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

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, 1971. Reproduced with permission from Mosby, Inc.)

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, 1997. Reproduced with permission from Springer-Verlag, New York.)

Estrogen actionsTarget 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

ESTROGEN ACTIONSHYPOTHALAMUS

Important estrogen preovulatory increase produces LH-RH and LH surge and ovulationDECREASED 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

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

CONTROL OV OVARIAN FUNCTION

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

Diagram showing the "Two Gonadotropin-Two Cell Concept" of follicle estrogen production. (Erickson, GF: Normal ovarian function. Clin Obstet Gynecol 21:31, 1978. Reproduced with

permission from Lippincott-Raven Publishers.)

OVARIAN CYCLE

ENDOMETRIAL

CYCLE

ENDOMETRIAL CYCLE DURING AN OVULATORY CYCLE

ENDOMETRIAL CYCLE DURING ORAL CONTRACEPTIVES TREATMENT

ASSESSMENT OF OVARIAN FUNCTION

ESTRADIOL PROGESTERONE FSH LHLHRH TEST SHBG PROLACTIN TESTOSTERONE (FREE) DHEA-S

BASAL BODY TEMPERATURE CERVICAL MUCUS ENDOMETRIAL BIOPSY ULTRASOUND EXAMINATION LAPAROSCOPY

ASSESSMENT OF OVARIAN FUNCTION

ESTRADIOL, FSH, LH, PROLACTIN

E2 FSH LH

LHRH test

+ -HYPOTHALAMUS PITUITARY

HYPOGONADOTROPIC HYPOGONADISM

E2 FSH LH

PROLACTINE2 FSH LH

HYPERGONADOTROPIC HYPOGONADISM

HIPERPROLACTINEMIA

MENSTRUAL PROBLEMS

PRIMARY AMENORRHEA SECONDARY AMENORRHEA OLIGOMENORRHEA DYSMENORRHEA

PRIMARY AMENORRHEA

HYPOTHALAMIC ORIGINIdiopatic hypogonadotropic hypogonadism Kallmann syndrome Prader-Willi syndromeSd. Lawrence-Moon-bardet-BiedltumorsHistiocytosisBrain irradiation malnutrition

SECONADRY AMENORRHEA

HYPOTHALAMIC ORIGINPostpubertal tumors of hypothalamusAnorexia nervosaPost-pill amenorrheaStress induced amenorrheaInduced by exercise

PRIMARY AMENORRHEAPITUITARYLh-Rh receptor defects Pituitary failurePitiatry tumorsOther: trauma, infiltrative diseases

SECONDARY AMENORRHEAPITUITARYPiruitary tumors (prolactinomas)autoimmuneHipofizectomyPituitary irradiationSheehan’s syndromehemochromatosis

Primary amenorrhea Of gonadal originGonadal dysgenesis with female phenotype45,x si variantsPure gonadal dysgenesis: 46, XX, 46, XYDefects gonadal steroids biosynthesis XX sau XYStar, 3-OHDH, 17 hidroxilase, 17-20 desmolase

Androgen insensivity syndromes

Congenital absence of the uterus

Secondary amenorrheaOf gonadal originPrecocious autoimmune menopauseOvariectomy

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 trimester

CLINICal data:Short stature <145 cm in forma 45,X, or less than -2 Sd from the normalmalformations: 200 malformatii somativ and visceralPrimary amenorrhea

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

TURNER’S SYNDROME AND ITS VARIANTS

TREATAMENT objectives:Growth• hrGH: 0,05 mg /kg bw/day with a growth increase of 8-10 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 days• progesterone is given later Pregnancy: surogate mothers

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.

Polycystic ovary disease (syndrome) ethiopathogenity

1. 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

2. 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

3. 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)

Polycystic ovary disease (syndrome) ethiopathogenity

1. 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.

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.

Abormal pattern of FSH and LH secretion, permanently increased LH,

decreased FSH, absence of preovulatory LH surge

Increased androgen

secretion by theca interna

Reduced ovarian aromatisation due

to low FSH

Reduced follicular maturation

Incresed estrogen production from

paripheral aromatisation

Estrogens increase adipose tissue proliferation and

aromatisation

Obesity, increased insulin and insulin

resistance

Abnormal receptivity of pituitary sensitivity to

LH-RH

Increased pituitary LH secretion and decreased

FSH secretion

Transvaginal ultrasound of a polycystic ovary. Note the increased number of antral follicles ringing the outside

of the ovary and the increased central stroma.

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

Acantosis nigricans

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.

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

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.

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

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 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)

Treatment of PCODReduction 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 30-35 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

Treatment of PCODTreatment 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

category is found in Table 6.

                                                                                                                                                                                    

                                                                                                                                                      

Suggested first line treatment plan for infertile women with PCOS

pregnancy.

                                                                                                                                                          

                                                                                                                                                                                                                    

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

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 YGonada: 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

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

Disgenezie gonadica completa 46,XY

Hipoplazia celulelor Leydig- defect de receptor pentru LH/hCG

Receptorul de androgeni

SINDROAME DE INSENSIBILITATE LA ANDROGENICODUL 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 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

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 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

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

SINDROMUL DE INSENSIBILITATE COMPLETA LA ANDROGENI