Download Current recommendations for the diagnostic evaluation of patients

Jinekolojik Endokrinolojide
Hormonal Değerlendirme
Dr.Engin Oral
İstanbul Üniversitesi
Cerrahpaşa Tıp Fakültesi
Kadın Hastalıkları ve Doğum ABD
Reprodüktif Endokrinoloji BilimDalı
Jinekolojik Endokrinolojide
Patolojiler
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Over rezervi
PKOS
Hiperandrojenemi
Hiperprolaktinemi
Amenore
Menopoz
Sonuç
Gonadotropinler
Laboratuar tetkikleri
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
Cut-off Values for the Most Commonly Used
Ovarian Reserve Tests
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
Over rezervini belirleme endikasyonları
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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
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.
The Hypothalamic–Pituitary–Ovarian
Axis and the Role of Insulin.
David A. Ehrmann, 2005
Criteria for the diagnosis of polycystic ovary
syndrome (PCOS)
• 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).
Klinik bulgular (%)
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Menstrüel düzensizlik
İnfertilite
Hirsutizm
Akne
Obezite
LH Artışı
T artışı
Hiperinsülinemi
– Obez
– Zayıf
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75
66
35
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80
30-40
Homburg R, 2003
ANDROGEN EXCESS SOCIETY, 2006
Endocrine and metabolic differences among phenotypic
expressions of polycystic ovary syndrome according
to the 2003 Rotterdam consensus criteria
Robert P. Kauffman, 2008
ANDROGEN EXCESS SOCIETY, 2006
Suggested diagnostic evaluation for
PCOS
Richard S. Legro, 2007
Ovarian hyperthecosis
ANDROJENLER
• Testosteron
%50 periferik dönüşüm
%50 over ve adrenal
%80 SHBG, %19 albumine
%1 serbest (kadınlarda)
• DHT
En güçlü
T,AD DHT
Androstenodiol glukuronid
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
SHBG
artıranlar
azaltanlar
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Obesite
Androjen fazlalığı
Kortikosteroid
Hipotiroidism
Cushing sendromu
Akromegali
Karaciğer hast.
Progestogen
Hiperinsülinemi
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Östrojen fazlalığı
Oral kontraseptifler
Gebelik
Hipertiroidism
ANDROJEN FAZLALIĞINDA CİLT
BULGULARI
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Hirsutizm
Akne
Androjenik alopesi
AN
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
Factors that are known to alter serum
testosterone concentrations
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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
Causes of hirsutism.
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• Polycystic ovary syndrome
• Idiopathic
• Late-onset congenital adrenal hyperplasia
• Cushing's syndrome
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° Cushing's disease (ACTH-secreting pituitary tumour)
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° 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)
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• Androgen-secreting tumours of the ovary
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° Sex-cord stromal cell tumours
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° Adrenal-like tumours of the ovary
• Androgen-secreting tumours of the adrenal
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° Adenomas
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° Adenocarcinomas
• Iatrogenic
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° Testosterone
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° Danazol
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° Glucocorticoids
Androgen Excess in Women:
Experience with Over 1000
Consecutive Patients
R. AZZIZ, 2004
Akantozis Nigricans
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.
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
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
Serum 17-OHP seviyesi (0.1 –0.8 ng/ml )
2-8 ng/ml
< 2 ng/ml
> 8 ng/ml
LOKAH
(-)
LOKAH
(+)
ACTH Stimülasyon
Testi
ACTH Stimülasyon
Testi Gereksiz
< 10 ng/ml
Normal
> 10 ng/ml
Heterozigot
LOKAH
LOKAH
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
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
Iatrogenic Causes
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Exogenous androgens
Androgenic steroids
Danazol
Glucocorticoids
“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
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 measurement
of serum testosterone, prolactin, and DHEA-S, followed by
additional testing when indicated
Martin KA, 2008
Differential diagnosis
ANDROGEN EXCESS SOCIETY, 2006
Prolaktin
• Prolaktin hipotalamustan dopaminin
inhibitör kontrolü altında
• Otonom hipersekresyon, pulsatil GnRH
sekresyonunu bozar.
• Hiperprolaktinemi
– Fizyolojik (< 50 ng/mL): gebelik, laktasyon,
uyku, yoğun egzersiz, stres, cinsellik, yemek
Causes of hyperprolactinaemia
PRL hormon biosentezi
• Orijinal matür PRL RNA sı 227 AA den oluşan sekansı kodlar
• Üretim sonrası molekül şu etkilere maruz kalır :
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Degradasyon
Polimerizasyon
Glikozilasyon (PRL etkinliğinin devamında gereklidir)
Fosforilasyon
• Bu etkiler sonucu oluşan moleküllerin bioaktiviteleri farklıdır
• Polimerizasyon oranında bioaktivite düşer (MakroPRL)
– Monomerik
– Dimerik
– Polimerik
% 80-90
% 8-20
% 1-5
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.
James Gibney, 2005
Hiperprolaktinemi
• PRL ölçümleri stressiz bir zamanda, sabah aç olarak
yapılmalıdır
• Testten hemen önce:
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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
Common causes of primary amenorrhea
Bachmann G,1982; Reindollar RH, 1986
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
Common causes of secondary amenorrhea
Reindollar RM, 1981
STRAW reproductive aging
system
Length
decreases
-2 days
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.
Hyperestrogenism in perimenopause
Santoro et al. J Clin Endocrinol Metab 1996.
The Menopausal Transition
A Committee Opinion
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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