LO & WO WEEK 1 ENDOCRINOLOGY AND METABOLISM

LUKY ADLINO
1. EMBRYOLOGI OF HYPOTHALAMUS, PITUITARY, DIENCEPHALON

- The central nervous system (CNS) appears at the beginning of the third week as a slipper-
shaped plate of thickened ectoderm, the neural plate. Its lateral edges soon elevate to
form the neural folds.
- With further development, the neural folds continue to elevate, approach each other in the
midline, and finally fuse, forming the neural tube. Fusion begins in cervical region and
proceeds in cephalic and caudal direction.
- Saat fusion sudah initiated, the open ends of neural tube form the cranial and caudal
neuropores (bagian ini yang masih berhubungan dengan amniotic cavity. Closure of the
cranial neuropore occurs at the 25th day, while closure of caudal neuropore occurs
approximately 3 days later.
- The cephalic end membentuk three dilations, the primary brain vesicles :
a. The prosencephalon or forebrain
b. The mesencephalon or midbrain
c. The rhombencephalon or hindbrain
- By five weeks of development, the primary brain vesicles uda jadi five secondary
vesicles. The prosencephalon forms the telencephalon and diencephalon, the
mesencephalon tetap, the rhombencephalon menjadi metencephalon and
myelencephalon. Each of the secondary vesicles will contribute a different part of the
brain.
- The main derivatives of these vesicles :
a. Telencephalon  cerebral hemisphere
b. Diencephalon  optic vesicle, thalamus, hypothalamus, pituitary
c. Mesencephalon  anterior and posterior coliculi
d. Metencephalon cerebellum, pons
e. Myelencephalon medulla oblongata
- The diencephalon, develops from the median portion of the prosencephalon, is thought to
consist of a roof plate and two alar plates. The roof plate of the diencephalon consists of a
single layer of ependymal cells covered by vascular mesenchyme. Together this layer
gives rise to the choroid plexus of the third ventricle. The most caudal part of the roof
plate develops into pineal body or epiphysis.
- The alar plates form the lateral wall of the diencephalon. Ada groove (hypothalamic
sulcus) divides the plate into a dorsal and a ventral region, the thalamus and
hypothalamus, respectively.
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- Proliferate  thalamus memenuhi lumen dari diencephalon, this expansion is so great
that thalamic regions dari kanan dan kiri fuse in the midline, forming the massa
intermedia, or interthalamic connexus.
- The hypothalamus forming the lower portion of the alar plate, differentiates into a
number of nuclear areas that regulates visceral functions including sleep, digestion, body
temperature, and emotional behavior. Termasuk terbentuk juga mammillary body
sepasang.
- The hypophysis or pituitary gland develops from two completely different parts : (1) an
ectodermal outpocketing of the stomodeum (primitive oral cavity) immediately in front
of the oropharyngeal membrane, known as Rathke’s pouch and (2) a downward extension
of the diencephalon, the infundibulum.

- Saat embryo 3 weeks, Rathke’s pouch grows dorsally towards the infundibulum. By the
end of second month, it loses its connection dengan oral cavity tapi dekat dengan
infundibulum.
- During further development cells in the anterior wall of Rathke’s pouch increase rapidly
in number and form the anterior lobe of the hypophysis (or adenohypophysis). A small
extension of this lobe, the pars tuberalis, grows along the stalk of the infundibulum and
eventually surrounds it. The posterior wall of Rathke’s pouch develops into the pars
intermedia (di human little significance).
- The infundibulum gives rise to the stalk and the pars nervosa, or posterior lobe of the
hypophysis (or neurohypophysis). It is composed of neuroglial cells. In addition, it
contains a number of nerve fibers from the hypothalamic area.

Clinical relevance
Hypophyseal defects  occasionally, small portion of Rathke’s pouch persists in the
roof of the pharynx as a pharyngeal hypophysis.
Craniopharyngiomas arise from the remnants of Rathke’spouch, they may form
within the sellaturcica or along the stalk of the pituitary. They may cause
hydrocephalus and pituitary dysfunction (e.g. Diabetes insipidus, growth failure).
LO & WO WEEK 1 ENDOCRINOLOGY AND METABOLISM
LUKY ADLINO
2. ANATOMY OF HYPOTHALAMUS, PITUITARY

- Landmarks that are visible on the ventral and medial surfaces of the brain define the
boundaries of the hypothalamus. The rostral boundary visible on the ventral surface of
the brain is formed by the optic chiasm while the mammillary bodies define the posterior
boundary. Between these structures the oval prominence from the floor of the third
ventricle is the tuber cinereum dan muncul dari tonjolan tersebut median eminence which
then tapers into the infundibular stalk  together form the inferior boundary of the
hypothalamus.
- On the medial (ventricular) surface of the brain other structure yang bisa terlihat
membatasi rostral boundary adalah lamina terminalis dan anterior commisure. Also
visible melalui medial surface ini adalah hypothalamic sulcus (perpanjangan dari sulcus
limitans) yang menjadi pembatas superior dari hypothalamus.
- Finally, the internal capsule that is only visible on coronal or horizontal sections of the
brain forms the lateral boundary.
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- Hypothalamus terdiri dari 3 longitudinally oriented cell columns, or zones, that run the
entire rostrocaudal length of the hypothalamus. These zones dibagi menjadi 4 nuclear
groups, or regions, based on rostrocaudal position.
- Zones. Immediately bordering the third ventricle is a thin layer of cells that comprise the
periventricular zone. This zone contains few distinct nuclei, but two that are very
prominent are the arcuate nucleus and the paraventricular nucleus, which are involved in
neuroendocrine and autonomic regulation. Immediately adjacent dari dari periventricular
zone adalah medial zone, terdiri dari beberapa nuclei yang berbeda fungsinya
berdasarkan lokasinya. Finally, the lateral zone, has few nuclei or clear landmarks, but
contains important fiber pathways such as the median forebrain bundle. Lateral zone is
involved in the regulation of the autonomic nervous system.

Hypothalamic zones

- Regions. Masing-masing dari zones itu dibagi menjadi regions based on rostrocaudal
landmarks. The anterior region runs from lamina terminalis to the caudal aspect of the
optic chiasm. Next is the tuberal region, batasnya adalah anterior region sampe ke tuber
cinereum. Finally, the posterior region, batasnya adalah tuberal region sampe ke
mammillary bodies.

Hypothalamic regions

- Nuclei. There are eleven major nuclei in the hypothalamus. Masing-masing punya letak
tersendiri :
a. Paraventricular nucleus
b. Arcuate nucleus
c. Supraoptic nucleus
d. Preoptic nucleus
e. Suprachiasmatic nucleus
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f. Dorsomedial nucleus
g. Ventromedial nucleus
h. Posterior nucleus
i. Mammillary nucleus
j. Lateral tuberal complex

- Blood supply of the hypothalamus  the arterial supply is derived from the perforating
vessels which spring from the various parts of the circle of Willis and pass through the
anterior and posterior perforated substances. Selain itu ada juga two vessels yaitu
superior hypophysial arteries (arise from internal carotid artery) which form an arterial
ring around the tuber cinereum. Branches from this ring supply the optic chiasma and
adjacent parts of the hypothalamus.
- Afferent and efferent neural pathways of the hypothalamus  major afferent tracts tend
to lie in the lateral parts of the hypothalamus while the efferent tracts lie nearer to the
midline, large numbers of both afferent and efferent non-myelinated nerve fibers connect
the hypothalamic nerve cells with the various parts of the cerebral hemispheres, brain
stem, and elsewhere and form a sort of capsule of nerve fibers around the hypothalamus.
A massive tract of myelinated fibers, the fornix, bring impulses from each temporal lobe
to the ipsilateral mammillary body. One major efferent tract, more medially situated, is
the mamillothalamic tract. It is composed of myelinated fibers and connects each
mammillary body with the ipsilateral anterior nucleus of the thalamus, from which
impulses are relayed to the frontal lobes. Another major efferent tract, composed almost
entirely of non-myelinated nerve fibers, is the hypothalamo-neurohypophysial tract
formed by the axons of neurosecretory nerve cells in the supraoptic and paraventricular
nuclei which carry neuro-hormones to the neural lobe of the pituitary (neurohypophysis).
This important neuroendocrine tract carries vasopressin and oxytocin.
- Pituitary gland (hypophysis) is an endocrine gland that lies in a bony cavity in the skull
 cavity itu lies di sphenoid bone and called sella turcica. The gland is attached by a
stalk (infundibular stalk) to the base of the brain and is contained in a capsule from the
duramater.
- The gland is composed of two main lobes, anterior (adenohypophysis) and posterior
(neurohypophysis). Between the two lobes ada intermediate lobe (pars intermedia). The
shape itu kaya reddish-grey bean shaped, 500-900 mg (female biasanya heavier). With
important anatomical relation itu dengan optic chiasm.
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LUKY ADLINO
- Blood supply  the superior hypophysial arteries send blood yang masuk ke primary
capillary plexus at the median eminence. Blood from this plexus flows down long portal
vessels (portal veins) to a secondary capillary plexus in the adenohypophysis. The portal
vessels run down the pituitary stalk (infundibulum) to arrive at the pituitary gland. This
system is known as the hypothalamo-hypophysial portal system. Posterior pituitary
also receives blood supply from the inferior hypophysial artery.

- Pineal gland is a small endocrine gland located within the brain which main function is
secretion of melatonin which then regulates the circadian rhythm of the body.
- Pineal gland is a small glandular body approx. 6 mm long, shaped like pinecone, consists
of two different cell type (1) Pinealocytes (hormone secreting cells) and (2) glial cells
(supporting cells). In middle age, the gland commonly become calcified and can be
subsequently identified on radiographs and CT scans of the head.
- Vasculature  the main supply are the posterior choroidal arteries (set of 10 branches
arise from the posterior cerebral artery) while the venous drainage is via the internal
cerebral veins.

Clinical relevance : Pineal Gland Tumor

- Are a diverse group of neoplasms, most common is a germ cell tumor, which arise
from the residual embryonic tissue in the gland.
- Present with the classical symptoms of Space Occupying Lesion – headache,
nausea, and vomiting.
- The tumor can also cause Parinaud syndrome (inability to move the eyes upward,
due to compression of superior colliculi
- In addition kalau obstruksi di cerebral aqueduct  hydrocephalus
LO & WO WEEK 1 ENDOCRINOLOGY AND METABOLISM
LUKY ADLINO
3. PITUITARY HORMONES AND THEIR CONTROL BY THE HYPOTHALAMUS

- Six major peptide hormones plus beberapa yang kurang penting are secreted by the
anterior pituitary, and two important peptide hormones are secreted by the posterior
pituitary. The hormones of anterior pituitary play major roles in the control of metabolic
functions throughout the body

- They are :
1) Growth hormone promotes growth of the entire body by affecting protein formation,
cell multiplication, and cell differentiation.
2) Adrenocorticotropin (corticotropin) controls the secretion of some of the
adrenocortical hormones, which affect metabolism of glucose, proteins, and fats.
3) Thyroid-stimulating hormone (thyrotropin) controls the secretion rate of thyroxine
and triiodothyronine by the thyroid gland, and these hormones control the rates of
most intracellular chemical reactions in the body.
4) Prolactin promotes mammary gland development and milk production.
5) Two separate gonadotropic hormones, Follicle-stimulating hormone and Luteinizing
hormone, control the growth of the ovaries and testes, as well as their hormonal and
reproductive activity.
- Two from the posterior are :
1) Antidiuretic hormone (vasopressin) controls the rate of water excretion into the urine,
thus helping to control the concentration of water in the body fluids.
2) Oxytocin helps express milk from the glands of the breast to the nipples during
suckling and helps in the delivery of the baby at the end of gestation.
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- The anterior pituitary gland contains several different cell types that synthesize and
secrete hormones. Biasanya ada satu jenis tipe sel for each major hormone. Dengan cara
special staining pake antibody high affinity buat lacak sel nya  sudah diidentifikasi 5
jenis sel type.

- 30 sampe 40 persen dari anterior pituitary sel adalah somatotropes, 20 persen itu
corticotrops, sisa nya masing-masing cuma 3-5 persen. Walaupun gitu tetap sekresi
hormone yang kuat untuk metabolic function of the body.
- Somatotropes stain strongly with acid dyes and are therefore called acidophils. Thus
pituitary tumors yang secrete lots of growth hormones disebut acidophilic tumors.
- Posterior pituitary hormones are synthesized by cell bodies in the hypothalamus. Yang
sekresi bukan dari pituitary gland, but are large neurons called magnocellular neurons,
located in the supraoptic and paraventricular nuclei of the hypothalamus. The hormones
are then transported.
- Hypothalamus controls pituitary secretion. Almost all di kontrol sama hypothalamus
either hormonal or nervous signals. Terbukti pas pituitary dipindah ke lain lokasi semua
produksi hormone nya menurun kecuali prolactin.
- Sekresi dari posterior pituitary is controlled by nerve signals that originate in the
hypothalamus and terminate in the posterior pituitary. In contrast, sekresi dari anterior
pituitary diatur dengan hormones called hypothalamic releasing and hypothalamic
inhibitory hormones (or factors) yang dialirkan melalui sistem hypothalamic-hypophysial
portal vessels.
- The hypothalamus receives signals from many sources in the nervous system. Misalnya
pain, depressing or exciting thought, smells, concentration of nutrients; electrolytes;
water; and various hormones. Makanya di sebut sebagai collecting center for information
 dipake infonya buat secrete lots of hormones dari pituitary.
- Median eminence itu adalah lowermost portion of the hypothalamus. Blood vessels
banyak yang penetrate dan kemudian keluarin cabang-cabang yang akhirnya bentuk
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primary capillaries plexus. Hypothalamic releasing and inhibitory hormones are secreted
into the median eminence. Awalnya releasing and inhibitory hormones itu dihasilkan
sama special neurons di hypothalamus, these neurons send their nerve fibers to the
median eminence and tuber cinereum (an extension of hypothalamic tissue into the
pituitary stalk). Setelah sampe di median eminence itu dia lepasin hormones2 itu ke tissue
fluids  hormones dengan cepat diserap into the hypothalamic-hypophysial system and
carried directly to the sinuses of anterior pituitary gland.

- Fungsi releasing and inhibitory hormones  mengatur sekresi dari anterior pituitary
hormones. Biasanya releasing hormones yang lebih dominan and important kecuali untuk
prolactin.

- Major hypothalamic releasing and inhibitory hormones are :

1) Thyrotropin-releasing hormone (TRH), which causes release of thyroid-stimulating
hormone
2) Corticotropin-releasing hormone (CRH), which causes release of adrenocorticotropin
3) Growth hormone-releasing hormone (GHRH), which causes release of growth
hormone, and Growth hormone-inhibitory hormone (GHIH) also called somatostatin,
which inhibits release of growth hormone
4) Gonadotropin-releasing hormone (GnRH), which causes release of the two
gonadotropic hormones, LH and FSH
5) Prolactin inhibitory hormone (PIH), which causes inhibition of prolactin secretion
6) Others seperti prolactin secretion stimulation, or other pasangan inhibitory lainnya.
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LUKY ADLINO
4. VISUAL FIELD TEST (CONFRONTATION TEST)

- Without moving our eyes, we see not only what is straight ahead, but some of what is
above, below, and off to either side. Most people are familiar with this as "peripheral
vision". The entire area that we see is called the visual field.
- Penglihatan (vision) itu terbaik pada lapang pandang tengah (middle of the visual field)
itu sebabnya kita turn our eyes toward objects that we want to see better. Semakin object
nya jauh dari lapang pandang tengah, maka semakin less clearly kita melihatnya.
- Visual field test measures two things :
1) How far up, down, left, and right the eye sees without moving
2) How sensitive the vision is in different parts of the visual field
- Kenapa perlu visual field test? To help doctors find early signs of disease misalnya
glaucoma yang damage vision gradually, some people do not notice any problem tapi
kalau di tes maka hasilnya akan terlihat bahwa peripheral vision is being loss.
- Tes ini juga berfungsi untuk find out more part of the nervous system that allows us to
see. Termasuk didalam nya retina, optic nerve, dan otak. Problem with any of this part
bisa affect the visual field  beberapa uda spesifik ciri khas hasil testnya sehingga
memudahkan diagnosis.
- There are several types of visual field test, tapi satu kesamaan yaitu pasien looks straight
ahead at one point and signals when an object or a light is seen somewhere off to the side
- The two most basic types of visual field tests are very simple:
 Amsler grid: The Amsler grid is a pattern of straight lines that make perfect squares.
The patient looks at a large dot in the middle of the grid and describes any areas
where the lines look blurry, wavy, or broken. The Amsler grid is a quick test that
measures only the middle of the visual field
 Confrontation visual field: The term "confrontation" in this test just means that the
person giving the test sits facing the patient, about 3 or 4 feet away. The tester holds
his or her arms straight out to the sides. The patient looks straight ahead, and the
tester moves one hand or the other inward. The patient gives a signal as soon as the
hand is seen. The confrontation visual field test measures only the outer edge of the
visual field.

5. VISUAL FIELDS (BLURRED EYES)

- Visual can be impaired by damage to the visual system anywhere from the eyes to the
occipital lobes. Bisa di lokalisasi dengan mapping the visual field deficiency by finger
confrontation and then correlating it with the topographic anatomy of the visual pathway.
Quantitative visual mapping itu is performed by computer-driven perimeters that present
a target of variable intensity at fixed positions in the visual fields.
- Kepentingan dari visual field test ini adalah untuk decide wheter a lesion is before, at, or
behind the optic chiasm.
- If the scotoma (gangguan penglihatan pada satu titik dikelilingi pandangan normal) is
confined to one eye, it must be due to a lesion anterior to the chiasm, involving either the
optic nerve or the retina. Damage di macula (center pigmented spot in retina) causes a
central scotoma.
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- Optic nerve disease produces characteristics patterns of visual field loss. Glaucoma
resulting in arcuate scotoma shaped like Turkish Scimitar. Arcuate or nerve fiber layer
scotomas also result from optic neuritis, ischemic optic neuropathy, optic disc drusen, an
branch retinal artery or vein occlusion. Damage to the papillomacular fibers causes a
cecocentral scotoma.
- At the optic chiasm, fibers from nasal ganglion cells decussate into the contralateral optic
tract. Crossed fibers are damaged more by compression than are uncrossed fibers. As a
result, mass lesions of the sellar region cause a temporal hemianopia in each eye.
Tumors anterior to the optic chiasm, such as meningiomas of the tuberculum sella,
produce a junctional scotoma. More symmetric compression of the optic chiasm by a
pituitary adenoma, meningioma, craniopharyngioma, glioma, or aneurysm results in a
bitemporal hemianopia. Bitemporal hemianopia bisa loss dari exam kalau ga di tes satu
persatu.
- It is difficult to localize a post-chiasmal lesion because injury anywhere in the optic tract
may produce homonymous hemianopia.
- Lesion of the optic radiations tend to cause poorly matched or incongruous field defects
in each eye  damage of the optic radiation in temporal lobe produce superior quadrantic
homonymous hemianopia, where as injury of the optic radiation in parietal lobe produce
inferior quadrantic homonymous hemianopia. Lesions of the primary visual cortex give
rise to dense, congruous hemianopic field defects.
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6. ANTERIOR PITUITARY TUMOR SYNDROMES

- Hypothalamic, pituitary and other sellar masses. Evaluation :

(1) Local mass effects  clinical manifestations may vary, depending on the anatomic
location of the mass and the direction of its extension. Look table 403-1. The dorsal
sellar diaphragm paling less resistance to soft tissue expansion makanya biasanya
tumor tumbuh dengan bentuk suprasellar direction. Headaches are common features
of small intrasellar tumors walaupun gada pembentukan suprasellar. Itu disebabkan
karena confined nature of pituitary jadi sedikit expansion aja di dural plate.
Suprasellar extension may lead to visual loss dengan berbagai mechanisms, most
common itu compression of the optic chiasm, rarely direct invasion to the optic
nerves or obstructions di cerebrospinal fluid flow leading to secondary visual
disturbances. Pituitary stalk compression bisa menghambat flow di portal vessels,
disrupting pituitary access to hypothalamic hormones and dopamine leading to early
hyperprolactinemia and latter concurrent loss of other pituitary hormones. This stalk
phenomenon bisa juga terjadi karena trauma, whiplash injury, or skull base fractures.
Lateral mass invasion may impinge on the sinus cavernous and compress its neural
contents kena saraf cranial 3,4,6 palsies dan bisa kena cabang ophthalmic dan
maxillary dari nerves ke 5. Patients may present with diplopia, ptosis,
ophthalmoplegia, and decreased facial sensation. Extension of the into the sphenoid
sinus indicates that massa nya uda eroded through the sellar floor. Aggressive tumor
rarely invade the palate roof and cause nasopharyngeal obstruction, infection, csf
leakage. Temporal and frontal lobe involvement may lead to uncinate seizures,
personality disorders, and anosmia. Kalau kena hypothalamic bisa metabolic
sequelae, including precocious puberty or hypogonadism, diabetes insipidus, sleep
disturbances, dysthermia, and appetite disorders.
(2) MRI  Sagittal and coronal T1-weighted MRI before and after administration of
gadolinium allows precise visualization of the pituitary gland with clear delineation
of the hypothalamus, pituitary stalk, pituitary tissue and surrounding suprasellar
cistern, cavernous sinuses, sphenoid sinus, and optic chiasm. CT scan is used to
define the extent of bony erosion or the present of calcification. Anterior pituitary
gland soft tissue consistency is slightly heterogeneous on MRI, and signal intensify
resembles that of brain matter on T1-weighted imaging. Adenoma density usually
lower than that surrounding normal tissue on T1-weighted imaging and signal
intensify increases with T2-weighted images. The high phospholipid content of the
posterior pituitary results in a “pituitary bright spot”. Sellar masses biasanya
ditemukan ga sengaja dan bisanya pituitary adenomas. Kalau dia kecil dan tanpa
hypersecretion maka bisa di control aja pake MRI setahun sekali apalagi kalau no
further growth, tetapi bila macroadenoma should consider resection karena
kebanyakan berubah menjadi ganas dan invasive. Kalau ada hypersecretion
hormones, specific therapy sudah ada. Kalau masses diatas 1 cm harus dd dengan
massa lain.
(3) Ophthalmologic evaluation  bisa dilakukan tes-tes perimetry techniques, biasanya
hasilnya Bitemporal hemianopia. Homonymous hemianopia biasanya kalau dia
postchiasmal compression while monocular temporal field loss from prechiasmal
compression. Invasion of the cavernous sinus can produce diplopia from ocular motor
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nerve palsy. Early detection reduce the risk of optic atrophy, vision loss, or eye
misalignment.
(4) Laboratory investigation  the presenting clinical features of functional pituitary
adenomas should guide the laboratory studies (table 403-2). Kalau gada riwayat
hormone excess, cari kemungkinan adanya hypopituitarism dan cari nature of the
mass. Kalau berdasar MRI ketemu pituitary adenoma, inisial hormonal evaluation
includes 1) basal prolactin (PRL); 2) inslin-like growth factor; 3)24-h urinary free
cortisol (UFC) and or overnight oral dexamethasone suppression test; 4) α subunit,
FSH, and LH; 5) thyroid function tests.
(5) Histologic evaluation  immunohistochemical staining of pituitary tumor
specimens obtained at transsphenoidal surgery confirms clinical and laboratory
studies and provides a histologic diagnosis. Jarang butuh electron microscopy study
for diagnosis.
- Selain pituitary adenoma, other sellar masses may arise from brain, hypothalamus, or
pituitary tissue. Contoh : Craniopharyngiomas, Rathke’s cyst, Sella chordomas,
meningiomas, histiocytosis X, pituitary metastases, hypothalamic hamartomas and
gangliocytomas, hypothalamic gliomas and optic gliomas, brain germ cell tumors.

- Treatment of hypothalamic, pituitary, and other sellar masses : successful management

of sellar masses requires accurate diagnosis as well as selection of optimal therapeutic
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modalities. Most of pituitary tumors are benign and slow-growing. Lifelong management
and follow up are necessary for these patients. MRI with gadolinium for visualization,
new advances in transsphenoidal surgery and in stereotactic radiotherapy (including
gamma-knife radiotherapy), and novel therapeutic agents have improved pituitary tumor
management.
1) Transsphenoidal surgery  lebih desired drpd transfrontal. Intraoperative
microscopy and microdissection bisa menggambarkan perbedaan between
adenomatous atau jaringan normal. Endoscopic techniques with 3D intraoperative
localization jg improved visualization. Pituitary surgery is indicated for mass lesions
that impinge on surrounding structures. Transsphenoidal surgery juga biasa dilakukan
kalau inginbiopsy untuk diagnosis. Sebisa mungkin harus diselamatkan jaringan yang
sehat jangan diangkat semua. Kalau non selective hemihypophysectomy or total
hypophysectomy dilakukan apabila  multifocal lesions, or the remaining
nontumorous pituitary tissue is obviously necrotic. Side effects : mortality (1%),
transient diabetes insipidus and hypopituitarism, permanent diabetes insipidus, cranial
nerve damage, nasal septal perforation, visual disturbances, CSF leak, carotid artery
injury, loss of vision, hypothalamic damage, and meningitis.
2) Radiation  is used either as a primary therapy for pituitary or parasellar masses or,
more commonly as adjunct to surgery or medical therapy. Beberapa yang perlu
diperhatikan nature of the tumor, age of the patient, and availability of surgical and
radiation expertise. Karena slow onset of action jadi biasanya dipake untuk adjunct
post op. dan dipake buat treat residual tumor and prevent regrowth.
3) Medical  highly specific and depends on tumor type. For prolactinomas, dopamine
agonists are indicated. ACTH-secreting tumor and non-functioning tumor are
generally not responsive to medications and requires surgery and or irradiation.

7. PITUITARY ADENOMA AND HYPERSECRETION SYNDROMES

- The most common cause of pituitary hormone hyper and hypo secretion syndromes.
- Pathogenesis. Are benign neoplasms that arise from 1 of the 5 pituitary cell types.
Clinical dan biochemical phenotypes tergantung masing-masing darimana di derived.
Terbagi menjadi klasifikasinya berdasar cell pembentuknya (table 403-3).
- Yang termasuk kedalam hormonally active tumor itu adalah yang keluarin hormone
dalam jumlah lebih banyak dari biasanya tetapi ditambah degan tidak berfungsinya
feedback mechanism. Hormone secretion does not always correlate with tumor size. Bisa
kecil tapi banyak secrete atau vice versa.
- About one third of all adalah non-functioning sehingga absence dari ciri-ciri
hypersecreting.
- Almost all pituitary adenoma itu adalah monoclonal in origin sehingga implying that
perlu adanya one or more somatic mutations that confer a selective growth advantage.
Karena dia clonal origin, jadi kalau sudah diangkat biasanya hormon hypersecretion
syndrome juga resolve. Beberapa hormone juga menyebabkan mitosis pada target organ
seperti GHRH and CRH sehingga bisa aja ada massa di tempat lain di tubuh (e.g. chest or
abdomen)
- Several etiologic genetic events have been implicated in the development of pituitary
tumors (e.g. Gsα in GH-secreting pituitary tumor), bisa juga loss of heterozygosity
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(LOH) terhadap tumor suppressor gene. May be juga karena activated several oncogenes
like RAS, Pituitary tumor transforming gene (PTTG), and inactivation of MEG3 (growth
suppressor)
- Ada beberapa genetic syndromes yang associated with pituitary tumors (table 403-4)

- Hyperprolactinemia. The most common pituitary hormone hypersecretion syndrome in

both men and women. PRL-secreting pituitary adenomas (Prolactinomas) are the most
common cause of PRL >200µg/L.
- Etiology of hyperprolactinemia
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- Presentation and diagnosis. Amenorrhea, galactorrhea, and infertility are the hallmarks of
hyperprolactinemia in women. Vertebral bone mineral density menurun, decreased libido,
weight gain, and mild hirsutism. In men, diminished libido, infertility, visual loss (karena
compressed) are the usual presenting symptoms. Gonadotropin suppression leads to
reduce testosterone, impotence, and oligospermia. True galactorrhea jarang di men.
- Laboratory investigation. Basal, fasting morning PRL levels (normally <20µg/L)should
be measured to assess hypersecretion. Hypothyroidism should be excluded by measuring
TSH and T4 levels.
- Treatment. Depends on the cause of hypersecretion. Aim to normalizing PRL levels to
alleviate suppressive effects on gonadal function, halt galactorrhea, and preserve bone
mineral density. Dopamine agonists are effective for most causes of hyperprolactinemia.
Withdrawn drugs yang bisa bikin hyperprolactinemia. Kalau granulomatous type bisa
pake glucocorticoid administration. Kalau CKD di dialysis nanti akan normal kembali,
begitu juga dengan thyroid replacement pada pasien hypothyroidism.

8. INTRODUCTION TO ENDOCRINOLOGY

- Coordination of body functions by chemical messenger. Activities dari sel-sel are

coordinated by the interplay of several types of chemical messenger system :
1) Neurotransmitter  released by axon terminals of neurons into the synaptic junctions
and act locally to control nerve cell functions.
2) Endocrine hormones  released by glands or specialized cells into the circulating
blood and influence the function of target cells at another location in the body.
3) Neuroendocrine hormones  sama kaya endocrine hormones tapi disecrete oleh
neurons.
4) Paracrines  secreted by cells into the ecf and affect neighboring target cells of a
different type.
5) Autocrines  secreted by cells into ecf and affect the same cells that produce them.
6) Cytokines  peptides secreted by cells ito the ecf and can function as autocrines,
para, or endocrine hormones.
- The edocrine hormones are carried by the circulatory system to cells throughout the body,
including the nervous system in some cases, where they bind to receptors and initiate
many cell reactions. Some endocrine hormones affect many different types of cells of the
body contohnya GH. Beberapa juga punya target khusus berupa jaringan contohnya
ACTH.
- Chemical structures and synthesis of hormones. Three general classes of hormones exists
:
1) Proteins and polypeptides, including hormones dari anterior and posterior pituitary
gland, pancreas, parathyroid gland, and many others.
2) Steroids, secreted by the adrenal cortex (cortisol and aldosterone), the ovaries (estro
and proges), the testes (testos), and the placenta (estro and proges)
3) Derivatives of the amino acid tyrosine, secreted by the thyroid (thyroxine and
triiodothyronine), adrenal medullae (epi and norepi).
- Most of the hormones in the body itu polypeptide and proteins. The smallest (3 amino
acids) itu adalah thyroid-releasing hormone, the biggest (200 amino acids) itu adalah GH
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and PRL. Secara umum, kalau dibawah 100 AA maka di called peptides, kalau diatas 100
AA itu di called proteins.
- Protein and peptide hormones are synthesized on the rough end of the ER. Biasanya
awalnya disintesa sebagai pre-prohormones terus cleaved menjadi smaller prohormones
in the ER. Lalu prohormones ini di transfer ke golgi apparatus buat di packed into
secretory vesicles. Lalu enzim di vesikel meng cleave prohormones menjadi active
hormones. Vesikel nya di stored di cytoplasm, many are bound to cell membrane until the
secretion is needed. Secretion of the hormones occurs when the secretory vesicles fuse
with the cell membrane lalu isinya keluar ke interstitial fluid atau ga ke blood langsung
using exocytosis.
- In many cases itu stimulus nya buat exocytosis adalah increased cytosolic calcium
concentration caused by depolarization of the plasma membrane. Other instances,
stimulation of an endocrine cell surface receptor causes increase cAMP and subsequently
activation of protein kinases that initiate secretion of hormones. Peptide hormones are
water soluble.
- Steroid hormones biasa disintesis dari kolesterol and are not stored. Lipid soluble and
consists of three cyclohexyl rings and one cyclopentyl ring combined into single
structure.
- Amine hormones are derived from tyrosine. Two groups of hormones derived from
tyrosine, the thyroid and the adrenal medullary hormones. The thyroid hormones are
synthesized and stored di thyroid gland, and incorporated into macromolecules of the
protein thyroglobulin, which is stored in large follicles within the thyroid gland. Hormone
secretion terjadi kalau amines split from the thyroglobulin and the free hormones then
released into the blood stream. After masuk ke darah, diiket sama thyroxine-binding
globulin, nanti baru diajak ke target tissues.
- Epi and norepi dibentuk di adrenal medulla, biasanya 4 kali lebih banyak secrete epi drpd
norepi. Sama mekanisme stored and released nya seperti protein hormones.
- Hormone secretion, transport, and clearance from the blood.
1) Hormone secretion bergantung jenis masing-masing, ada yang di stimulus bbrp detik
langsung kerja dan hasil maksimal, ada juga kaya growth hormone yang harus
berbulan-bulan baru kerja maksimal.
2) Jumlah dari circulating hormone sangat rendah paling dikit itu 1 picogram sampe
dengan beberapa micrograms per ml blood.
3) Feedback control of hormone secretion  negative feedbacks prevent overactivity of
hormone systems. Bisa juga beberapa berupa positive feedback mechanism,
contohnya LH.
4) Cyclical variation does occur in hormone release. Misalnya Gh malam hari early
period of sleep markedly increased, but is reduced during the later stages of sleep.
5) Hormone transport. Water-soluble hormones are dissolved in the plasma and
transported from their sites of synthesis to target tissues where they diffuse out of the
capillaries into the interstitial fluid and ultimately the target cells. Steroid and thyroid
hormones in contrast mainly circulate di blood while being mainly bound to plasma
proteins. Kurang dari 10 persen steroid and thyroid di plasma itu exist free in
solution. However protein-bound hormones can not easily diffuse across the
capillaries and gain access to their target cells jadi disebut inactive unless lepas dr
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proteinnya. Binding of hormones to plasma proteins greatly slows the clearance from
the plasma.
6) Clearance of hormones from the blood. Ada 2 faktor yang mempengaruhi naik turun
nya kadar hormone dalam darah. Pertama adalah rate of hormone secretion into the
blood. Kedua adalah rate of removal dari darah yang disebut metabolic clearance rate
and is usually expressed dengan milliliters of plasma cleared of the hormone per
minute. Buat hitung nya pake (1) rate of disappearance of the hormone from the
plasma and (2) plasma concentration of the hormone. Lalu metabolic clearance rate
dihitung dengan formula

MCR = Rate of disappearance of hormone from the plasma / concentration of

hormone.

Hormone are cleared from the plasma in several ways : (1) metabolic destruction in
the tissue, (2) binding with the tissues, (3) excretion by the liver into the bile, (4)
excretion by kidneys into the urine.

- MOA of hormones. Hormone receptor and their function  the first step of hormone’s
action is to bind to specific receptors at the target cell. Sel yang gada receptor do not
respond. Beberapa receptor ada yang di cell membrane ada yang di sitoplasma or in the
nucleus. Begitu sudah cocok, akan menginduce cascade yang makin lama makin besar
energy nya sehingga kerja hormone diakhir akan maksimal. Biasanya receptor yang ada
di cell membrane itu for protein, peptide and catecholamine hormones; yang di
sitoplasma itu buat steroid hormones; yang di nucleus contohnya thyroid hormones.
- Kerja hormone bisa down regulate atau up regulate, artinya down regulate the receptors
(kalau uda banyak yang ikat dengan hormone maka jumlah receptor akan berkurang
sehingga cell tidak sensitive lagi) tetapi yang up regulate sebaliknya (ketika hormone
ikatan berhasil maka sel semakin sensitive terhadap hormone yang bersangkutan).
- Intracellular signaling terjadi setelah hormone-receptore complex formed. Beberapa
contoh hasil pembentukan hormone-receptor complex adalah :
1) Ion channel-linked receptors, bisa direct effect ke channel atau via G protein.
2) G protein-linked receptors, ada seven transmembrane receptor yang akan ikat G
protein lalu melepas α subunit untuk ke signaling berikutnya (bisa ke channel,
enzyme dsb.). ada Gi (inhibitory G proteins) ada Gs (stimulatory G proteins).
3) Enzyme-linked receptors, receptors yang teraktivasi menjadi enzim or are closely
related dengan enzyme yang akan mereka aktivasi. Contoh enzyme-linked receptors
adalah tyrosine kinase dengan contoh hormone yang menggunakan pathway ini
adalah leptin.
4) Beberapa hormone yang lipid soluble itu bisa masuk melalui cell membrane makanya
biasanya receptor mereka ada di dalam sel. Setelah bounded langsung menuju
specific regulatory (promoter) sequence of the DNA to activate atau malah repress
transcription of specific genes and formation of messenger RNA. Beberapa
mempunyai receptor intracellular yang sama tapi genes yang bakal di induce beda-
beda.
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- Ada mekanisme second messenger (bukan hormone yang secara langsung induce
melainkan substansi lain yang meneruskan kerja hormone di intracellular. Beberapa jenis
second messenger :
1) cAMP
2) cell membrane phospholipid (via phospholipase C then ubah PIP2 menjadi IP3)
3) Calcium-calmodulin (habis calcium masuk, ikat calmodulin then bisa activate or
inhibit activity di dalam cell.
- Hormone yang bekerja utama di genetic dari cell. Steroid hormone increase protein
synthesis. Thyroid hormone increase gene transcription in the cell nucleus.
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