse determination to yield a false-positive pulse detection rate of less than 2.5%. Accordingly, a nadir cluster size of 2 and peak size of 2 together with f-statistic values of 2.1/2.1 were chosen. A quadratic equation was used in the TSH pulse deter¬ mination program to estimate the within-sample variance as a function of the hormone levels (13). Details of this calculation equation have been described
previously (14).
Since normal distribution of the data series could not be assumed, the data were transformed logarithmically. Two-way analysis of variance and Student's £-test were employed where appropriate. A p
