Effects of hormonal treatment on dermatological outcome in transgender people: a multicentric prospective study (ENIGI).

PURPOSE: The aim of our study was to assess dermatological changes in transgender people after the start of gender-affirming hormonal treatment (GAHT) and to investigate whether various hormonal preparations differently affect dermatological changes in trans AFAB (assigned female at birth) people. METHODS: In a multicenter prospective study, 484 participants (193 assigned male at birth/AMAB and 291 AFAB) were evaluated at baseline (T0), 6 (T1) and 12 months (T2) after the start of GAHT. Hair growth was assessed by the Ferriman-Gallwey (FG) score, acne by the Global Acne Grading Scale (GAGS), and alopecia by the Norwood Hamilton (NH) score. RESULTS: In AFAB people, a significant increase in FG score and NH grade was observed across time, as well as in GAGS score in a subsample of 71 individuals (p < 0.001). Testosterone (T) undecanoate and esters showed a higher increase in hair distribution at T2 vs. T1 as compared to T gel (p < 0.01). T esters showed a significantly higher impact in GAGS score modifications at T1 and at T2 vs. T0 compared to T gel (p = 0.021 and p = 0.003, respectively). In trans AMAB people, a significant decrease of FG score was observed across time (p < 0.001), although 51.3% of individuals still reported an FG score higher than eight after 12 months. CONCLUSION: T treatment increased hair growth, acne and alopecia prevalence in AFAB people, with T undecanoate and esters influencing hair growth more than T gel. Opposite dermatological changes were observed in AMAB people.

Functional ovarian reserve in transgender men receiving testosterone therapy: evidence for preserved anti-Müllerian hormone and antral follicle count under prolonged treatment.

STUDY QUESTION: Is the functional ovarian reserve in transgender men affected by testosterone therapy? SUMMARY ANSWER: Serum anti-Müllerian Hormone (AMH) levels slightly decrease during testosterone treatment but remain within the normal range, suggesting preserved follicular ovarian reserve. WHAT IS KNOWN ALREADY: Few small studies have investigated the impact of gender-affirming treatment on reproduction in transgender men. Conflicting results were reached concerning ovarian morphology and AMH levels in this context. STUDY DESIGN, SIZE, DURATION: The study consisted of two arms. The first arm was a prospective pilot study, which enrolled 56 transgender men (median age 22.5 [interquartile range (IQR)-19-27.7] years), 27 of whom had polycystic ovary syndrome (PCOS), prior to the initiation of gender-affirming testosterone therapy. A structured assessment was conducted prior to, and at 3 and 12 months after treatment initiation. The second arm was a cross-sectional study that comprised 47 transgender men (median age 24 [IQR-20-31] years) who received testosterone for a median duration of 35 [IQR 13-62] months. The main outcome measures were serum AMH and antral follicle count (AFC) as indices of ovarian follicular reserve. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at a tertiary center for transgender health. Gender-affirming therapy was administered according to standard practice. AFC was determined by pelvic (abdominal or transvaginal) ultrasound and blood collection for measurements of AMH, testosterone, estradiol, LH and FSH was performed at the designated time-points. MAIN RESULTS AND THE ROLE OF CHANCE: Prospective arm for the entire group we observed a decrease of 0.71 ng/ml in AMH levels between baseline and 12 months (P = 0.01). When expressed in age-specific percentiles, AMH went from the 47.37th to the 40.25th percentile at 12 months (P < 0.001). In a sub-group analysis, a decline of 9.52 points in age-specific percentile was seen in subjects with PCOS (P < 0.001), while no changes were detected in the non-PCOS group. Testosterone treatment did not affect AFC over time in the entire cohort. In the sub-group analysis, a mean decrease of 5.0 follicles was detected between baseline and the 12 months assessment (P = 0.047) only in subjects with PCOS. In the cross-sectional study, AMH inversely correlated with age but not with treatment duration. Notably AMH did not deviate from the 50th age-specific percentile. Finally, four men fathered biological children after being under testosterone treatment for up to 12 years. LIMITATIONS, REASONS FOR CAUTION: The limited sample size of the pilot study should be kept in mind. An additional limitation is the lack of a control group in the prospective study, as each participant served as his own control. Also, roughly 40% of the ultrasound examinations were performed transabdominally, potentially affecting the accuracy of the AFC measurements.As study participants were quite young, our reassuring data may not apply to older transgender men, either because of an age-related decline in ovarian reserve or to possible long-term effects of testosterone therapy. Furthermore, the chances for fertility preservation may be more limited in subjects with PCOS. WIDER IMPLICATIONS OF THE FINDINGS: This is an additional contribution to the emerging evidence that prolonged testosterone treatment may not be a major obstacle to later fertility potential in transgender men desirous of having children. Larger confirmatory studies, and particularly more with reproductive outcome data, are needed for evidence-based fertility counseling prior to treatment initiation in these subjects. STUDY FUNDING/COMPETING INTEREST(S): This study received no funding. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results.

PURPOSE: Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly. METHODS: CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs. RESULTS: Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed. CONCLUSIONS: OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each. Trial registration NCT03252353 (August 2017), NCT01412424 (August 2011).

Ghrelin stimulation by hypothalamic-pituitary-adrenal axis activation depends on increasing cortisol levels.

Ghrelin plasma concentration increases in parallel to cortisol after a standardized psychological stress in humans, but the physiological basis of this interaction is unknown. We aimed to elucidate this question by studying the ghrelin response to pharmacological manipulation of the hypothalamic-pituitary-adrenal (HPA) axis. Six lean, healthy male volunteers were examined under four experimental conditions. Blood samples were collected every 30 min for two sequential periods of two hours. Initially, a baseline period was followed by intravenous injection of a synthetic analog of ACTH (250 µg). Subsequently, a single dose of metyrapone was administered at midnight and in the following morning, blood samples were collected for 2 h, followed by an intravenous injection of hydrocortisone (100 mg) with continued sampling. We show that increased cortisol serum levels secondary to ACTH stimulation or hydrocortisone administration are positively associated with plasma ghrelin levels, whereas central stimulation of the HPA axis by blocking cortisol synthesis with metyrapone is associated with decreased plasma ghrelin levels. Collectively, this suggests that HPA-axis-mediated elevations in ghrelin plasma concentration require increased peripheral cortisol levels, independent of central elevation of ACTH and possibly CRH levels.

Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists.

OBJECTIVE: Clinically nonfunctioning pituitary adenoma (NFPA) remains the only pituitary tumor subtype for which no effective medical therapy is available or recommended. We evaluated dopamine agonist (DA) therapy for preventing growth of postsurgical pituitary tumor remnants. DESIGN: The study design included historical cohort analysis of clinical results at two pituitary referral centers with different standard practices for postoperative NFPA management: DA therapy or conservative follow-up. METHODS: Seventy-nine patients followed for 8.8±6.5 years were treated with DA, initiated upon residual tumor detection on postoperative MRI (preventive treatment (PT) group, n=55), or when tumor growth was subsequently detected during follow-up (remedial treatment (RT) group, n=24). The control group (n=60) received no medication. Tumoral dopamine and estrogen receptor expression assessed by quantitative RT-PCR and immunostaining were correlated with response to treatment. RESULTS: Tumor mass decreased, remained stable, or enlarged, respectively, in 38, 49, and 13% of patients in the PT group, and in 0, 53, and 47% of control subjects; shrinkage or stabilization was achieved in 58% of enlarging tumors in the RT group, P < 0.0001.Fifteen-year progression-free survival rate was 0.805, 0.24, and 0.04, respectively, for PT, RT, and control groups (P<0.001). About 42% of patients in the control group required additional surgery or radiotherapy, compared with 38 and 13% subjects in the RT and PT groups, respectively (P=0.002). Outcome measures were not related to NFPA D2R abundance. CONCLUSIONS: Dopamine agonist therapy in patients with NFPA is associated with decreased prevalence of residual tumor enlargement after transsphenoidal surgical resection.

The acute ghrelin response to a psychological stress challenge does not predict the post-stress urge to eat.

Ghrelin is a growth hormone and cortisol secretagogue that plays an important role in appetite and weight regulation. It is not known whether ghrelin is involved in the eating response to stress in humans. In the present study we examined the effects of psychologically induced stress on plasma ghrelin levels in patients with binge-eating disorder (BED) (n=8) and in healthy subjects of normal (n=8) or increased (n=8) body mass index (BMI). Volunteers were subjected to the standardized trier social stress test (TSST). Heart rate, blood pressure, serum cortisol, serum prolactin, and plasma ghrelin levels were measured throughout the test. In addition, subjects were requested to rate their feelings of anxiety, tension, urge to eat uncontrollably and desire to eat sweets by means of a visual analog scale both before and after the TSST. There was a significant rise in the systolic blood pressure (p=0.003) in the study population, reflecting induction of physiological changes by the psychological challenge. Basal ghrelin levels were higher in healthy normal weight (385.4+/-79 pg/ml) than in obese (170.4+/-15.7 pg/ml) subjects (p<0.033). Basal ghrelin levels in patients with BED (240+/-40.8 pg/ml) were at an intermediate level between thin and healthy obese subjects, but this difference did not attain statistical significance. There were no differences in ghrelin levels throughout the test among the groups after correction for BMI, age and gender. A significant difference in the trend time of ghrelin was revealed when the three groups were analyzed according to their cortisol response to stress. Ghrelin levels increased in cortisol responders whereas no change or a decrease in ghrelin levels occurred in cortisol non-responders (p=0.038). Furthermore, a positive correlation was found between the change in ghrelin and the change in cortisol during TSST (r=0.444, p=0.029) but not between the change in ghrelin and the change in systolic blood pressure. The combined score of stress and anxiety was higher in subjects in the higher quartile of ghrelin response in comparison to the lower quartile both before (28.3+/-6.5 vs. 6.6+/-3.3, p=0.0077) and after (61.6+/-9 vs. 28.3+/-11.3, p=0.033) TSST. On the other hand, eating related scores did not differ according to quartiles of ghrelin response. Our findings indicate that a psychological stress may induce an increase in plasma ghrelin levels in humans, and that the post-stress induced urge for uncontrolled eating is not acutely modulated by stress related elevations in ghrelin levels. Furthermore, the stress induced increase in plasma ghrelin was associated with the acute response of serum cortisol to stress, but was independent of BMI or the presence of BED.

Low-dose ACTH (1 microg) salivary test: a potential alternative to the classical blood test.

OBJECTIVES: Salivary cortisol is unaffected by cortisol binding globulin (CBG) and hence allows CBG-related variations in serum total cortisol to be bypassed. We assessed whether or not salivary cortisol can be used for the low-dose (1 microg) ACTH test in subjects with presumed normal and elevated levels of CBG. PATIENTS/METHODS: We measured serum and salivary cortisol responses to intravenous administration of 1 microg ACTH in 14 healthy volunteers, 14 'hyperoestrogenic' women [in their first or early second trimester of pregnancy, using oral contraceptives (OC) or on hormone replacement therapy (HRT)] and 10 patients with secondary hypoadrenalism. Cortisol levels were recorded before as well as 30 and 60 min (+30; +60 min) after ACTH administration. RESULTS: Baseline salivary cortisol did not differ significantly between the hypoadrenal and healthy patients (7.11+/-1.4 and 12.13+/-1.59 nmol/l; P=0.48) but there was a significant difference between hypoadrenal and hyperoestrogenic patients (18.94+/- 3.44 nmol/l; P=0.01). The largest difference between hypoadrenal patients and healthy individuals was observed at+30 min (9.16+/-2.8, 52.65+/-8.78 and 48.81+/- 6.9 nmol/l, in the hypoadrenal, healthy and hyperoestrogenic patients, respectively; P< 0.05). At this time-point values< 24.28 nmol/l were found in all hypoadrenal patients and cortisol levels >or= 27.6 nmol/l were found in 26 out of 28 healthy volunteers. ACTH-stimulated serum cortisol but not salivary cortisol was significantly higher in hyperoestrogenic women than in the healthy volunteers at either+30 or+60 min. CONCLUSIONS: The salivary low-dose ACTH test yields results that parallel the response of circulating cortisol to ACTH and may provide an alternative to the blood test, particularly in situations where increased CBG levels complicate the changes in serum cortisol levels.

Postoperative treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists decreases tumour remnant growth.

OBJECTIVE: There is no consensus as to the optimal postoperative treatment of patients with clinically nonfunctioning pituitary adenomas (NFPA) in whom total tumour removal has not been achieved. In this study we assessed whether dopamine agonist (DA) treatment can prevent postoperative remnant enlargement in NFPA. DESIGN AND METHODS: Thirty-three patients (25 men/8 women; mean age, 61.7 +/- 11.2 years; mean follow-up, 40.6 +/- 4.8 months) were treated with DA, and their outcome was compared to that of 47 untreated patients (33 men/14 women; mean age, 59 +/- 2 years; mean follow-up, 42.9 +/- 4.2 months). RESULTS: Tumour mass decreased or remained stable in 18/20 patients in whom DA treatment was initiated upon detection of residual tumour on postoperative MRI (group I). In 13 subjects (group II), DA therapy was started when tumour remnant growth became evident during the course of routine follow-up. Tumour growth stabilized or decreased in 8/13 (61.5%) of these patients. In contrast, tumour size remained stable in only 38.3% (18/47) of the untreated subjects (P < 0.0001 for comparisons among the three groups) and increased in the remaining 29 patients. Tumour enlargement free mean survival time was 103.7 +/- 8.8 months (CI 86.3-121) for group I, 43.9 +/- 9.6 months (CI 25.2-62.8) for group II and 36.7 +/- 3.8 (CI 29.2-44.2) for the control group (P = 0.0017). Treatment vs. control hazard ratio for tumour enlargement was 0.135 for group I (P = 0.007, 95% CI 0.032-0.577) and 0.892 for group II (P = 0.817; 95% CI 0.34-2.34). CONCLUSIONS: Dopamine agonist therapy is associated with a decreased prevalence of residual tumour enlargement in patients with nonfunctioning pituitary adenomas, particularly when treatment is instituted before tumour remnant growth is detected.

Postoperative surveillance of clinically nonfunctioning pituitary macroadenomas: markers of tumour quiescence and regrowth.

BACKGROUND: Postoperative management of clinically nonfunctioning pituitary adenomas (NFPA) presents difficult challenges. There are no good serum markers for presence or growth of the tumour, medical treatment is not effective and radiotherapy carries the risk of significant side-effects. OBJECTIVE: The purpose of this study was to investigate the natural history and biological behaviour of surgically treated NFPA, with a special effort to identify characteristics indicative of a more aggressive course that could assist in the clinical decision-making process. STUDY DESIGN: Patients operated on at our institution for NFPA undergo uniform routine clinical follow-up at the endocrine clinic. Magnetic resonance imaging (MRI) studies are performed 3, 6 and 12 months after transsphenoidal surgery and yearly thereafter for the first 5 years. Subsequently, imaging is performed once every 2 years or as clinically indicated. From 1992 onwards, no patient received immediate postoperative radiation therapy. PATIENTS: One hundred and twenty-two patients (78M/45F) operated on at our institution since 1989 and with a minimal follow-up of 1 year comprised the study group. MEASUREMENTS: Tumour size and characteristics were determined by MRI using a modification of Hardy's and Wilson's classifications. Maximal tumour height was also recorded and the information was routinely stored in a computerized database. RESULTS: Mean (+/- SD) follow-up was 51 +/- 31 months. Fourteen patients received postoperative radiation therapy. Subsequent tumour growth was observed in five of them, reduction in tumour size in four and no size changes in five. One hundred and eight patients did not receive postoperative radiation. Tumour enlargement occurred in 41 of 78 and in six of 30 patients with and without residual tumour after operation (P = 0.0024). The presence of cavernous sinus invasion before surgery [P = 0.02, odds ratio (OR) 2.72; confidence interval (CI) 1.1-6.43] and the extent of suprasellar extension in the postoperative tumour remnant (P = 0.0054 for presence of stage A, OR 4.4; 95% CI 1.5-12.5; and P = 0.012 for presence of stages B or C, OR 16.2; CI 1.8-144) were strong independent predictors of tumour enlargement. CONCLUSION: Our data may ease the selection of patients in whom radiation therapy is likely to be necessary for tumour control, and confirms that close postoperative follow-up is an adequate primary approach in low-risk patients.

Risk factor clustering in hypertensive patients: impact of the reports of NCEP-II and second joint task force on coronary prevention on JNC-VI guidelines.

INTRODUCTION: Although the association of hypertension with established risk factors has been noted in several population studies, the recent redefinition of dyslipidaemia, hypertension and diabetes calls for reassessment of the prevalence and pattern of risk factor clusters in essential hypertension. OBJECTIVE: To analyse the risk factor profile of Israeli patients with essential hypertension seen by primary care physicians and in hypertension specialty clinics, based on current definitions of dyslipidaemia hypertension and diabetes and JNC-VI guidelines for the assessment of risk factors. DESIGN AND SETTING: We analysed the risk profile of 324 Israeli hypertensive subjects using the JNC-VI risk table and risk grouping. A total of 122 consecutive patients were recruited from primary care clinics and 212 consecutive patients were recruited from a hospital based hypertension clinic. RESULTS: Amongst hypertensive individuals with no known target organ damage, only 1.5% had no risk factors other than hypertension, whereas all hypertensives with coronary artery disease had additional risk factors. Of the six listed major JNC-VI risk factors (smoking, dyslipidaemia, diabetes, age, sex, family history of cardiovascular disease), hypertensive subjects without coronary artery disease (coronary artery disease-negative) had 3.02 +/- 0.10 risk factors, whereas hypertensive subjects with coronary artery disease (coronary artery disease positive) had 3.6 +/- 0.07 risk factors other than hypertension (P < 0.01). Dyslipidaemia defined by NCEP-II criteria was the most common associated risk factor identified in 93% of coronary artery disease-positive and 77% of the coronary artery disease-negative hypertensive subjects. The most common dyslipidaemic abnormality was an increased LDL cholesterol (79.2% of the cohort), followed by hypertriglyceridaemia (31.7%) and low HDL cholesterol (22.3%). Nevertheless, in nearly half of the coronary artery disease-negative patients, LDL cholesterol concentrations were within 30 mg dL-1 of the target levels. The most common dyslipidaemic variant was isolated hypercholesterolaemia (42%), whereas the syndrome X dyslipidaemic combination of hypertriglyceridaemia and low HDL was strikingly uncommon, observed in 2.8% of the coronary artery disease-positive and 0.8% of the coronary artery disease-negative patients. CONCLUSIONS: (i) JNC-VI group risk A patients (no risk factors) comprise a very small minority in this cohort (< 5%); (ii) dyslipidaemia is exceedingly common with mild hypercholesterolaemia being the most prevalent variant and hypertriglyceridaemia with low HDL the least common form.

Low-dose (1 microgram) adrenocorticotrophin (ACTH) stimulation as a screening test for impaired hypothalamo-pituitary-adrenal axis function: sensitivity, specificity and accuracy in comparison with the high-dose (250 microgram) test.

OBJECTIVE: We have shown previously that in contrast to the standard high-dose 250-microgram ACTH test, a low-dose 1-microgram ACTH stimulation test correctly identified all patients with pituitary disease who had impaired hypothalamo-pituitary-adrenal (HPA) function. In this study we further compared the performances of these two tests as screening procedures for possible HPA impairment. DESIGN: A comparison of the 1-microgram and the 250-microgram ACTH stimulation tests in healthy controls and in patients with pituitary disease whose HPA axis status was characterized formally by a gold standard test. SUBJECTS: A total of 89 subjects were investigated: 27 healthy normal controls, 43 patients with pituitary disease and normal HPA function, and 19 patients with various pituitary diseases and impaired HPA function. MEASURES: All 89 subjects underwent stimulation with 1 microgram ACTH; 80 also underwent the high-dose 250-microgram ACTH test. A receiver operating characteristic analysis (ROC) was performed to compare the tests. RESULTS: Using a stimulated cortisol > 500 nmol/l as the criterion for a normal response, the 1-microgram ACTH stimulation identified 18 of the 19 subjects with impaired HPA function (94.7% sensitivity with a likelihood ratio of 0.0588 for a negative test). In contrast, 15/16 passed the high-dose test (a 6.2% sensitivity with a likelihood ratio of 0.875 for a negative test). All normal controls, and 36/43 patients with preserved HPA function, passed the 1-microgram ACTH test (90% specificity). This degree of accuracy was unrivalled by the high dose test at all the cut-off levels considered. CONCLUSIONS: More sensitive and accurate, the low-dose 1-microgram ACTH test is as simple and safe as the standard 250-microgram test. We suggest it should replace it in screening for adrenal insufficiency.

Effect of TRH on beta-gonadotropin subunits in patients with pituitary microincidentalomas.

OBJECTIVE: To explore the hypothesis that most of the pituitary abnormalities compatible with the diagnosis of microadenoma, and detected in about 10% of the normal adult population, represent asymptomatic gonadotropinomas. DESIGN: Patients diagnosed with pituitary microincidentalomas at the Institute of Endocrinology of the Tel Aviv Medical Center were evaluated. Circulating beta-subunits of gonadotropin hormones were measured before and 30, 45, 60 and 90 min after the intravenous injection of 400 microgram TRH. PATIENTS: Twenty-two patients with pituitary incidentaloma and 16 normal volunteers were tested. RESULTS: In 16 of the 22 patients, an abnormal beta-subunit response was detected after the TRH challenge. Three patients had an abnormal increase in both beta-FSH and beta-LH after TRH administration. Isolated pathological beta-FSH or beta-LH responses were demonstrated in five and eight patients respectively. Six patients had normal basal and stimulated gonadotropin subunit values, raising the possibility that their lesions were not pituitary microadenomas. There was a significant overall difference between the response to TRH of the patient and control groups. In the gonadotropin positive group, comprising 16 patients, serum beta-FSH increased from 6.4+/-1.6 ng/ml to 9.2+/-1.3 ng/ml (P=0.042) 1 h after TRH stimulation, whereas no changes were detected in the control group after TRH injection (basal: 4.1+/-0.8 ng/ml, peak: 5.1+/-0.8 ng/ml; P=0.15). Serum beta-LH increased from 10.5+/-3.2 ng/ml to 23.4+/-4.9 ng/ml (P=0.0037) at this time, in contrast to a lack of response in controls (basal: 6.4+/-1.5 ng/ml, peak: 8.2+/-2.3 ng/ml; P=0.24). CONCLUSION: In about 73% of patients with pituitary incidentalomas smaller than 10 mm, TRH elicits an increase in gonadotropin beta-subunits. This observation raises the possibility that non-functioning pituitary micro- and macroadenomas, which share a similar response to TRH, originate in a common ancestor cell type, probably a pituitary gonadotrope.

TRH is a tonic secretagogue in growth hormone secreting but not in nonfunctioning pituitary tumors.

In most patients with growth hormone (GH) secreting pituitary adenomas and clinically nonfunctioning pituitary tumors (NFPT) the intravenous injection of thyrotropin releasing hormone (TRH) augments the secretion of GH and subunits of gonadotropin hormones respectively. Similar hormone responses to TRH have been detected in rat pituitary cell lines and in primary human pituitary tumor cultures in vitro. Nevertheless the TRH effect on tumor hormonal secretion has not been well characterized. In the present study we examined TRH-induced hormone secretion in GH secreting tumors and in NFPT in vitro. Cultured cells secreted betaLH and betaFSH (NFPT) or GH (GH secreting adenomas) up to 14 days in culture. In NFPT TRH (10(-8) mol/l) elicited peak betaLH and betaFSH secretion at 60 to 90 min, with no further increase at 24 h. TRH-stimulated GH secretion peaked at 90-120 min, and decreased after 3 h, but a secondary rise occurred after 24 h of incubation. Chronic daily exposure to TRH followed by an acute TRH challenge resulted in a further increase of GH secretion after one hour. In contrast, acute TRH administration following chronic exposure did not elicit increased P-subunits secretion in NFPT. Coadministration of cycloheximide did not change TRH induced beta-subunits secretion in NFPT. However, when it was administered 24 h prior to TRH, it blocked both basal and TRH induced beta-subunits levels in NFPT. Cycloheximide had no effect on basal or stimulated GH secretion when administered concomitantly or 24 h before TRH. Incubation of cultured GH secreting tumors with cycloheximide during 5 days blocked both basal and TRH stimulated GH secretion, thus indicating dependency on protein synthesis during the chronic, secondary phase. Since the acute secretion was not affected by coadministration of cycloheximide, these early increases in hormone levels apparently reflect the release of stored hormone. In summary, GH secreting adenomas and NFPT differ significantly in their hormonal response to continuous exposure to TRH. The mechanisms underlying the sustained effect of TRH on GH secretion in vitro remain to be investigated. If endogenous TRH exerts a similar continuous effect it may contribute to the disregulated GH secretion in acromegaly.

The use of beta-subunits of gonadotrophin hormones in the follow-up of clinically non-functioning pituitary tumours.

OBJECTIVE: Clinically nonfunctioning pituitary adenomas (NFA) are mostly of gonadotroph origin. However, increased levels of circulating hormones or subunits in patients with NFA usually do not cause clinical symptoms, nor are they used as biological tumour markers. In this study we assessed the value of measuring beta subunits of gonadotrophin hormones in the post-operative follow-up of patients bearing these tumours. DESIGN: Patients harbouring NFA were studied before and three months after transphenoidal pituitary surgery. beta-LH and beta-FSH levels were measured before and following TRH administration on the two occasions. Hormone levels were analyzed in relation to imaging studies performed before and after surgery. PATIENTS: Twenty four patients operated at the Tel Aviv-Sourasky Medical Centre for NFA. RESULTS: Pathological beta-FSH and beta-LH levels were detected in 79% and 60% of patients respectively. beta-LH levels decreased after surgery but there were no significant changes in beta-FSH levels. There was a tendency for tumours with high basal beta-LH levels to be larger and to have a poor surgical outcome. Normalization of beta-LH levels post-operatively was usually associated with a decrease in tumour mass or complete removal of the tumour. Persistent pathological responses of beta-LH to TRH after surgery were common in patients with residual tumours on imaging. Nevertheless there were exceptions to this pattern, rendering post-operative beta-LH levels insufficiently reliable as a marker for the presence of residual tumour. CONCLUSION: Although there appears to be a relationship between beta-LH levels, tumour size and surgical outcome, this association is presently insufficient to allow the routine use of either basal or TRH induced beta-LH responses in the post-surgical follow-up of clinically nonfunctioning pituitary adenomas.

Increased body weight associated with prolactin secreting pituitary adenomas: weight loss with normalization of prolactin levels.

OBJECTIVE: Hyperprolactinaemia in humans may be associated with a high prevalence of obesity but the nature of this link is poorly defined. The aim of this study was to establish the relationship between hyperprolactinaemia and body weight in patients with prolactin-secreting pituitary tumours. DESIGN: We conducted a retrospective study of prolactinoma patients treated at the Endocrine Institute of the Tel Aviv Medical Center, Israel, during the period 1989-1996. Patients with clinically non-functioning pituitary macroadenomas (NFA) served as the control group. Data on demographic parameters, body weight before and during treatment, clinical presentation including history of weight fluctuations, tumour size as measured by computed tomography or magnetic resonance imaging, modalities and response to treatment, and pituitary function before and during treatment were recorded from medical files. PATIENTS: Forty-two patients with prolactinomas (PR) and 36 patients with clinically non-functioning macroadenomas (NFA) comprised the study population. RESULTS: Mean weight was 93 +/- 3.4 kg and 78 +/- 2.7 kg in male patients with PR and NFA respectively (P = 0.0007). Recent weight gain (8 to 22 kg) was a presenting symptom in 13 PR patients, whereas only one NFA patient had this clinical presentation (P = 0.001). Seventeen PR patients lost weight (mean change -8.3 +/- 1.5 kg, range -2-28 kg), during prolactin lowering therapy, 11 of whom had entirely normalized prolactin levels. Fourteen of the 18 patients who did not lose weight still had elevated prolactin levels (P = 0.01). Weight loss in patients with PR could not be attributed to altered pituitary function nor to compression of the third ventricle. In contrast to PR, no significant weight loss was observed in NFA patients. CONCLUSION: Weight gain and elevated body weight are frequently associated with prolactinomas regardless of a mass effect on the hypothalamus or pituitary function. In this series, weight loss was recorded in 70% of prolactinomas patients and in 90% of male patients who normalized their prolactin levels. We propose the inclusion of hyperprolactinaemia in the differential diagnosis of endocrine obesity and weight gain.

Remission of acromegaly caused by pituitary carcinoma after surgical excision of growth hormone-secreting metastasis detected by 111-indium pentetreotide scan.

GH-secreting carcinomas of the pituitary are extremely rare. We describe a 37-yr-old woman with refractory acromegaly 15 yr after transphenoidal surgery and radiotherapy, with no evidence of a recurrent pituitary mass. Scanning with 111-indium pentetreotide revealed an area of intense activity in the left neck. A 3.5 x 2.5-cm mass was excised from the neck after demonstrating an arterio-venous GH gradient of 7:1. GH levels (50 ng/mL) dropped to 0.8 ng/mL 3 h after surgery and remained normal. GH gene expression was demonstrated in the metastasis by Northern and Western blot analyses and by positive immunocytochemistry and immunoelectron microscopy. In vitro cultured cells responded to GHRH and TRH by increasing GH levels (P < 0.01). Medium GH was identical to authentic pituitary GH, as demonstrated by high pressure liquid chromatography. RT-PCR of hypothalamic hormone receptor messenger RNA in the mass revealed somatostatin receptor subtypes 2, 3, and 5 and GHRH, TRH, and dopamine receptor expression. No GH gene amplification, rearrangement, or gsp mutation was found. RB gene deletion and H-ras mutations, previously reported in PRL- and ACTH-secreting carcinomas, were not detected. In conclusion, clinical and molecular features of a GH-secreting pituitary carcinoma are presented. This metastatic lesion synthesized GH and expressed functional hypothalamic hormone receptors.

Diagnosis and management of nonfunctioning pituitary tumors.

It is now recognized that most clinically nonfunctioning pituitary tumors express gonadotropin hormones or their subunits in vitro, and sometimes in vivo. Many of these tumors are diagnosed by sensitive imaging techniques while patients are still asymptomatic. We outline an overview of the diagnosis and clinical management of these tumors.

Relative sparing of anterior pituitary function in patients with growth hormone-secreting macroadenomas: comparison with nonfunctioning macroadenomas.

Pre- and postoperative anterior pituitary function was assessed in 26 subjects with nonfunctioning macroadenoma (NFMA) and in 15 acromegalic subjects with macroadenomas. Preoperatively, NFMA patients had a higher prevalence of secondary hypogonadism (78% vs. 40%; P < 0.05), hypothyroidism (23% vs. 0%; P = 0.06), and hypoadrenalism (43% vs. 7%; P = 0.02) compared to individuals with GH-secreting macroadenoma (GHMA). Patients with NFMA also had a higher prevalence of more severe pituitary failure compared with acromegalic patients; 56% of the patients in this group had more than one pituitary hormone axis impaired compared to only 8% in the acromegalic group. These differences could not be accounted for by tumor grade and/or stage. Transsphenoidal pituitary surgery led to a significant improvement in anterior pituitary function in the NFMA group. Nevertheless, the prevalence of pituitary deficiency postoperatively was still significantly greater in NFMA patients than in the acromegalic group (68% vs. 17%, respectively; P < 0.04). The results suggest that anterior pituitary function is better preserved in GHMA than in NFMA and that this difference is independent of tumor size. The mechanism underlying the lower rate of hypopituitarism in acromegalics with macroadenomas remains to be elucidated.