Suppression of the TSH response to TRH by thyroxine therapy in differentiated thyroid carcinoma patients.

Absent response of serum thyrotrophin (TSH) after stimulation with 200 micrograms synthetic thyrotrophin-releasing hormone (TRH) was used as a criterion of adequate suppression of TSH in the treatment of thyroid carcinoma patients with thyroxine. The mean causing total suppression of the response was 223 micrograms of thyroxine per day. At this dose level about 40% of the patients had serum thyroxine concentrations above the upper reference interval and only 10% had elevated triiodothyronine concentrations. In some patients the TSH response to TRH varied between absent and low normal when tested at long intervals. The ideal dose of thyroxine is obviously slightly higher than the smallest one causing total suppression of the TSH response to TRH, i.e. about 250 micrograms a day. The individual dose must be found using the TRH stimulation test because serum thyroid hormone levels cannot be used as a guideline for adequate dosage. In some patients the thyroid remnant of apparently normal thyroid tissue was not totally suppressed although the thyroxine dose was definitely above the level causing suppression of the response to TRH.     

Effect of D-thyroxine on serum sex hormone binding globulin (SHBG), testosterone, and pituitary-thyroid function in euthyroid subjects

Concentrations of serum sex hormone binding globulin (SHBG) and free testosterone (T) were examined in 10 euthyroid subjects (5 men and 5 women) before, during and after 30 days of the daily ingestion of 1 or 4 mg D-thyroxine (D-T4), the thyroxine analog that has only 1-15% of the calorigenic effect of L-thyroxine (L-T4). No changes in serum L-T4 or triiodothyronine (T3), serum cholesterol, SHBG, T, progesterone, estradiol-17 beta, or free T concentrations were observed in response to the 1 mg dose, but there was a slight elevation in the free thyroxine index (FTI) and a significant (p less than 0.02) suppression of the thyrotropin (TSH) response to thyrotropin releasing hormone (TRH). The 4 mg dose of D-T4 induced an increase in SHBG levels in all but one man. There was a significant negative correlation between the SHBG and percent free T (p less than 0.05) although the mass of free T did not change. As a group, the women responded with a greater increase in SHBG and decrease in percent free T than the men. Serum cholesterol decreased (p less than 0.01), all serum thyroid hormone values measured by RIA were increased (p less than 0.01), and the TSH response to TRH was completely suppressed. Despite these changes, the subjects remained clinically euthyroid. Concentrations of testosterone, progesterone and estradiol-17 beta remained unchanged. Serum luteinizing hormone (LH), which was evaluated in the men only, also did not change during the daily administration of 4 mg D-T4.     

SERUM THYROGLOBULIN AFTER MANTLE IRRADIATION FOR HODGKIN''S DISEASE

Thyroid function and serum thyroglobulin levels were studied in 66 subjects whose Hodgkin's disease had been previously treated by cervical, mediastinal and axillary lymph node (mantle) irradiation. Three patients were already undergoing treatment for thyroid disorders (one for primary hypothyroidism, two for Graves' disease) and a fourth was found to have euthyroid Graves' disease. 36 (Group I) of the remaining 62 patients had normal free thyroxine indices, normal basal thyrotrophin (TSH) levels and normal TSH response to thyrotrophin releasing factor (TRH). In 20 patients (Group II) free thyroxine indices were normal but either basal TSH levels were raised or normal basal TSH levels were associated with an exaggerated response to TRH. In 6 patients (Group III) free thyroxine indices were subnormal. Although results of thyroid function tests in group I lay within the normal range, the mean free thyroxine index was significantly lower and mean basal and peak TSH levels were significantly higher than those of a group of 35 normal subjects, indicating mild thyroid hypofunction. Elevated thyroglobulin levels were demonstrated in 11 irradiated subjects (18%). Mean thyroglobulin levels were significantly raised in each of the three groups of irradiated subjects. Significant positive correlations were found between log serum thyroglobulin and log basal TSH (r = 0.453, P less than 0.001) and log peak TSH (r = 0.515, P less than 0.001) levels. Mild thyroid hypofunction is common after mantle irradiation for Hodgkin's disease and raised serum thyroglobulin levels are a sensitive indicator of TSH stimulation of the damaged thyroid gland.     

Possible altered dopaminergic modulation of pituitary function in normal-menstruating women with insulin dependent diabetes mellitus (IDDM)

In order to assess whether a possible altered dopamine activity in normal-menstruating diabetic patients may influence the pituitary hormone secretion we have measured the basal serum concentrations of Prl, LH and FSH in 28 patients with insulin dependent diabetes mellitus (IDDM) and in 55 normal-menstruating women at day 3 to 6 of the menstrual cycle. In addition basal levels of oestradiol-17 beta, TSH, thyroxine (T4), triiodothyronine (T3) and resin-T3 uptake (RT3U) were determined in 17 patients with IDDM and in 17 controls. The responses of FSH, LH, Prl, GH and TSH to metoclopramide (MTC) administration (10 mg iv) were studied in 17 patients and 17 controls. In 10 patients with IDDM and 8 controls the short-term variations in pituitary hormones and blood glucose concentration were evaluated. Patients with IDDM had significantly lower basal levels of Prl (P less than 0.01) and TSH (P less than 0.05) and significantly (P less than 0.05) higher basal levels of GH than normal women. No significant (P greater than 0.05) differences were found regarding basal serum concentrations of FSH, LH, oestradiol, T4, T3 and RT3U. During the 3 h period the mean coefficient of variation of Prl, FSH, LH and GH was not significantly (P greater than 0.05) different between diabetic patients and controls. Both groups responded significantly (P less than 0.01) in Prl and TSH to MTC but the TSH response was significantly (P less than 0.05) lower in patients with IDDM. The Prl response to MTC was not significantly (P greater than 0.05) different within the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

RAPID ADAPTATION OF PITUITARY RESPONSIVENESS TO TRH IN THE POST-SURGICAL STATE. THE ROLE OF FREE T3

In eight clinically and biochemically euthyroid patients undergoing routine major non-thyroidal surgery preoperative and daily postoperative serum concentrations of total and free thyroid hormones were measured. Thyrotro-phin-releasing hormone (TRH) tests were performed preoperatively and on the first 3 postoperative days. There was a significant fall in mean serum total and free triiodothyronine (T3) concentrations on the postoperative days and mean reverse T3 concentrations rose reciprocally. There was no significant change in mean basal thyroid-stimulating hormone (TSH) values, but there was a significant increase in the mean TSH response to TRH on the first postoperative day. The mean TSH response then declined sequentially until day 3 while mean free T3 concentrations remained significantly depressed. Mean serum free thyroxine (T4) concentrations remained normal during the study. Intrapituitary conversion of T4 to T3 or other down regulatory mechanisms could explain this rapid adaptation of the pituitary axis.     

The effects of pyridoxine on pituitary hormone secretion in amenorrhea-galactorrhea syndromes

Six patients with amenorrhea, five of whom had galactorrhea and elevated PRL levels, were evaluated on a metabolic ward. All had normal sella tomograms, normal thyroid functions, and routine laboratory evaluations. None of the patients had taken any medication in the previous 6 months. On alternate days, five patients received 500 microgram of TRH iv with the measurement of PRL, TSH, FSh, LH, and hGH; 500 mg L-dopa orally with the measurement of PRL, FSH, and LH; a bolus infusion of 300 mg pyridoxine (B6) with measurement of PRL, hGH, TSH, FSH, and LH; and 25 mg chlorpromazine (CPZ) im with the measurement of PRL, LH, and FSH. The patients were then discharged on 600 mg oral pyridoxine/day and were readmitted for a repeat of the complete protocol 21 days later. The patients were continued on 600 mg oral pyridoxine for 3-4 months with monthly evaluations of serum PRL, LH, and FSH levels. These evaluations continued for 3 months after discontinuing pyridoxine. There was no demonstrable change in serum PRL after acute or chronic B6 therapy, mor was there a significant change in the response of PRL to CPZ, L-dopa, or TRH. The mean basal PRL was 97.5 +/- 9.7 ng/ml and after 3-4 months of oral pyridoxine was 97.1 +/- 14.8. In addition, there was no significant change in LH or FSH levels in response to acute or chronic B6, TRH, L-dopa, or CPZ. Neither acute B6 infusion nor chronic B6 therapy had any effect on TSH or the TSH response to TRH. Finally, acute B6 infusion had no effect on hGH levels and there were no paradoxical hGH responses to TRH. Two patients began having regular menses while on chronic pyridoxine. Their hormonal responses did not differ from those of the group, however.     

Effect of prolonged oral administration of TRH on plasma levels of thyrotrophin and prolactin in normal individuals and in patients with primary hypothyroidism.

Forty mg TRH/day was given orally for 3 weeks to 10 euthyroid women and 10 women with primary hypothyroidism on low replacement doses of thyroxine. Once weekly oral TRH was replaced by an iv TRH-test (0.4 mg) with measurement of serum concentration of TSH, prolactin (PRL), thyroxine (T4), triiodothyronine (T3) and cholesterol. In the normal group, mean serum T4 concentration increased after one week and remained elevated. Serum TSH concentration showed a slight tendency to decline. Maximal rise in TSH concentration after iv TRH (deltaTSH) fell from a mean of 4.0 ng/ml to 1.4 ng/ml within one week and stayed low. T3, cholesterol, PRL and deltaprl were normal and unchanged throughout. In the hypothyroid group T4, T3, cholesterol, PRL and deltaPRL were not influenced by the TRH administration. In 2 patients (with the highest serum T4 concentrations) serum TSH concentration was normal and resistant to iv TRH. Of the 8 patients with elevated TSH, basal level and deltaTSH did not change in 2 (with subnormal T4 levels and the highest TSH levels). In the other 6 (with intermediate T4 levels) basal TSH fell from a mean of 10.1 ng/ml to 4.2 ng/ml, and deltaTSH from 10.0 ng/ml to 3.3 ng/ml after three weeks. It is concluded that in addition to feed-back effect of thyroid hormones, the pituitary response to long-term administration of TRH is determined by other factors. Among these may be reduced pituitary TRH receptor capacity and the activity of the TSH producing cells.     

PROLACTIN, TSH, LH AND FSH RESPONSES TO A COMBINED LHRH/TRH TEST AT DIFFERENT STAGES OF THE MENSTRUAL CYCLE

A combined test with LHRH and TRH was investigated in the normal female subject during the menstrual cycle. LH and FSH responses were not affected by raised prolactin or TSH levels after TRH.
No correlation was seen between either basal levels or responses of prolactin and TSH after TRH, and no difference in responses on days 4 or 24 were observed. The increments in prolactin and TSH were significantly greater in female than in male subjects.
Although FSH responses to LHRH+TRH were not significantly different, LH responses on day 24 were greater than on day 4. A significant linear correlation between FSH and LH responses to LHRH was seen.
The results indicate that prolactin and TSH responses to TRH are greater in female than male subjects and that changes in LH and FSH after LHRH do affect these responses. Normal ranges for hormone responses after LHRH and TRH are defined.     

Effect of Synthetic Thyrotrophin Releasing Hormone (TRH) in Man

Summary: Synthetic TRH (200 μ g) administered intravenously to twelve normal subjects produced a consistent rise in serum thyrotrophin (TSH) levels reaching a peak 20 – 30 mins following the injection. No reproducible effects were seen on plasma levels of GH, LH, FSH or 11 -hydroxycorticoids measured concomitantly with TSH. Mean free thyroxine index following TRH rose by 23% at 60 and 120 mins. Two subjects treated with triiodothyronine and 17 untreated thyrotoxic patients showed marked impairment of TSH response to TRH. Reduced or absent TSH responses were likewise observed in five euthyroid patients with Graves' disease, two with ophthalmopathy as the sole manifestation of the disease. In ten patients with primary hypothyroidism, synthetic TRH evoked further increases of elevated basal TSH levels with exaggerated over-all responses. Five of seven euthyroid patients with pituitary tumours showed blunted TSH responses whereas all six patients with secondary hypothyroidism (resulting from pituitary or suspected hypothalamic lesions) exhibited normal or slightly exaggerated responses.
It is concluded that synthetic TRH is a specific stimulus to pituitary TSH release with considerable potential in the diagnosis of mind disturbances of thyroid function. Its use should promote better understanding of hydothalamic-pituitary-thyroid relationships.     

Thyroid function in patients in clinical remission after medical treatment of thyrotoxicosis.

This paper described the changes in the levels of serum triiodothyronine, serum thyroxine,serum thyrotrophin and other indices of thyroid function between 2-5 y after completion of antithyroid drug therapy in 35 patients who were euthyroid on clinical criteria. There was a small but significant elevation of the mean triiodothyronine and thyroxine levels with a relative hypersecretion of Triiodothyronine. No correlation was found between the levels of either thyroid hormone measured or their ratio and the radioiodine uptakes and clearance rate, the plasma inorganic iodine level, the absolute iodine uptake or the serum TSH level. There was no case of clinical hypothyroidism but in one patient the TSH level was at the upper limit of the nrmal range and an exaggerated TSH response to TRH was found.     

TSH secretion in Cushing's syndrome: relation to glucocorticoid excess, diabetes, goitre, and the 'sick euthyroid syndrome'

Thyrotrophin (TSH) secretion was studied in 63 patients with Cushing's syndrome (53 patients with pituitary dependent Cushing's disease, eight with adrenocortical tumours, and two with the ectopic ACTH syndrome). Prior to treatment, TSH response to 200 micrograms of TRH intravenously was significantly decreased compared to controls; TSH response was 'flat' (increment less than 2 mU/l) in 34 patients (54%). Patients with a flat response to TRH had significantly higher morning and midnight cortisol levels than patients with a TSH response of 2 mU/l and more; this was not due to differences in serum thyroid hormone levels. Basal TSH, TSH increment after TRH, and stimulated TSH value, but not serum triiodothyronine, were correlated with cortisol measurements (0800 h serum cortisol, midnight cortisol, and urinary free corticoid excretion). After exclusion of 40 patients with additional disease (severe systemic disease, diabetes mellitus, or goitre), cortisol-TSH correlations were even more pronounced (r = -0.73 for midnight cortisol and stimulated TSH levels), while in the patients with additional complications, these correlations were slight or absent. Successful treatment in 20 patients was associated with a rise in thyroid hormone levels and the TSH response to TRH. These results indicate that (1) the corticoid excess but not serum T3 is the principal factor regulating TSH secretion in Cushing's syndrome, (2) a totally flat response to TRH is rare, and (3) TSH suppression and lower than normal serum thyroid hormone levels are reversible after treatment. Since factors like severe systemic disease, diabetes mellitus and goitre also affect TSH secretion, they tend to obscure the statistically significant correlations between cortisol excess and TSH secretion.     

Human pituitary chronoendocrinology: repetitive stimulation with LRH/TRH at different times of the day

To determine whether human pituitary is characterized by a circadian periodicity in response to repetitive injection of hypothalamic hormones, 8 healthy subjects were challenged iv with a triple stimulation with 50 micrograms of LRH and 100 micrograms of TRH in a single bolus at 0, 90 and 180 min, receiving the first pulse of hypothalamic hormones either at 02.00 h (02.00 h test) or at 09.00 h (09.00 h test). In addition, a placebo was injected instead of LRH/TRH to evaluate the spontaneous hormonal changes during the 02.00 h test. The LH, FSH, Prl and TSH basal levels were similar in the two phases studied. The mean LH, FSH and TSH peaks after each injection of LRH/TRH were similar among them. The mean Prl peak responses to the third pulse of LRH/TRH, in both the 02.00 h and the 09.00 h tests, were lower (P less than 0.05) than those after the first pulse of LRH/TRH. Placebo did not significantly change circulating LH, FSH, Prl or TSH during nocturnal sampling. The mean LH, FSH and Prl levels after LRH/TRH during the 02.00 h test were similar to those during the 09.00 h test. The mean TSH levels 15 min after the second and third pulses of LRH/TRH during the 02.00 h test were higher (P less than 0.05) than those of the 09.00 h test. Thus, thyrotropes responsiveness to pulsatile stimulation with LRH/TRH is greater during the night than in the morning, while LH, FSH and Prl responses remain constant at the two phases studied.     

The pituitary-thyroid axis after hemithyroidectomy in euthyroid man

The pathogenesis of euthyroid goiter is assumed to be TSH dependent, but most studies have not demonstrated elevation of serum TSH. To elucidate the early events involved in thyroid growth, we studied thyroid function in eight euthyroid patients subjected to hemithyroidectomy for solitary cold nodules preoperatively and 2, 15, 60, and 90 days and 36 months, postoperatively. Although within the euthyroid range, serum T4 decreased at 30 days and thereafter up to 90 days (P less than 0.01). Basal serum TSH rose significantly by the 30th day and remained elevated for the entire 90-day period (P less than 0.001). The serum TSH response to TRH was exaggerated from days 15-90 (P less than 0.001). Thirty-six months postoperatively, all parameters of thyroid function were similar to control values, with the exception of one patient who showed an exaggerated response of serum TSH to TRH. We conclude that 1) the dynamic phase of recuperation post hemithyroidectomy is TSH dependent, 2) the serum TSH increase occurs within normal limits and is a temporary event, and 3) 3 yr postoperatively, a new steady state is achieved with normal parameters of thyroid function. Thus, we believe that TSH plays a dominant role in the genesis of goiter.     

EFFECT OF FENOLDOPAM, A DOPAMINE D-1 RECEPTOR AGONIST, ON PITUITARY, GONADAL AND THYROID HORMONE SECRETION

The influence of fenoldopam, a dopamine (DA) D-1 receptor agonist, on basal and GnRH/TRH stimulated PRL, GH, LH, TSH, testosterone and thyroid hormone secretion was studied in nine normal men. All men received 4-h infusions of either 0.9% saline or fenoldopam at an infusion rate of 0.5 microgram/kg min, 12-16 ml/h, adjusted according to weight. After 3 h of infusion, 50 micrograms GnRH and 100 micrograms TRH was given i.v. Blood samples were collected every 15 min from 1 h before to 1 h after the infusion for a total of 6 h for measurements of PRL, LH, FSH, GH, TSH, testosterone, T4 and T3. The median PRL concentration increased significantly (P less than 0.01) to 128%, range 87-287, of preinfusion levels, compared to the decline during control infusion (85%, 78-114). Basal TSH levels declined significantly to 71% (60-91) during fenoldopam compared with 82% (65-115) during control infusion (P less than 0.05). Basal LH, FSH, GH and thyroid hormones were similar during fenoldopam and control infusions (P greater than 0.05). The LH response to GnRH/TRH was significantly (P less than 0.02) increased by fenoldopam infusion. Basal and stimulated testosterone concentration was lower during fenoldopam (P less than 0.01) infusion compared with control. Other hormones were similar after GnRH/TRH stimulation during fenoldopam and saline infusions. These results suggest that DA D-1 receptors are involved in the modulation of pituitary hormone secretion. We suggest that the effect of fenoldopam on PRL and TSH is mainly at the hypothalamic level. Regarding the effect on LH concentrations, an additional direct effect of fenoldopam on testosterone regulation can not be excluded.     

Evidence for a thyrotropin inhibitory effect of histamine in man.

Because of certain side effects of cimetidine therapy which may be hormonally mediated (e.g. gynecomastia), there has been recent interest in the possible endocrine effects of this H2 histamine receptor-blocking agent used in the treatment of peptic ulcer disease. Accordingly, the effect of chronic cimetidine therapy on anterior pituitary function was examined in 12 adult men with mild peptic ulcer disease. TRH and insulin-hypolycemic stimulation tests were performed by standard methods. Serum for TSH and PRL RIA was obtained after TRH; serum for GH, cortisol, and PRL RIA was obtained after insulin-induced hypoglycemia. In addition, serum for LH, FSH, testosterone, and PRL was obtained every 4 h for 24 h. After these baseline studies, 300 mg cimetidine were administered orally 4 times a day for 4--8 weeks and the studies were repeated as before. Chronic treatment with cimetidine caused a significant increase in the peak TSH response to TRH at 30 min (mean peak TSH value before cimetidine, 7.0 microU/ml; after cimetidine, 10.2 microU/ml; P less than 0.05) as well as a significant increase in the TSH area under the curve. There was no statistically significant effect of cimetidine on basal TSH or basal or stimulated PRL secretion. Cimetidine had no effect on the GH, PRL, or cortisol response to insulin-induced hypolycemia or the 24-h secretion of LH, FSH, testosterone, or PRL.     

The thyrotrophin response to thyrotrophin releasing hormone during treatment in patients with Graves' disease.

Thyrotrophin releasing hormone (TRH) tests were performed at 4 or 8 weeks intervals, after the initiation of anti-thyroid treatment in 15 patients with Graves' disease. All TRH test were negative as long as the serum levels of thyroxine (T4) and triiodothyronine (T3) were elevated, and normalization of the serum levels of these hormones always occurred before the response to iv TRH was restored. In 13 patients the time from the patients for the first time were registered as biochemically euthyroid varied from 0-9 months (mean 3.1 months), before TRH response was restored. Two patients were still TRH non-responsive at the end of the study, even though they had been biochemically euthyroid for as long as 17 and 18.5 months. The TRH test, therefore, is not helpful in the evaluation of the effect of anti-thyroid treatment in patients with Graves' disease. There was an increase in the serum level of (TSH) from 3.4 +/- 0.3 (SEM) to 4.3 +/- 0.5 (SEM) ng/ml (P less than 0.05), and a decrease in the serum level of total T4 from 19.4 +/- 1.1 (SEM) to 5.8 +/- 0.8 (SEM) microng/100 ml in 13 patients from the first examination until the last time they were examined before restored TRH response. This finding shows that the pituitary gland has retained its ability to synthesize and secrete TSH even though no TSH could be released by iv TRH. In 6 TRH non-responsive patients with Graves' disease, serum TSH levels were suppressed from 2.5 +/- 1.2 (SEM) ng/ml before the administration of a single dose of 3 mg T4 orally, to 0.9 +/- 0.2 (SEM) ng/ml, 7 days after the T4 administration. Thus, the negative feed-back effect on the pituitary gland of the thyroid hormones is operating in these patients. This finding indicates that the TRH non-responsiveness in euthyroid patients with Graves' disease is not due to pituitary depletion of TSH, since the negative feed-back effect of the thyroid hormones is operating normally.     

Pituitary stimulation by combined administration of four hypothalamic releasing hormones in normal men and patients

Ten normal young men (22-28 yr of age), within 10% of their ideal body weight, were given the four releasing hormones (TRH, 200 micrograms; GnRH, 100 micrograms; ovine corticotropin-releasing hormone, 50 micrograms; GH-releasing hormone, 80 micrograms) iv on separate days and then in combination on the same day. Plasma TSH, PRL, FSH, LH, cortisol, ACTH, and GH were measured by RIA in samples collected from 20 min before to 120 min after injection. There were no significant differences in responses to the separate and combined tests for FSH, LH, cortisol, ACTH, and GH. The plasma TSH (0.001 less than P less than 0.01) and PRL (P less than 0.001) responses were significantly higher after the combined test. The tolerance was identical to that of TRH alone. In eight patients studied after pituitary surgery, combined administration provided results comparable to those obtained after separate administration of TRH, GnRH, and insulin.     

Effects of starvation in rats on serum levels of follicle stimulating hormone, luteinizing hormone, thyrotropin, growth hormone and prolactin; response to LH-releasing hormone and thyrotropin-releasing hormone.

Adult male Sprague-Dawley rats averaging 300 g each were subjected to complete food removal for 7 days (acutely starved), 7 days complete food removal followed by 2 weeks of 1/4 ad libitum food intake (chronically strved), 7 days complete food removal and 2 weeks of 1/4 ad libitum intake followed by ad libitum feeding for 7 days (refed), or fed ad libitum throughout (controls). Serum LH, FSH, TSH, PRL, and GH levels were measured by radioimmunoassays for each group of rats. The in vivo response to the combination of synthetic LHRH and TRH also was tested in each group of rats. Circulating LH, TSH, GH, and PRL were significantly depressed in acutely and chronically starved rats, and FSH was lowered only in acutely starved rats. After 7 days of refeeding, serum levels of LH and FSH were significantly greater than in ad libitum fed controls, PRL returned to control levels, and TSH and GH increased but were still below control levels. After LHRH + TRH injection serum LH and TSH were increased significantly in all groups of rats, FSH and PRL rose in acutely but not in chronically starved rats, and GH was not elevated in any group. The increases in serum LH, FSH, TSH and prolactin in response to LHRH + TRH injection in acutely or chronically starved rats were equal to or greater than in the ad libitum fed controls. These data indicate that severe reductions in food intake result in decreased release of at least 5 anterior pituitary hormones, and this is due primarily to reduced hypothalamic stimulation rather than to inability of the pituitary to secrete hormones.     

Pituitary-thyroid function in trophoblastic disease.

Pituitary-thyroid function was assessed in 12 patients with trophoblastic disease (4 hydatidiform mole, 3 invasive mole, and 5 choriocarcinoma). Thyroid-stimulating activity was detectable, by means of the McKenzie bioassay, in 6 patients (Group 1) but not in the other 6 patients (Group 2). In Group 1 serum thyrotropin (TSH) determined by radioimmunoassay was mostly undetectable and did not respond to the administration of thyrotropin-releasing hormone (TRH) determined by radioimmunoassay was mostly undetectable and did not respond to the administration of thyrotropin-releasing hormone (TRH), while in Group 2 basal TSH was detectable in half of the patients and responded to TRH in all cases. Serum concentrations of total thyroxine (T4) (18.7 +/- 2.0 mug/100 ml, mean +/- SE), free T4 (4.9 +/- 0.04 ng/100 ml), total triiodothyronine (T3) (352 +/- 72 ng/100 ml), and free T3 (0.57 +/- 0.11 ng/100 ml) in Group 1 were statistically greater than those in Group 2 (total T4, 9.2 +/- 1.0 mug/100 ml, free T4, 2.0 +/- 0.2 ng/100 ml; total T3 156 +/- 20 ng/100 ml, and free T3 0.23 +/- 0.03 ng/100 ml). Free T4 and T3 fractions were within normal limits in both groups. After treatment of 5 patients in Group 1, the thyroid stimulating activity determined by bioassay dropped to undetectable levels, the serum concentrations of thyroid hormones decreased to normal limits, and TSH response to TRH became positive. These findings indicate that an abnormal thyroid stimulator, derived from the trophoblastic tissue, stimulated the thyroid hormone secretion from the thyroid gland and in turn suppressed TSH response to TRH in some patients with trophoblastic disease.     

Hypothyroidism and amenorrhea due to hypothalamic insufficiency. A study in four young women.

Four women, aged 17 to 23, were evaluated for secondary amenorrhea of 12 to 36 months' duration. All were considered to have hypothalamic hypothyroidism on the basis of low thyroxine (T4) concentrations, inappropriately low thyrotropin (TSH) levels, with a normal TSH response to thyrotropin-releasing hormone (TRH, 500 microgram intravenously) in three, and absence of a pituitary lesion. Nevertheless, menses did not resume after adequate replacement with thyroid hormone. Investigation of the pituitary-gonadal axis revealed a normal increase in both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) following the intravenous administration of gonadotropin-releasing hormone (GnRH). Three subjects received clomiphene citrate, 100 mg/day for five days, but a normal menstrual cycle was not induced. It is concluded that the amenorrhea was not due to thyroid hormone deficiency but, like the hypothyroidism, to a hypothalamic abnormality involving secretion of the appropriate releasing hormone.