The pituitary-testicular axis in microgravity: analogies with the aging male syndrome.

Extraterrestrial exploration has gone on for decades before reversible testicular failure was shown to be a consequence of space flight in humans and animals at the end of the XXth century. This phenomenon was initially thought to depend on the psycho-physical stress expected to derive from a decidedly unusual environment, but the lack of consistent data concerning cortisol increase and/or gonadotrophin suppression pointed to the possibility of a primary defect. This was indirectly confirmed by the observation that a continuum of testicular androgen secretion potential exists from microgravity to centrifuge-derived hypergravity. Further experiments using tissue slices and suspended cells confirmed a direct inhibitory effect of microgravity upon testicular androgen production. A parallel deterioration of major physiological parameters, such as bone density, muscle mass/force, red blood cell mass, hydration and cardiopulmonary performance, has been repeatedly described during space missions, which, luckily enough, fully recover within days to weeks after landing, the time lag depending on single organ/system adaptation rates. According to the Authors of the present review, when taking together all reported changes occurring in space, a picture emerges closely resembling the so-called aging male syndrome, which is currently the object of daily screening and clinical care in their endocrine unit, so that microgravity may become a tool for better understanding subtle mechanisms of testicular senescence.

Leptin and aging: correlation with endocrine changes in male and female healthy adult populations of different body weights.

Aging is associated with changes in plasma levels of several hormones. There are conflicting reports on whether circulating leptin levels change during aging, the possible explanation for which is that alterations in adiposity and body mass index (BMI) also occur. In this study we measured plasma leptin and other hormonal parameters known to influence leptin in 150 men and 320 women of a wide age (18-77 yr) and BMI (18.5-61.1 kg/m2) range. Subjects of each gender were separated into 2 groups of similar BMI, i.e. nonobese (BMI, <30) and obese (BMI, >30), and treated separately. Statistical analysis was performed, treating each group of subjects as a whole population or divided into age groups (<30, 30-50, and >50 yr). BMI-adjusted leptin levels were progressively lower with increasing age in women, with a consistent fall after menopause (-21%; P < 0.001); in men, leptin levels also tended to be lower in subjects more than 50 yr of age, but the reduction was not significant. Multiple linear regression analysis, performed on subjects treated either as a whole population or divided into obese and nonobese, showed that in both genders BMI and age were independent contributors of leptin levels, and there was an inverse relationship between leptin and age in both obese (standardized coefficient beta = -0.25 in women and -0.23 in men; P < 0.01) and nonobese (-0.22 in women and -0.20 in men; P < 0.05) subjects. The correlation of leptin and age with plasma levels of sex and thyroid hormones, GH, insulin-like growth factor I, PRL, and insulin was also evaluated. The variables that correlated with leptin were included in a multiple regression model that included BMI and age. Testosterone in men (-0.43 in nonobese and -0.19 in obese; P < 0.05) and estradiol in women (0.22 in nonobese and 0.24 in obese; P < 0.05) were important contributors to leptin levels; also, dehydroepiandrosterone sulfate in obese women (-0.16) and sex hormone-binding globulin in obese subjects of both genders (0.15 in women and 0.19 in men) were significant determinants in the model. However, none of the hormonal parameters abolished the negative correlation between leptin and age or the gender difference in leptin levels. In conclusion, our data show that in adult humans of different body weight, serum leptin gradually declines during aging; leptin reduction is higher in women than in men, but it is independent from BMI and other age-related endocrine changes.

Gender affects the pattern of neuroendocrine response to head-up tilt.

One of the major concerns in space medicine is post-mission postural hypotension. Since the beginning, most of the studies have been aimed at the identification of mechanical and neuroautonomic mechanisms within the cardiovascular system potentially involved in this phenomenon. Some gender differences in the cardiovascular reactivity to changing posture have been described so far, which still need better clarification. Moreover, the neuroendocrine contribution to postflight readaptation deserves more indepth studies. Sudden passive head-up tilting is considered to be a good simulation method for hemodynamic changes occurring during transition from 0xg to 1xg. The aim of this study was to verify whether cardiovascular or neuroendocrine changes occurring after sudden passive +70 degrees head-up tilt (HUT) became already evident within 10 min and were similar in healthy young-adult men and women.

Indirect evidence of CNS adrenergic pathways activation during spaceflight.

BACKGROUND: Microgravity causes cephalad fluid shift and compensatory mechanisms. Hormonal changes suggestive of peripheral sympathetic (catecholaminergic) nervous system activation have been recently found in astronauts during flight. Simulation studies showed increased perivascular sympathetic fiber density in the rat brain. HYPOTHESIS: Intracranial microcirculatory adaptations might also occur in astronauts, involving an increase in the turnover rate of catecholamines, i.e., norepinephrine (NE) and its precursor, Dopamine (DA). DA is known to inhibit prolactin (PRL) release and to enhance growth hormone (GH) secretion by the pituitary. Therefore, increased brain dopaminergic activity would result into lower circulating PRL concentrations. At the same time, plasma levels of GH and of its effector insulin-like growth factor-1 (IGF-1) would increase during flight. METHODS: Circulating cortisol (CS), PRL, GH and IGF-1 levels were measured 2 d preflight, inflight (4-5 d after launch) and on different days postflight in four astronauts involved in the Spacelab D-2 mission. RESULTS: No significant changes were found in CS concentrations. PRL decreased while GH and IGF-1 increased inflight (p < 0.05). After flight no statistically relevant hormonal changes were found with respect to preflight. CONCLUSION: The observed hormonal changes were consistent with the original hypothesis that spaceflight might activate CNS adrenergic pathways. They occurred in the absence of two typical markers of stress, namely CS and PRL increase, thus ruling out any non-specific effect of acute stress on the results. In agreement with the most recent results of real and simulated microgravity studies performed in both the experimental animal and in man, these data lend support to the hypothesis that the CNS adrenergic pathways are also activated in the human during spaceflight.

The effect of microgravity on testicular androgen secretion.

BACKGROUND: Spaceflight causes a number of physiological changes in the human body. Most would consider space travel to be a stressful event even for well-trained astronauts. Should this be true, pituitary gonadotrophins (mainly LH) and testicular androgens, like testosterone (T), should decrease inflight in male astronauts. We therefore hypothesized that lowered testicular androgen levels might occur in men during spaceflight, due to stress-dependent lowered LH concentrations. METHODS: In order to test this hypothesis, on different day pre-, in- and postflight we assayed wake-time salivary and urinary T in four astronauts, as well as wake-time plasma levels of adrenocorticotropin (ACTH), cortisol (CS), LH, T and its peripherally active metabolite 3-alpha-diol glucuronide (3ADG). In order to compare clinical to subjective data, all 7 male crewmembers anonymously answered a daily questionnaire from pre- to postflight asking them to self-rate sexual drive and potency, muscle strength and mood. RESULTS: Salivary, urinary and plasma T, as well as 3ADG, decreased during flight, while LH unexpectedly increased inflight (p < 0.05). A parallel decrease in sexual drive was observed (p < 0.05). A dramatic recovery of salivary T was found on R + 1. CONCLUSIONS: This was the first time that spaceflight was demonstrated to cause temporary, still dramatic hypoandrogenism which was not due to blunted pituitary gonadotrophin secretion. The cause for hypoandrogenism is unknown but it may depend on fluid shift affecting testicular function or androgen distribution in various body compartments.

Changes in human adrenal and gonadal function onboard Spacelab.

Astronauts have to face chronic stress during the mission period. This might cause: (i) increased adrenocortico-trophin (ACTH) and cortisol (Cort) secretion; (ii) impaired luteinizing hormone (LH) output with consequent testosterone (T) hyposecretion in men. Moreover, should the subjects prove not to synchronize their inner clocks to the time shift protocols defined by NASA, most results would be questionable. The aim of this study was to verify if plasma testicular androgens were lower than baseline and Cort biorhythm was preserved in male astronauts during a short duration flight.

[Nonpalpable lesions of breast carcinoma in elderly patients]. / Lesioni non-palpabili da carcinoma mammario nelle pazienti anziane.

Breast cancer is the most frequent form of tumour in women. The only weapon at our disposal to reduce the mortality rate for breast cancer is early diagnosis. A number of studies have shown, using appropriate prevention programmes, an increasing number of minimum 20-30% lesions. The probability that a non-palpable lesion is malignant increases with age, with a positivity of 37-39% is women aged over 50. Localisation using FNAB requires studies with greater statistical value so that it can be inserted in current prevention programmes, given that the percentage of false negative is > 8%. At present, excisional biopsy with bioptic tests continues to be the standard reference method for the diagnosis of non-palpable lesions; this diagnostic procedure allows the lesion to be removed in positive cases, and avoids re-operating as in the case of suspected or inadequate cytological tests.

[Cancer in the elderly. Clinico-epidemiologic considerations]. / Il cancro negli anziani. Considerazioni clinico-epidemiologiche.

The elderly population is rapidly increasing in Western countries. Old age indirectly represents one of the most important risk factors for the development of neoplasias. In Italy in 1991 a total of 14,572 deaths from tumours were recorded, equivalent to 27% of all deaths; of these over 66% affected individuals aged over 65 years old. In the 65-74 age bracket mortality caused by tumour is the prime cause of death in Italy and is undergoing an exponential increase over time. The most frequently found tumours and above all the cause of the greatest number of deaths in the elderly population are lung cancer, prostate cancer, breast cancer, colorectal cancer, stomach cancer. To date the only weapon that has proved efficacious in some tumours (breast, colon-rectal, prostate, melanoma) is early diagnosis through screening and adequate treatment. The elderly are an extremely heterogeneous population and it is therefore not easy to provide guidelines that are applicable to the entire population. Firstly, it is important to provide more information in order to permit effective and targeted prevention. In order to fulfil this objective, structures offering the necessary equipment and skills will have to be create; training must be provided for personnel in this type of preventive medicine; lastly, the awareness of doctors towards this type of medicine must be increased by providing the correct information.

[Clinico-epidemiological findings in breast carcinoma in elderly patients]. / Rilievi clinico-epidemiologici del carcinoma mammario nelle pazienti anziane.

Old age certainly represents one of the major risk factors for the development of neoplasia. In breast cancer the incidence rises with age and continues until the age of 84. In EEC countries approximately 140,000 new cases are reported every year and at the end of the 80s there were 10,983 deaths from breast cancer in Italy, an increase of over per 1000 women each year. Fifty par cent of new cases were diagnosed in women aged over 65. The efficiency of a screening programme is evaluated by the fall in mortality rates in the population included in the programme compared to that not included. Results from controlled studies have confirmed the efficacy of breast cancer screening in women aged between 50-70, showing a significant drop in mortality rates which range between 21 and 36%. Adequate diagnostic and therapeutic management are of primary importance and screening programmes are organised in highly efficient structures using specifically trained staff. This underlines the need to set up appropriate services and structures for the prevention and treatment of breast cancer in elderly women, given that the latter represent the most frequently affected age group. Old age should be considered a natural extension of life and all elderly women have the right to receive treatment to prevent breast cancer.

Thyrotropin-releasing hormone enhances event-related brain potentials and growth hormone release in man.

Changes in contingent negative variation (CNV), a brain-evoked potential related in arousal, as well as in serum triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), prolactin (PRL), cortisol and growth hormone (GH) levels were recorded in 12 male volunteers receiving either thyrotropin-releasing hormone (TRH) or saline infusion. Only during TRH administration an increase in CNV (P less than 0.02) and, 30 min later, in GH (P less than 0.05) occurred; thyroid hormones and PRL increased as well, in the absence of any correlation with CNV areas. Cortisol was not affected by TRH. As dopamine (DA) agonistic drugs notoriously increase both CNV areas and GH levels and experimental evidence for prodopaminergic properties of TRH has accumulated in animal models, a possible explanation of the results here presented might be the activation of DA pathways by TRH also in the human.

[Effect of acute intravenous administration of thyroliberin on circulating reverse-T3]. / Effetto del carico endovenoso acuto di tiroliberina (TRH) sulla reverse-T3 (rT3) circolante.

Some of the Authors previously demonstrated a significant precocious serum T3 increase after 200 micrograms TRH acute intravenous administration (TRH test). Reverse-T3 (rT3) is now known to interfere with T4 conversion to T3. We therefore compared spontaneously occurring to TRH test-induced changes in T3 and rT3 serum levels within a group of four healthy women in fertile age. Maximum rT3 increase during TRH test did not differ significantly from the maximum spontaneous variation at the same time of the day. Maximum T3 increase, on the contrary, was significantly higher than observed maximum spontaneous variation (0,81 ng/ml versus 0,39 ng/ml increase, p less than 0,01). Possible implications are discussed in the text.

[Comparison between spontaneous changes in circulating triiodothyronine (T3 and reverse-T3) and those induced by acute intravenous administration of thyroliberin]. / Confronto tra le variazioni spontanee delle triiodotironine circolanti (T3 e rT3) e quelle indotte da carico endovenoso acuto di tiroliberina (TRH).

Some of the Authors had previously observed a slight-non significant decrease in T3 serum levels 10 minutes after TRH intravenous administration. On the other hand, it is now well known that reverse T3 (rT3) inhibits T4 conversion to T3. We therefore investigated the changes in T3 and rT3 serum levels within the first ten minutes of a 200 micrograms TRH test in a group of 10 healthy women in fertile age. No significant change in T3 was demonstrated. On the other hand, rT3 showed a significant-yet slight-decrease 6 minutes after TRH injection (from 0,27 to 0,21 ng/ml, p less than 0,05). Some feasible explanations for this phenomenon are given in the text.

[Preliminary observations on the existing relationship between plasma levels of prolactin and hypophyseal reserves of FSH and LH in the male]. / Osservazioni preliminari sui rapporti esistenti tra livelli plasmatici di prolattina e riserva ipofisaria di FSH ed LH nei maschi.

PRL plasma levels and FSH and LH pituitary reserve were tested in ten apparently healthy male subjects. A good correlation was found between PRL on one hand and FSH plasma levels (p less than 0,05), LH plasma levels (p less than 0,01) and FSH pituitary reserve (p less than 0,01) on the other hand. This seems to support the current hypothesis that prolactin may cause a progressive clinically latent impairment in the spermatogenetic function of the testis. Further evidence is needed.

[Behavior of triiodothyronine, tetraiodothyronine and thyrotropin during the TRH test]. / Comportamento della triiodotironina, della tetraiodotironina e della tireotropina in corso di TRH test.

Much confusion seems to exist on the timing and intensity of thyroid hormones (T4 and T3) response to TRH. As a first approach to the problem, the Authors performed TRH test in 5 healthy women. TSH showed a significant increase immediately after the TRH injection and kept high until the 90th minute. T3 decreased at first-still not significantly--then increased steadily and at 60 min it reached values significantly higher than the basal ones. Some increase was seen for T4 too, but it did not show to be statistically significant within 180 minutes. The Authors give revelance to the significance of precious (60 min) T3 increase in such a small casuistry.

[Relationship between benign breast cancer and plasma levels of prolactin]. / Rapporto tra mastopatia benigna e livelli plasmatici di prolattina.

Prolactin (PRL) plasma levels were measured in the follicular phase of the cycle in 75 normally menstruating women divided into three groups: group I was normal (n. = 39), group II showed benign breast disease (n. = 26), group III hyperandrogenism (n. = 10). PRL levels were higher (670,8 +/- 61,2 microunits/ml) in the second group than in the first (216,0 +/- 12,0 microunits/ml; p less than 0,001) and in the third group (426,0 +/- 75,2 microunits/ml; p less than 0,02). Two mechanisms are hypothesized as a possible explanation for the results: a) hyperprolactinemia primarily alters progesterone/oestradiol ratio which secondarily initiates benign breast disease, or b) relative hyperestrogenism causes an increase in PRL plasma levels, which, in turn, interact with oestradiol to give mammary gland hypertrophy. Further studies are needed in order to elucidate the problem.

[Changes in blood prolactin in relation to the menstrual cycle]. / Comportamento della prolattinemia in rapporto al ciclo mestruale.

Scientists are in general agreement on the hypothesis of a prolactin surge at midcycle. In order to test this hypothesis the Authors measured radioimmunoassayable circulating prolactin in the follicular phase and at midcycle in 15 normally menstruating health women. Due to the well known individual variability, mean prolactin values showed statistically poor differences in the two phases of the cycle. Though, a very good positive correlation (r = 0.72, p less than 0.01) was shown when individual follicular values were plotted against the corresponding midcycle values. The Authors conclude that at midcycle prolactin increases significantly and discuss physiological significance of this phenomenon.

[Extrarenal excretion of epitestosterone in the adult male]. / Considerazioni sulla increzione extrasurrenalica dell'epitestosterone nell'uomo adulto.

Twentyfour hour-urinary 17-oxo-steroids (17 KS), epitestosterone (ET) and testosterone (T) were measured before and after a 5-day-HCG-stimulation test performed in 65 healthy male volunteers aged 30 to 76 years. Subjects whose basal urinary T was higher than average physiological values showed a lower increase (p less than 0,001) in ET excretion rate after HCG stimulation than the rest of the casuistry. Neither T nor 17 KS increase after HCG stimulation showed any significant differences in the two subgroups. As ET behaves differently as compared both to the typical testicular androgen, and to the testicular-adrenal metabolites, the adrenal glands may not be the only nor even the main source of ET in the urine of healthy men.