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THE OVARY DETERMINATION:

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Presentation on theme: "THE OVARY DETERMINATION:"— Presentation transcript:

1 THE OVARY 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

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5 In human females, all primordial follicles are formed in the fetus between 6 and 9 months' gestation. During this period, there occurs a marked loss of oocytes due to apoptosis. The number of primordial follicles decreases progressively as a consequence of recruitment, until very few if any are present after the menopause at ~50 years of age. (Baker TG: Radiosensitivity of mammalian oocytes with particular reference to the human female. Am J Obstet Gynecol 110:746, Reproduced with permission from Mosby, Inc.)

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15 The early differentiation of the granulosa cells during preantral folliculogenesis involves the expression of FSH receptors. Animal studies support the concept that this process involves an activin autocrine/paracrine mechanism. (Erickson GF: Dissociation of Endocrine and Gametogenic Ovarian Function. In Lobo, R. (ed.): Perimenopause. Serono Symposia, Springer-Verlaag, Reproduced with permission from Springer-Verlag, New York.)

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22 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

23 ESTROGEN ACTIONS 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

24 PRGESTERONE 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

25 CONTROL OV OVARIAN FUNCTION

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

27 Diagram showing the "Two Gonadotropin-Two Cell Concept" of follicle estrogen production. (Erickson, GF: Normal ovarian function. Clin Obstet Gynecol 21:31, Reproduced with permission from Lippincott-Raven Publishers.)

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30 OVARIAN CYCLE

31 ENDOMETRIAL CYCLE

32 ENDOMETRIAL CYCLE DURING AN OVULATORY CYCLE

33 ENDOMETRIAL CYCLE DURING ORAL CONTRACEPTIVES TREATMENT

34 ASSESSMENT OF OVARIAN FUNCTION
ESTRADIOL PROGESTERONE FSH LH LHRH TEST SHBG PROLACTIN TESTOSTERONE (FREE) DHEA-S BASAL BODY TEMPERATURE CERVICAL MUCUS ENDOMETRIAL BIOPSY ULTRASOUND EXAMINATION LAPAROSCOPY

35 ASSESSMENT OF OVARIAN FUNCTION
ESTRADIOL, FSH, LH, PROLACTIN E2 FSH LH E2 FSH LH PROLACTIN E2 FSH LH LHRH test HIPERPROLACTINEMIA - + HYPOTHALAMUS PITUITARY HYPOGONADOTROPIC HYPOGONADISM HYPERGONADOTROPIC HYPOGONADISM

36 MENSTRUAL PROBLEMS PRIMARY AMENORRHEA SECONDARY AMENORRHEA OLIGOMENORRHEA DYSMENORRHEA

37 PRIMARY AMENORRHEA SECONADRY AMENORRHEA HYPOTHALAMIC ORIGIN
Idiopatic hypogonadotropic hypogonadism Kallmann syndrome Prader-Willi syndrome Sd. Lawrence-Moon-bardet-Biedl tumors Histiocytosis Brain irradiation malnutrition SECONADRY AMENORRHEA Postpubertal tumors of hypothalamus Anorexia nervosa Post-pill amenorrhea Stress induced amenorrhea Induced by exercise

38 PRIMARY AMENORRHEA SECONDARY AMENORRHEA PITUITARY
Lh-Rh receptor defects Pituitary failure Pitiatry tumors Other: trauma, infiltrative diseases SECONDARY AMENORRHEA Piruitary tumors (prolactinomas) autoimmune Hipofizectomy Pituitary irradiation Sheehan’s syndrome hemochromatosis

39 Primary amenorrhea Secondary amenorrhea Of gonadal origin
Gonadal dysgenesis with female phenotype 45,x si variants Pure gonadal dysgenesis: 46, XX, 46, XY Defects gonadal steroids biosynthesis XX sau XY Star, 3-OHDH, 17  hidroxilase, desmolase Androgen insensivity syndromes Congenital absence of the uterus Secondary amenorrhea Precocious autoimmune menopause Ovariectomy

40 TURNER’S SYNDROME AND ITS VARIANTS
PREVALENCE: 1/5000 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 <145 cm in forma 45,X, or less than -2 Sd from the normal malformations: 200 malformatii somativ and visceral Primary amenorrhea

41 TURNER’S SYNDROME AND ITS VARIANTS
Genetics: 45,X, 45, X/46,XX, 46, X Xqi, 46, X X “ring chromosome” Diagnostics: absence of Barr body low estradiol FSH/LH increased ( over 40 mIU/mL) ultrasound and other diagnostic methods for malformation

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47 TURNER’S SYNDROME AND ITS VARIANTS
TREATAMENT objectives: Growth hrGH: 0,05 mg /kg bw/day with a growth increase of cm than without treatment ± oxandrolone: 0,0625 mg/kg/day Development of secondary sexual characteristics and menses: conjugated estrogens 0,3 mg /zi 21 day , or EE2 =5 microg /day 21 days progesterone is given later Pregnancy: surogate mothers

48 Polycystic ovary disease (syndrome)
PCOD or PCOS is a complex entity with a pathogenicy not fully understood which can affec 5-10 % of women in their reproductive age. Is the most frequent cause of endocrine infertility. The disease is characterized by the following criteria: Clinical: chronic anovulation, hirsutism (excess of facial and body hair sometimes with male-like distribution), menstrual abnormalities, obesity Biological (hormonal): increased plama androgens, LH/FSH ratio increased over 2 Histological and ultrasound: the presence of at least 10 cystic follicle on every ovary . The biological picture may be seen without polycystic ovary on ultrasound or polycystic ovary in ultrasound examination with apparently normal ovarian function.

49 Polycystic ovary disease (syndrome) ethiopathogenity
Initial neuro endocrine abnormality with increased amplitude and frequency of pulses of LH-RH due to lost of inhibitory control physiologically produced by dopamine and opioids with permanently increased LH level. Permanently increased LH levels are responsible for increased androgen secretion in the theca interna and chronic anovulation Initial increased secretion of ovarian androgens may be the result of a genetic increased activity of 17 α hydroxilase (p450 C17α). In some cases an increased production of adrenal androgens due to late onset of CAH with 21 hydroxilase deficiency or 11 hydroxilase deficicency Functional deficiency in androgen aromatisation. In the concept of “two cell-two gonadotropins” control of ovarian function the PCOD may rezult from a desechilibrium between factors that facilitate androgen secretion (LH and insulin) and those which control aromatisation, selection of dominant follicle, proliferation of theca granulosa (FSH, inhibin hypersecretion)

50 Polycystic ovary disease (syndrome) ethiopathogenity
Primary insulin resistance or insulin resistance secondary to obesity. Insulin is known to normally stimulate androgen secretion in the ca interna. Increased insulin level produces theca interna stimulation of androgens, decreases Sex Hormone Binding Globulin (SHBG) therefore increasing testosterone biodisponibility to tissues. In the adipose tissue it is and increased aromatisation of peripheral androgens with increase extraovarian production of estradiol that in turn decreases FSH and rezults in chronic anovulation.

51 Polycystic ovary disease (syndrome) pathophysiology
Irrespective of initial event that triggers PCOD this has a trend to perpetuate itself “in a vicious circle” which must be known in order to allow an efficient tratment. Permanently increased LH level increases androgen production in theca interna. Androgen excess produces clinical signs as: hirsutism, acne, seborheea, frontal balding and facilitate truncal obesity, woth in turn produces and increases insulin resistance. Insulin excess is responsible for further increase of androgens and in association with low FSH produces anovulation. FSH deficiency results in functional deficiency of aromatisation and also in anovulation. Estrogens from peripheral aratisation of androgens further increse LH, decrease FSH. All these events result in chronic anovulation, infertility, progesterone deficiency, menstrual abnromalities, hirsutism, permanently increase LH and decreased FSH levels.

52 Reduced follicular maturation
Abormal pattern of FSH and LH secretion, permanently increased LH, decreased FSH, absence of preovulatory LH surge Increased pituitary LH secretion and decreased FSH secretion Increased androgen secretion by theca interna Reduced ovarian aromatisation due to low FSH Abnormal receptivity of pituitary sensitivity to LH-RH Reduced follicular maturation Incresed estrogen production from paripheral aromatisation Obesity, increased insulin and insulin resistance Estrogens increase adipose tissue proliferation and aromatisation

53 Transvaginal ultrasound of a polycystic ovary
Transvaginal ultrasound of a polycystic ovary. Note the increased number of antral follicles ringing the outside of the ovary and the increased central stroma.

54 Polycystic ovary disease (syndrome) Clinical signs
Signs of androgen excess: hirsutism (assessed by Ferriman–Gallwey score), seborrhea, exceptional frontal balding Metrual abnormalities: oligoamenorrhea that evolvs to secondary amenorrhea, functional bleeding. Primary amenorrhea is rare. Chronic anovulation and infertility Obesity: troncular, abdominal associated with insulin resistance. Aconathosis nigricans a sign of insulin resistance is frecquently seen especially in those who will develop type 2 diabetes mellitus

55 Acantosis nigricans

56 making the comparison of clinical studies often difficult if not impossible.
                                                                                                                                                                                                                                                                                                                                           Recommended diagnostic schemes for PCOS by varying expert groups. All recommend excluding possible other etiologies of these signs/symptoms and more than one of the signs or symptoms must be present to make a diagnosis. Red box- not –required for diagnosis, black box- mandatory criteria, white box possible diagnostic criteria but not necessarily required to be present. Hyperandrogenism may be either the presence of hirsutism or biochemical hyperandrogenemia.

57 Hormonal picture of PCOD
Gonadotropin abnormalities: increased LH., decreased FSH, LH/FSH ratio> 2, increased response of LH to LH-RH Androgen excess: increased total testosterone and DHEA Increase estrogens from periferal conversion especially estrone Reduced SHBG Moderately increased prolactine levels in some cases

58 Ultrasound picture of PCOD
Ovarian ultrasound is essential for diagnosis: criteria for PCOD are: more than 10 cyst of 2-9 mm. (15 cyst in vaginal ultrasound examination) in crown under the ovarian capsule. Increased density and volume of ovarian stroma.

59 Complications of PCOD Produced by estrogens of periferal conversion: endometrial carcinoma, fibroids of the uterus, ncreased risk of breast carcinoma, especially in infertile women that remain infertile and are treated with ovulation inductors Produced by follicular maturation abnormalities: major risk for spontaneous abortion, Due to insulin resistance and obesity: type 2 diabetes mellitus, hipertrigliceridemia, arterial hypertension, miocardial infarctus (7 fold more frequent) Emtional, due to hirsutism and infertility

60 Treatment of PCOD Depends of woman’s option in a given period of her life: normal cycles, fertility Goals of treatment: Weight loss which may be associated with spontaneous ovulation in 30 % of women with PCOD Treatment of insulin resistance and improvement of insulin action post receptor ( metformin, thiazolidindiones) Cyclic progesterone in order to replace progesteron deficiency due to anovulation: Medroxiprogesterone acetate 10 mg for 10 days starting from the 16th day od the cycle (other progestatoves: didrogesterone 10 mg, micronized progesterone (utrogetan)

61 Treatment of PCOD Reduction of androgen excess and its effects in target tissues Oral contraceptives with estrogen and progestatives ( not derived from nortestosterone with can stimulate hirsutism). To prefer OC with μg ethinil estradiol and a sinthetic progestative. Cyproterone acetate and or drospirenone ( a progestative that block androgen action to its receptor) are the best option In those women who do not tolerate OC a progestoreone must be given in cyclic regimen in association with spironolactone that block androgen receptor

62 Treatment of PCOD Treatment of infertility
Clomiphene cytrate is the first choice If not active cyclic human recombinant FSH and LH with previous treatment with LR-RH long actiong analogs (triptoreline)monitoring the follicule development with ultrasound and Estradiol levels Last option: Laparoscopic ovarian drilling

63 Suggested first line treatment plan for infertile women with PCOS
category is found in Table 6.                                                                                                                                                                                                                                                                                                                                            Suggested first line treatment plan for infertile women with PCOS

64 pregnancy.                                                                                                                                                                                                                                                                                                                                                                                Suggested first line treatment plan for women with PCOS not seeking pregnancy.

65 VARIANTE X-CROMATIN NEGATIVE ALE SINDROMULUI DE DISGENEZIE GONADICA
Mozaicisme care contin linii 45,X in diferite combinatii: 45X/46 XY, 45 X/47 XXY, 45 X/46XY/47 XYY si/sau anomalii structurale ale cromozomului Y Gonada: streak gonada bilateral streak gonada de o parte si testicul disgenetic de cealalta parte rar testicul aparent normal bilateral - disgenezie gonadica mixta 45x/46xy Fenotip Feminin cu stigmate de Turner Intersexualitate Masculin cu putine stigmate de Turner, o raportare cu fenotip masculin si stigamte de Turner si fertilitate pastrata

66 DISGENEZIA GONADICA COMPLETA 46,XY (Sd.Swyer)
Alte anomalii cromozomiale: displazia camptomelica cu determinata de mutatii ale genei SOX9, cromozom 17 cu nanism deletii: 9p-, 10q- nefrita interstitiala sau insuficienta renala Anomalii ectodermale sau cardiace Diagnostic: citogenetic Management: Rezectia gonadei independent de gradul de diferentiere riscul de neoplasm: gonadoblastom, disgerminon sau seminon este de pina la 30 % administrare de estrogeni si progesteron pentru inducerea si mentinerea caracterelor sexuale secundare exceptional la subiectii cu intersexualitate cu identitate de gen masculina: testosteron

67 Disgenezie gonadica completa 46,XY

68 Hipoplazia celulelor Leydig- defect de receptor pentru LH/hCG

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70 Receptorul de androgeni

71 SINDROAME DE INSENSIBILITATE LA ANDROGENI
CODUL GENETIC penru repcetorul de androgeni: cromozomul Xq11-12 TIPURI DE SINDROAME DE INSENSIBILITATE LA ANDROGENI: tip 1: fenotip masculin fara ambiguitati dar cu anomalii de virilizare pubertara sau ale spermatogenezei tip 2 a: fenotip masculin cu hipospadias izolat tip 2 b: fenotip masculin cu hipospadias = scrot bifid si micropenis tip 3 a: intersexualitate evidenta cu micropenis (asemanaror cu o hipertrofie clitoridiana si orificiu uretral perineal tip 3 b: intersexualitate evidenta cu micropenis (asemanaror cu o hipertrofie clitoridiana si orificiu uretral care face parte din sinus uro-genital asociat cu un mic vagin inchis “ in fund de sac” tip 4 a: fenotip predominant feminin cu discreta virilizare: hipertrofie clitoridiana, fuziune labiala si sinus uro-genital tip 4 b: fenotip predominant feminin cu discreta virilizare: hipertrofie clitoridiana, fuziune labiala partiala si deschidere separata a uretrei si vaginului 5 fenotip feminin fara ambiguitati

72 SINDROAME DE INSENSIBILITATE LA ANDROGENI
DIAGNOSTICUL BIOLOGIC Inainte de pubertate: administrarea de hCG determina cresterea exploziva a testosteronului si DHT si permite diagnosticul diferential cu deficite ale steroidogenezei dupa pubertate: LH, FSH net crescuti (lipsa feed-back negativ) testosteronul este crescut, iar produsul T x LH crescut pledeza pentru AIS Teste in vivo specifice pentru AIS: Stimularea productiei de testosteron cu hCG si determinarea gradului de reducere a nivelului de SHBG administrarea uni steroid anabolic: stanozol 0,2 mg/zi oral seara 3 zile si determinarea SHBG in zilele: 5,6,7, sau 8. Raportul dintre cel mai redus nivel al SHBG si nivelul bazal dinainte de test da informatii asupra existentei insensibilitatii la androgeni dar si asupra severitatii acestui deficit. Testul nu are sensibilitate suficienta inainte de 6 luni

73 SINDROAME DE INSENSIBILITATE LA ANDROGENI
CERCETAREA “ IN VITRO” A ACTIVITATII REEPTORULUI DE ANDROGENI Legarea androgenilor marcati de fibroblastii din pielea genitala absenta legarii este observata in insensibilitatea completa la androgeni expresia mARN pentru receptorul de androgeni prin Northern blot analiza determinarea activitatii de transactivare a receptorului androgenic in celule co-transfectate cu receptorul mutant

74 SINDROMUL DE INSENSIBILITATE COMPLETA LA ANDROGENI

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