TEXTBOOK OF PEDIATRIC GYNECOLOGY - 2013

Chapter 5. DISORDERS OF SEXUAL DEVELOPMENT IN GIRLS

Studies of hypothalamic neurosecretion, mechanisms regulating reproductive function, and improvements in diagnostic Methods for hormonal Homeostasis serve as the foundation for an in-depth study of pathologies related to sexual development in girls (Table 15).

Table 15. Classification of Disorders of Sexual Development in Girls

The incidence of anomalies in sexual development is approximately 2.5%. Chromosomal and genetic pathologies account for 30% of cases of precocious puberty (PP). Hereditary predisposition, influenced by environmental damaging factors, plays a certain role in The Development of PP. The physiological process of sexual development follows a specific genetic sequence—from 10 to 16–17 years of age. Disorders of sexual development can result from organic and functional disorders of The Nervous System, qualitative and structural anomalies of sex Chromosomes, as well as anatomical and functional Pathologies of the Endocrine glands.

Classification of Disorders of Sexual Development (according to V. P. Smetnik and L. G. Tumilovich)

1. Anomalies of sexual development without impaired sexual differentiation: precocious puberty (PP), delayed puberty (DP).

2. Anomalies of sexual development accompanied by impaired sexual differentiation: congenital adrenogenital syndrome (AGS), gonadal dysgenesis, and Malformations of the Uterus and Vagina.

The appearance of secondary sexual characteristics in girls under the age of 8 is considered precocious puberty.

Precocious puberty can manifest as either an isosexual or heterosexual type. Isosexual precocious puberty is accompanied by the premature appearance of sexual characteristics consistent with the child's genetic and Gonadal Sex. Heterosexual precocious puberty occurs when the child's genetic sex does not correspond to their sexual characteristics, namely feminizing syndromes in boys and virilizing syndromes in girls.

Depending on the degree of expression of secondary sexual characteristics and the presence of menstruation, complete and incomplete forms of central precocious puberty are distinguished.

The complete form is characterized by the development of all secondary sexual characteristics and the presence of menstruation As a result of the activation of the entire hypothalamic-pituitary-ovarian axis. In this case, The sequence of appearance of secondary sexual characteristics is not disrupted. Girls exhibit accelerated physical development, manifested by a lead over chronological and "bone age." Due to the early closure of bone growth plates, dysplastic body proportions are formed. Consequently, these women tend to be of short stature with short limbs, a long torso, and a wide pelvis.

Modern classifications are based on a pathogenetic approach that links the Development of the disease to the early Activation of a specific link within the Hypothalamus–pituitary–Gonads–adrenal glands axis.

True, or central, precocious puberty develops as a result of the premature activation of processes within the hypothalamic-pituitary-gonadal axis driven by organic or functional Disorders of the central nervous system. In this case, the increased secretion of sex Steroids by the gonads is a consequence of gonadotropic stimulation.

Pseudoprecocious puberty is caused by the hypersecretion of Sex Hormones from hormone-secreting tumors of the gonads or adrenal glands and is independent of gonadotropin secretion.

The classification of precocious puberty specifically distinguishes the so-called gonadotropin-independent forms—McCune–Albright–Braitsev syndrome and familial male-limited precocious puberty (testotoxicosis)—in which independent activation of gonadal function occurs without gonadotropic stimulation and is not associated with gonadal tumorigenesis. All forms of the condition exhibit characteristics of progressive puberty: In addition to the development of secondary sexual characteristics, gonadal volume increases, and the rates of growth and skeletal maturation accelerate, reflecting the systemic effects of sex steroids on the child's body, categorized as the complete form of precocious puberty. Furthermore, incomplete (partial) forms of PP are identified, characterized by the isolated development of secondary body Hair (premature pubarche) and isolated breast enlargement (premature thelarche). There are also variants of PP that do not fit any of the listed forms of the disease: PP against the Background of decompensated primary hypothyroidism, and PP following late Treatment of congenital adrenal hyperplasia.

Clinical and Pathogenetic Classification of Precocious Puberty (after Kless Fetzer-Greengill):

1. Ovarian form.

2. Adrenal (suprarenal) form.

3. Cerebral form.

4. Constitutional form.

Classification of Various Forms of Premature Thelarche (O. A. Predtechenskaya, 2000)

1. Premature thelarche as the onset of PP development.

2. Premature thelarche associated with ovarian follicular cysts.

3. Premature thelarche due to hypothyroidism.

4. Isolated premature thelarche.

International Classification of Diseases (10th Revision, Geneva, 2001):

E30.1. Precocious puberty associated with:

— Hyperfunction of the anterior Pituitary gland (E22.8);

— Pineal Gland tumor (E34.8).

E25. Female heterosexual precocious pseudopuberty associated with:

— adrenal hyperfunction (E25.8);

— congenital adrenal hyperplasia (E25.0);

— ovarian hyperandrogenism (E28.1);

— benign adrenal neoplasm (D35.0);

— malignant adrenal neoplasm (C74.9).

E28.0. Hyperestrogenism:

— benign ovarian neoplasm (D27);

— follicular ovarian cyst (N83.0).

Q78.1. McCune-Albright syndrome

Q87.1. Silver-Russell syndrome

E03.9. Hypothyroidism (acquired)

E02. Subclinical hypothyroidism

E30.8. Other disorders of puberty — premature thelarche

E30.9. Disorder of puberty, unspecified

The causes of precocious puberty in girls (pubertas praecox) have been systematized and thoroughly studied by obstetricians and gynecologists at Odesa National Medical University. According to O. O. Zelinsky's classification (2000), the following types are distinguished (Fig. 8):

Fig. 8. Diagram of precocious puberty (according to O. O. Zelinsky, 2000)

I. True precocious puberty.

1. Constitutional (idiopathic) — precocious puberty is observed along the maternal line of the girl (grandmothers, mother, aunts, sisters). This hereditary variant is normal for the family and does not require medical intervention. Besides the familial form, true idiopathic precocious puberty may sometimes be sporadic.

2. Of central origin — CNS disorders that lead to increased secretion of gonadotropin-releasing hormone or gonadotropic hormones, or to regulatory disruptions in the hypothalamic-pituitary system:

a) tumor-induced:

— hypothalamic hamartoma;

— astrocytoma;

— glioma (in neurofibromatosis, etc.);

— pinealoma (including ectopic);

— arachnoid cyst;

— pituitary adenoma;

— craniopharyngioma;

— tumors associated with tuberous sclerosis;

b) caused by Brain damage:

— Radiation therapy or Chemotherapy;

— surgical interventions;

— traumatic brain injury;

— encephalitis, meningitis, or meningoencephalitis;

c) CNS developmental anomalies;

d) Hydrocephalus;

e) delayed treatment of congenital adrenal hyperplasia, which leads to increased secretion of gonadotropin-releasing hormone and gonadotropins.

II. Pseudoprecocious (incomplete) puberty

1. Isosexual:

— ovarian tumors and cysts with a feminizing effect through estrogen production (granulosa-Cell luteoma);

— estrogen-producing adrenal tumors (very rare);

— iatrogenic causes (intake of sex hormones, gonadotropic hormones, or cimetidine, an H₂-receptor blocker);

— dietary factors (consumption of phytoestrogens such as soy, legumes, or "steroid meat" like imported poultry).

2. Heterosexual:

— congenital adrenal hyperplasia (CAH);

— masculinizing ovarian tumors with androgen secretion (androblastoma, dysgerminoma, teratoma, Choriocarcinoma);

— androgen-secreting adrenal tumors (androblastoma, adenoma, carcinoma).

III. Conditions associated with precocious puberty syndrome:

— Van Wyk — Grumbach syndrome — primary hypothyroidism (excess TSH secretion along with PRL and gonadotropic hormones);

— McCune — Albright — Braitsev syndrome (gonadotropin-independent ovarian hyperfunction);

— Russell — Silver syndrome (hypersecretion of gonadotropic hormones);

— Kabuki syndrome (86 cases of this syndrome have been described, occurring in Japan and characterized by Eyeball defects and isolated thelarche);

— Rubinstein — Taybi syndrome (a genetic disorder in which premature thelarche is a frequent finding);

— Ovarian Cysts (observed in normal sexual development, true precocious puberty, and premature thelarche).

IV. Incomplete forms of precocious puberty:

— isolated premature thelarche;

— isolated premature adrenarche;

— isolated premature menarche.

Girls with organic brain lesions and clinical manifestations of precocious puberty typically exhibit intellectual developmental delay and emotional lability (aggressiveness, sharp mood swings).

Cerebral pathology is dominated by functional-type autonomic and Metabolic Disorders: hyperhidrosis, acrocyanosis, subfebrile Temperature, and moderate obesity.

Signs of precocious puberty in organic lesions appear later than neurological symptoms, whereas in functional central nervous system disorders, they typically precede them and sometimes serve as the sole symptoms of hypothalamic dysfunction. In the cerebral form of precocious puberty, height, body weight, bone age, and The production of gonadotropins, estrogens, and 17-KS exceed age-related norms (see Table 14).

Precocious puberty associated with hormonally active ovarian tumors (granulosa cell, theca cell) is linked to the secretion of significant amounts of estrogens. The clinical picture is characterized by irregular bloody vaginal discharge against the background of minimal secondary sexual development. External and internal genitalia exhibit signs of estrogenic influence (vulvar cyanosis, developed vaginal rugae, "pupil" sign, enlarged uterine size). Estrogen production corresponds to that of adult women, while gonadotropin secretion is minimal. Bone age corresponds to chronological age, with no accelerated somatic development.

Constitutional precocious puberty presents with no pathology in the pituitary region or ovaries. The sequence and rate of sexual development are undisturbed. Puberty in such girls appears to be shifted to an earlier age.

Heterosexual precocious puberty (congenital adrenogenital syndrome, virilizing adrenal tumor) is associated with androgen overproduction and is characterized by accelerated growth of bones and Muscle tissue, as well as premature and excessive hair growth. Growth acceleration is observed in girls aged 2 to 5 and 10 to 12 years. Pubic hair appears at 3-5 years of age, and axillary hair at 6-7 years.

Hair growth on the face, trunk, and extremities appears later. Clitoral hypertrophy is evident. Mammary Glands do not develop. Menstruation is absent. Excretion of 17-KS is elevated.

The treatment of these disorders involves two aspects: first, treating the underlying pathology that triggered the accelerated development, and second, suppressing the precocious maturation process.

For CPP caused by a brain tumor, neurosurgical intervention is recommended. To slow down sexual development, medications that suppress pituitary gonadotropic function are used: hydroxyprogesterone acetate, cyproterone acetate (Androcur), and danazol. The daily dose of cyproterone, an antiandrogen with pronounced progestogenic properties, is 50-75 mg. Long-term use of danazol (17 months at 9-17 mg per kg of body weight) causes reduction of the mammary glands and cessation of menstrual function, while bone maturation is not accelerated because the drug does not affect the closure of growth plates.

Gonadotropin-releasing hormone agonists (GnRH agonists) are used to eliminate the effects of sex steroids, treat hyperandrogenism and polycystic Ovary syndrome (PCOS) complicated by genital Endometriosis and uterine fibroids. These drugs are also employed to diagnose pituitary reserve capacity in patients with hypogonadotropic Amenorrhea and in assisted reproductive technology programs for infertile patients.

The drug "Buserelin" in the form of a strictly metered intranasal spray is a high-quality GnRH agonist, the treatment with which is initiated on the 1st–2nd day of the Menstrual cycle. It is known that, in accordance with the biphasic MECHANISM OF ACTION of GnRH agonists under a prolonged regimen, the initial hyperstimulation effect on the pituitary and ovarian systems transforms within 1–2 weeks into pituitary desensitization and an exponential drop in sex steroid levels, which induces menstruation-like bleeding (MLB). The administration of buserelin at a daily dose of 900 mcg intranasally (150 mcg three times daily in each nasal passage) effectively blocks steroidogenesis.

Treatment of AGS involves lifelong hormone replacement therapy to compensate for adrenal insufficiency and suppress excessive androgen secretion. Plastic surgery of the external genitalia—such as amputation of the hypertrophied Clitoris or dissection of the urogenital sinus—is performed when clinically indicated. Maintenance doses of glucocorticoids (prednisolone) are applied: up to 5 years — 5 mg; 6–12 years — 5–7.5 mg; 13–18 years — 10–15 mg. Glucocorticoid therapy accelerates female-pattern puberty. Girls who begin treatment within the first decade of life exhibit early breast development and the onset of menstrual function. Rapid feminization is attributed to the functional activity of their own ovaries. In cases of salt-wasting, alongside hormone replacement therapy, sodium supplementation and the administration of 11-deoxycorticosterone are recommended.

Delayed puberty refers to the underdevelopment or absence of secondary sexual characteristics and menarche at an age exceeding the population mean by two standard deviations (2SD). Clinically, it manifests as the absence of breast development in girls aged 13 and older, and the absence of menstruation after the age of 15.

Classification of causes of delayed puberty (by L. St. L. O’Dea, S. F. Siegel, P. A. Lee, as modified by Yu. A. Gurkin, 2000)

I. Absence of sexual development

1. Hypergonadotropic hypogonadism:

— autoimmune oophoritis;

— galactosemia;

— gonadal agenesis or dysgenesis;

— resistant ovary syndrome;

— secondary ovarian destruction;

— chemotherapy;

— infectious process;

— radiation therapy;

— surgical gonadectomy;

— bilateral Torsion of the uterine appendages;

— ovarian trauma;

— impaired steroidogenesis due to enzymopathies.

2. Hypogonadotropic hypogonadism (lesions at the hypothalamo-pituitary level):

— autoimmune diseases;

— craniopharyngioma;

— hypothalamic or pituitary tumor;

— Hodgkin's lymphoma;

— idiopathic Hypopituitarism;

— female variant of Kallmann syndrome;

— secondary lesion of the hypothalamo-pituitary connection due to a tumor, trauma, or surgical intervention;

— septo-optic Dysplasia;

— Laurence—Moon—Biedl syndrome;

— Prader—Willi syndrome.

3. Functional (pseudo-)hypogonadism:

— anorexia nervosa;

— endointoxication;

— chronic diseases (enterocolitis, rheumatoid Arthritis, cystic fibrosis, etc.);

— constitutional delay of puberty;

— endocrine disorders (Cushing's syndrome, Diabetes Mellitus, Growth Hormone deficiency, hypothyroidism, hyperprolactinemia).

Nosological forms of gonadal dysgenesis:

1. Typical form of gonadal dysgenesis (Turner syndrome).

2. «Pure» form of gonadal dysgenesis (Rokitansky—Mayer syndrome, ovarian agenesis).

3. Mixed form of gonadal dysgenesis or testicular dysgenesis (testicular, asymmetric dysgenesis).

4. «Stigmatized» (mild/attenuated) forms of gonadal dysgenesis.

II. Partial delayed puberty (primary amenorrhea with developed mammary glands):

1. Hypergonadotropic state:

— incomplete ovarian resistance;

— refractory endometrium syndrome;

— androgen insensitivity syndrome.

2. Normal or low gonadotropin levels:

1) anatomical causes: hymenal atresia:

— vaginal atresia;

— Mayer—Rokitansky—Küster—Hauser syndrome;

2) pituitary causes: hyperprolactinemia:

— hypothyroidism;

— Cushing's Disease.

III. Delayed puberty with virilization:

— 5α-reductase deficiency;

— congenital adrenal hyperplasia;

— virilizing ovarian and adrenal tumors;

— mixed gonadal dysgenesis;

— 17-Ketosteroid reductase defect.

Forms of delayed puberty (V. P. Yurovskaya, 2004)

I. Cerebral (central) forms of delayed puberty:

A. By etiological factors:

1. Delayed puberty associated with organic CNS lesions (trauma, infections (encephalitis), Epilepsy, hypothalamic tumors).

2. Delayed puberty associated with stress (adolescent neuroses).

3. Delayed puberty associated with weight loss (anorexia nervosa).

4. Delayed puberty associated with extragenital pathology:

— endocrinopathies (diabetes mellitus, hypothyroidism, obesity);

— cardiovascular diseases (neurocirculatory dystonia, cardiopathy, arterial Hypertension);

— gastrointestinal disorders (chronic gastroduodenitis, enterocolitis);

— chronic Urinary System diseases;

— frequent infectious-toxic conditions (ARVI, chronic tonsillitis, Influenza, Pneumonia, rheumatism, childhood infections).

5. Constitutional form of delayed puberty (hereditary hypofunction of the hypothalamo-pituitary system).

B. Central forms of delayed puberty According to the level of lesion:

1. Hypothalamic, hypogonadotropic hypogonadism:

— hypogonadotropic eunuchoidism (Kallmann syndrome, olfactogenital syndrome);

— Laurence-Moon-Bardet-Biedl syndrome;

— Hand-Schüller-Christian disease.

2. Pituitary hypogonadotropic hypogonadism (empty sella syndrome, panhypopituitarism).

II. Gonadal (ovarian) form of delayed puberty (gonadotropin-resistant ovaries).

Hormonal disorders in delayed sexual development are underpinned by decreased gonadotropic pituitary function, leading to deficient estrogenic activity of the ovaries. Menstruation is absent in such girls (occasionally presenting as scant periods 1–2 times a year). There is increased height due to elongation of the arms and legs, with a slight increase in transverse pelvic dimensions. Bone age of the pelvis corresponds to chronological age. Secondary sexual characteristics are underdeveloped. Gynecological examination reveals hypoplasia of the external and internal genitalia, with uterine hypoplasia being more pronounced than ovarian hypoplasia. Microscopically, parabasal Cells predominate in vaginal smears.

Delayed puberty of ovarian origin in girls may result from functional ovarian insufficiency (following measles, mumps) and gonadal dysgenesis.

Functional ovarian insufficiency is characterized by a sharp decline in their hormonal activity against the background of hypergonadotropic pituitary activity. The cytological picture of the vaginal smear shows a greater degree of hypoestrogenism than in centrally originated delayed puberty. Ovarian stimulation is ineffective; the cellular COMPOSITION OF THE vaginal smear remains virtually unchanged following the administration of human chorionic gonadotropin (hCG). Clinically, there is an absence of menstruation, bone age typically lags behind chronological age, secondary sexual characteristics are underdeveloped, and uterine and ovarian hypoplasia is detected.

Gonadal dysgenesis involves significant impairments in sexual development. It is a genetically determined condition associated with an abnormal chromosome Complement. An example of gonadal dysgenesis is Turner syndrome, which features a wide range of Chromosomal aberrations: 45,X0, X0/XY, and X0/XXX. Such patients are characterized by a stocky build, a short webbed neck (so-called sphinx neck), micrognathia, epicanthus, ptosis, strabismus, low hair growth line, and Syndactyly. Secondary sexual characteristics and mammary glands are absent, and pubic and axillary hair growth is sparse. The vaginal mucosa is thin and shiny, and vaginal smear findings indicate atrophic processes. Amenorrhea is one of the primary symptoms of gonadal dysgenesis, although ovarian dysfunction resembling hypomenstrual syndrome may also occur. Sex Chromatin is absent. Laboratory tests indicate elevated urinary gonadotropin levels driven by FSH, with FSH excretion exceeding normal values by 13–15 times. Laparoscopy reveals various variants: genetically male individuals may have a formed uterus and fallopian tubes with rudimentary male gonads in place of ovaries, whereas variants with "masculinization" present with male gonads and a rudimentary uterus.

The "pure" form of gonadal dysgenesis is characterized by a 46,XX or 46,XY karyotype, with sex chromatin levels either reduced or normal. The hallmark clinical manifestation of this form is pronounced sexual infantilism in the absence of somatic developmental anomalies. Typically, these patients are of normal or tall height with a female phenotype. The body habitus is dysplastic, mammary glands are absent or underdeveloped, hair growth is sparse, external and internal genitalia are hypoplastic, and vaginal smears show an atrophic pattern. Urinary 17-ketosteroid (17-KS) excretion remains within normal limits.

The "mixed" (or "asymmetrical") form of gonadal dysgenesis is a specific variant of intersexuality. Pathogenetically, it is caused by sex chromosome pathology involving impaired testicular differentiation. A functional insufficiency develops and manifests during Embryogenesis; Müllerian ducts persist alongside a characteristic female phenotype, absence of sex chromatin, and an intersex Structure OF THE genitalia with a female predominance, including a uterus and vagina. A Connective Tissue remnant occupies the site of the ovaries. Mammary glands are absent. Pubic hair is prominent, frequently accompanied by hypertrichosis and clitoral hypertrophy. Somatic anomalies are absent. This form of the disorder is characterized by an increased predisposition to tumorigenesis.

Treatment for various disorders of sexual development depends on their specific form and may include surgery, normalization of diencephalic function, estrogen and progestogen replacement therapy, and correction of somatic abnormalities.

Management of centrally originated delayed puberty depends on the underlying cause; surgical intervention is indicated for pituitary tumors. For Other forms of the disease, general strengthening therapy, cyclical vitamin therapy, and measures aimed at normalizing diencephalic structures are recommended, along with neurological and psychotherapeutic consultations. In severe cases of delayed puberty marked by profound underdevelopment or absence of secondary sexual characteristics, hormone therapy is prescribed. Hypothalamic forms of delayed puberty are treated with pulsatile gonadotropin-releasing hormone (GnRH) administration (subcutaneously at 2 mcg every 90 minutes for 6 weeks).

Diagnosis of gonadal forms of delayed puberty is based on the Clinical presentation, hormone level assays, ultrasound, and laparoscopy findings.

Treatment of gonadal forms of delayed puberty. Gonadal dysgenesis raises the question of whether gonadectomy is necessary, as some patients exhibit potential blastomatous activity in dysgenetic gonads. Gonadectomy is recommended in all cases where gonadal tumor development is suspected in patients with a 45,X0 or 46,XX karyotype (or variants thereof) and is mandatory if a Y chromosome is present in the karyotype.

Exogenous sex hormone replacement is proposed using preparations containing natural estrogens, specifically estradiol valerate or 17β-estradiol. Drugs of choice include Divigel, Divina, and Divitren. Divigel is an alcohol-based transdermal gel containing 1 or 0.5 mg of estradiol hemihydrate. A single daily application of the drug to the Skin of the iliac Regions of the abdomen, upper thighs, or buttocks over an area equivalent to 1–2 palms ensures active drug absorption within the first 30 minutes and maintains stable plasma concentrations until the next dose. The main advantage of transdermal therapy is the delivery of the lowest effective dose of estradiol directly into the systemic Circulation through the skin, bypassing the enzymatic and metabolic effects of first-pass hepatic METABOLISM. Transdermal estrogen administration preserves the biological activity of estradiol in Blood Plasma by avoiding primary hepatocyte metabolism. Furthermore, transdermal delivery eliminates any impact on the gastric and duodenal mucosa. Divigel-0.5 is selected for monotherapy with estradiol in non-menstruating girls aged 10–12 years suffering from gonadal dysgenesis, while Divigel-1 is used to rapidly reverse estrogen deficiency in girls over 16. For progestogen supplementation alongside continuous Divigel administration, oral medroxyprogesterone acetate (Provera) at 10–20 mg or dydrogesterone (Duphaston) at 10 mg daily is administered for 10–12 days during each cycle. The ultimate goal of hormone replacement therapy is to achieve not only proportional somatic development, but also the treatment of sexual infantilism.