Sexually Transmitted Diseases - I. I. Mavrov 2005

Anomalies of the Urogenital System Development
Hypogonadism. Hypergonadism

Hypogonadism is delayed Puberty caused by reduced secretion of Sex Hormones, characterized by underdeveloped sex Organs and secondary sex characteristics.

Primary hypogonadism develops as a direct result of pathological damage to the Gonads or castration; secondary (hypogonadotropic) hypogonadism occurs due to decreased or halted secretion of gonadotropic hormones caused by pituitary and hypothalamic lesions; neurogenic hypogonadism stems from impaired neural Regulation of the sex organs.

Recently, a relatively straightforward Classification of the causes of this pathology has become widely accepted. They can be divided into constitutional, non-endocrine systemic, and endocrine causes. Constitutional causes include growth retardation, delayed maturation of Bone tissue, and underdevelopment of external genitalia. These phenomena may occur in members of the same family (siblings): upon reaching a certain age, they exhibit similar disorders. At their core lies insufficient Central Nervous system development, where the hypothalamic-pituitary-gonadal system fails to mature completely. Growth retardation is typically marked by the absence of a physiological response of hypothalamic gonadotropic releasing factors to stimuli that normally regulate the secretion of these hormones. Furthermore, it is possible that in such individuals, neurohormone secretion fails to reach the required age-appropriate levels (Herbert S. Kupperman, 1988).

Non-endocrine systemic causes. Puberty is significantly delayed in individuals with nutritional disorders resulting from impaired intestinal absorption, as well as from starvation or anorexia nervosa.

Pubertal delay can be triggered by A number of Hereditary diseases caused by impaired mucopolysaccharide METABOLISM with their accumulation in organs and Tissues (Mucopolysaccharidoses), and impaired Carbohydrate Metabolism due to a deficiency of the enzyme galactose-1-phosphate uridylyltransferase (galactosemia). This manifests as galactose accumulation in the Blood, jaundice, hepatomegaly, cataracts, and delayed physical and mental development. These conditions are accompanied by the destruction of ovarian follicles due to the buildup of toxic products, leading to Female Infertility.

Any chronic illness can potentially cause delayed puberty due to overall bodily weakness, impaired hormone transport, and reduced receptor activity. It can be triggered by severe cardiovascular pathology (including Congenital Heart defects), gastrointestinal disorders, and chronic lung and Liver diseases.

Anorexia nervosa, heavy physical exertion, and stressful situations (such as during athletic competitions) can also lead to delayed puberty, as they negatively impact the balance of activity within the Hypothalamus-pituitary-thyroid axis.

Endocrine causes. Patients with endocrine-Etiology hypogonadism primarily include individuals with conditions caused by hyperthyroidism or hypothyroidism, lesions of the hypothalamic nuclei, anterior pituitary hormone deficiency (panhypopituitarism), congenital adrenal hyperplasia (Cushing's Disease), or pituitary micro- or macroadenomas.

High doses of corticosteroids used to treat allergic conditions (Bronchial Asthma) and certain dermatological diseases can inhibit the action of gonadotropic hormones, thereby delaying puberty and disrupting the normal development of sex organs.

Hypogonadotropic hypogonadism syndrome manifests as delayed puberty in male and female adolescents, caused by a selective gonadotropin deficiency or a blocked pituitary response to hypothalamic releasing hormones. This category includes certain central nervous system lesions that can disrupt impulse transmission from the hypothalamus to the pituitary if the affected area lies along the hypothalamo-pituitary pathways, as well as a deficiency of hypothalamic gonadotropic releasing factors, observed notably in olfactogenital syndrome (Kallmann syndrome). It is characterized by reduced or absent SENSE OF SMELL caused by underdevelopment of the central olfactory structures of the Brain. Males may exhibit gynecomastia, sometimes accompanied by cryptorchidism; females may exhibit labial fusion.

Laurence-Moon-Biedl syndrome is an autosomal recessively inherited disorder associated with Lipid Metabolism abnormalities and sexual dysfunction. The most characteristic symptoms of this disease are excessive subcutaneous adipose tissue development (from birth), mental retardation (oligophrenia), and pigmentary retinopathy, typically accompanied by polydactyly or Syndactyly and hypogonadotropic hypogonadism. Diabetes Mellitus may sometimes be diagnosed. The syndrome is believed to be linked to hypothalamic center dysfunction.

Prader-Willi syndrome is an autosomal recessively inherited metabolic disorder. Affected individuals are characterized by mental retardation, underdevelopment of sex organs, a round face, small yet broad hands and feet, and muscular hypotonia. The underlying cause is a hypothalamic defect accompanied by bulimia (excessive food intake), obesity, and hypogonadism.

Hypergonadotropic hypogonadism syndromes with delayed or absent puberty also include Turner syndrome (Shereshevsky-Turner syndrome), a chromosomal disorder in females caused by the absence of one X chromosome in the karyotype, which leads to impaired gonadal development. The core of the syndrome lies in sex chromosome nondivision during gamete division and The formation of a zygote with an abnormal karyotype (in most cases, 45, X). Under The Influence of maternal estrogens, the fetus develops a FEMALE Reproductive System. Nail hypoplasia, a short neck, and lymphedema of the extremities are noticeable even during the neonatal period. Later on, it manifests as underdevelopment of Primary and secondary sex characteristics, the presence of pterygium colli (webbed neck) extending downward from the mastoid processes, true gonadal dysgenesis, ovarian resistance syndrome (Savage syndrome), and androgen insensitivity syndrome (typically observed in individuals with well-developed breasts, but lacking a Uterus, pubic and axillary Hair, and presenting a short rudimentary Vagina). A male karyotype without breast development and with normal testosterone levels can occur in females; typically, testosterone levels are normal in males with insensitivity syndrome and elevated in females. Furthermore, gonadotropin levels are elevated in this variant, whereas they are low or normal in "pure" androgen insensitivity syndrome. Treatment focuses on stimulating growth (anabolic Steroids) and feminization of the patients (estrogens).

Other hypergonadotropic hypogonadism syndromes include ovarian failure primarily driven by genetic factors that lead to immune-mediated ovarian damage. Such patients may present with multiple endocrine disorders (adrenocortical and parathyroid insufficiency, Hashimoto's thyroiditis). Additionally, myasthenia gravis, systemic lupus erythematosus, and systemic candidiasis may be observed.

In females, deficiencies of steroid 17-alpha-hydroxylase, 5-alpha-reductase, or 17-ketoreductase can cause severe Anomalies of the external genitalia alongside normally developed internal reproductive organs.

Several types of hypergonadotropic hypogonadism syndrome occur in males. One of them—bilateral undescended Testes in boys—requires immediate medical intervention. If cryptorchidism is the underlying cause of the undescended testes, gonadotropin secretion will not increase; however, if anorchia is present, gonadotropin secretion may be high. Therefore, to establish a Differential Diagnosis, it is vital to determine as early as possible—without waiting for puberty—whether the patient has testes and whether they are capable of functioning.

Examples of pathology marked by hypergonadotropic delayed puberty include Turner syndrome, which is accompanied by a pathological karyotype, and Noonan syndrome, which features a normal karyotype and elevated gonadotropin levels. Boys with a typical presentation of Turner syndrome but without characteristic chromosomal anomalies sometimes exhibit congenital heart defects of the right heart. Hypoplasia of the testes or cryptorchidism is evident in all these cases. A germ Cell and androgen secretion defect is typical for this syndrome. Occasionally, patients with the classic clinical picture of Turner syndrome show no signs of delayed puberty.

Klinefelter's syndrome is a chromosomal abnormality in males caused by sex chromosome polysomy. It typically manifests during puberty. The most characteristic feature is the discrepancy between marked testicular atrophy and relatively normal penile size. Patients with this pathology may exhibit breast enlargement (gynecomastia), eunuchoidism, underdevelopment of secondary sex characteristics, and lack of Spermatogenesis. In adults, sexual dysfunction and infertility are observed. As Aging progresses, testicular cytoarchitecture disorders worsen, eventually leading to tubular hyalinosis and absolute azoospermia. Leydig Cells in such patients appear histologically normal, yet their number is reduced. Prior to puberty, the diagnosis can only be established by determining sex Chromatin or karyotype; afterward, it is made based on characteristic symptoms and the detection of elevated gonadotropin excretion. Treatment is administered during puberty using sex hormones (androgens).

Hypergonadism is precocious puberty caused by the excessive secretion of sex hormones relative to age norms. Precocious puberty is defined as the appearance of secondary sex characteristics at an age more than two standard deviations below the average normal age of puberty (8 years for girls, 9 years for boys).

Potential causes include tumors, central nervous system trauma, Epilepsy, prenatal or perinatal infections, encephalopathy, meningitis, neurofibromatosis, granulomatous diseases (e.g., sarcoidosis), Syphilis, tuberculosis, Ovarian Cysts, ovarian and adrenal tumors, and others.

Both isosexual and heterosexual forms of precocious development are distinguished. The isosexual form is characterized by the Early Development of secondary sex characteristics matching the child's biological sex (e.g., breast development and early menstruation in girls; enlarged genitalia and voice deepening in boys). Isosexual precocious puberty can be complete (true) and incomplete (pseudo-precocious).

Causes of complete puberty include early maturation of the hypothalamic-pituitary system or its damage resulting from congenital anomalies, inflammatory changes, Brain Tumors, etc. In this scenario, receiving stimulation from the pituitary, the gonads mature prematurely and begin functioning earlier, which in turn leads to the early development of secondary sex characteristics. The excretion of sex hormones exceeds age norms, though it does not surpass comparable levels in sexually mature individuals.

Idiopathic complete isosexual precocious puberty arises from localized damage to the hypothalamic area regulating gonadotropic function. Patients with this form of puberty exhibit a series of abnormalities detectable on an Electroencephalogram: pubic hair appears, breasts develop, and sometimes the Labia minora enlarge. The Developmental Stages of secondary sex characteristics mirror normal puberty. Meanwhile, the true nature of puberty confirms the cerebral genesis of the disorder.

Complete isosexual precocious puberty can be triggered by various central nervous system conditions (tumors, trauma, encephalitis, brain abscesses, neurofibromatosis, Various Forms of epilepsy, etc.), sarcoidosis, tuberculosis, and severe forms of hypothyroidism.

Tumors such as ependymomas, astrocytomas, optic pathway gliomas, germinomas, and teratomas typically impinge upon the hypothalamic region, disrupting its normal neurochemical connections with the Pituitary Gland. They are more frequently observed in males than in females and can be either hormonally active or non-secretory. Granulomas accompanying sarcoidosis or tuberculosis can also cause hypothalamic compression and precocious puberty. Similarly, in neurofibromatosis (von Recklinghausen disease), hypothalamic function can be disrupted by neurofibroma gliomas developing within the central nervous system. Neurofibromatosis may manifest not only as precocious puberty but also as its delay. Treatment: surgical intervention; anti-inflammatory, resorptive, and dehydrating medications.

Incomplete isosexual precocious puberty is caused by increased sex hormone secretion triggered by hormonally active gonadal tumors, such as teratomas or teratocarcinomas. An excess of sex hormones leads to The Development of secondary sexual characteristics; however, the intact gonad remains immature and non-functional, making spermatogenesis in boys and a regular Menstrual cycle in girls impossible. Pathological secretion of human chorionic gonadotropin (hCG) in males can sometimes be extremely difficult to differentiate from idiopathic precocious puberty. In females, hCG typically stimulates ovarian function and increases estrogen secretion, resulting in breast development and pseudomenstrual bleeding.

Precocious puberty can be triggered by various defects in adrenal steroid metabolism. Among these, the most common is 21-hydroxylase deficiency, which regulates The conversion of progesterone to 11-deoxycorticosterone and 17-α-hydroxyprogesterone to 11-deoxycortisol. The blocked Synthesis of the latter leads to decreased cortisol secretion, which, via feedback mechanisms, disrupts the normal function of the hypothalamus-pituitary axis. Consequently, the secretion of dehydroepiandrosterone and androsterone increases, leading to subsequent virilization. Partial steroid-11-β-hydroxylase deficiency is less common than 21-hydroxylase deficiency, yet it specifically blocks the conversion of 11-deoxycortisol to cortisol. This likewise increases the secretion of androgen precursors, dehydroepiandrosterone and androstenedione. Both of these Metabolic Disorders are observed in congenital adrenal hyperplasia and are inherited in an autosomal recessive manner. Numerous adrenal tumors capable of secreting androgens—primarily dehydroepiandrosterone—are generally classified as adrenocortical carcinomas. Treatment is surgical, whereas congenital adrenal hyperplasia is managed with hormone therapy (glucocorticoids).

Many ovarian tumors can be accompanied by isosexual precocious puberty in girls. Simple follicular cysts frequently lead to precocious development because they secrete sufficient steroids to cause periodic uterine bleeding and incomplete isosexual precocious development (J. W. Towne et al., 1975). Follicular cysts should be differentiated from Germ Cell Tumors, which comprise a range of histologically diverse ovarian neoplasms developing from embryonic primitive Germ Cells. These tumors account for approximately 60% of all malignant ovarian tumors diagnosed in patients under 20 years of age. In 50% of patients, the tumors are palpable, with pain being the primary symptom. Approximately 10% of patients with these tumors present with signs of incomplete isosexual precocious puberty manifested as vaginal bleeding, breast development, and areolar pigmentation. Following surgical removal of the tumor, these symptoms regress completely.

In girls with tumor-induced isosexual precocious puberty, granulosa-theca cell tumors are most commonly identified, though other endocrine tumors—either pure or mixed forms (benign cystic teratoma, malignant teratoma, mixed germ cell tumor, endodermal sinus tumor, Sertoli cell tumor)—are also possible.

Precocious puberty can be caused by medications containing sex Steroid Hormones. Many firming creams, ointments, and Skin lotions contain estrogens, and their use by a child can lead to the onset of precocious puberty symptoms.

Certain variants of sexual development cannot be classified as either complete or incomplete isosexual precocious puberty (for instance, chronic perineal irritation caused by helminthic infections or diarrhea may lead to the appearance of pubic hair on the inner surface of the labia minora). The bone age of the child remains completely normal in these cases; therefore, this syndrome is not considered true 'acceleration' of puberty. Occasionally, a child may exhibit premature unilateral or bilateral breast enlargement without other signs of increased estrogen secretion, which may either spontaneously regress or persist for several years. In pre-pubertal boys, gynecomastia is frequently observed due to an altered estradiol-to-testosterone ratio. As a rule, these manifestations resolve on their own with age.

In heterosexual precocious puberty, secondary sexual characteristics correspond to those of the opposite sex. A frequent cause in girls is congenital adrenal hyperplasia. Excessive adrenal androgen production leads to male-pattern pubertal hair growth, enlargement and virilization of the Clitoris, enhanced muscular development, while female secondary sexual characteristics fail to develop. Less commonly, heterosexual precocious puberty in girls is caused by a virilizing ovarian tumor (arrhenoblastoma, lipid cell tumor, etc.) or an adrenal tumor (androsteroma). In such cases, The Structure of the external genitalia at birth is normal, and signs of heterosexuality appear postnatally. In boys, heterosexual precocious puberty is rare and is invariably caused by a feminizing adrenocortical tumor (corticoestroma). This condition leads to true gynecomastia, pubertal hair growth, a female distribution of subcutaneous fat, hypoplasia of the genital apparatus, and other signs. The Pathogenesis is associated with the action of Female Sex Hormones, blood levels of which significantly exceed age norms. The diagnosis is established based on elevated urinary estrogen levels and radiological findings of the adrenal region.