|Year : 2020 | Volume
| Issue : 3 | Page : 998-1002
Study of the role of kisspeptin in constitutional delayed puberty in boys
Abdallah M Attia1, Belal A Montaser2, Mohamed R. M. Ellotf1
1 Department of Dermatology, Andrology and STDs, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||29-Nov-2018|
|Date of Decision||24-Dec-2018|
|Date of Acceptance||30-Dec-2018|
|Date of Web Publication||30-Sep-2020|
Mohamed R. M. Ellotf
Source of Support: None, Conflict of Interest: None
To assess the level of kisspeptin in the serum of boys with constitutional delayed puberty (CDP) and to study its correlation with the main hormones of reproduction [follicle-stimulating hormone (FSH), testosterone, and prolactin).
CDP is a common problem with a prevalence of 2–2.5% of population, with unclear etiopathogenesis.
Patients and methods
This study was done on 25 boys; aged 14–18 years and having CDP (Tanner's stages I, II, and III) as the patient group and another 25 boys age-matched with full pubertal manifestations (Tanner's stage V) as a control group with exclusion of delayed puberty due to other causes, for example; hypogonadotropic or hypergonadotropic hypogonadism and exclusion of any diseases, operations, or drugs that may affect the onset of puberty.
The result showed that serum kisspeptin is much significantly lower in the CDP group compared with the control. Serum kisspeptin is positively correlated to both testosterone and FSH and have no relation with prolactin. There was no significant differences between chronological and bone age of the control group, while in the CDP group, bone age is significantly delayed compared with their chronological age as well as the bone age of the control group. Weight and height are significantly less in the CDP group than that of the control. Serum testosterone and FSH is significantly lower in CDP compared with the control group, while serum prolactin showed no significant differences between both groups.
Further studies on CDP on a larger number of patients with trial of kisspeptin drug as a line of treatment for such cases.
Keywords: constitutional delayed puberty, delayed puberty, kisspeptin
|How to cite this article:|
Attia AM, Montaser BA, Ellotf MR. Study of the role of kisspeptin in constitutional delayed puberty in boys. Menoufia Med J 2020;33:998-1002
|How to cite this URL:|
Attia AM, Montaser BA, Ellotf MR. Study of the role of kisspeptin in constitutional delayed puberty in boys. Menoufia Med J [serial online] 2020 [cited 2021 Mar 5];33:998-1002. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/998/296681
| Introduction|| |
Delayed puberty (DP) is defined as the lack of pubertal development by an age that is 2–2.5 SD beyond the population mean. Although it generally represents a normal variant in pubertal timing, there is concern that DP could be the initial presentation of a serious underlying disorder . The most common etiology of DP is the constitutional delay of puberty (CDP), which is a nonpathological state in which the maturation of the hypothalamic–pituitary–gonadal (HPG) axis is delayed and puberty will begin at an age at the extreme end of the normal spectrum. CDP is a diagnosis of exclusion . The kisspeptin/kisspeptin receptor (KISS1/KISS1R) system is a critical component of the HPG axis, responsible for the production of kisspeptin and is necessary for pubertal onset. Kisspeptin plays a role in regulating puberty and fertility through their actions on hypothalamic gonadotropin-releasing hormone (GNRH) production . De Roux et al.  and Seminara et al. , stated that two independent study groups of impaired pubertal development in patients with hypogonadotropic hypogonadism (HH) showed that 'inactivating' point mutations and deletions in KISS1R ,. Mutations in KISS1R were demonstrated in both consanguineous families and in nonconsanguineous patients. In addition, KISS1R-deficient and KISS1-deficient mice displayed a virtually identical phenotype . So intact kisspeptin-signaling pathway is a necessary requisite for the onset of mammalian puberty, especially in rodents and humans. Thus, some researchers have suggested that 'puberty begins with a KISS' . To the best of our knowledge, few studies were published regarding the role of kisspeptin in male puberty ,, and few studies published that evaluate its serum level in cases of CDP . The aim of this study was to assess the level of kisspeptin in the serum of boys with CDP and to study its correlation to the main hormones of reproduction [follicle-stimulating hormone (FSH), testosterone, and prolactin].
| Patients and Methods|| |
This case–control study was carried out on boys recruited from the Dermatology and Andrology Outpatient Clinic, Menoufia University Hospitals. The study involved 50 patients who were classified into two groups:
- Group 1: 25 cases of boys aged 14–18 years with CDP Tanner's stages I, II, and III
- Group 2: 25 boys age matched to the case group with full puberty Tanner's stage V as controls.
The study was approved by the ethics committee of medical research of Faculty of Medicine, Menoufia University. Informed consent was taken from all participants after simple and clear explanation of the research objectives.
All participants were subjected to the following:
- Full history taking with emphasis on: main complaint, age, family history of DP, manifestation of puberty, nutritional status, chronic diseases, trauma, operations, or drug intake
- General examination including: general condition, body built, secondary sexual characters, gynecomastia, weight, height, span, upper–lower body segments and signs of systemic diseases
- Local examination with emphasis on testicular size, scrotum, penis, and pubic hair distribution and determination of Tanner's stage of puberty
- Radiography for hand and wrist bones to determine the bone age of the boy. It was done for the left hand for those who are right-handed and vice versa
- Laboratory investigations: total testosterone, FSH, prolactin, serum kisspeptin.
- Five milliliters of blood sample was collected from each individual after 12 h fasting, under aseptic condition by clean venipuncture without venous stasis
- Blood samples were in a sterile plain tube. The blood was left to clot at 37°C and rapidly centrifuged at 4000 rpm for 10 min and then stored at −80°C for assessment of kisspeptin and hormonal profile (FSH, prolactin, and total testosterone).
The results were statistically analyzed by SPSS, version 20 (SPSS Inc., Chicago, Illinois, USA). Two types of statistics were done: descriptive, for example, percentage (%), mean and SD and analytical. Mann–Whitney test: which is also known as the Wilcoxon rank sum test, which is used to determine whether there are statistically significant differences between two groups used with nonparametric data (typically, ordinal data); it is a nonparametric test of Student's t test. Spearman's and Pearson's correlation analyses are used to show strength and direction of association between two quantitative variables. P value less than 0.05 and P value less than 0.01 were set to be statistically significant and P value less than 0.001 and P value less than 0.0001 for highly significant changes.
| Results|| |
Both the CDP group and the control group are age matched with no significant differences between both. This means good selection of the cases. The results of this study showed also that the bone age in CDP is highly significantly delayed compared with the bone age of control (P = 0.0001) [Table 1] and compared with their chronological age (P = 0.0001) [Table 2], while in the control group, no significant differences were found between the bone and the chronological age (P = 0.22) [Table 2]. Compared with the control group, statistical analysis of the results showed that both weight and height of our CDP group were highly significantly lower than that of the control group (P = 0.0001) for both [Table 1]. Comparing serum levels of total testosterone and FSH in CDP to control, the results showed that both total testosterone and FSH are highly significantly lower in CDP compared with controls (P = 0.0001) for both [Table 3]. Also, our results showed that there are insignificant differences in serum prolactin level (P = 0.879) between both groups [Table 3]. We also found that the serum kisspeptin level is highly significantly lower in CDP boys in Tanner (I, II, and III) compared with the control group (tanner V) (P = 0.0001) [Table 3]. Kisspeptin is positively correlated to testosterone, FSH [Table 4] like study of Zhu et al. , and has significant correlation with prolactin (P = 0.031) [Table 4].
|Table 1: Comparison between the two studied groups according to age (years), bone age, weight, and height|
Click here to view
|Table 2: Chronological age (years) compared with bone age (years) in both control and constitutional delayed puberty groups|
Click here to view
|Table 3: Comparison between the two studied groups according to hormonal profile (total testosterone, follicle-stimulating hormone, prolactin, kisspeptin)|
Click here to view
|Table 4: Correlation between (serum kisspeptin, total testosterone, follicle-stimulating hormone, prolactin, bone age, height, and weight) in constitutional delayed puberty|
Click here to view
| Discussion|| |
DP is defined as no signs of start of puberty by the age of 14 years or not completed by the age of 18 years. This delay may be pathological due to various causes that are globally categorized into hypergonadotropic or hypogonadotropic or constitutional causes. The latter represents the most common type . CDP is mostly a self-limited condition and the affected boy enters puberty spontaneously prior to reaching the age of 18 years. CDP is a common problem with a prevalence of 2–2.5% of population in Western countries and it is more common in boys than in girls . CDP is considered as a temporary state of HH and diagnosed after careful evaluation and exclusion of the other potential underlying causes of HH. Up till now, CDP remains a diagnosis of exclusion . The exact etiopathology of CDP remains unclear. Genetic basis with positive family history, environmental causes (pollutants), nutritional causes due to undernutrition and deficiency of zinc, low leptin levels and excess estrogen production due to increased aromatase activity in the subcutaneous tissue are all blamed to be causes of CDP but none of them is finally proved . Since the discovery of kisspeptin hormone and kisspeptin receptor , an understanding of neurobiological mechanisms of the HPG axis and the role of them in puberty has evolved dramatically . Kisspeptin and its receptor are distributed both peripherally and centrally. Peripheral kisspeptin is present in the small intestine, thymus, spleen, lung, stomach, kidney, liver, adrenal gland, vessels, adipose tissue, ovary, testis, pancreas, endothelial cells of the aorta, coronary artery, and umbilical vein and the highest peripheral concentration is found in the placenta of pregnant women. Centrally kisspeptin neurons were found to be present in these areas of hypothalamus (infundibular nucleus and preoptic area in close apposition with GNRH neurons) . Kisspeptin was found to play an important role in the onset of puberty through the stimulation of GNRH which in turn stimulates the release of gonadotrophic hormones (FSH and luteinizing hormone) from the anterior pituitary. In addition to having a potential therapeutic role for treating certain forms of infertility they also play a role in regulating glucose homeostasis, insulin secretion, and body weight ,. The role of kisspeptin in CDP etiopathology is unclear and very few researches in this regard exist. So, we aimed by this work to investigate its level in CDP in boys and to study its correlation with testosterone, FSH, and prolactin in a trial to elucidate the role of this hormone in the etiopathogenesis of CDP. To approach our goal, we selected 25 boys, aged 14–18 years and having CDP (Tanner's stages I, II, and III) as the patient group and another 25 boys, age matched with full pubertal manifestations (Tanner's stage V) as a control group.
Statistical analysis of the results showed that both the CDP group and the control group are age matched with no significant differences between both. This means good selection of the cases. The results of this study showed also that the bone age in CDP is highly significantly delayed compared with the bone age of control and with their chronological age. While in the control group, no significant differences were found between the bone and the chronological age. These results go with that reported by Rogol et al. . They reported that in CDP the bone age does not advance 1 year for each calendar year, it progressively deviates from the chronologic age. This is also agreed with the study by El-Eshmawy and Aal . In CDP bone age retardation is more than 2 years and may reach up to 5 years behind the chronological age . This is considered now as one of the criteria that must be considered in the diagnosis of CDP. Compared with the control group, statistical analysis of the results showed that both weight and height of our CDP group were highly significantly lower than that of the control group for both. These results agree with that of El-Eshmawy and Aal  and Hasegawa . This is may be due to malnourishment or delayed testosterone secretion (anabolic hormone). Comparing the serum levels of total testosterone and FSH in CDP to control, the results showed that both total testosterone and FSH are highly significantly lower in CDP compared with controls for both. This is consistent with El-Eshmawy and Aal  and Harrington and Palmert . This is accepted as our patients were selected in Tanner's stages I, II, and III who are still sexually immature and CDP is considered as a case of transient HH. A low level of total testosterone and FSH indicates that the HPG axis does not start to secrete GNRH which will stimulate gonadotrophins to be secreted. The results also showed that there are insignificant differences in serum prolactin level between both groups. This indicates that our CDP group is accurately selected and has no other causes for DP. Ali and Adeel  reported also the same results. Regarding kisspeptin and its role in DP, few studies exist and point to the decrease in its level or mutation in its genes or receptors ,,, but its role in CDP in particular one study exists to the best of our knowledge. The results of this study showed that in CDP kisspeptin level is significantly lower compared with the control group. Zhu et al.  also reported the same results in boys with DP. Is this deficiency of kisspeptin in CDP is a cause or a result, no answer exists. The results also showed that kisspeptin is positively correlated with both total testosterone and FSH. This may point to an etiological relationship but further studies are needed before final answers.
| Conclusion|| |
From this study, we conclude that kisspeptin is significantly lowered in CDP boys; and it is positively correlated to the main hormones of sexual maturation (testosterone) and reproduction (FSH). This means that its depression in these boys may be a cause and not a result of their delay.
We recommend further studies on CDP on a larger number of patients with trial of kisspeptin drug as a line of treatment for such cases.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Roberts SA, Stafford DEJ. Delayed puberty and hypogonadism in Pediatric Endocrinology. In: Pediatric Endocrinology Textbook. Ch. VI. Switzerland: Springer Nature. 2018. p. 569–588.
Lawaetz JG, Hagen CP, Mieritz MG, Blomberg JM, Petersen JH, Juul A. Evaluation of 451 Danish boys with delayed puberty: diagnostic use of a new puberty nomogram and effects of oral testosterone therapy. J Clin Endocrinol Metab 2015; 100
Hussain MA, Song WJ, Wolfe A. There is Kisspeptin. And then there is kisspeptin. Trends in Endocrinol Metab 2015; 26
De Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003; 100
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349
De Tassigny XDA, Fagg LA, Dixon JP, Day K, Leitch HG, Hendrick AG, et al.
Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci 2007; 104
Dungan HM, Clifton DK, Steiner RA. Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion. J Endocrinol 2006; 147
Skorupskaite K, George JT, Anderson RA. The kisspeptin- GnRH pathway in human reproductive health and disease. Hum Reprod Update 2014; 20
Zhu HJ, Li SJ, Pan H, Li N, Zhang DX, Wang LJ, et al
. The changes of serum leptin and kisspeptin levels in chinese children and adolescents in different pubertal stages. Int J Endocrinol 2016; 2016
Styne DM. Disorders of the hypothalamic–pituitary axis. in Pediatric Endocrinology. In: Pediatric Endocrinology Textbook. Ch. 3. Switzerland: Springer International Publishing; 2016. p. 17–27.
Cassatella D, Howard SR, Acierno JS, Xu C, Papadakis GE, Santoni FA, et al
. Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures. Eur J Endocrinol 2018; 178
Giri D, Patil P, Blair J, Dharmaraj P, Ramakrishnan R, Das U. Testosterone therapy improves the first year height velocity in adolescent boys with constitutional delay of growth and puberty. Int J Endocrinol Metab 2017; 15
Lee JM, Wasserman R, Kaciroti N, Gebremariam A, Steffes J, Dowshen S, et al
. Timing of puberty in overweight versus obese boys. Pediatrics 2016; 137
Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, et al
. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 1996; 88
Terasawa E, Guerriero KA, Plant TM. Kisspeptin and puberty in mammals. Adv Exp Med Biol 2013; 784
Herbison AE, de Tassigny Xd, Doran J, Colledge WH. Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 2010; 151
Prague JK, Dhillo WS. Potential clinical use of kisspeptin. Neuroendocrinology 2015; 102
Rogol AD, Clark PA, Roemmich JN. Growth and pubertal development in children and adolescents: effects of diet and physical activity. Am J Clin Nutr 2000; 72
El-Eshmawy MM, Aal IAA. Association of ghrelin and leptin with reproductive hormones in constitutional delay of growth and puberty. Reprod Biol Endocrinol 2010; 8
Hasegawa T. Disorders of pubertal development principals of molecular medicine. In: Runge MS, Hmana C. Principles of Molecular Medicine. 2nd ed. Springer Nature (Switzerland) Press Inc.; 2007. p. 453–465.
Harrington J, Palmert MR. Clinical review: distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests. J Clin Endocrinol Metab 2012; 97
Ali L, Adeel A. Role of basal and provocative serum prolactin in differentiating idiopathic hypogonadotropic hypogonadism and constitutional delayed puberty – a diagnostic dilemma. J Ayub Med Coll Abbottabad 2012; 24
[Table 1], [Table 2], [Table 3], [Table 4]