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Jinekolojik Endokrinolojide Hormonal Değerlendirme Dr.Engin Oral İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi Kadın Hastalıkları ve Doğum ABD Reprodüktif.

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1 Jinekolojik Endokrinolojide Hormonal Değerlendirme Dr.Engin Oral İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi Kadın Hastalıkları ve Doğum ABD Reprodüktif Endokrinoloji BilimDalı

2 Jinekolojik Endokrinolojide Patolojiler Over rezervi PKOS Hiperandrojenemi Hiperprolaktinemi Amenore Menopoz Sonuç


4 Gonadotropinler

5 LH FSH TSH Prolactin Lipid panel (cholesterol, HDL, LDL, and triglycerides) Fasting insulin level 2-hour 75-g glucose tolerance test DHEAS Testosterone Free testosterone 17-Hydroxyprogesterone Laboratuar tetkikleri


7 Cut-off Values for the Most Commonly Used Ovarian Reserve Tests

8 Assessment of ovarian reserve with anti-Müllerian hormone: a comparison of the predictive value of anti-Müllerian hormone, follicle-stimulating hormone, inhibin B, and age Ryan M. Riggs, 2008

9 Over rezervini belirleme endikasyonları İleri kadın yaşı (>35 yaş ?) Geçirilmiş over cerrahisi Tek over Açıklanamayan infertilite Sigara kullanımı Daha evvelki tedavilerde başarısızlık Ailede erken menopoz hikayesi Kemoterapi, radyoterapi Evre III-IV endometriozis HERKESE

10 POLYCYSTIC OVARY SYNDROME (PCOS) Sixty-five to 85% of all women with androgen excess are diagnosed as having PCOS The findings in PCOS are variable, with 40% to 60% of patients obese, 60% to 90% hirsute, 50% to 90% oligoamenorrheic, and 55% to 75% infertile.

11 The Hypothalamic–Pituitary–Ovarian Axis and the Role of Insulin. David A. Ehrmann, 2005


13 Criteria for the diagnosis of polycystic ovary syndrome (PCOS)

14 Oligo- or anovulation: Ovulation occurs less than once every 35 days. Hyperandrogenism: Clinical signs include hirsutism, acne, alopecia (male-pattern balding) and frank virilization. Biochemical indicators include raised concentrations of total testosterone and androstendione, and an elevated free androgen index that entails the measurement of total testosterone and sex hormone binding globulin (SHBG). However, the measurement of these biochemical markers for hyperandrogenism has proved markedly inconsistent due to problems with various assays. Polycystic ovaries: The presence of 12 or more follicles in either ovary measuring 2–9 mm in diameter and/or increased ovarian volume (>10 mL).

15 Klinik bulgular (%) Menstrüel düzensizlik66 İnfertilite75 Hirsutizm66 Akne35 Obezite38 LH Artışı40 T artışı30 Hiperinsülinemi –Obez 80 –Zayıf Homburg R, 2003


17 Endocrine and metabolic differences among phenotypic expressions of polycystic ovary syndrome according to the 2003 Rotterdam consensus criteria Robert P. Kauffman, 2008


19 Suggested diagnostic evaluation for PCOS Richard S. Legro, 2007

20 Ovarian hyperthecosis

21 ANDROJENLER Testosteron %50 periferik dönüşüm %50 over ve adrenal %80 SHBG, %19 albumine %1 serbest (kadınlarda) DHT En güçlü T,AD  DHT Androstenodiol glukuronid

22 ANDROJENLER DHEAS,DHEA Zayıf Adrenal kaynaklı Gebelikte E3 prekürsörü Puberte başında pubik kıllanma diğer androjenlerin prekürsörü  AD Aktif değil Over, adrenal kaynaklı T,DHT’ye dönüşür

23 Obesite Androjen fazlalığı Kortikosteroid Hipotiroidism Cushing sendromu Akromegali Karaciğer hast. Progestogen Hiperinsülinemi Östrojen fazlalığıÖstrojen fazlalığı Oral kontraseptiflerOral kontraseptifler GebelikGebelik HipertiroidismHipertiroidism S H B G azaltanlar artıranlar

24 ANDROJEN FAZLALIĞINDA CİLT BULGULARI Hirsutizm Akne Androjenik alopesi AN

25 Free T or free T index were felt to be most sensitive methods of hyperandrogenemia Measurement of total T only may not be a sensitive marker of AE A fraction of patients may have DHEAS elevation Routine assessment of androstenedione is not recommended Which androgen to measure? ESHRE/ASRM Consensus 2003

26 Factors that are known to alter serum testosterone concentrations Physiological factors Pulsatile release during the day Diurnal rhythm: am > pm Menstrual cycle: luteal > follicular Season (no variation in total testosterone free testosterone shows 30% difference): summer > winter Age (years) in women with and without polycystic ovary syndrome (PCOS): 20s > 40s Analytical factors Cross reactivity with other endogenous steroids Interference by endogenous antibodies Poor performance in the female range: < 8 nmol/l

27 Causes of hirsutism.  Polycystic ovary syndrome  Idiopathic  Late-onset congenital adrenal hyperplasia  Cushing's syndrome  ° Cushing's disease (ACTH-secreting pituitary tumour)  ° Ectopic ACTH secretion by non-pituitary tumour (bronchus Table, thyroid)  ° Autonomous cortisol secretion by adrenal or ovarian tumour  ° Ectopic corticotrophin secretion by tumour (very rare)  Androgen-secreting tumours of the ovary  ° Sex-cord stromal cell tumours  ° Adrenal-like tumours of the ovary  Androgen-secreting tumours of the adrenal  ° Adenomas  ° Adenocarcinomas  Iatrogenic  ° Testosterone  ° Danazol  ° Glucocorticoids

28 Androgen Excess in Women: Experience with Over 1000 Consecutive Patients R. AZZIZ, 2004

29 Akantozis Nigricans

30 Hyperthecosis previously considered hyperthecosis to be a variant of PCOS, it should be noted that the term hyperthecosis simply refers to the histopathologic finding of islands of hyperplastic theca cells located between collections of small atretic follicles (i.e., “cysts”). Most women with hyperthecosis demonstrate high circulating androgen levels, and consequently lower circulating LH and FSH levels (4–8 mIU/mL) Androgen-secreting tumor.

31 Non-Classic Adrenal Hyperplasia (NCAH) 1% to 5% of hyperandrogenic women are deficient in the activity of adrenal enzymes, particularly 21-hydroxylase (21-OHase) autosomal recessive 17-hydroxyprogesterone (17-HP) hirsutism, acne, and oligo- and/or amenorrhea

32 ACTH Stimülasyon Testi AD 3-7 günleri Sabah saat mg sentetik ACTH (Cortrosyn) IV * IM yapılmamalı Başlangıçta ve 1 saat sonra kan

33 Serum 17-OHP seviyesi (0.1 –0.8 ng/ml ) < 2 ng/ml > 8 ng/ml2-8 ng/ml LOKAH (+) LOKAH (-) ACTH Stimülasyon Testi Gereksiz ACTH Stimülasyon Testi > 10 ng/ml < 10 ng/ml LOKAH Normal Heterozigot LOKAH

34 Cushing Syndrome adrenal neoplasm, ectopic ACTH-producing tumor, or pituitary tumor/Cushing disease centripetal fat distribution, thinning of the skin with striae, glucose intolerance, osteoporosis, and proximal muscle weakness menstrual irregularities

35 Androgenic Tumors ovary or adrenal onset of hyperandrogenism is sudden, and when progression is rapid, or when frank virilization is present Virilizing ovarian tumors, including Sertoli-Leydig cell and lipoid cell tumors, generally exhibit low malignancy potential In young women the possibility of an androgen-secreting tumour should be considered with the following: – serum testosterone values above 150 ng/dl ; –serum-free testosterone values above 2 ng/dl ; –serum dehydroepiandrosterone sulphate values above 700 µg per dl

36 Iatrogenic Causes Exogenous androgens Androgenic steroids Danazol Glucocorticoids

37 “Idiopathic” Hirsutism Approximately 15% to 30% of hirsute women do not have ovulatory abnormalities and usually have normal levels of circulating androgens In many of these patients, skin 5-reductase activity is excessive, leading to higher skin concentrations of the active androgen dihydrotestosterone It is important to note that approximately 40% of hirsute women claiming to have “regular menstrual cycles” are actually oligo-ovulatory when evaluated more carefully

38 Hirsutism The Endocrine Society Clinical Practice Guidelines recommend biochemical testing in women with moderate or severe hirsutism, or hirsutism of any degree if it is sudden in onset and rapidly progressive, or associated with irregular menses, obesity, or evidence of virilization (clitoromegaly) The Guidelines suggest first measuring an early morning total testosterone concentration. Although a free testosterone concentration is a more sensitive indicator of androgen excess, most available assays are inaccuratetestosterone Another approach that many clinicians use, is initial measurement of serum testosterone, prolactin, and DHEA-S, followed by additional testing when indicatedtestosterone Martin KA, 2008

39 Differential diagnosis ANDROGEN EXCESS SOCIETY, 2006

40 Prolaktin Prolaktin hipotalamustan dopaminin inhibitör kontrolü altındaProlaktin hipotalamustan dopaminin inhibitör kontrolü altında Otonom hipersekresyon, pulsatil GnRH sekresyonunu bozar.Otonom hipersekresyon, pulsatil GnRH sekresyonunu bozar. HiperprolaktinemiHiperprolaktinemi –Fizyolojik (< 50 ng/mL): gebelik, laktasyon, uyku, yoğun egzersiz, stres, cinsellik, yemek

41 Causes of hyperprolactinaemia

42 PRL hormon biosentezi Orijinal matür PRL RNA sı 227 AA den oluşan sekansı kodlar Üretim sonrası molekül şu etkilere maruz kalır : –Degradasyon –Polimerizasyon –Glikozilasyon (PRL etkinliğinin devamında gereklidir) –Fosforilasyon Bu etkiler sonucu oluşan moleküllerin bioaktiviteleri farklıdır Polimerizasyon oranında bioaktivite düşer (MakroPRL) –Monomerik % –Dimerik% 8-20 –Polimerik% 1-5

43 Macroprolactin PRL may form immune complexes, generally with an immunoglobulin G antibody, to produce a biologically inactive form called ‘macroprolactin’, which has a molecular mass of more than 150 kDa. This is registered by most PRL immunoassays and hence serum PRL levels are reported to be high. Since misdiagnosis of hyperprolactinaemia due to the presence of macroprolactin may lead to patient mismanagement, this possibility should be considered in cases with no apparent hyperprolactinaemic symptoms. Polyethylene glycol precipitation is the method of choice to confirm macroprolactinaemia, which in itself has no clinical significance, although it should be remembered that genuine pituitary pathology may co-exist in nearly 5% of such cases.

44 James Gibney, 2005

45 Hiperprolaktinemi PRL ölçümleri stressiz bir zamanda, sabah aç olarak yapılmalıdır Testten hemen önce: –Göğüs muayenesi –Koitus –Pelvik muayene –Egzersiz yapılmamalı Çok yüksek PRL düzeyleri immunoassay de yanlış negatif sonuç verebileceği için (hook effect – kanca etkisi) makroadenom takiplerinde 1/100 dilüsyon ile PRL ikinci kez tekrar edilmelidir

46 Common causes of primary amenorrhea Bachmann G,1982; Reindollar RH, 1986

47 Suggested flow diagram aiding in the evaluation of women with amenorrhea. The Practice Committee of the American Society for Reproductive Medicine 2008 The initial useful laboratory tests are FSH, TSH, and prolactin.

48 Common causes of secondary amenorrhea Reindollar RM, 1981

49 STRAW reproductive aging system Length decreases -2 days

50 Physiology: perimenopause Variable hormone levels Estrogen and progesterone levels fluctuate erratically Very high serum estrogen levels may result Slight decline in testosterone with age Santoro et al. J Clin Endocrinol Metab Burger et al. J Clin Endocrinol Metab 2000.

51 Hyperestrogenism in perimenopause Santoro et al. J Clin Endocrinol Metab 1996.

52 The Menopausal Transition A Committee Opinion Revised January 2008 In perimenopausal women, estradiol production fluctuates with FSH levels and can reach higher concentrations than those observed in young women under age. Estradiol levels generally do not decrease significantly until late in the MT Despite continuing regular cyclic menstruation, progesterone levels during the early MT are lower than in women of mid-reproductive age and vary inversely with body mass index Testosterone levels do not vary appreciably during the MT a decrease in secretion of inhibin A and inhibin B, and a corresponding increase in activin production may favor increased FSH secretion in the absence of any decrease (and perhaps an increase) in estradiol production. Diagnosis of the MT is based on clinical signs and symptoms. Although hormonal changes occur during the MT, hormone measurements are not useful for predicting the stage of MT or the final menstrual period. Practice Committee of the American Society for Reproductive Medicine

"Jinekolojik Endokrinolojide Hormonal Değerlendirme Dr.Engin Oral İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi Kadın Hastalıkları ve Doğum ABD Reprodüktif." indir ppt

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