H. M. Schulte

DIURNAL SALIVARY CORTISOL PATTERNS DURING PREGNANCY AND AFTER DELIVERY: RELATIONSHIP TO PLASMA CORTICOTROPHIN‐RELEASING‐HORMONE

The circadian rhythm of salivary cortisol was studied in 10 healthy women every 4 weeks throughout pregnancy. In addition, in 12 women the diurnal patterns of salivary cortisol, serum cortisol, plasma ACTH, plasma CRH and serum progesterone were analysed in late third trimester pregnancy and again 3–5 days after delivery. Salivary cortisol profiles exhibited a clear circadian rhythm during pregnancy with an increase in mean salivary cortisol from the 25th to 28th week onwards reaching concentrations in late pregnancy more than twice as high as in non‐pregnant controls, rapidly returning to normal concentrations after delivery. The coefficient of variation of salivary cortisol profiles decreased in third trimester pregnancy due to a parallel upward shift of cortisol concentrations (40.2 |Mp 3.4%vs 77.6 |Mp 6.6% after delivery, P > 0.01). A diurnal pattern was also found for plasma ACTH and serum cortisol before and after delivery with lower concentrations post‐partum (P > 0.01). In late pregnancy, progesterone concentrations were significantly higher in the evening (930 + 85 nmol/1 vs 813 |Mp 74 nmol/1 at 0900 h, P > 0.01) but showed no diurnal variation post‐partum. Plasma CRH was significantly elevated in late third trimester pregnancy (1.22 |Mp 0.23 μg/1 at 0900 h) but showed no diurnal change (1.30 |Mp 0.28 μg/1 at 1900 h). Moreover, no correlation between the free cortisol increase in late pregnancy and plasma CRH was noted despite a wide range of CRH levels (0‐13‐3.60 μg/1). In contrast, a significant correlation was observed between the serum progesterone increase and the salivary cortisol increase in late pregnancy (r = 0.70, P > 0‐05). These findings demonstrate that placental CRH is not the only regulator of maternal ACTH and cortisol release. Instead, our study suggests that placental CRH has little influence on baseline maternal adrenocortical function in pregnancy. The elevated salivary cortisol levels in pregnancy may be explained by glucocorticoid resistance owing to the antiglucocorticoid action of high progesterone concentrations.

THE CORTICOTROPHIN RELEASING HORMONE TEST IN LATE PREGNANCY: LACK OF ADRENOCORTICOTROPHIN AND CORTISOL RESPONSE*

Biologically active corticotrophin‐releasing‐hormone (CRH) is produced by the placenta in large amounts and can be measured in the maternal circulation during third trimester of pregnancy. Its physiological significance is unknown. To further investigate the action of CRH in pregnancy, we performed a standard CRH‐test (1 μg/kg synthetic human CRH) in seven pregnant women 1 week prior to their calculated delivery data and 4‐5 weeks post‐partum. No response of plasma ACTH to CRH administration could be measured in any of the third trimester pregnant women. Post‐partum, basal ACTH levels were significantly lower (1.6 |Mp 0.3 vs 5.3 |Mp 0.2 pmo1/1) and reacted promptly to CRH administration (1.6 |Mp 0.3–4.2 |Mp 0.5 pmol/1; P < 0.05). Concentrations of cortisol in plasma and salivary cortisol paralleled the ACTH response to administration of CRH. However, one pregnant woman experienced physical and emotional stress during the CRH‐test and reacted with a sharp rise in cortisol secretion. The lack of the ACTH and cortisol response in this study to exogenously administered CRH in third trimester pregnancy may be due to high circulating glucocorticoid concentrations, desensitization of the pituitary corticotroph and/or in part due to circulating specific CRH‐carrier protein.

5-HT1A receptor responsivity in unipolar depression Evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls

The selective 5-HT1A receptor ligand ipsapirone (IPS) induces corticotropin (ACTH) and cortisol secretion in humans. To explore 5-HT1A receptor-mediated hypothalamic-pituitary-adrenal (HPA) system activation in depression, 24 subjects (12 patients with unipolar depression and 12 individually matched controls) were given 0.3 mg/kg IPS or placebo in random order. Compared with controls, the depressed patients exhibited significantly decreased ACTH and cortisol responses to IPS in association with increased basal cortisol secretion. The impaired HPA response following 5-HT1A receptor challenge in unipolar depression could have resulted from glucocorticoid-dependent subsensitivity of the (post-synaptic) 5-HT1A receptor itself and/or from a defective postreceptor signaling pathway [inhibitory guanine nucleotide-binding protein (Gi)-adenylate cyclase complex function], thus supporting the hypothesis that a disintegrated 5-HT and HPA system interaction may be present in depression. Future studies of the HPA response to direct-acting 5-HT1A ligands, such as IPS, should facilitate the assessment of 5-HT/HPA system integrity in various affective disorders and its involvement in psychotropic drug effects.

Long-term fluoxetine treatment decreases 5-HT1A receptor responsivity in obsessive-compulsive disorder

Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor with therapeutic benefit in patients with obsessive-compulsive disorder (OCD). To evaluate the effect of chronic FLX treatment on 5-HT1A receptor responsivity, hypothermic, neuroendocrine, and behavioral responses to the selective 5-HT1A receptor ligand ipsapirone (IPS) were examined in patients with primary OCD. A single dose of 0.3 mg/kg of IPS or placebo were given under double-blind, random-assignment conditions to ten patients before and during FLX treatment. The ability of IPS to induce hypothermia and ACTH/cortisol release was significantly attenuated during chronic FLX as compared to the pretreatment IPS challenge. The behavioral effects of IPS, though minimal, were less pronounced during FLX treatment. While FLX was effective in reducing the severity of OC symptoms, no significant correlation between attenuation of 5-HT1A receptor-mediated functional measures and FLX-induced improvement in OC symptoms was detected. These findings are consistent with the development of adaptive hyporesponsivity of the 5-HT1A receptor-effector system complex possibly involving subsensitivity of the 5-HT1A receptor itself and/or decreased functional activity of the postreceptor signal transduction. Modulation of 5-HT1A receptor-effector system function may be critical to the antidepressant/anti-OC efficacy of 5-HT reuptake inhibitors.

Subsensitivity of the 5-hydroxytryptamine1A (5-HT1A) receptor-mediated hypothermic response to ipsapirone in unipolar depression.

The selective 5-HT1A receptor ligand ipsapirone (IPS) induces hypothermia in humans. To explore 5-HT1A receptor-mediated thermoregulation in depression, 24 subjects (12 patients with unipolar depression and 12 individually matched controls) received 0.3 mg/kg IPS or placebo in random order. Compared with controls, the depressed patients exhibited significantly attenuated hypothermic responses to IPS. The impaired hypothermic response following 5-HT1A receptor activation in unipolar depression could have resulted from subsensitivity of the (presynaptic) 5-HT1A receptor and/or related effector mechanisms, thus supporting the hypothesis that altered serotonergic activity may be present in affective disorders. Future studies of the hypothermic response to direct-acting 5-HT1A ligands, such as IPS should facilitate the assessment of 5-HT receptor function in various affective disorders and its involvement in psychotropic drug effects.

5-HT1A receptor-effector system responsivity in panic disorder

To explore 5-HT1A receptor responsivity in panic disorder (PD), hypothermic, neuroendocrine and behavioral responses to the selective partial 5-HT1A receptor agonist ipsapirone (IPS) were investigated in patients with primary PD and healthy controls. Fourteen patients and matched controls received a single oral dose of 0.3 mg/kg IPS or placebo under double-blind, random-assignment conditions. IPS induced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior. Compared with controls, the patients with PD exhibited significantly attenuated thermoregulatory and neuroendocrine responses to IPS. Although the healthy subjects reported increased drowsiness and the PD patients rated themselves more nervous and less calm following administration of IPS, no consistent changes in ratings of anxiety or panic symptoms were recorded. The impaired hypothermic and ACTH/cortisol responses following 5-HT1A receptor activation reflects subsensitivity of both the pre- and post-synaptic 5-HT1A receptor-effector system, thus supporting the hypothesis that a 5-HT1A receptor-related serotonergic dysfunction may be linked to the pathophysiology of PD. Future studies of 5-HT1A receptor-effector complex function in conjunction with assessment of the responsivity of other subtypes (e.g. 5-HT2, 5-HT3) should promote the evaluation of 5-HT system integrity in anxiety disorders and its involvement in anxiolytic drug effects.

Endocrine responses to growth hormone‐releasing hormone, thyrotropin‐releasing hormone and corticotropin‐releasing hormone in depression

ABSTRACT– To explore and to compare hypothalamic‐pituitary‐somatotropic (HPS), hypothalamic‐pituitary‐thyroid (HPT) and hypothalamic‐pituitary‐adreno‐cortical (HPA) axis function in depression, 30 subjects (15 patients with a major depressive episode and individually matched controls) received 50μg growth hormone‐releasing hormone‐44 amide at 9:00, 200 μg thyrotropin‐releasing hormone (TRH) at 9:00 and 100 μg human corticotropin‐releasing hormone (CRH) at 18:00 on consecutive days as an i.v. bolus dose. Compared with controls, depressed patients showed blunted growth hormone (GH) responses to GHRH, decreased TRH‐induced thyrotropin (TSH) release and reduced corticotropin (ACTH) but normal cortisol secretion following CRH. ACTH secretion following CRH and TRH‐induced TSH release were positively correlated across depressed patients and controls but no significant correlations between GH responses to GHRH and TRH‐induced TSH release or ACTH and cortisol secretion following CRH administration were demonstrated. Our findings suggest that altered HPT and HPA axis function associated with depression are triggered by factors that are at least partly different from those that cause HPS system dysfunction. We conclude that the pathophysiological process resulting in aberrant neuroendocrine secretory dynamics associated with depression may primarily occur at a suprapituitary site, and that HPS, HPT and HPA axis dysfunction may be precipitated by complex central and peripheral regulatory mechanisms involving largely independent factors.

Abnormal responsiveness of growth hormone to human corticotropin-releasing hormone in major depressive disorder

Plasma growth hormone (GH) release after injection of 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) was investigated in 11 patients with major depressive disorder and normal controls matched for gender, age, body weight and ovarian status. In contrast to controls, who exhibited no significant GH response to CRH, depressed patients showed a significant net increase in GH secretion following CRH administration. The abnormal GH response to CRH was not correlated with baseline corticotropin (ACTH) and cortisol nor with CRH-induced ACTH and cortisol response. The implications of these findings are discussed with reference to such factors as alpha-adrenergic hyperactivity, hypothalamic-pituitary system dysregulation, drug interference, non-specific stress responses and abnormal neuroendocrine circadian rhythms in major depression.

Delta sleep-inducing peptide response to human corticotropin-releasing hormone (CRH) in major depressive disorder: Comparison with CRH-Induced corticotropin and cortisol secretion

Twenty-four subjects (12 patients with major depressive disorder and 12 controls matched for sex and age) received 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) as an iv bolus dose. Healthy subjects exhibited a slight, but sustained, increase of plasma delta sleep-inducing peptide (DSIP) concentrations, whereas a marked reduction of DSIP levels was found in depressives. Compared to controls, depressed patients showed a significant attenuation of corticotropin (ACTH) responses, whereas cortisol secretion in response to hCRH was normal. Basal DSIP and cortisol concentrations were highly correlated and were higher in depressives than in controls. Both were negatively correlated with the DSIP responses to hCRH. These findings are compatible with the hypothesis that hypothalamic-pituitary-adrenal (HPA) overactivity in the depressive state is primarily due to central hypersecretion of CRH and support the view of a modulatory function of DSIP in the complex regulatory mechanism of the HPA system and of its pathophysiological significance for aberrant HPA axis function in major depressive disorder.

Control of prolactin‐secreting macroadenomas with parenteral, long‐acting bromocriptine in 30 patients treated for up to 3 years

OBJECTIVE We investigated the effect of intramuscular injections of long‐acting bromocriptine in patients with macroadenomas.