The female genital and urinary system consists of primitive mesoderm and endoderm. Because of this co-development, urinary and genital system anomalies can be seen together.
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Embryological
differentiation |
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Undifferentiated Period |
Female |
Male |
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primitive gonad |
ovary |
Testis |
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Primordial germ cells |
Oogonia |
spermatogonia |
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coelomic epithelium |
Granulosa cells |
Sertoli cells |
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urogenital protrusion |
Theca cells |
Leydig cells |
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Wolf duct (mesonephric duct) |
Epoophoron, paraoophoron, Gartner cyst |
Epididymis, ductus deferens vesicle seminalis |
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Müller duct (paramesonephric duct) |
Tuba uterina, uterus, cervix, upper 2/3 of vagina, Morgagni cyst |
Testicular appendix, prostatic utricle |
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urogenital sinus |
Lower 1/3 of the vagina, vulva, urethra, bladder, paraurethral
glands, hymen |
urethra, prostate, bulbourethral glands, bladder |
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genital tubercle |
Clitoris |
glans penis |
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urogenital fold |
labia minora |
prepicium |
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labioscrotal swelling |
labia majora |
Scrotum |
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gubernaculum |
Lig. ovarii proprium, Lig. rotundum |
Gubernaculum testis |
• The genital system is capable of differentiating to both sexes at the beginning of pregnancy, which is called the "undifferentiated stage" of the embryonic period. Determination of gender (sex) consists of 4 components.
► Genetic sex ( 46;XX)
► Gonadal gender (over)
► Internal genital ductal sex (tubules, uterus, 2/3 proximal of the vagina)
► External genital sex (1/3 distal of the vagina, vulva)
DEVELOPMENT OF GENETIC STRUCTURE (CHROMOSOMAL SEX)
• The genetic structure (chromosomal structure) is determined during fertilization and is determined according to the sex chromosome (X or Y) carried by the sperm that fertilizes the secondary oocyte. While the female genotype is 46,XX, the male genotype is 46,XY.
Development in the female form is the basic developmental pathway of the human embryo.
Development of Gonads (Gonadal Sex)
• In the 3-4th week of embryonic life, the primordial germ cells begin to be produced in the endoderm adjacent to the vitelline sac (yolk sac), and in the 6th week, they reach the posterior wall of the mesenchyme with amoeboid movements over the posterior intestinal mesentery (allantois) and form a double gonadal protrusion just medial to the mesonephros. If the germ cells cannot reach the posterior wall of the mesenchyme, gonadal development does not occur and gonadal agenesis (agonadism) occurs.
• In the first 6 weeks of pregnancy, the genital protuberance is bipotent, contains both cortical and medullary areas, and has the capacity to develop into either sex (can differentiate into testis or ovary), whether it has an XX or an XY chromosome. This period is called the undifferentiated phase. Primitive gonad in this stage; The primitive sex cords are composed of germ cells, germinal epithelium (granulosa/sertoli) and mesenchyme (theca/leydig).
• TDF (testis determining factor) encoded by the SRY (sex determining region} gene region on the short arm of the Y Chromosome differentiates the primitive gonad, which would normally differentiate into the ovary, towards the testis (6-7 weeks). It also causes the medullary region of the gonad to differentiate into Sertoli cells (7th week).
• As soon as Sertoli cells are formed, they begin to secrete anti-Müllerian hormone (AMH), a glycoprotein (week 8). stimulates differentiation (8th week).
• Testosterone is started to be produced from Leydig cells at 8-9 weeks. Testosterone stimulates the mesonephric (Wolff) duct, resulting in the formation of the ductus deferens, epididymis, ejaculatory ducts and vesicula seminalis in the male fetus.
Sertoli ➔ AMH ➔ Regression of the paramesonephric (Müller) duct
Leydig ➔ Testosterone ➔ Progression of the Mesonephric (Wolff) duct
• In the absence of TDF, the medulla of the primitive gonad regresses and the primordial sex cords are also fragmented to form individually clustered islets of cells (primordial follicles}. Thus, the primordial gonad differentiates into the ovary (8th week). .
• While the ovaries are initially located in the thoracic region of the embryo, they later descend to their normal location in the pelvis. The gubernaculum is responsible for this descent. One end of the gubernaculum is attached to the ovary, while the other end is attached to the labium majus. After the ovaries descend into the pelvis with the gubernaculum , the proximal part of it turns into the ovarian ligament. The distal part becomes the round ligament
spermatogenesis
• In spermatogonia, unlike females, meiosis begins at puberty and spermatogenesis lasts between 64 and 74 days, and no polar bodies are formed.
• From the primary spermatocyte with 46 chromosomes (2n-diploid), 2 secondary spermatocytes with 23 chromosomes are formed (n-haploid) with the first meiosis division. These, too, divide by the 11th meiosis and form 4 spermatids with 23 chromosomes (n-haploid).
oogenesis
• With ovarian differentiation, a rapid mitotic proliferation begins (oogenesis) in germ cells at the 8th week of pregnancy and oogonia with 46 chromosomes develop (2n-diploid). Since germ cell mitosis ends at the 20th gestational week, oogoniums reach their maximum number of 6-7 million at the intrauterine 20th week. After this week, reproduction by mitosis ends.
• 11-12th week of pregnancy, oogoniums enter the I. meiosis division and transform into primary oocyte (2n-diploid). Factors released from rete ovarii are responsible for the initiation of I. meiosis in oogoniums. 18-20th of pregnancy primary in weeks The oocytes are surrounded by a single line of flat pregranulosa cells and primordial follicles begin to form. Except for the primary oocytes, which are surrounded by pregranulosa cells just before birth, they undergo atresia, leaving 1-2 million primordial follicles at birth and approximately 300,000 at puberty.
• The process of the first meiosis from the prophase to the diplotene stage continues throughout the entire pregnancy and the first meiosis stops in the primary oocytes that reach this stage. From this pause; OMI released by granulosa cells (oocyte maturation
inhibitor) is responsible. OMI released from granulosa cells reaches the oocyte via gap junctions.
• The primary oocyte, which is in the dominant follicle, gets rid of the gap junctions for the first time as a result of the peak oscillation of LH at puberty and completes the first meiosis division just before ovulation and two cells with 23 chromosomes (n-haploid) are formed. Of these, the cell with most of the cytoplasm is called the secondary oocyte, while the other cell, which has a similar chromosome structure but does not have a cytoplasm, is called the I. polar body.
• With ovulation, the gap junctions that connect the oocyte to the granulosa cells are broken and thus the oocyte is freed from the OMI effect. Secondary oocyte formed immediately II. enters meiosis and pauses in metaphase of meiosis. The pp39mos protein encoded by the cmos protooncogene in the oocyte is responsible for this pause.
• With fertilization (sperm contact with shingles), calpain, a calcium-dependent cysteine protease, is released in the oocyte and pp39mos protein is degraded.
Thus, the second meiosis is completed at the stage where it pauses, and the nhaploid mature oocyte with 23 chromosomes and the polar with 23 chromosomes. polar body develops
• The fact that meiosis lasts for such a long time in women increases the chance of errors, and accordingly, the risk of chromosomal anomaly increases in advanced maternal age. In women, only 400-500 follicles ovulate in a lifetime.
Development of Internal Genital Organs (Ductal Development)
• Until the 8th week of the embryo, ducts of both sexes coexist and these channels are in the nephrogenic protrusion.
• Male internal genital system develops from the mesonephric duct (Wolff's duct): Ductus deferens, epididymis, vesicle seminalis, ejaculatory ducts
• The female internal genital system develops from the paramesonephric duct (Müller's duct): Tuba uterina, uterus, cervix, upper 2/3 of the vagina
• The development process is under the influence of ipsilateral gonadal activity, and while one of the channels regresses (completely disappears at 12 weeks), the other continues to develop. The factor that determines which ductal system will continue to develop; They are androgens released from Leydig cells and AMH released from Sertoli cells.
• In case of testis; Paramesonephric (Müller) duct regresses first with the effect of AMH secreted from Sertoli cells. The male internal genital ductal system (vas deferens, epididymis, ejaculatory ducts, seminal vesicle) develops from the mesonephric (Wolff) duct system under the influence of testosterone released from the Leydig cell.
• In case of absence of testis; The paramesonephric (Müllerian) duct develops and forms the internal genital organs (tuba uterina, uterus, cervix and upper 2/3 of the vagin).
The cranial parts of the paramesonephric ducts, which do not fuse, form the tuba, while the confluent caudal vertical parts form the uterus, cervix, and upper 2/3 of the vagina.
Since it is not androgen, the mesonephric (Wolff) duct regresses.
AMH is present at all stages of life in men, but not before puberty in women.
Testosterone is required to stimulate male sex development, but female sex development is not dependent on the presence of ovaries or hormones.
Mesonephric and Paramesonephric Duct Residues
In 1:4 of women, Wolff duct regression is not complete and there may be Wolff (mesonephric) duct remnants. Since these embryological remnants rarely cause symptoms, they do not require treatment.
Paraovarian cysts: They are located in the hilum of the ovary
Epoophoron (Rosenmüller organ): They are located laterally and above the ovary.
Paroophoron: They are located between the ovary and the uterus.
Gartner duct cysts: They are located on the lateral walls of the vagina and rarely on the lateral wall of the uterus.
The cranial part of Müller's duct sometimes does not join the structure of the tuba and remains separate and forms a remnant called Morgagni hydatid cyst.
DEVELOPMENT OF EXTERNAL GENITAL ORGANS (GENITAL SEX)
• External genital organs develop from the urogenital sinus and genital tubercle in both sexes. In the 5th week of development, the genital tubercle occurs. This then elongates to form the phallus. In the seventh week, the urorectal septum divides the cloaca anteriorly into the urogenital sinus and posteriorly into the anorectal canal. Development of external genitalia in female at 11 weeks; In men, it is completed in the 14th week.
• Masculinization of external genitalia is androgen dependent; For differentiation in the male direction, testosterone must be converted to DHT by the 5-a reductase enzyme in the urogenital sinus and genital tubercle. Masculinization occur in the eleventh and twelfth week of development.
• In the presence of dihydrotestosterone (DHT):
► Scrotum
► preputium
► Prostate
► penis
• In the absence of dihydrotestosterone (DHT): (E88)
► labium majus
► Labium minus
► Lower 1:3 part of the vagina
► Clitoris
DHT activity is the only factor that directly determines the differentiation of the external genitalia.
Genital Organ Anomalies
Ovarian Anomalies
Congenital absence of ovaries
► There are two types, agenesis and agonadism. While the draft gonad is not formed at all in agenesis; In agonadism, there is gonad at the beginning and later it degenerates.
Line gonad (streak gonad)
► gonad is formed by not progressing in differentiation steps. Primitive germ cells migrate to the gonads; however, very few of them form true follicles. All remaining germ cells degenerate and no germ cells are seen in the gonads after 6 months. After birth, the sex characteristics remain infantile, as the gonads cannot secrete hormones. Although this anomaly is characteristic of gonadal dysgenesis, it can also occur as a result of genetic mutation or hereditary disease. There is no hormoneogenesis and no gametogenesis.
Uterovaginal anomalies
• These malformations occur as a result of incomplete fusion of the paramesonephric ducts, insufficient development of a paramesonephric duct, or failure of the vagina and urogenital sinus to unite. The incidence of congenital uterine anomaly is 3-4%.
In women with Müller duct anomaly; urinary system anomalies (most common), skeletal system anomalies and hearing loss risk increase.
Classification of the anomalies of the Müller canal
Group 1. Segmental Müllerian agenesis or hypoplasia
a. Vaginal
b. cervical
c. uterine fundus
d. tubal
e. Combined (RKMH Syndrome)
Group 2. Unicornu uterus
A. Those with rudimentary horns
1. Connected with uterus
2. Disconnected from uterus (not recognizable by HSG)
3. Those without a cavity
B. Those without rudimentary horns
Group 3. Uterus didelphis
Group 4. Bicornus uterus
a. Complete (extend to internal os)
b. Partial
Group 5. Uterine septus
a. complete septum
b. incomplete septum
Group 6. Arcuate uterus
Group 7. Diethylstilbesterol-related changes
Genital anomalies due to DES
1. Hypoplastic uterus (most common)
2. T-shaped uterine cavity
3. Transverse vaginal septum
4. Tubal anomalies
5. Cervical anomalies
• Fusion defects (didelphis, bicornu, arcuate, unicornu uterus) occur when the caudal Müller canals are not fully or partially fused. Resorption defects (septate uterus) occur when the septum is not separated after the Müller canals unite.
► Uterus didelphis (uterus bicornus bikollis): It occurs as a result of the failure of both Müllerian ducts to develop completely and fusion. There are two separate cervixes (N-99). The probability of successful pregnancy is 70%.
► Uterus bicornus unicollis: It occurs as a result of partial fusion of both Müllerian ducts.
► Arcuate uterus: It is the mild form of the bicornu uterus. It is the type of uterine anomaly with the best pregnancy prognosis and the least associated with obstetric complications such as spontaneous abortion, malpresentation, and preterm delivery.
► Uterus unicornis unikollis: It occurs as a result of complete or partial development of one of the Müllerian canals. If there is a rudimentary horn, it should be removed.
► Septa uterus: It is the only resorption anomaly among uterine anomalies. The risk of abortion is 88% and it is the most common uterine anomaly in recurrent pregnancy loss. The septum benefits the most from surgical repair in terms of pregnancy prognosis.
While the incidence of urinary system anomaly increases in fusion anomalies (didelphis, bicornu, arcuate, unicorn); It does not increase in resorption anomalies (uterine septa). Therefore, IVP should be performed in the presence of fusion anomalies.
• Some of the uterine anomalies can be diagnosed by routine pelvic examination (uterus didelphis). While three-dimensional ultrasonography is very successful in diagnosing uterine anomalies, two-dimensional standard ultrasonography is not a specific method for distinguishing uterine anomalies. MRI is the most effective method in diagnosing uterine anomaly and determining whether mullerian structures are present. Hysterosalpingography (HSG), hysterosonography, hysteroscopy and laparoscopy are other helpful diagnostic methods in the diagnosis of uterine anomalies.
In the differential diagnosis of uterine septum from bicornuate uterus, hysteroscopy or HSG alone is not sufficient, and laparoscopy should be used together with MRI or hysteroscopy.