Pierre C. Sizonenko

Evidence for a reduction of growth potential in adolescent female gymnasts

The goal of this prospective study was to assess whether intensive physical training during puberty could alter the growth potential of adolescent female athletes. Height, sitting height, leg length, weight, body fat, and pubertal stage of 22 gymnasts aged 12.3 +/- 0.2 years (mean +/- SEM), with an average training period of 22 hr/wk, and of 21 swimmers aged 12.3 +/- 0.3 years (average training period 8 hr/wk) were recorded half-yearly for a mean period of 2.35 years (range 2.0 to 3.7 years). Adult height predictions were performed with the methods of Bayley and Pinneau; Roche, Wainer, and Thissen, and Tanner et al. Growth velocity of gymnasts was significantly lower than that of swimmers from 11 to 13 years of bone age (p < 0.05), with a mean peak height velocity of 5.48 +/- 0.32 cm/yr versus 8.0 +/- 0.50 cm/yr for swimmers. Height standard deviation score decreased significantly in gymnasts with time (r = -0.747; p < 0.001). This observation was not associated with a significant alteration of chronologic age/bone age ratio. By contrast, height standard deviation score remained unchanged in swimmers (r = -0.165; p = 0.1). A marked stunting of leg-length growth was observed in gymnasts from 12 years of bone age, resulting in a marked difference in overall sitting-height/leg-length ratio (gymnasts 1.054 +/- 0.005 vs swimmers 1.100 +/- 0.005; p < 0.001). Concomitantly, predicted height of gymnasts decreased significantly with time (Tanner et al.: r = 0.63, p < 0.001; Bayley-Pinneau: r = 0.44, p < 0.001), whereas those of swimmers did not change. We conclude that heavy training in gymnastics (> 18 hr/wk), starting before puberty and maintained throughout puberty, can alter growth rate to such an extent that full adult height will not be reached. The mechanisms underlying these observations are not settled; we suggest that prolonged inhibition of the hypothalamic-pituitary-gonadal axis by exercise, together with or because of the metabolic effects of dieting, is responsible for them.

Hormonal changes in puberty. I. Correlation of serum luteinizing hormone and follicle stimulating hormone with stages of puberty, testicular size, and bone age in normal boys.

Extract: The concentration of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in serum was determind using a double antibody radioimmunoassay method in each of 106 normal boys aged 5-16 years. The boys were grouped according to the stage of puberty (P1-P5) using the classification of TANNER.The serum LH and FSH, LH/FSH ratio, and testicular volume index (TVI) for boys prepuberty (P1) and at different stages of puberty (P2-P5) are shown in figure l and table. The mean value of LH in prepubertal boys was 4.2 ng/ml, which steadily rose to a concentration of 5.3 ng/ml at P4-5. The differences between the values for LH in early puberty (P2) and at a more advanced stage of puberty (P4-5) were statistically significant. The mean value for serum FSH in the prepubertal boy was 1.4 ng/ml. Serum FSH rose steadily through the early stages of puberty (P1-P3) with no further rise from P3 to P4-5. These changes were reflected in the LH/FSH ratio which fel between P1 and P2, but increased between P2 and P4. Tesricular size (TVI) showed a gradual increase from P1 through P4-5.A comparison of serum LH and FSH, LH/FSH ratio. and TVI with chronological age is indicated in table II. A slight increase in the mean levels of serum LH and FSH was observed from age 9 to age 12 with a continued rise to 15 years and older. Serum LH and FSH was obsereved from age 9 to age 12 with a continued rise to 15 years and older. Serum LH seemed to rise at an earlier age than serum FSH. The TVI showed a definite increase from chronologic age 8 through 11. A pronounced change in testicular size from age 11 through 15 was observed during the period of sharp rise in serum FSH.The correlation of bone age with concentrations of LH and FSH in serum, LH/FSH ratio, and TVI is shown in table III. A significant rise in LH was seen in boys with a bone age of 9-10 years, with a further increase at a bone age of 13-15 years and older. Serum FSH showed a steady increment from a bone age of 11 to 14 years. The most pronounced increase in TVI was seen at a bone age of 11 through 15 years.The relation of concerntrations of LH and FSH in serum and LH/FSH ratio to the TVI is presented in table IV. Mean LH and FSH showed a gradual rise from a TVI of <2 to 10.1-12. Serum LH rose and serum FSH fell, however, with the increase in TVI from 10.1-12 to 12.1-16.In four patients with chromatin-positive seminiferous tubular dysgenesis (Klinefelters syndrome), the mean serum LH concentration was 11.3 ng/ml and the mean serum FSH concerntration was 21.6 ng/ml.The mean serum LH in 14 patients with multiple pituitary hormone deficiencies was 2.1 ng/ml and the mean serum FSH was 1.5 ng/ml. The small diffrences in the concentration of LH and FSH in prepubertal boys compared with that observed in children with hypopituitarism stress the need for further definition of the sensitivity of the assay for serum samples. The serum values reported are of relative not absolute significance.Speculation: The detection of serum FSH and LH prior to puberty, and the increase in serum FSH and LH coincident with advancing puberty suggests 1) that the hypothalamic-pituitary-testicular axis is functional befor puberty, and 2) that the onset of puberry may be associated with a change in sensitivity of the hypothalamus to feedback by testicular steriods.

Hormonal Changes in Puberty II. Correlation of Serum Luteinizing Hormone and Follicle Stimulating Hormone With Stages of Puberty and Bone Age in Normal Girls

Extract: The concerntration of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) was determined using a double antibody radioimmunoassay in 129 normal girls. Of theis group, 48 were prepubertal (P1) and 81 girls were at varying stages of pubertal development from P2 to P5. The mean serum LH concentration was similar in the prepubertal (P1) and nonmenstruating girls (P2-4) (3.8—4.2 ng/ml) (table I, fig. 1). A difference was observed in the serum FSH levels that increased steadily from 1.70 ng/ml at P1 to 3.4 ng/ml at stage P8 of puberty. No further change in the concentration of serum FSH was seen in girls P3 to P4. The LH/FSH ratio was lower in girls at P2 than in the prepubertal girls.In the menstruting girls (P5), means concentration of serum LH was within the same range (5.1—4.6 ng/ml) during the three phases of the menstrual cycle. Changes in the concerntration of serum, FSH was observed in menstruating girls: phase I (days 1-12), 3.99 ng/ml; phase II (days 13-18), 3.59 ng/ml; and phase III (days 19-30), 2.51 ng/ml.The relation of the serum LH and FSH levels and LH/FSH ratio to chronologic age was studied (table III). The concerntration of LH was not significantly different in girls 8-12 years. Serum FSH increased from 9 to 13 years. The LH/FSH ratio decreased at 9 years of age with no further change from 10 to 15 years. In addition, serum LH and FSH levels and LH/FSH ratio were compared with bone age (table IV). Serum LH was slightly but significantly less in girls with a bone age of 8 years than in those with a bone age of 6 years. A significant increase in FSH and LH levels was observed in girls with a bone age of 12 years compared with those with a bone age of 8 years.In 14 children with multiple pituitary hormone deficiencies, the serum LH concerntration was 2.2 ng/ml and the serum FSH concentration was 1.5 ng/ml. In 12 patients with XO gonadal dysgenesis of pubertal age, the mean concerntration of serum LH was 11.2 ng/ml and mean concerntration of serum FSH was 54.5 ng/ml. In two patients with XO gonadal dysgenesis, agred 6.5 and 9 years, the serum LH values were 2.5 and 4.5 ng/ml, and the serum FSH values were 1.5 and 2.75 ng/ml, respectively.The serum values descibed are of relative not absolute significance. Although the results indicate that small amounts of gonadotropins are secreted prior to the onset of signs of puberty, it is important to emphasize the necessity of better difinig the lower limits of sensitivity of the assays for serum samples.Speculation: The detection of serum FSH and LH in prepubertal children suggests that the hupothalamic-pituitary gonadal axis is at a low level of activity and already operative at this stage of development. The precise time of initiation of cyclical secretion of LH and FSH (the FSH and LH ovulatory surge) in pubertal girls and its relation to maturational changes in the ovary is not known but it seems likely that the licrease in estrogen secretion by the ovary as puberty advances acts as a positive feedback signal.

Delayed sexual maturation induced by daily melatonin administration eliminates the LH response to naloxone despite normal responsiveness to GnRH in juvenile male rats

Daily administration of melatonin (MT) markedly delays sexual maturation in the male Wistar rat. In this study, we have evaluated pituitary responsiveness to GnRH and the level of tonic inhibition by endogenous opioids in normal juvenile male rats and in rats with delayed sexual development induced by daily afternoon MT injection (100 micrograms, s.c.) starting at 20 days of life. Plasma LH responses to repetitive intravenous GnRH administration (100 ng/100 g body weight), or to different doses of GnRH administered subcutaneously (5-100 ng/100 g body weight) were normal in MT-treated rats both at 30 and 40 days of life despite significantly lower number of pituitary GnRH receptors and decreased pituitary gonadotropin content. One naloxone (NAL) injection (2.5-5.0 mg/kg, s.c.) produced a significant increase of plasma LH in normal 40- and 55-day-old rats, which was not seen in MT-treated rats of the same age. In contrast, no increase of plasma LH was seen in 30-day-old control rats nor in MT-treated rats at this age. Pretreatment with morphine sulfate (10 mg/kg, s.c.), or with the potent Met-enkephalin analog FK 33-824 (1.0 mg/kg, s.c.) prevented the NAL-induced rise of plasma LH in control rats at day 40 of life. In all instances, plasma PRL levels were decreased after NAL both in untreated and in MT-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The secretion of adrenal androgens and growth patterns of patients with hypogonadotropic hypogonadism and idiopathic delayed puberty

Plasma concentrations of adrenal androgens (DHEA and DHEA-S) and the growth patterns of four male patients with hypogonadotropic hypogonadism have been compared and contrasted with those of eight male patients wit idiopathic delayed puberty. As a group the patients with HH presented at an older age with delayed puberty and normal heights; the growth rate and pattern have been normal except for an absence of the pubertal growth spurt. Adrenal androgens were usually normal for chronologic age and high for bone age. The patients with IDP presented at a younger age, usually with short stature, low adrenal androgens relative to the chronologic age, but normal relative to the bone age. Patients with IDP appear to exhibit a delay in maturation of both the adrenal cortex and the hypothalamo-pituitary gonadal axis usually with short stature and retardation of the bone age. The importance in measurements of adrenal androgens in the diagnosis of HH and of IDP is emphasized.

Hormonal Changes during Puberty

Longitudinal studies of plasma dehydroepiandrosterone sulfate (DHEA-S) and dehydroepiandrosterone (DHEA) were made in 13 girls aged 7 years and 14 aged 10 years, during 3 years, at 6-month intervals.

Diurnal rhythm of melatonin action on sexual maturation of male rats.

Immature male Wistar rats with a 12:12 h light-dark cycle received daily s.c. melatonin injections of 100 micrograms from 20 to 40 days of age. Melatonin administration during the late photophase (9 h after the onset of light) or during the late scotophase (9 h after the onset of darkness) caused reduced weights of testes and seminal vesicles, lowered plasma levels of testosterone, LH and FSH, and decreased number of pituitary GnRH receptors, a series of observations which reflects delayed sexual maturation at 40 days. In contrast, no effect was observed when melatonin was injected during the early photophase of scotophase (5 h after the onset of light or darkness, respectively). In order to better investigate the night hours, melatonin action was studied in rats that were born and raised with a shifted 12:12 h light-dark cycle. When the light phase was shifted by 5 and 17 h 1 week before the animals were born, sensitivity to melatonin action was unchanged. The responsiveness of the neuroendocrine-reproductive axis to exogenous melatonin was then studied throughout the day-night cycle. The inhibitory influence of melatonin increased gradually during the late photophase and reached a peak just before the onset of darkness. No effect was observed during the first 7 h of the dark phase; however, melatonin injected 9 h after the onset of darkness again had an inhibitory influence equivalent to about 50% of that observed in the late photophase , whereas administration 2 h later remained without effect. These results demonstrate that the time of administration of melatonin within the day-night cycle is critical for melatonin action.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of adrenergic stimulation and blockade on melatonin secretion in the human.

Publisher Summary The mechanisms that control release of melatonin from the human pineal gland are unknown. This chapter mentions experimental data in animals which are relevant to the present study in humans. It has been established in animals, that the pineal gland is innervated by post-ganghonic fibers from the superior cervical ganglia, which secrete the neurotransmitter noreprinephrine. The presence of β -adrenergic receptors on pineal cell membranes has been demonstrated by the ability of β -adrenergic receptor antagonists to competitively inhibit norepinephrine-induced actions in pinealocyte metabolism. Among the more important of these actions are the activation of adenyl cyclase and the induction of N-acetyl transferase activity, resulting eventually in increased melatonin synthesis. The ability of pharmacologic p-agonists such as isoproterenol to produce an increase of N-acetyl transferase activity, and of &blockers such as propanolol to inhibit it, confirms that, in the rat, melatonin synthesis and presumably release, are mediated by a β -adrenergic system. Further, the sensitivity of these receptors to stimulation appears to vary inversely with the extent of previous stimulation. In addition to a β -adrenergic system, there is some evidence of a dopaminergic influence on melatonin synthesis, as dopamine increases melatonin production in organ culture. In addition, L-dopa increases rat pineal melatonin concentration and N-acetyl transferase activity.

In vitro production of pregnancy-associated plasma protein A by human decidua and trophoblast

Immunohistochemical techniques and direct measurements of pregnancy-associated plasma protein A (PAPP-A) have demonstrated the presence of PAPP-A in trophoblast and decidua. The purpose of the present study was to investigate the possibility that these tissues are capable of producing PAPP-A in vitro. Trophoblast and decidua were obtained from term deliveries and from legal surgical terminations of pregnancy (7 to 12 weeks). In addition to trophoblast and decidua, myometrium was also obtained during two hysterectomies in the first trimester of pregnancy. Tissues were incubated in medium 199 at 37 degrees C under an oxygen/carbon dioxide atmosphere. Media containing either pregnancy-associated serum or non-pregnancy-associated serum were changed after 8 hours of incubation in medium 199 alone. In addition to PAPP-A, human placental lactogen (hPL) and prolactin (Prl) were measured in homogenates and media by radioimmunoassays in order to confirm the viability of the cultured tissues. Addition of pregnancy-associated serum to the media induced a significant release of PAPP-A from trophoblast and decidua when compared to that in control cultures. Non-pregnancy-associated serum had no effect. Myometrium did not release any measurable PAPP-A into the medium even in the presence of pregnancy-associated serum. Cycloheximide added to pregnancy-associated serum significantly inhibited the release of PAPP-A from trophoblast and decidua. These last tissues, irrespective of the culture condition, released significantly more PAPP-A as well as hPL and Prl than was initially present in the tissue. These data demonstrate that PAPP-A is released in vitro by trophoblast and decidua (but not by myometrium) and that this release can be magnified by a factor present only in pregnancy-associated serum. The release of PAPP-A, hPL, and Prl is considered as a de novo production since concentration of these proteins are higher in media and tissues after incubation compared to concentrations initially present in the tissue before culture and since cycloheximide significantly inhibits the release of PAPP-A, Prl, and hPL from the cultured tissues.

Plasma Growth Hormone, Insulin, and Glucagon Responses to Arginine Infusion in Children and Adolescents with Idiopathic Short Stature, Isolated Growth Hormone Deficiency, Panhypopituitarism, and Anorexia Nervosa

Extract: The effects of intravenous infusion of arginine (20 g/m2) after an overnight fast on plasma immunoreactive growth hormone (GH), insulin (IRI), and glucagon (IRG), and blood glucose were examined in five groups of children and adolescents: 10 normal individuals, 18 with idiopathic short stature, 6 with isolated growth hormone deficiency, 8 with panhypopituitarism, and 6 with anorexia nervosa. The mean fasting plasma GH concentration was significantly elevated in the group with anorexia nervosa (P < 0.05), and similar to the value for the normal group in all other groups. After arginine infusion, four- to sixfold increases of plasma GH were observed in the normal children, and similar increases were seen in those with idiopathic short stature as well as in those with anorexia nervosa; whereas, in the children with isolated growth hormone deficiency or panhypopituitarism, there was no significant increase in plasma GH. Fasting blood glucose concentrations were significantly lower than normal in subjects with isolated growth hormone deficiency (p < 0.05), panhypopituitarism (P < 0.001), and anorexia nervosa (P < 0.001), whereas fasting plasma IRI and IRG concentrations were similar to the values in the normal group. Plasma IRI increased eightfold at the end of the 30-min arginine infusion in the normal subjects; the increase was slightly but not significantly less in those with idiopathic short stature, and significantly less in those with isolated growth hormone deficiency (P < 0.05), panhypopituitarism (P < 0.001), and anorexia nervosa (P < 0.05). Arginine infusion resulted in two- to threefold increases of plasma IRG in the normal group, and similar increases were observed in all of the other groups tested. These results suggest that whereas pancreatic β cell responsiveness may be deficient in children and adolescents with isolated growth hormone deficiency, panhypopituitarism, or anorexia nervosa, pancreatic α cell responsiveness, to arginine at least, appears to be intact under these conditions.Speculation: Although plasma glucagon responses to arginine infusion were not less in subjects with hypopituitarism or anorexia nervosa than in normal subjects, relative hypoglucagonemia may have existed, since both basal and postarginine infusion plasma glucagon levels were not higher than normal in the presence of significantly lower blood glucose values. Thus, the present study does not exclude a deficient pancreatic α cell response to hypoglycemia. Alternatively, nonavailability of substrates for gluconeogenesis may have a more important influence than hormonal factors in the genesis of the hypoglycemia observed in these states.