Poros HPO dalam regulasisistem reproduksi wanita

Andon Hestiantoro

Divisi Imunoendokrinologi ReproduksiDepartemen Obstetri dan Ginekologi

Fakultas Kedokteran Universitas IndonesiaRS. 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 point-to-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.

Mechanisms of Intercellular Communication

Endo

crin

eN

ervo

us

Hypothalamus and Pituitary Gland

NeuronGnRH

Eminensiamediana

Kelenjar hipofisis anterior

Basofilik

Asidofilik

Sinusoid

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

PyroGlu

His Trp Ser Tyr Gly Leu Arg Pro Gly CONH2

Endopeptidase Carboxyamidepeptidase

PyroGlu

His Trp Ser Tyr Leu Arg Pro NH-Ethylamide

D-his D-ser

D-trpD-leu

Gonadotropin releasing hormone (GnRH alamiah)

GnRH agonist

GnRH agonist

GnRhalamiah

FSH

FSH

Hari

FSH

GnRHagonist

GnRHantagonist

GnRhalamiah

GnRhalamiah

Jam

Hari

(Pulsatil)

(Kontinyu)

ReseptorGnRh

GnRHagonist

(Pulsatil)

FSH

Hari7

“Flare-Up”

“Down regulated”

GnRHagonist

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 pulsatilKadar tertinggi di pagi hariLebih rendah pada siang hari

• Sekresi fisiologik PRL↑– Saat nyeri– Rangsangan puting susu– Kehamilan– Pemeriksaan pelvik– Olah Raga– Tidur

TIDA: Tuberoinfundibular Dopamin

PHDA: Periventricular hypophysialDopamin

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 40-50%– “Non-functioning adenoma” 30%– Sel adenoma Gonadotroph 10-15%– Akromegali 10%– Cushing's disease– Adenoma mengeluarkan TSH

Diagnosis adenoma hipofisis

• MRI : untuk jaringan lunak

• CT scan : untuk jaringan tulang (dekstruksisela tursika)

Macro

Micro

Prolaktinoma

• Grade 1 : mikroadenoma (<10 mm)

• Grade 2 : makroadenoma

• Grade 3 : kerusakan tulangterlokalisasi

• Grade 4 : kerusakan tulang meluas

Gejala KlinikHiperprolaktinemia

• 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 lapangpandang

• Ekstensi lateral extension (ke dalam sinus cavernous)– Penekanan syaraf kranial 3, 4, 5, 6

• Ekstensi ke dalam lobus temporalis : kejang-k j

Dampak negatif hiperprolaktinemia

• Poros hipotalamus-hipofisis-ovariumpada 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

• Mikroadenoma1-5% akan menjadi makroadenoma

• Makroadenoma25% bertambah besardan timbul gejala 15-35%

Melatonin dan GnRH

Retina SCN PVN Spinal Cord

Superior Cervical GanglionPostganglionic Simpatic Nerve

NESerotonin

Melatonin

GnRH

Pineal membrane

-

Gelap

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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