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Jinekolojik Endokrinolojide Hormonal Değerlendirme

Jinekolojik Endokrinolojide Hormonal Değerlendirme. Dr.Engin Oral İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi Kadın Hastalıkları ve Doğum ABD Reprodüktif Endokrinoloji BilimDalı. Jinekolojik Endokrinolojide Patolojiler. Over rezervi PKOS Hiperandrojenemi Hiperprolaktinemi Amenore

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Jinekolojik Endokrinolojide Hormonal Değerlendirme

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  1. Jinekolojik Endokrinolojide Hormonal Değerlendirme Dr.Engin Oralİstanbul Üniversitesi Cerrahpaşa Tıp FakültesiKadın Hastalıkları ve Doğum ABD Reprodüktif Endokrinoloji BilimDalı

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

  3. Gonadotropinler

  4. 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

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

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

  7. 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

  8. POLYCYSTIC OVARY SYNDROME (PCOS) • Sixty-five to 85% of all women with androgen excess arediagnosed as having PCOS • The findings in PCOS are variable, with 40% to60% of patients obese, 60% to 90% hirsute, 50% to 90%oligoamenorrheic, and 55% to 75% infertile.

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

  10. Criteria for the diagnosis of polycystic ovary syndrome (PCOS)

  11. Oligo- or anovulation: Ovulation occurs less than once every 35 days. • Hyperandrogenism: Clinical signs include hirsutism, acne, alopecia (male-patternbalding) and frank virilization. Biochemical indicators include raised concentrationsof total testosterone and androstendione, and an elevated free androgen index thatentails the measurement of total testosterone and sex hormone binding globulin(SHBG). However, the measurement of these biochemical markers for hyperandrogenismhas proved markedly inconsistent due to problems with various assays. • Polycystic ovaries: The presence of 12 or more follicles in either ovary measuring2–9 mm in diameter and/or increased ovarian volume(>10 mL).

  12. Klinik bulgular (%) • Menstrüel düzensizlik 66 • İnfertilite 75 • Hirsutizm 66 • Akne 35 • Obezite 38 • LH Artışı 40 • T artışı 30 • Hiperinsülinemi • Obez 80 • Zayıf 30-40 Homburg R, 2003

  13. ANDROGEN EXCESS SOCIETY, 2006

  14. Endocrine and metabolic differences among phenotypicexpressions of polycystic ovary syndrome accordingto the 2003 Rotterdam consensus criteria Robert P. Kauffman,2008

  15. ANDROGEN EXCESS SOCIETY, 2006

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

  17. Ovarian hyperthecosis

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

  19. 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

  20. azaltanlar artıranlar S H B G • Obesite • Androjen fazlalığı • Kortikosteroid • Hipotiroidism • Cushing sendromu • Akromegali • Karaciğer hast. • Progestogen • Hiperinsülinemi • Östrojen fazlalığı • Oral kontraseptifler • Gebelik • Hipertiroidism

  21. ANDROJEN FAZLALIĞINDA CİLT BULGULARI • Hirsutizm • Akne • Androjenik alopesi • AN

  22. Which androgen to measure? • 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 ESHRE/ASRM Consensus 2003

  23. 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 shows30% 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

  24. 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

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

  26. Akantozis Nigricans

  27. Hyperthecosis • previously considered hyperthecosis tobe a variant of PCOS, it should be noted that the termhyperthecosis simply refers to the histopathologic finding ofislands of hyperplastic theca cells located between collectionsof small atretic follicles (i.e., “cysts”). • Most women with hyperthecosis demonstrate highcirculating androgen levels, and consequently lower circulatingLH and FSH levels (4–8 mIU/mL) • Androgen-secretingtumor.

  28. Non-Classic Adrenal Hyperplasia (NCAH) • 1% to 5% of hyperandrogenicwomen 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

  29. ACTH Stimülasyon Testi • AD 3-7 günleri • Sabah saat 08.00-10.00 • 0.25 mg sentetik ACTH (Cortrosyn) IV * IM yapılmamalı • Başlangıçta ve 1 saat sonra kan

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

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

  32. Androgenic Tumors • ovary or adrenal • onset of hyperandrogenism is sudden,and when progression is rapid, or when frank virilization ispresent • Virilizing ovarian tumors, including Sertoli-Leydigcell and lipoid cell tumors, generally exhibit low malignancypotential • Inyoung women the possibility of an androgen-secretingtumour should be considered with the following: • serum testosteronevaluesabove 150 ng/dl ; • serum-free testosteronevalues above 2 ng/dl ; • serumdehydroepiandrosteronesulphatevaluesabove700 µg per dl

  33. Iatrogenic Causes • Exogenousandrogens • Androgenic steroids • Danazol • Glucocorticoids

  34. “Idiopathic” Hirsutism • Approximately 15% to 30% of hirsute women do not haveovulatory abnormalities and usually have normal levels ofcirculating androgens • In many of these patients,skin 5-reductase activity is excessive, leading tohigher skin concentrations of the active androgen dihydrotestosterone • It is important to note that approximately40% of hirsute women claiming to have “regularmenstrual cycles” are actually oligo-ovulatory when evaluatedmore carefully

  35. 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 inaccurate • Another approach that many clinicians use, is initial measurementof serum testosterone, prolactin, and DHEA-S, followed by additional testing when indicated Martin KA, 2008

  36. Differential diagnosis ANDROGEN EXCESS SOCIETY, 2006

  37. Prolaktin Prolaktinhipotalamustandopaminin inhibitör kontrolü altında Otonom hipersekresyon, pulsatilGnRHsekresyonunu bozar. Hiperprolaktinemi Fizyolojik (< 50 ng/mL): gebelik, laktasyon, uyku, yoğun egzersiz, stres, cinsellik, yemek

  38. Causes of hyperprolactinaemia

  39. 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 % 80-90 • Dimerik % 8-20 • Polimerik % 1-5

  40. Macroprolactin • PRL may form immune complexes, generally with an immunoglobulin G antibody, toproduce a biologically inactive form called ‘macroprolactin’, which has a molecularmass of more than 150 kDa. This is registered by most PRL immunoassays and henceserum PRL levels are reported to be high. Since misdiagnosis of hyperprolactinaemiadue to the presence of macroprolactinmay lead to patient mismanagement, this possibilityshould 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 thatgenuine pituitary pathology may co-exist in nearly 5% of such cases.

  41. James Gibney,2005

  42. 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

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

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

  45. Common causes of secondary amenorrhea Reindollar RM, 1981

  46. STRAW reproductive aging system Length decreases -2 days

  47. 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 2000. Burger et al. J Clin Endocrinol Metab 2000.

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