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Hypoglycemia, But Not Insulin, Acutely Decreases LH and T Secretion in Men

Departments of Internal Medicine I (K.M.O., B.F.S., W.K., H.L.F., A.P.) and Clinical Neuroendocrinology (J.B.), Medical University of Luebeck, D-23538 Luebeck, Germany

Address all correspondence and requests for reprints to: Dr. Kerstin M. Oltmanns, Department of Internal Medicine I, Medical University of Luebeck, D-23538 Luebeck, Germany.

Abstract

Hypoandrogenemia is frequently associated with hyperinsulinemia in men with the metabolic syndrome. We questioned whether insulin or changes in blood glucose levels influence pituitary gonadotropin secretion or testicular steroidogenesis in healthy men. Also, the relationship between hypoglycemia-induced activation of the hypothalamus-pituitary-adrenal axis and altered steroidogenesis was examined.

Euglycemic and hypoglycemic clamp experiments were performed in 30 healthy men over a period of 6 h. Half of the men were infused with insulin at a rate of 1.5 mU/min·kg; the other half were infused at a rate of 15.0 mU/min·kg. Plasma glucose was held constant during a euglycemic clamp session and was decreased stepwise in a hypoglycemic clamp session.

LH and total/free T concentrations decreased under hypoglycemic conditions regardless of the rate of insulin infusion. With euglycemic conditions, LH and T levels remained unchanged. Dehydroepiandrosterone concentrations increased during hypoglycemia, but not during the euglycemic conditions. The FSH concentration was not affected by insulin or glycemic clamps.

Hypoglycemia acutely suppresses T secretion, and this effect is apparently mediated by pituitary LH. Insulin is ineffective. As counterregulation to hypoglycemia begins at normoglycemic ranges in poorly controlled type 2 diabetes and probably also in patients with long-term perturbed glucose regulation in the metabolic syndrome, control of glucose-responsive neurons in the brain may contribute to hypoandrogenemia. Apart from down-regulation of hypothalamic release of GnRH, concurrent activation of the pituitary-adrenal axis (i.e. increased release of dehydroepiandrosterone) may add to the suppressive effect of hypoglycemia on gonadal steroidogenesis.

HYPERINSULINEMIA AND increased glucose concentrations are both negatively correlated with total and free T levels in men (1). Although it has been suggested that low levels of T play a role in the development of insulin resistance and type 2 diabetes (2), the cause of the decrease in T remains obscure. Insulin-induced hypoglycemia is known to suppress the pulsatile secretion of LH in rats and sheep (3, 4, 5, 6) as well as the pulse generator frequency of hypothalamic GnRH in rats and rhesus monkeys (3, 7). In men, insulin-induced hypoglycemia was followed by a rapid decrease in serum T levels (8). However, it remains unclear whether this is an effect of insulin or of changes in blood glucose levels.

Additionally, decreased T levels in patients with the metabolic syndrome could be a direct consequence of perturbed function of the hypothalamic-pituitary-adrenal (HPA) axis (9, 10). It is known that a counterregulatory response of the HPA axis, including cortisol release, to hypoglycemia begins at normoglycemic ranges in poorly controlled type 2 diabetes (11), and the epinephrine response during hypoglycemia is enhanced (12). In vitro, glucocorticoids caused a decrease in LH and an increase in FSH in rat pituitary cells (13, 14), and ACTH directly reduced T secretion in testicular cells of guinea pigs (15). In men, elevation of cortisol levels resulting from insulin-induced hypoglycemia or administration of hydrocortisone was followed by a rapid decrease in serum T levels without accompanying changes in LH secretion (8).

This study determined whether insulin, or rather hypoglycemia, suppresses pituitary gonadotropin secretion and testicular steroidogenesis in men. Furthermore, it was examined to which extent these effects coincide with alterations of pituitary ACTH and adrenal dehydroepiandrosterone (DHEA) as well as cortisol release.

Subjects and Methods

Subjects

Thirty young healthy men participated in the experiments. Exclusion criteria were chronic or acute illness, current medication of any kind, smoking, alcohol or drug abuse, adiposity, and diabetes or hypertension in first degree relatives. Each volunteer gave written informed consent, and the study was approved by the local ethics committee.

Experimental design

Each subject underwent a hyperinsulinemic hypoglycemic clamp and a hyperinsulinemic euglycemic clamp experiment, separated by an interval of at least 4 wk. The order of conditions was balanced across subjects, and experiments were performed in a single blind fashion. The 30 subjects were randomly assigned to 2 groups of 15 subjects each. In 1 group insulin was infused at a rate of 1.5 mU/min·kg during both clamp sessions (low insulin), whereas in the other group insulin was infused at a rate of 15.0 mU/min·kg during both clamp sessions (high insulin). The low insulin group had a mean age (±SEM) of 26.0 ± 1.0 yr (range, 22–32 yr) and a mean body mass index of 22.5 ± 0.6 kg/m² (range, 18.6–25.5 kg/m²); the high insulin group had a mean age of 25.4 ± 0.6 yr (range 23–29 yr) and a body mass index of 23.2 ± 0.5 kg/m² (range, 19.9–26.0 kg/m²).

All subjects were requested to abstain from alcohol, not to perform any kind of exhausting physical activity, and to go to bed no later than 2200 h on the day preceding the study. On the days of the study, subjects came to the medical research unit at 0800 h after an overnight fast of at least 10 h. The experiments took place in a sound-attenuated room with the subjects lying on a bed with the trunk in an almost upright position (60°). A cannula was inserted into a vein on the back of the hand, which was placed in a heated box (50-55 C) to obtain arterialized venous blood. A second cannula was inserted into an antecubital vein of the contralateral arm. Both cannulas were connected to long thin tubes, which enabled blood sampling and adjustment of the rate of dextrose infusion from an adjacent room without awareness of the subject. After a 1-h baseline period, insulin (H-insulin, Hoechst, Frankfurt, Germany) was infused at a continuous rate of either 1.5 or 15.0 mU/min·kg, respectively, depending upon the group. A 20% dextrose solution was simultaneously infused at a variable rate to control plasma glucose levels. Arterialized blood was drawn at 5-min intervals to measure the plasma glucose concentration (glucose analyzer, Beckman Coulter, Inc., Munich, Germany). In euglycemic clamp sessions, plasma glucose was held stable between 5.0 and 5.5 mmol/liter. In hypoglycemic clamp sessions, plasma glucose levels were reduced in a stepwise manner to achieve four respective plateaus of 4.2, 3.6, 2.9, and 2.3 mmol/liter. Each plateau was maintained for a 45-min period, and the next lower plateau was induced gradually within the next 45 min. Blood samples for determination of insulin, LH, T, SHBG, FSH, DHEA, cortisol, and ACTH were collected every 30 min. During high dose insulin infusion, potassium concentrations were monitored at 30-min intervals, and substitution was given whenever the level fell below 4.0 mmol/liter.

Assays

All blood samples were immediately centrifuged, and the supernatants were stored at -24 C until assay. Serum insulin was measured by RIA [Pharmacia Insulin RIA 100, Pharmacia Biotech, Uppsala, Sweden; interassay coefficient of variation (CV), <5.8%; intraassay CV, <5.4%]. Electroluminescence immunoassays were used for determination of serum FSH (Elecsys FSH immunoassay, Roche, Mannheim, Germany; interassay CV, <6%; intraassay CV, <3%), serum LH (Elecsys LH immunoassay, Roche; interassay CV, <6%; intraassay CV, <5%), and serum T (Elecsys T immunoassay, Roche; interassay CV, <6%; intraassay CV, <5%). SHBG was measured by immunoenzymometric assay (RADIM, Rome, Italy; interassay CV, <8.7%; intraassay CV, <5.8%). The free T concentration was calculated by the ratio of total T to SHBG. Plasma ACTH was measured by electroluminescence immunoassay (LUMI test ACTH, Brahms Diagnostica, Berlin, Germany; interassay CV, <12%, intraassay CV < 8%). Serum cortisol was measured by ELISA (Enzymun-Test Cortisol, Roche Molecular Biochemicals; interassay CV, <3.0%; intraassay CV, <4.2%). Serum DHEA was measured by enzyme immunoassay (Diagnostics Systems Laboratories, Inc., Sinsheim, Germany; interassay CV, <8.3%; intraassay CV, <11.8%).

Statistical analysis

Values are presented as the mean ± SEM. Statistical analysis was based on ANOVA for repeated measurements, including the factors group (low vs. high insulin) and time (duration of the clamp). The interaction effect of these two factors was termed group by time. Concentrations of FSH, LH, total/free T, ACTH, cortisol, and DHEA were compared by paired t test, following the model of Mitrakou et al. (16), who developed a standard procedure to evaluate glycemic thresholds for counterregulatory hormone secretion and symptoms using this statistical method. Multivariate linear stepwise forward regression analysis was used to assess correlations between variables. P < 0.05 was considered statistically significant.

Results

Glucose and insulin

Plasma glucose concentrations did not differ between the high and low insulin groups during either the euglycemic (Fig. 1A) or the hypoglycemic (Fig. 1B) clamp sessions. Mean serum insulin concentrations were approximately 40-fold higher in the high insulin than in the low insulin group during both the euglycemic clamp (543 ± 34 vs. 24,029 ± 1,595 pmol/liter; P < 0.001; Fig. 1A) and the hypoglycemic clamp (622 ± 32 vs. 23,624 ± 1,587 pmol/liter; P < 0.001; Fig. 1B) sessions.

View larger version (19K): [in this window] [in a new window]   Figure 1. Mean (±SEM) plasma or serum concentrations of glucose and insulin during the euglycemic clamp session (A) and concentrations of glucose and insulin during the hypoglycemic clamp session (B). The low insulin group (dotted) and the high insulin group (solid) consisted of 15 healthy men each. The SEMs of serum insulin concentrations were smaller than the sizes of the symbols.

In the low insulin group, serum LH concentrations did not essentially change during the euglycemic clamp, but during the hypoglycemic clamp, LH levels distinctly decreased after 30 min. Paired t test between euglycemic and hypoglycemic values indicated significance for this decrease after 120 min (P < 0.05; Fig. 2). In parallel, total T concentrations and free T decreased during the hypoglycemic clamp sessions, but did not do so under euglycemic conditions. The difference became significant after 120 min (P < 0.05; Figs. 3 and 4).

View larger version (18K): [in this window] [in a new window]   Figure 2. Mean (±SEM) serum LH concentrations in the low insulin group (dotted) and the high insulin group (solid) during an euglycemic (circle) and a hypoglycemic (triangle) clamp. *, P < 0.05; **, P < 0.01; ***, P < 0.001 (euglycemia vs. hypoglycemia; n = 15, for each group). 0 min, Start of insulin infusion.

View larger version (19K): [in this window] [in a new window]   Figure 3. Fig. 3. Serum T concentrations. See Fig. 2 for details.

View larger version (18K): [in this window] [in a new window]   Figure 4. Free T concentrations. See Fig. 2 for details. Concentrations were calculated by the ratio of total T to SHBG concentrations.

Under euglycemic as well as under hypoglycemic conditions, there was no significant difference between the low and high insulin groups in LH or total/free T concentrations (Table 1).

There was no appreciable alteration in serum FSH concentrations (Fig. 5). In neither the low insulin nor the high insulin group did FSH values change significantly under the different clamp conditions. Also, FSH concentrations did not differ between the low and high insulin groups (Table 1).

View larger version (17K): [in this window] [in a new window]   Figure 5. Serum FSH concentrations. See Fig. 2 for details.

In the low insulin group, plasma ACTH concentrations remained nearly the same during euglycemic clamp sessions, but increased during hypoglycemic conditions. Pairwise t tests revealed this increase to reach significance after 150 min (Fig. 6). Similarly, serum DHEA concentrations increased electively under hypoglycemic conditions, with this increase reaching significance after 240 min (Fig. 7). Serum cortisol concentrations decreased from 223.9 ± 15.6 to 162.2 ± 18.3 nmol/liter during the euglycemic session and increased clearly from 214.5 ± 25.2 to 648.2 ± 34.3 nmol/liter under hypoglycemic conditions (euglycemia vs. hypoglycemia, P = 0.76 at baseline and P < 0.001 at the end of the clamp).

View larger version (18K): [in this window] [in a new window]   Figure 6. Plasma ACTH concentrations. See Fig. 2 for details.

View larger version (20K): [in this window] [in a new window]   Figure 7. Serum DHEA concentrations. See Fig. 2 for details.

Multivariate linear stepwise forward regression analysis

Multivariate linear stepwise forward regression analysis revealed that the T concentration was negatively correlated to the ACTH concentration (mean ± SEM, -0.157 ± 0.065; P < 0.05), whereas insulin, cortisol, and DHEA remained nonsignificant.

Discussion

The present results demonstrate that hypoglycemia, rather than insulin, is the factor that acutely decreases LH and T levels during insulin-induced hypoglycemia in men. LH dropping in parallel with T levels points to an influence of hypoglycemia on the hypothalamo-pituitary level of the gonadal axis. Glucose-responsive neurons have been detected in the hypothalamus, especially in the arcuate nucleus, where the GnRH pulse generator is localized as well (17, 18, 19). No such glucose sensitivity was found for pituitary cells. This led to the speculation that the suppressive effect of hypoglycemia on LH and T release involves mechanisms of hypothalamic glucose regulation. Our data confirm and extends previous observations of decreased LH secretion during hypoglycemia in animals (3, 4, 5, 6). An effect of hypoglycemia mediated via suppression of hypothalamic GnRH release rather than a such specific action on the pituitary level is supported by FSH concentrations that remained the same during the 6-h clamp session. The FSH response to GnRH suppression in vivo is known to be more sluggish than the LH response. Thus, Grady et al. (20) did not observe any changes in FSH levels until 12 h after suppression by a GnRH antagonist, whereas LH levels showed a dose-dependant 20–50% decrease by 2 h. As our clamp lasted for 6 h, glycemia-induced suppression of GnRH could well be responsible for the selective decrease in LH concentration, leaving FSH levels unaffected.

As the low and high insulin groups did not differ in any of the investigated hormone concentrations (Table 1), insulin is unlikely to mediate the suppression of the hypothalamus-pituitary-gonadal axis in men with metabolic syndrome. However, regulation of glucose-responsive neurons in the brain seems to contribute to hypoandrogenemia in this disease. These results seem to be contradictory to the findings of Bruning et al. (21) in male knockout mice lacking the central nervous system insulin receptor, which exhibited impaired spermatogenesis accompanied by a 60% reduction of the circulating LH concentration. However, those mice also developed obesity, with increases in body fat, plasma leptin, plasma insulin, and blood triglyceride, i.e. a metabolic syndrome. A counterregulatory response to hypoglycemia begins at normoglycemic ranges in patients with poorly controlled type 2 diabetes and probably also in patients with long-term perturbed glucose regulation in the metabolic syndrome. Thus, correspondent with the present data, suppression of the reproductive axis in those mice could result from changes in blood glucose levels associated with the metabolic syndrome rather than be a direct consequence of the central nervous system insulin receptor defect. Also, activation of the HPA axis, typically occurring in the metabolic syndrome, might add to the suppression of the pituitary-gonadal system in these animals.

Our results further demonstrate that the decrease in LH and T concentrations during hypoglycemia coincides with increased concentrations of ACTH, cortisol, and DHEA. It is well known that hypoglycemia has a stimulating effect on HPA secretory activity in men (22, 23, 24). HPA activity could, in turn, add to the suppression of the reproductive axis. Immunocytochemical evidence has been provided for synaptic connections between cells containing CRH and GnRH in the preoptic area of the rat (25). Moreover, in vitro CRH inhibited GnRH release in a dose-related manner in vitro (26). In vivo, CRH antagonists delayed the inhibition of GnRH pulse generator frequency (7), and CRH lowered pituitary LH by inhibiting the release of GnRH (27, 28). Whether HPA activation exerts an inhibitory influence on the reproductive axis also at the pituitary level is not known. Some researchers found that glucocorticoids inhibit LH and enhance FSH secretion (13, 14) in vitro and that CRH lowers plasma LH levels in the absence of circulating steroids (29). Others failed to find any effect of CRH/ACTH or cortisol on LH secretion in vivo (6, 30, 31). On the testicular level, glucocorticoids and ACTH were found to inhibit T secretion independently of LH alteration both in vitro and in vivo in animals (15, 32, 33). In men, circulating T levels were acutely suppressed after the administration of cortisol or ACTH, without accompanying changes in LH (8, 34). Together, these observations indicate that acute activation of the HPA axis can suppress hypothalamus-pituitary-gonadal activity, with more profound effects at the hypothalamic and testicular levels. On this background, it is likely that HPA activation during hypoglycemia added to the suppression of LH/T release, and that both the hypothalamic and testicular levels are involved in mediating this contribution.

The finding of increased adrenal DHEA concentrations under hypoglycemic conditions in conjunction with increased ACTH and cortisol release indicates a strong activation of the HPA axis upon hypoglycemic stress. More importantly, the increase in the DHEA concentration indicates that hypoglycemia suppresses testicular, but not adrenal, T production by conversion of DHEA. As adrenal T production in males plays a minor role, the increase is irrelevant for testicular function. This is the opposite of the situation in women. Up to 67% of female T synthesis is of adrenal origin. Thus, our data might be of clinical relevance for women with metabolic syndrome and its special form, the polycystic ovary syndrome (PCOS), which is frequently associated with hyperandrogenism, disturbed LH/FSH ratio, infertility, and noninsulin-dependent diabetes mellitus. As activation of the HPA axis occurs in metabolic syndrome, this might explain the low T concentrations in men, but high levels in women with PCOS. Women suffering from PCOS showed significantly higher plasma ACTH and cortisol levels under basal conditions as well as after the administration of CRH (35). Moreover, there is evidence that excessive androgen concentrations in obese hyperinsulinemic women with PCOS are mainly the result of enhanced adrenal secretion (36). Also, about half of these patients are characterized by moderately increased secretion of DHEA in response to ACTH (37).

Our data contribute to the understanding of hypogonadism observed under conditions of hypoglycemia. However, the study did not determine the mechanism of the suppression of LH and T during hypoglycemia. Glucose deprivation and other components of the array of neuroendocrine responses during hypoglycemia (e.g. catecholamines) might be involved. Additionally, only short-term hyperinsulinemia was studied, whereas disorders such as PCOS, type 2 diabetes, or the metabolic syndrome involve long-term hyperinsulinemia. Thus, further investigations would be desirable to elucidate remaining questions.

Acknowledgments

We thank Christiane Zinke and Steffi Baxmann for their expert and invaluable laboratory assistance, and Anja Otterbein for her organizational work. We gratefully thank Dr. Thomas Kohlmann for his methodological advice, and Dr. Dan H. Burdon for his language advice.

Footnotes

Abbreviations: CV, Coefficient of variation; DHEA, dehydroepiandrosterone; HPA, hypothalamic-pituitary-adrenal; PCOS, polycystic ovary syndrome.

Received February 6, 2001.

Accepted June 4, 2001.

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