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Physiology of the endocrine glands
Oral PHYSIOLOGY
Medicine
OF THE
ENDOCRINE
GLANDS
Introduction This pal)rr will Ijresent a brief r~%umQ of the ~tturc important functions It will dt~aI with the hormones of the of the glands of internal secretion. pituitary, thyroid, l)aralhyroitls, adrenal gl:~nds, ovaric3, testes, pancreas, and Special attention \vill be paid to the inter.gastrointestinal tract, in order. relations between the various glands of internal secretion. The Pituitaxy The pituitary consists of an anterior lobe, posterior lobe. The anterior lobe is the largest endocrine point of view. No clear-cut endocrine mined for the intermediate lobe. The posterior with water metabolism and contraction of smooth
an intermediate lobe, and a and most important from an function has yet been deterlobe is concerned primarily muscle.
Anterior Lobe.--The anterior lobe develops from the roof of the mouth and ascends to its position in the base of the skull where it is partially SWrounded by the spheroid bone which forms the sclla trlrcica. In rare instances ascends along with the rpithelium from the roof of the 1)rimitive pharynx cells which form the anterior lohe an(l gives rise latc~r in lifr to a ~raniopharyngioma.
The t?sact ~l~t~bcl~ OU ho1.1tlon(‘s l)roduct>d 1)~ this xli~n(l is st,ill un(aertain, stwet ion whit It but there is no doubt that it is it complex glaiicl of ilitcrnal to 1)(’ 110 tlOl1l)t lllilt influences many func+ions in the hotly: iltlC1 tlll?l? it]‘l)Cat’S The cvitlrnct> avwil;rbl~~ suggests that t hc following it ~~roduclrs several hormones. hormonrs arc produced by the ;Ititc~ritW Iohc:
--
1. Growth hormone. 9-. Tliyrotixq~ic bormctne. ;<. Parathyrotropic hormone ( ‘!) . hormone ( AL~TH) . 4. Adrenocorticotropic 5. Follicle-stimulating hormone. hormone. 6. Luteinizing 7. Lactogeiiic+ or luteolt.oltic hormonr.
From the Jh?partment of lrlternat hledicinc, lyniv~!rsity d lllilwis C’ollege cif hIc;,iicitle, l’hv Research anti Educational Hospital, The Grant Hospital, and The Renrotin Hospital. Read before the Sevepth .Annual Seminar for the Stucly &n~l Pr;rctice of Dental Mmliein?, The Desert Inn, Palm Sprmga, Calif., Ott. 18. 1950. 603
604
w.
0.
THOMI’SON
Growth. Ho~ww~w.-T~~~ growth hormone influnces the length of the skelet,on, causes retention of nitrogen, affects carbohydrate metabolism, and appears to cause combustion of fat. Its influence on skeletal growth is similar to that of the thyroid hormone in that both affect the length of the skeleton. However, The growth hormone of the pituitary there are three important differenres. is the only hormone which will cause gigantism when present in excess before closure of the the epiphyses. The thyroid hormone does not have this effect. It is the only hormone which will cause acromegalic changes after closure of Pituitary dwarfs usually have normal intelligence, whereas the epiphyses. The growth hormone affects not only cretins are very defectively mentally. the growth of the skeleton but also the growth of all other tissues including muscle and connective tissue. This is very well illustrated by the overgrowth of all tissues that occurs in patients with acromegaly. The growth hormone of the pituitary exercises an important influence on It appears to interfere with the utilization of carbocarbohydrate metabolism. hydrates. Its administration to a dog for a period of only ten days may produce permanent diabetes with degeneration of the islands of Langerhans. It has been suggested that the insulin-producing cells of the pancreas become exhausted and degenerate in their effort to keep pace with the demand for insulin. Thyrotropic Hormone.-The anterior lobe of the pituitary produces material which stimulates the function of the thyroid. In the absence of this material the thyroid atrophies and fails to produce its hormone, and the metabolism drops to the level seen in thyroidless individuals. Examples of alterations in thyroid function, secondary to alterations in pituitary function, are observed clinically. Hypothyroidism, secondary to hypopituitarism, is seen in patients with chromophobe adenomas ; and hyperthyroidism, secondary to hyperpituitarism, is seen in some patients with acromegaly. In fact, some patients with acromegaly present all the earmarks of exophthalmic goiter, including exophthalmos, goiter, tachyeardia, and loss of weight. The administration of thyrotropic hormone to a man with a normal level of basal metabolism usually produces all the earmarks of exophthalmic goiter, with the exception of exophthalmos. It will cause an exacerbation of toxic goiter and will cause nontoxic goiter to become thyrotoxic. As long as there is any thyroid tissue capable of functioning, thyrotropic hormone will stimulate it to increased activity. It has no effect in patients whose thyroid gland is absent or destroyed by infection. Exophthalmos has been produced in experimental animals by the administration of thyrotropic hormone, but not in man. Exophthalmic goiter at the present time is considered to be the result of overstimulation of the thyroid by the anterior lobe of the pituitary, the overactivity of which may in turn be It has been possible in some caused by some disturbance in the hypothalamus. patients to cure exophthalmie goiter by irradiation of the pituitary, although most of, the therapeutic attacks up to the present time have been directed at the thyroid, as, for example, radioactive iodine and antithyroid drugs.
PHYSIOLOGY
OF ENDOCRINE
605
GLAXDS
It is probablr that there arc two types of 1~3.perth?-i,oitlivlll? a primary type which originates from solllc disturbance in the thyroid itscl I’, and ii sccOllClZl~~iypc which is the result of o\-ci~stimnlatioil of the thpoid 1)~ the pilllitary. The mechanism by which the th\-rot ropic hortnouc stimulates thyroid l’unction has not bcc~n calearly detcrnlined. Tn-o l~~~~thcscs lla\-c IM.YI~suggested : 1. Tllat. it a~c*clclatcs rclcasc~ of hortnonc from the colloid of thri tlryroicl iIc*ini which, ill Iurn, stimulates the cells of the acini to increased activity. 2. That it stimulates the ~11s of the acini dircctl~- to increased activity. ~‘~r.clth?l,.of,,/,pic, Hol.))lo,tf.---l’hc I)ar;rtll~roid-stinlItlating effect of the pituif:try has tlot been as (‘lt’iirl!- clefiiiccl HS the tllr-roi(l-stimnlatiiig effect. It is 110t un~~omnion to observe sonic incrcasc ill serum calcium in l)aticnts with acromegsly, as well as abnormal deposition 01’ caalcium salts. Howe~cr, cases of hyperparathyroidism, secondary to hyperI,itnitarism, have not been cleaialy defined, although they probably exist. Adrenocorticot~opi~ Homon~ (ACTII).-Col1i.p described an adrenal-stimulating effect of t,lie pituitary almost twenty years ago. Four or five years ago Evans and Li isolated a fairly pure adrcnocorticotropic hormone from the anterior lobe, w&h was shown to stimulate the three main functions of the adrenal cortex-electrolyte metabolism, carbohydrate metabolism, and androgen production. The effect of the adrenocorticotropic hormone will be dealt with in a separate paper on “ The Clinical Applications of 1ZCTH and Cortisone. ” Since the adrcnocorticot ropic hornronc was first isolated in Evans’ laboratory, it, has beerr l’1irtlir~r l)urifird, ilIlt t.lle ilrnlou~ T,;il)oratorics have reccntl~ announced a preparation one l~uncl~~l times as efYecti\c as the original one. The administratiol~ oI‘ this hormone appears to inhibit all I’rrltc+ons of lht anterior lobe and may (aause a temporary remission in patients with exophthalmic goiter. prrsumahly b,v inhibiting the output of tliyrotropk liormone.
IIO~II~OTLC,. ----The dcyelof)lllt!tlt oi: thr fcrrlale I,~w~s~ is controllrtl factors, in(+luding hctfjgc’rlic* ll()!*lxl()ile, k!St t’O~ell, i{ll(l Some doubt still tksts as to the precise role of these factors. gwterone. It has been suggested that the main t’unction of the lactogenic hornlolle is to stimulate secretion of milk after t hc breast has been primed 1)). estrogen. Lacto~et&
l)y various
~J4.!pjl:l]ts
~ll’ll-
606
W. 0. THOMPSON
However, estrogen appears to stimulate growth of the breast only in the presIt, has, therefore, been suggested that the lactogenic horence of the pituitary. mone or some other material in the pituitary is involved in breast growth as well as in secretion of milk. Other Pituitary Homwrcc~s~-A diabetogenic hormone, a ketogenic hormone, and a pancreatropic hormone were originally ascribed to the anterior lobe of The evidence available at present appears to indicate that the the pituitary. influence of the pituitary on carbohydrate metaboiism is exerted through the adrenocorticotropic hormone and the growth hormone, although adequate experiments with purified growth hormone have not been carried out. A separate ketogenic hormone probably is not produced, the ketogenic effect presumably The presence of a pancreatropic horbeing exerted bx the growth hormone. mone, which was supposed to be responsible for normal development of the islands of Langerhans, has not been established.
Posterior Lobe.-The
posterior lobe of the pituitary, also known as the pars nervosa, develops from the base of the brain, and its function is closely related to the hypothalamus. It produces material which has antidiuretic, pressor, and oxytocic properties. According to Abel, one substance is responsible for all of these effects. On the other hand, two active factors were extracted in fairly pure form several years ago by Kamm and one of his associates, Stehle. To these two substances they gave the names Pitressin and Pitocin. According to these two authors, Pitressin is the pressor and antidiuretic factor that produces the following effects : 1. In man, a brief fall in pulse rate, oxygen consumption, and cardiac output, followed by a more prolonged rise. These changes were thought to be a result of an effect on coronary circulation. 2. An increase in the respiratory rate, interspersed with periods of apnea in unanesthetized animals. 3. A marked antidiuretic effect lasting several hours in patients with diabetes insipidus or in persons who had previously ingested water. This change is thought to be produced by a direct effect on the kidneys, caused by increased reabsorption of water by certain cells in the tubule. 4. Stimulation of the musculature of the intestine. Pitocin is the oxytocic factor which causes contraction of the uterus. The effect of this material on the uterus is thought to depend upon the following factors : 1. The phase of the menstrual cycle. 2. The presence or absence of pregnancy. There is very little effect in early pregnancy, 3. The stage of pregnancy. a more marked effect later in gestation, a maximum effect during parturition, and almost no effect in the pnerperium. Both Pitressin and Pitocin are said to cause hyperglycemia and to act as antagonists to insulin., Commercial Pituitrin contains both pressor and oxytocic factors. It is standardized for its oxytocic activity only.
PHYSIOLOGY
Posterior
pituitary
extract
OF
ENDOCRINE
is also reported
607
QLASDS
lo possess the following
1. A serum fat depressing action in man. 2. Production of gastric ulcers and markctl rabbits.
anemia
effects:
when injected
into
The Thyroid The thyroid gland, according to all arailablc c~vidt~llt*t~,p~~111t~csonly one hormone. which appears to bc thyroxin in chc‘nCt*al (.omhination. The form in although it. appears which the hormone is secreted by the gland is unrcrtain, to he released from the gland in the form cithcr of thyroglobulin or a polypeptide. The levorotatory Sorm is wuc~h mor~c act ivc than the dextrorotatory form, and ~henlical cvidcncAc intlit*atcs that 0111\-tjic levorotatory form may ho secreted by the gland. The thyroid hormone acts as a caatalyst ant1 accelera1es all functions of the body. It. influences skelctal growth, devc~lopnlc~nt, of the brain, sex function, However, ihe mechanisms inand carbohydrate, protein, and fat metabolism. volved are not entirely clear. When a thyroid deficiency is present durin, ~1’the first year of life, the deThe skeleton can withstand velopment of the brain does not ?)eeome normal. a much longer absence of thyroid function than the brain and recover almost completely. Thus a cretin, in whom tzeatment is delayed until the age of 3 or 4 years, may become almost normal in height, in spite of being very defective mentally. The brain tloubles in size during the first, \-ear oE life, and Ann adequate concentration of thyroid hormone is absolutely essential for this develop111cnt,. A thyroid tleficienq. durin, 0‘ childhood results in Illarkcd Delano in dentition, as well as in the tle~t~loj~ment cry’the whole skeleton.
The Parathyroids 111 nK~st Tlrc j~arathviGt1 gl~ricls van- in number from one to four~lrrn. individuals two plsnds arc j,resrrit on each side. They lit ,jllst j)oster’ior to the capsule of the thyroid, hut arc sometimes einbedtlcd in tlic gland. Their exact anatomic lot~wtion shows a Wnsitlerahle amount of variation.
608
W.
0.
THOMPSON
The concentration of phosphorus in the serum varies inversely with t,he Thus in concentration of calcium at different levels of parathyroid function. hyperparathyroidism it is low and in h-poparathyroidism it, is high. The thyroid hormone, like the parathyroid hormone, will cause an excessive excretion of calcium? but it does so without an>- influence on the concentration of calcium in serum.
The Adrenal Glands Each adrenal gland has a medulla and a cortex, the functions different.
of which are
The Medulla.-The main function of the adrenal medulla is to produce adrenalin, which affects the function of the sympathetic nervous system.. Its administration stimulates the production of adrenocorticotropic hormone by the anterior lobe of the pituitary. Tumors of the adrenal medulla (pheochromocytomas) may develop which produce an excess of adrenalin, characterized by transitory attacks of hypertension, palpitation, tachycardia, cyanosis, and pallor of the extremities. No clear-cut clinical entity related to deficient production of adrenalin has been described. Production of adrenalin by the adrenal glands is not essential for life, but its administration may be a lifesaving measure in patients with various types of foreign protein reactions. The Cortex.-The
adrenal
,cortex influences
three main functions
in the
body : 1. Sodium and potassium metabolism. 2. Carbohydrate metabolism. 3. Androgen production. These three functions appear to be affected by different portions of the adrenal cortex which, like the anterior lobe of the pituitary, must be thought of as a complex gla.nd of internal secretion, which produces more than one hormone. The adrenal cortex produces material which maintains the concentration of sodium and potassium in body fluids within normal limits. When present in excess, this material will cause abnormal retention of sodium, chloride, and water, and cause the concentration of potassium to drop to dangerously low levels. An excess of the material will also cause hypertension. All of these effects can be produced by the synthetic material desoxycorticosterone which, when administered in large doses to t.he rat, will cause flaccid paralysis, associated with a reduction in the concentration of potassium in body These paralyses can be cured by the administration of potassium salts. fluids. The adrenal cortex also produces a cortisone-like material, which affects carbohydrate metabolism primarily by causing the conversion of protein to carbohydrate (gluconeogenesis) . This effect is seen in patients with Cushing ‘s disease, who not only may be diabetic, but may also have an excessive secretion of nitrogen in the urine. This effect on carbohydrate metabolism, while mediated by ACTH from the pituitary, is different from the effect of growth hormone.
PHYSIOLOGS
OF
ENDOCRINE
GLANDS
609
The growth hormone appears to interfere with utilization of’ carbohydrate. The anterior lobe of the pituitary must, therefore, be thought of as influencing carbohydrate metabolism in two ways. The adrenal cortex produces androgens, and a variety of androgens have been isolated from the gland. Their fun&ion in the body has not been precisely defined. but there appears to be no doubt that. thp;v arc involved in nitrogen retention, growth of pubic and axillar*J- hair in both sexes, and in maturation of bone. Most androgens also have some effect on the retention of sodium, chloride, and water, although the effect is not as great as that of desoxycorticosterone. A tumor of the adrenal cortex, which produces an HXWXSof androgens 01 hyperplasia of the ~11s which produces androgcns7 will cause precocious puberty in young boys and masculinizat,ion in young girls and women. Excessive production of androgen by the adrenal cortex sufficiently early in embryonic life may cause the development of pseudohermaphrodism in the female. Occasionally children are born with hyperplasia of androgen-producing cells of the adrenal cortex, which causes a very early development of rnale characteristics, and these children, at the same time, occasionally have a deficiency of the adrenal hormones essential for life, so that the) actually have Addison’s disease. These observations illustrate the complexity of the functions of the adrenal cortex which, at the same time, may produce an excess of one hormone and a deficiency of others. A similar type of alteration in function is somet,imes seen in the anterior lobe of the pituitary. The influence of the adrenal cortex on sodium and potassium metabolism and its influenc+e on carbohydrate metabolism appear to be essential for life. Androgcn production is not. Maximum improvement in patients with Addison’s disease can he producc~tl only- when substitution therapy is given for both the electrolyte and carbohydrate functions of the gland.
The Ovaries The ovary produces two hormones, es1rogcn and progesterone, the production of which in turn is influenced b?; the two gonadotropic hormones of the Estrogen is produc*ed both by t,hc developing anterior lobe of the pituitaq-. ProKcslerone is pj*oduced only by the cxorpus follicle illltl by tll? (‘Or~1IlS l~lttl~Ill. I uteum. Thr !;ilas 01 111~’~;\at~,~.<*rjtltilills c*:>!~s::-l1ic*l: IX’SCWl~Jl~~ ihV ;rtlc!l.c,~-rri-;:i.c,c~~l~ilrp These wlls somet imrs ilnrtergo wlls in the reiicitlar zon(L of t tlf? il~llY’1lill c*ot*trX. tiyperplasia and tumor formation, anti givcl rise to Inasc~uliliization. Estrog;rn influcnc,cs Illost functions Of tllc I)ody illltf. is IY~Sponsiblc i'0r dcveloprnent of’ the sec*ontlar~ sex cliarac*teristics in I he femalCP inc+ludinp growth of the genitalia, growth ol’ the ,bt,easts, skeltltal ntouhlinp. retclntion of calcium, emotional changes? and callara&lristi(* l’emininr distribution of fat. T)uring the r~~enstrual (cycle it ~‘aus~ II?-pcbq)lasia of the r~terinc ylantls and Further thic~krning of the glands ;ind cpithetium of the \aginal epit helium.
610
W.
0.
THOMPSON
and tortuosify and proliferation of the uterine arteries are caused by progesterone. Progesterone is also report,ed to have some effect on the growth of acinar tissue in the breast.
The Testes The testes have two main functions 1. Production 2. Production
:
of spermatozoa by the seminiferous tubules. of androgenic material by the interstitial
cells of Leydig.
An interrelationship appears to exist between the functions of these two portions of the testis, an adequate concentration of androgenic material being necessary for normal function of the seminiferous tubules. However, in rare instances an adequate number of spermatozoa may be produced, in spite of an androgen deficiency. Production of estrogen has been ascribed to the Sertoli cells in the seminiferous tubules, but the evidence is inadequate. The androgen produced by the testis influences most funcbions of the body and is responsible for the development of secondary sex characteristics, which include : 1. 2. 3. 4. 5. 6. 7.
Growth of the external genitalia. Development of the prostate. Development of the musculature. Growth of hair in masculine areas, Lowering of the pitch of the voice. Skeletal moulding. Normal emotional reactions.
The Pancreas The exact number of hormones produced by the pancreas is uncert,ain. Insulin is secreted by the islands of Langerhans and plays an important role in carbohydrate metabolism. It appears to be involved primarily in the conversion of glucose to glycogen, but all phases of its activity are not clearly worked out. It has. b,een claimed that the pancreas produces a hormone which increases the level of the blood sugar, but the data are inadequate. A few years ago Dragstedt reported the isolation of a hormone from the pancreas which he called lipocaic. dccording to Dragstedt this hormone affected fat metabolism by enabling the liver to transform fat into phospholipid, which is the utilizable form. The exact status of lipocaic and its site of formation in the pancreas are uncertain.
Gastrointestinal Ivy and others reported the isolation the upper gastrointestinal tract :
Tract of the following
six hormones from
1. Gastrin which stimulates the formation of acid by the stomach. 2. Secretin which stimulates the output of water and bicarbonate pancreas.
by the
PHYSIOLOGY
OF
ENDOCRINE
GLANDS
611
3. Pancreozymin which increases the concentration of enzymes in pancreatic juice. 4. Cholecystokinin which causes the gall bladder to contract and evacuate. 5. Enterogastrone which inhibits the motility of the stomach and the secretion of acid by the stomach in the presence of a 10 per cent concentration of fat in the small intestine. g&l& to secrete an alkaline, 6. Duocrinin which stimulates Briinner’s mucilaginous fluid in copious quantities. Gastrin is formed in the gastric mucosa, principally at the pyloric end of the stomach. The other hormones are produced in the mucosa of the upper portion of the small intestine. It is claimed that these six materials are true hormones in the sense that they are secreted into the blood stream and are carried by the blood to the target organ.
Other Hormones Hormonal function has been ascribed to the pineal, and in rare instances cases of gigantism have been reported which were thought to be caused by hyperfunction of this organ. However, the pineal has not been definitely proved to be a gland of internal secretion. Various hormones have been ascribed to the liver and other organs, but their status is uncertain.
Medicine
OF THE
ENDOCRINE
GLANDS
Introduction This pal)rr will Ijresent a brief r~%umQ of the ~tturc important functions It will dt~aI with the hormones of the of the glands of internal secretion. pituitary, thyroid, l)aralhyroitls, adrenal gl:~nds, ovaric3, testes, pancreas, and Special attention \vill be paid to the inter.gastrointestinal tract, in order. relations between the various glands of internal secretion. The Pituitaxy The pituitary consists of an anterior lobe, posterior lobe. The anterior lobe is the largest endocrine point of view. No clear-cut endocrine mined for the intermediate lobe. The posterior with water metabolism and contraction of smooth
an intermediate lobe, and a and most important from an function has yet been deterlobe is concerned primarily muscle.
Anterior Lobe.--The anterior lobe develops from the roof of the mouth and ascends to its position in the base of the skull where it is partially SWrounded by the spheroid bone which forms the sclla trlrcica. In rare instances ascends along with the rpithelium from the roof of the 1)rimitive pharynx cells which form the anterior lohe an(l gives rise latc~r in lifr to a ~raniopharyngioma.
The t?sact ~l~t~bcl~ OU ho1.1tlon(‘s l)roduct>d 1)~ this xli~n(l is st,ill un(aertain, stwet ion whit It but there is no doubt that it is it complex glaiicl of ilitcrnal to 1)(’ 110 tlOl1l)t lllilt influences many func+ions in the hotly: iltlC1 tlll?l? it]‘l)Cat’S The cvitlrnct> avwil;rbl~~ suggests that t hc following it ~~roduclrs several hormones. hormonrs arc produced by the ;Ititc~ritW Iohc:
--
1. Growth hormone. 9-. Tliyrotixq~ic bormctne. ;<. Parathyrotropic hormone ( ‘!) . hormone ( AL~TH) . 4. Adrenocorticotropic 5. Follicle-stimulating hormone. hormone. 6. Luteinizing 7. Lactogeiiic+ or luteolt.oltic hormonr.
From the Jh?partment of lrlternat hledicinc, lyniv~!rsity d lllilwis C’ollege cif hIc;,iicitle, l’hv Research anti Educational Hospital, The Grant Hospital, and The Renrotin Hospital. Read before the Sevepth .Annual Seminar for the Stucly &n~l Pr;rctice of Dental Mmliein?, The Desert Inn, Palm Sprmga, Calif., Ott. 18. 1950. 603
604
w.
0.
THOMI’SON
Growth. Ho~ww~w.-T~~~ growth hormone influnces the length of the skelet,on, causes retention of nitrogen, affects carbohydrate metabolism, and appears to cause combustion of fat. Its influence on skeletal growth is similar to that of the thyroid hormone in that both affect the length of the skeleton. However, The growth hormone of the pituitary there are three important differenres. is the only hormone which will cause gigantism when present in excess before closure of the the epiphyses. The thyroid hormone does not have this effect. It is the only hormone which will cause acromegalic changes after closure of Pituitary dwarfs usually have normal intelligence, whereas the epiphyses. The growth hormone affects not only cretins are very defectively mentally. the growth of the skeleton but also the growth of all other tissues including muscle and connective tissue. This is very well illustrated by the overgrowth of all tissues that occurs in patients with acromegaly. The growth hormone of the pituitary exercises an important influence on It appears to interfere with the utilization of carbocarbohydrate metabolism. hydrates. Its administration to a dog for a period of only ten days may produce permanent diabetes with degeneration of the islands of Langerhans. It has been suggested that the insulin-producing cells of the pancreas become exhausted and degenerate in their effort to keep pace with the demand for insulin. Thyrotropic Hormone.-The anterior lobe of the pituitary produces material which stimulates the function of the thyroid. In the absence of this material the thyroid atrophies and fails to produce its hormone, and the metabolism drops to the level seen in thyroidless individuals. Examples of alterations in thyroid function, secondary to alterations in pituitary function, are observed clinically. Hypothyroidism, secondary to hypopituitarism, is seen in patients with chromophobe adenomas ; and hyperthyroidism, secondary to hyperpituitarism, is seen in some patients with acromegaly. In fact, some patients with acromegaly present all the earmarks of exophthalmic goiter, including exophthalmos, goiter, tachyeardia, and loss of weight. The administration of thyrotropic hormone to a man with a normal level of basal metabolism usually produces all the earmarks of exophthalmic goiter, with the exception of exophthalmos. It will cause an exacerbation of toxic goiter and will cause nontoxic goiter to become thyrotoxic. As long as there is any thyroid tissue capable of functioning, thyrotropic hormone will stimulate it to increased activity. It has no effect in patients whose thyroid gland is absent or destroyed by infection. Exophthalmos has been produced in experimental animals by the administration of thyrotropic hormone, but not in man. Exophthalmic goiter at the present time is considered to be the result of overstimulation of the thyroid by the anterior lobe of the pituitary, the overactivity of which may in turn be It has been possible in some caused by some disturbance in the hypothalamus. patients to cure exophthalmie goiter by irradiation of the pituitary, although most of, the therapeutic attacks up to the present time have been directed at the thyroid, as, for example, radioactive iodine and antithyroid drugs.
PHYSIOLOGY
OF ENDOCRINE
605
GLAXDS
It is probablr that there arc two types of 1~3.perth?-i,oitlivlll? a primary type which originates from solllc disturbance in the thyroid itscl I’, and ii sccOllClZl~~iypc which is the result of o\-ci~stimnlatioil of the thpoid 1)~ the pilllitary. The mechanism by which the th\-rot ropic hortnouc stimulates thyroid l’unction has not bcc~n calearly detcrnlined. Tn-o l~~~~thcscs lla\-c IM.YI~suggested : 1. Tllat. it a~c*clclatcs rclcasc~ of hortnonc from the colloid of thri tlryroicl iIc*ini which, ill Iurn, stimulates the cells of the acini to increased activity. 2. That it stimulates the ~11s of the acini dircctl~- to increased activity. ~‘~r.clth?l,.of,,/,pic, Hol.))lo,tf.---l’hc I)ar;rtll~roid-stinlItlating effect of the pituif:try has tlot been as (‘lt’iirl!- clefiiiccl HS the tllr-roi(l-stimnlatiiig effect. It is 110t un~~omnion to observe sonic incrcasc ill serum calcium in l)aticnts with acromegsly, as well as abnormal deposition 01’ caalcium salts. Howe~cr, cases of hyperparathyroidism, secondary to hyperI,itnitarism, have not been cleaialy defined, although they probably exist. Adrenocorticot~opi~ Homon~ (ACTII).-Col1i.p described an adrenal-stimulating effect of t,lie pituitary almost twenty years ago. Four or five years ago Evans and Li isolated a fairly pure adrcnocorticotropic hormone from the anterior lobe, w&h was shown to stimulate the three main functions of the adrenal cortex-electrolyte metabolism, carbohydrate metabolism, and androgen production. The effect of the adrenocorticotropic hormone will be dealt with in a separate paper on “ The Clinical Applications of 1ZCTH and Cortisone. ” Since the adrcnocorticot ropic hornronc was first isolated in Evans’ laboratory, it, has beerr l’1irtlir~r l)urifird, ilIlt t.lle ilrnlou~ T,;il)oratorics have reccntl~ announced a preparation one l~uncl~~l times as efYecti\c as the original one. The administratiol~ oI‘ this hormone appears to inhibit all I’rrltc+ons of lht anterior lobe and may (aause a temporary remission in patients with exophthalmic goiter. prrsumahly b,v inhibiting the output of tliyrotropk liormone.
IIO~II~OTLC,. ----The dcyelof)lllt!tlt oi: thr fcrrlale I,~w~s~ is controllrtl factors, in(+luding hctfjgc’rlic* ll()!*lxl()ile, k!St t’O~ell, i{ll(l Some doubt still tksts as to the precise role of these factors. gwterone. It has been suggested that the main t’unction of the lactogenic hornlolle is to stimulate secretion of milk after t hc breast has been primed 1)). estrogen. Lacto~et&
l)y various
~J4.!pjl:l]ts
~ll’ll-
606
W. 0. THOMPSON
However, estrogen appears to stimulate growth of the breast only in the presIt, has, therefore, been suggested that the lactogenic horence of the pituitary. mone or some other material in the pituitary is involved in breast growth as well as in secretion of milk. Other Pituitary Homwrcc~s~-A diabetogenic hormone, a ketogenic hormone, and a pancreatropic hormone were originally ascribed to the anterior lobe of The evidence available at present appears to indicate that the the pituitary. influence of the pituitary on carbohydrate metaboiism is exerted through the adrenocorticotropic hormone and the growth hormone, although adequate experiments with purified growth hormone have not been carried out. A separate ketogenic hormone probably is not produced, the ketogenic effect presumably The presence of a pancreatropic horbeing exerted bx the growth hormone. mone, which was supposed to be responsible for normal development of the islands of Langerhans, has not been established.
Posterior Lobe.-The
posterior lobe of the pituitary, also known as the pars nervosa, develops from the base of the brain, and its function is closely related to the hypothalamus. It produces material which has antidiuretic, pressor, and oxytocic properties. According to Abel, one substance is responsible for all of these effects. On the other hand, two active factors were extracted in fairly pure form several years ago by Kamm and one of his associates, Stehle. To these two substances they gave the names Pitressin and Pitocin. According to these two authors, Pitressin is the pressor and antidiuretic factor that produces the following effects : 1. In man, a brief fall in pulse rate, oxygen consumption, and cardiac output, followed by a more prolonged rise. These changes were thought to be a result of an effect on coronary circulation. 2. An increase in the respiratory rate, interspersed with periods of apnea in unanesthetized animals. 3. A marked antidiuretic effect lasting several hours in patients with diabetes insipidus or in persons who had previously ingested water. This change is thought to be produced by a direct effect on the kidneys, caused by increased reabsorption of water by certain cells in the tubule. 4. Stimulation of the musculature of the intestine. Pitocin is the oxytocic factor which causes contraction of the uterus. The effect of this material on the uterus is thought to depend upon the following factors : 1. The phase of the menstrual cycle. 2. The presence or absence of pregnancy. There is very little effect in early pregnancy, 3. The stage of pregnancy. a more marked effect later in gestation, a maximum effect during parturition, and almost no effect in the pnerperium. Both Pitressin and Pitocin are said to cause hyperglycemia and to act as antagonists to insulin., Commercial Pituitrin contains both pressor and oxytocic factors. It is standardized for its oxytocic activity only.
PHYSIOLOGY
Posterior
pituitary
extract
OF
ENDOCRINE
is also reported
607
QLASDS
lo possess the following
1. A serum fat depressing action in man. 2. Production of gastric ulcers and markctl rabbits.
anemia
effects:
when injected
into
The Thyroid The thyroid gland, according to all arailablc c~vidt~llt*t~,p~~111t~csonly one hormone. which appears to bc thyroxin in chc‘nCt*al (.omhination. The form in although it. appears which the hormone is secreted by the gland is unrcrtain, to he released from the gland in the form cithcr of thyroglobulin or a polypeptide. The levorotatory Sorm is wuc~h mor~c act ivc than the dextrorotatory form, and ~henlical cvidcncAc intlit*atcs that 0111\-tjic levorotatory form may ho secreted by the gland. The thyroid hormone acts as a caatalyst ant1 accelera1es all functions of the body. It. influences skelctal growth, devc~lopnlc~nt, of the brain, sex function, However, ihe mechanisms inand carbohydrate, protein, and fat metabolism. volved are not entirely clear. When a thyroid deficiency is present durin, ~1’the first year of life, the deThe skeleton can withstand velopment of the brain does not ?)eeome normal. a much longer absence of thyroid function than the brain and recover almost completely. Thus a cretin, in whom tzeatment is delayed until the age of 3 or 4 years, may become almost normal in height, in spite of being very defective mentally. The brain tloubles in size during the first, \-ear oE life, and Ann adequate concentration of thyroid hormone is absolutely essential for this develop111cnt,. A thyroid tleficienq. durin, 0‘ childhood results in Illarkcd Delano in dentition, as well as in the tle~t~loj~ment cry’the whole skeleton.
The Parathyroids 111 nK~st Tlrc j~arathviGt1 gl~ricls van- in number from one to four~lrrn. individuals two plsnds arc j,resrrit on each side. They lit ,jllst j)oster’ior to the capsule of the thyroid, hut arc sometimes einbedtlcd in tlic gland. Their exact anatomic lot~wtion shows a Wnsitlerahle amount of variation.
608
W.
0.
THOMPSON
The concentration of phosphorus in the serum varies inversely with t,he Thus in concentration of calcium at different levels of parathyroid function. hyperparathyroidism it is low and in h-poparathyroidism it, is high. The thyroid hormone, like the parathyroid hormone, will cause an excessive excretion of calcium? but it does so without an>- influence on the concentration of calcium in serum.
The Adrenal Glands Each adrenal gland has a medulla and a cortex, the functions different.
of which are
The Medulla.-The main function of the adrenal medulla is to produce adrenalin, which affects the function of the sympathetic nervous system.. Its administration stimulates the production of adrenocorticotropic hormone by the anterior lobe of the pituitary. Tumors of the adrenal medulla (pheochromocytomas) may develop which produce an excess of adrenalin, characterized by transitory attacks of hypertension, palpitation, tachycardia, cyanosis, and pallor of the extremities. No clear-cut clinical entity related to deficient production of adrenalin has been described. Production of adrenalin by the adrenal glands is not essential for life, but its administration may be a lifesaving measure in patients with various types of foreign protein reactions. The Cortex.-The
adrenal
,cortex influences
three main functions
in the
body : 1. Sodium and potassium metabolism. 2. Carbohydrate metabolism. 3. Androgen production. These three functions appear to be affected by different portions of the adrenal cortex which, like the anterior lobe of the pituitary, must be thought of as a complex gla.nd of internal secretion, which produces more than one hormone. The adrenal cortex produces material which maintains the concentration of sodium and potassium in body fluids within normal limits. When present in excess, this material will cause abnormal retention of sodium, chloride, and water, and cause the concentration of potassium to drop to dangerously low levels. An excess of the material will also cause hypertension. All of these effects can be produced by the synthetic material desoxycorticosterone which, when administered in large doses to t.he rat, will cause flaccid paralysis, associated with a reduction in the concentration of potassium in body These paralyses can be cured by the administration of potassium salts. fluids. The adrenal cortex also produces a cortisone-like material, which affects carbohydrate metabolism primarily by causing the conversion of protein to carbohydrate (gluconeogenesis) . This effect is seen in patients with Cushing ‘s disease, who not only may be diabetic, but may also have an excessive secretion of nitrogen in the urine. This effect on carbohydrate metabolism, while mediated by ACTH from the pituitary, is different from the effect of growth hormone.
PHYSIOLOGS
OF
ENDOCRINE
GLANDS
609
The growth hormone appears to interfere with utilization of’ carbohydrate. The anterior lobe of the pituitary must, therefore, be thought of as influencing carbohydrate metabolism in two ways. The adrenal cortex produces androgens, and a variety of androgens have been isolated from the gland. Their fun&ion in the body has not been precisely defined. but there appears to be no doubt that. thp;v arc involved in nitrogen retention, growth of pubic and axillar*J- hair in both sexes, and in maturation of bone. Most androgens also have some effect on the retention of sodium, chloride, and water, although the effect is not as great as that of desoxycorticosterone. A tumor of the adrenal cortex, which produces an HXWXSof androgens 01 hyperplasia of the ~11s which produces androgcns7 will cause precocious puberty in young boys and masculinizat,ion in young girls and women. Excessive production of androgen by the adrenal cortex sufficiently early in embryonic life may cause the development of pseudohermaphrodism in the female. Occasionally children are born with hyperplasia of androgen-producing cells of the adrenal cortex, which causes a very early development of rnale characteristics, and these children, at the same time, occasionally have a deficiency of the adrenal hormones essential for life, so that the) actually have Addison’s disease. These observations illustrate the complexity of the functions of the adrenal cortex which, at the same time, may produce an excess of one hormone and a deficiency of others. A similar type of alteration in function is somet,imes seen in the anterior lobe of the pituitary. The influence of the adrenal cortex on sodium and potassium metabolism and its influenc+e on carbohydrate metabolism appear to be essential for life. Androgcn production is not. Maximum improvement in patients with Addison’s disease can he producc~tl only- when substitution therapy is given for both the electrolyte and carbohydrate functions of the gland.
The Ovaries The ovary produces two hormones, es1rogcn and progesterone, the production of which in turn is influenced b?; the two gonadotropic hormones of the Estrogen is produc*ed both by t,hc developing anterior lobe of the pituitaq-. ProKcslerone is pj*oduced only by the cxorpus follicle illltl by tll? (‘Or~1IlS l~lttl~Ill. I uteum. Thr !;ilas 01 111~’~;\at~,~.<*rjtltilills c*:>!~s::-l1ic*l: IX’SCWl~Jl~~ ihV ;rtlc!l.c,~-rri-;:i.c,c~~l~ilrp These wlls somet imrs ilnrtergo wlls in the reiicitlar zon(L of t tlf? il~llY’1lill c*ot*trX. tiyperplasia and tumor formation, anti givcl rise to Inasc~uliliization. Estrog;rn influcnc,cs Illost functions Of tllc I)ody illltf. is IY~Sponsiblc i'0r dcveloprnent of’ the sec*ontlar~ sex cliarac*teristics in I he femalCP inc+ludinp growth of the genitalia, growth ol’ the ,bt,easts, skeltltal ntouhlinp. retclntion of calcium, emotional changes? and callara&lristi(* l’emininr distribution of fat. T)uring the r~~enstrual (cycle it ~‘aus~ II?-pcbq)lasia of the r~terinc ylantls and Further thic~krning of the glands ;ind cpithetium of the \aginal epit helium.
610
W.
0.
THOMPSON
and tortuosify and proliferation of the uterine arteries are caused by progesterone. Progesterone is also report,ed to have some effect on the growth of acinar tissue in the breast.
The Testes The testes have two main functions 1. Production 2. Production
:
of spermatozoa by the seminiferous tubules. of androgenic material by the interstitial
cells of Leydig.
An interrelationship appears to exist between the functions of these two portions of the testis, an adequate concentration of androgenic material being necessary for normal function of the seminiferous tubules. However, in rare instances an adequate number of spermatozoa may be produced, in spite of an androgen deficiency. Production of estrogen has been ascribed to the Sertoli cells in the seminiferous tubules, but the evidence is inadequate. The androgen produced by the testis influences most funcbions of the body and is responsible for the development of secondary sex characteristics, which include : 1. 2. 3. 4. 5. 6. 7.
Growth of the external genitalia. Development of the prostate. Development of the musculature. Growth of hair in masculine areas, Lowering of the pitch of the voice. Skeletal moulding. Normal emotional reactions.
The Pancreas The exact number of hormones produced by the pancreas is uncert,ain. Insulin is secreted by the islands of Langerhans and plays an important role in carbohydrate metabolism. It appears to be involved primarily in the conversion of glucose to glycogen, but all phases of its activity are not clearly worked out. It has. b,een claimed that the pancreas produces a hormone which increases the level of the blood sugar, but the data are inadequate. A few years ago Dragstedt reported the isolation of a hormone from the pancreas which he called lipocaic. dccording to Dragstedt this hormone affected fat metabolism by enabling the liver to transform fat into phospholipid, which is the utilizable form. The exact status of lipocaic and its site of formation in the pancreas are uncertain.
Gastrointestinal Ivy and others reported the isolation the upper gastrointestinal tract :
Tract of the following
six hormones from
1. Gastrin which stimulates the formation of acid by the stomach. 2. Secretin which stimulates the output of water and bicarbonate pancreas.
by the
PHYSIOLOGY
OF
ENDOCRINE
GLANDS
611
3. Pancreozymin which increases the concentration of enzymes in pancreatic juice. 4. Cholecystokinin which causes the gall bladder to contract and evacuate. 5. Enterogastrone which inhibits the motility of the stomach and the secretion of acid by the stomach in the presence of a 10 per cent concentration of fat in the small intestine. g&l& to secrete an alkaline, 6. Duocrinin which stimulates Briinner’s mucilaginous fluid in copious quantities. Gastrin is formed in the gastric mucosa, principally at the pyloric end of the stomach. The other hormones are produced in the mucosa of the upper portion of the small intestine. It is claimed that these six materials are true hormones in the sense that they are secreted into the blood stream and are carried by the blood to the target organ.
Other Hormones Hormonal function has been ascribed to the pineal, and in rare instances cases of gigantism have been reported which were thought to be caused by hyperfunction of this organ. However, the pineal has not been definitely proved to be a gland of internal secretion. Various hormones have been ascribed to the liver and other organs, but their status is uncertain.