Role of estrogen and androgen in pubertal skeletal physiology

Since both estrogen and androgen are present in each sex, it has been difficult to discern the exact role that each sex steroid plays in skeletal physiology. However, studying clinical syndromes in which there is either only estrogen or androgen action has allowed us to gain insight into the unique role that each sex steroid plays in the growing skeleton. In complete androgen insensitivity syndrome (AIS) the only functional sex steroid receptor is that for estrogen. Effected XY females have a pubertal growth spurt that is typical of normal females, both in magnitude and timing. Individuals with AIS have a mild reduction in bone density but it is difficult to distinguish whether this is the result of androgen resistance or estrogen deficiency. These observations suggest that estrogen action only is sufficient to induce a normal pubertal growth spurt, epiphyseal maturation, and near normal bone mineral accretion in women. Until recently, the skeletal effects of estrogen were not thought to be of importance in the male. Conventional wisdom dictated that, in the male, testosterone mediated these skeletal changes. The notion that estrogen is of little importance in the male has been challenged by the recent discovery of two human syndromes in which estrogen action is lacking. In males with either estrogen resistance (inability to respond to circulating estrogen) or aromatase deficiency (inability to synthesize estradiol), as a result of the lack of estrogen action, a pubertal growth spurt does not appear to occur. Furthermore, complete epiphyseal maturation does not take place allowing for continued growth in adulthood and resultant tall stature. Finally normal bone mineral accretion does not take place resulting in severe osteoporosis. These findings indicate that estrogen plays a critical role in skeletal physiology of males as well as females.     

Estrogens and growth: review

Longitudinal bone growth occurs in the growth plate through a process where resting zone chondrocytes are recruited to start active proliferation and then undergo differentiation, followed by apoptosis and later mineralization. Bone growth is controlled by several hormones and growth factors acting systemically and/or locally in the growth plate. From studies of individuals with aromatase deficiency and a man with defective estrogen receptor (ER)-alpha it has become clear that estrogen action is indispensable for normal pubertal growth and growth plate fusion. Any functional role of ERbeta has not yet been defined in the human growth plate. As new specific modulators of estrogen receptors are developed, these could offer more specific ways to modulate longitudinal growth and growth plate fusion. It is difficult to extrapolate data obtained in experimental animals, as clear species differences exist, emphasizing the need for new models allowing studies in human growth plate cartilage.     

Androgen and estrogen treatment, alone or in combination, differentially influences bone maturation and hypothalamic mechanisms that time puberty in the male rhesus monkey (Macaca mulatta)

In higher primates, the mechanisms that govern the ontogeny of gonadotropin-releasing hormone pulse generator activity and that, therefore, dictate the timing of the onset of puberty remain intriguingly elusive. Groups of three infant agonadal male monkeys were treated with sex steroids [17beta-estradiol (E(2)), testosterone (T), or dihydrotestosterone (DHT)] for the first year of life to advance bone age (BA). E(2) and T resulted in a significant advancement of BA, and a pubertal BA of 130 wk was attained at a mean chronological age of 64 and 67 wk, respectively. In contrast, DHT failed to advance BA during treatment but stimulated linear growth. All animals exhibited a pubertal resurgence in LH secretion, but the timing of this developmental event did not differ between treatment and control groups (the mean for all animals was 117.7 +/- 8.9 wk). Two of the three T-treated animals, however, displayed a pubertal LH resurgence at a remarkably young age (70 and 76 wk of age) that coincided with T withdrawal. During the period of steroid treatment, all three groups were significantly heavier than the controls. The rate of body weight gain was most rapid in the DHT-treated group. Steroid treatments also resulted in accelerated linear growth. Body weight gain and linear growth continued at the same rate as controls after withdrawal of treatment. These data indicate that attainment of a pubertal BA may be a necessary but not a sufficient factor to trigger the onset of puberty. The results not only are consistent with the view that androgen-induced skeletal maturation in males is mediated by estrogen receptor activity but also indicate that androgen receptor activity contributes to the pubertal growth spurt in males.     

Oxandrolone therapy in patients with Turner syndrome.

Long-term, low-dosage androgen treatment of patients with Turner syndrome results in more rapid growth and significantly greater adult height than in control patients who receive only estrogen for pubertal development. Seventeen patients treated with oxandrolone for one year and ten treated for two years had significantly greater growth velocities during than before treatment. Mean adult height of 25 patients treated with oxandrolone, fluoxymesterone, or both was significantly taller than the height of adult patients with Turner syndrome treated with estrogen only. Excessive skeletal maturation was not generally observed.     

Effects of phytoestrogen on sexual development

Phytoestrogen is an estrogenic compound that occurs naturally in plants. The most common sources of phytoestrogen are soybean products, which contain high levels of isoflavones. This compound, which has structural similarity with estrogen, can act as an estrogen receptor agonist or antagonist. Animal studies provide evidence of the significant effects of phytoestrogen on sexual development, including altered pubertal timing, impaired estrous cycling and ovarian function, and altered hypothalamus and pituitary functions. Although human studies examining the effects of phytoestrogen on sexual development are extremely limited, the results of some studies agree with those of the animal studies. In this paper, we review the possible mechanism of phytoestrogen action and the evidence showing the effects of phytoestrogen on sexual development in animal and human studies.     

Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia

OBJECTIVES: To assess the efficacy of the anti-estrogens tamoxifen and raloxifen in the medical management of persistent pubertal gynecomastia. STUDY DESIGN: Retrospective chart review of 38 consecutive patients with persistent pubertal gynecomastia who presented to a pediatric endocrinology clinic. Patients received reassurance alone or a 3- to 9-month course of an estrogen receptor modifier (tamoxifen or raloxifene). RESULTS: Mean (SD) age of treated subjects was 14.6 (1.5) years with gynecomastia duration of 28.3 (16.4) months. Mean reduction in breast nodule diameter was 2.1 cm (95% CI 1.7, 2.7, P <.0001) after treatment with tamoxifen and 2.5 cm (95% CI 1.7, 3.3, P <.0001) with raloxifene. Some improvement was seen in 86% of patients receiving tamoxifen and in 91% receiving raloxifene, but a greater proportion had a significant decrease (>50%) with raloxifene (86%) than tamoxifen (41%). No side effects were seen in any patients. CONCLUSION: Inhibition of estrogen receptor action in the breast appears to be safe and effective in reducing persistent pubertal gynecomastia, with a better response to raloxifene than to tamoxifen. Further study is required to determine that this is truly a treatment effect.     

Mechanisms of reduced body growth in the pubertal feminized male rat: unbalanced estrogen and androgen action on the somatotropic axis

It is well known that the sex difference in body growth at puberty is modulated by a complex interplay between sex steroids and somatotropic axis; however, the exact role played by sex steroids remains a matter of controversy. The aim of this study was to assess the mechanisms by which sex steroids regulate body growth during pubertal development. Flutamide, a non-steroid-blocking androgen receptor, was subcutaneously administered to 30-d-old male Wistar rats for 4 wk. The blockade of the androgen receptor led to a marked elevation in serum testosterone and an increment in serum estradiol. Flutamide administration decreased body weight gain, serum IGF-I levels, hepatic IGF-I mRNA, and GH receptor mRNA content. There were no significant changes in serum GH concentration, pituitary GH reserve, and pituitary GH mRNA content. Flutamide lowered hypothalamic somatostatin mRNA content and augmented hypothalamic immunoreactive somatostatin stores, but did not alter hypothalamic immunoreactive GH-releasing factor stores. Our findings indicate that during pubertal development of the male rat, the imbalance between androgen and estrogen actions determines an abnormal somatic growth, which is at least partly exerted through the peripheral or hepatic modification of the somatotropic axis that occurs under the high or exclusive action of estrogens. Potential implication of coincident sex-specific regulated mode of pulsatile GH secretion cannot be excluded from this random serum GH sample study.     

Adolescent gynecomastia. Differential diagnosis and management

Gynecomastia signifies a transient or permanent disturbance in steroid hormone physiology and occurs when the male breast is exposed to a decreased ratio of androgen to estrogen. This article discusses pubertal and pathologic gynecomastia, diagnostic approach, and treatment.     

Preadolescent and adolescent endocrinology: physiology and physiopathology. II. Hormonal changes during abnormal pubertal development.

Based on the knowledge of the physiology of regulation of gonadotropins and gonadal steroids, basal levels of these hormones might be indicative of the etiologic factors of abnormal pubertal development. In addition, stimulatory tests may help in the diagnosis of such conditions. It is interesting that the pubertal maturation of the adrenal cortex is independent of the hypothalamic-pituitary-gonadal axis. The role of the adrenal cortex for the pubertal development remains questionable: adrenal androgens are low in isosexual precocious puberty, low in delayed adolescence, and normal in hyper- or hypogonadotropic hypogonadism. The importance of this role is doubled in congenital virilizing adrenal hyperplasia. When the disease is untreated, although adrenal androgens in excess advance bone age and hypothalamic maturation, girls remain prepubertal. When the therapeutic control is good, normal puberty occurs. The action of the adrenal androgens on growth and puberty remains to be determined.     

Menstrual disorders. Amenorrhea.

Adolescent patients with amenorrhea often present to primary care providers. A basic understanding of menstrual and pubertal physiology enables clinicians to initiate the clinical evaluation. A thorough history and physical examination focusing on pubertal development indicate the appropriate diagnostic algorithm. Usually, an accurate diagnosis can be obtained quickly. Management includes restoring ovulatory cycles if possible, replacing estrogen when necessary, reassurance, and re-evaluation.     

Leptin levels in boys with pubertal gynecomastia

BACKGROUND: It has been reported that there is a relationship between circulating leptin and sex steroid hormones and leptin is able to stimulate estrogen secretion by increasing aromatase activity in adipose stromal cells and breast tissue. Leptin receptors have been also shown in mammary epithelial cells and it has been suggested that leptin is involved in the control of the proliferation of both normal and malignant breast cells. AIM: To investigate circulating leptin levels in boys with pubertal gynecomastia. METHODS: Twenty boys with pubertal gynecomastia who were in early puberty and had no obesity, and 20 healthy individuals matched for age, pubertal stage and body mass index (BMI) with the study group, were enrolled in the study. Body weight, height and left midarm circumference (MAC) and left arm triceps skinfold thickness (TSF) were measured and BMI was calculated. A fasting blood sample was collected and routine hormonal parameters including prolactin, beta-human chorionic gonadotropin (betaHCG), total and free testosterone, estradiol, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, androstenedione (AS) and dehydroepiandrosterone sulfate (DHEAS) levels were studied. Serum leptin levels were analyzed using radioimmunoassay. RESULTS: The mean ages of the study and control group were not different (13.9 +/- 0.89 and 14.2 +/- 0.66, respectively). No significant difference was found for BMI, MAC and TSF values between the two groups. There was no significant difference for hormonal parameters including FSH, LH, total and free testosterone, estradiol, AS, DHEAS and estradiol/total testosterone ratio between boys with pubertal gynecomastia and the controls. Serum leptin levels were found significantly higher in the study group compared with the healthy controls (5.58 +/- 0.81 and 2.39 +/- 0.29 ng/ml, respectively; p <0.001). No correlation could be determined between serum leptin levels and hormonal parameters. CONCLUSION: The presence of higher leptin levels in boys with pubertal gynecomastia indicates that leptin may be involved in the pathogenesis of pubertal gynecomastia. The role of circulating leptin in pubertal gynecomastia is probably related to increase in estrogen and/or estrogen/ androgen ratio by the stimulating effect of leptin on aromatase enzyme activity in both adipose and breast tissues, or a direct growth stimulating effect of leptin on mammary epithelial cells, or increase in sensitivity of breast epithelial cells to estrogen with inducing functional activation of estrogen receptors by leptin in breast tissue.     

Ultrasonic assessment of the development of the uterus in childhood

In 150 girls from the newborn period up to the 18. year the size of the uterus was measured by sonography. In all children the length, width, depth and volume of the uterus as well as its shape and other signs of development were determined. In the newborn period and in the following first months of life an estrogen stimulated uterus with the shape of a drop could be shown. The size of the uterus decreased till the end of the first year. The length of the uterus in the neonatal period was 4.0 +/- 0.5 cm, the volume was 3.6 +/- 1.9 cm3. In the following rest phase up to the age of 8 years the length of the uterus was 2.8 +/- 0.4 cm and the volume was 1.2 +/- 0.4 cm3. The shape of the uterus in this age group was tubular. One to two years before secondary pubertal signs could be shown, sonography already demonstrated the beginning of pubertal uterus growth. In the postpubertal period the uterus had the typical pear shape with a corpus/cervix-relation of 2:1. In the postpubertal period the length was 6.8 +/- 1 cm with a volume of 33 +/- 22 cm3. The knowledge of the normal developmental dates of the uterus in children is essential for the diagnosis of malformations and tumours of the pelvis, but also for the diagnosis of distorted puberty such as pubertas praecox, pubertas tarda, amenorrhea and growth retardation.     

Growth Hormone Treatment in Short Children with Chronic Renal Failure and after Renal Transplantation: Combined Data from European Clinical Trials

Growth retardation is common in children with chronic renal failure (CRF). To investigate the efficacy and safety of recombinant human growth hormone treatment in such children and in children after renal transplantation, 43 prepubertal children with CRF, and 30 prepubertal and 25 pubertal patients with a renal transplant were studied. Data are reported for 31, 26 and 17 of these patients, respectively. Median height velocity increased from 4.2 to 9.8 cm/year during the first year of treatment, and to 6.8 cm/year during the second year of treatment in the patients with CRF. In the prepubertal transplant group, median height velocity changed from 3.5 to 8.4 cm/year during the first year and to 5.4 cm/year during the second year. In the pubertal transplant group, median height velocity increased from 3.2 to 6.6 cm/year during the first year and was 4.5 cm/year during the second year. The gain in height SDS for the prepubertal children in both the CRF and transplant groups was approximately 1 SD over 2 years. Treatment was well tolerated, and renal function did not change significantly in any group.     

Leptin and soluble leptin receptor levels in obese children in fasting and satiety states

AIM: To investigate the role of soluble leptin receptors in leptin resistance in obese children. METHODS: Thirty-one obese children (16 boys and 15 girls) with a median age of 12.1 years and 15 age- and sex-matched controls were included in the study. Leptin and soluble leptin receptor levels were measured in fasting and satiety states. RESULTS: Serum leptin levels were significantly higher and soluble leptin receptor levels were significantly lower in obese children compared to controls in fasting and satiety states. In obese children, there was a high and inverse correlation between leptin levels and soluble leptin receptor levels after fasting. Prepubertal obese children had lower leptin and higher soluble leptin, receptor levels compared to pubertal children in both states. CONCLUSION: In this study, being the first to consider both fasting and satiety states, obese children were found to have higher leptin, but lower soluble leptin receptor levels, compared to controls. With these findings, it can be postulated that leptin resistance in obese children originates from a defect of soluble leptin receptor production.     

Prediction of Pubertal Growth at Start of Estrogen Replacement Therapy in Turner Syndrome

In estrogen replacement therapy in Turner syndrome, there is no report which recommends the timing of the start of estrogen therapy in relation to height or adult height prediction. We have established a prediction model for pubertal growth (height difference from the start of estrogen therapy until adult height) at the start of estrogen replacement therapy. Twenty-seven Turner girls without spontaneous puberty were divided into two groups according to birth years; Group I consisted of 16 patients born from 1980–1989 and Group II consisted of 11 patients born before 1980. Using clinical characteristics from Group I, stepwise multiple regression analysis taking pubertal growth as an independent factor, and chronological age, bone age (TW2 RUS method standardized for Japanese children), height and height SDS as dependent factors revealed following formula (p<0.001, R2=0.737): (pubertal growth) = – 1.01x (Chronological age at start of E) – 0.326x (height at start of E) – 1.779x (bone age at start of E) + 90.997. Predicted adult height was obtained by adding predicted pubertal growth to height at the start of estrogen therapy. The mean absolute difference between real adult height (tallest height after height velocity less than 1 cm/yr) and predicted adult height was 1.6 ± 0.9 cm (0.3–2.8 cm) in Group I. When this prediction model was applied to Group II, The mean absolute difference between real adult height and predicted adult height was 1.0 ± 0.7 cm (0.1–2.0 cm). A prediction model for pubertal growth at start of estrogen therapy in Turner syndrome was obtained. Using this prediction model, the timing of the start of estrogen therapy can be decided in consideration of the patient’s desired adult height.     

Randomised controlled trial of recombinant human growth hormone in prepubertal and pubertal renal transplant recipients. British Association for Pediatric Nephrology.

AIMS: To evaluate the efficacy (height velocity (HV), change in height standard deviation score (delta HSDS)), and safety (glomerular filtration rate (GFR), incidence of rejection, and calcium and glucose metabolism) of recombinant human growth hormone (rhGH) treatment after renal transplantation. DESIGN: A two year randomised controlled trial. SUBJECTS: Fifteen prepubertal and seven pubertal children: mean (SD) age, 13.0 (2.6) and 15.2 (2.4) years, respectively; mean (SD) GFR, 51 (30) and 48 (17) ml/min/1.73 m2, respectively. Six prepubertal and three pubertal children were controls during the first year; all received rhGH in the second year. RESULTS: In the first year, mean (SE) HV and delta HSDS in the prepubertal treated group increased compared with controls: 8.1 (0.9) v 3.7 (0.6) cm/year and 0.6 (0.1) v -0.3 (0.2), respectively. In the pubertal treated group, mean (SE) HV and delta HSDS were also greater: 10.1 (0.6) v 3.9 (1.3) cm/year and 0.6 (0.1) v -0.1 (0.2), respectively. Comparing all treated and control children, there was no significant change in GFR: treated group, mean (SE) 9.9 (5.4) ml/min/1.73 m2 v control group, -1.6 (7.6) ml/min/1.73 m2. There were also no differences in the incidence of rejection in the first year: eight episodes in 13 patients v five episodes in nine patients, respectively. Phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and fasting insulin concentrations rose during the first year of treatment, but not thereafter. In the second year of treatment, HV remained above baseline. CONCLUSION: Treatment with rhGH improves growth in prepubertal and pubertal children with renal transplants, with no significant change in GFR or the incidence of rejection. Phosphate, ALP, PTH, and insulin increased during the first year of treatment.     

Relationship of somatomedin-C concentrations to pubertal changes

The plasma somatomedin-C concentration increases above adult values during the teenage years. We studied the relationship of pubertal variables and the adolescent growth spurt to the changes in plasma total Sm-C concentration in normal volunteers and in boys with delayed puberty. The rise in plasma Sm-C concentrations was gradual and correlated positively with pubertal variables rather than with age. By midpuberty, plasma Sm-C had usually risen twofold. The Sm-C level in midpubertal girls (3.1 +/- 1.1, SD, U/ml) was greater than that in midpubertal boys (1.9 +/- 0.50, P less than 0.05). The Sm-C concentration in sexually mature teenagers was two to three times greater than that of adults. Both estrogens and androgens correlated independently with the plasma Sm-C concentration. The data are compatible with the hypothesis that pubertal estrogen or testosterone levels cause an increase in Sm-C, an effect possibly mediated by stimulation of growth hormone secretion, whereas greater estrogen exposure inhibits Sm-C generation, possibly by a direct effect. Plasma Sm-C concentrations correlated significantly with linear growth velocity until the age of peak pubertal growth velocity. Maximum Sm-C values were observed after the peak pubertal growth velocity was achieved, as height velocity was decelerating, and remained above adult levels for at least two to six years, at which time linear growth had virtually ceased. In boys with delayed puberty, Sm-C values resembled those of boys of like pubertal stage more closely than those of boys of similar age. Depressed plasma Sm-C values were found in some boys with delayed puberty; however, these did not preclude subsequent normal linear growth during sexual maturation.     

Rathke's cleft cysts in children and adolescents: association with female puberty

There are few pediatric data regarding manifestations and outcomes of Rathke's cleft cysts (RCC). We retrospectively reviewed 13 cases treated at Massachusetts General Hospital over 10 years. Age at presentation was 12-17 years, except for one 7-year-old who presented with sexual precocity. There was a female preponderance [11 females, 2 males, p = 0.01], and all were pubertal at diagnosis. Common features at presentation were headaches (11/13), endocrine abnormalities (5/13) and visual disturbances (2/13). Four patients underwent transsphenoidal surgery. Symptoms improved in all but one, in whom headaches persisted. Recurrent growth in one patient was treated successfully by excision. For conservatively treated patients, cyst size was unchanged over follow-up (6 months-5 years). Female preponderance and pubertal presentation suggest a possible link between sex hormones and RCC pathogenesis. Although estrogen and progesterone receptor immunostaining was negative in the cyst lining, estrogen receptor immunostaining was positive in adjacent pituitary cells. Further investigations regarding this issue are warranted.     

Acute bacterial meningitis in The Gambia: a four-year review of paediatric hospital admissions

Over a 4 year period, 1991 to 1994, 420 patients with acute bacterial meningitis were admitted to a tertiary urban hospital in The Gambia. Organisms were isolated from the cerebrospinal fluid in 64 per cent of cases. In the neonatal period Streptococcus pneumoniae was the single most common organism isolated. Amongst infants and children the two major pathogens were Haemophilus influenzae and S. pneumoniae. In the first year of life, children with S. pneumoniae meningitis were younger than those with H. influenzae infection (median age 3 months versus 6 months, p < 0.00003) and they had a higher case fatality rate (37 per cent versus 17 per cent, p = 0.002). In view of the high case fatality rate, there is a need to review overall case management. This will include a review of more effective antibiotics, the possible role of dexamethasone, and the inclusion of efficacious vaccines against H. influenzae and S. pneumoniae disease.     

Effects of growth hormone (GH) and insulin-like growth factor-I therapy in patients with gene defects in the GH axis

We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, a GH1 signalling peptide mutation, or a GH receptor mutation, with particular regard to treatment modalities (GH, rhIGF-I) and final height. Patients with GH1 gene defects developed anti-GH antibodies (GH-Ab) following GH treatment. Surprisingly, growth response to GH was unrestricted in one girl, who reached a final height within her target height range, whereas her cousin with the identical genetic defect responded far less favourably. Variability in the growth inhibiting potency of GH-Ab may therefore depend on genetic disposition, specific epitopes, or induction of immunological tolerance. Growth response during rhIGF-I treatment carried out in three of the patients was moderate, but pubertal development and bone age acceleration occurred in the two patients treated at pubertal age. GH resistance, either caused by GH-Ab or GH receptor mutations, is still difficult to treat and results in a heterogeneous outcome.