Puberty
• Puberty is the transition period from childhood to adulthood when the gonads reach their endocrine and reproductive potential. It is the period when secondary sex characters begin to develop and sexual and reproductive characteristics are acquired.
• Average age of entry for girls; 8-13 years, 9-14 years for boys. The pubertal development process takes about 4.5 years in girls.
• Factors affecting the onset of puberty:
► The most important determinant of the onset of puberty is genetic structure.
► On the other hand, geographical location, exposure to light (melatonin), obesity, general health status, nutritional status and psychological factors also play a role in puberty.
• The effect of total body weight and body composition on the age of menarche:
► For menarche, the body fat rate should reach 17%.
► Leptin, secreted by adipose tissue, regulates eating behaviors and energy balance by acting on CNS neurons. At puberty, leptin levels increase in boys and girls.
► Patients with anorexia nervosa, whose adipose tissue and leptin secretion are low, and those who do heavy sports have late menstruation.
Girls with early menarche have high leptin levels.
• The anterior pituitary begins to form in the 4-5th week of pregnancy and in the 10-13th week. The vascular relationship of the pituitary with the hypothalamus is established in the first week.
• GnRH begins to be released from the hypothalamus of the fetus at week 10, and from the pituitary at 10-13th week. FSH and LH begin to be secreted within weeks. FSH-LH levels peak at 20-23 weeks of fetal life. After this week of pregnancy, a hypersensitivity to steroids develops and this sensitivity increases and reaches its peak in late infancy. Until this period, gonadotropins are suppressed by steroids.
• High placenta is the reason for the suppression in fetal life! are steroids.
• As the placental steroids are withdrawn from the environment with delivery, an increase in gonadotropins is observed. While this increase occurs mostly in FSH in girls in the postnatal period, LH does not show much increase.
• After this postnatal rise, an inhibition of gonadotropins begins and gonadotropins decrease to their lowest levels at 1-2 years of age. This suppression period continues until at least 8-10 years of age and is called gonadostat.
• The mechanism responsible for gonadostat is hypersensitivity of the hypothalamohypophyseal system to very low levels of estrogen in early childhood.
• Gonadal steroids are not responsible for gonadostat because the same suppression occurs in individuals with gonadal dysgenesis.
Hormonal Changes at Puberty
• Hormonal changes occur before physical changes in pubertal development. Around the age of two, the major adrenal androgens, DHEA and DHEA-S, begin to be released. The amount of release increases (adrenarche) at the age of 7-8 years and continues in this way until the age of 13-15. An increase in DHEAS is the best sign of adrenarche.
• Among the estrogens that start to be released 2 years after androgens, while estrone is dominant before puberty, the ratio of estradiol to estrone increases gradually during puberty. This reveals the importance of estradiol in the maturation of the girl child.
• In girls, estradiol secretion from the ovary increases steadily throughout puberty. Estradiol increase occurs first during the day, but the basal level rises both during the day and at night. Estrone from the ovary and the periphery also increases during puberty and plateaus at midpuberty. For this reason, the El/E2 ratio gradually decreases at puberty.
• Puberty; It begins with the termination of the gonadostat as a result of the decrease in the sensitivity of the hypothalamo-pituitary system to sex steroids, and the suppression of GnRH as a result of the disappearance of the (-) feedback effect.
• Kispeptin is an important mediator in the regulation of GnRH secretion and puberty does not occur in case of mutation. Neurokinin B is also held responsible for the onset of puberty, like cispeptin.
• GnRH pulses first begin at night during sleep and FSH-LH release occurs nocturnally. It is then spread over 24 hours. With the increase of gonadotropins, estradiol is started to be made from the gonads (gonadarch).
• At the beginning of puberty, together with gonadotropin secretion, growth hormone release begins with the effect of increasing estrogen. Growth hormone levels in girls increase with puberty, are maximum during menarche, and then decrease.
• With the effect of increasing growth hormone, IGF-1 levels also increase. After puberty, it goes down to the prepubertal level, although gonadal steroids are high. Growth hormone and IGF have significant effects on changes in body composition that occur at puberty.
• The first indication that pubertal development is approaching is the appearance of acne behind the nasal crest and pinna (auricle).
Puberty Stages
• Although the first sign of puberty is accelerated growth, the first noticeable change in puberty is breast budding.
• While changes in isosexual puberty are compatible with the phenotypic sex structure of the individual;
In heterosexual puberty, the phenotypic features of the opposite sex are dominant.
Accelerated Growth (8-9 years)
► It begins 2 years earlier in girls than boys and peaks 2 years after the onset of breast development. An elongation of 6-11 cm occurs in length.
► This period is dependent on growth hormone, IGF-1, gonadal estrogen and adrenal androgens. Estrogen is the most important stimulus in the puberty spike in both sexes.
Thelarche (10 years old)
► Breast development usually begins at the age of 10 (8-13) and ends at approximately 14 years of age.
► Thelarche is formed by the effect of ovarian estrogen and progesterone. Estrogen initiates breast development and in the following years, the breast turns into an adult shape with the effect of progesterone.
Pubarche (Pubic hair growth) (10-11 years)
► Increased secretion of adrenal androgens causes pubic and axillary hair. Pubarche is the specific name given to pubic hair growth.
► Pubic hair begins to grow 6-12 months after thelarche. 1 year after this, axillary hair growth occurs.
Menarche (13 years)
► It is the first menstrual bleeding and it happens with the effect of increasing estrogen. It usually happens between the ages of 10-16.
► Initially, the cysts are anovulatory. However, it becomes ovulatory after 1-1.5 years at the earliest. During this period, irregular bleeding can be seen in girls.
Breast development and pubic hair growth are expressed in Tanner stages.
Puberty Developmental Disorders
Precocious Puberty
• It is the case that any of the pubertal changes occur before the age of 8 years. It is 20 times more common in girls.
- The most common cause of precocious puberty is idiopathic (constitutional) causes (90%).
- Cases younger than 4 years of age usually have CNS disease.
Central (Real) Precocious puberty
► Hypothalamic GnRH increases the release of gonadotropin prematurely and initiates the production of ovarian sex stroids.
► Etiology
0 idiopathic
0 Hypothalamic causes
- Hypothalamic tumors
• Hamartoma (most common): Produces pulsatile GnRH.
- Congenital malformations:
■ Hydrocephalus, craniostenosis, arachnoid cysts, septo-optic dysplasia
- Infiltrative lesions (Langerhans cell histiocytosis)
- Radiation, chemotherapy
- trauma
- Infections
• The most important long-term effect of the disease is short stature. These children are taller than their peers for a short time, but remain short (less than 152 cm) because the epiphyseal line closes early.
Peripheral (Pseudo) Precocious puberty
► It occurs due to excessive secretion of endogenous sex steroids independently of hypothalamic GnRH or due to exogenous sex hormones.
► Etiology
0 Gonadal cysts and tumors
- Granulosa and theca cell tumors (most common)
- Gonadal sex cord tumors
- Arrhenoblastomas
- Teratomas
- Small functional ovarian cysts; may cause transient precocious puberty.
0 McCune Albright Syndrome: There is polyostatic fibrous dysplasia in the bone + cafe-au-lait spots on the skin + GnRH-independent precocious puberty triad. It is accompanied by hyperfunction endocrinopathies (functional ovarian cyst, hyperthyroidism, hypercortisolism, hyperprolactinemia, acromegaly, hyperparathyroidism).
0 Congenital adrenal hyperplasia (most common cause of heterosexual precocious puberty)
0 Adrenal tumors (adenoma, carcinoma)
0 Ectopic gonadotropin secreting tumors ;
- Ectopic germinomas (pinealomas)
- Choriocarcinomas
- Teratomas
- Hepatoblastoma
0 Exogenous estrogen / androgen intake
0 Extreme aromatase syndrome
0 Glucocorticoid resistance
0 Primary hypothyroidism
In long-term hypothyroidism, increased TSH may cause precocious puberty by stimulating FSH release.
Primary hypothyroidism is the only cause of precocious puberty with retardation in bone age.
Differential Diagnosis of Precocious Puberty
► The first step in prepubertal examination is to measure basal gonadotropin levels (FSH, LH).
► Thyroid function tests are performed to rule out primary hypothyroidism (TSH, T4).
► In case of detection of elevated LH levels (which may actually cross-react with hCG), gonadotropin-secreting tumors should be considered.
► In cases of low or pubertal level of gonadotropin detection, estrogens in cases with isosexual precocious puberty; Androgens should be measured in cases with heterosexual precocious puberty.
► Increased estrogen levels should suggest an estrogen-secreting tumor.
► Increased testosterone levels should suggest an androgen-secreting tumor. Congenital adrenal hyperplasia should be considered in case of increased DHEA-5 and 17a-OHP levels.
► Abdominal ultrasonography, CT and MRI are important for the diagnosis of pathologies in the ovaries and adrenals.
► If the estrogen level is compatible with pubertal development, the central nervous system should be investigated with MRI or CT.
► Bone age must be determined in the cases.
► GnRH stimulation test can be used to differentiate premature thelarche from pubertal Precocious (central or peripheral). If LH increases more than 15 mIU/mL following administration of 100 µgr GnRH, it is GnRH-dependent precocious puberty.
Treatment
► Purposes in the treatment of precocious puberty:
0 Diagnosing and treating intracranial diseases
0 Stopping development until normal pubertal age
0 To prevent short stature
0 To provide supportive treatment for etiology
► In idiopathic cases, GnRH analogues are used to stop development until puberty. With these, FSH-LH is suppressed and estradiol falls below 10 pg/ml. Thus, growth stops until puberty and amenorrhea develops. When the age of puberty is reached, treatment is stopped and growth continues.
► Fulvestrant, a pure estrogen receptor antagonist, is promising in the treatment of McCune Albright Syndrome.
GnRH agonists have no place in the treatment of peripheral pseudopuberty precox.
Puberty Tarda
• Delayed puberty:
► The absence of secondary sex characteristics at the age of 13, or
► Absence of menarche at age 15 or
► It is the absence of menstruation even after 5 years after the onset of pubertal development.
• It is seen more in men.
• The most common cause of puberty tarda is constitutional delay. Other causes must be ruled out before this diagnosis can be made.
Etiology of pubertal tarda
A. Hypergonadotropic Hypogonadism (FSH/LH > 30 mIU/mL) o/o43
1. Gonadal dysgenesis (other than constitutional, it is the most common cause of pubertal tarda)
a. Turner syndrome (most common)
b. 46.XX pure gonadal dysgenesis
c. 46,XY pure gonadal dysgenesis (Swyer syndrome)
D. Early gonadal failure in patients with normally developing ovaries
B. Hypogonadotropic Hypogonadism (FSH/LH < 10 mIU/mL) 31%
1. Physiological (constitutional) delay
2. Isolated gonadotropin deficiency
a. Kallmann Syndrome
b.Prader-Labhart-Willi Syndrome
c.Laurence-Moon-Bardet-Biedl Syndrome
3. Diabetes insipidus
4. Lesions of the hypothalamo-pituitary region
a. Craniopharyngiomas (The tumor most associated with delayed puberty.)
b. Pituitary adenomas (prolactinomas)
5. Infiltrative disorders
a. Langerhans cell type histiocytosis
b. Hand-Schüller-Christian disease
6. Radiation exposure of the CNS
7. Serious chronic diseases and malnutrition
a. celiac disease
b. Crohn's disease
c. sickle cell anemia
d. Cystic fibrosis
8. Anorexia nervosa
9. Severe hypothalamic amenorrhea
10. Antidopaminergic and GnRH inhibitory agents (psychotropes and opiates)
11. Primary hypothyroidism
12. Cushing's syndrome
13. Chemotherapeutic use (especially alkylating agents)
C. Normogonadotropic Hypogonadism (FSH/LH 10-30 mIU/mL) 26%
1. Imperforate hymen (most common anatomic disorder alone in puberty)
2. Müllerian agenesis (RKMH syndrome)
3. Transverse vaginal septum
The diagnosis and treatment of pubertal tarda is treated like primary amenorrhea.
• The most important point in the evaluation of puberty tarda is anamnesis and physical examination, which focuses on growth. Chronic diseases must be ruled out.
• FSH and prolactin levels should be checked in cases with pubertal tarda who have not developed secondary sexual characteristics. Bone age should also be evaluated in these patients.
• Karyotype analysis should be performed in cases with pubertal tarda with elevated FSH.
Asynchronous Pubertal Development
It is the condition of not following the normal order of pubertal development. There is breast development up to Tanner stage 3 that is disproportionate to the amount of pubic and axillary hair.
Androgen insensitivity is its most characteristic example.
Heterosexual Puberty
• It is the development of opposite sex characteristics during normal puberty.
• Causes of heterosexual puberty:
► Polycystic ovary syndrome (PCOS) (most common cause)
► Nonclassical form of congenital adrenal hyperplasia
► Idiopathic hirsutism
► Mixed gonadal dysgenesis
► Reifenstein syndrome
► 5a reductase enzyme deficiency
► Cushing's syndrome
► Androgen-secreting tumors