No semen after puberty
Introduction
Introduction Patients with bilateral congenital adrenal hyperplasia develop hairy, muscular, amenorrhea and breast development. The reproductive organs of male patients are unusually large. Excessive androgen inhibits the secretion of gonadotropins, causing testicular atrophy. In extremely rare cases, hyperplastic adrenal cortical remnants in the testicles increase and harden the testes, and most patients have no semen after puberty. The cause of this disease is not clear. Most scholars disagree with the pathogenesis of ACTH-dependent to non-dependent transition. It has been confirmed that AIMAH can be caused by factors other than ACTH. It has been found that abnormal expression of gastric inhibitory peptide (GIP), arginine vasopressin (AVP), and 2-adrenergic receptor in the adrenal gland can cause AIMAH.
Cause
Cause
The cause of this disease is not clear. Most scholars disagree with the pathogenesis of ACTH-dependent to non-dependent transition. It has been confirmed that AIMAH can be caused by factors other than ACTH. It has been found that abnormal expression of gastric inhibitory peptide (GIP), arginine vasopressin (AVP), and 2-adrenergic receptor in the adrenal gland can cause AIMAH.
(1) Causes of the disease
Almost all CYP21 mutations are the result of recombination between CYP21 and CYP21P (unequal exchange or conversion). Approximately 20% of the mutant alleles carry deletion mutations. Approximately 75% of the mutant alleles are the result of gene conversion. In 32% of patients with salt loss, there is a large fragment deletion or mutation in one allele, and 56% of point mutations in intron 2 on one allele cause RNA splicing abnormalities. These mutations were confirmed in vitro to completely or almost completely lose 21-hydroxylase activity. In the simple male type, the most common mutant allele (35%) is the substitution mutation of the amino acid codon 172 (Ile becomes Asn), and only retains 2% to 11% of the activity of normal 21-hydroxylase. The most common (39%) mutation in the non-classical type is the mutation of amino acid 281 (Val becomes Leu). There is a high correlation between genotype and phenotype. Therefore, DNA analysis can predict enzyme activity to a certain extent, and then predict clinical manifestations.
(two) pathogenesis
Adrenal synthesis of 3 steroids: 1 glucocorticoid (cortisol is the most important one); 2 mineralocorticoid (aldosterone is the most important one); 3 androgen. Cortisol secretion has a circadian rhythm, which is crucial in stress situations; its lack causes adrenal crisis including hypotension and hypoglycemia, which can lead to death if not treated in time. Excessive production of adrenal androgen can lead to intrauterine masculinization. Female babies have genital malformations at birth, and adrenal glands appear prematurely in older males and females. Adrenal and gonad androgen production disorders can lead to male masculinization and lack of puberty development. In CAH, steroid synthase activity decreases to varying degrees, leading to abnormal secretion of glucocorticoids, mineralocorticoids and sex hormones, resulting in varying degrees of clinical manifestations. The degree of decline in enzyme activity and clinical phenotype are determined by the severity of the mutation and the type of mutation. In order to better understand the clinical manifestations of CAH, it is necessary to briefly understand the biochemical and related genes of adrenocortical steroid hormones.
1. The P450SCC gene (CYP11A) is a 20 kb single gene located on the long arm of chromosome 15 (15q23-24). Expressed in all steroid cells.
2.3 -HSD (3-hydroxysteroid Dehydrogenase II, 3-hydroxysteroid dehydrogenase II). This microsomal hydroxysteroid dehydrogenase binds to the membrane and is associated with the smooth endoplasmic reticulum. It catalyzes the conversion of the hydroxyl group of carbon atom 3 to a keto group and the isomerization of a double bond from the B ring (delta5 steroid) to the A ring (delta4 steroid). It acts on four substrates, pregnenolone is converted to progesterone, 17-hydroxypregnenolone is converted to 17-hydroxyprogesterone, and dehydroepiandrosterone (DHEA) is converted to androstenedione, androstenedione Turned into testosterone. There are two different isozymes: type II is active in the adrenal glands and gonads, and type I is active in other tissues (skin, placenta, breast, etc.). The 3-HSD gene (HSD1 and HSD2) has 93% homology and is located on chromosome 1 (1p13.1).
3. P450C17 (17-hydroxylase/17,20 lyase). P450C17 is a microsomal enzyme that binds to the smooth endoplasmic reticulum. Two different and completely independent reactions are catalyzed: 17-hydroxylase and 17,20 lyase reaction. By 17-hydroxylation, the pregnenolone is converted to 17-hydroxypregnenolone and the progesterone is converted to 17-hydroxyprogesterone. These two substrates are cleaved by C17 and 20 carbon chains to form dehydroepiandrosterone and androstenedione, respectively. The gene encoding this enzyme is a single gene (CYP17) located on chromosome 10 (10q24.3). When P450C17 is completely deficient (such as globular band), aldosterone can be synthesized, but cortisol and sex hormones cannot be synthesized. If only 17-hydroxylase activity is present, cortisol can be synthesized, and sex hormones must rely on two activities, 17-hydroxylase and 17,20 lyase activity. For example, before puberty, the synthesis of adrenal cortisol is normal, but there is no synthesis of sex hormones, indicating 17-hydroxylase activity but no 17,20 lyase activity.
4. P450C21 (21-hydroxylase). P450C21 is also bound to the smooth endoplasmic reticulum and actually competes with P450C17 for electrons derived from membrane-bound P450 reductase. It converts progesterone and 17-hydroxyprogesterone into 11-deoxycorticosterone (DOC) and 11-deoxycortisol, respectively. Two CYP21 genes are located on chromosome 6 (6p21.3), in the middle of human leukocyte antigen (HLA), between HLA-B and HLA-DR. The CYP21 gene encodes a biologically active enzyme. The pseudogene is called CYP21P. CYP21P shares more than 93% homology with CYP21, but because of the presence of some deleterious mutations in CYP21P, this gene does not transcribe the mRNA of P450C21. It is precisely because of the high homology between CYP21P and CYP212 genes that gene transfer occurs, which is also a reason for the high incidence of CYP21 gene mutation.
5. P450C11 (C11-hydroxylase). In the adrenal gland, it is active, mainly involved in the synthesis of cortisol. Located in the mitochondrial inner membrane, the mitochondrial inner membrane converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. Its coding gene is located on chromosome 8 (8q 21-22).
Mutations in the above-mentioned steroid hormone-encoding genes and hormonal synthesis disorders lead to CAH. Defects in CYP21 and CYP11 cause masculinization in women, while HSD32, CYP17 and StAR defects cause androgen synthesis disorders, resulting in male masculinization. Some types of HSD32 deficiency can cause mild masculinization in women.
The gonads and adrenal glands have the same steroidogenic pathways. Therefore, some clinical manifestations are caused by abnormal steroid synthesis in the gonads, but not by abnormalities of adrenal hormones. In the fetal period, the degradation of the Miao tube structure is due to the presence of non-steroidal substances produced by the testes, the Miao tube inhibitor. Therefore, a fetus without a testicle will have a normal female internal genital anatomy regardless of the level of androgen. Fetuses with normal testes, regardless of the level of androgen, Müller tube structure will not develop.
Examine
an examination
Related inspection
Seminal vesicle examination
[clinical manifestations]
Increased ACTH secretion causes bilateral adrenal hyperplasia. The hyperplastic cortex continues to synthesize androgen and hypertensive mineral corticosteroids in large quantities. The lack of 20-22 carbon chain enzymes leads to rare congenital fatty adrenal hyperplasia, often with complete barriers to steroidogenesis. If there is not enough replacement therapy, the baby will die early.
The lack of 3-hydroxysteroid dehydrogenase isomerase leads to synthetic barriers to progesterone, aldosterone and cortisol, and dehydroepiandrosterone is overproduced. This unusual syndrome is characterized by hypotension, hypoglycemia and male leave. Sexual deformity. Women are uncommon hairy and have varying melanin. Insufficient or lack of 21-hydroxylase can not convert 17-carboxyprogesterone to cortisol, the most common deficiency is two forms: (1) a variety of sodium, aldosterone low or lack; (1) more common The non-sodium type, hairy, masculine, hypotension and pigmentation are common.
17-hydroxylase deficiency, most commonly seen in female patients, some to adulthood with low levels of cortisol, ACTH compensatory increase. Primary amenorrhea, sexually naive, few male pseudohermaphroditism. Excessive secretion of salt corticosteroids causes hypertension, mainly due to increased 11-deoxycorticosterone.
11-hydroxylase deficiency hindered the formation of cortisol and corticosterone, ACTH release was too high, resulting in deep melanin deposition, high blood pressure due to excessive secretion of 11-deoxycorticosterone, no obvious abnormalities.
Lack of 18-hydroxysteroid dehydrogenase, rare in skin disease, is caused by the specific block of the last step of aldosterone biosynthesis. Therefore, patients with more loss of urinary sodium, causing dehydration and hypotension.
After puberty, masculine manifestations such as hairy and amenorrhea are rarely found, and masculinity occurs by chance in middle age. This acquired abnormality of the adrenal mild enzyme is called benign masculinization of the adrenal cortex.
The newborn genital genitalia has severe hypospadias and cryptorchidism. The boy is mostly normal at birth. There are excessive androgen in the fetus in the uterus, so there is obvious abnormality.
Untreated patients develop hairy, muscular, amenorrhea, and breast development. The reproductive organs of male patients are unusually large. Excessive androgen inhibits the secretion of gonadotropins, causing testicular atrophy. In extremely rare cases, hyperplastic adrenal cortical remnants in the testicles increase and harden the testes, and most patients have no semen after puberty. Due to adrenal hyperplasia, the height of the patient is soaring at 3 to 8 years old, which is much higher than that of children of the same age. About 9 to 10 years old, excessive androgen causes early fusion of the epiphysis, which causes the growth to terminate, and the patient is shorter after adulthood. Both men and women have provocative behaviors and increased sexual desires, and social problems and disciplinary problems are particularly prominent in some boys.
[Auxiliary inspection]
The level of urinary 17-ketosteroids is higher than that of normal age of the same sex. Early rise in progesterone levels in the urine (which is more sensitive than the level of urinary 17-KS, because progesterone is a precursor of androgen), elevated blood levels of 17-hydroxyprogesterone are the most sensitive indicators for children The chromosome check is normal. X-ray examination will find early bone age. Lateral urethra cystography will show the vagina, urethra and bladder. A highly hyperplastic adrenal gland can be seen on the CT scan. The urethra can see the vagina that opens to the posterior wall of the urethra, and can also enter the vagina and see the uterus.
Diagnosis
Differential diagnosis
Many congenital malformations affecting external genital development resemble adrenal syndrome, including:
(1) severe hypospadias and cryptorchidism;
(2) Non-adrenal female pseudo-hermaphroditism (due to excessive androgen or progesterone taking during pregnancy);
(3) male pseudohermaphroditism;
(4) True hermaphroditism, these children are not ahead of any hormonal abnormalities, bone age and maturity.
