Poros HPO dalam regulasi sistem reproduksi wanita Andon Hestiantoro Divisi Imunoendokrinologi Reproduksi Departemen Obstetri dan Ginekologi Fakultas Kedokteran Universitas Indonesia RS. Dr. Cipto Mangunkusumo Jakarta
Endocrine vs. Nervous System • Major communication systems in the body • Both are crucial to coordinated functions of highly differentiated cells, tissues and organs • Unlike the nervous system, the endocrine system is anatomically discontinuous.
Nervous system The nervous system exerts pointto-point control through nerves, similar to sending messages by conventional telephone. Nervous control is electrical in nature and fast.
Hormones travel via the bloodstream to target cells The endocrine system broadcasts its hormonal messages to essentially all cells by secretion into blood and extracellular fluid. Like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.
Nervous
Endocrine
Mechanisms of Intercellular Communication
Hypothalamus and Pituitary Gland
Neuron GnRH
Eminensia mediana
Kelenjar hipofisis anterior Sinusoid Basofilik
Asidofilik
SRIF = somatotropin release inhibiting factor = somatostatin
Dudas B and Merchenthaler I. Journal of Neuroendocrinology 2006;18:79–95
Dudas B and Merchenthaler I. Journal of Neuroendocrinology 2006;18:79–95
Dudas B and Merchenthaler I. Journal of Neuroendocrinology 2006;18:79–95
GnRH • Dekapeptida • BM=1200 kDa • t1/2=2-10 menit
Timing of GnRH pulses • • • • •
LH pulse mean frequency Early follicular phase : 90 minutes Late follicular phase : 60-70 minutes Early luteal phase : 100 minutes Late luteal phase : 200 minutes
Gonadotropin releasing hormone (GnRH alamiah) Pyro Glu
His
Trp
Ser
Tyr
Gly
Leu
Endopeptidase
GnRH agonist Pyro Glu
His
Trp
D-leu
Ser
Tyr
Gly
CONH2
Carboxyamide peptidase
D-trp
Leu D-his
Pro
Arg
D-ser
Arg
Pro
NH-Ethylamide
GnRH agonist
FSH GnRh alamiah
GnRH agonist
(Pulsatil)
(Pulsatil)
Reseptor GnRh
Jam
FSH GnRh alamiah
GnRH agonist
(Kontinyu)
Hari
FSH GnRh alamiah
GnRH antagonist
Hari
“Flare-Up”
FSH
GnRH agonist
“Down regulated”
7
Hari
Feedback Control of Hormone Production Feedback loops are used extensively to regulate secretion of hormones in the hypothalamic-pituitary axis. An important example of a negative feedback loop is seen in control of estrogen ovarian secretion
(GnRH)
(FSH/LH)
Ovarium (Estrogen)
Perkembangan poros HPO
Marshall JC, et al. Recent Prog Horm Res 1991;47:155-189
PROLAKTIN • Dibawah regulasi hypothalamus (“tonic inhibition”) • 2 faktor hypothalamus – PIF (PRL-inhibiting factor) Dopamine – PRF (PRL-releasing factor) TRH, VIP (vasoactive intestinal polypeptide)
Prolaktin = PRL •
A “stress hormone”
•
Sekresi secara pulsatil Kadar tertinggi di pagi hari Lebih rendah pada siang hari
•
Sekresi fisiologik PRL↑
– – – – – –
Saat nyeri Rangsangan puting susu Kehamilan Pemeriksaan pelvik Olah Raga Tidur
TIDA: Tuberoinfundibular Dopamin PHDA: Periventricular hypophysial Dopamin
Hiperprolaktinemia (>25 ng/ml)?? • Patogenesis (“basic mechanism”) – Defisiensi dopamin di hipotalamus
• • • •
Tumor hipotalamus “AV malformation” Proses inflamasi Obat tertentu:
– methyldopa (Aldomet), reserpine – Defek mekanisme transport dopamin
• Tumor hipofisis atau tumor tangkai hipofisis • Trauma kepala • Pemotongan tangkai hipofisis
Hiperprolaktinemia • Patogenesis (“basic mechanism”) – Lactotroph insensitif terhadap dopamin • “dopamine receptor blocking agents” – phenothiazine (chlorpromazine) – butyrophenones (haloperidol) – benzamide: metoclopamide, sulpiride, domperidone
– Stimulasi terhadap “lactotrophs” • • • • •
Hipotiroidism TRH Estrogen Rangsangan/Trauma dada: herpes zoster, surgery Tumor menghasilkan PRL
Tumor Hipofisis • 10% dari brain tumor – – – – – –
Prolaktinoma “Non-functioning adenoma” Sel adenoma Gonadotroph Akromegali Cushing's disease Adenoma mengeluarkan TSH
40-50% 30% 10-15% 10%
Diagnosis adenoma hipofisis • MRI : untuk jaringan lunak • CT scan : untuk jaringan tulang (dekstruksi sela tursika)
Macro Micro
Prolaktinoma • Grade 1 : mikroadenoma (<10 mm) • Grade 2 : makroadenoma • Grade 3 : kerusakan tulang terlokalisasi • Grade 4 : kerusakan tulang meluas
Gejala Klinik Hiperprolaktinemia •
Menars yang terlambat
•
Gangguan siklus haid (60-90%)
– Amenore – Oligomenore – Infertilitas •
Galactorrhea (30-80%)
•
Defisiensi Estrogen
– Libido menurun – Vagina kering – Dispareunia
Dampak negatif massa tumor • Ekstensi suprasellar : bitemporal hemianopia • Ekstensi posterior : homonimus defek lapang pandang • Ekstensi lateral extension (ke dalam sinus cavernous) – Penekanan syaraf kranial 3, 4, 5, 6
• Ekstensi ke dalam lobus temporalis : kejangk j
Dampak negatif hiperprolaktinemia • Poros hipotalamus-hipofisis-ovarium pada 3 lokasi – Tingkat hipotalamus • Mempengaruhi tonus dan sekresi siklik GnRH (LHRH)
– Tingkat hipofisis • desensitisasi respons gonadotropin terhadap GnRH
– Tingkat ovarium • Gagal produksi progesteron (an-ovulasi) (oleh sel granulosa ovarium)
Kehamilan dengan prolaktinoma • Mikroadenoma 1-5% akan menjadi makroadenoma • Makroadenoma 25% bertambah besar dan timbul gejala 15-35%
Gelap
Melatonin dan GnRH
Retina
SCN
PVN
Spinal Cord
Postganglionic Simpatic Nerve
NE
Superior Cervical Ganglion
Serotonin GnRH Melatonin Pineal membrane
-
The Blood-Brain Barrier • Endothelial cells in blood vessels in the brain fit closely together • Only some molecules can pass through • Protects the brain from foreign molecules and hormones and neurotransmitters from other parts of the body • Can be damaged by infections, head trauma, high blood pressure, etc.
Aromatase inhibitor and ovulation induction
Aromatase Inhibitor
Klomifen Sitrat
