Post-natal hormonal adaptation.
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Biological Clocks↗
Biomedical subjects
P C Sizonenko
Publications and source records attributed to P C Sizonenko.
Metabolic studies in primary tubular hypomagnesaemia-hypokalaemia.
13 1/2 year old boy with short stature and pubertal delay had infrequent episodes of tetany. Biochemical determinations demonstrated low plasma and high urinary magnesium and potassium levels, hypocalciuria, slightly increased plasma bicarbonate, slightly reduced fractional distal reabsorption of chloride and sodium, high plasma renin activity and high urinary excretion of prostaglandins (E2, F2 alpha). The other parameters of renal functions were normal. Endocrine evaluation of short stature and pubertal delay was normal. Intracellular magnesium and potassium levels in lymphocytes and erythrocytes were within normal limits. Cyclooxygenase blockade with Indomethacin 2.5 mg/kg daily during 4 weeks normalized urinary excretion of prostaglandins and corrected in part low plasma and high urinary potassium levels, but had no effect on magnesium, calcium, sodium and chloride handling. These data raise the possibility that tubular hypomagnesaemia-hypokalaemia could be solely explained by a low renal threshold for magnesium.
Adolescent↗
Short-term and long-term effects of melatonin on GnRH-stimulated gonadotropin secretion in pituitaries of sexually maturing rats.
Melatonin administration has been shown to delay sexual maturation in male rats, through an action which involves decreased binding of gonadotropin-releasing hormone (GnRH) in the pituitary and lower pituitary gonadotropin contents. It has been suggested that melatonin must act at a level higher than the pituitary to provoke these effects, but a direct action of melatonin on the pituitary has not been excluded. Using a cell culture system, the gonadotroph responsiveness to GnRH was studied. Pituitaries were obtained either from rats chronically treated with melatonin and showing delayed sexual maturation, or from control rats. In vitro luteinizing hormone and follicle-stimulating hormone response to GnRH was significantly lower when pituitaries were obtained from melatonin-treated rats. However, this diminished response was directly proportional to the amount of gonadotropin contents in cells, so that relative responsiveness, calculated as the amount of gonadotropins released in relation to the gonadotropin content was similar in cells from control and melatonin-treated rats. It is concluded that the effect of melatonin on the pituitary of male rats results from a decrease of gonadotroph growth or gonadotropin synthesis, as a consequence of a change located at the hypothalamic rather than at the pituitary level. This conclusion is further supported by results showing that melatonin added directly in culture medium prior to GnRH does not modify the pituitary responsiveness to GnRH.
Aging↗
Plasma growth hormone (GH) response to intravenous GH-releasing factor (GRF) in adult rats: evidence for transient pituitary desensitization after GRF stimulation.
The ability of human (h)GRF-(1-29)NH2 to stimulate GH secretion was studied in cannulated adult rats. In order to suppress endogenous GRF secretion and the inhibitory action of hypothalamic somatostatin (SRIF), rats were anesthetized with sodium pentobarbital. Intravenous administration of hGRF-(1-29)NH2 elicited a dose-dependent response of plasma GH, with 250 ng/kg being the smallest effective dose in male rats. In female rats, for each dose tested (250 to 70,000 ng/kg), the GH response represented only about 60% that of male rats. Repeated iv stimulations with hGRF-(1-29)NH2 at short time intervals (45 min) produced transient desensitization of pituitary responsiveness to GRF: a blunted GH response to the second and third stimulations was observed both in male and in female rats and for each dose tested. Similar blunted responses were also obtained with repeated injections of native hGRF-(1-44)NH2. The possibility that these blunted responses could be due to incomplete suppression of hypothalamic SRIF secretion by sodium pentobarbital was excluded by the use of rats that were passively immunized against SRIF; in these rats, it was shown that at least 65% of the inhibition of the GH response after the second GRF stimulation was unrelated to SRIF action. Similar transient desensitization to repeated hGRF-(1-29)NH2 stimulations was also observed in conscious rats that were passively immunized against SRIF. This occurrence of blunted responses was shown to be related to the length of the time interval between GRF stimulations, with longer intervals resulting in less or no desensitization. It appears thus that modulation of pituitary responsiveness to the action of GRF is mediated by at least two independent mechanisms in the rat: in addition to the inhibitory action imposed by hypothalamic SRIF, which induces periods of refractoriness to the action of GRF, it was shown in this study that in the pituitary level each GRF stimulation also induces a transient desensitization of somatotrophs for about 1 h. This period of refractoriness might not be due to excessive stimulation with GRF, since it was also observed with the lowest dose of hGRF-(1-29)NH2 that gave a significant release of GH. Finally, a sex difference was confirmed for the response of anesthetized adult rats to stimulation with hGRF-(1-29)NH2, reflecting a sex steroid-induced modification of pituitary responsiveness to GRF stimulation.
Anesthesia, General↗
Lack of bromocriptine-induced reduction of predicted height in tall adolescents.
Fifteen girls and five boys with excessive predicted adult height (chronological age, 10.1-14.6 yr; bone age, 11.0-14.0 yr) were treated with bromocriptine (two doses; 2.5 mg/day) to reduce their final height. After a mean treatment period of 1.14 yr (range, 0.6-1.75 yr) we did not find a reduction of predicted adult height [difference, -0.5 +/- 3.5 (+/- SD) cm according to Bayley and Pinneau's tables (P = NS) and +0.2 +/- 2.5 (+/- SD) cm according to the method of Tanner (P = NS)]. Mean peak plasma GH concentrations after TRH administration before and during bromocriptine were 51.5 +/- 49.4 and 58.5 +/- 50.7 mU/L, respectively. The wide range of the GH values may be explained by physiological variation in this age group. After ingestion of 2.5 mg bromocriptine a significant increase in plasma GH occurred within 3 h in six adolescents tested. Our results do not support the concept that bromocriptine may reduce predicted adult height in tall adolescents by decreased GH secretion or acceleration of skeletal maturation.
Adolescent↗
Cryptorchidism: a morphological study of 670 biopsies.
Among a series of 512 boys with an empty scrotum, 495 (96.7%) were found to have cryptorchidism, 4 had ectopia and 13 unilateral anorchia. Cryptorchidism was bilateral in 106 boys (21.4%). The only anomaly consistently associated with cryptorchidism was a detached epididymis, present in 31 patients. A total of 670 biopsies were studied, 441 of which came from cryptorchid and 229 from scrotal testes. Spermatogonial counts, performed according to Mancini's method, showed the germ cell population to be diminished in nearly all cryptorchid testes. The seven boys who still had a well preserved germ cell population were found in a group of 51 patients operated before age three; four of the seven boys with normal counts were below age one. No difference in the mean spermatogonial counts was found between uni- und bilateral cryptorchidism and ectopia, with the exception of bilaterally intraabdominal testes whose spermatogonial cell loss was particularly severe. Mean counts remained constant during childhood, no gradual increase with age having been observed. The scrotal testes in unilateral cryptorchidism showed cell loss in 30.1% of the cases, the germ cell depletion being severe in one out of every six cases. In the remaining scrotal testes, the counts were in the low normal range with a significantly lower mean than that found in scrotal testes associated with anorchia. Control biopsies were performed several months or years after orchidopexy in 18 boys with unilateral and in 24 boys with bilateral cryptorchidism. Orchidopexy does not improve the number of germ cells in either originally cryptorchid or in scrotal testes, the only postoperative change being an increase in tubular diameter. A search for malignant tumours which could have developed in this series has remained negative. According to our data, no optimal time for orchidopexy can be proposed. The damage to germ cells, once established, seems to remain unchanged during childhood at least after age three, and does not warrant special timing for operative correction of cryptorchidism.
Adolescent↗
Pharmacodynamics of [D-Ser (t-Bu)6,Des-Gly10]GnRH ethylamide (Buserelin) in 6 normal volunteers. Its usefulness to monitor treatment of central precocious puberty.
The disappearance rate of [D-Ser(t-bu)6,des-Gly10]GnRH ethylamide (Buserelin, HOE 766) was studied in plasma and urine after intranasal (300 micrograms) or sc (10 micrograms/kg) administration. A radioimmunoassay for HOE 766 was developed using 125I[D-Trp6,Des-Gly10]GnRH ethylamide as tracer and an antiserum raised against HOE 766. Cross-reaction with native GnRH was only 1.7%. Sensitivity was 1 pg/tube. In 6 male adolescents, the mean plasma HOE 766 concentration (+/- SEM) was 0.46 +/- 0.08, 0.50 +/- 0.10, 0.28 +/- 0.04, 0.24 +/- 0.04, 0.13 +/- 0.03, and 0.08 +/- 0.02 micrograms/l 30, 60, 90, 120 and 180 min after the intranasal administration, respectively. Concomitant urinary excretion of HOE 766-like material was 9.43 +/- 1.96 micrograms/4 h. There was a good correlation between integrated plasma levels and urinary excretion (r = 0.92). In the same 6 volunteers, the plasma HOE 766 levels were 21.2 +/- 3.0, 25.9 +/- 0.8, 21.2 +/- 0.9, 17.1 +/- 0.7, 12.8 +/- 1.1, 8.9 +/- 0.4, and 5.9 +/- 0.8 micrograms/l 20, 40, 60, 90, 120, 180 and 240 min after sc injection, respectively. The mean urinary excretion was 543 +/- 61 micrograms/4 h. In two girls with precocious puberty treated during 12 to 15 months with intranasal administration of HOE 766, urinary excretion of HOE 766-like material was shown to correlate well with the degree of inhibition of plasma 17 beta-E2 and of plasma LH and FSH responses to a GnRH challenge. Thus, monitoring of HOE 766 in urine appears to be helpful for evaluating of intranasal therapy with a GnRH analog in precocious puberty.
Administration, Intranasal↗
Normal sexual maturation.
Puberty represents a period of important changes which lead to sexual maturation and active functions of reproduction. Sequences of the somatic and hormonal changes are presented both in boys and girls. Mean ages of onset of puberty are 10.9 and 11.2 in girls and boys, respectively. Menarche occurs at a mean age of 13.4 years and may be related to a critical weight. In boys, testicular growth above 4 cm2 or 4 ml is the first clinical sign of gonadal pubertal maturation. In girls, the first sign is the budding of the breast. At onset of puberty, the hypothalamus resumes a marked pulsatile secretion of gonadotropin-releasing hormone, leading to an increased secretion of pituitary gonadotropins which in turn stimulate the gonadal functions, i.e. the secretion of testosterone or estradiol and maturation of the spermatogenesis or the ovarian follicle. Neuroendocrine factors which probably control the onset of puberty are numerous: adrenergic or dopamine neurotransmitters, endogenous opioids, melatonin from the pineal gland. Gonadal maturation (gonadarche) is preceded in the infant by a postnatal surge of luteinizing hormone and at age 7-8 years by an adrenal maturation called adrenarche.
Adolescent↗
Delayed sexual maturation.
Absence of any sign of gonadal development (i.e. increase in size of the testes or presence of breast budding) before the age of 13 years in girls and 14 years in boys represents the condition of delayed sexual maturation. After this age, the patient should be thoroughly clinically examined and a basic biological work-up should be performed. Pathological conditions such as hypergonadotropic hypogonadism with a bone age usually greater than 13 years can be easily diagnosed. Hypogonadotropic hypogonadism is more difficult to differentiate from delayed adolescence of good prognosis. Means of diagnosis as well as therapy are discussed. In addition, micropenis and primary amenorrhea are frequent clinical observations.
Adolescent↗
[Hypothalamic factors: current findings].
The last few years have seen the isolation, characterization and synthesis of two new hypothalamic peptides, the growth-hormone releasing factor (GRF) and the corticotrophin-releasing factor (CRF). GRF selectively stimulates pituitary growth hormone. It is interesting to note that GRF was isolated from two pancreatic tumors which were responsible for an acromegalic condition in the two patients. Hypothalamic GRF (1-44) has been found to be identical to this pancreatic GRF. CRF was isolated first from ovine hypothalamus and later characterized in several species and in the human. CRF specifically stimulates the secretion of ACTH and of beta-endorphins, and other fragments of the common precursor named pro-opiomelanocortin. Chemical synthesis of analogues of hypothalamic peptides, and in particular of GnRH (gonadotrophin-releasing hormone), has made available new molecules which form agonists as well as antagonists. After a short period of gonadotrophin stimulation GnRH agonists induce desensitization of the pituitary and a decrease in secretion of the gonadotrophins and the sex steroids by the gonads. Their usefulness is presently being tested in several conditions such as prostate cancer, endometriosis, breast cancer and idiopathic precocious puberty, and as a contraceptive method. On the other hand, pulsatile administration of GnRH restores deficient reproductive functions in certain conditions such as anovulation or azoospermia.
Adrenocorticotropic Hormone↗
Progesterone dependence and extratrophoblastic origin of pregnancy-associated plasma protein-A (PAPP-A) in early pregnancy.
Pregnancy-associated plasma protein-A (PAPP-A) is a macromolecular glycoprotein produced in increasing concentration as pregnancy advances. PAPP-A is not specific to pregnancy since measurable levels have been found in non-pregnant females and in males. In non-pregnant females, PAPP-A is probably produced by the endometrium. The origin of PAPP-A in pregnant women is still controversial. In-vitro trophoblast and decidual explants both produce PAPP-A. So far, it is not known if the same applies to the in-vivo situation and to what extent these two tissues contribute to the circulating levels of PAPP-A. This study compares the circulating concentrations of PAPP-A and beta-hCG and progesterone in different pathological situations. In hydatidiform moles, beta-hCG levels are very high demonstrating an intense trophoblastic activity, whereas PAPP-A levels remain in the normal range. With spontaneous abortions, beta-hCG levels decline to very low values whereas PAPP-A continues to increase. These observations furnish indirect evidence for a major contribution to circulating PAPP-A levels by extratrophoblastic sites. Furthermore, PAPP-A levels decrease after administration of an anti-progesterone (RU486) either in-vivo or in-vitro. This is considered as a proof that PAPP-A levels in early pregnancy are progesterone dependent.
Abortifacient Agents, Steroidal↗
Nocturnal urinary melatonin excretion and plasma cortisol levels in children and adolescents after a single oral dose of dexamethasone.
In the present study, the possible relationship between melatonin secretion as reflected by nocturnal melatonin excretion (2000 h-0800 h) and the pituitary-adrenocortical axis was investigated. Nocturnal urinary melatonin excretion and plasma cortisol levels were determined in 41 children with weight problems before and after a single oral dose of dexamethasone. A first group of 15 individuals with normal cortisol cycle (12.2 +/- 1.4 at 0800 h and 3.1 +/- 0.5 micrograms/100 ml at 1700 h), and levels below 1.0 microgram/100 ml after dexamethasone, showed a highly significant increase in melatonin excretion during the night following dexamethasone treatment (63.5 +/- 5.5 ng/12 h vs 33.6 +/- 3.0 for the control night, P less than 0.001). This increase was observed from prepuberty to young adulthood (pubertal stages PI-PV). In a second group of 16 subjects with mean cortisol levels similar at 0800 h and 1700 h (10.7 +/- 1.3 and 9.3 +/- 1.5 micrograms/100 ml respectively), but with a normal cortisol suppression after dexamethasone administration, nocturnal melatonin excretion increased from 21.2 +/- 2.1 to 33.4 +/- 3.0 ng/12 h (P less than 0.01). A significant increase was found in prepubertal children (PI) whereas no change was observed at the end of pubertal development (stages PIV-PV). A third group of 10 patients with both low amplitude cortisol cycles (16.2 +/- 2.5 and 10.8 +/- 2.4 micrograms/100 ml) and abnormal cortisol suppression after dexamethasone administration (9.1 +/- 2.4 micrograms/100 ml), showed no increase in melatonin excretion (24.2 +/- 2.7 and 24.9 +/- 3.7 ng/12 h).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Pulsatile secretion of pregnancy-associated plasma protein-A (PAPP-A) in non-pregnant women.
No changes in PAPP-A levels could be detected when plasma samples were obtained every second day throughout the entire menstrual cycle in three healthy women. But when measured every 30 min throughout 12 consecutive hours, in four healthy women, PAPP-A followed a pulsatile pattern which may originate in the endometrium since no PAPP-A pulses were detected in a long-term hysterectomized woman, or in two men. The pulses were not related to levels of oestradiol, progesterone, FSH or LH.
Adult↗
Failure of dehydroepiandrosterone enanthate to promote growth.
Adrenal androgens may promote pubertal growth. To assess this possibility, we administered dehydroepiandrosterone (DHEA) enanthate in monthly im injections in a dose of 70 mg/m2 for 1 yr to five boys with constitutional short stature (aged 11-13 4/12 yr) and one boy (aged 13 4/12 yr) with panhypopituitarism (coincidentally receiving T4 and human GH). All had bone age delay of at least 3 yr and subnormal levels of DHEA and DHEA sulfate (DHEA-S) for their chronological age. Pretreatment growth velocity ranged from 3-5 cm/yr. After DHEA enanthate injection, plasma DHEA levels were increased 10-fold after 8 days, 2.6-fold after 15 days, and 1.8-fold after 22 days. At the same times, plasma DHEA-S concentrations were 14-, 6-, and 4-fold increased, respectively. There was no rise in plasma testosterone and delta 4-androstenedione, which remained at prepubertal levels. During the year of therapy and for 1 yr after therapy, there was no significant change in growth velocity, and the rate of skeletal maturation assessed by x-ray was not affected. Three of the five boys with constitutional short stature entered puberty within 1 yr after discontinuation of therapy. These results demonstrate that this long-acting form of DHEA administered for 1 yr did not raise plasma testosterone above prepubertal levels and did not accelerate either growth or skeletal maturation. These findings do not support the possibility that DHEA plays a role in normal growth.
Adolescent↗
Growth hormone response to thyrotropin-releasing hormone in children and adolescents: a reappraisal.
In normal subjects, thyrotropin-releasing hormone (TRH) is not involved in the control of growth hormone secretion. Paradoxical growth hormone (GH) responses to TRH have been described in acromegalic subjects and, recently, in some constitutionally tall children. To confirm this finding, we have examined the GH response to combined LHRH-TRH tests performed to assess the pituitary function of children with GH deficiency, tall stature before and during bromocriptine therapy, precocious or delayed puberty as well as in a group of patients of average height and normal bone age. Unlike prolactin, the GH "response" to TRH, in children followed longitudinally, is particularly heterogeneous with an unpredictable pattern of secretion in repeated tests. Over 90% of children display peaks of GH (greater than or equal to 5 ng/ml), of which 38% occur twice during the test period. Amplitude and frequency of GH peaks appear to be independent of height, chronological age or bromocriptine therapy. Secretory rate estimated by integrated surface area increases in parallel to sex steroids impregnation. The pattern of GH secretory episodes, the increase in mean GH secretion in parallel to the production of gonadal sex steroids and the failure of bromocriptine to affect GH secretion in constitutionally tall children allow to speculate that what is measured after TRH injection is normal spontaneous GH rhythm rather than a direct effect of TRH on GH secretion.
Adolescent↗
Puberty in the rat: modulation by melatonin and light.
Although a role has been found for melatonin in species which have a seasonal reproductive cycle, very little is known on the role of melatonin in species such as the rat where seasonal cycles are a minor component of reproduction. But the rat is a photosensitive species, because it responds to changes in the lighting environment. Females do not become quiescent but they can have irregular estrous cycles, another way of controlling population dynamics. In this species, exogenous melatonin can exert an antigonadotropic action, providing conditions which apply to other species are also respected for the rat: melatonin must be given at the right time of the day, 9 to 12 hours after the onset of light, and at a given period of life, before the onset of puberty. Melatonin probably acts on the pattern of GnRH pulsatile secretion and the subsequent alterations of the hypothalamic-gonadal axis differ according to the sex of the animal. Endogenous melatonin rhythms are modified by the lighting environment, and results obtained with exogenous melatonin suggest that they could be one of the factors controlling timing of sexual maturation.
Animals↗
Neuroendocrine changes characteristic of sexual maturation.
A general scheme of neuroendocrine factors influencing the onset of puberty is presented. Gonadotropin-releasing hormone (GnRH) is secreted in pulsatile fashion by the arcuate nucleus of the hypothalamus. Amplitude and probably frequency of the secretory pulses of GnRH increase at the time of puberty, stimulating the secretion of pituitary gonadotropins (LH and FSH). In turn, the gonadotropins induce the maturation of the ovarian follicles in the girls, spermatogenesis in the boys, and the secretion of estradiol or testosterone. The increase of the pulsatile secretion of GnRH is sufficient for explaining the onset of puberty. The response of the pituitary gonadotropins to GnRH would depend on the presence of sex steroids through the feedback mechanisms. The secretion of GnRH may be influenced by neurotransmitters. Norepinephrine, epinephrine and dopamine would stimulate GnRH secretion. Such effect, in fact, depends on the steroid milieu. Opposite effects can be observed in absence of estradiol. Serotonin has a negative effect on the GnRH secretion. Melatonin appears also to block GnRH secretion at the time of puberty. Finally, beta-endorphins decrease the frequency of GnRH secretion only in the presence of steroids. It is probable that stress and underweight act in blocking the pubertal development through the action of neurotransmitters, in particular catecholamines and beta-endorphins.
Adolescent↗
The pineal and pubertal development.
The pineal gland, through its major secretory product melatonin, influences seasonal breeding in species such as the hamster and the sheep. Recent studies from our laboratory have shown that melatonin also affects sexual development in the rat. A role for melatonin in humans has not yet been found. The laboratory rat is sensitive to daily administration of melatonin at the beginning of sexual maturation. The male rat is most sensitive between day 20 and day 30 of life. Melatonin does not permanently inhibit sexual maturation, since normal but delayed sexual development occurs after 45 days of life whether melatonin administration is discontinued or maintained indefinitely. In female rats, daily injection of melatonin during the prepubertal period delays the vaginal opening and disrupts the normal cyclicity of the first oestrous cycles. In both male and female rats, the inhibitory action of melatonin is highly dependent upon the time of injection, with maximal effects when melatonin is given in the late photoperiod. The inhibitory action of melatonin is most likely exerted at the hypothalamic level, possibly through interference with the control of pulsatile secretion of gonadotropin-releasing hormone. In contrast to some published work, our experiments provide no evidence for modifications of diurnal or nocturnal melatonin secretion during puberty in humans. Our results with the rat indicate that melatonin may be an important factor for the timing of sexual maturation.
Adolescent↗