Precocious Puberty Animal Models
Leveraging Precocious Puberty Animal Models for Preclinical Research
Precocious puberty, one of the frequently observed conditions in pediatric endocrinology, significantly impacts the physiological, psychological, and long-term health of children. Moreover, this disorder is associated with increased risks of various diseases [1].
Precocious puberty is an endocrine disorder caused by abnormal secretion of sex hormones. It typically refers to the onset of puberty and secondary sexual characteristics in children before the age of 8 in girls and 9 in boys. Symptoms in girls include breast budding, axillary and pubic hair growth, and early menarche, while in boys, it includes testicular and scrotal enlargement, axillary and pubic hair growth, voice change, and beard growth [2]. Depending on whether gonadotropin-releasing hormone (GnRH) is relied upon, precocious puberty can be categorized into central, peripheral, and partial types:
- Central Precocious Puberty (CPP, also termed GnRH-dependent): CPP is usually caused by the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, which stimulates GnRH secretion. In addition to early development of secondary sex characteristics, these children also exhibit precocious development of the gonads.
- Peripheral Precocious Puberty (PPP, also termed GnRH-independent): Unlike the central type, PPP is not driven by the HPG axis. Instead, some factors trigger the premature development of secondary sexual traits and elevated sex hormone levels. Usually, the gonadal axis remains immature without early gonad development.
- Partial Precocious Puberty: This category only shows certain characteristics of precocious puberty, such as breast development, pubic hair growth, or early menarche.
What causes precocious puberty?
The common causes of Central Precocious Puberty include:
- Idiopathic: This category is attributed to the hypothalamus’s decreased sensitivity to the negative feedback of sex hormones, leading to increased GnRH secretion. It accounts for more than 80% of girls and about 40% of boys with central precocious puberty.
- Secondary: This is common in children with central nervous system abnormalities, such as tumors or space-occupying lesions (hypothalamic hamartomas, cysts, granulomas), central nervous system infections, acquired injuries (trauma, postoperative, radiation, chemotherapy), congenital developmental abnormalities (hydrocephalus, septo-optic dysplasia), and other diseases (such as hypothyroidism).
The causes of peripheral precocious puberty include gonadal tumors, adrenal diseases, other diseases, or exposure to exogenous hormones. Additionally, obesity is associated with precocious puberty, with obese children being more susceptible.
How is precocious puberty diagnosed and treated?
When precocious puberty is suspected in a child, the following indicators are typically examined:
- Blood hormones (follicle-stimulating hormone, luteinizing hormone): These indicators help determine if the HPG axis in the child has developed prematurely
- Bone age: X-rays of a child’s wrist and hand can show whether the bones are maturing too early
- Ultrasound: This tool is used to inspect the development of ovaries and uteri in girls, and testes and adrenal glands in boys
- CT or MRI: These scans are necessary if a brain tumor or adrenal disease is suspected.
Children diagnosed with precocious puberty should receive appropriate treatments based on the causes of their disease. Although precocious puberty itself is not generally life-threatening, its progression can result in shorter adult height, impact on self-esteem, increased depression risk, and decreased quality of life.
Animal models of precocious puberty
The pubertal development of rodents and non-human primates is similar to that of humans, with clear characteristics of gonadal development, making them commonly used animal models in the study of the pathogenesis of precocious puberty and preclinical research. Chemicals, hormones, diet, environment, and radiation can be used to induce precocious puberty in experimental animals. Vaginal opening, estrus cycle, serum hormone level, hypothalamic gene expression level, sexual organs, and other indicators are used to evaluate precocious puberty. The Urogenital and Endocrine Disease Platform of WuXi Biology specializes in services of pharmacological verification and related testing for urogenital and endocrine system diseases, including two rodent models of precocious puberty (Figure 1).
Figure 1: The Urogenital and Endocrine Disease Platform of WuXi Biology
Danazol-Induced Rat Model of Precocious Puberty
The Danazol-induced female rat model of precocious puberty is a preclinical model used to explore the causes of precocious puberty and to validate pharmacodynamics [3]. Danazol is a synthetic derivative of 17α-ethinyl testosterone and has various effects on the reproductive system. It is also used to treat endometriosis and fibrocystic breast disease. However, for neonates whose nervous system is not yet fully developed, especially animals within 7 days after birth, Danazol can prematurely activate the HPG axis, leading to a precocious puberty phenotype in rats. The WuXi AppTec team validated this model after Danazol induction (Figure 2). The vaginal opening day and the first estrus day of the pups were advanced by 11 days and 6 days, respectively. GnRH analogs (GnRHa) act on pituitary GnRH receptors to regulate hormone secretion and are commonly used drugs for treating precocious puberty in children. In the Danazol-induced rat model of precocious puberty, treatment with GnRHa beginning before weaning showed that it can effectively improve the advanced estrus of the model animals, and continuous treatment can delay the first estrus of the model animals by 10 days.
Figure 2: Danazol-induced Rat Model of Precocious Puberty (Source: Internal Data from WuXi Biology)
A. Body Weight; B. Age at Vaginal Opening; C. Age at First Estrus; D-F. Estrus Cycle (From top to bottom: Control group, Model group, Treatment group)
High-Fat Diet (HFD) Induced Mouse Model of Precocious Puberty
Childhood obesity, especially in girls, is often associated with precocious puberty. Studies have shown a positive correlation between obesity and precocious puberty. Given the high prevalence of childhood obesity worldwide, obesity and its complications represent a significant clinical and societal challenge. In animal experiments, HFD is commonly employed to study metabolic imbalance, obesity and related complications [4]. Scientists at WuXi AppTec induced prepubertal obesity and hair loss in female pups through HFD during lactation and after weaning. The HFD also advanced the vaginal opening day and the first estrus day by 4 days. (Figure 3).
Figure 3: High-Fat Diet Induced Mouse Model of Precocious Puberty (Source: Internal Data from WuXi Biology)
A. Body Weight; B. Food Intake after Weaning; C. Body Fat Rate (BFR) at Postnatal Day 45; D. Prepubertal Hair Loss; E-F. Estrus Cycle (From top to bottom: Control group, HFD group); G. Age at Vaginal Opening; H. Age at First Estrus
Conclusion
The rising rate of precocious puberty in children has drawn increasing attention to this disorder. With deepening understanding of its mechanisms and the development of new drugs, the application of preclinical models is becoming more and more important. WuXi Biology has successfully induced precocious puberty in rats and mice using Danazol induction and HFD feeding, contributing to preclinical research on precocious puberty treatment.
References
- Bradley SH, Lawrence N, Steele C, Mohamed Z. Precocious puberty. BMJ. 2020. 368:l6597
- Latronico AC, Brito VN, Carel JC. Causes, diagnosis, and treatment of central precocious puberty. The Lancet. Diabetes & Endocrinology. 2016. 4(3):265-274.
- Morishita H, Takemoto M, Kondo H, Higuchi K, Aono T. Induction of true precocious puberty by neonatal treatment with Danazol in female rats. Neuroscience Letters. 1993. 157(1):33-6.
- Ullah R, Su Y, Shen Y, Li C, Xu X, Zhang J, Huang K, Rauf N, He Y, Cheng J, Qin H, Zhou YD, Fu J. Postnatal feeding with high-fat diet induces obesity and precocious puberty in C57BL/6J mouse pups: a novel model of obesity and puberty. Frontiers of Medicine. 2017. 11(2):266-276.
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