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The many advantages of registered bioidentical sex hormones over registered, conventional, non-bioidentical menopausal hormone therapy (MHT) are considered. The transdermal route of estrogen administration avoids excess venous thromboembolic and ischemic stroke events. There is some indication that conjugated equine estrogens are more thrombogenic and most likely induce some hypertensive responses; estradiol might also be superior to conjugated equine estrogens (CEE) in terms of global cardiovascular health. The most valid evidence presently suggests that CEE-only treatment does not increase the risk of breast cancer and even may reduce it. But its combination with a synthetic progestogen (mainly medroxyprogesterone acetate) is a critical issue since it seems to be primarily associated with an increased incidence of breast cancer, however similar to or lower than that associated with some common lifestyle factors. Though not yet proven in a randomized, controlled trial, MHT continuously combining oral micronized progesterone with transdermal estradiol can presently be considered as the optimal MHT. It is not only safer than custom-compounded bioidentical hormones but also than oral conventional MHT and has the best breast profile; registered products for such optimal MHT are available around the world and must be preferred.

Wide rejection of conventional hormone therapy (HT) after the initial publication of the Women's Health Initiative (WHI) led to unjustified use of custom-compounded bioidentical hormones. In the USA, it became an unregulated drug manufacturer industry in disguise, without proper control and making false claims and misleading advertisements. Manufacturing quality is not ensured. Unspecific harm from compounding has occurred on a large scale, such as deaths from infected products and end-stage renal failure plus carcinoma due to confusion between different Chinese herbs. Oral estrogens increase venous thromboembolic and ischemic stroke events, even more when overdosed; these excess risks can be avoided by non-oral administration, readily accessible in custom-compounded HT by administering estradiol through diverse routes (of which transdermal is the best documented). Another risk specific to custom-compounded HT, resulting from estrogen/progestogen imbalance, might be excess endometrial carcinomas. HT can be optimized by continuously combining transdermal estradiol with progesterone (when required). Registered preparations do exist for such a more physiological treatment and therefore must be preferred. Custom compounding is only seldom legitimate, for example in case of allergy (such as to peanut oil) or to prescribe different combinations, doses or components (e.g. estriol, dehydroepiandrosterone or testosterone), even when not approved by local regulatory authorities despite being scientifically acceptable.

The 24th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 6th November 2015. The meeting was attended by 77 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short 'flash' presentations in association with particular posters and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, isotopic separation and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Dr Rebekka Hueting (University of Oxford, UK) and afternoon sessions chaired by Dr Sofia Pascu (University of Bath, UK) and by Dr Alan Dowling (Syngenta, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK)., (Copyright © 2016 John Wiley & Sons, Ltd.)

Hormone replacement therapy (HRT) remains the gold standard for treatment of climacteric symptoms in menopausal women; it is relatively safe in healthy subjects for at least 5 years, provided it had been initiated before the age of 60 years and/or within 10 years from menopause. Estrogen probably adds some cardioprotection, that can, however, be obscured by progestogens, especially medroxyprogesterone acetate (MPA). Oral HRT is associated with an increased risk of venous thromboembolism (VTE), gallbladder disease and possibly stroke. The increased occurrence of all these events can be prevented by the use of the transdermal route of estradiol administration; this route seems also advantageous for women with diabetes, hypertension and other cardiovascular risk factors, and also especially with advancing age. Endometrial protection by any progestogen is insufficient in the mid to long term when cyclical, sequential regimens are used; full protection can be secured only by continuous combined estrogen + progestogen. Natural, 'body-identical' progesterone, devoid of any androgenic as well as glucocorticoid activities but being slightly hypotensive due to its antimineralocorticoid activity, appears to be the optimal progestogen in terms of cardiovascular effects, blood pressure, VTE, probably stroke and even breast cancer (contrary to synthetic progestogens and particularly MPA, which appear to be mitogenic on breast cells, in synergism with estrogen). HRT optimization can thus be achieved by combining low doses of estrogen given transdermally with micronized oral progesterone; such optimized HRT will allow us to treat symptomatic women for as long as required. Asymptomatic women at risk of (osteoporotic) fractures can also be treated with this optimized HRT as long as their individual risk/benefit ratio remains favorable (thanks to the absence of increased risks of VTE, stroke and breast cancer).

Asphyxiating thoracic dysplasia (Jeune syndrome) is an osteochondrodysplasia with autosomal recessive inheritance, characterised by a nanism with rhizomelic predominance, associated with a narrow thorax. It induces an alteration of the respiratory function that conditions the prognosis, which is worsened in case of associated visceral lesions (probably related to mutations of genes implicated in ciliary development, as recently described). We report the observation of two severe cases of Jeune syndrome to emphasize the advancement of imaging, especially echography, and molecular biology in establishing prenatal diagnosis as well as prognosis of this syndrome., ((c) 2009 Elsevier Masson SAS. All rights reserved.)

Hormone replacement therapy (HRT) in young postmenopausal women is a safe and effective tool to counteract climacteric symptoms and to prevent long-term degenerative diseases, such as osteoporotic fractures, cardiovascular disease, diabetes mellitus and possibly cognitive impairment. The different types of HRT offer to many extent comparable efficacies on symptoms control; however, the expert selection of specific compounds, doses or routes of administration can provide significant clinical advantages. This paper reviews the role of the non-oral route of administration of sex steroids in the clinical management of postmenopausal women. Non-orally administered estrogens, minimizing the hepatic induction of clotting factors and others proteins associated with the first-pass effect, are associated with potential advantages on the cardiovascular system. In particular, the risk of developing deep vein thrombosis or pulmonary thromboembolism is negligible in comparison to that associated with oral estrogens. In addition, recent indications suggest potential advantages for blood pressure control with non-oral estrogens. To the same extent, a growing literature suggests that the progestins used in association with estrogens may not be equivalent. Recent evidence indeed shows that natural progesterone displays a favorable action on the vessels and on the brain, while this might not be true for some synthetic progestins. Compelling indications also exist that differences might also be present for the risk of developing breast cancer, with recent trials indicating that the association of natural progesterone with estrogens confers less or even no risk of breast cancer as opposed to the use of other synthetic progestins. In conclusion, while all types of hormone replacement therapies are safe and effective and confer significant benefits in the long-term when initiated in young postmenopausal women, in specific clinical settings the choice of the transdermal route of administration of estrogens and the use of natural progesterone might offer significant benefits and added safety.

Unlabelled: Small cell ovarian tumors are rare and highly malignant, occurring mainly in young patients. Early mortality is high due to the lack of an effective treatment. The first adjuvant therapy is usually chemotherapy., Case: During laparotomy for renal transplant in a 17-year-old girl, the right ovary exhibited a suspicious mass, whose pathological diagnosis was Stage 1A small cell ovarian tumor. Prognosis was poor (young age, hypercalcemia, tumor >10 cm, and presence of large cells). Since chemotherapy is contraindicated for dialysed patients, only radiotherapy was given. The patient is still alive and disease-free ten years after diagnosis., Conclusion: This is the first case with a poor prognosis reported in the literature that has been successfully cured by surgery plus adjuvant radiotherapy only.

Objectives: A 1-year, open-label, non-comparative study evaluated the long-term tolerability and acceptability of a new generation matrix patch in post menopausal women with estrogen deficiency., Methods: Menopausal women (224) from 37 centres in five European countries received OESCLIM 50 microg/d (17-beta estradiol) for 3 months, titrated if necessary to either 25 or 100 microg/d for a further 9 months. Patients received either a continuous or discontinuous estradiol regimen with concomitant sequential progestogen (except hysterectomised patients). Skin tolerability was assessed by patient diaries and questionnaires. Global tolerability, efficacy, laboratory parameters and global acceptability were also monitored., Results: Almost two-thirds of women did not experience any kind of skin reaction and only 4.3% of all applications (752/17,702) caused site reactions. Of these, the majority caused only slight or no discomfort (63.2%). Only 0.37% of total applications required patch removal; none required therapy. A low percentage of patients withdrew due to tolerability issues: 2.7% due to skin reactions; 7.5% due to hyperestrogenism. The mean number of hot flushes experienced by symptomatic women reduced by 91% from 4.0 at baseline to 0.4 after 2 months. Total cholesterol reduced by 3.9% and LDL cholesterol by 5.1%, with no increase in triglyceride levels. Investigators assessed treatment as effective in 96.8% of cases; well tolerated locally in 93.1% and well tolerated generally in 89.5%. At the end of this 1 year study, 79% of patients wished to continue therapy., Conclusion: OESCLIM is well tolerated locally and systemically in long-term therapy with a high proportion of patients wishing to continue therapy after 1 year.

Objective: We assessed the efficacy and safety of the new, long-acting dopamine agonist drug cabergoline during long-term therapy of hyperprolactinaemia., Design: Open, prospective, multicentre study., Patients: One hundred and sixty-two females with either a microprolactinoma (n = 100), idiopathic hyperprolactinaemia (n = 54), empty sella syndrome (n = 7) or residual hyperprolactinaemia after surgery for a macroprolactinoma (n = 1). All had previously been treated with cabergoline or placebo for 4 weeks as part of a dose-finding study., Measurements: Menstrual pattern, adverse symptoms, blood pressure and pulse, serum PRL, blood count, liver and renal function were assessed after one month and subsequently at two-monthly intervals., Results: Treatment was started at doses of 0.25 mg (n = 3), 0.5 mg (n = 8), 1 mg (n = 150) or 2 mg (n = 1) per week, given either as a single weekly dose (n = 8) or divided into twice-weekly doses (n = 154), and was continued for at least 49 weeks in 123 patients. Final treatment doses ranged from 0.25 mg fortnightly to 2 mg twice weekly: most patients finished the study taking 0.5 mg once (n = 31) or twice (n = 77) weekly. Stable normalization of PRL levels was achieved in 138 subjects (85%), in 129 of whom the effective dose was < 1 mg per week. In the subset of 114 patients completing 49 weeks of therapy and having dose adjustments according to the protocol, the biochemical success rate was 92%. Fifty-nine of the 65 previously amenorrhoeic women (91%) and 44 of the 49 (90%) who were previously oligomenorrhoeic resumed regular menses and/or became pregnant during the study. Adverse events were reported in 64 patients (39.5%). In 84% of cases with adverse events, the symptoms were of mild or moderate severity and most occurred during the first few weeks of therapy; five patients (3%) discontinued treatment because of poor tolerance. The most frequent symptoms were dizziness (13% of patients), headache (13%), nausea (10%) and weakness and/or fatigue (10%). Of 27 patients who had previously been poorly tolerant of other dopamine agonists, 17 (63%) did not experience any side-effects and only one was intolerant of cabergoline. No adverse haematological or biochemical effects were detected except for a slight downward trend in haemoglobin which may have been related to the resumption of regular menses in previously amenorrhoeic or oligomenorrhoeic women. A mild hypotensive effect was observed, mean systolic and diastolic blood pressures falling by 5 and 4 mmHg respectively during treatment., Conclusions: The results provide evidence for the long-term effectiveness and safety of cabergoline in the treatment of hyperprolactinaemia. Its ability to normalize PRL and restore gonadal function compares favourably with reported data on reference compounds while its tolerability profile and simple administration schedule offer potential advantages in terms of patient acceptability.

Objective: Dopamine agonists have a well established place in the treatment of hyperprolactinaemic disorders but their use is associated with a high incidence of adverse effects. We have investigated the biochemical efficacy and side-effect profile of a range of doses of the novel, long-acting dopamine agonist, cabergoline, in suppressing prolactin (PRL) in hyperprolactinaemic women., Design: Multicentre, prospective, randomized, placebo controlled and double blind., Patients: One hundred and eighty-eight women with hyperprolactinaemia secondary to microprolactinoma (n = 113), idiopathic disease (n = 67), empty sella syndrome (n = 7) or following failed surgery for a macroprolactinoma (n = 1)., Measurements: Weekly assessment of adverse symptoms, blood pressure and pulse, serum PRL, blood count, liver and renal function., Results: Patients received either placebo (n = 20) or cabergoline 0.125 (n = 43), 0.5 (n = 42), 0.75 (n = 42) or 1.0 mg (n = 41) twice weekly for 4 weeks. The five treatment groups were comparable in age (mean 31.8, range 16-46 years), diagnosis, previous therapy, and pretreatment serum PRL. PRL was suppressed to below half the pretreatment level in 5, 60, 90, 95 and 98% and normalized in 0, 30, 74, 74 and 95% of patients taking placebo or cabergoline 0.125, 0.5, 0.75 or 1.0 mg twice weekly respectively (Armitage's test, chi 2 = 39.3, P < 0.01). Cabergoline therapy (all doses) restored menses in 82% of the amenorrhoeic women not previously treated with dopamine agonists. Adverse events were recorded in 45% of patients in the placebo group and in 44, 50, 50 and 58% of those taking 0.125, 0.5, 0.75 and 1.0 mg cabergoline twice weekly (Armitage's test, P > 0.05). Over 95% of reported symptoms were relatively trivial, most frequently transient nausea, headache, dizziness, fatigue and constipation. More severe adverse events, interfering significantly with the patients' lifestyle, occurred in 13 (7.7%) patients taking cabergoline; treatment withdrawal was necessary in only one case. No adverse effects were detected on blood pressure or haematological or biochemical parameters., Conclusions: We have shown a linear dose-response relationship for cabergoline in the treatment of hyperprolactinaemia in the range 0.125-1.0 mg twice weekly, with normalization of PRL in up to 95% of cases and acceptable tolerability throughout the dose range.

The discovery of a panel of peptides produced by normal and cancerous cells and capable of stimulating cell growth in an autocrine and paracrine fashion has been witnessed in recent years. This article focusses on the local growth factors thought to play a role in the biology of breast cancer and reviews which growth factors' receptors have been associated with prognosis of primary breast cancer. The potential of those growth factors for the development of new anticancer treatment strategies is also briefly discussed.

Studies in rodents have shown that triazolam, a commonly used hypnotic, may shift circadian rhythms, with the direction and magnitude of the phase-shifts being dependent on the time of drug administration. To determine whether benzodiazepine, taken at standard bedtime, modifies the amount and/or temporal organization of hormonal secretion, six normal men were studied during basal conditions and on the first and third days of treatment with 0.5 mg triazolam. In each study, sleep was polygraphically monitored and plasma cortisol, growth hormone (GH), melatonin, and prolactin (PRL) (i.e., hormones influenced by circadian rhythmicity and/or sleep) were measured at 20-min intervals for 24 h. The sleep latency and the number and duration of awakenings were reduced during triazolam treatment as compared to baseline conditions. The only alteration of sleep architecture was a partial suppression of stages III + IV (SW) in late sleep. Triazolam did not affect the mean cortisol and melatonin levels or the total amount of GH secreted over the 24-h span. The circadian timings of the onsets of cortisol and melatonin secretions were essentially unaltered. The nocturnal rise of melatonin was prolonged by 45 to 60 minutes. Sleep-associated GH release was not modified by triazolam. Sleep-associated PRL secretion persisted, but in half of the nights studied was enhanced almost threefold. This effect of the drug on nocturnal PRL secretion was not specific to either the first or the third night of treatment, nor was it specific to certain subjects. Irrespective of the magnitude of the nocturnal elevation, morning PRL levels were slightly but consistently higher after triazolam treatment than under basal conditions. Normal PRL levels resumed around noon. In conclusion, administration of 0.5 mg triazolam at normal bedtime (2230) for three consecutive days may induce a transient hyperprolactinemia, but does not abolish sleep-related hormone secretion and does not affect the timing of endocrine events controlled by the circadian clock. These findings are consistent with studies in hamsters where treatment with triazolam in the early subjective night was also without effect on the rodent circadian clock.

Human prolactin blood levels were determined by radioimmunoassay in basal condition and in response to various inhibiting and/or stimulating agents (levodopa, water overload, insulinic hypoglycaemia, synthetic TRH, sulpiride) in cases of disturbed hypothalamo-pituitary axis (failure to lactate, prolactin-secreting pituitary adenomas, acromegaly, other pituitary tumours, clinical panhypopituitarism). A blunted prolactin response to suckling was evidenced in 2 post-partum women who were unable to breast feed. Hyperprolactinaemia, whether related to the existence of a prolactin-producing adenoma or not, was associated with the disappearance of the normal circadian pattern of prolactin secretion and with a blunted relative response to TRH; the latter phenomenon occurred also in acromegaly regardless of the basal prolactinaemia, and during the last trimester of pregnancy. Water overload was unsuccessful to suppress prolactin during the last trimester of pregnancy while the acute administration of levodopa was quite effective in about half of the patients with pituitary tumour. Therefore none of the dynamic tests presently studied allowed us to attribute a hyperprolactinaemia to a pituitary tumour rather than to a functional disturbance. On the contrary, stimulation tests can help to locate the level of a defect in cases of hypopituitarism.

The response of plasma PRL to exercise, as performed on a bicycle ergometer under conditions below and above the anaerobic threshold, was studied in 10 normal young men. One hour of submaximal work against a workload at which blood lactic acid remained below 4 mmol/liter (anaerobic threshold) was accompanied by a slight decrease in plasma PRL levels, similar to the changes occurring under control conditions in the same subjects. However, during graded maximal ergometric exercise until exhaustion, plasma PRL rose promptly and significantly (P less than 0.05) when the anaerobic threshold was reached. These data suggest that PRL levels increase provided that the intensity of exercise is such that the anaerobic threshold is reached.

Serum prolactin has been measured in blood samples collected daily during 51 menstrual cycles using an homologous human radioimmunoassay for 17 cycles and an homologous ovine radioimmunoassay for 34 cycles. There was a progressive and significant increase in serum prolactin during the late follicular phase, with a maximal value concomitant to the LH peak. Serum prolactin levels were also significantly higher during the luteal phase than during early follicular phase. In some 70% of the individual cycles, the highest serum prolactin level was found at mid-cycle. Similar patterns were obtained with both radioimmunoassays. However, when using the same laboratory serum standard, the average serum prolactin level calculated for the entire cycle was 1.6 times higher with the homologous ovine assay than with the homologous human assay. The overall pattern of serum prolactin during the menstrual cycle resembles that reported for circulating 17beta-estradiol.

Sixty-eight mothers who did not want to breast-feed their babies were submitted to one of the following regimes: an intramuscular injection of estrogen (25 mg) within 1 h after delivery (n = 24) or the administration of bromocriptine for 15 or 23 days (n = 21 and 23, respectively). A careful clinical evaluation was performed every day by the same examiner during the first 7 days postpartum; blood samples were collected on days 0, 3 and 5 for human prolactin (hPRL) and estradiol, also in some cases on day 17; assays were measured by radioimmunoassay. An evaluation of the coagulation parameters was performed on day 5 in 9 estrogen-treated patients and in 25 bromocriptine-treated patients. Only 5 (11%) out of the 44 patients treated with bromocriptine experienced at least one undesirable effect of breast engorgement, in contrast to 16 (67%) out of the 24 estrogen-treated patients; this difference was statistically highly significant (P less than 0.001). Dizziness was a significant side-effect of bromocriptine treatment, occurring in 20% of the cases. In the patients in whom the administration of bromocriptine was withdrawn after 15 days, a significant mean rebound elevation of hPRL levels above the normal range occurred on the 17th day. The latter observation gives some support to earlier proposals to continue bromocriptine for up to a total 3 wk in order to avoid rebound lactation. There was no significant alteration of fibrinogen, Howell time, activated partial thromblastin time (APTT), prothrombin time (PT), thrombin time and coagulation time; mean plasminogen levels were comparable in both treated groups, while mean antithrombin III levels were increased in the bromocriptine-treated group. The significance of the latter finding requires further evaluation.

Eighteen hyperprolactinaemic patients were orally treated for up to 16 months with pergolide mesylate, a new potent long-lasting dopaminergic ergot derivative. In all cases, Prl normalization (less than 25 ng/ml) was achieved at a once-a-day dose of 50-300 micrograms. All women recovered and/or exhibited normal menstrual function. Among the 6 women wishing to become pregnant, 4 of them conceived within 4 months; there were other causes for infertility than hyperprolactinaemia in the 2 other couples. A macroprolactinoma man experienced important improvement in well-being as well as objective regression of his visual fields defect. This suggests a shrinkage effect of pergolide on the tumoural process. Another man regained normal potency and normal testosterone within 2 weeks. While 10 patients were completely free of any side effect, 7 experienced transiently mild gastro-intestinal side effects or postural hypotension. Only one patient discontinued her treatment because of dizziness. The present study demonstrates the high potency, the good tolerance and the excellent efficacy of pergolide in the treatment of hyperprolactinaemia.

LRH tests were performed in 6 adult men with intravenous injections of 25 mug, before and one week after an intramuscular injection of 250 mg testosterone oenanthate (Testoviron Depot). One week after intramuscular injection of Testoviron the tonic secretion of LH was completely suppressed, but the reactivity or the reserve capacity of LH secretion, as tested by LRH, remained unchanged. In contrast, the tonic secretion of FSH and the reactivity of FSH secretion to LRH were both partly suppressed. Three months after the Testoviron injection, the basal levels of LH were still significantly lower than the control values, but the basal levels of FSH were identical to the control values. These data indicate that, in man, the feedback action of testosterone on gonadotrophin secretion could be exerted, at least for LH, at the hypothalamic level rather than at the pituitary level . No significant effects of LRH were noted on the circulating levels of growth hormone and sugar. There was a distinct rise in serum prolactin, which was occasionally significant, within 30 min after LRH injection; this is considered to be without physiological significance.

The duration of the inhibition of Prl secretion by pergolide, a new dopaminergic ergoline, was investigated in 5 hyperprolactinaemic women after a single oral 50 micrograms dose. In each subject, blood samples were collected every 2 h for 18-24 h to establish baseline Prl level and then every 3 h for 48-51 h after pergolide administration. In each subject, levels were potently suppressed by at least 80% of baseline and brought down to the normal range. Prolactin suppression was quite sustained throughout the study period in 4 patients and to a lesser degree in the remaining subject. This potent long-lasting inhibition of Prl secretion should enhance the efficacy and acceptability of the chronic treatment of hyperprolactinaemia with this new dopamine agonist and, for example, allow drug intake only once every other day.

Six post-menopausal women were submitted, at 1 month interval, to oral oestriol treatment for 14-day periods at daily doses of 2 and 6 mg. Blood samples were collected for LH, FSH and PRL measurements (by RIA) every other day during treatments as well as during a 14-day control period. Through the effect on LH levels was questionable, oestriol resulted in a clear and significant, although moderate, gradual decrease of mean FSH levels. At the doses used, which are effective in thetreatment of menopausal symptoms, but are devoid of any proliferative effect upon the endometrium, oestriol failed to induce any stimulatory effect on basal PRL secretion in these post-menopausal women.

A study of the secretion of prolactin and plasma gonadotrophins was carried out comparatively in 3 groups of patients: histologically confirmed prolactin adenoma (group 1), idiopathic or iatrogenic amenorrhoea/galactorrhoea syndrome (group 2), empty sella turcica syndrome (group 3). The last group differs fundamentally from the two previous by the presence of a normal basal LH and FSH levels and normal LH-RH stimulation. Prolactin is not increased. It may be suppressed by L-dopa and stimulated by TRH. There exist no differences, apart from neuroradiological criteria, between the other two groups. The level of LH is slightly decreased but the response to LRH is positive, this effect often being more clear on FSH. Prolactin levels are raised, this no doubt explaining the negative response to TRH and chlorpromazine stimulation. Suppression by L-dopa is positiive, reflecting the absence of autonomy of prolactin adenomata. The water load test is unsatisfactory. There exists at the present time no method sufficiently discriminating to exclude the presence of a tumour at the origin of an amenorrhoea-galactorrhoea syndrome.

Plasma prolactin (PRL) levels were measured at 15-minute intervals for 24 hours in 18 men suffering from major endogenous depressive illness and in 7 age-matched healthy men. Eleven of the 18 depressed patients were restudied during clinical remission following either electroconvulsive therapy or treatment with amitriptyline hydrochloride. During the acute phase of the illness, the unipolar depressed patients had fragmented patterns of PRL secretion with an early timing of the nocturnal secretory phase of PRL, which started, on the average, 2 hours earlier than in healthy subjects. Moreover, the amplitude of the circadian variation of PRL was reduced in these patients, with subnormal PRL levels occurring during the midsleep period. This latter abnormality was also observed in bipolar patients, who had otherwise normal PRL profiles. These lower midsleep PRL concentrations were associated with a significant increase in the amount of time spent awake during the same period. Antidepressant treatment did not consistently correct the abnormalities in the patterns of PRL release observed during the acute phase of the illness. These results indicate that early timing of nocturnal PRL secretion and damping of the nighttime PRL elevation may be found in men with endogenous depressive disorders. In contrast to disturbances of the corticotropic and somatotropic axes, these abnormalities of PRL secretion may still be present during clinical remission following antidepressant treatment.

Four normally cycling women received an iv injection of 20 mg Premarin (conjugated estrogens equivalent to 20 mg estrone sulfate) on the seventh day of two consecutive cycles; the second experiment was performed under sulpiride-induced hyperprolactinemia (mean PRL level = 906 microU MRC standard 71/222 per ml; significantly 7.8 times greater than mean control level of 115 microU MRC standard 71/222 per ml, P less than 0.001). In comparison to the control experiment, sulpiride-induced hyperprolactinemia prevented the occurrence of any gonadotropin peak within the 84 h of estrogen administration; the negative feedback effect of estrogen on gonadotropin secretion was maintained and was even potentiated. These alterations of feedback mechanisms of estrogen were considered to be related to hyperprolactinemia itself rather than to sulpiride. Five other normally cycling women received iv injections of 100 microgram LRH on the 22nd day of a cycle under sulpiride-induced hyperprolactinemia since the onset of menstruation. Their mean LH response was somewhat greater (although not statistically significant) and their mean FSH response was considerably greater (P less than 0.001 at all times) than those of a control group of 10 women tested in their luteal phase. The results of these LRH tests under sulpiride-induced hyperprolactinemia give some support to the concept that hyperprolactinemia interferes at the hypothalamic or higher level with cyclic release of indogenous LRH.

Impaired LH response to LH-RH has been found in 2/4 cases of primary amenorrhoea, in 2/8 cases of psychogenic secondary amenorrhoea, in 2/4 cases of secondary amenorrhoea associated to a pituitary tumour and in 1/5 cases of iatrogenic secondary amenorrhoea post hormonal contraception. Therefore, this test appears not to differentiate these pathologic conditions.

Twenty patients with hypogonadism (19 women with amenorrhoea and 1 man with impotence and infertility), galactorrhoea and hyper-prolactinaemia (range: 36 to 344 ng/ml) were studied. The radiological study of the sella turcica, including in all cases hypocycloidal tomograms, allowed classification of the patients into 3 groups: group I (n = 4) had a grossly enlarged sella turcica, group II (n = 12) had localized alterations indicating the probable existence of a prolactin-secreting microadenoma ("microdeformation") while group III patients presented no radiological abnormality. Before treatment, all the patients were submitted to a complete evaluation of the function of their anterior pituitary, including the LH and FSH responses to iv administration of Gn-RH. All the group I patients had low basal LH levels and a blunted response to Gn-RH. The basal LH and in response to Gn-RH were normal in most of the group II patients and in all of the group III patients. An exaggerated FSH response to Gn-RH was observed in 6/12 patients with microdeformation (group II) but not in groups I and III patients. A low LH and a blunted LH response to Gn-RH is highly suggestive of the existence of a pituitary prolactin-secreting adenoma in case of amenorrhoea and hyper-prolactinaemia patients; a normal response does not however rule out such a diagnosis. The reasons for a exaggerated FSH response to Gn-RH in patients with suspected prolactin-secreting microadenoma remain to be investigated though this pattern can also occur in other cases of amenorrhoea. Hence the Gn-RH test might contribute to the assessment of the hypothalamo-pituitary axis of patients with hyper-prolactinaemia. Six patients treated for 4 months with bromocriptine (CB-154) were submitted to re-evaluation of their pituitary gonadotrophins reserve. All the women experienced restoration of menses with 39 days of treatment and the male patient regained potency. It was observed that bromocriptine treatment and subsequent normalized prolactin levels in the 4 group II women tested were associated with normalization of their previously exaggerated FSH response to Gn-RH; LH responses were also diminished in these cases. These data are compatible with the hypothesis that hyper-prolactinaemia per se could interfere with the endogenous secretion of Gn-RH at the hypothalamic level. In one patient with grossly enlarged sella turcica and a previous lack of an LH and FSH response to Gn-RH, bromocriptine treatment restored a normal gonadotrophins response, confirming that, in this case, the alteration of this response was indeed due to a prolonged lack of endogenous Gn-RH secretion.

Gonadotrophin secretion by the pituitary was tested by i.v. injections of synthetic LH and FSH releasing hormone (LHRH) in five normal women between day 21 and day 25 of the luteal phase of the cycle, in twelve women receiving contraception with i.m. injection of medroxyprogesterone acetate and in eight women taking combined oral contraceptives of different varieties. Treatment with oral contraceptives led to a decrease or even to complete suppression of the response and possibly the reserve capacity of both LH and FSH secretions. Treatment with medroxyprogesterone acetate for several years lowered basal serum LH and FSH as did oral contraceptives but had much less effect on the responses to LRH. In long-term steroid contraception, progestogens alone seem to exert much less deleterious effect on gonadotrophin function than when used in combination with an oestrogen.

In order to investigate the effect of cyproheptadine, a compound with antiserotoninergic activity, on the secretion of thyrotrophin (TSH) and prolactin (PRL), the nocturnal secretory patterns of these hormones have been studied in 4 normal men in the basal state and after an oral treatment with the drug. In addition, the TSH and PRL responses to TRH of 6 women were compared in the basal conditions and after cyproheptadine treatment. The TSH nocturnal secretion was slightly modified by drug treatment. The response to TRH as well as the basal levels were comparable in the treated and non-treated subjects. In contrast, the PRL secretion measured through the nocturnal investigation was significantly inhibited by cyproheptadine administration as were the PRL basal levels in the TRH test. The PRL response to TRH was comparable in both situations.

A double-blind clinical study was conducted to compare the therapeutic activity of veralipride and placebo in menopausal sudden flushes. Comparison of final numerical rate showed a statistical significant superiority for veralipride. Tolerance was excellent and no significant difference was observed between clinical side effects, or biological parameters studied (blood counts and differential, and blood bilirubin, transaminases, glucose, cholesterol, or creatinine levels) in the two groups.

Normal men and normally menstruating women received i.m. injections of 0.1 to 4.0 mg/kg sulpiride. This psychotropic drug induced a very rapid (already significant after 5 minutes) and sustained (still significant after 7 hours) elevation of prolactin (PRL) concentrations in all subjects with no consistent modification of LH and FSH. After injection of 4.0 mg/kg, there was similarly no modification of mean TSH concentrations in the women tested in the luteal phase, as well as of mean GH levels in men. Sulpiride prevented the inhibitory effect on PRL levels of 500 mg levodopa, administered orally simultaneously; levodopa administered 2 hours prior to sulpiride failed to counteract the PRL-stimulatory effect of sulpiride. Under chronic sulpiride-induced hyperprolactinaemia, levodopa exhibited however a very slight inhibitory effect on PRL concentrations. These data are in agreement with the hypothesis that sulpiride acts mainly at the pituitary level by blocking dopamine receptors of the lactotropes and support the concept that the menstrual cycle perturbations observed under chronic sulpiride administration result from hyperprolactinaemia itself or from a mechanism quite similar to that by which sulpiride induces hyperprolactinaemia.

Chronic hyperprolactinaemia was induced in 10 women since the onset of a cycle for 2 or 3 consecutive cycles by administration of sulpiride (3 X 50 mg/day) or tiapride (100-200 mg/day). The resulting perturbations of the menstrual cycle included short luteal phase cycles, anovulatory cycles and amenorrhoea. The analysis of the hormonal profiles under treatment, as compared to the control cycles, indicate an impact of hyperprolactinaemia both preferentially at the hypothalamic (alteration of the secretion or endogenous LRH) and accessorily at the ovarian (lack of progesterone secretion by the near mature follicle) levels.

Orchidectomy in postpubertal 55 day old rats, compared to sham-operated controls, led beyond 2 months to a decrease in body weight (87% of controls by 120 d), tibial length (97% of controls) and in tibial calcium content (85% of controls). Bone plasma flow increased three times to reach a peak at 31 days; it was decreased but no significantly at 86 and 120 days. The number of osteoclasts was maximal at 51 days (X 2.3) and was still elevated at 120 days. The calcium accretion rate increased briefly at 31 days (110% of controls) and was diminished at 86 and 120 days (78% of controls). The initial 'physiological' changes in the tibia occurred before any weight change and might be directly due to the lack of androgens. They can be interpreted as inducing the conditions for enhanced bone resorption. Testosterone replacement therapy, initiated after the initial haemodynamic response, inhibited the negative effect of castration on bone growth.