THE GONADS - UMF IASI 2015



THE GONADS

THE TESTIS

Sex determination

Genes involved in the creation of undifferentiated gonad

WT1 – gene : its abnormality is associated with failure of gonadal differentiation

Deny-Drash syndrome:

- failure in gonadal differentiation

- nephropaty

- Wilms’tumour

Frasier’s syndrome:

- failure of gonadala differentiation

- gonadoblastoma

WAGR syndrome:

- Wilms’tumour

- aniridia

- genital abnormalities, mental retardation

Hiort O., Holterus P-M: The mollecular bases of male sexual diffrentiation. Eur.J.Endocrinol. 2000, v. 142, 101-110

Genes involved in the creation of undifferentiated gonad

LIM-1 gene: homozygous deletion: failure of development of both gonads and kidney

In humans renal and gonadal abnormalities associated with brain

abnormalities were reported

FTZ-1-F1 – gene for SF-1 – steroidogenic factor 1 encodes a nuclear orphan receptor. Its mRNA is found in the genital ridge, adrenals and hypothalamus

Its deletion in mice determines failure of developing gonads, adrenals and hypothalamus

Roles of SF-1: gonadal differentiation, adrenal and hypothalamus differentiation, regulates enzyimes involved in steroidogenesis, regulates transcription of anti-Mullerian hormone (AMH)

Hiort O., Holterus P-M: The mollecular bases of male sexual diffrentiation. Eur.J.Endocrinol. 2000, v. 142, 101-110

Testis determining factor (TDF) = SRY – sex-determining region of the Y chromosome

A single exon gene that:

- binds to the promoter of AMH-gene induces the expression of AMH and prevents the formation of Mullerian ducts

- genetic engineering: female xx embrios transfected with sry develop a normal male phenotype

SRY mutations are associated with complete sex reversal in 46, xy individuals

SRY mutations were described in true hermaphroditism with both testicular and ovarian tissues development

Autosomal genes involved in male sex determination

SOX-9 (SRY-box related) transcribed following SRY expression in male genital structures. It is also an activator of the type 2 collagen gene. Defects in SOX-9 determine sex reversal in 46.xy individuals and skeletal malformations known as campomelic dysplasia

Chromosome 10q: its terminal deletion is associated with genital malformations and mental retardation

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Attract attention: most the images presented in these courses are taken from: Besser MG and Thorner MO.: Clinical Endocrinology, Mosby 2nd ed. 1004

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The testis has an ovoid shape with the longest diameter of 4.6 cm (3.5-5.5 cm) and a volume of 18.6 ± 4.8 ml.

The testis has 2 compartments:

Seminal tubules in which spermatogenesis takes place under the control of FSH and with determining contribution of Sertoli cell.

Interstitial compartment where are located Leydig cell which produce testosterone

Spermatogenesis in humans takes 74 ± 4 days. During fetal life until puberty the number of spermatogonia from which spermatogenesis increases from 300,000 to 600 millions.

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Spermatogenesis has and endocrine control and a paracrine control.

Endocrine control of spermatogenesis

FSH stimulates Sertoli cell to produce Androgen Binding Protein (ABP) which carries testosterone produced within Leydig cells from the interstitial compartment to spermatozoa to stimulate spermatogenesis. During spermatogenesis residual bodies result, that are engulfed by Sertoli cells. In this way Sertoli cells are informed about the timing and quality of spermatogenesis and produces a protein called inhibin. This is formed by two chains α and β and has the ability to inhibit FSH by feed-back. Sertoli cells also produce a protein called activin that stimulates FSH. When spermatogenesis is impaired or absent inhibin production decreases and FSH increases. An increase of FSH over 40 IU/ml mean a severe impairment of absence of spermatogenesis.

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Endocrine function of the testis

Leydig cell from the interstitial compartment produces testosterone which is responsible for morphogenetic, metabolic and behavioral actions. Testosterone may act itself or after transformation into a more potent metabolite – dihydrotestosterone (DHT) which is formed from testosterone within target cell due to the enzyme called 5 α reductase. All actions are possible due to androgen receptor situated within the cytoplasma of target cells. After coupling with testosterone, DHT or other androgens the receptor is translated into the nucleus, binds to Androgen Responsive Element situated in the nuclear DNA and activates transcription process for mRNA . mRNA is translated into cytoplasma and in the endoplasmic reticulum controls the synthesis of different proteins and enzymes that represent the genetic programmed response of target cells to steroid signal.

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Androgen receptor

Testosterone secretion is controlled by LH which is produced under stimulation of hypothalamic Gn-RH. Increased level of androgen decrease Gn-RH and LH secretion by feed-back phenomenon.

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ULTRASOUND APPEARENCE OF THE TESTIS

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CONGENITAL PREPUBERTAL HYPOGONADOTROPIC HYPOGONADISM

ISOLATED

• Kallmann syndrome with anosmia - Xp22.3

Associated with neurological diseases:

• Sindromul Prader Willi syndrome (15 chormosome)

• Laurence Moon syndrome

• Bardet Biedl syndrome

HYPOGONADOTROPIC PREPUBERTAL HYPOGONADISM

CLINICAL FEATURES

• testis volume under 5 ml

• samll penis

• eunucoid body proportions vertx-pubis < pubis -floor

• absent sexual hair

• high pitch voice

• reduced muscle mass

• absent libido

• osteoporosis

KALLMANN SYNDROME

Hypogonadotropic hypogonadism with anosmia or hypoosmia

PREVALENCE:

1/10,000 males and 5-7 times less frequent in females

- at birth an undescended testis or micropenis evokes the syndrome

Familial forms:

- X-linked (KAL-1)

- autosomal dominant (KAL-2)

- autosomal recessif (KAL-3)

Other associated abnormalities:

- neurological: controlateral imitation syncinesis ( mirror movements, visual attention abnormality, abnormalities of ocular movements, ptosis, deafness,

- non-neurological: aplastic kidney, labial or palatinal dehiscence, dental agenesis

During fetal development Gn-RH secreting neurons have a migration from the medial part of the olfactive epithelium to the hypothalamus in close relationship with olfactory accessory nerves: vomero- nasal and terminal. Than these neurons enter the brain just behind the olfactory bulbs and finally reach the hypothalamus.

In a 19 week fetus with x-linked Kallmann’s syndrome the Gn-RH secreting neurons do not reach the hypothalamus and accumulate outside the brain in the nasal region Thus the final way of Gn-RH secreting neurons is dependent of KAL-1 gene.

KAL-1 gene encodes a protein named ANOSMINE -1 a nerve-adhesion protein that is not present in nasal epithelium and hypothalamus in Kallmann’s syndrome

DIAGNOSTIC: T, LH, FSH low, positive test LH-RH TREATAMENT: LH-RH , hrFSH, testosterone

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Acquired hypogonadopropic hypogonadism prepubertal or postpubertal

Hypotalamic anf pituitary tumors

• chraniofaringioma

• Pituitary adenomas

• other

Infiltration of the hypothalamus nad/or pituitary

• Sarcoidosis, histicytosis, hemochromatosis

• Hipofisitis

Pituitary nechrosis

Functional

• hyperprolactinemia

• malnutrition

• drugs: androgens, anabolic steroids, LH-RH agonists, corticoisteroids

CONGENITAL HYPERGONADOTROPIC HYPOGONADISM

• vanishing testis

• sindrom Klinefelter 47, xxy

• 46 xx males, 45,xo

• XX males with SRY+

• pure gonadal dysgenesis with XY genotype

• Syndromes of androgen insensivity

ACQUIRED HYPERGONADOTROPIC HYPOGONADISM

• orchitis: mumps

• testicular trauma

• iradiation, chemotherapy

• drugs : salazopirine

• alcohol consumption

• LOH (hypogonadism in the aging male)

Klinefelter’s syndrome

47 XXY, (80 %), 48, XXXY, 49, XXXXY, mozaicuri

Prevalence : 1/ 500, sporadic

Clinical data :

• testicular volume under < 4 ml

• slow and incomplete pubertal development

• gynecomastia

• less developed sexual hair

• eunucoid proportions

• osteoporosis

• intelectual impairment

• pectus escavatum

• diabetes

Hormonal data :

• FSH increased

• inhibin B decreased

• low/normal testosterone

• azoospermia

Treatment of Klinefelter’s syndrome

Testosterone when the hormone has the trend to decrease

Detection and treatment of comorbidities: hCG tumors, peptic ulcer, diabetes mellitus, autoimmune diseases, varicous veins.

When individuals with klinefelter’s syndrome are around the age of normal puberty they may still have sperm cell. O biopsy of the testis made at this age may provide sperm cells that could be preserved for fertilization. After the age of puberty most of seminiferous tubules become atrophic , sclerohialin and infertility is definitive.

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The ovary

Genetic determination:

DAX-1 gene on the short arm of X chromosome Xp21

DAX-1 = Dosage Sensitive Sex Reversal / Adrenal hypoplasia congenita on the x chromosome

Anatomy of the ovary

Anatomy of female internal genitalia

Mature ovary has an ovoid shape , with the dimensions: 2.5x2x1 cm. and weight of 4-8 g. at 20 week the ovary contains 7 million of primordial follicles. Primordial follicle contains an ovocyte surrounded by a tiny layer of granulosa cell. Just before birth an important number of ovarian follicles suffer athresia and only 300,000-400,000 follicle will remain.

Mature ovary has a outher cortical area with ovarian follicles in different stages of their maturation within a sroma of connective tissue and a medulla with vessel and cell that resemble Leydig cells and produce androgens..

The ovary has two functions that work into a coordinate manner:

- monthly liberation of a mature oocyte – ovulation at every 28-30 days

- production of specific steroids: estrogens, progesterone and small quantities of androgens that act on genital and extragenital receptors making reproduction possible.

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The development of ovarian follicle, ovulation and formation of yellow body

Ovarian cycle represents a cycle of events during 28-30 days and is formed of :

- follicular phase dominated by estrogen production

- ovulation

- luteal phase with progesterone and estrogen production

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Mature oocyte development

Follicular development begins long before the beginning of follicular phase by a phenomenon of “recruitment” of a cohort of primary follicles due to small concentration of FSH. Of this cohort only some follicles are “selected” to follow their development, and one follicle becomes “dominant” and follows full maturation.

Follicular phase is initiated by FSH secreted by the pituitary under Gn-RH stimulation.

1. Initial follicular phase - days 2-6 of ovarian cycle (counted from the first day of menstruation):– in important proliferation of cells from theca granulosa takes place (primary follicle)

2. Median follicular phase – further proliferation of theca granulose cells and formation of the surrounding theca interna. Between cell of the ca granulosa large spaces filled with liquid containing estrogens are formed: the secondary follicule (days 7-10 of the ovarian cycle)

3. Late follicular phase – the spaces between granulosa cells form a large cavity called follicular antrum and mature oocyte remain inside linked with antral wall by a group of granulose cells – cumulus proliger. The follicle is surrounded by theca externa formed of connective tissue and smooth muscle cells. Theca granulosa and theca interna will cooperate to produce estrogens during follicular phase, theca externa has no hormonal activity. In the late follicular phase, or preovulatory phase the follicle is also called Graffian follicle.

During follicular phase there is an continuous increased secretion of estrogens. Their concentration increase from 20 pg/mL at the beginning of ovarian cycle to 200 pg/mL during late follicular phase just before ovulation.

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Ovulation (day 14 of ovarian cycle) is triggered by positive feed back exerted by estrogen increase that stimulates hypothalamic Gn-RH surge, which in turn stimulates LH surge from the pituitary. During follicular phase LH is not liberated but stored within the pituitary. Due to sharply increase of LH the following events lead to ovulation:

- increased intra-follicular pressure in the antrum

- prostaglandin stimulation of contraction of the smooth muscle cells from theca externa

- enzymatic action on theca externa due to colagenase and prostaglandins. All these events result in the rupture of follicular wall, extrusion of the oocyte that is directed to the fallopian tube to be fertilized

- collapse of the follicular walls and formation of yellow body by luteinisation of both theca granulose and theca interna. Luteinisation means surge with an yellow pigment of the theca and appearance of progesterone secretion.

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Ovulation

Lutheal phase – days 15-28. The yellow body produce estrogens and progesterone . Yellow body has a genetically determined life of 14 days and in absence of ovulation suffer involution and is transformed by fibrosis into corpus albicans. Progesterone secretion along with estrogen secretion exerts a negative feed-back over hypothalamus-pituitary system decreasing FSH and LH.

Hormonal secretion of the ovary and its control

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Control of ovarian function – two gonadotropins – two cells hypothesis

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Estrogen synthesis is possible due the cooperation between granulose cells and theca interna cells. Theca interna cells have all enzymes needed to produce androgens: androstendione and testosterone (19C) under LH stimulation. Both androgens are transported into granulose cell where under the control of FSH aromatization of androgens takes place: androstedione is transformed in estrone and testosterone in 17 β estradiol the main estrogen produced by the ovary. 17 β estradio is liberated into circulation and in small quantities in the follicular fluid in the antrum. Small quantities of estradiol are formed into peripheral tissues skin, fat tissues, liver by local aromatization of circulating androgens produced by the adrenals and ovary.

Estrogens produce a positive feed-back on Gn-RH and LH during preovulatory phase when they increase after a certain pattern and a negative feed-back along with progesterone during follicular phase of the cycle.

Granulosa cells also produce inhibin that inhibit FSH secretion.

Progesterone is produced by corpus luteum and long with estrogens exerts a negative feed-back on hypothalamo-pituitary-gonadal axis.

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CONTROL OF OVARIAN FUNCTION : THE 2 CELL – 2 GONADOTROPIN HYPOTHESIS

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Estrogens circulate in blood in a free form, directly accessible to tissues and most of estrogens are bound to Sex hormone Binding Globulin

Progesterone is bound to Transcortin and in a free form.

Estrogens exert their action through acting on specific estrogen-receptors.

There are two estrogen receptor (ER) subtypes, known as α and β, and they are encoded by two separate genes (ESR1 on chromosome 6 and ESR2 on chromosome 14 respectively). Hormone binding to the receptor triggers migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins which are responsible for the transcription of downstream DNA into mRNA and finally protein. Hormone activated ERs form homodimers (ERαα or ββ) or heterodimers (ERαβ). Different ligands may differ in their affinity for α and ß isoforms of the estrogen receptor. Thus, 17-ß-estradiol binds equally well to both receptors, estrone binds preferentially to the α receptor, and estriol prefers the ß receptor. Subtype selective estrogen receptor modulators (SERMs) preferentially bind to either the α- or β-subtype of the receptor. (Patrick M. Woster, Ph.D.: Principles of Pharmacotherapy 8: Women’s & Men’s Health,

Age Related Issues in Pharmacotherapy, PBL Intensive)

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Estrogen receptor and estrogen action on the target cells

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Progesterone – receptor and its action in the target cells rex.nci.RESEARCH/basic/lrbge/cl1.jpg

Estrogen actions

|Target tissues |ACTIONS |

|M YOMETRIUM AND EMDOMETRIUM |Myometrial proliferation and proliferation of endometrial glands and stromal |

| |tissue |

|CERVIX |Stimulation of water and mucopolysacharides production making cervical mucus |

| |better for spermatozoa motility during ovulation |

|VAGINA |Stimulation of the proliferation of vaginal mucosa and glycogen production |

|BREAST |Duct proliferation |

|HYPOTHALAMUS |Important estrogen preovulatory increase produces LH-RH and LH surge and |

| |ovulation |

| |DECREASED BASAL BODY TEMPERATURE |

|PITUITARY |FSH inhibition and LH accumulation in the pituitary |

|BONE |Stimulation of bone formation and maturation |

|PROTEIN METABOLISM |Increased protein synthesis |

|SUGAR METABOLISM |Natural estrogens increase and synthetic estrogen decrease glucose tolerance |

|FAT METABOLISM |Increased HDL-col si triglycerides |

Progesterone actions

|TARGET TUSSUES |ACTIONS |

|MYOMETRIUM and ENDOMETRIUM |Decreased myometrial contractility |

| |Stimulation of “secretory” pattern of endometrium |

|Cervix |Decreased water content of cervical mucus thus inhibiting migration of |

| |spermatozoa after ovulation |

|VAGINA |Reduced mucosal growth |

|Breast |Proliferation of breast secretory activity |

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Menstrual cycle

In the follicular phase FSH and estrogens increase and stimulate proliferation of the endometrium which is formed by endometrial glands, connective tissue and vessels. In the first 14 days of the cycle thickness of the endometrium increases from less than 1 mm to 8-10 mm, glands and vessel proliferate – proliferative phase of the endometrium. Estrogens act on brain decreasing basal body temperature that reaches the lowest value just before ovulation.

In the luteal phase glands and vessels of the endometrium still proliferate under estrogen and progesterone stimulation but endometrial thickness remains the same. Therefore glands and vessels become to spiral and histological aspect of the endometrium is “lace like” and is called secretory phase of the endometrium. The glands produces a nourishing material to sustain nutrition of fertilized oocyte in its first days of life. This aspect is characteristic for a good endometrial stimulation by estrogens and progesterone and the best witness for a good ovarian function. Endometrial biopsy still remain a good tool for assessment of ovarian function.

In the late luteal phase estrogen and progesterone secretion drop if conception does not occur and the hormonal support for endometrial survival is reduced. As a consequence contractions of the vessels occur at the limit between functional and permanent layer of the endometrium occur, with ischemia of the functional layer endometrium that becomes necrotic and is eliminated with a variable quantity of blood as menstruation.

With de development of o new ovarian follicle estrogens will produce heeling of the endometrium and a new cycle of endometrial growth will begin. If conception takes place the hormone called Human Chorionic Gonadotropin (hCG), is produced by the zygote (fertilized oocye) and will stimulate corpus luteum to live and secrete progesterone and to maintain secretory endometrium that will serve to nourish the zygote until development of placenta will occur.

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ASSESSMENT OF OVARIAN FUNCTION

Basal assessment: estradiol, progesterone, testosterone, LH, FSH, inhibin, prolactin

Tests:

- progesterone test: after a period of amenorrhea (if pregnancy is excluded) progsterone administration will produce menstrual bleeding if endomtrium had enough estrogen stimulation, but no progesterone due to anovulation (useful in the assessment of primary and secondary amenorrhea, hyperprolactinemia, polycystic ovary disease, other causes of chronic anovulation)

- estrogen/progesterone test: in amenorrhea that is not responding to progesterone estrogen and progesterone will produce bleeding if endometrium is in place and no bleeding in the absence of the uterus of endometrium

- Gn-RH test: 100 μg of Gn-RH will produce LH and FSH increase if pituitary is normal and no response in pituitary diseases

Test that assess the response of target organs to estrogens and progesterone:

- Basal body temperature. The higher levels of estrogen present during the pre-ovulatory (follicular) phase of the menstrual cycle lower BBTs. The higher levels of progesterone released by the corpus luteum after ovulation raise BBTs. The rise in temperatures can most commonly be seen the day after ovulation, but this varies and BBTs can only be used to estimate ovulation within a three day range. If pregnancy does not occur, the disintegration of the corpus luteum causes a drop in BBTs that roughly coincides with the onset of the next menstruation. If pregnancy does occur, the corpus luteum continues to function (and maintain high BBTs) for the first trimester of the pregnancy. It is used as ovulation test for those women who desire to become pregnant or to avoid pregnancy by natural contraceptive methods (avoiding coitus 3 day bafore and after ovulation)

- Cervical mucus. The cervical glands proliferate under the influence of oestrogen secreted during the follicular stage of the ovarian cycle . The glands become longer as the follicular cycle progresses. The glandular epithelial cells become larger and start to secrete a mucus that is initially thick and viscous.Under the influence of estrogen and as the time of ovulation approaches, the quality of the cervical mucus begins to change. From about the 10th day of the cycle till ovulation on the 14th - 16th day, the mucus becomes profuse, more watery and tenacious. It begins to resemble egg-white - clear, profuse, and slippery. The mucus becomes so tenacious that it can be stretched in threads up to 10-15cm long at the time of ovulation. This quality of the mucus is called 'spinnbarkeit' and is used for the thread test to diagnose ovulation. During this time, if the cervical mucus is collected on a clean glass slide and is allowed to dry, it will form a characteristic pattern that resembles the fronds of a fern. This can be observed under a microscope and is known as 'ferning' or the 'fern test'. It is another important diagnostic criteria of ovulation. Ferning can be seen from the 6th to the 22nd day of the cycle. images%5Ccervicalmucus.jpg

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Cervical Mucus at Ovulation

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Fern Test at Ovulation

Endometrial biopsy: is one of the best test to assess normal ovarian function. It is done in day 21 of the cycle and the endometrium must have the “lace-like” appearance. It is also used to detect endomterial abnormalities such as endomtrial hyperplasia, adenomatosis or endometrial cancer

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Laparoscopic examination of the ovaries

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Is useful in ovarian diseases such as polycystic ovary disease (associated with ovarian drilling), endometriosis, ovarian cyst and cancer

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Classification of ovarian disfunctions – most of ovarian dysfucntions are associated with chages in the pattern of menses as follows:

- PRIMARY AMENORRHEA menses does not occur till the chronological age of 16 years

- SECONDARY AMENORRHEA – menses stop after a period of normal or abnormal cycles for at least 6 month

- OLIGOMENORRHEA : menses are delayed from 45 days to 6 month

- DYSMENORRHEA – pain associated with menses

Causes of amenorrhea:

| | |

|PRIMARY AMENORRHEA |SECONADRY AMENORRHEA |

| | |

|HYPOTHALAMIC ORIGIN |HYPOTHALAMIC ORIGIN |

|Idiopatic hypogonadotropic hypogonadism |Postpubertal tumors of hypothalamus |

|Kallmann syndrome |Anorexia nervosa |

|Prader-Willi syndrome |Post-pill amenorrhea |

|Sd. Lawrence-Moon-bardet-Biedl |Stress induced amenorrhea |

|tumors |Amenorrhea induced by exercise |

|Histiocytosis | |

|Brain irradiation | |

|Malnutrition | |

|PRIMARY AMENORRHEA |SECONDARY AMENORRHEA |

|PITUITARY |PITUITARY |

|Lh-Rh receptor defects |Piruitary tumors (prolactinomas) |

|Pituitary failure |autoimmune |

|Pitiatry tumors |Hipofizectomy |

|Other: trauma, infiltrative diseases |Pituitary irradiation |

| |Sheehan’s syndrome |

| |hemochromatosis |

|Primary amenorrhea |Secondary amenorrhea |

|Of gonadal origin |Of gonadal origin |

|Gonadal dysgenesis with female phenotype |Precocious autoimmune menopause |

|45,x si variants |Ovariectomy |

|Pure gonadal dysgenesis: 46, XX, 46, XY | |

|Defects gonadal steroids biosynthesis XX sau XY | |

|Star, 3(-OHDH, 17 ( hidroxilase, 17-20 desmolase | |

|Androgen insensivity syndromes | |

|Congenital absence of the uterus | |

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TURNER’S SYNDROME AND ITS VARIANTS

PREVALENCE: 1/5000 phenotypic female newborn

99 % of fetuses 45,X do not survive over 20 week of gestation

15 % of spontaneous abortions of the first trimester

CLINICAL data:

Short stature ................
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