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.)
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.)
22 Estrogen actions Target tissues ACTIONS M YOMETRIUM AND EMDOMETRIUM Myometrial proliferation and proliferation of endometrial glands and stromal tissueCERVIXStimulation of water and mucopolysacharides production making cervical mucus better for spermatozoa motility during ovulationVAGINAStimulation of the proliferation of vaginal mucosa and glycogen productionBREASTDuct proliferation
23 ESTROGEN ACTIONS HYPOTHALAMUS Important estrogen preovulatory increase produces LH-RH and LH surge and ovulationDECREASED BASAL BODY TEMPERATUREPITUITARYFSH inhibition and LH accumulation in the pituitaryBONEStimulation of bone formation and maturationPROTEIN METABOLISMIncreased protein synthesisSUGAR METABOLISMNatural estrogens increase and synthetic estrogen decrease glucose toleranceFAT METABOLISMIncreased HDL-col si triglycerides
24 PRGESTERONE ACTIONS TARGET TUSSUES ACTIONS MYOMETRIUM and ENDOMETRIUM Decreased myometrial contractilityStimulation of “secretory” pattern of endometriumCervixDecreased water content of cervical mucus thus inhibiting migration of spermatozoa after ovulationVAGINAReduced mucosal growthBreastProliferation of breast secretory activity
39 Primary amenorrhea Secondary amenorrhea Of gonadal origin Gonadal dysgenesis with female phenotype45,x si variantsPure gonadal dysgenesis: 46, XX, 46, XYDefects gonadal steroids biosynthesis XX sau XYStar, 3-OHDH, 17 hidroxilase, desmolaseAndrogen insensivity syndromesCongenital absence of the uterusSecondary amenorrheaPrecocious autoimmune menopauseOvariectomy
40 TURNER’S SYNDROME AND ITS VARIANTS PREVALENCE: 1/5000 FEMALE NEWBORN99 % of fetuses 45,X do not survive over 20 week of gestation15 % of spontaneous abortions of the first trimesterCLINICal data:Short stature <145 cm in forma 45,X, or less than -2 Sd from the normalmalformations: 200 malformatii somativ and visceralPrimary 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 bodylow estradiolFSH/LH increased ( over 40 mIU/mL)ultrasound and other diagnostic methods for malformation
47 TURNER’S SYNDROME AND ITS VARIANTS TREATAMENT objectives:GrowthhrGH: 0,05 mg /kg bw/day with a growth increase of cm than without treatment± oxandrolone: 0,0625 mg/kg/dayDevelopment of secondary sexual characteristics and menses:conjugated estrogens 0,3 mg /zi 21 day , or EE2 =5 microg /day 21 daysprogesterone is given laterPregnancy: 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, obesityBiological (hormonal): increased plama androgens, LH/FSH ratio increased over 2Histological 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 anovulationInitial 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 deficicencyFunctional 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 surgeIncreased pituitary LH secretion and decreased FSH secretionIncreased androgen secretion by theca internaReduced ovarian aromatisation due to low FSHAbnormal receptivity of pituitary sensitivity to LH-RHReduced follicular maturationIncresed estrogen production from paripheral aromatisationObesity, increased insulin and insulin resistanceEstrogens 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 baldingMetrual abnormalities: oligoamenorrhea that evolvs to secondary amenorrhea, functional bleeding. Primary amenorrhea is rare.Chronic anovulation and infertilityObesity: 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
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-RHAndrogen excess: increased total testosterone and DHEAIncrease estrogens from periferal conversion especially estroneReduced SHBGModerately 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 PCODProduced 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 inductorsProduced 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 PCODDepends of woman’s option in a given period of her life:normal cycles, fertilityGoals of treatment:Weight loss which may be associated with spontaneous ovulation in 30 % of women with PCODTreatment 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 PCODReduction of androgen excess and its effects in target tissuesOral 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 optionIn 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 choiceIf 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 levelsLast 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 nanismdeletii: 9p-, 10q-nefrita interstitiala sau insuficienta renalaAnomalii ectodermale sau cardiaceDiagnostic:citogeneticManagement:Rezectia gonadei independent de gradul de diferentiereriscul de neoplasm: gonadoblastom, disgerminon sau seminon este de pina la 30 %administrare de estrogeni si progesteron pentru inducerea si mentinerea caracterelor sexuale secundareexceptional la subiectii cu intersexualitate cu identitate de gen masculina: testosteron
71 SINDROAME DE INSENSIBILITATE LA ANDROGENI CODUL GENETIC penru repcetorul de androgeni: cromozomul Xq11-12TIPURI DE SINDROAME DE INSENSIBILITATE LA ANDROGENI:tip 1: fenotip masculin fara ambiguitati dar cu anomalii de virilizare pubertara sau ale spermatogenezeitip 2 a: fenotip masculin cu hipospadias izolattip 2 b: fenotip masculin cu hipospadias = scrot bifid si micropenistip 3 a: intersexualitate evidenta cu micropenis (asemanaror cu o hipertrofie clitoridiana si orificiu uretral perinealtip 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-genitaltip 4 b: fenotip predominant feminin cu discreta virilizare: hipertrofie clitoridiana, fuziune labiala partiala si deschidere separata a uretrei si vaginului5 fenotip feminin fara ambiguitati
72 SINDROAME DE INSENSIBILITATE LA ANDROGENI DIAGNOSTICUL BIOLOGICInainte de pubertate: administrarea de hCG determina cresterea exploziva a testosteronului si DHT si permite diagnosticul diferential cu deficite ale steroidogenezeidupa pubertate:LH, FSH net crescuti (lipsa feed-back negativ)testosteronul este crescut, iar produsul T x LH crescut pledeza pentru AISTeste in vivo specifice pentru AIS:Stimularea productiei de testosteron cu hCG si determinarea gradului de reducere a nivelului de SHBGadministrarea 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 ANDROGENILegarea androgenilor marcati de fibroblastii din pielea genitalaabsenta legarii este observata in insensibilitatea completa la androgeniexpresia mARN pentru receptorul de androgeni prin Northern blot analizadeterminarea activitatii de transactivare a receptorului androgenic in celule co-transfectate cu receptorul mutant
74 SINDROMUL DE INSENSIBILITATE COMPLETA LA ANDROGENI