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Once hormone replacement therapy (HRT) has been commenced, it becomes extremely difficult to advise women approaching the menopause on the need for contraception. In this study of twenty women, neither the regularity of their pre-existing menstrual cycle nor a random FSH concentration predicted the likelihood of subsequent ovulation whilst taking HRT. HRT is not reliably contraceptive and women commencing HRT whilst still menstruating spontaneously must be advised on the need for additional contraception.

PIP: In Scotland, providers determined the incidence of ovulation before and during use of oral hormone replacement therapy (HRT) among 20 women aged 42-52 attending the Family Planning and Well Woman Services menopause clinic in Edinburgh and their need for contraception. Ovulation was defined as a pregnanediol concentration of more than 0.5 mmol/g creatine. HRT consisted of 1.25 mg/day of conjugated estrogens with 150 ug cyclical norgestrel for 12 of 28 days (Prempak-C). Women with irregular cycles were older than those with regular cycles (47.3 vs. 45.5 years; p 0.02). They also had considerably higher mean follicle stimulating hormone (FSH) levels (26 vs. 14.2 IU/l; p 0.001). One woman had a very high FSH level (67 IU/l) before HRT use and ovulated in the subsequent cycle with urinary pregnanediol levels indicating normal ovarian function. All 10 women who had regular cycles ovulated before HRT use. Six still ovulated during HRT use. Among women with irregular cycles, 4 of the 10 women ovulated before HRT use. Three of these women had anovulatory cycles during HRT use while 3 of the 6 who did not ovulate before HRT use ovulated during HRT use. These findings reveal that HRT with the higher dose Prempak-C does not suppress ovulation and that an elevated FSH does not always indicate the absence of ovulation. They also show that neither age nor regularity of menstrual cycles can be used to predict the need for contraception in perimenopausal women using HRT.

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OBJECTIVE: To investigate whether the measurement of maternal plasma creatine kinase concentration is of clinical value in the diagnosis of tubal ectopic pregnancy. DESIGN: A retrospective observational study covering a three month period. SETTING: The gynaecological emergency service of a UK teaching hospital. SUBJECTS: One hundred and twenty women presenting with clinical suspicion of an ectopic pregnancy such that plasma human chorionic gonadotrophin (hCG) concentration was measured. MAIN OUTCOME MEASURES: Plasma hCG and creatine kinase concentrations were measured. Pregnancies were classified as ectopic pregnancy, complete miscarriage, incomplete miscarriage or ongoing pregnancy. Pregnancies were further classified as uncertain diagnosis if the diagnosis was not clear after initial investigation. RESULTS: Twenty-one of the patients had an ectopic pregnancy. Diagnosis was classified as uncertain in 48% of pregnancies studied and in 54% of ectopic pregnancies during the study period. The mean plasma creatine kinase was higher in ectopic pregnancies than other pregnancies in the study group (P < 0.01) and remained higher in the subgroup of patients with uncertain diagnosis (P < 0.05) but there were significant overlaps in creatine kinase concentrations in all four clinical groups. When a cut-off point of 45 iu/l is used, the measurement of plasma creatine kinase activity has a sensitivity of 0.57 and a specificity of 0.67 for the diagnosis of ectopic pregnancy.

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OBJECTIVE: To identify the date of ovulation in pregnant women with Type 1 diabetes in order to assess the validity of the concept of early growth delay. DESIGN: Identification of ovulation by measurement of urinary luteinising hormone and assessment of fetal growth using ultrasound scan. SETTING: Diabetic pre-pregnancy and antenatal clinic in a teaching hospital. SUBJECTS: Twenty women with Type 1 diabetes who had attended a pre-pregnancy clinic. MEASURES: Urinary LH, by laboratory and kit methods, during conception cycles. Human chorionic gonadotrophin measured in early pregnancy. Early ultrasound scans by a single observer blind to menstrual and ovulation dates. OUTCOME: Gestation calculated from ovulation date and gestation estimated from menstrual dates, compared with gestation at age indicated by early ultrasound scan. RESULTS: When the date of ovulation was identified in 20 women with Type 1 diabetes there was no evidence of growth delay in any pregnancy. When gestation was estimated from menstrual dates there was apparent early growth delay in six pregnancies. CONCLUSION: This study, together with others discussed, indicates that early growth delay is probably an artefact of incorrectly estimated ovulation date.

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The clinical usefulness of measuring serum concentrations of progesterone, human chorionic gonadotrophin (HCG) and the free beta-subunit of HCG in distinguishing between early viable and non-viable pregnancy, before an accurate ultrasound diagnosis is possible, was evaluated in a prospective study of patients presenting to our emergency gynaecology service with a clinical suspicion of ectopic pregnancy. Patients were selected on the basis of initial HCG concentrations; samples with HCG 25-10,000 IU/l were later analysed for progesterone and free beta HCG. Of the 181 patients studied, 38 (21%) had an ectopic pregnancy, 108 (60%) had a spontaneous abortion and 35 (19%) had a viable intra-uterine pregnancy. Concentrations of HCG and free beta HCG in the group with viable pregnancies were significantly higher than in the group with ectopic pregnancy (P < 0.001) and than those destined to miscarry (P < 0.01). Progesterone concentrations were also significantly higher in the viable versus the ectopic and the spontaneous abortion groups (P < 0.001 in each case). Despite these highly significant differences there was a degree of overlap such that it was impossible to devise a cut-off level for any hormone analysed, either singly or in combination, which would offer a clinically useful predictor of outcome.

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A human ovarian adenocarcinoma cell line (PE04) has been established as a xenograft in nude mice. In vitro, this cell line is estrogen receptor (ER)-positive and its growth is stimulated by 17 beta-estradiol at concentrations between 10(-12) and 10(-6) M. When xenografted, PE04 cells remain ER-positive and also possess progesterone receptors (PR); treatment with 17 beta-estradiol reduces the concentration of ER and increases levels of PR. Growth of the xenograft is reduced in ovariectomized animals while implantation of estrogen pellets also results in growth inhibition. Similar treatment with estrogen does not inhibit the ER-negative HOX 60 ovarian xenograft, and stimulates growth of the ER-positive ZR-75-I breast carcinoma xenograft. Serum measurements of 17 beta-estradiol confirm that ovariectomy reduces the level of 17 beta-estradiol while implantation of estrogen pellets results in raised levels of the hormone. Tamoxifen inhibits growth of the PE04 xenograft but not that of the HOX 60 xenograft, consistent with ER status. These results indicate that ER-positive PE04 ovarian cancer cells are sensitive to 17 beta-estradiol in vivo but that the response may be of a different type from the in vitro response. This lends further support to the concept that ovarian cancer may be hormone-sensitive and potentially responsive to endocrine therapy.

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Mifepristone (RU 486) is a potent antigestagen and antiglucocorticoid which when given at a dose of 25-600 mg disrupts folliculogenesis, inhibits ovulation and induces menses in healthy women. This study reports the effects of much lower doses of mifepristone than used previously, given for the duration of a complete menstrual cycle. Healthy female volunteers (n = 11) with regular menstrual cycles were given mifepristone at a daily dose of 5 mg (n = 6) or 2 mg (n = 5) for 30 days, beginning immediately after an ovulatory placebo cycle. Mifepristone prevented menstruation for the duration of the treatment period, with recurrence of menses 15-29 days after replacement of mifepristone with placebo. Daily mifepristone given in either 5 mg or 2 mg doses inhibited ovulation, as indicated by the lack of a rise in urinary pregnanediol excretion. The excretion of oestrone glucuronide in urine rose during treatment, suggesting ovarian follicular development. Inhibition of ovulation appeared to result from a failure of the positive feedback effect of oestradiol on the hypothalamo-pituitary axis, as no surges of luteinizing hormone were seen despite pre-ovulatory levels of oestrone glucuronide being measured during exposure to mifepristone. The cycle immediately following treatment was shorter than the pre-treatment cycle, with lower peak levels of pregnanediol glucuronide, suggesting an inadequate luteal phase. Recovery from the effects of mifepristone treatment was more rapid after 2 mg than after 5 mg and one subject conceived in the immediate post-treatment phase, indicating adequate ovulation and luteinization.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Physicians at the Centre for Reproductive Biology in Edinburgh, Scotland, followed 11 healthy 29-39 year old women with normal menstrual cycles for 3 consecutive menstrual cycles to examine the effect of 2 mg or 5 mg doses of RU-486 taken daily during 1 menstrual cycle on concentrations of ovarian steroids and luteinizing hormone and to compare this with the menses pattern. The women took either a placebo or low-dose RU--486 daily during the first menstrual cycle. Then they took each day the item they did not take during the first cycle (second cycle). The third cycle involved taking the item they did not take during the second cycle. RU-486 prevented menstruation during the treatment period. Menstruation returned significantly later after cessation of RU-486 treatment than after placebo treatment (cycle lengths in days at 5 mg dose, 52.5 vs. 29.6, p .001; at 2 mg dose, 43.6 vs. 27.4, p .02). The lack of an increase in urinary pregnanediol excretion indicated that low doses of RU-486 inhibited ovulation. Urinary estrone glucuronide levels did rise, however, demonstrating that RU-486 did not interfere with follicular development. No rapid rises of luteinizing hormone occurred, suggesting that failure of the positive feedback effect of estradiol on the hypothalamo-pituitary axis suppressed ovulation. The post-treatment cycle was not as long as the treatment cycle and had reduced peak levels of pregnanediol glucuronide, denoting an inadequate luteal phase. Women who took 2 mg RU-486 recovered more quickly than those who took 5 mg. All the women ovulated during the post-treatment cycle. 1 woman became pregnant during the post-treatment cycle, suggesting satisfactory return to ovulation and luteinization. Pre- and post-treatment adrenocorticotrophic hormone and cortisol levels in the blood indicated that these low doses of RU-486 did not affect the pituitary-adrenal axis. These results suggest that low-dose RU-486 has the potential to be an oral contraceptive. Further studies are needed, however.

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Twenty women with symptomatic uterine fibroids were treated with the luteinizing hormone-releasing hormone (LHRH) agonist goserelin (Zoladex) combined with medroxyprogesterone acetate (MPA) in an open pilot study comparing two protocols. Ten women received goserelin 3.6 mg monthly combined with oral MPA 15 mg daily for 6 months. The mean uterine volume (497 cm3) measured by ultrasound fell by only 18% after 3 months, with no further reduction at 6 months. The other 10 women received goserelin alone for the initial 3 months, followed by combined treatment for 3 months. The mean uterine volume (557 cm3) fell by 39% after 3 months with no significant regrowth by 6 months. At 6 months post-treatment, uterine volume had not returned to pretreatment size. MPA significantly reduced the frequency of vasomotor side-effects. There were no differences in plasma oestradiol, luteinizing hormone or follicle stimulating hormone concentrations between the protocols and good symptomatic relief was experienced by both groups. Two years after completion, three women in each group have requested surgical treatment. The results indicate that MPA may be a useful adjunct to LHRH analogues in women with fibroids, reducing side-effects and possibly prolonging the response, although positive effects on bone density have yet to be confirmed. The optimum regimen of administration remains to be clarified as the clinical results were the same with both protocols.

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Cyclofenil is a triphenylethylene derivative, similar in structure to clomiphene citrate, which is used to induce ovulation in anovulatory women. The effects of cyclofenil on a group of 10 normal cyclic and 10 oligomenorrhoeic subjects were examined in a double blind controlled cross-over study. Both groups of women were administered either cyclofenil or, following a washout cycle, a placebo in two treatment cycles. Urinary oestrone and pregnanediol excretion were measured daily and ultrasound scans performed to assess follicular development. Frequent sampling of blood was performed on day 6 to study luteinizing hormone (LH) and follicle stimulating hormone (FSH) pulsatile release. Cervical mucus changes and sperm-cervical mucus interaction were studied after identification of the LH peak. There were no significant differences between cyclofenil and placebo cycles in the following: ovulation rates, daily urinary oestrone and pregnanediol excretion, the number or size of developing follicles, LH pulsatility (parameters studied: number of peaks, pulse interval, pulse amplitude, pulse area and mean nadir LH), mean FSH level on day 6, cervical mucus and sperm-cervical mucus interaction. In view of our inability to demonstrate an effect on any parameter of endocrine function in normal and oligomenorrhoeic women, these results throw doubt on the therapeutic value of cyclofenil in its present dosage and formulation.

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We used quantitative assays to measure the activity of the bone, liver, and intestinal forms of alkaline phosphatase in plasma in 75 patients with endstage chronic renal failure undergoing hemodialysis. The results were correlated with radiological and other biochemical indices of bone disease and with biochemical indices of liver disease. The total activity of alkaline phosphatase in plasma increased in 28 patients. In 10 of these patients, nine of whom had increased activity of gamma-glutamyltransferase in plasma, the increase in total activity of alkaline phosphatase was from the liver isoenzyme alone (nine patients) or from the liver and bone isoenzymes together (one patient). Intestinal alkaline phosphatase in plasma, although greater than 23 U/L in eight patients, was solely responsible for the increase in total alkaline phosphatase in one patient (who had normal gamma-glutamyltransferase). Bone alkaline phosphatase in plasma was increased in 25 patients, seven of whom had normal total alkaline phosphatase, and was closely correlated (r = 0.78) with osteocalcin concentration in plasma, which was increased in a much greater proportion of patients (99%). Both total and bone alkaline phosphatase were correlated with parathyrin in plasma (r = 0.46 and 0.50, respectively) and with osteocalcin (r = 0.60 and 0.78, respectively). Osteocalcin and bone alkaline phosphatase, but not parathyrin, decreased with age, implying that the skeletal response to parathyrin may be age dependent. In patients with increased total alkaline phosphatase undergoing hemodialysis, the concurrent measurement of gamma-glutamyltransferase may help identify whether the enzyme increase originates from the liver or bone, but this approach wrongly identified the source of the increase in three of 28 patients. Therefore, we recommend a separate measurement of the bone isoenzyme of alkaline phosphatase.

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Ten men with Klinefelter's syndrome were studied to assess the effect of testosterone replacement on plasma lipids and apolipoproteins. Measurements taken before the insertion of a testosterone ester implant were compared with those obtained 1 week and 4 weeks later. Mean plasma testosterone, androstenedione, total cholesterol and calculated LDL-cholesterol increased significantly after 1 and 4 weeks. No significant changes were seen in total plasma concentrations of HDL-cholesterol, HDL-cholesterol subfractions 2 and 3 or in apoplipoproteins A-I, A-II or B. A significant correlation was seen between total cholesterol and plasma oestradiol concentrations (Rs = 0.61; P less than 0.001). A significant negative correlation was seen between the concentrations of total testosterone and total triglyceride (Rs = -0.56; P less than 0.005) but not with the other lipid parameters. Testosterone replacement is associated with slight but potentially adverse changes in plasma cholesterol levels.

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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.

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Serum estradiol (E2) levels were measured in 451 men attending an infertility clinic and 80 fertile men attending for vasectomy. The normal range of E2 levels found in fertile men was 70 to 200 pmol/l. Subfertile men had lower mean E2 levels than fertile men (P less than 0.05), but there was no relationship to obesity, cigarette smoking, age, or the male infertility diagnostic category. E2 levels in the subfertile group gave no prognostic information concerning future fertility. The authors conclude that E2 measurements in male patients are not useful in clinical infertility practice.

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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.

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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.

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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.

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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.

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In view of the increasing number of in-vitro tests of thyroid function, rationalization of the biochemical assessment of patients with suspected thyroid disease was attempted. In addition to clinical examination of 285 consecutive new referrals to a thyroid clinic, measurements were made of serum total and free triiodothyronine (T3) and thyroxine (T4) and of thyrotropin (TSH) by radioimmunoassay before and 20 min after thyrotropin-releasing hormone (TRH) and basal TSH by immunoradiometric assay (IRMA). Analysis of these results demonstrated that: (i) a detectable and normal TSH (IRMA) result indicates that the patient is euthyroid and obviates the need for measurement of thyroid hormones and (ii) a raised or undetectable TSH (IRMA) level should be followed by measurement of free T4 (and rarely also free T3) to distinguish between subclinical and overt hypothyroidism and hyperthyroidism. This policy would considerably reduce the number of in-vitro thyroid function tests without resulting in either a delay in diagnosis or a reduction in its accuracy.

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In twenty-eight men with dermatitis herpetiformis (DH) the mean serum testosterone levels were within normal limits, but high levels were found in three patients with partial villous atrophy and two who had normal jejunal biopsies. The introduction of a gluten-free diet in patients with villous atrophy produced a statistically significant fall in the testosterone level in those able to discontinue their drug treatment but not in those noticing no change or only a reduction in drug requirements. The serum levels of luteinizing hormone or follicle-stimulating hormone were increased in nine patients; only one of these had a raised testosterone level and six were over 60 years of age. Four out of twenty married males with DH had no children, a figure higher than expected. Three of these men had elevated gonadotrophin levels although none had an increased serum testosterone. Thus, raised levels of testosterone and gonadotrophin were found in only a minority of men with DH, in contrast to the more marked changes previously reported in males with coeliac disease.

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The value as a thyroid function test of a new, rapid, and highly sensitive immunoradiometric assay for thyroid stimulating hormone (TSH) was assessed in 188 consecutive new patients with suspected hyperthyroidism. The diagnosis was made on clinical grounds and on the basis of serum total triiodothyronine and thyroxine concentrations and the response of TSH to thyrotrophin releasing hormone (TRH) as measured by radioimmunoassay. In all except one patient the basal TSH concentration by immunoradiometric assay predicted the response of TSH by radioimmunoassay to TRH, an undetectable value being recorded in patients with a subnormal response and a measurable value in those with a normal test result. This clear relation was not observed for basal TSH concentrations as measured by radioimmunoassay. In a series of 39 hospital inpatients with acute or chronic non-thyroidal illness, of whom 11 had low concentrations of total thyroxine or triiodothyronine, or both, basal TSH concentrations were detectable by both radioimmunoassay and immunoradiometric assay in all cases and were associated with normal responses to TRH. The immunoradiometric assay for TSH, which is commercially available, may therefore obviate the need for the more time consuming TRH test and simplify the approach to thyroid function testing in patients with suspected hyperthyroidism.

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