The thyrotropin (TSH) profile in isolated gonadotropin deficiency: a model to evaluate the effect of sex steroids on TSH secretion.

This study evaluated the effect of estrogens and androgens on TSH secretion in hypogonadal male and female patients with isolated gonadotropin deficiency (IGD). The IGD subjects were clinically euthyroid and had normal circulating levels of thyroid hormones and T4-binding globulin (TBG). The patients were challenged with TRH (200 micrograms) in the untreated state, during treatment, and 1 month after cessation of hormonal replacement therapy. For the study, five females were treated with ethinyl estradiol (0.05 mg twice daily) for 21 days; after stopping for 7 days, the treatment schedule was repeated for another two cycles. The remaining female was given a similar regimen with conjugated estrogens (0.625 mg daily). Five males were treated with hCG (5000 IU twice weekly) for 3 months; two were treated with hCG and Pergonal. The female patients had significantly decreased basal TSH levels as well as impaired TSH responses to TRH. After 3 months of ethinyl estradiol treatment, there was a rise in TBG, total serum T4 and T3 levels and a decrease in T3 resin uptake; the free T4 index was unchanged. During estrogen administration, there was no change in basal TSH, but there was an increase in the peak TSH response to TRH, which became identical to that of the controls. Cessation of estrogen was associated with a reduction in releasable TSH, and the profile reverted to the pretreatment state. In addition, serum TBG levels, with the associated changes in thyroid hormones, also returned to normal. The male patients had TSH responses to TRH identical to those of the male controls. After 3 months of hCG treatment, there was a marked rise in serum estradiol as well as testosterone. Serum T4 was reduced without a change in T3, T3 resin uptake, or TBG. Furthermore, there was no alteration in the TSH response to TRH. On the other hand, the administration of ethinyl estradiol (0.1 mg daily for 2 weeks) to two male IGD subjects produced an increase in TBG. This was associated with elevation of serum T4 and T3 levels and reduction of T3 resin uptake. During estradiol administration, there was an increase in the TSH response to TRH. These data are compatible with the hypothesis that estrogens are required to maintain a normal TSH response to TRH in the female. However, testosterone may counteract the effect of estradiol, which may explain why normal males tend to have a lower TSH response to TRH than females.

Gonadotrophin, testosterone and prolactin interrelationships in cadmium-treated rats.

We have investigated the long-term effect of a single subcutaneous injection of cadmium chloride on plasma testosterone and gonadotrophin levels and the prolactin response to the dopaminergic antagonist metoclopramide in the rat. Twelve days after treatment with cadmium there was testicular necrosis, associated with a decrease in testosterone concentration and atrophy of the accessory sexual glands. By 185 days, partial recovery of the accessory sexual glands indicated by Leydig cell regeneration and a slight rise in testosterone levels had occurred. There was, however, persistent damage to the germinal epithelium. Concentrations of LH increased eightfold above controls by day 12, remained raised until 60 days and then decreased to threefold above controls at 280 days. In contrast, FSH levels reached a maximum between 60 and 130 days and remained persistently raised. The peak prolactin response to metoclopramide in cadmium-treated rats was depressed 12 days after cadmium administration and levels remained low at 19 and 75 days. Normal prolactin responses to metoclopramide were obtained 130 days after cadmium treatment using 1:0 mg metoclopramide/kg or 280 days after treatment using 0.25 mg/kg. When control and cadmium-treated rats were castrated at 280 days and then given metoclopramide 10 days later, the prolactin response was significantly reduced. It is concluded that the impaired prolactin response to metoclopramide in cadmium-treated rats is reversible. Prolactin returns to normal in parallel with regeneration of the Leydig cells, partial restoration of the accessory sex organ weight, slight increase in plasma testosterone and decrease in LH levels. These results suggest that testosterone is not solely responsible for the maintenance of normal prolactin secretion in the male rat.

Increased prolactin response to thyrotropin-releasing hormone in primary ovarian failure.

To investigate prolactin (PRL) and thyrotropin-stimulating hormone (TSH) secretion in ovarian failure, 14 women with primary ovarian failure were challenged with luteinizing hormone-releasing hormone (LHRH) (100 micrograms) and thyrotropin-releasing hormone (TRH) (200 micrograms) given intravenously at 30-minute intervals. Responses were compared with those of 13 healthy female controls. In the patient group, basal follicle-stimulating hormone (FSH), LH, and peak gonadotropin responses to LHRH were higher and basal estrone and estradiol levels were lower than in the controls (P less than .001). Mean basal PRL levels were similar in the 2 groups. However, the mean peak and integrated PRL responses in the patients were greater than in the controls (P less than .05). Ten patients had a markedly exaggerated PRL response to TRH. The mean basal TSH levels and the peak TSH response to TRH were similar to those of the controls. Estrogens are known to stimulate PRL secretion. These subjects had increased PRL responses with low circulating estrogens. The mechanism underlying the findings is not known, but could be related to increased aromatization of androgens to estrogens in the hypothalamus. Alternatively, other factors could be responsible for the exaggerated PRL responses to TRH noted in these patients with primary ovarian failure.

Exaggerated prolactin response to thyrotropin-releasing hormone and metoclopramide in primary testicular failure.

Twenty-eight severely oligospermic and azoospermic men aged 20 to 42 years were challenged with luteinizing hormone (LH)-releasing hormone (LHRH), thyrotrophin-releasing hormone (TRH), and the dopaminergic antagonist, metoclopramide, given at 30-minute intervals. According to basal gonadotropin levels, the patients were subdivided into three groups: those with severe testicular failure (basal LH > 20 mIU/ml and FSH > 14 mIU/ml); those with moderate testicular failure with predominant seminiferous tubule involvement (LH < 20 mIU/ml and FSH > 14 mIU/ml) and those with mild testicular failure (LH < 20 mIU/ml and FSH < 14 mIU/ml. With one exception, mean basal prolactin (PRL) levels were normal in all patients. In all three groups, however, there was an exaggerated PRL response to TRH, the response in severe and moderate testicular failure being greater than that in mild testicular failure. The response to metoclopramide was increased only in the first two groups, not in the group with mild testicular failure. When individual patients and control subjects were considered together, the peak PRL response to TRH correlated with both basal and peak gonadotropin responses to LHRH. However, the PRL responses did not correlate with 17 beta-estradiol, estrone, testosterone, or the estradiol-testosterone ratio. It is concluded that oligospermic and azoospermic subjects with the most severe testicular failure and the highest gonadotropin levels have the greatest PRL increases after TRH and metoclopramide, indicating that the PRL response is related to the degree of testicular failure.

Elevated serum progesterone levels during pituitary suppression may signify adrenal hyperandrogenism.

OBJECTIVE: To investigate whether elevated serum P levels after pituitary down-regulation signify adrenal enzyme defects or hyperandrogenism. DESIGN: Prospective study. SETTING: Assisted reproduction unit in a university medical center. PATIENT(S): Two hundred twenty-seven IVF patients treated by the long down-regulation protocol. INTERVENTION(S): Oral dexamethasone (DEX) administration if P level exceeded 0.8 ng/mL (conversion factor to SI unit, 3.180) after pituitary suppression. MAIN OUTCOME MEASURE(S): Serum concentrations of P, E2, LH, DHEAS, and 17 alpha-hydroxyprogesterone and ACTH stimulation tests. RESULT(S): In eight patients (3.5%), serum P levels exceeded 0.8 ng/mL and E2 and LH levels confirmed pituitary down-regulation. Mean DHEAS levels in the patients in this group were significantly higher than in the other patients. All eight patients demonstrated a significant decrease in serum P level after DEX administration. In five patients the ACTH stimulation test suggested an adrenal defect. Five pregnancies were achieved after the addition of DEX to the treatment protocol. CONCLUSION(S): High serum P levels after pituitary down-regulation appear to be of adrenal origin and may be the first indication of an adrenal enzyme defect. Further investigation such as an ACTH stimulation test is recommended, followed by treatment with DEX if indicated.

The dissociation of the exaggerated prolactin and thyrotropin responses in seminiferous tubule failure following the administration of a double-pulse of thyrotropin-releasing hormone.

PRL and TSH secretion has been evaluated in 11 patients with seminiferous tubule failure and 9 controls. When compared to the controls, the patients had increased basal FSH, TSH and PRL levels. However, LH, E2, T and thyroid hormone levels were similar to the controls. Both groups were given two pulses of TRH (200 micrograms) at 30 min intervals. Following the initial pulse of TRH, the patients demonstrated exaggerated TSH and PRL responses. The administration of a second pulse of TRH led to a further increment of TSH secretion in the patients. There was, however, no PRL response to the second TRH pulse in either patients or controls although mean PRL levels remained significantly greater in the patients.

The interrelationships between prolactin and thyrotrophin secretion following dopaminergic blockage in patients with mild hyperprolactinaemia without any demonstrable pituitary tumour.

PRL, TSH and gonadotrophin responses to the dopaminergic antagonist, metoclopramide, were studied in mildly hyperprolactinaemic patients with normal sella radiology and CT scan. Eleven female patients with basal PRL levels ranging from 23 to 124 ng/ml were challenged with intravenous metoclopramide (10 mg) and on subsequent occasions with TRH (200 micrograms) and LHRH (100 micrograms). On the basis of the PRL secretory pattern following metoclopramide and TRH stimulation, the patients were divided into two groups. Group I comprised six subjects who were PRL non-responsive to TRH and metoclopramide. Group II (five subjects) demonstrated PRL responses to TRH and metoclopramide indistinguishable from female controls. Mean +/- SD basal PRL levels were 68.5 +/- 29.9 ng/ml in Group I and not different in Group II (40.6 +/- 12.0 ng/ml). Basal LH levels were increased in Group II, whereas FSH was increased in Group I. Basal TSH levels were lower in Group I than the controls. Following metoclopramide, Group I patients had an increase in TSH from a basal of 2.4 +/- 0.7 microU/ml to a peak of 5.9 +/- 2.7 microU/ml (P less than 0.005) which occurred at 30 min. TSH values were increased above basal at all time intervals following metoclopramide. In contrast, TSH levels did not change in Group II patients or the controls after metoclopramide administration. Both patient groups had TSH responses to TRH similar to the controls. Following LHRH, the LH increase was greater in Group II and the FSH in Group I. In neither group nor the controls did gonadotrophin levels change after metoclopramide. In Group II females, PRL responsiveness to metoclopramide was associated with TSH non-responsiveness. In Group I females, PRL levels failed to rise, whereas TSH increased. The PRL and TSH profile in Group I females is typical of a prolactinoma. It is concluded that PRL as well as TSH determinations following metoclopramide are useful indices in the assessment of hyperprolactinaemia and may be of value in differentiating the functional state from that of a pituitary tumour.

Dopaminergic regulation of prolactin secretion in the hyperprolactinemic syndrome.

The prolactin responses to an oral challenge of L-dopa (0.5 g) and bromocriptine (2.5 mg) were studied in 31 hyperprolactinemic females without radiological abnormalities of pituitary fossa, in 12 hyperprolactinemic patients with minor radiological evidence suggesting the presence of a pituitary adenoma and in 16 normal volunteers in the early puerperium with physiological hyperprolactinemia. Administration of bromocriptine was followed by a similar suppression of prolactin secretion in the functional as well as the adenomatous hyperprolactinemic patients. By contrast, a significantly blunted response to L-dopa was noted in the patients with pathological hyperprolactinemia (with and without radiological abnormalities of the pituitary fossa). These results suggest that the L-dopa suppression test might serve as a reliable indicator to detect prolactin-secreting microadenomas in patients with persistent hyperprolactinemia and radiologically normal pituitary fossae.

The origin of serum progesterone during the follicular phase of menotropin-stimulated cycles.

The study was designed to investigate the source of progesterone secretion during pituitary suppression and ovarian stimulation. It involved 416 women undergoing in-vitro fertilization (IVF) who were treated with gonadotrophin-releasing hormone agonist (GnRHa) and human menopausal gonadotrophin (HMG) (group I), 139 women undergoing ovulation induction with HMG only (group II) and nine women who were diagnosed previously as late-onset adrenal hyperplasia and treated continuously with dexamethasone, in addition to ovulation induction (group III). During HMG treatment, serum oestradiol and progesterone were measured every 1-2 days. If progesterone concentration exceeded 3.0 nmol/l, at least 36 h before human chorionic gonadotrophin (HCG) administration, the patients were prospectively randomized to treatment with dexamethasone or not and the hormones concentrations were measured again 12 h later. Mean age and pretreatment serum concentrations of dehydroepiandrosterone sulphate, androstenedione, testosterone and luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio, were not significantly different in the patients with and without progesterone elevation. Pituitary down-regulation did not reduce the incidence of progesterone elevation (13.9 and 12.2% in groups I and II respectively), while in group III, progesterone concentrations did not increase. After dexamethasone administration a significant decrease in serum progesterone concentration was demonstrated (mean +/- SD, -2.1 +/- 1.4 and -1.6 +/- 1.2 in groups I and II respectively, while in the untreated patients it increased (+1.9 +/- 1.9 and +4.2 +/- 4.8). The increase in serum progesterone concentrations was not accompanied by an increase in cortisol and 11-deoxycortisol but by an increase in LH. After dexamethasone administration the concentrations of cortisol, 11-deoxycortisol and LH significantly decreased. Progesterone concentration was positively correlated with both oestradiol concentration (r = 0.290; P < 0.05) and the number of oocytes retrieved (r = 0.207; P < 0.05). We conclude that at least a part of serum follicular-phase progesterone appears to be of adrenal origin. High oestrogen concentrations (or other ovarian factors) may cause changes in the hypothalamic-pituitary-adrenal axis and in adrenal enzyme activity as a part of the complex 'cross-talk' between the hypothalamic-pituitary-ovarian and the hypothalamic-pituitary-adrenal axes.

Clomiphene citrate does not modify the exaggerated thyrotrophin response to thyrotrophin-releasing hormone occurring in primary testicular failure.

Patients with primary testicular failure have increased basal TSH levels and an exaggerated TSH response to TRH in the presence of normal circulating levels of thyroid hormones. In order to evaluate it this TSH profile is an oestrogen-related phenomenon, sixteen patients with primary testicular failure were challenged with 200 micrograms TRH prior to and after the administration of clomiphene citrate. The latter was given in a dose of 100 mg/day for 4 weeks to ten patients; 200 mg/day for 4 weeks to three patients and 100 mg/day for 2 months to the final three patients. The patients demonstrated increased mean basal TSH levels with an exaggerated TSH response to TRH. Following the administration of clomiphene citrate, there were no changes in T4, T3 sephadex or total T3 levels and in basal or stimulated TSH levels. Clomiphene did produce an increase in oestradiol, testosterone, basal gonadotrophins and LH response to LHRH. Since the oestrogen antagonist, clomiphene citrate, had no effect on TSH secretion, it is unlikely that the exaggerated TSH response to TRH is mediated by oestrogens.

Effect of non aromatizable androgens on LHRH and TRH responses in primary testicular failure.

We have assessed the gonadotropin, TSH and PRL responses to the non aromatizable androgens, mesterolone and fluoxymestrone, in 27 patients with primary testicular failure. All patients were given a bolus of LHRH (100 micrograms) and TRH (200 micrograms) at zero time. Nine subjects received a further bolus of TRH at 30 mins. The latter were then given mesterolone 150 mg daily for 6 weeks. The remaining subjects received fluoxymesterone 5 mg daily for 4 weeks and 10 mg daily for 2 weeks. On the last day of the androgen administration, the subjects were re-challenged with LHRH and TRH according to the identical protocol. When compared to controls, the patients had normal circulating levels of testosterone, estradiol, PRL and thyroid hormones. However, basal LH, FSH and TSH levels, as well as gonadotropin responses to LHRH and TSH and PRL responses to TRH, were increased. Mesterolone administration produced no changes in steroids, thyroid hormones, gonadotropins nor PRL. There was, however, a reduction in the integrated and incremental TSH secretion after TRH. Fluoxymesterone administration was accompanied by a reduction in thyroid binding globulin (with associated decreases in T3 and increases in T3 resin uptake). The free T4 index was unaltered, which implies that thyroid function was unchanged. In addition, during fluoxymesterone administration, there was a reduction in testosterone, gonadotropins and LH response to LHRH. Basal TSH did not vary, but there was a reduction in the peak and integrated TSH response to TRH. PRL levels were unaltered during fluoxymesterone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

TSH secretion in thalassemia.

Thyroid function has been evaluated in 6 prepubertal male and 9 female thalassemic patients. Four of the latter were sexually immature (Group I), with very low estradiol levels and the remainder had more advanced sexual development (Group II). Subjects were challenged with TRH and the response compared to adult controls and a group of 15 males aged 13-18 years with constitutional delayed adolescence. All patient groups and controls had normal levels of T4, T3 and T3 resin uptake. When compared to adult controls or males with constitutional delayed adolescence, the male thalassemic patients had increased basal TSH levels with an exaggerated response to TRH. Long term testosterone enanthate led to a decrease in integrated TSH secretion, showing that androgens may decrease the TSH response to TRH. The more sexually mature females of Group II also had increased basal and stimulated TSH levels; however, the sexually immature females of Group I had basal TSH and TSH responses to TRH equivalent to female controls. In Group I patients there were, moreover, no changes in TSH response during administration of estradiol valearate for 3 months and conjugated estrogens for 8 months. The high basal and stimulated TSH levels in the males and Group II females are most likely due to subclinical primary hypothyroidism. This has been previously described in thalassemia. On the other hand, failure of estrogens to increase the TSH response to TRH in Group I females is evidence of pituitary involvement, which is also well documented in this clinical condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolactin response to metoclopramide and chlorpromazine in primary testicular failure and isolated gonadotrophin deficiency.

The aim of the present study was to measure the PRL response to metoclopramide (MET) and chlorpromazine (CPZ) in seventeen patients with primary testicular failure and eight patients with isolated gonadotrophin deficiency (IGD). The responses were compared with those to TRH. Basal gonadotrophins and peak responses to LHRH were increased in testicular failure and reduced in IGD. Basal PRL levels were normal in both groups of patients. However, when compared with controls, the PRL response to both MET and CPZ as well as to TRH was exaggerated in primary testicular failure, whereas the responses wee decreased in IGD. In both patient groups, as well as in the controls, the PRL response to MET exceeded that to TRH and CPZ. It is suggested that alterations in the steroid milieu are responsible for the exaggerated PRL response to MET, CPZ and TRH in primary testicular failure and the reduced response observed in IGD.