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DF= dominant follicule Prima meta del ciclo mestruale.

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Presentazione sul tema: "DF= dominant follicule Prima meta del ciclo mestruale."— Transcript della presentazione:

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2 DF= dominant follicule Prima meta del ciclo mestruale

3 Seconda meta del ciclo mestruale

4 androstenedione (A) estradiol (E) keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and Kit ligand (KL).

5 FIG. Proposed schematic of thecal cell-granulosa cell interactions during follicular development. Mesenchyme-derived thecal cells produce KGF and HGF that regulate epithelial-derived granulosa cell functions. Granulosa cell expression of KL is stimulated (1) by KGF and HGF. Granulosa cell-derived KL feed back on thecal cells to regulate thecal cell growth and differentiated functions. Thecal cell expression of KGF and HGF is stimulated (1) by KL. Also illustrated is the previously established positive effect (1) of KL on oocyte development. Endocrine regulation of ovarian development is represented at the top with the actions of FSH and LH. Thecal cells produce androstenedione (A) under the control of LH. Androstenedione is aromatized to estradiol (E) by granulosa cells under the control of FSH. High levels of estradiol further stimulate androstenedione production by thecal cells. LH also stimulates granulosa cell function during later stages of follicular development (not shown).

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7 Gli estrogeni giocano un ruolo importante nello sviluppo e il mantenimento della funzione sessuale e riproduttiva. Sia nelluomo che nella donna esercitano una varietà di effetti a livello cardiovascolare, muscolo scheletrico sistema immunitario e sistema nervoso centrale. Lestrogeno più potente è il 17 -estradiolo detto E2. Due metaboliti dellE2 sono lestrone e lestriolo i quali sono agonisti molto più deboli al recettore degli estrogeni (ER ed ER ). ESTROGENI 17 -estradiolo

8 ESTROGENI di sintesi

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10 Receptor Actions in Cells (B. Katzenellenbogen et al. Recent Prog. Horm. Res.,2000)

11 Gli estrogeni hanno unazione morfogena e quest azione morfogenica è evidente in strutture quali lutero, le ovaie le ghiandole mammarie, la prostata, i polmoni e il sistema nervoso centrale di topi knockout per entrambi i recettori degli estrogeni ER ed ER. A livello di promotori genici i due recettori ER ed ER hanno effetti opposti e quindi la risposta proliferativa allE2 è il risultato di un equilibrio tra i segnali mandati dallattivazione del recettore ER e quello ER FIG. 3. Model representing the mechanistically distinct molecular pathways used in the regulatory actions of ERs. The classical (direct) pathway includes ligand activation and a direct DNA binding to estrogen response elements (ERE) before modulation of gene regulation. The tethered pathway includes protein-protein interaction with other transcription factors after ligand activation, and thereby gene regulation is affected by indirect DNA binding. A third mechanism, also called nongenomic with rapid effects, is not as well understood as the genomic mechanism but has been observed in many tissues. The ligand activates a receptor, possibly associated with the membrane; either it is a classical ER (33, 138, 243), an ER isoform (141, 305), or a distinct receptor (38) or, alternatively, a signal activates a classical ER located in the cytoplasm. After this rather unclear event, signaling cascades are initiated via second messengers (SM) that affect ion channels or increase nitric oxide levels in the cytoplasm, and this ultimately leads to a rapid physiological response without involving gene regulation. The ligand-independent pathway includes activation through other signaling pathways, like growth factor signaling. In this case, activated kinases phosphorylate ERs and thereby activate them to dimerize, bind DNA, and regulate genes.

12 1)Morfogenesi della ghiandola mammaria: Laccrescimento dei dotti della ghiandola mammaria dipende dalla presenza dei recettori ER in quanto non avviene in topi knockout per questo recettore. 2) Gli effetti degli estrogeni sulla crescita neuronale sono mediati da sostanze neurotrofiche quali il nerve growth factor (NGF) e i suoi recettori nei neuroni colinergici, il Transforming growth factor (TGF- ) nellipotalamo, il brain-derived neurotrophic factor (BDNF) nella corteccia cerebrale, i recettori del Nerve growth factor (NGF) in neuroni sensori e dall insulin- like growth factor e i suoi recettori nellipotalamo. 3. Morfogenesi polmonare. I recettori per gli estrogeni giocano un ruolo importante nella formazione di tessuto elastico.

13 Ruolo degli estrogeni nella crescita ossea Figure 1 Summary of possible pathways for androgens to regulate bone mass in males. Experimental animal studies using mouse models with inactivation of the androgen receptor (AR), estrogen receptor a (ERa), ERb or the recently suggested ER GPR30 have demonstrated that the AR and ERa, but not ERb or GPR30, are involved in the regulation of cortical and trabecular bone in males. ERa activation resulted both in preserving the thickness and number of trabeculae.

14 The story of the development of tamoxifen as a pioneering medicine in cancer treatment has its origins in two separate areas of research that converged almost by accident, in the early 1970s. The first research path, followed between 1900 and 1974, sought to understand why only some of the women who developed breast cancer, responded to endocrine therapies. The second research path, which started in 1958, was unconnected to the first and started with the chance discovery of nonsteroidal antioestrogens, in the pharmaceutical industry. Antiestrogeni

15 I modulatori selettivi dei recettori degli estrogeni (SERMs), quali il toremifene, droloxifene and idoxifene) erano basati sulla struttura del tamoxifene. Questi agenti non hanno mostrato nessun ulteriore beneficio rispetto al tamoxifene ed hanno mostrato anche unattività di parziale agonismo ed alcuni studi hanno dimostrato una resistenza crociata tra i SERMs di prima generazione. Raloxifene ed arzoxifene rappresentano i SERMs di seconda generazione. Il fulvestrant, rappresenta lultima generazione ed è un antagonista puro con nessun effetto di parziale agonismo ed è utilizzato nel cancro alla mammella avanzato in donne in post menopausa Droloxifeneidoxifene SERMs

16 Usi terapeutici dei SERMS

17 Clomiphene citrate versus high doses of gonadotropins for in vitro fertilisation in women with compromised ovarian reserve: a randomised controlled non- inferiority trial Guido RagniGuido Ragni, 1 Paolo E Levi-Setti, 2 Rubens Fadini, 3 Claudio Brigante, 4 Claudia Scarduelli, 1 Federica Alagna, 1 Veronica Arfuso, 2 Mario Mignini-Renzini, 3 Massimo Candiani, 4 Alessio Paffoni, 1 and Edgardo Somigliana 1Paolo E Levi-SettiRubens FadiniClaudio BriganteClaudia ScarduelliFederica AlagnaVeronica ArfusoMario Mignini-RenziniMassimo Candiani Alessio PaffoniEdgardo Somigliana Background The aim of the present randomised controlled non-inferiority trial is to test whether in women with compromised ovarian reserve requiring in vitro fertilisation, a protocol of ovarian stimulation using exclusively clomiphene citrate performs similarly to a regimen with high doses of gonadotropins. Methods Women with day 3 serum FSH > 12 IU/ml on at least two occasions or previous poor response to hyper- stimulation were recruited at four Italian infertility units. Selected women were allocated to clomiphene citrate 150 mg/day from day 3 to day 7 of the cycle (n=145) or to a short protocol with GnRH agonist 0.1 mg and recombinant FSH 450 IU daily (n=146). They were randomised by means of a computer-generated list into two groups. The study was not blinded. The main outcome of the study was the delivery rate per started cycle. Results The study was interrupted after the scheduled two years of recruitment before reaching the sample size. 148 women were allocated to clomiphene citrate and 156 to the short protocol with high doses of gonadotropins; 124 and 125 participants were analysed in the groups, respectively. Women allocated to high doses of gonadotropins retrieved more oocytes and had a higher probability to perform embryo- transfer. However, the chances of success were similar. The delivery rate per started cycle in women receiving clomiphene citrate and high-dose gonadotropins was 3% (n=5) and 5% (n=7), respectively (p=0.77). The mean estimated cost per delivery in the two groups was 81,294 and 113,107 Euros, respectively. No side-effects or adverse events were observed. Conclusions In women with compromised ovarian reserve selected for in vitro fertilisation, ovarian stimulation with clomiphene citrate or high-dose gonadotropins led to similar chances of pregnancy but the former is less expensive.

18 Progesterone Il progesterone viene sintetizzato dal pregnenolone che a sua volta è un prodotto del metabolismo del colesterolo

19 Espressione dei recettori per il progesterone I recettori per il P4 sono presenti nelle cellule della granulosa e nelle cellule del corpo luteo.

20 Il progesterone è il più importante progestinico nelluomo. E sintetizzato nelle ovaie, nei testicoli e nelle ghiandole surrenali a partire dal colesterolo. Grandi quantità sono anche sintetizzate e rilasciate in circolo dalla placenta durante la gravidanza. Nelle ovaie è prodotto principalmente dal corpo luteo. Inoltre il progesterone serve come precursore nella sintesi di estrogeni, androgeni e corticosteroidi. Negli uomini vengono secreti da 1 a 5 mg di progeterone al giorno. Le concentrazioni ematiche di progesterone nelle donne è leggermente più alto nella fase luteale del ciclo mestruale. Nella fase luteale e nel primo trimestre di gravidanza la donna secerne dai 10 ai 20 mg al giorno di progesterone e molti di più durante la parte finale del parto. Nel plasma il progesterone è legato per il 90% allalbumina e alla Corticosteroid Binding Globulin.

21 Gli effetti del progesterone sono: 1)Conversione di un endometrio proliferativo in un endometrio secretorio 2)Riduce lefficacia del sistema immunitario 3)Diminuisce la contrattilità uterina 4)Produce un aumento della temperatura corporea durante lovulazione 5)Aumenta la proliferazione delle cellule epiteliali mammarie 6)La sua carenza insieme allestradiolo produce osteoporosi Uso: 1)Minacce di aborto 2)Miomi uterini Ci sono evidenze negli ultimi anni che il progesterone (P4) abbia potenti effetti neuroprotettivi e neurogenerativi a livello dellippocampo e della corteccia cerebrale.

22 Il progesterone ha un effetto inibitorio sulla motilità delle tube di fallopio riducendo la frequenza delle contrazionei nella fase luteale. (Lindblom et al., 1980).

23 Norethindrone Levonorgestrel PROGESTINICI

24 Uso Progestinici

25 KEY POINTS -Hormonal contraceptives have a number of noncontraceptive benefits, such as regulating the menstrual cycle. -The Pearl index is the number of unintended pregnancies per 100 women per year. Rates are 15% using male condoms, 8% with oral contraceptives, 3% with depot medroxyprogesterone acetate (Depo-Provera) injections, and less than 1% with intrauterine devices or female or male sterilization. -Estrogen-containing products should be avoided in patients with hypertension or who are at risk of venousthromboembolism.

26 Enovid, the pill formulated by Dr. John Rock and Dr. Gregory Pincus in the 1950s, contained 150 μg of mestranol (equivalent to 90 μg of ethinyl estradiol) and 9.85 mg of norethynodrel, a very potent progestin. Our current oral contraceptive pills contain much lower hormone doses and have fewer androgenic side effects. DOSAGGIO CONTRACCETTIVI

27 Pillola contraccettiva

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30 Nomegestrol acetate-17b-estradiol for oral contraception Anne Burke Johns Hopkins University School of Medicine, Baltimore, MD, USA Correspondence: Anne Burke, Johns Hopkins University School of Medicine, Bayview Medical Center, 4940 Eastern Ave, A-101, Baltimore, MD 21224, USA Oral contraceptives remain a popular method of contraception over 50 years after their introduction. While safe and effective for many women, the failure rate of oral contraception is about 8%. Concerns about the risk of venous thromboembolism continue to drive the search for the safest oral contraceptive formulations. The oral contraceptive NOMAC-E2 contains nomegestrol acetate (NOMAC) 2.5 mg + 17b-estradiol (E2) 1.5 mg. The approved dosing regimen is 24 days of active hormone, followed by a 4-day hormone-free interval. NOMAC is a progestin derived from testosterone, which has high bioavailability, rapid absorption, and a long half-life. Estradiol, though it has a lower bioavailability, has been successfully combined with NOMAC in a monophasic oral contraceptive. Two recently published randomized controlled trials demonstrate that NOMAC- E2 is an effective contraceptive, with a Pearl Index less than one pregnancy per 100 woman-years. The bleeding pattern on NOMAC-E2 is characterized by fewer bleeding/spotting days, shorter withdrawal bleeds, and a higher incidence of amenorrhea than the comparator oral contraceptive containing drospirenone and ethinyl estradiol. The adverse event profile appears to be acceptable. Few severe adverse events were reported in the randomized controlled trials. The most common adverse events were irregular bleeding, acne, and weight gain. Preliminary studies suggest that NOMAC-E2 does not seem to have negative effects on hemostatic and metabolic parameters. While no one oral contraceptive formulation is likely to be the optimum choice for all women, NOMAC-E2 is a formulation with effectiveness comparable with that of other oral contraceptives, and a reassuring safety profile.

31 Il feedback negativo indotto dai progestinici diminuiscono la frequenza di rilascio del GnRH ipotalamico. Una riduzione di questo ormone fa rilasciare meno FSH ed LH dallipofisi anteriore. Livelli plasmatici ridotti di FSH non porteranno a maturazione del follicolo con una ridotta produzione di estrogeni. Il feedback negativo dei progestinici e la mancanza del feedback positivo degli estrogeni sul rilascio di LH prevengono il picco di LH a metà ciclo con mancata ovulazione. Inoltre si osserva un muco cervicale più denso impedendo allo sperma di risalire; si è osservato che la pillola contraccettiva inoltre inibisce il trasporto dello sperma a livello delle tube. Meccanismo di azione della Pillola contraccettiva

32 Gli effetti collaterali più comuni sono : nausea, dolore alle mammelle, cloasma (macchie di pelle scura nel volto) e occasionalmente effetti di alterazione della sfera emotiva e funzione sessuale. Un effetto collaterale pericoloso della pillola contraccettiva è il tromboembolismo venoso che ha unincidenza di 1-2 casi su donne ogni anno. In donne che hanno ipertensione arteriosa e fumano tabacco, la pillola contraccettiva aumenta in modo significativo lincidenza di infarto del miocardio e ictus cerebrale. Effetti collaterali pillola contraccettiva Changes in: Weight Sexual desire Vaginal discharge Menstrual flow Breast size Blood pressure Complexion (macchie di pelle scura) Other Common side effects: Breakthrough bleeding Nausea headaches Urinary tract infection Depression Gum inflammation

33 Uso degli estrogeni nella terapia ormonale di rimpiazzo Estrogeno coniugato

34 Estrogeni presenti nella formulazione Enjuvia

35 Rischi da trattamento con estrogeni nella HRT

36 Uso degli estrogeni nellendometriosi

37 Novel oral contraceptive for heavy menstrual bleeding: estradiol valerate and dienogest Sally RafieSally Rafie, 1 Laura Borgelt, 2 Erin R Koepf, 3 Mary E Temple-Cooper, 4 and K Joy Lehman 5Laura BorgeltErin R KoepfMary E Temple-CooperK Joy Lehman Abnormal uterine bleeding (AUB) is associated with significant direct medical costs and impacts both society and the quality of life for individual women. Heavy menstrual bleeding, a subset of AUB, also referred to as menorrhagia, is defined as menstrual blood loss greater than 80 mL or the patients perception of excessive blood loss. The newest treatment option available is a novel combination oral contraceptive product containing estradiol valerate (E2V) and dienogest (DNG). As with other combination oral contraceptives, E2V/DNG works primarily by preventing ovulation. However, in contrast with other combination oral contraceptives, it is the progestin component of E2V/DNG that is responsible for endometrial stabilization. Use of E2V/DNG for six months has led to significant reductions in heavy menstrual bleeding with an average 65% reduction in mean blood loss. Approximately half of the women with heavy menstrual bleeding who received E2V/DNG for six months demonstrated an 80% reduction in mean blood loss. Additionally, significant improvements in hematologic indicators (ie, ferritin, hemoglobin, and hematocrit) have been shown. Based on its chemical properties, E2V/DNG may have fewer adverse effects on lipid and glucose metabolism and reduced risk of thromboembolic complications compared with other combination oral contraceptives. This has not yet been shown in clinical trials and until then it should be assumed that E2V/DNG has a safety profile similar to other combination oral contraceptives containing 35 μg or less of ethinyl estradiol. E2V/DNG has been compared with another combination oral contraceptive in healthy women without heavy menstrual bleeding and demonstrated improved bleeding patterns. E2V/DNG has not been compared with the levonorgestrel intrauterine device or other treatments for heavy menstrual bleeding. When compared with some other treatment options for AUB, E2V/DNG provides the added advantage of effective contraception.

38 Int J Womens Health. 2013; 5: 313–321.

39 Patient Prefer Adherence. 2013; 7: 777–785. Role of the levonorgestrel intrauterine system in effective contraception Abdelhamid M AttiaAbdelhamid M Attia, 1 Magdy M Ibrahim, 1 and Ahmed M Abou-Setta 2Magdy M IbrahimAhmed M Abou-Setta The levonorgestrel-releasing intrauterine system (LNG IUS) provides a long-acting, highly effective, and reversible form of contraception, with a pearl index of 0.18 per 100 women-years. The locally released hormone leads to endometrial concentrations that are 200–800 times those found after daily oral use and a plasma level that is lower than that with other forms of levonorgestrel-containing contraception. The contraceptive effect of the LNG IUS is achieved mainly through its local suppressive effect on the endometrium, leading to endometrial thinning, glandular atrophy, and stromal decidualization without affecting ovulation. The LNG IUS is generally well tolerated. The main side effects are related to its androgenic activity, which is usually mild and transient, resolving after the first few months. Menstrual abnormalities are also common but well tolerated, and even become desirable (eg, amenorrhea, hypomenorrhea, and oligomenorrhea) with proper counseling of the patient during the choice of the method of contraception. The satisfaction rates after 3 years of insertion are high, reaching between 77% and 94%. The local effect of the LNG IUS on the endometrium and low rates of systemic adverse effects have led to its use in other conditions rather than contraception, as for the treatment of endometrial hyperplasia, benign menorrhagia, endometriosis, adenomyosis, and uterine fibroids.

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41 Progestinici di sintesi

42 1993

43 2005

44 Il regime di trattamento Yuzpe (0.1 mg etinilestradiolo e 0.5 mg levonorgestrel somministrato entro le 72 h del rapporto sesuale e ripetuta dopo) è stato il più comune metodo usto nella contraccezione di emergenza. Altri metodi sono oggigiorno la somministrazione di levonorgestrel 0.75 mg, ripetuti dopo 12 h oppure in una singola dose di 1.5 mg, oppure una singola dose di 10 mg di mifepristone detto anche RU486. Pillola del giorno dopo

45 CountryAvailability IrelandRequires a visit to a doctor or family- planning clinic RussiaRequires a prescription SpainRequires a visit to the doctor CanadaConsultation with a pharmacist United KingdomAvailable OTC to women only 16 & older RomaniaRequires a medical prescription ItalyRequires a medical prescription FinlandAvailable without a prescription, but only 1 pack may be purchased at a time United StatesAvailable without prescription to men and women 17 and older with no limitations Emergency Contraception around the World:

46 Most Common Adverse EventsPlan B One-Step N = 1,359 (%) Heavier menstrual bleeding30.9 Nausea13.7 Lower abdominal pain13.3 Fatigue13.3 Headache10.3 Dizziness9.6 Breast tenderness8.2 Delay of menses ( > 7 days)4.5 Plan B One-Steps Adverse Reactions

47 ORMONE ANTIMULLERIANO


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