|Year : 2018 | Volume
| Issue : 1 | Page : 6-13
Evaluation of status of puberty in children and adolescents with end-stage renal disease undergoing maintenance hemodialysis
Mohamed Abdelaziz El-Gamasy1, Nagy M Aboelhana1, Maher A Abdelhafez1, Mohamed K Zahra2
1 Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Clinical Pathlogy, Tanta Faculty of Medicine, Tanta, Egypt
|Date of Web Publication||26-Mar-2018|
Dr. Mohamed Abdelaziz El-Gamasy
Department of Pediatric, Tanta University Hospital, El Giesh Street, Tanta, Gharbia
Source of Support: None, Conflict of Interest: None
Background and Objectives: The testosterone and estradiol sex hormones are susceptible to significant pathophysiological alterations in children with chronic renal failure under regular hemodialysis, leading to delayed pubertal maturation. This study aims to evaluate the plasma levels of testosterone and estradiol hormones in children and adolescents with end-stage renal disease (ESRD) under regular hemodialysis. Materials and Methods: This study was carried out on 40 children with ESRD under regular hemodialysis (20 males and 20 females) who were attending the Pediatric Department of Tanta University Hospital. Forty children, age- and sex-matched, were chosen and served as controls. All patients and controls were subjected to full history taking, thorough clinical examination including weight, height, body mass index (BMI), mid-arm circumference (MAC), arterial blood pressure, pubertal assessment according to Tanner's classification, routine laboratory investigation including complete blood count, blood urea, blood urea nitrogen, serum creatinine, serum albumin, serum electrolytes (ionized calcium, potassium, and phosphorus), serum total testosterone levels in boys, and serum estradiol levels in girls. Results: The mean values of weight, height, BMI, and MAC of patients' group was significantly lower than that of control group. The total male serum testosterone level in the male patients' group and the serum estradiol level in the female patients' group was significantly lower than that in control group. There were significant positive correlations between the age development and Tanner's stage development, male total serum testosterone level and female serum estradiol levels in both patients and control groups. Conclusions: The pubertal development of children and adolescents with ESRD is usually delayed as proven by decreased serum male total testosterone and female Estradiol hormones levels which suggest a state of hypogonadism. Nutritional therapy especially optimizing protein intake to prevent hypoproteinemia, adequate dialysis and correction of anemia are clinical trials.
Keywords: Adolescents, chronic renal failure, children, estradiol, testosterone
|How to cite this article:|
El-Gamasy MA, Aboelhana NM, Abdelhafez MA, Zahra MK. Evaluation of status of puberty in children and adolescents with end-stage renal disease undergoing maintenance hemodialysis. J Integr Nephrol Androl 2018;5:6-13
|How to cite this URL:|
El-Gamasy MA, Aboelhana NM, Abdelhafez MA, Zahra MK. Evaluation of status of puberty in children and adolescents with end-stage renal disease undergoing maintenance hemodialysis. J Integr Nephrol Androl [serial online] 2018 [cited 2018 Oct 20];5:6-13. Available from: http://www.journal-ina.com/text.asp?2018/5/1/6/228491
| Introduction|| |
The sex hormones are susceptible to pathophysiological alterations in chronic renal failure, which may lead to delayed or arrested pubertal maturation. These endocrine disorders result in growth failure  and increase the difficulties of transition from childhood to adulthood, and thus sexual dysfunction is followed. Puberty delay was reported in more than half of the girls and one-third of the boys with end-stage renal disease (ESRD). Variable mechanisms were attributed to delayed puberty in these children  including neuroendocrine impairment in the pituitary-gonadal axis, peripheral alterations due to uremia, gonadal damage and impaired regulation of gonadotropin secretion.
The aim of the work
This study aims to evaluate the plasma level of testosterone and estradiol hormones in children and adolescents with chronic renal failure under regular hemodialysis.
| Materials and Methods|| |
This study was carried out on 40 children and adolescents with ESRD under regular hemodialysis. Their ages ranged from 10 to 18 years with a mean value of 14.63 ± 2.66 years, they were 20 males and 20 females who were attending the Pediatric Nephrology Unit of Pediatric Department of Tanta University Hospital from May 2016 to May 2017. Forty children, age- and sex-matched, were chosen and served as controls (20 males and 20 females). The study was conducted after approval from the ethical committee of the Faculty of Medicine, Tanta University and informed written parental consents.
All patients were undergoing regular hemodialysis; dialysis was started when glomerular filtration rate is equal or <15 mL/min/1.73 m 3. Hemodialysis sessions were performed times per week with each dialysis session lasting for 3 to 4 h. Patients were dialyzed on Fresenius 4008-B dialysis machine (Germany) at blood flow rate = 2.5 × weight (kg) +100 mL/min, using polysulfane hollow fiber dialyzers suitable for the surface area of the patients (Fresenius F3 = 0.4 m 2, F4 = 0.7 m 2, F5 = 1.0 m 2, and F6 = 1.2 m 2). Bicarbonate dialysis solutions were used. All patients were receiving supportive therapy in the form of subcutaneous erythropoietin in a dose of 50 IU/kg/session, IV iron dextran 100 mg/kg/week, oral folic acid 1 mg/day, oral calcium 1000 mg/day, oral vitamin D (one alpha) in a dose of 0.01–0.05 μg/kg/day, and oral antihypertensive medications for hypertensive patients.
All children with ESRD and treated by regular maintenance hemodialysis.
Patients of primary endocrinal diseases (e.g. Type 1 Diabetes mellitus) using drugs known to affect testosterone or estradiol hormone levels, Children who completed puberty before the onset of ESRD.
All patients and controls were subjected to the following.
Full history taking
It includes age and sex. Child's previous growth and development, the precise timing and sequence of the physical and behavior changes of puberty, timing of appearance of axillary and pubic hair, onset of menarche (the onset of menstruation) for females and onset of the first ejaculation for males.
For assessment of nutritional and developmental status  which include:
Weight – Which was recorded with minimal clothing using electronic weight scale in Kilograms.
Height – Measuring the distance from the vertex to the base of the heel in centimeters using a stadiometer in standing position
Body mass index (BMI) – Which was calculated by Formula
BMI = weight (kg)/(height [m])2.
Mid-arm circumference (MAC) – Measurement of the circumference of the left upper arm at the mid-point between the tip of the shoulder (olecranon process) and the tip of the elbow (the acromion process) in centimeters.
Including arterial blood pressure which was measured by auscultatory method using a mercury sphygmomanometer, in the semi-sitting position after 10 min of rest, in the nonfistula arm using an appropriate sized cuff and was taken as the mean value of 3 successive readings in 3 different days.
Rating of genital development was assessed according to Tanner's classification  which assess:
- In both sexes – Pubic and axillary hairs.
- In male only:
- The length and width of the left and right testicles was measured by metered tape
- The stretched penile length in the flaccid state was measured with a rigid tape from the pubopenile skin junction to the top of the penis, excluding the prepuce under maximal but not painful extension
- The penile circumference was measured at the base of the penis “close to the pubis” with a measuring tape
- For obese males, the abdominal adipose tissue was shifted manually to one side to measure penile length and circumference).
In females only:
- Bras are labeled with letter indicating the depth of the cups which cradle the breasts
- Breast volume measurement using graduated cylinder and elevation and areola is determined.
Puberty is preceded by adrenarche (the early appearance of axillary and pubic hair) between 6 and 10 years of age. Which can be transient and disappear before the onset of true puberty.
On average, girls begin puberty at ages 10–11 years. And usually complete puberty by ages 15–17, while boys begin puberty at ages 11–12 years, and usually complete puberty by ages 16–17 years. Onset of menarche for females between ages 12 and 13 years while onset of the first ejaculation for males at the age of 13 years.
Delayed puberty is defined as the absence of pubertal onset by the expected age or once puberty has commenced, failure of appropriate progression. Boys are considered to have delayed puberty if they reach the age of 13 years without evidence of pubertal changes.
Routine laboratory investigation
- Complete blood count: By an automated analyzer
- Blood urea, blood urea nitrogen (BUN), and serum creatinine
- Serum albumin and serum electrolytes (ionized calcium, potassium, and phosphorus)
- Venous blood morning samples were withdrawn just before dialysis sessions.
Serum total Testosterone levels in boys
- Kit supplied by (TOSOH BIOSCIENCE).
Serum Estradiol levels in girls
- Samples were collected in puberty girls during the follicular phase of menstrual cycle (from the day 7 to the day 10, from last menstrual period to record the estrogen surge)
- Kit supplied by (TOSOH BIOSCIENCE).
Statistical package for social science (SPSS) version 18.0 Research Methodology, Methods and Techniques, 2nd, New Delhi, India was used for analysis of data. Data were summarized as mean ± standard error of the mean. Nonparametric test (Mann–Whitney) was used for analysis of 2 independent quantitative variables. Pearson's correlation was also done where the r value was considered weak if <0.25, mild if >0.25–<0.5, moderate if >0.5–<0.75, and strong if >0.75. P value was considered statistically significant if <0.05.
| Results|| |
[Table 1] summarizes demographic data of the studied patients and control groups as regard age, sex, and weight.
The age ranged from 10 to 18 years with mean 14.63 ± 2.66 in patients group and 14.25 ± 2.64 in control group. Duration of dialysis in patients group ranged from 13 to 144 months with mean 57.15 ± 37.18. The mean values of anthropometric measurements including weight, height, BMI, and MAC of patients group was significantly lower than that of control group. Both systolic and diastolic blood pressures of the patient's group were significantly higher than that in control group (P< 0.05).
[Table 2] summarizes routine laboratory data of the studied patients and control groups, there was significant increase in levels of blood urea, BUN, serum creatinine serum potassium, and serum phosphorus levels in patients group when compared to control group (P< 0.05).
|Table 2: Routine investigations of the cases group and the control group|
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However, there was a significant decrease in levels of hemoglobin (Hb) percentage, hematocrit values, platelet count total leukocytic count/white blood cells count, serum albumin, and serum ionized calcium in patients group when compared to control group.(P< 0.05).
[Table 3] and [Figure 1] show no statistically significant difference between the patients and the control groups as regard Tanner's stage development (P > 0.05).
|Table 3: Tanner's stage distribution between the patients and control groups|
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[Table 4] clarifies serum levels of sex hormones in the studied patients and control groups; the total male serum testosterone level in the male patient's group was significantly lower than that in the male control group. The female serum estradiol level in the female patient's group was significantly lower than that in the female control group (P< 0.05).
|Table 4: Serum levels of sex hormones in the studied patients and control groups|
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[Table 5] shows that there was significant positive correlations between the age development and Tanner's stage development in both the patient's group where (P = 0.001) [Figure 2], and the control group (P = 0.001), but less significant in cases group.
|Table 5: Correlation between the age development and tanner's stage development and serum sex hormones levels in both the patents and the control groups|
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|Figure 2: Correlation between tanner stages and age of the studied patients|
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Furthermore, there was a significant positive correlation between the age development and male total serum testosterone level in both male patients group (P = 0.01) [Figure 3], and male control group where P = 0.002 but less significant in patients group.
|Figure 3: Correlation between serum testosterone levels and age of the studied patients|
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There was also significant positive correlation between the age development and female serum estradiol level in both female patients group (P = 0.001) [Figure 4] and female control group (P = 0.001) but less significant in cases group.
|Figure 4: Correlation between serum estradiol levels and age of the studied patients|
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| Discussion|| |
Pubertal development is frequently delayed or disordered in children with chronic renal failure. Both neuroendocrine and peripheral alterations due to uremia have been hypothesized to explain the impairment in the pituitary-gonadal axis.
Furthermore, chronic renal failure (CRF) was found to be associated with gonadal damage and decreased testosterone and estradiol levels together with impaired regulation of gonadotropin secretion.
In the present study, laboratory assessment of sex hormones (testosterone and estradiol) was done to assess gonadal dysfunctions in ESRD children and adolescence on regular hemodialysis therapy.
In pediatric patients with CRF, only a few studies have been performed to evaluate the status of the hypothalamo–pituitary–gonadal axis. Most of these deal with the endocrine changes that occur during adolescence. The problem is unsolved if in CRF hormonal alterations comparable to those of adult patients occur before the onset of puberty or not.
As far as clinical pubertal assessment of the studied ESRD patients was concerned, delayed pubertal development was found among them. This is in agreement with Giusti et al., 1993, Harold et al. 1983 and Castellano et al., 1993 who stated that pubertal progression occurs in dialyzed uremic children, although it is delayed for chronological age.,,
Sexual dysfunction is common in adolescents with ESRD. Disturbances of pubertal development are commonly encountered in adolescent patients with chronic renal failure.
Delayed puberty is also a common finding with CRF, half of the girls and one-third of the boys with CRF reach sexual maturity later than 95% of the normal population.
The onset of puberty is usually delayed in adolescents with CKD. At least 50% of adolescents with ESRD enter puberty later than the normal range and achieve the pubertal milestones beyond the normal age range.
Late puberty is observed both in children on dialysis and after renal transplantation. In the Cooperative Study for Pubertal Development in CKD, the onset of puberty was delayed by 2–2.5 years on average.
The start of genital maturation was delayed by 1.8 years in uremic and 2.5 years in transplanted boys. Full genital maturation was achieved with a delay of 2.2 and 3.2 years, respectively. Thus, once started, puberty appears to proceed at a normal rate. However, in individual patients, particularly on long-term dialysis, pubertal maturation may arrest for years. Almost half of the girls treated by dialysis or renal transplantation fail to menstruate before the upper normal age limit of 15 years. Menarche even tends to occur later in transplanted than in dialyzed girls.
Unlike the development of secondary sexual characteristics, which is delayed but not permanently halted in CKD, reproductive function may be permanently impaired, These changes do not appear reversible after renal transplantation.
In our study, serum testosterone and estradiol levels were found significantly lower in patients than in controls, which was in agreement with Giusti et al., 1993 and Oertel et al., who stated that testosterone and estradiol levels were lower in cases of CRF with or without dialysis.,
Low plasma testosterone and estradiol levels were reported in boys and girls with chronic renal failure.
In male children with renal failure, plasma testosterone levels are decreased or in the low normal range.
In 1999, Palmer suggested that hypogonadism and low testosterone and estradiol levels (which agrees with our findings), may be caused by primary gonadal damage, presence of circulating luteinizing hormone (LH) receptor inhibitor that might contribute to gonadal-cell resistance and impaired feedback mechanism at the hypothalamic–pituitary level, in addition to presence of hyperprolactinemia.
Secondary gonadal failure due to siderosis of the pituitary gland or primary gonadal failure due to iron deposition in testes and ovaries due to repeated blood transfusion and iron overload.
In adults with CKD plasma concentrations of testosterone (T) and Estradiol (E2) are usually low or low normal, due to reduced synthesis and perhaps, increased metabolic clearance rate.
In prepubertal children with predialytic renal failure, low total and free T and dihydrotestosterone (DHT) plasma concentrations have been reported. However, since the adrenal cortex is the major site of androgen production before puberty and specific adrenal androgens are also low in children with CKD. Low prepubertal plasma androgen levels do not provide evidence for gonadal damage before puberty. In pubertal patients, normal or slightly subnormal plasma Testosterone concentrations are observed. In late puberty, however, DHT concentrations are significantly reduced in children with CKD compared with healthy or posttransplanted children. Impaired conversion of T to DHT due to decreased 5-reductase activity has been suggested.
Estradiol plasma concentrations in the low normal range are observed in females with CKD.
In pubertal girls with CKD, estradiol plasma levels were normal or low when related to pubertal stage.
An inverse correlation between serum creatinine levels and estradiol concentrations was found in patients with predialytic CKD.
Palmer, 1999 stated that disturbances in pituitary-gonadal axis rarely normalize with the initiation of hemodialysis or peritoneal dialysis; moreover, they may progress that matching with our study. This was explained by him that plasticizers in dialysis tubing, such as phytate may play a role in propagating the abnormalities in pituitary-gonadal axis.
In addition, Schmidt et al., 2002 stated that impairment of hypothalamo–pitutary–gonadal axis is not reversed by initiation of otherwise effective hemodialysis or peritoneal dialysis therapy.
Growth parameters were evaluated in the current study revealing that all Anthropometric measurements (weight, height, BMI, and MAC) were significant low in all patients if compared with normal children and adolescents.
These results are supportive of data from multiple centers showing that children with a history of ESRD have poor growth and low BMI compared with children in general population.,,
These changes are associated with alteration in body composition. Both primary retention of uremic toxins and the resulting metabolic and hormonal changes may play a role.
The height gain achieved during the pubertal growth spurt is usually reduced. In a longitudinal analysis of the growth curves of 29 adolescents with various degrees of CKD, the growth spurt started with an average delay of 2.5 years. The degree of the delay was correlated with the duration of uremia. Although a distinct acceleration of growth during puberty occurred, the total pubertal height gain was reduced in both sexes to approximately 50% of normal maturing children. This reduction was due to a marked suppression of the late prespurt height velocity, a subnormal peak height velocity, and a shortening of the pubertal growth period by 1 year in boys and 1.5 years in girls. Notably, the prolonged prepubertal growth phase, resulting from the delayed onset of the pubertal growth spurt.
The pathogenesis of growth failure in children with ESRD is clearly multifactorial but recent research by Wong et al., 2000 who has shown that endocrine-related factors might be largely responsible for growth impairment in these children with renal failure.
Growth failure in CKD has been associated with both increased morbidity and mortality. Growth failure in the setting of kidney disease is multifactorial and is related to poor nutritional status as well as comorbidities, such as anemia, bone and mineral disorders, and alterations in hormonal responses, as well as to aspects of treatment such as steroid exposure.
The patients in our study exhibit significant low Hb% and Hct. This was in agreement with Harmon and Jabs, 1998 who reported that CRF was followed by renal anemia which has been contributed to several factors as erythropoietin deficiency, decrease erythrocyte survival and increase blood loss.
Chatterjee et al., 2000 explained the association of anemia with disturbed hypothalamo–pituitary–gonadal axis by the presence of some metabolic factors including chronic ill health, chronic hypoxia, underweight, and low BMI. In addition, iron overload due to repeated blood transfusion may cause secondary gonadal failure due to siderosis of the pituitary gland or primary gonadal failure due to iron deposition in testes and ovaries. This significant correlation indicates the importance of correcting anemia for a normal pubertal development.
| Conclusions|| |
The pubertal development of children and adolescents with ESRD is usually delayed as proven by decreased serum male total testosterone and female Estradiol hormones levels which suggest a state of hypogonadism. Nutritional therapy especially optimizing protein intake to prevent hypoproteinemia, adequate dialysis and correction of anemia are clinical trials of controversy and worthy of considering to optimize pubertal development until these patients are transplanted.
It is necessary to regularly follow up children with ESRD for early detection of endocrinal complications to improve their quality of life. Improving the efficiency of dialysis plays a role in improving sexual function and normalization of sex hormones levels. Improving nutritional status helps these patients to attain normal pubertal growth. Keeping Hb level within normal is recommended for normal pubertal development. Patients with delayed puberty in need to be further investigated to measure follicular stimulating hormone and LH to assess hypothalamic–pituitary–gonadal axis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]