Medroxyprogesterone acetate with Zoladex for long-term treatment of fibroids: effects on bone density and patient acceptability.

A randomized trial was carried out to investigate the effect of 12 months administration of the gonadotrophin-releasing hormone agonist (GnRHa) Zoladex in combination with either placebo or medroxyprogesterone acetate (MPA) from the third month. Bone density, markers of bone resorption, symptoms and uterine volume were monitored in 24 women with symptomatic fibroids or menstrual problems. A total of 21 women were recruited to act as controls for the assessment of bone parameters. Vasomotor side-effects were reduced significantly in the MPA-treated group. The reduction in uterine volume in women with fibroids was not impaired by the addition of MPA. The bone markers osteocalcin and alkaline phosphatase were assessed in plasma, and the cross-links pyridinoline and deoxypyridinoline measured in urine. Changes in these markers are reported which suggest increases in bone resorption during the period of observation. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry at the spine and forearm. The net reduction in BMD at the spine in the treated groups was 4.30 +/- 0.59% at 6 months and 7.50 +/- 0.78% at 1 year, with no change in the control group. No change was seen in forearm BMD. No protective effect was observed when MPA was added. At 1 year after the completion of treatment, BMD remained significantly below baseline, and this has implications for the prolonged use of GnRHa.

Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. I: Plasma luteinizing hormone, follicle stimulating hormone, testosterone, estradiol, and inhibin concentrations.

Sex-steroid based male contraceptive regimes induce azoospermia in only 40-70% of Caucasian men. The reason(s) why the remainder maintains a low level of spermatogenesis (oligozoospermia) despite gonadotrophin suppression is unclear. In order to improve our understanding of this phenomenon, we examined the changes in sperm density and plasma LH, FSH, testosterone (T), oestradiol (E2), and inhibin (IN) in 28 normal men who received 200 mg testosterone enanthate (TE) im weekly during a male contraceptive efficacy trial. Gonadotrophins were measured by an ultrasensitive time-resolved immunofluorometric assay (DELFIA) with a sensitivity of 0.04 U/L, to determine the adequacy of suppression. Seventeen of the 28 men achieved azoospermia; the other 11 remained oligozoospermic (sperm density 3.3-4.7 x 10(6)/mL) after 6 months of TE exposure. Azoospermic subjects displayed a more rapid decline in sperm density, a significant difference being apparent by 5 weeks after starting TE. During TE treatment, both LH and FSH were consistently suppressed to below the limits of detection, whereas there was a 2.5-fold rise in T and E2 with a similar decrease in IN. There were no consistent differences in any of these hormone concentrations between the azoospermic and oligozoospermic groups. Recovery of sperm density to baseline levels or above 20 x 10(6)/mL was significantly slower in the azoospermic group. During the recovery phase, the azoospermic men exhibited significantly higher LH and FSH levels compared to baseline and to the oligozoospermic subjects even though no differences in circulating T, E2, or IN were observed. We conclude that incomplete gonadotrophin suppression or differences in sex steroid or inhibin levels are unlikely to be responsible for the maintenance of minor degrees of spermatogenesis in some men during TE administration. The rebound rise in gonadotrophins in azoospermic but not oligozoospermic responders during recovery may reflect a more profound degree of spermatogenic suppression in the former group.

PIP: In the UK, 28 healthy, fertile, white 23-40 year old men received an intramuscular injection of 200 mg testosterone enanthate (TE) during a male contraceptive efficacy trial. Only 17 men achieved azoospermia. Researchers used ultrasensitive immunofluorometric assay to measure gonadotropins and took venous blood samples right before the next TE injection to measure circulating steroid and inhibit (IN) levels. They wanted to determine whether gonadotropin suppression or changes in circulating steroid and IN levels during TE administration maintain some level of spermatogenesis in the 11 oligozoospermic men. At 5 weeks after beginning TE administration, azoospermic men experienced a more rapid fall in sperm density than oligozoospermic men (18.7 x 1 million/mL vs. 48.4 x 1 million/mL; p .05). In both groups, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were always lower than the assay detection limit during TE administration. On the other hand, after TE administration, testosterone (T) and estradiol (E2) levels increased 2.5 times while IN levels fell 2.5 times. Azoospermic men recovered sperm density at or above 20 x 1 million/mL at a slower rate than did oligozoospermic men (p .01). They had significantly higher LH and FSH levels during the recovery phase compared to baseline levels and to those of oligozoospermic men (p .05). Yet, circulating levels of T, E2, or IN were essentially the same in both groups. These results suggest that neither incomplete suppression if pituitary gonadotropins nor differences in sex steroid or IN levels would likely account for the differences in the degree of spermatogenic suppression in the 2 groups of men receiving exogenous TE administration. The faster rise in gonadotropins in azoospermic men during recovery may intimate that they experience a more profound degree of spermatogenic suppression.

Non-isotopic, two-step free thyroxine immunoassay: a better measure of free thyroxine than analogue radioimmunoassay.

Plasma or serum free thyroxine (T4) was measured by a novel non-isotopic, two-step immunoassay in 373 consecutive patients attending a thyroid clinic, in whom thyroid status was categorized according to clinical findings, supported by routine thyroid function tests. The 95% confidence limit of free T4 in the euthyroid patients (n = 112) was 7-20 pmol/L. Free T4 concentrations within the reference range were found in six of 40 patients with primary hypothyroidism and nine of 182 patients with overt thyrotoxicosis, six of whom had T3 toxicosis. Serum or plasma free T4 measured by the two-step method showed improved diagnostic specificity over an analogue RIA in selected groups of euthyroid patients in whom abnormal binding of analogue T4 can affect the validity of the result. Free T4 results found by analogue RIA and the two-step method in 58 patients who were receiving thyroxine replacement therapy were similar. The between-assay precision of the two-step method was poor ranging from a coefficient of variation of 9.7% to 19.3% over a free T4 concentration range of 5.0 to 46.0 pmol/L. We conclude that the two-step methodology offers diagnostic advantages for a laboratory which receives specimens from such patients for exclusion of thyroid disease but that improved assay precision is required before it could be used in a routine situation.

Different hepatic responses to thyroxine replacement in spontaneous and 131I-induced primary hypothyroidism.

The serum levels of a range of analytes known to change with thyroid status were measured in two groups of patients with primary hypothyroidism commencing T4 replacement therapy. One group (group 1; n = 9) had spontaneous hypothyroidism whilst in the second (group 2; n = 10), hypothyroidism had resulted from radioiodine therapy. The replacement dose was increased in 50 micrograms increments each month to 200 micrograms/day; this produced similar serum concentrations of thyroid hormones and TSH in the two groups at each dose. Dose-dependent increases in glutathione S-transferase (GST) were seen in both groups but changes in alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) activities occurred only in group 1 patients. Group 1 patients had significantly higher levels of GST than group 2 at the 150 micrograms (P less than 0.01) and the 200 micrograms (P less than 0.005) doses of T4, and they had higher activities of ALT (P less than 0.01) and GGT (P less than 0.02) at the 200 micrograms dose. Seven patients in group 1 had abnormalities in GST and four had high levels of ALT, whereas three patients from group 2 had high GST concentrations and all had ALT activities within reference limits. The concentrations of the other analytes measured in serum showed the same response to T4 in the two groups, particularly the concentrations of certain transport proteins whose serum concentrations depend on hepatic protein synthesis. These data suggest that patients with spontaneous primary hypothyroidism are more susceptible to hepatocellular damage than patients who have radioiodine-induced primary hypothyroidism when given oral doses of thyroxine greater than 150 micrograms/day.

Restoration of normal thyrotrophin secretion reduces the abnormally high serum glutathione S-transferase levels found in patients receiving thyroxine replacement therapy.

The peripheral tissue thyroid status of 12 patients receiving thyroxine replacement therapy was investigated both when pituitary secretion of TSH was suppressed and later, when on a lower dose of thyroxine that restored thyrotroph responsiveness. Heart rate and various analytes in serum known to be sensitive to thyroid status were measured in addition to TSH by immunoradiometric assay. Initially, the serum T4 concentration was raised in seven patients and free T4 raised in nine; all patients had normal T3 concentrations. Later, on the lower dose of thyroxine, most patients had concentrations of thyroid hormones within reference limits. Concentrations of the liver-specific form of glutathione S-transferase (GST) in serum decreased (P less than 0.01) after the reduction in thyroxine dose; abnormally high GST levels, found in eight patients when TSH was suppressed, returned to normal in six of these patients when normal basal and TRH-stimulated TSH concentrations had been restored. The response of the pituitary to excess thyroxine may be more representative of other tissues (e.g. the liver) than previously thought.

Thyroid function and endocrine abnormalities in elderly patients with severe chronic obstructive lung disease.

Serum pituitary and thyroid hormones, testosterone, and the response of pituitary hormones to thyrotrophin releasing hormone were measured in 20 inpatients (mean age 68, range 42-81 years) with severe chronic obstructive lung disease and in 15 control convalescent inpatients (mean age 73, range 57-83 years) who had normal respiratory function. No significant differences were found in total and free thyroid hormone concentrations and basal concentrations of thyrotrophin, growth hormone, and prolactin; and their increments after injection of thyrotrophin releasing hormone were similar in patients with chronic obstructive lung disease, and control patients. Three patients with chronic obstructive lung disease, however, had no thyrotrophin responses to thyrotrophin releasing hormone. In men, low testosterone concentrations were found both in patients with chronic obstructive lung disease and in controls. Luteinising hormone concentrations were higher in men with chronic obstructive lung disease (p less than 0.02), whereas concentrations of follicle stimulating hormone in the two groups were not significantly different. There was no significant correlation between arterial blood gas tensions and these hormone measurements. General effects of age and illness may be more important than direct effects of hypoxia in determining hypothalamic-pituitary function in elderly patients with chronic obstructive lung disease.

Laboratory and diagnostic performance of a coated well immunoradiometric assay for serum thyrotrophin.

A new, coated well immunoradiometric assay (IRMA) for thyrotrophin (TSH) in serum has been evaluated with a view to its use as a first-line test of thyroid function. The Amerwell TSH IRMA is simple, rapid to perform (2.5 h) and the assay sensitivity was 0.07 mU/L with a working range (intra-assay CV less than 10%) of 0.3-100 mU/L. The mean inter-assay CV was 6.6% for TSH concentrations of 0.30-30.7 mU/L. The method compared favourably with an in-house TSH radioimmunoassay and an alternative commercial IRMA. In consecutive referrals to a thyroid clinic all patients with overt hyperthyroidism (n = 103) had undetectable TSH concentrations and in those with subclinical hyperthyroidism (n = 14). TSH was undetectable in 10 and below the reference range in four. The 95% confidence interval for 63 euthyroid serum samples was 0.36-4.3 mU/L. All hypothyroid patients (n = 20) had increased TSH concentrations. TSH concentrations in pregnancy did not differ significantly from euthyroid TSH values. From 1916 routine tests, 13 undetectable TSH values were found in which thyroid hormone levels were normal and the patients had no known thyroid disorder. The assay appears suitable as a first-line test of thyroid function, but further assessment in a routine laboratory setting is required.

Free T4 measurement is preferred to the T4 test for thyroid evaluation in lithium treated patients.

Free T4 (fT4) measurement provides a more sensitive test of thyroid function than the commonly used T4. Recent commercial development of fT4 kit assays has made fT4 assessment widely available. Evaluation of the fT4 Amerlex kit in 26 lithium-treated patients illustrates its utility as a sensitive laboratory test of thyroid function in this group of patients. This finding together with fT4's known superiority over T4 in identifying thyroid dysfunction suggests that fT4 should replace T4 estimations in the routine monitoring of thyroid function in lithium-treated patients.

Value and limitations of a highly sensitive immunoradiometric assay for thyrotropin in the study of thyrotroph function.

Using a highly sensitive and specific immunoradiometric assay for thyrotropin, we studied thyrotroph function in 232 new patients referred to a thyroid clinic and in 13 patients after treatment for hyperthyroidism. Significant thyrotroph responsiveness to thyroliberin (thyrotropin-releasing hormone, TRH) was found in all patients with values for basal thyrotropin greater than 0.1 milli-int unit/L. In no overtly hyperthyroid patient was any increment in thyrotropin recorded at 20 min after thyroliberin administration. In seven patients, four subclinically hyperthyroid and three who had received treatment, increments in thyrotropin from undetectable basal values were recorded, consistent with incomplete thyrotroph suppression. By use of assays with even higher sensitivity, one may be able to distinguish these patients from overtly hyperthyroid patients.

Relationship between pituitary and other target organ responsiveness in hypothyroid patients receiving thyroxine replacement.

This study was undertaken to compare the sensitivity of the thyrotrophs to that of other tissues to T4 treatment in hypothyroid patients. To do so, we measured serum total and free thyroid hormones and TSH, in addition to several serum markers of peripheral tissue response to thyroid status, in 21 hypothyroid patients treated with 50-micrograms increments of T4 to a maximum of 200 micrograms daily (group I) and in 104 clinically euthyroid patients receiving a long term constant replacement dose (group II). In group I patients, dose-dependent increases (P less than 0.05) in serum glutathione S-transferase, sex hormone-binding globulin, and angiotensin-converting enzyme occurred, whereas serum T4-binding globulin, creatine kinase, and creatinine levels decreased (P less than 0.05). In both patient groups, abnormally high levels of glutathione S-transferase, sex hormone-binding globulin, angiotensin-converting enzyme, alanine aminotransferase, and gamma-glutamyl transferase were found in some patients during treatment. One or more of these biochemical abnormalities suggestive of hyperthyroidism occurred in 15 (71%) group I patients and 27 (26%) group II patients. These were associated with an undetectable serum TSH (less than 0.1 microU/ml) and raised free T4 concentrations in 13, and raised free T3, T4, and T3 concentrations in only 8, 6, and 1 group I patients, respectively. In group II patients, they were more closely associated with an undetectable TSH (67%) or raised free T4 (85%) level than with raised concentrations of free T3 (33%), T4 (26%), or T3 (0%). The use of high sensitivity TSH assays will permit more accurate adjustment of T4 replacement and minimize abnormalities in peripheral tissue biochemistry indicative of overtreatment.

Effects of seizure duration on serum TSH concentration after ECT.

Serum thyroid stimulating hormone (TSH) concentrations were measured by a sensitive immunoradiometric assay in 14 patients immediately before and after the first treatment of a course of electroconvulsive therapy (ECT). There was a close correlation (r = +0.70, p less than 0.01) between the increase in TSH concentration 15 min after ECT and the duration of seizure activity as measured by EEG. This observation may help clarify previous contradictory findings on the effects of ECT on TSH concentrations. There was no correlation between the increase in serum TSH concentration and the extent of recovery from depressive illness.

SimulTRAC simultaneous radioimmunoassay of thyrotropin and free thyroxin evaluated.

We assessed the analytical and diagnostic performance of a dual-isotope RIA for thyrotropin (TSH) and free thyroxin (FT4) in serum. The mean interassay CVs for these analytes were 7.9% and 5.0%, respectively. The mean minimum detection limit for TSH was 0.25 milli-int. unit/L, the mean analytical recovery 110%. There was good agreement with values for TSH and FT4 measured by alternative RIA procedures. Euthyroid patients were well distinguished from those with overt thyroid disease, although there was a small overlap in the case of TSH. Combining the two results better discriminated these categories and identified those patients with subclinical thyroid disease who had abnormal TSH concentrations but FT4 concentrations within reference limits. Euthyroid women taking estrogen-containing oral contraceptives had normal results for TSH and FT4, as did most pregnant women studied. During the third trimester of pregnancy, TSH concentrations of women with low FT4 concentrations were within reference limits. Similarly, euthyroidism was confirmed in patients with low FT4 due to nonthyroidal illness by the simultaneous finding of a normal TSH concentration.

An improved approach to thyroid function testing in patients with non-thyroidal illness.

We have compared the results of serum thyrotrophin (TSH) measurements using a sensitive immunoradiometric assay (IRMA) with those of conventional thyroid function tests in 299 hospital inpatients with a range of non-thyroidal illnesses. Levels of total thyroxine (T4), free T4, total tri-iodothyronine (T3) and free T3 in the hypothyroid range were recorded in 8%, 15%, 19% and 49% of patients, respectively, whereas TSH (IRMA) was abnormally low in 1%. Furthermore, basal TSH (IRMA) accurately predicted the result of the thyrotrophin-releasing hormone test in 72 of the 74 patients in whom this test was performed and, unlike thyroid hormone measurement, identified patients with subclinical thyroid disease. It would appear that a single basal TSH (IRMA) measurement is the most appropriate screening test for thyroid dysfunction in patients with concomitant acute or chronic illness.

Limitations of new thyroid function tests in pregnancy.

Sensitive immunoradiometric assays (IRMA) for TSH and radioimmunoassay (RIA) kits for free thyroid hormones (fT4, fT3) are becoming increasingly used for routine thyroid investigations. We have assessed these tests in 93 euthyroid pregnant women. Mean fT4 and fT3 values decreased with gestation by 24-27% and 14-35%, respectively, using several analogue RIA kits. Some patients had free hormone values which fell below the reference range derived from non-pregnant euthyroid patients. By contrast, the fT4 concentrations measured by direct equilibrium dialysis fell by only 16% with all values within the reference range. Serum non-esterified fatty acid (NEFA) levels (non-fasting) did not correlate with fT4 and fT3 but a spurious effect of serum albumin levels on the free hormone kits was suggested. TSH results showed that the majority of subjects had lower values measured by IRMA than by RIA. Three patients had basal TSH (IRMA) below the mean detection limit of the assay; this could have been falsely interpreted as indicating hyperthyroidism. We conclude that, as with longer established thyroid function tests, special care must be taken in interpreting results of these new thyroid function tests in pregnancy.

Accuracy and precision of five analog radioimmunoassays for free thyroxin compared.

We compared the precision of free thyroxin (FT4) measurements by kits involving analog RIA and the use of antibody-coated tubes (Becton Dickinson and Coat-A-Count), magnetic separation (Amerlex Magnetic and Corning Magic), or centrifugation of antibodies linked to solid beads (Amerlex). Results of kits with magnetic separation were the most reproducible. Amerlex, Amerlex Magnetic, and Becton Dickinson kits gave values comparing best with those obtained by direct equilibrium dialysis. Coat-A-Count and Corning Magic results differed significantly from dialysis values, both for patients' samples and kit standards. The kits had equal diagnostic efficiency in patients with suspected thyroid disease. On measurement of FT4 some patients were reclassified from "subclinical thyroid disease" to "overt disease." Most patients with triiodothyronine thyrotoxicosis had increased FT4. Several kit values were low for pregnant women and patients with nonthyroidal illness but the Amerlex and Amerlex Magnetic assays had fewer low results. The Amerlex Magnetic FT4 assay gave the best precision, agreement with the reference method, and diagnostic efficiency.

Raised plasma glutathione S-transferase values in hyperthyroidism and in hypothyroid patients receiving thyroxine replacement: evidence for hepatic damage.

Using plasma glutathione S-transferase measurements hepatocellular integrity was assessed in groups of hyperthyroid and hypothyroid patients before and after treatment. Ten of 14 hyperthyroid patients had clearly raised plasma glutathione S-transferase values at presentation and in each patient treatment with either iodine-131 or carbimazole resulted in a significant fall in glutathione S-transferase. The eight hypothyroid patients had normal glutathione S-transferase values at presentation and all showed a significant increase in these after thyroxine replacement therapy. In three of these patients in whom standard doses of replacement therapy were associated with a raised free thyroxine (T4) concentration but normal total and free triiodothyronine (T3) values glutathione S-transferase was increased. Similar though less consistent changes were seen in the results of standard chemical tests of liver function. It is concluded that hyperthyroidism may produce subclinical liver damage in a high proportion of patients and that this resolves with effective treatment. More important, the data suggest that hypothyroid patients receiving thyroxine replacement therapy may have similar subclinical liver damage. Patients receiving thyroxine should be monitored by the measurement of free, not total hormone concentrations, and in those in whom free T4 is raised the dose of thyroxine should be reduced. It would also be expedient to include periodic biochemical assessment of liver function in patients receiving thyroxine.