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anomalii genitale

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  Developmental Abnormalities of the Female Reproductive Organs INTRODUCTION  An understanding of congenital anomalies as they are encountered in clinical practice is greatly enhanced by not only a knowledge of normal embryology and the mechanism of formation of normal infants, but also an insight into the processes that result in the development of anomalies. 1, 2, 3, 4  An awareness of malformations and a systematic examination and appraisal of every neonate will greatly increase the number of such anomalies found. In some instances, e.g., congenital adrenal hyperplasia, imperforate anus, diaphragmatic hernia, and esophageal atresia, early detection and prompt intervention may be lifesaving. In adults, amenorrhea is an important clue and may suggest an imperforate hymen, vaginal septum or absence of the uterus. The finding of one anomaly should stimulate a careful gynecologist to carry out a complete study to detect renal and ureteral anomalies, particularly the solitary pelvic kidney which might be removed as a “pelvic mass”. Many anomalies occur infrequently so that only physicians in large medical centers may see them frequently enough to be aware of the possible anomalies and their causation, prognosis, and, in some cases, correction. The identification and interpretation of such abnormalities constitute a real challenge to the clinician. A knowledge of the problems and pitfalls in the MANAGEMENT of these defects will benefit both the obstetrician and the gynecologic surgeon. CAUSES OF MALFORMATIONS  The causes of congenital malformations or abnormalities present at birth may be either environmental or genetic (chromosomal abnormalities). 5 It is not always easy to separate the two factors; both may be at work in the same embryo or fetus. Rapidly growing embryonic organs are the most sensitive to environmental influences. Millen 6  has classified the mechanisms of anomaly production as follows: 1.   Developmental arrest — cessation of development before completion 2.   Agenesis or aplasia — failure of normal development 3.   Hyperplasia or local overgrowth 4.   Aberrant development 5.   Failure of normal resorption (either too much or too little) or resorption in the wrong locations  6.   Secondary degeneration of normally developed structures Millen also emphasizes “that the period when environmental agents may affect the development of an embryo is very short, being nearly over by the end of the eighth week of pregnancy . Organogenesis occurs from day 13 to day 60; teratogenic (G. teras,  monster) agents are most dangerous during this period. There is a time relationship between specific organ systems and sensitivity to environmental factors as well as a relationship between specific teratogens and specific organ systems. Examples are rubella infections occurring in the first trimester, with a high incidence of cataracts, deafness, and cardiac malformations, and use of thalidomide, with varied malformations of arms and legs. Nugent 7  has evaluated in detail the mechanisms of action of various environmental teratogenic factors. These include the following: 1.   Ionizing radiation 2.   Vital disease and related infections 3.   Chemical factors 4.   Immunologic disturbances 5.   Hormones 6.   Nutritional factors Ionizing radiation is probably one of the best known damaging factors. Infections such as rubella virus, cytomegalovirus, and Toxoplasma gondii  can cause severe damage to the eyes and central nervous system. Chemicals include aminopterin (causing skeletal defects and nervous system damage), methotrexate, and thalidomide. Immunologic disturbances include Rhesus incompatibilities. Hormone damage is particularly interesting: the administration of exogenous testosterone, synthetic progestogens, and similar preparations can cause iatrogenic deformities of the female genitalia. Pathologic hyperandrogenemia, as seen in luteomas of pregnancy, can result in virilization in the female newborn. Environmental factors, such as exposure to diesel fumes, have also been associated with virilization due to inhibition of aromatase and accumulation of excess testosterone. 8  Nutritional factors apparently have little direct teratogenic effect on the fetus.  CYTOGENETICS  In 1923, Painter reported that there were 48 chromosomes in the normal human cell. The correct number of 46 was established in 1956 by Tijo and Levan. 9  In 1956, Down syndrome, Turner syndrome, and Klinefelter syndrome were shown to be the result of chromosomal anomalies. Porter 10  pointed out that we can now distinguish every individual chromosome and different regions of each chromosome. Normal variants can be defined reliably, extra chromosomes involved in abnormalities can be identified accurately, small defects previously missed can now be recognized, and structural defects can be mapped accurately by tracing exchange segments of chromosomes. A clear cytogenetic diagnosis can serve as a guide to a rational plan of  MANAGEMENT, to counseling with regard to prognosis and genetic problems, and in the monitoring of pregnancies in people with an increased risk of having children with defects. There are hundreds of chromosomal abnormalities; most involve visible morphologic defects which should alert the clinician to the possibility of chromosomal anomalies. Disorders of gonadal development such as Klinefelter syndrome (47XXY) and Turner syndrome (45X) have been described with sex chromosome aneuploidy. Even deletions within regions of the X or Y chromosome can be deleterious to normal development. Gene deletions in the distal arms of the X chromosome (Xp22.3) cause short stature, mental retardation, X linked ichthyosis, and Kallman syndrome. 11  The distal region of the Y chromosome contains the sex-determining region Y chromosome (SRY) that encodes the gene for testis-determining factor (TDF). 12  Deletions in this region cause gonadal dysgenesis and streak gonads. Transfer of this region to the X chromosome causes an XX male. Another region of interest within the Y chromosome is the azoospermia factor region (AZF) that is related to spermatogenesis. It has been discovered that one subset of gene rearrangements on the Y chromosome, micro-deletions , is a major cause of male infertility in some populations. 13  With refined cytogenetic mapping, we will be able to better correlate phenotype with genotype. The complexity of the rapidly changing field of cytogenetics is not only startling but also a fascinating promise of new knowledge, new discoveries, and new clinical tools. With these new tools, challenges emerge for the obstetrician/gynecologist, reproductive endocrinologist, and pediatrician. Genetic analysis may become routine for every embryo, fetus or neonate. Embryos can be biopsied and a single cell screened for aneuploidy prior to implantation. 14  This technique has the potential to improve pregnancy outcomes and decrease miscarriage rates, especially in couples with multiple fetal losses. 15  The public health implications are startling and indications for testing are increasing. GAMETOGENESIS  The union of a spermatozoon and ovum marks the beginning of a new individual. The fertilization of an ovum is an amazingly complex act. Egg formation (oogenesis) and sperm formation (spermatogenesis) have many similarities, although they differ with regard to sex determination. There are 44 somatic chromosomes and two sex chromosomes in the normal human cell. 9  Human oogenesis begins with the formation of a primary oocyte which contains 44 + XX chromosomes. The number of germ cells is fixed during fetal development and cannot be regenerated. The oocyte undergoes meiosis, a process that generates haploid gametes through a specialized process that consists of one round of DNA replication followed by two rounds of cell division. In humans, the oocyte begins meiosis during embryogenesis and remains arrested in prophase I until ovulation, when meiosis resumes. Completion of this first division resumes with ovulation and the normal, or diploid number of chromosomes, found in the body cells is reduced to the haploid (G. haplous,  single) number. This occurs so that the normal chromosomal number of 44 somatic chromosomes and two sex chromosomes will be restored after fertilization. During this first  maturation division, the secondary oocyte (22 + X) retains most of the cytoplasm, while the other half of the nucleus remains as a small first polar body. A second maturation division results in the formation of the mature ovum (22 + X) plus a second polar body. Meiosis is a requisite step in sexual reproduction and is critical for generating genetic diversity through recombination. In humans, meiotic errors lead to reproductive failure via aneuploidy, spontaneous abortion or infertility. 16, 17  The progression through meiosis in the male is continuous, and in humans, begins with puberty. This is in sharp contrast to the female where meiosis is begun during embryogenesis, but is maintained in a state of prophase I arrest until after puberty when ovulation occurs. The oocyte can be maintained in prophase arrest for over 40 years. The spermatogonium is formed in the testis, with a chromosome complement of 44 + XY. This Y sex chromosome determines male development. The spermatogonium develops into a relatively large spermatocyte (44 + XY). This in turn undergoes a first maturation (meiotic) division to form secondary spermatocytes, half of which are 22 + X and half of which are 22 + Y. During a second maturation division, the secondary spermatocytes again divide into spermatids, half of which are 22 + X and half of which are 22 + Y. After 1 or 2 weeks the spermatids become mature spermatozoa. Unlike the female where a single primary oocyte yields a single mature oocyte, a single spermatogonium yields four mature spermatozoa. These spermatozoa must undergo further changes before they can fertilize an ovum. The first change, known as capacitation, is a physiologic change probably associated with removal of a protective coating. 18  Following this, an acrosome reaction occurs at the anterior extremity of the spermatozoon, where small perforations develop in the wall. Enzymes passing through these openings digest a path for the sperm through the corona and the zona pellucida. Ovum transport   is the mechanism by which the nonmotile ovum is carried by a stream of peritoneal fluid into the infundibulum of the tube. This stream is produced by sweeping movements of the fimbriae. The ovum is carried into the tubal ampulla partially by muscular contractions of the tube but mostly as a result of ciliary action. At any given normal intercourse, over 300 million sperm are deposited in the vagina near the cervical os. Only a few thousand sperm reach the oviducts and only a few hundred reach the ampulla, where fertilization usually occurs. As the sperm head advances, it reaches the surface of the ovum and attaches so that its nucleus is within the membrane of the ovum. As a result, the zona pellucida changes and the entrance of other spermatozoa is inhibited. At the same time, the secondary oocyte is completing its second meiotic division and expelling the second polar body. The male and female pronuclei come into contact near the center of the ovum and mingle their chromosomes. During the process of fertilization, the chromosomes of father and mother mingle, the diploid number (46) of chromosomes is restored, and sex is determined by the presence or absence of the Y, or male, chromosome. Cleavage The fertilized egg undergoes a series of rapid mitotic divisions while passing down the tube. After several days, a ball of cells called the “morula” (L.   morus,  mulberry) is formed. After 5 days, a fluid-filled space appears in the morula, which is now called the “blastocyst” (G.   blastos,  germ) (Fig. 1.). An inner cell mass appears on one side of the blastocyst cavity at the site of the embryo. By 6 days the blastocyst has implanted and the trophoblast cells invade the succulent endometrium or decidua. During the second week, the embryo becomes a bilaminar disc (Fig. 2). Fig. 1. Human blastocyst, showing inner cell mass at 9 o'clock position and trophectoderm lining periphery.
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