A. Barbarino

Corticotropin-releasing hormone inhibition of gonadotropin secretion during the menstrual cycle

To determine whether corticotropin-releasing hormone (CRH) exerts an inhibitory action on gonadotropin secretion in normal fertile women, the effects of CRH on luteinizing hormone (LH), follicle-stimulating hormone (FSH), and cortisol secretion were studied during the menstrual cycle. CRH had no effect on LH release during the midfollicular phase of the cycle. By contrast, IV injection of 100 micrograms CRH elicited significant decreases in LH concentrations during late follicular (-50%) and midluteal (-52%) phases of the cycle. LH concentrations decreased during the four-hours following injection of CRH and returned to those observed during the control period five hours after injection. Similarly, CRH elicited a significant decrease in FSH secretion during the midluteal phase of the cycle. CRH injection induced an increase in cortisol release during all phases of the cycle. These data demonstrate that exogenous CRH administration results in inhibition of gonadotropin secretion in late follicular and midluteal phases of the cycle. These results suggest that elevated endogenous CRH levels resulting in increased cortisol secretion could contribute to decreased gonadotropin secretion and, thus, disruption of reproductive function during stressful conditions in women.

PRESENCE OF POSITIVE FEEDBACK BETWEEN OESTROGEN AND LH IN PATIENTS WITH KLINEFELTER'S SYNDROME, AND SERTOLI‐CELL‐ONLY SYNDROME

In five adult patients with Klinefelters syndrome and two with Sertoli‐cell‐only syndrome, exogenous administration of 17β‐oestradiol, resulting in a sustained and prolonged elevation of circulating oestrogen levels, had a biphasic effect on LH release. After an initial decrease, a dramatic rise in peripheral levels of LH (positive feedback) was observed in all patients. The timing and magnitude of the induced LH surge was similar to that observed in postmenopausal women after administration of large doses of Ethinyloestradiol. A similar positive feedback effect on the secretion of FSH could not be demonstrated. In two patients with the Sertoli‐cell‐only syndrome, oestrogen treatment induced marked variations in serum testosterone levels, which appeared to be related to the LH changes. Similar changes were not present in patients with Klinefelters syndrome, indicating a decrease in the sensitivity of the testicular Leydig cell. These experiments demonstrate that positive feedback between oestrogen and luteinizing hormone is present in the adult hum an male.

Estradiol Modulation of Basal and Gonadotropin-Releasing Hormone-Induced Gonadotropin Release in Intact and Castrated Men

In 6 intact and 4 castrated adult men a daily intramuscular administration of 1.5 mg estradiol benzoate (E2B) (at 08.00 h) for 7 days induced an initial suppression of circulating gonadotropins with a subsequent rise in LH, which occurred after 96 h of treatment in intact men and after 120 h in castrated men. The magnitude of the LH surge was greater in castrated than in intact men. The changes in basal LH levels were concomitant with a variation in the LH responses to GnRH infusion (0.2 µg/min × 4 h) suggesting a modulatory effect of estrogen on the two pools of pituitary LH. A dramatic decrease in the LH response during the first hour (first pool) was observed after 24-48 h of treatment, followed by a significant increment of this response, which occurred at 96 h in intact men and at 120 h in castrated subjects. During E2B administration, a progressive increment in the delayed response of LH (second pool) was seen, indicating an augmentation of the pituitary capacity. The basal FSH levels progressively decreased and the pattern of FSH response to gonadotropin-releasing hormone (GnRH) infusion was not significantly changed during E2B treatment. The present results demonstrated that:(1) the maintenance for 96-120 h of serum E2 concentrations similar to those present in women at midcycle induced a LH release both in intact and castrated men. (2) The magnitude of LH peak is blunted in the presence of circulating testosterone. (3) E2 induced a biphasic effect on the two pools of pituitary LH similar to that observed in women. Finally, our present data confirm our previous findings that the modulation of gonadotropin secretion in men is not influenced by the perinatal exposure of the hypothalamic-pituitary unit to androgens.

Relationships between Intracranial Pressure and Diurnal Prolactin Secretion in Primary Empty Sella

The role of the intracranial pressure (ICP) in the development and/or maintenance of the primary empty sella has been evaluated by recording the ICP during sleeping and waking periods in 11 women who had this syndrome. Concomitantly, plasma PRL levels, measured at 2-hour intervals during a 24-hour period, were compared with the changes in ICP. Daily PRL variations were also measured in 5 normally cycling and 5 postmenopausal women. ICP was abnormally increased in 8 patients with PES. In 3 of them, increased values were recorded during waking and sleeping periods, while in 5 subjects abnormal values were observed only during sleep. In the remaining 3 patients the ICP was normal in all conditions tested. 8 patients with elevated ICP presented an absent or blunted nocturnal PRL increase. In 3 patients with normal ICP, the circadian periodicity of PRL was preserved. The normalization of ICP obtained in 4 patients by a surgical shunting procedure was accompanied by the return to normal of the circadian PRL periodicity. Our observations demonstrate that the finding of a normal ICP during wakefulness is not sufficient to rule out an actual increase in ICP, since a rise in the CRF pressure can occur during sleep. Our data also demonstrated a correlation between an abnormal rise in ICP and an absent or blunted nocturnal increment in PRL secretion.

Prolactin-secreting adenomas: surgical results and long-term follow-up

Transsphenoidal surgery is an efficacious treatment for patients with prolactin (PRL)-secreting adenomas, even if disrupted pituitary-hypothalamic relationships may persist and/or a recurrence of the PRL-secreting tumor can occur. In this paper, we analyze the long-term follow-up of 119 consecutively treated women who underwent transsphenoidal microsurgery for PRL-secreting adenomas. Apparent total removal of the tumor was achieved in 98 patients who had enclosed tumors (58 with Grade-I tumors and 40 with Grade II). In the remaining patients, the removal was considered partial. Persistent normal basal PRL levels were achieved in 61 patients who had apparent total removal of the adenoma (44 with Grade I tumors and 17 with Grade II). Of the remaining 37 patients in whom surgical removal of the adenomatous tissue was thought to be total, 30 had persistent nonevolutive, high PRL levels ranging from 21 to 196 ng/ml, without clinical and radiological signs of tumor regrowth, and 7 with PRL levels ranging from 56 to 560 ng/ml had a recurrence of the PRL-secreting tumor. These data seem to indicate that a slightly elevated postsurgical PRL value does not imply that tumoral tissue is still present. Nontumoral conditions (i.e., a secondary empty sella) could induce functional hyperprolactinemia.

Evaluation of pituitary-thyroid axis response to acute myocardial infarction

We have studied with seriated controls for a period of 9 days 18 patients admitted to our hospital for acute myocardial infarction (AMI). Slight, but non significant variations in thyroidal hormone pattern were observed: slight decrease of T3 and T4 levels, increase of reverse T3 on day 3, low free T4 levels, slight increase of TSH levels until the 3rd day. However, hormonal pattern was clearly different in patients who presented a clinical improvement (group Ia) and in patients who died for AMI (group Ib). In fact, a significant TSH increase was recorded in patients of group Ia; on the contrary, a significant decrease of TSH, T4 and free T4 concentrations was observed for subjects of group lb, suggesting an inadequate response of pituitary-thyroid axis. In conclusion, the evaluation of thyroid hormones and thyrotropin levels can be of clinical usefulness in the management of patients with AMI. The decrease of plasma T4 and free T4 concentrations, accompanied with low TSH levels, can be associated with unfavorable course of the disease and therefore can be considered a bad prognostic sign.

Cerebrospinal fluid pressure and prolactin in empty sella syndrome

In 58 female patients with the primary empty sella (PES) syndrome, a study of the CSF dynamics was done by evaluating both the absorptive reserve by a lumbar infusion test at constant rate, and/or the ICP increase occurring during REM phase of nocturnal physiological sleep. In 33, prolactin (PRL) dynamics were also investigated evaluating both the response to sequential stimulating test with thyrotropin-releasing hormone (TRH) and metoclopramide (MCP) and/or the circadian variation of PRL levels. Impairment of CSF dynamics was found in the 84% who had a hormonal pattern characterized by an increase of the PRL response to TRH and MCP and a decrease of the PRL circadian variation. Twenty-one patients with impaired CSF dynamics underwent CSF shunting procedures with disappearance of the signs of intracranial hypertension. They also had restoration of normal PRL dynamics but the endocrine alterations improved only moderately. Altered CSF dynamics play a role in the pathogenesis of the PES syndrome. A correlation between elevated ICP and the hypothalamo-hypophyseal control of PRL secretion may exist.

Evaluation of metabolic status in amiodarone-induced thyroid disorders: plasma coenzyme Q10 determination

In previous works we have demonstrated that Coenzyme Q10 (CoQ10) levels have a significant inverse correlation with thyroid hormone concentration in patients with spontaneous hyper- or hypothyroidism. In order to verify whether this correlation is maintained in patients on long-term amiodarone therapy, in whom thyroid metabolism is altered by the iodine contained in the drug, we have studied 30 patients with thyroid dysfunction induced by chronic amiodarone treatment. We have distinguished four groups of patients: group A (n = 8): patients with true hyperthyroidism induced by drug administration; group B (n = 11): patients with mild hyperthyroid symptoms, but isolated thyroxine increase or dissociation between different indexes of thyroid function; group C (n = 5): patients with normal thyroid hormone levels, but increased TSH levels; group D (n = 6): patients who appeared really clinically euthyroid, with normal thyroid hormone levels and normal TSH response to TRH. In group A patients, plasma CoQ10 levels averaged 0.49 ± 0.03 μg/ml, significantly lower than those in normal subjects and similar to those observed in spontaneous hyperthyroid patients. In group B patients, CoQ10 levels were in the normal range (0.88 ± 0.10 μg/ml). In group C patients, CoQ10 levels were lower than those in normal subjects and similar to those of group A patients (0.49 ± 0.04 μg/ml); they differed, in regards to CoQ10 values, in comparison with spontaneous primary hypothyroid patients, who had very high levels of plasma CoQ10. Finally, in group D patients, CoQ10 levels were in the normal range (0.77 ± 0.04 μg/ml). The present investigation demonstrated that, in patients on amiodarone treatment, CoQ10 levels correlated better with metabolic status than with thyroid hormone levels; CoQ10 determination could be useful in discriminating ‘true’ from ‘pseudo’-hyperthyroid conditions, due to a contaminating effect of the iodinerepleted drug amiodarone.

Growth hormone response to propranolol and l-dopa in obese subjects

Oral administration of propranolol and L-dopa produced a marked increase in plasma growth hormone values in 12 obese subjects who had failed to respond to L-dopa alone. GH values after propranolol and L-dopa in obese subjects were not significantly different from those of normal subjects after L-dopa at 60, 90, and 120 min. Association of propranolol and L-dopa appears to be a simple means of investigating GH response in obese subjects.

Sex-related naloxone influence on growth hormone-releasing hormone-induced growth hormone secretion in normal subjects

The effect of opiate-receptor antagonist naloxone on growth hormone (GH) release after growth hormone-releasing hormone (GHRH) 1-44 administration was investigated in ten normal men and 18 normal women during different phases of their menstrual cycle. Naloxone was infused at a rate of 1.6 mg/h in women and 1.6- and 3.2 mg/h in men, starting one hour before GHRH administration (50 micrograms iv as a bolus). On different day sessions, naloxone, GHRH, or saline were administered as controls. Naloxone infusion reduced the GHRH-induced GH release in normal women. The mean % inhibition of peak GH response was 83% during follicular phase, 46.5% during periovulatory phase, and 77.6% during luteal phase. On the contrary, in normal men, both doses of naloxone infusion were ineffective in blunting the GH response to GHRH. Our studies indicate that naloxone infusion was capable of inhibiting GH release induced by direct stimulation with GHRH in normal women, suggesting an opiate-antagonist action at the anterior pituitary level. The absence of such an effect in normal men strongly indicates a sex dependence of naloxone effects and suggests a role of the sexual steroid environment in opioid modulation of pituitary hormone secretion.