Hormonal replacement therapy (HRT) in postmenopause: a reappraisal.

Hormone replacement therapy (HRT) is the most effective treatment currently available for vasomotor and urogenital symptoms and decreased libido. Because harmful effects were evidenced in some clinical trials, health authorities now consider that risk-benefit considerations do not favour the use of HRT for prevention of cardiovascular diseases and bone fractures in postmenopausal women. However, experimental and clinical studies indicate that adverse effects of HRT may largely depend on the estrogen and progesterone/progestin formulation, dosage, mode of administration, patient's age, associated diseases, and duration of treatment. All estrogen formulations and modes of administration have similar beneficial effects on vasomotor and urogenital symptoms and on bone structure. But cardiovascular and invasive breast cancer risks are higher with oral estrogen than with transdermal estradiol, and also higher with many progestin compounds than with micronized progesterone. The combination of transdermal estradiol+micronized progesterone appears to be effective and relatively safe if elementary precautions are taken, and seems to be presently the best choice for HRT in most postmenopausal women. In the author's--heterodox--opinion, HRT may also be a good therapeutic choice to prevent bone loss, since alternative medications, including raloxifene and bisphosphonates, may have dramatic harmful effects in some patients. It might also have beneficial effects on the development of coronary disease in young postmenopausal women. HRT requires careful adjustment to each individual patient and continuous monitoring of clinical evolution. In the future, this adjustment could benefit from genetic screening to maximize in each individual the ratio between positive and adverse effects.

Prolactin secretion in Cushing's disease.

PRL secretion was evaluated in 11 patients with Cushing's disease (7 women, 4 men). Basal morning levels were elevated when compared to normal subjects. PRL reactivity to TRH and hypoglycemia was normal in most patients. The 24-h mean PRL levels were elevated, with partial or total alteration of the nyctohemeral rhythm. Cure of Cushing's disease by selective pituitary adenomectomy restored a normal PRL secretion.

A quantitative estimation of growth hormone secretion in normal man: reproducibility and relation to sleep and time of day.

Recent reports, based on measurements of plasma GH levels, have challenged the concept that GH secretion is dependent on sleep and not modulated by circadian rythmicity. Because plasma levels reflect not only the secretory process, but also the effects of distribution and degradation, temporal limits of active secretion and, consequently, synchrony with other physiological events cannot be accurately estimated from circulating concentrations. The present study was undertaken to examine the roles of sleep and time of day in modulating pulsatile GH secretion, using a mathematical procedure (deconvolution) allowing secretory rates to be estimated from peripheral levels. Eight young nonobese healthy men participated each in six separate 16-h studies involving either normal or delayed sleep. Plasma GH levels were measured at 15-min intervals, and GH secretory rates were calculated by deconvolution. Each individual study was preceded by one night of habituation, and sleep was polygraphically recorded in all studies. Repeated measurements of plasma insulin-like growth factor-I (IGF-I) were performed in all subjects. Deconvolution revealed the existence of approximately 20% more GH pulses than detected in the plasma profiles. Large peaks of plasma GH concentrations often reflected the occurrence of a succession of secretory pulses. The total amount of GH secreted varied 10-fold across individual studies, but the within-subject variability (32%) was less than half the across-subject variability (65%). IGF-I levels were also more reproducible for a given subject than across subjects (11% vs. 36% variability) and did not correlate with the amount of GH secreted. During normal waking hours, the GH secretory rate was similar in the evening and the morning. This secretory rate was doubled during wakefulness at times of habitual sleep and tripled during sleep, even when sleep was delayed until 0400 h. A pulse starting within 30 min after sleep onset was present in all profiles with normal sleep and in 13 of 16 profiles with delayed sleep. The amount of GH secreted in response to sleep onset was tightly correlated with the level of secretion during wakefulness (r = 0.92). Almost 70% (57 of 83) of the pulses occurring during sleep were associated with slow wave (SW) stages. The amount of GH secreted in SW-associated pulses was correlated with the amount of SW occurring during the pulse, even when sleep-onset pulses were not considered. We conclude that in normal adult men, the amount of GH secretion and the levels of IGF-I are more reproducible within than across individuals.(ABSTRACT TRUNCATED AT 400 WORDS)

Sleep, awakenings, and insulin-like growth factor-I modulate the growth hormone (GH) secretory response to GH-releasing hormone.

To delineate possible factors influencing the magnitude of the GH response to GH-releasing hormone (GHRH), eight young healthy men participated in seven 16-h studies involving saline infusions or injections of 0.3 micrograms/kg GHRH at various times of day and stages of sleep. GH responses were quantified by deconvolution, a procedure allowing for secretory rates to be estimated from peripheral levels. While the plasma responses were monophasic, deconvolution revealed that the secretory response to GHRH generally included several distinct bursts in rapid succession. The intersubject variability of GH responses was very wide, but for a given subject, the response was quite reproducible (mean +/- SEM coefficient of variation, 21 +/- 3%). When GHRH was given during the waking period, the magnitude of the response was directly related to the amount of spontaneous GH secretion, negatively correlated with circulating levels of insulin-like growth factor-I (IGF-I) and was not influenced by time of day. When GHRH was given during slow wave sleep, the magnitude of the response was enhanced. When GHRH was given during rapid eye movement sleep, the response was similar to that observed during wake. Awakenings during sleep consistently inhibited the secretory response to GHRH, and resumption of sleep was associated with a reappearance of the secretory process. Thus, in normal men of similar age and body weight, the GH response to GHRH is dependent on the sleep or wake condition, circulating levels of IGF-I, and, possibly, genetic and lifestyle factors.

Effects of a 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men.

To assess the effects of prolonged administration of a novel analog of GH-releasing peptide (MK-677), nine healthy young men participated in a randomized, double blind, three-period cross-over comparison of orally administered placebo and 5- and 25-mg doses of MK-677. Each period involved bedtime administration of the drug for 7 consecutive days. At the end of each period, plasma levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were measured at 0745 h, and 24-h profiles of plasma GH and cortisol were obtained at 15-min intervals together with the 24-h urinary excretion of free cortisol. Profiles of plasma free cortisol were calculated at hourly intervals. The amounts of GH secreted were similar in all three conditions, but GH pulse frequency was increased with both dosages of the drug, primarily because of an increase in the number of low amplitude pulses. Plasma IGF-I levels were increased in a dose-dependent manner, whereas IGFBP-3 levels were increased only with the highest dosage. There was a positive relationship between GH pulse frequency and IGF-I increase. Except for an advance in the nocturnal nadir and in the morning elevation, MK-677 had no effect on cortisol profiles. In particular, 24-h mean levels of plasma total and free cortisol and urinary excretion of free cortisol were similar under all conditions. The present data suggest that the use of MK-677 for the treatment of relative somatotropic deficiency, particularly in older adults compromised by such deficiency, deserves further investigation.

Effects of bedtime administration of zolpidem on circadian and sleep-related hormonal profiles in normal women.

Short-acting benzodiazepine hypnotics may phase-shift circadian rhythms and improve adaptation of sleep patterns to abrupt time shifts, depending on the timing of administration. The aim of the present study was to determine whether bedtime administration of zolpidem, a non-benzodiazepine hypnotic, causes alterations in circadian rhythmicity or in the normal interactions between sleep and hormones. Eight normal women (aged 21-33 years) each participated in a baseline study and a study with zolpidem administration. On each occasion, blood samples were obtained at 20-minute intervals for 25 hours, starting at 1000 hours. Zolpidem (10 mg) was given orally at 2245 hours. Zolpidem administration was associated with an increase in stages III + IV sleep. Cortisol, melatonin, thyrotropin and growth hormone profiles were similar in both experimental conditions. In contrast, though remaining in the normal range, the nocturnal elevation of prolactin was enhanced two-fold in all subjects after zolpidem during early sleep, and prolactin levels were still 50% higher than baseline in late sleep. Morning levels were similar in both studies. In conclusion, bedtime administration of 10 mg zolpidem, a standard clinical dosage, systematically induces a transient moderate hyperprolactinemia, but does not alter other sleep-related hormonal secretions or endocrine markers of circadian rhythmicity.

Effects of the short-acting benzodiazepine triazolam, taken at bedtime, on circadian and sleep-related hormonal profiles in normal men.

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.

Serum levels of gonadotrophins and steroid hormones in the post-menopause and later life.

Changes in the serum levels of gonadotrophins and steroid hormones with increasing age were studied in 449 women aged 40 and over to investigate the relationships between these hormones even very late in life. The levels of oestradiol (E2) and dehydroepiandrosterone sulphate (DHEA-S) fell after age 50 and remained low thereafter. However, while serum oestrone (E1), testosterone (T), delta-4-androstenedione (A) and prolactin (PRL) concentrations also decreased initially after age 50 they subsequently rose again progressively and this increase was in fact significant in the case of E1. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) rose after age 50, but whereas FSH remained elevated, LH decreased late in life. Cortisol (F) increased significantly after age 70. There was a significant correlation between androgens and E1 as well as between E2 and LH, even after age 60. Owing to the great heterogeneity of the population studied, it is not yet possible to speculate as to the physiopathological significance of these observations. It would seem, however, that the negative feedback effect of oestrogens on LH secretion remains operational very late in life.

Choice of parameter for expressing bone mineralization.

In this cross-sectional study, the relative importance of anthropometric factors and that of biological parameters on bone mineralization were evaluated and their practical implications inferred on the choice of the parameter to be used for the estimation of bone mineralization. A close relationship between anthropometric factors and bone mineral content (BMC) was observed and this relationship was shown to be independent of age. Furthermore, by regression analyses, anthropometric parameters appeared to explain a large part of the variance in BMC and preceded the hormonal parameters in the stepwise analysis of this model. Using bone mineral density (BMD) data, however, we observed a weaker relationship between anthropometric factors and bone mineralization and a relatively stronger relationship between steroid hormones and bone mineralization than those observed using the BMC data. Furthermore, by multiple regression analysis the hormonal factors preceded the anthropometric parameters in the stepwise analysis of the model. As strong epidemiological and clinical evidence exists on the relationship between steroid hormones and bone loss, these results constitute a supplementary argument for the use of BMD for the estimation of bone mineralization.

The pubertal spurt: effects of sex steroids on growth hormone and insulin-like growth factor I.

In puberty, the growth spurt and the appearance of secondary sex characteristics occur concomitantly with an increase of sex steroids, growth hormone (GH) and insulin-like growth factor I (IGF-I). A number of experiments indicate that sex steroids exert a stimulatory action on the somatotropic axis. This effect is due to an amplifying action of oestradiol (secreted by the ovaries or after testosterone aromatization) on the neuroendocrine regulation of pulsatile GH release.

Amenorrhoea, sterility and hyperprolactinaemia. Importance of complex movement tomographic x-ray study and follow-up of the sella turcica.

In a 24 y.o. woman complaining of primary amenorrhoea and infertility, hyperprolactinaemia and clearly enlarged sella turcica on standard x-rays in 1975 led to the diagnosis of a pituitary prolactin-producing adenoma, later confirmed surgically. Galactorrhoea never occurred spontaneously and could not be provoked at physical examination. In the course of a previous investigation in 1967, the standard x-ray of the sella turcica, although showing already a minor duplication of the anterior wall of the sella, had been misinterpreted as being normal. It is clear from the present observation that repeated, for example at yearly intervals, radiological examinations and prolactin determinations (not available before 1971) would allow an early diagnosis. It is furthermore stressed that a tomographic radiological examination using complex movement (spiral or hypocycloidal) should be mandatory in any case of amenorrhoea with hyperprolactinaemia in order to assess or not the possible existence of a prolactin-producing pituitary adenoma. Indeed, dynamic studies of anterior pituitary secretions cannot allow a differential diagnosis between tumoural and functional hyperprolactinaemia.

[Clinical evolution of LH-RH reactivity in gynecology (author's transl)]. / Evaluation clinique du test au LH-RH en gynécologie

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.

PIP: Responses to luteinizing hormone-releasing hormone (LH-RH) 100 mcg iv in 25 women with 5 different gynecologic disorders and in 12 controls aged 18-28 in the luteal phase were compared. Impaired LH release occurred in 2 of 4 women with primary amenorrhea, in 3 of 8 women with psychogenic amenorrhea, in 1 of 5 women with iatrogenic amenorrhea afterstopping oral contraceptives, in 2 of 4 women with pituitary tumors, and in none of 4 women with isolated galactorrhea. The results did not permit differential diagnosis of these disorders, with the exception of those with intact hypothalmus-pituitary function.

Menstrual disorders in adolescence: pathophysiology and treatment.

Menstrual problems including amenorrhea, oligomenorrhea, irregular cycles, abnormal uterine bleeding or dysmenorrhea represent 50% of adolescents' gynecologic complaints. Irregular and anovulatory cycles are common during the first postmenarcheal years and may reflect a normal transient step of ovarian hyperandrogenism, but they may also result from hormonal abnormalities affecting the adrenals, the ovaries or the pituitary. Amenorrhea may be a sign of late puberty or of a problem affecting the hypothalamus, the pituitary or the ovaries. Evaluation includes a complete physical examination, basal hormonal determinations of the hypothalamic-pituitary-ovarian function, of the thyroid, of the androgens and of the nutritional and growth parameters. This first evaluation must be completed by a karyotype analysis in case of primary amenorrhea or by the measurements of free testosterone, androstanediol glucuronide and testosterone glucuronide in case of hirsutism, and may be followed by X-rays, echography or dynamic tests depending on the first results. Therapy will always be directed towards the etiology of the disease. Abnormal uterine bleeding is generally the result of anovulatory cycles and responds to hormonal therapy, but a systemic illness, a local pathology or a complicated pregnancy must always be excluded. In case of dysmenorrhea, endometriosis must be excluded. Simple dysmenorrhea is generally suppressed by antiprostaglandins.

Menstrual disorders associated with hyperprolactinemia.

In hyperprolactinemia, menstrual disorders ranging from irregular bleeding, insufficient luteal phase, spanio-amenorrhea, to anovulatory cycles and amenorrhea, are frequent. Multiple mechanisms are involved in these disorders: hyperprolactinemia could act at the hypothalamic level on LHRH secretion and directly on LH and sex steroids secretion. Hyperprolactinemia could also act by impairing fertilization or implantation at the endometrial level.

Male pseudohermaphroditism due to 17-ketoreductase deficiency: report of a case without gynecomastia and without vaginal pouch.

A black adult subject, exhibiting complete virilization at puberty with psychological female orientation, was investigated. An older sister had similar physical habitus. Hormonal data showed an androstenedione/testosterone ratio greater than 1. This led us to the diagnosis of 17-ketoreductase deficiency, with possible genetic transmission of the defect.

Somatomedins and steroids.

Somatomedin levels measured by radioreceptor assay, competitive protein-binding assay or radioimmunoassay are normal in hypercortisolism; the decrease of somatomedin activity consistently found in this condition is due to an increase in circulating somatomedin inhibitors resulting in an inhibition of somatomedin action. Progestagens could possibly have a direct stimulatory effect on somatomedin-C (Sm-C) production. During puberty, the increase of Sm-C is correlated with the increase in plasma estradiol and testosterone. In young subjects, relatively low doses of estrogens and of testosterone enhance Sm-C secretion, and in adult menstruating women, a positive relationship is found between testosterone and Sm-C values. An inhibitory effect of estrogens on Sm-C is observed with higher doses and/or in older subjects. Thus, somatomedin levels might be modulated by variations of sex steroids.

Regulation of maternal IGF-I by placental GH in normal and abnormal human pregnancies.

Throughout gestation, maternal insulin-like growth factor I (IGF-I) increases progressively despite suppressed pituitary growth hormone (GH) secretion. We have previously shown that in normal pregnancy, a specific placental GH variant, rather than human placental lactogen (hPL), substitutes for pituitary GH in the regulation of maternal IGF-I. We studied the maternal IGF-I secretion in a cohort of 286 normal and abnormal pregnancies (617 blood samples). Regardless of pathology and gestational age, IGF-I values correlated with corresponding placental GH but not with hPL values. Similar correlations were evidenced for each 2-wk gestational period between 32 and 39 wk. In pathological pregnancies, when only those hormonal results that are obtained before any treatment are considered and diabetes is excluded, IGF-I levels were closely related to corresponding placental GH, but not to hPL. In women with a fetoplacental unit disorder, low placental GH levels resulted in low IGF-I and in a secondary pituitary GH increase, whereas in patients without detectable impairment of the fetoplacental unit normal placental GH corresponded to normal IGF-I. These results suggest that in pathological as well as in normal pregnancy, placental GH, and not hPL, substitutes for pituitary GH to regulate the maternal IGF-I secretion.

Insulin-like growth factor I values in patients on maintenance hemodialysis: relationship to growth hormone and albumin levels.

Twenty-seven uremic patients (blood urea: 58.2 +/- 2.2 mmol/l; blood creatinine: 1,069 +/- 53 mumol/l; mean +/- SE) on maintenance dialysis were investigated immediately before and after a dialysis session. Control data were obtained from 30 normal volunteers. Before dialysis, circulating levels of insulin-like growth factor I (IGF-I) were similar in anuric and nonanuric patients, averaging 305 +/- 24 micrograms/l, a value not different from that observed in normal controls (262 +/- 16 micrograms/l). IGF-I levels were not modified by dialysis. In contrast, GH values were significantly higher in uremic patients (3.6 +/- 0.6 microgram/l) than in normal controls (2.5 +/- 0.5 microgram/l) and decreased significantly after the dialysis session (0.8 +/- 0.1 microgram/l). IGF-I values were positively correlated with GH and albumin, but not with the various parameters of renal insufficiency, suggesting that in chronic renal failure, synthesis of IGF-I appears to be regulated, as in normal subjects, by growth hormone and nutritional status.