Sex Hormones Abnormalities Dr. Amal Baalash Hormones Steroid Hormones Characteristics: Are made from cholesterol, are lipophilic & can enter target cell Are immediately released from cell after synthesis Interact with cytoplasmic or nuclear receptors Activate DNA for protein synthesis Are slower acting and have longer half-life than peptide hormones Examples: cortisol, estrogen & testosterone Steroid Hormones: Action Figure 7-7: Steroid hormone action Some Genetic Abnormalities of Gonadal Function Many things can go wrong with sexual development in both males and females; fortunately rarely. Only at a few that clearly result from the inheritance of single-gene mutations. Inherited mutations in both copies of the gene encoding the GnRH receptor result in failure to develop at puberty. Mutations in the gene encoding the LH receptor prevent normal sexual development in both sexes. Genetic Abnormalities of Gonadal Function Mutations in the gene encoding the FSH receptor block development of the gonads in both males and females. Mutations in any of the genes encoding the enzymes for synthesis and metabolism of testosterone interfere with normal sexual function in males. A similar spectrum of disorders in males can be caused by mutations in the genes encoding the androgen receptor. Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia is a group of autosomal recessive disorders resulting from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. The most frequent is steroid 21-hydroxylase deficiency, accounting for more than 90 percent of cases. Steroid 21-hydroxylase (CYP21, also termed CYP21A2 and P450c21) is a cytochrome P-450 enzyme located in the endoplasmic reticulum. It catalyzes the conversion of 17- hydroxyprogesterone to 11-deoxycortisol, a precursor of cortisol, and the conversion of progesterone to deoxycorticosterone, a precursor of aldosterone. Owing to this loss of enzyme function, patients with 21-hydroxylase deficiency cannot synthesize cortisol efficiently, and as a result, the adrenal cortex is stimulated by corticotropin and overproduces cortisol precursors. Some of these overproduced precursors are diverted to the biosynthesis of sex hormones, which may cause signs of androgen excess, including ambiguous genitalia in newborn girls and rapid postnatal growth in both sexes. Concomitant aldosterone deficiency may lead to salt wasting with consequent failure to thrive, hypovolemia, and shock. Genetics Mutations in the CYP21(CYP21A2) gene. CYP21 mutations can be grouped into three categories according to the level of enzymatic activity. The first group consists of mutations such as deletions or nonsense mutations that totally ablate enzyme activity; these are most often associated with salt-wasting disease. The second group of mutations, consisting mainly of the missense mutation, yields enzymes with 1 to 2 percent of normal activity. The final group includes mutations such as Val281Leu (V281L) and Pro30Leu (P30L) that produce enzymes retaining 20 to 60 percent of normal activity; these mutations are associated with the nonclassic disorder. Clinical Picture: Early appearance of male characteristics. In a newborn girl with this disorder, the clitoris is enlarged with the urethral opening at the base (ambiguous genitalia, often appearing more male-like than female). The internal structures of the reproductive tract (ovaries, uterus, and fallopian tubes) are normal. As she grows older, masculinization of some features takes place, such as deepening of the voice, the appearance of facial hair, and failure to menstruate at puberty. In a newborn boy no obvious abnormality is present, but long before puberty normally occurs, the child becomes increasingly muscular, the penis enlarges, pubic hair appears, and the voice deepens. Affected males may appear to enter puberty as early as 2-3 years of age. At puberty, the testes are small. Some forms of congenital adrenal hyperplasia are more severe and cause adrenal crisis in the newborn due to salt wasting. In this salt-losing form of congenital adrenal hyperplasia, newborns develop symptoms shortly after birth. These include vomiting, dehydration, electrolyte changes, and cardiac arrhythmias. Untreated, this condition can lead to death within 1-6 weeks after birth. About 1 in 10,000 to 18,000 children are born with congenital adrenal hyperplasia. Androgen insensitivity syndrome A person who is genetically male (has one X and one Y chromosome) is resistant to male hormones (androgens). As a result, the person has some or all of the physical characteristics of a woman, despite having the genetic makeup of a man. Causes Androgen insensitivity syndrome (AIS) is caused by various genetic defects on the X chromosome that make the body unable to respond to the hormones responsible for the male appearance. The syndrome is divided into two main categories: Complete AIS Incomplete AIS Complete androgen insensitivity prevents the development of the penis and other male body parts. The child born appears to be a girl. The complete form of the syndrome occurs in as many as 1 in 20,000 live births. Symptoms A person with complete AIS appears to be female but has no uterus, and has very little armpit and pubic hair. At puberty, female secondary sex characteristics (such as breasts) develop, but menstruation and fertility do not. There may be: A vagina but no cervix or uterus Inguinal hernia with a testis that can be felt during a physical exam Normal female breast development Testes in the abdomen or other unusual places in the body Persons with incomplete AIS may have both male and female physical characteristics. Many have partial closing of the outer vaginal lips, an enlarged clitoris, and a short vagina. The degree of sexual ambiguity varies widely in persons with incomplete AIS. eg breast development in men, failure of one or both testes fail to descend into the scrotum after birth, and hypospadias, a condition where the opening of the urethra is on the underside, rather than at the tip, of the penis. Also included in the broad category of incomplete AIS is infertile male syndrome, which is sometimes due to an androgen receptor disorder. Exams and Tests Complete AIS is rarely discovered during childhood, unless a mass is felt in the abdomen or groin that turns out to be a testicle when it is explored surgically. Most people with this condition are not diagnosed until they fail to menstruate or have difficulties becoming pregnant. Incomplete AIS, however, is often discovered during childhood because the person may have both male and female physical characteristics. Tests used to diagnose this condition may include: Blood work to check levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) Genetic testing (karyotyping) Pelvic ultrasound Other blood tests may be done to help tell the difference between AIS and androgen deficiency. Klinefelter syndrome Alternative Names 47 X-X-Y syndrome Definition of Klinefelter syndrome: Klinefelter syndrome is the presence of an extra X chromosome in a male. Klinefelter syndrome is one of a group of sex chromosome problems. It results in males who have at least one extra X chromosome. Usually, this occurs due to one extra X (written as XXY). Klinefelter syndrome is the most common disorder of sex chromosomes in humans found in about 1 out of every 500 - 1,000 newborn males. Women who have pregnancies after age 35 are slightly more likely to have a boy with this syndrome than younger women. Clinical Picture 47,XXY males may present with hypospadias, small phallus or cryptorchidism, developmental delay ... language delay, learning disabilities, or behavioral problems ... delayed or incomplete pubertal development, gynecomastia, and small testes. Adults are often evaluated for infertility or breast malignancy ... replacement therapy should begin at puberty, around age 12 years ... Affected individuals have longer arms and legs ... Testicular volume is typically less than 10 ml in postpubertal 47,XXY individuals ... most patients with Klinefelter syndrome are infertile ... few patients with reports of pregnancy without assisted medical technology ... wide range of intelligence quotient (IQ) has been noted ... breast carcinoma in 47,XXY is relatively increased ... Associated endocrine complications include diabetes mellitus, hypothyroidism, and hypoparathyrodism ... lupus erythematosus, Sjogren syndrome, and rheumatoid arthritis, are more common patients will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Turner syndrome A disorder in women caused by a chromosomal defect. This disorder inhibits sexual development and causes infertility. Causes, incidence, and risk factors: Turner syndrome is usually caused by a missing X chromosome. It affects 1 out of 3,000 live births. It is usually sporadic meaning that it is not inherited from a parent. Rarely, a parent silently carries rearranged chromosomes that can result in Turner syndrome in a daughter; this is the only situation in which Turner syndrome is inherited. Turner syndrome There are many manifestations of this syndrome, but the main features are short stature, webbing of the skin of the neck, absent or retarded development of secondary sexual characteristics, absence of menstruation, coarctation (narrowing) of the aorta, and abnormalities of the eyes and bones. The condition is either diagnosed at birth because of the associated anomalies, or at puberty when there is absent or delayed menses and delayed development of normal secondary sexual characteristics. Turner’s syndrome (Classic 45-XO) Mosaic (46-XX / 45-XO) Exams and Tests Turner syndrome can be diagnosed at any stage of life. It may be diagnosed before birth if chromosome analysis is done during prenatal testing. Physical exam shows signs of underdevelopment. Infants with Turner syndrome often have swollen hands and feet. The following tests may be performed: Blood hormone levels (luteinizing hormone and follicle stimulating hormone) Echocardiogram Karyotyping MRI of the chest Ultrasound of reproductive organs and kidneys Pelvic exam Turner syndrome may also alter various estrogen levels in the blood and urine.
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