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25 DISEASES OF SEXUAL GLANDS IN CHILDREN
Bugubaeva Makhabat Mitalipovna
Vaseekaran Chidambaram
(1, HOD Clinical disciplines-2, Associate professor, International Medical Faculty, Osh State University, Osh, Kyrgyzstan.)
2, Student, International Medical Faculty, Osh State University, Osh, Kyrgyzstan. Email : vasee056@gmail.com)
ABSTRACT
Diseases of the sexual glands in children, such as premature sexual development (precocious puberty), hypogonadism, and delayed sexual development, form a complex range of disorders. They have different causes and significant effects on health. These conditions can result from genetic issues, hormonal imbalances, problems in the hypothalamic-pituitary-gonadal axis, issues with the gonads or adrenal glands, and environmental factors.
Clinical signs vary widely. They include early development of secondary sexual traits, ambiguous genitalia, delayed puberty, and reduced reproductive ability. These can negatively affect growth, social adjustment, and future fertility.
Diagnosis requires a careful process. This includes taking a thorough medical history, performing a physical exam, assessing hormone levels in the lab, conducting genetic tests, and using imaging studies. This helps identify the specific disorder and differentiate between central and peripheral causes, as well as primary and secondary ones.
Management involves a team of specialists and often includes hormone therapy, surgery, and ongoing psychological support. Regular follow-up care is crucial for monitoring growth, puberty progression, bone health, and mental well-being, along with facilitating the transition to adult healthcare.
Early identification and proper management can improve long-term outcomes and quality of life for children and adolescents facing these challenges.
INTRODUCTION
Diseases of the sexual glands in children are a group of conditions that affect the timing and development of sexual maturity. The sexual glands, mainly the testes and ovaries, are essential for puberty. Puberty involves the development of secondary sexual traits, the ability to reproduce, and achieving adult body composition. Disorders of these glands can cause premature sexual development (precocious puberty), hypogonadism, or delayed puberty. This range of issues has significant clinical, social, and psychological effects.
NORMAL SEXUAL DEVELOPMENT
Sexual development usually follows a closely controlled timeline. The hypothalamic-pituitary-gonadal (HPG) axis regulates sexual maturation, starting in fetal life and then pausing until puberty. Puberty begins between ages 8 and 13 in girls, and between 9 and 14 in boys. This process relies on the rhythmic release of gonadotropin-releasing hormone (GnRH). This hormone triggers the pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn lead to the production of gametes and sex steroids (estradiol in girls and testosterone in boys).
ETIOPATHOGENESIS
The causes of sexual gland diseases in children are varied and can be grouped as follows:
1. Genetic and Chromosomal Abnormalities
Turner Syndrome (45,X0): This affects females with streak ovaries and primary ovarian failure. The lack of an X chromosome causes a loss of oocytes and estrogen deficiency, resulting in primary amenorrhea and delayed sexual development.
Klinefelter Syndrome (47,XXY): This male condition arises from an extra X chromosome, leading to underdeveloped testes, low testosterone levels, tall stature, gynecomastia, and infertility.
Disorders of Sex Development (DSD): Mutations in genes like SRY (sex-determining region Y gene), SOX9, WT1, DAX1, SF1, and others can lead to mixed or unclear sexual characteristics. These disorders often present with ambiguous genitalia and mismatched chromosomal, gonadal, and physical sex. .
2. Hypothalamic-Pituitary Axis Abnormalities
Congenital GnRH Deficiency: Kallmann syndrome features a loss of the sense of smell along with hypogonadotropic hypogonadism due to faulty migration of GnRH neurons, leading to absent or incomplete puberty.
Tumors, Trauma, and Infections: Conditions such as craniopharyngiomas, pituitary adenomas, CNS radiation, or trauma can disrupt normal GnRH secretion and pituitary function.
3. Gonadal and Adrenal Disorders
Congenital Adrenal Hyperplasia (CAH):Autosomal recessive enzyme deficiencies, primarily 21-hydroxylase, cause cortisol shortage, excessive ACTH, and high androgen levels, leading to precocious puberty or ambiguous genitalia in girls.
Gonadal Tumors: Tumors in Leydig or Sertoli cells (testicular) and granulosa or theca cells (ovarian) can produce excess hormones, which may cause precocious puberty or features of masculinization.
Primary Gonadal Failure: Conditions like anorchia, cryptorchidism, and testicular regression syndrome result in primary testicular failure, leading to low testosterone levels in boys.
4. Peripheral Environmental and Acquired Factors
Exogenous Hormone Exposure: Unintentional exposure to steroids or estrogens, environmental disruptors, or maternal hormone overproduction can lead to early or abnormal pubertal changes.
Chronic Systemic Disease: Conditions such as chronic kidney disease, malnutrition, or thalassemia can cause secondary hypogonadism.
CLINICAL FEATURES
1. Premature Sexual Development (Precocious Puberty)
Definition: The appearance of secondary sexual traits before age 8 in girls or 9 in boys. This can be GnRH-dependent (central) or GnRH-independent (peripheral).
Central Precocious Puberty: This involves early activation of the HPG axis and can be idiopathic or related to CNS disorders. Signs include:
- Breast development and menstruation in girls
- Testicular enlargement, growth of the penis, and body odor in boys
- Increased height growth with early bone maturation
- Social and emotional challenges due to early physical changes
Peripheral Precocious Puberty: This results from hormone production from the adrenal glands, gonads, or ectopic sources, or from external hormone exposure. Symptoms include:
- Masculinization in girls (deep voice, enlarged clitoris, excessive hair growth)
- Feminization in boys (gynecomastia and feminized body shape)
- Lack of the normal progression of puberty and coordination in secondary sexual trait development.
2. Hypogonadism
Definition: Low production of sex steroids by the gonads, leading to delayed or absent sexual development.
Primary (hypergonadotropic): The gonads do not produce enough sex steroids, resulting in high LH/FSH levels.
- In girls: primary amenorrhea, no puberty, short stature (as seen in Turner syndrome), and lack of breast development.
- In boys: small testes and penis, no deepening of voice, absent facial hair, limited muscle growth, and low libido.
Secondary (hypogonadotropic): A deficiency in the pituitary or hypothalamus leads to low LH/FSH and sex steroids. The symptoms may resemble those of primary hypogonadism, but often have additional neurological signs (such as vision problems or loss of smell in Kallmann syndrome) and signs of pituitary hormone deficiencies (like hypothyroidism or growth hormone shortage).
3. Delayed Sexual Development
Definition: Absence of breast development in girls by age 13 or absence of testicular enlargement in boys by age 14; or more than 5 years without menstruation after thelarche.
- This condition may be constitutional (common, familial, temporary), but pathological causes include different forms of hypogonadism and chronic diseases.
- Signs include short stature, childlike body proportions, and psychological stress from feeling different from peers, along with delays in reproductive capability.
4. Ambiguous Genitalia/DSDs
- External genitalia that does not look clearly male or female can be seen in enzyme deficiencies, androgen insensitivity, and gonadal dysgenesis.
- Possible presentations include enlarged clitoris, fused labial folds, micropenis, hypospadias, or a mix of ovarian and testicular tissue.
CLINICAL FEATURES
1. Premature Sexual Development (Precocious Puberty)
Definition: The appearance of secondary sexual traits before age 8 in girls or 9 in boys. This can be GnRH-dependent (central) or GnRH-independent (peripheral).
- Central Precocious Puberty: This involves early activation of the HPG axis and can be idiopathic or related to CNS disorders. Signs include:
- Breast development and menstruation in girls
- Testicular enlargement, growth of the penis, and body odor in boys
- Increased height growth with early bone maturation
- Social and emotional challenges due to early physical changes
- Peripheral Precocious Puberty: This results from hormone production from the adrenal glands, gonads, or ectopic sources, or from external hormone exposure. Symptoms include:
- Masculinization in girls (deep voice, enlarged clitoris, excessive hair growth)
- Feminization in boys (gynecomastia and feminized body shape)
- Lack of the normal progression of puberty and coordination in secondary sexual trait development.
2. Hypogonadism
Definition: Low production of sex steroids by the gonads, leading to delayed or absent sexual development.
- Primary (hypergonadotropic): The gonads do not produce enough sex steroids, resulting in high LH/FSH levels.
- In girls: primary amenorrhea, no puberty, short stature (as seen in Turner syndrome), and lack of breast development.
- In boys: small testes and penis, no deepening of voice, absent facial hair, limited muscle growth, and low libido.
- Secondary (hypogonadotropic): A deficiency in the pituitary or hypothalamus leads to low LH/FSH and sex steroids. The symptoms may resemble those of primary hypogonadism, but often have additional neurological signs (such as vision problems or loss of smell in Kallmann syndrome) and signs of pituitary hormone deficiencies (like hypothyroidism or growth hormone shortage).
3. Delayed Sexual Development
Definition: Absence of breast development in girls by age 13 or absence of testicular enlargement in boys by age 14; or more than 5 years without menstruation after thelarche.
- This condition may be constitutional (common, familial, temporary), but pathological causes include different forms of hypogonadism and chronic diseases.
- Signs include short stature, childlike body proportions, and psychological stress from feeling different from peers, along with delays in reproductive capability.
4. Ambiguous Genitalia/DSDs
- External genitalia that does not look clearly male or female can be seen in enzyme deficiencies, androgen insensitivity, and gonadal dysgenesis.
- Possible presentations include enlarged clitoris, fused labial folds, micropenis, hypospadias, or a mix of ovarian and testicular tissue.
DIAGNOSIS
1.Initial Clinical Evaluation
- A thorough review of birth, development, and family history (including parental/sibling pubertal milestones)
- An assessment of dietary habits and chronic diseases
- Growth evaluation and plotting on standard growth charts
- Tanner staging for breast, genital, and pubic hair development.
2.Laboratory Assessment
- Hormonal Analysis: Testing levels of LH, FSH, estradiol/testosterone, DHEAS, 17-hydroxyprogesterone, TSH, and prolactin, with preferred morning samples.
- Bone Age X-ray: Identify delays in bone age for hypogonadism or constitutional delay; accelerated bone age in cases of precocious puberty.
- GnRH Stimulation Test: Distinguishes central (pubertal response) from peripheral (prepubertal response) puberty.
- Karyotyping and Genetic Testing: Recommended in cases of ambiguous genitalia, unexplained primary amenorrhea, or dysmorphic syndromes.
3.maging
- MRI of the Brain: Recommended for boys and young girls experiencing central precocious puberty, hypogonadism, or any unusual neurological signs.
- Pelvic/Testicular Ultrasound: Used to examine internal anatomy and check for the presence of Müllerian or Wolffian structures, cysts, or tumors.
- Additional Imaging: Echocardiograms and renal ultrasounds may be necessary in syndromic hypogonadism, like Turner syndrome.
DIFFERENTIAL DIAGNOSIS
1.For Precocious Puberty
- Central Precocious Puberty (CPP): Often idiopathic (more frequent in girls), CNS issues (like tumors or infections).
- Peripheral Causes: Congenital adrenal hyperplasia, tumors of the ovaries or testicles, McCune-Albright syndrome, external hormone exposure, hypothyroidism.
2.For Delayed Or Absent Puberty
- Constitutional delay (familial, normal variations).
- Primary gonadal failure(conditions like Turner, Klinefelter syndromes, or damage from radiation/chemotherapy, or orchitis).
- Secondary hypogonadism (Kallmann syndrome, CNS tumors, chronic illness, or anorexia).
3.For DSDs/Ambiguous Genitalia
- Enzyme deficiencies (like 21-hydroxylase deficiency).
- Androgen insensitivity, 46,XX testicular disorders, ovotesticular disorders.
- Mixed gonadal dysgenesis.
- Exogenous androgen or estrogen exposure.
TREATMENT
1.For Central Precocious Puberty
- GnRH Analogue Therapy: Continuous use of GnRH agonists (like leuprolide or triptorelin) lowers LH/FSH levels, helping to normalize the pace of puberty and support adult height potential. Monthly or three-month injections are preferred.
- Address underlying CNS issues: Surgery or radiation for any identified CNS tumors.
2.For Peripheral Precocious Puberty
- Treat tumors: Surgery or chemotherapy for adrenal or gonadal tumors.
- Management of CAH: Lifelong treatment with glucocorticoids and mineralocorticoids, along with surgical correction for ambiguous genitalia.
- Stop outside hormones: Review and halt any external hormone sources.
3.For Hypogonadism/Delayed Puberty
- Constitutional Delay: Offer reassurance and monitoring. If psychological distress is high, use low-dose sex steroids briefly to promote puberty.
- Primary Hypogonadism:
- For girls: Gradually introduce puberty using low-dose estrogen, adding cyclic progestin once the uterus matures.
- For boys: Gradual testosterone replacement (injection or topical); monitor for signs of masculinization, bone health, and psychological wellbeing.
- Secondary Hypogonadism: Address root causes (like tumor removal or hormone replacement for the pituitary).
- Fertility treatments: hCG/FSH or pulsatile GnRH to induce sperm production or ovulation in select secondary hypogonadism patients.
4.For DSDs/Ambiguous Genitalia
- Team approach: Include endocrinologists, surgeons, geneticists, psychiatrists, and ethicists.
- Surgical correction: Timing should consider family, patient, and psychological factors; this can be a controversial choice in infancy and should be tailored to individual family circumstances.
- Psychosocial support: Provide ongoing counseling for gender identity and psychological needs.
MEDICAL FOLLOW-UP
- Growth and Development: Continue to assess growth, sexual development, bone maturation, and weight changes, adjusting therapies as needed.
- Hormone Monitoring: Track sex steroid, LH/FSH levels; adjust hormones based on age and sex-specific goals.
- Bone Health: Use DEXA scans as necessary, supplement calcium and vitamin D, and encourage weight-bearing exercise.
- Fertility Surveillance: Offer counseling and consider assisted reproductive techniques (sperm or egg retrieval) where possible, along with appropriate induction of puberty.
- Tumor Surveillance: Monitor patients on treatment for hormone-secreting tumors or those at increased risk for malignancy.
- Psychosocial and Neurocognitive Wellbeing: Provide continuous support for self-esteem, gender identity, and any educational or job-related issues.
- Transition to Adult Care: Start systematic handoff to adult endocrinologists, fertility specialists, and psychological support teams.
CASE EXAMPLES
Case 1: Turner Syndrome
A 15-year-old girl with short stature and primary amenorrhea shows streak ovaries and high gonadotropin levels. She receives estrogen replacement, growth hormone support, psychological counseling, and regular cardiac and renal screenings.
Case 2: Central Precocious Pubert
A 7-year-old girl develops early breast and pubic hair, with advanced bone age and high LH/FSH levels from stimulation tests, but a normal brain MRI. She is treated with depot GnRH analogues while being monitored for growth and psychological adjustment.
Case 3: Kallmann Syndrome
A 16-year-old boy absent of secondary sexual traits and with no sense of smell presents low LH/FSH/testosterone. Puberty is induced with low-dose testosterone, and fertility management is offered with hCG and pulsatile GnRH if desired.
Case 4: CAH with Ambiguous Genitalia
A newborn with ambiguous genitalia is diagnosed with classic salt-wasting CAH (21-hydroxylase deficiency). Treatment includes glucocorticoids, reconstructive surgery, and ongoing family counseling.
CONCLUSION:
Diseases affecting the sexual glands in children, such as precocious puberty, hypogonadism, and ambiguous genitalia, are complex and sensitive areas within pediatric endocrinology. Early identification, understanding the causes, multidisciplinary management, psychological support, and ongoing monitoring are essential for the best outcomes. Progress in genetics, endocrinology, and reproductive medicine continues to change prognoses, with care tailored to each patient and their family being crucial.
REFERENCES:
Disorders of Sex Development: Classification, Review, and Impact on Fertility
Male Hypogonadism in Children – MSD Manuals
Precocious Puberty and Normal Variant Puberty
Precocious Puberty – Cleveland Clinic
A Current Perspective on Delayed Puberty and Its Management
StatPearls, Approach to Pediatric Sexual Development Disorders
