Changing sensitivity of the pubertal gonadal hypothalamic feedback mechanism in man.

Clomiphene citrate in doses which stimulate gonadotropin production in the adult suppresses urinary follicle stimulating hormone (FSH) excretion and plasma testosterone concentration in prepubertal children. Such results indicate that feedback between gonad and hypothalamus is operative and highly sensitive in prepubertal humans. Puberty in man, as in the rat, is accompanied by a decrease in the sensitivity of the feedback mechanism.

Follicle-stimulating hormone (FSH) and luteninizing hormone (LH) in the urine of prepubertal children.

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) have been measured by specific bioassays in pooled urine samples from prepubertal children, aged 2-6 yr, and from male adults. For children the mean urinary excretion of FSH was 2.2 U 2nd International Reference Preparation (2nd IRP) per liter and the mean urinary excretion of LH was 0.44 U 2nd IRP per liter. For adults the mean FSH excretion was 5.6 U 2nd IRP per liter and the mean LH excretion was 4.7 U 2nd IRP per liter. Our data show a 2.5-fold increase of FSH, a 10.7-fold increase of LH, and a consequent decrease in the FSH: LH ratio from 5 to 1 between childhood and adulthood. FSH and LH in urine from three patients with gonadal abnormalities have also been studied. The results from normal children, adults, and abnormal patients form a spectrum and reveal that sexual maturity is accompanied by a marked increase in the excretion of LH with relatively smaller increases in FSH.

Perturbations of negative feedback sensitivity in agonadal patients undergoing estrogen replacement therapy.

UNLABELLED: Urinary gonadotropin excretion was measured in 30 patients with gonadal dysgenesis, aged 2 months to 17 yr. Between bone ages 3-8 yr, mean FSH excretion (575 mIU/h) was elevated 8-fold in agonadal individuals compared to levels in intact prepubertal girls; mean urinary LH (49 mIU/h) in agonadal patients during this time period was increased nearly 2-fold over results from normal prepubertal females. Nine of 10 patients given 0.3 to 0.6 mg conjugated estrogen (Premarin) daily to initiate puberty exhibited prompt suppression of urinary gonadotropin levels from markedly elevated levels to within or very close to the normal prepubertal range. Such a response was found in only two of seven patients given 0.15 mg of the same drug. All instances of suppression were followed by escape from low levels of gonadotropin excretion as treatment was continued. Prior exposure to exogenous or endogenous estrogen markedly reduced the suppressive potential of treatment with 0.3 or 0.6 mg Premarin. A favorable advance of bone maturation in relation to chronological age was achieved by the administration of 0.15 mg Premarin daily, a dose which caused a satisfactory onset of secondary sex characteristics. IN CONCLUSION: 1) a component of gonadotropin restraint in midchildhood is supplied by the ovary; 2) adult castrate levels of gonadotropins are achieved in the agonadal patient of peripubertal age in the presence of a highly sensitive negative feedback axis between sex hormones and gonadotropins; 3) sex steroids themselves may modify the gonadotropin-gonadal negative feedback axis in patients with gonadal dysgenesis; and 4) puberty may be initiated favorably with conjugated estrogens in an oral dose of 0.15 mg daily.

Urinary follicle-stimulating hormone during pregnancy: relationship to sex of fetus.

FSH excretion was determined by RIA in 111 urine samples from 23 pregnant women. The use of acetone extraction allowed a 20-fold concentration of urine and the accurate quantitation of hormone levels. Between 10 weeks of gestation and term, FSH secretion was consistently low, with a mean excretion of 18 mIU/h; this amount compares to levels found in other states of marked hCG excess (e.g. choriocarcinoma) and is considerably less than the FSH excretion by prepubertal children. Maternal levels of urinary FSH did not differ with sex, suggesting a primary maternal pituitary origin for pregnancy FSH.

Response of the prepubertal ovary to acute chorionic gonadotropin administration: absence of modulation by growth hormone.

Twenty-five short term hCG stimulation tests were performed in seven prepubertal girls, aged 3-11 yr, who were being evaluated for short stature. Provocative testing revealed GH deficiency in all patients, but reevaluation of one girl at a later date showed normal somatotropin levels. The study protocol lasted 18 months and included testing before, during, and after 1 yr of GH therapy. Delta 4-Androstenedione, testosterone, estrone, and estradiol were determined 0, 24, 48, and 72 h after initiation of a two-injection course of CG. Significant responses (approximately 2-fold over baseline) to the stimulation tests occurred for all steroids except testosterone, though no augmented effects were found in the presence of human GH. The results indicate functional capability of the prepubertal ovary when exposed acutely to a LH-like material, but no role for somatotropin in gonadal steroid production in the prepubertal female.

Spironolactone stimulation of gonadotropin secretion in boys with delayed adolescence.

Spironolactone (Aldactone) acts as an antiandrogen by blocking testosterone synthesis and competing with testosterone for the androgen receptor. These properties of the mineralcorticoid antagonist were used in an attempt to interrupt the gonadal-pituitary-hypothalamic negative feedback axis and thereby stimulate LH and FSH in 7 boys with delayed puberty. Following administration of aldactone (5 mg/kg) daily for one week, there was a significant (P less than .01) mean increase in serum LH of 60%. In all 7 boys an absolute rise in LH was observed, but these changes were statistically significant in only 5 individuals. While mean FSH levels increased by 60% in this group of boys, the individual responses were variable. No rise in gonadotropin levels occurred in 2 patients with Kallmann's syndrome, who also received 5 mg/kg of spironolactone daily for 1 week. Large doses of the drug appeared necessary to stimulate gonadotropin secretion since a dose of 3 mg/kg per day did not cause LH or FSH increments in 2 additional patients with delayed puberty. Progesterone and 17alpha-hydeoxyprogesterone levels increased to a greater extent than LH and FSH in response to spironolactone, reflecting either adrenal or testicular enzyme inhibition. Spiornolactone is the first drug shown to be capable of stimulating gonadotropin secretion by interrupting negative feedback inhibition in boys with delayed puberty.

Circadian rhythms in gonadotropin excretion in prepubertal and pubertal children.

Timed urinary collections were obtained during sleep and waking hours from 27 prepubertal children ranging in age from 2-12 years and from 13 subjects in various stages of puberty, 12-18 years old. The urine samples were extracted with acetone and introduced into FSH and LH radioimmunoassays. Results of the study indicate a significant nocturnal augmentation of LH secretion in pubertal subjects, confirming existing reports using blood sampling techniques. Increased LH and FSH excretion during sleep was also found in prepubertal children.

Usefulness of urinary gonadotropin measurements to assess luteinizing hormone releasing factor (LRF) responsiveness in hypogonadotropic states.

Multiple blood sampling techniques and short-term, timed urine collections were employed before and after luteinizing hormone releasing factor (LRF) administration to 51 individuals on 58 occasions. Correlation of blood and urine per cent responses to LRF were significant for LH (P less than .05) and FSH (P less than .001), indicating that urine measurements provide an adequate means of assessing response to LRF. In 7 patients with basal blood gonadotropin levels below assay sensitivity, urine measurements provided the only means of accurately determining a response to LRF. Per cent response to LRF was negatively correlated with basal LH levels in the urine (P less than .02) but not in the blood. A significant negative correlation between basal levels and per cent response was demonstrated for FSH in blood and urine (P less than .01). Accurate measurement of basal gonadotropins and the expression of LRF responses as per cent increments aided in distinguishing between patients with hypothalamic and pituitary diseases. A marked response to LRF in the presence of very low basal LH levels was found in patients with hypothalamic disorders, a finding revealed only by using urine determinations. Low per cent responses to LRF were seen primarily in patients with pituitary disease, a situation most clearly delineated by blood FSH measurements.

Hypothalamic-pituitary-gonadal axis function in pubertal male and female siblings with glucocorticoid-treated nonsalt-wasting 3 beta-hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia.

We report pubertal maturation and dynamic studies of gonadotropin and gonadal hormone secretion in long term glucocorticoid-treated siblings with nonsalt-wasting classic adrenal and gonadal 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) deficiency. The 18-yr-old female siblings spontaneously developed thelarche and menarche at 10 and 12 yr, respectively, and manifested irregular menses, hirsutism, and polycystic ovaries at 17 yr. The 16-yr-old male sibling spontaneously developed secondary sex characteristics at age 11 yr and exhibited Tanner IV-V pubic hair, a 6.5 x 3.0-cm surgically repaired penis, and enlarged nonnodular testes. Overnight (2200-0700 h) plasma gonadotropin (every 20 min) and gonadal steroid levels (every 2 h) under ACTH adrenal suppression revealed the following. In the male sibling, there were overall normal Tanner V male LH (3-21 mIU/mL) and FSH (1.2-13 mIU/mL) levels, normal peak frequency and amplitude of LH (70 +/- 62 min and 15 +/- 3 mIU/mL, respectively) and FSH (65 +/- 28 min and 13 +/- 3 mIU/mL), and low normal Tanner V testosterone (T) levels (11.4-17.9 nmol/L). In the female sibling, there were normal follicular phase range LH (10-28 mIU/mL) and FSH (5.1-17.2 mIU/mL) levels, normal peak frequency and amplitude of LH (96 +/- 17 min and 22 +/- 4.5 mIU/mL, respectively) and FSH (62 +/- 27 min, 13 +/- 4 mIU/mL), and early follicular phase estradiol (E2) levels (100-170 pmol/L). The LH-releasing hormone-stimulated LH response was in the normal adult range in the male and normal for the early follicular phase in the female. In contrast, ACTH and adrenal delta 5-steroid responses to CRH administration were elevated in each sibling. Gonadal suppression via Norlutin administration (30 mg/day for 3 days) after prolonged adrenal suppression by dexamethasone resulted in suppression of dehydroepiandrosterone (DHEA) and E2 in the female and DHEA and T in the male. Gonadal stimulation via hCG administration (5000 IU/day for 3 days, im) during continuous adrenal suppression resulted in a low E2 response in the female (200 pmol/L; control, 295-660 pmol/L) and a low T response in the male (15.3 nmol/L; control, 17-39 nmol/L), whereas delta 5-17-hydroxypregnenolone and DHEA levels rose 2- to 4.7-fold in each sibling. In conclusion, despite partial gonadal 3 beta HSD deficiency, the dynamics of gonadotropin and gonadal hormone secretion in these siblings indicate the absence of increased LH secretion, in contrast to the markedly increased ACTH secretion resulting from adrenal 3 beta HSD deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Responsiveness of gonadotropin secretion to infusion of an opiate-receptor antagonist in hypogonadotropic individuals.

We tested the hypothesis that suppressive effects of endogenous opiate substances are involved in certain hypogonadotropic states. For this purpose, we studied gonadotropin secretion in idiopathic hypopituitarism (five children), constitutionally delayed adolescence (five boys), and Kallmann's syndrome (three men). Endogenous opiate pathways were antagonized by the iv infusion of naloxone hydrochloride at a dose previously shown to elicit a prompt and significant increase in serum levels of LH in normal men. Under these conditions, naloxone did not increase serially sampled serum concentrations or mean urinary levels of LH: or FSH in eight patients with idiopathic hypopituitarism or Kallmann's syndrome. Gonadotropin concentrations in four of five patients with constitutional delay of adolescence also were unaffected. In one boy with clinical and biochemical indices of late pubertal development, naloxone elicited a significant increase in LH levels in blood and urine, similar to the pattern observed in normal men. In contrast to results in experimental animals, naloxone did not suppress serum PRL concentration significantly in any subject. These observations suggest that: 1) endogenous opiate mechanisms are unlikely to constitute a principal factor in maintaining hypogonadotropism in idiopathic hypopituitarism, delayed adolescence, or Kallmann's syndrome, at least acutely; 2) endogenous opiate mechanisms also cannot be implicated in the acute regulation or PRL secretion in children; and 3) the capability of adult men, but not early pubertal boys, to respond with increased gonadotropin secretion during inhibition of opiate receptors suggests that maturation of the opiate-related neuroendocrine system occurs during the course of sexual development in the human.

Integration of pulsatile gonadotropin secretion by timed urinary measurements: an accurate and sensitive 3-hour test.

The integration of pulsatile gonadotropin secretion by the radioimmunoassay of an acetone precipitation from a short-term urine sample was evaluated. FSH and LH excretion over a 3-h period was compared to the mean level of 10 blood samples obtained every 20 min for a similar time period from 71 patients. A highly significant correlation existed between blood and urine results. In addition, the gonadotropin levels obtained from a 3-h sample correlated well with the 24 h excretion of FSH and LH from the same individual. A 3-h urine collection can provide a simple, sensititve, and accurate means of assessing circulating FSH and LH levels.

Children with organic growth hormone deficiency have elevated cortisol responses to stimuli.

The aim of this study was to investigate hypothalamic-pituitary-adrenal (HPA) function in children with GH deficiency. Ninety-four patients were evaluated for GH deficiency and cortisol (F) deficiency using clinical criteria and L-dopa and insulin-induced hypoglycemia stimulation tests. They were assigned to three diagnostic groups: organic GH deficient (OGHD), idiopathic GH deficient (IGHD), and not GH-deficient (NGHD). Time series, cross-sectional, regression analysis revealed statistically significantly elevated F [>828 nmol/L (30 microg/dL)] in the OGHD group vs. the NGHD group. The value for F in the IGHD group was not different from the NGHD group. This finding suggests that dysregulation of the HPA axis is present in most children with OGH deficiency and significantly less often in children with IGH deficiency or without GH deficiency. Anatomical disruption of the control pathways for the HPA axis or stress may cause the dysregulation.

Effects of estrogen or testosterone on self-reported sexual responses and behaviors in hypogonadal adolescents.

The purpose of this study was to investigate the effects of administration of sex steroids on self-reported sexual responses and behaviors in hypogonadal adolescents. We used a randomized, double blind, placebo-controlled, cross-over, clinical trial as the experimental design. The subjects were 39 boys and 16 girls with delayed puberty. We treated girls with oral conjugated estrogen and boys with testosterone enanthate in 3 dose levels intended to simulate early, middle, and late pubertal levels. We administered a modification of the Udry sexual behavior questionnaire after each 3-month placebo and treatment period to detect the effect of sex steroids on self-reported sexual behaviors and responses. We employed a strict intent to treat statistical analytical model. The data showed significant effects of the administration of testosterone to boys causing increases in nocturnal emission and touching behaviors at the mid- and high doses. No other treatment effects on sexual behaviors or responses were seen in boys. For girls, there was a significant increase in necking caused by the administration of estrogen only at the late pubertal dose. No other treatment effects on sexual behaviors or responses were seen in girls. We noted some gender differences for thinking about sex, sexual "turn-on," and the nature of sexual behavior. The administration of physiological doses of sex steroids to boys or girls with delayed puberty have few effects on sexual behaviors and responses.

Estrogen or testosterone increases self-reported aggressive behaviors in hypogonadal adolescents.

A randomized, double-blinded, placebo-controlled cross-over clinical trial was used to determine the role of sex steroids on the development of aggressive behaviors in 35 boys and 14 girls. Depo-testosterone (to boys) or conjugated estrogens (to girls) was administered in 3-month blocks alternating with placebo at three dose levels approximating early, middle and late pubertal amounts. The Olweus Multifaceted Aggression Inventory was administered after each placebo and treatment period to ascertain the effect of sex steroids on self-reported aggressive behaviors. We employed a strict intent-to-treat analytical model. The data demonstrated significant hormone effects on physical aggressive behaviors and aggressive impulses, but not in verbal aggressive behaviors nor aggressive inhibitions in both boys and girls. These results are the first to causally relate the administration of physiological doses of sex steroids to changes in aggressive behaviors in adolescents.

The effect of chronic childhood malnutrition on pubertal growth and development.

Pubertal growth and development were compared in 342 privileged, urban children and 347 impoverished rural adolescents from Kenya. Measurements of height, weight, upper arm circumference, and triceps skinfolds revealed marked differences between the two study groups just before the onset of sexual maturation. These differences were also found in the early stages of puberty but notable catch-up was evident throughout the later period of the maturational process. Early stages of sexual maturity were delayed by 3 yr in malnourished boys with a 2.1-yr lag in the age of onset of menarche in rural girls. Derived estimates of body fat as well as direct anthropometry revealed that the onset of puberty is not size related under the circumstances of chronic childhood malnutrition.

Age of puberty: data from the United States of America.

In an attempt to determine whether the secular trend toward an earlier onset of puberty has continued over recent decades in the United States of America, published reports concerning the age of attainment of pubertal events have been reviewed. Such reports are very limited and vary in both design and inclusive ages of study subjects. Among females, two recent large cross-sectional studies indicate that fifty percent of females in the United States attain Tanner breast stage 2 at 9.5 to 9.7 years of age. This is younger than previously thought, although adequate earlier studies of girls in the United States are not available for comparison. These two studies also indicate that about 14% of girls attain Tanner stage 2 while 8 years of age; one study extends earlier reporting that about 6% exhibit onset of breast development while 7 years of age. There is no evidence that the age of menarche or the attainment of adult (Tanner 5) breast development has decreased over the past 30 years. The data also suggest an earlier onset of Tanner stage 2 pubic hair but no change in attainment of stage 5. Among males, pubic hair may be appearing at younger ages, but data are inadequate or too inconsistent to allow firm interpretation. The lack of standardization of genital criteria of pubertal onset in the male makes any conclusions regarding secular trends impossible. In summary, earlier secular trends over recent decades related to better health, improved nutrition or socio-economic status, or any putative influence by endocrine disrupters cannot be verified.

Body composition development of adolescent white females: the Penn State Young Women's Health Study.

OBJECTIVE: To obtain simultaneous and longitudinal measures of height, weight, total body bone mineral content, total body bone mineral density, percentage of body fat, lean body mass, and body mass index in healthy white females between the ages of 11 and 18 years. DESIGN: A longitudinal, observational study. SETTING: University medical center in a small city. STUDY PARTICIPANTS: At initiation in 1990, 112 premenarchal, healthy girls were enrolled. Results presented in this report are based on measurements made on the 82 participants who remained in the study in 1996 and for whom we had comprehensive measurements. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Dual-energy x-ray absorptiometry was used to obtain measurements of total body bone mineral content, total body bone mineral density, percentage of body fat, and lean body mass every 6 months for the first 4 years of the study and yearly thereafter. RESULTS: The mean age for peak velocity and peak accumulation for each measurement was as follows: height, 11 1/2 and 17 1/2 years, respectively; weight, 11 1/2 and 17 1/2 years; body mass index, 11 1/2 and 17 1/2 years; percentage of body fat, 11 1/2 and 13 1/2 years; lean body mass, 12 and 17 1/2 years; total body bone mineral content, 13 1/2 and 17 1/2 years; and total body bone mineral density, 13 1/2 and 17 1/2 years. CONCLUSIONS: Among a healthy population of white females, the age of peak velocities for height, weight, body fat, and lean body mass occur at 11 1/2 to 12 years. Thus, peak soft-tissue velocities precede hard-tissue velocities by about 2 years, with peak accumulation of all tissue components being reached, on average, by age 17 1/2 years.

Plasma testosterone response to short-term human chorionic gonadotropin administration in men with follicle-stimulating hormone suppressed by exogenous estrogen.

In order to investigate the role of FSH in Leydig cell function, six men were given four daily injections of HCG (4,000 IU) while receiving oral ethinyl estradiol. The peak testosterone levels in these subjects were contrasted to the results obtained in seven men who received HCG without additional exogenous steroid treatment. Urinary and plasma FSH was suppressed to 26% and 50%, respectively, of basal values by the estrogen treatment. Peak plasma testosterone determinations following HCG did not differ in the two groups of subjects. Additionally, an early pubertal boy had a normal HCG-induced testosterone rise while his urinary FSH was suppressed by estradiol to lower than prepubertal levels. The data indicate the short-term FSH suppression does not alter testicular responsivity to short-term HCG administration. A role for FSH in Leydig cell testosterone production in men has yet to be demonstrated.

The effect of long-term opiate antagonist administration to pubertal boys.

To test further the hypothesis that opiatergic pathways controlling gonadotropin production may be functional during early to mid adolescence, nine pubertal boys with bone ages ranging from 10 to 15 were given the long-acting opiate antagonist, naltrexone, for up to 4 weeks. Urinary gonadotropin measurements were assessed before, during, and after drug administration. In three early to mid-pubertal boys who received naltrexone for 3 to 4 weeks, LRH testing was also performed. No evidence of a stimulatory FSH or LH response to naltrexone was found in any of the patients evaluated. The data do not support the operation of an opiate-mediated mechanism in the control of pubertal onset in man.

Adolescent pregnancy in Africa: a programmatic focus.

An increasing age of marriage coupled with high rates of premarital sexual activity have caused notable changes in the incidence of out-of-wedlock pregnancies in much of the developing world. In Africa, local policy makers are beginning to perceive the medical implications of these changes as the youth component of illicit abortion, maternal mortality, and sexually transmitted disease becomes more visible. Other social issues, which include school leaving, unemployment, violence and drug abuse, are emerging among the young people of Africa as elsewhere. A successful approach to these problems will require a multi-disciplinary perspective of the adolescent with professional contributions from the arenas of health, behavior, education and sociology. This report stresses the thesis that adolescents constitute a unique sub-population whose special needs must be recognized in Africa; strong institutional facilities are required, backed by committed advocates and leadership for the youth sector. Programs initiated in Kenya and Zimbabwe serve as useful models for other African locales.