Poros HPO dalam regulasi sistem reproduksi wanita

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

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