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Ovulation and pregnancy in acromegaly
Ovulation and pregnancy in acromegaly VASIL TRUCHLY, M.D.* IVEN S. YOUNG, M.D. PAUL BECK, M.D.** HERBERT S. KUPFERMAN. PH.D .. M.D. New York, New J'ork
associatcd with acromegaly. as \\!'II as o11r concept of treatment of the acromegalic female in the childbearing age.
I N 1886, Marie 1 described the clinical entity which we know now as acromegaly. The clinical state that ensues is due to an excessive production of growth hormone at a time when the epiphyses are already closed. In the initial sta,ges of the disease, the modification in the general appearance of the patient may be insidious and is neither readily apparent to the patient. nor to the people with whom he is in close continuous contact. The classical clinical picture pn·~·ents acral enlargement, prognathism, frontal bossing and coarsening of the facial features, including thickenin.g of the lips and enlargenwnt of the nose. ThPre is great \·ariability in the progression of the disease and at times even spontaneous remission may occur. Hypopituitarism may eventually develop either due to advancement of the disease i tsdf or to therapy, resulting in multiglandular defioenctes. In the female, following therapeutic radiation, secondary ovarian failure due to pituitary gonadotropic insufficiency is common. Thl' cases presented in this paper will illustrate that pituitary gonadotropic insufficiency is not always permanent, as menses, ovulation, and even pregnancy may occur. The report herein will briefly summarize the clinical picture and laboratory flndin~s
Manifestations of acromegaly
Enlargement of the sella turcica has bv<'ll reported in as high as 93 per C('tlt and as low as 25 Pf'r cf'nt of these patients." Hcadaclw is a frequent ntanifestation but the so-called typical retrobulbar lwadaclw of pituitan tumor is not common."· ., Hamwi. Skilltnan, ancl Tufts'' obsen·ed 2 patients wlto had ,.i,twl Jicld impairment without gross enlargl'llWilt of the sella turcica, as wcJI as matt\· patit•nV; with normal visual fields accompanil·cl h: massive enlar~ement of the sella. The di1 nsity of the ftndings depends on the direction of the ,growth of the tumor, and pn·ssure ext'rted on surrounding structures.'' The most common visual field impairrnent not1~d i-: ;t hilt'rnporal 11f'mianopsia, with tfw u ppcr nu tn quadrants being; most frequ!'ntly aJlcctecl.' Enlargement of thr ramus of tlw mandihlt• and the frontal sinuses arc cbaractcrist ic fittdings of the changes of tlte sktdl Enbr~t· rncnt of the nw.ndible usually re-;ults in Jmlc:·nathism and widening of the span·s het\\"l'l'rt the spacings of tht' teeth. The l)(lllV changt•., in the vertebral column that !lM,. IH: seen aJ•· those of ltypertrophv and incn·
From the Department of Therapeutic.r, New York University Medical Center. *Present address: Presbyterian-St. Luke's Hospital, Chicago, Illinois. **Present address: The Brookdale Hospital Center, Brooklyn, New r ork.
174
Volume 9ti ~uwlwr ~
of the pores and exaggeration of the skin markings along with the oiliness and excessive sweating are frequent complaints during the actiYe disease state. An increased incidence of lipomas, multiple nevi, or papillomatous skin tags may be encountered. Hirsutism may be another manifestation. Enlargement of the viscera is a common occurrence. The tongue may at times show considerable enlargement with furrowing. Lactorrhea may be present although it is relatively infrequent. 9 The thrust of the enlarged tongue against the teeth of the mandible may contribute further to the diastasis between the teeth. A more recent observation of diagnostic importance has been the increase in thickness of the soft tissue of the heel. Normally, the measurement from the calcaneum to the bottom of the foot is about 16 mm; in acromegaly the same area measures some 22 mm. or more. Laboratory findings
A decrease in glucose tolerance is noted in about 60 per cent of the patients during the active phase of the disease. 10 Some of these patients1 " will show evidence of insulin resistance, and this may be demonstrated by the insulin tolerance testY The most typical finding during the active phase of the disease is the retention of phosphorus, so that the serum phosphorus is usually above 4.5 mg. per cent. Multiple determinations are advisable because of spontaneous fluctuations in serum phosphorus level. Elevation of the 17hydroxysteroids and 17 -ketosteroids also may be observed during the active phase. Assays for growth hormone have been developed more recently, and while such tests are most specific for the detection of active acromegaly, their use is limited, since they are still not readily available to most laboratories. Another assay that has been reviewed is an indirect procedure which use~ the fact that the cartilage of hypophysectomized rats has a reduced ability to incorporate sulfate into chondroitin sulfate. This may be corrected by giving growth horrnone. 12 This principle is used in the assay described by Daughaday, Salmon, and Alcxander/ 3 and is known as the sulfation factor. An immunologic assay
Acromegaly
175
was developed by Read and Bryant/1 usiug the hemagglutination inhibition technique. An ingenious assay similar to the radioisotopic immunoassay of insulin as developed by Yalow and Berson15 has been adapted to the assay of growth hormone. 1 " Case reports Case 1. Mrs. 0. G., a 48-year-old married woman of Czechoslovakian origin, was in good health until 1938, when she noted the onset of severe headaches, weight gain, and, subsequently, increasing facial and general body hair. The patient not<'d a marked change in her regular cyclic menstrual pattern. At first hypomenorrhea ensued, but this progressed to complr~te amenorrhea by 1941. Over the next year she noted enlargement of her hands and feet and changes in her facial features. At that time she sought medical attention and was informed that she had acromegaly. She received x-ray treatment directed to the pituitary in 1943, and again in 1944. During the following year she noted symptomatic improvement. In 1954 -;he was hospitalized because of generalized convnlsions and subsequently was maintained on anticonvulsive therapy. She was later seen in the endocrine clinic of Bellevue Hospital whrre she has since b<'en followed. Physical examination in 1955 revealed an obese 38-year-old woman with coarsened facial features, moderate prognathism, increased spacing of the teeth, and enlarged spadelike hands. Blood pressure was 130/80, weight 193 pounds, height 63 im·hes. There was mild facial hirsutism and hair on the areolae of the breasts. Examination of the heart, lungs, and abdomen was unremarkable as was the pelvic examination, except for a slightly enlarged clitoris. Neurologic examination showed a constriction of the right upper temporal visual field and increased deep tendon reflexes in the right <"Xtn·mities. Laboratory findings revealed a normal blood count and urinalysis. The serum calcium was 9.0 mg. per cent, phosphorus 3.4 mg. per cent, and the alkaline phosphatase 2.8 Bodansky units. There was decreased glucose tolerance accompanied by insulin resistance (Fig. 1). The protein-bound iodine was 5.0 gamma per rent, cholesterol 225 mg. per cent, 17-hydroxysteroids 7.1 mg. per 24 hour urine (normal 4 to 8), 17ketosteroids 27.8 mg. per 24 hours (normal 8 to 12 mg.), and the FSH was less than 6.6
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Fig. 1. Giucose and insulin tolerance tes ts of Case I. Mrs. 0. G.
Fig. 2. Enlargement and ir reg ularity of scll
:M. U. (norma l 6.6 to 52.8
~'vi. U. ). X-ray of the skull shm..-ed an enlargement of the sella turcica (Fig. 2) , and prognathism. X-ray of the hands revealed tufting of the distal phalanges (Fig. 3). Spinal fl uid ana lysis, pneumoencepha logram, and left carotid arteriogram were normal. The electroencephalogram showed a focal abnormality of the left frontotemporal motor area. The vaginal smear revealed estrogen defi ciency. C ourse. Over the n ext several months she lost weight on a low calorie diet. Because of th e elevation of 17-ketosteroids along with h ir-
_,uiti sJJJ and an enlarged clitoris. ;Jdreua l sup JH''s.. ; ion th c r~lj>}' \vi th prednisone :2 .:.• 111g. thrv!'· tinu·.s a day w as initiated. After Ollt: month of therapy, the 17-ketosteroids were depressed to R. 'l mg. per 2 - ~ hours, substantiating the diagnosis uf the acquired adrcnogen ital syml rOIJl ('. M cnsvs, ho\\'l' l'cr, did not return . Prcgn::ltlt lll are S<'l'lllll was indft·rt il · ~ in ind ucing m cnsc:;. She subs"quenlly rccciwd cydic therapy with chlorutrian iscnc (Tace*) and progesterone and menstruated in n:sponse to this treatment. During tlw nex t '*Tl1e Wm. S.
Mcr r~ll
Company, Cincilluati, Ohiu.
Volume 9G \'umbt:r 2
Acromegaly
177
Fig. 3. Tufting of th e terminal phalanges, Case 1. years, the patient showed a response with menses to progesterone without exogenous estrogen. This indicated rrsumption of some pituitary gonadotropic secretion associated with endogt•nous release of estrogen from the ovary. In 1959, intravem>us Prema rin* induced ovulation as don•mented by basa l b(Jdy temperature chart and pregnanediol determination . Subsequently, the patient showed evidence of spontaneous ovulation and finally becam e pregnant. This pregnancy terminated in a spontaneous abortion at 6 wt~eks' gestation. In the postabortion period she was amenorrheic again for a period of several months and cyclic treatment with progesterone was reinstituted. Spontaneous menses an d ovulation eventually re~umed , and in July, 1963, she repo rtt ~d that hrr last nH·nstrual period was June 12 to 17. A pn.:gnancy test was positive on .July 17, and the pregnanediol level was 2.0 mg. per 24 hour urine. A pre-gnanediol level on July 3 1, was 8.3 mg., which was relatively low and, therdon~, the patient was st:~rted on I ,000 mg. of oral progesterone daily. She had an uneventful pre
March 20, and a normal 5 pound, 5 ounce female infant was delivered. The patient's postpartum course was uneventful and she and her baby were discharged from the hospital in goPd condition. Case 2. Mrs. L. P ., a 48-year-old white femak , was well until 1944, when she noted a coarsenin~ of her facial features, enlargement of the nos t~, acne, facial and body hirsutism, and, finally, enlargement of her hands and feet. She also complained of headaches but reported no visual diffi culties. Menarche occurred at the age of l.">Y2 years and cycles occurrt>d at regubr monthlv intervals. With the onset of disease hn periods, became very irregular and reased entirely by 1949. She was a gravida ii, para ii (first pregnancy in 1940, second in 1942 ) . In 1951, when she sought medical attention, a diag-nosis of acromegaly wa$ made and radiation the;apy was initiated. She received a total of 3,400 r to the pituitary, and subsequently not•·d a decrease in headaches and reg ression of the initial findings. In 1955, she had two spontaneous menstrual periods. Endometrial biopsies revcakd proliferat ive endometrium. She was seen in the Endocrine Clinic of the University H ospital in December 1955, where she presented as a '!> 7vear-old woman with acromegalic facies and enlarged spadelike hands. The blood pressure was 140/ 100, pulse rate 80, RR 12. Eyes: pupils were r qual, reacted to light, the fundi were normal. Thyroid was palpable but not enlarged. The
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lungs were clear and the heart had a regular VE'ntricular beat of 80, no murmurs were heard. The liver, spleen, kidneys, and abdomen \vere not palpably enlarged. Extremities showed no edema. Skin was unremarkable except for some coarsening. There was increased facial and hodv hair. Neurological examination was within normal limits except for a bitf'mporal \'isual field defect. Laboratory findings revealed normal blood count and urinalysis. The serum calcium was 10.5 mg. per cent, phosphorus 4.2 mg. per cent, alkaline phosphatase 3..1 Bodansky units, and cholesterol 190 mg. ]Wr rent. The glucose tolerance test is noted in Fig. J. The 24· hour urinary excretion of 17-ketostC'roids was 30.2 mg., 17 -hydroxysteroids 7.3 mg., pn•g11;mrdio1 0.6 mg., and pregnanetriol 1.3 mg. Vaginal smear revealed estrogen defirienr:y. Skull x-rays .showed a markedly enlarged sella turcica.
Course. Due to the elevated 17-ketosteroids. suppression therapy with glucocorticoids was instituted (prednisone 2.::l mg. three times a day) . On this regime the 17ketosteroids suppressed to 10.3 mg. and was accompanied by resumption of regular menses. In 195 7, an endometrial biopsy revealed a secertory endometrium. In .1960, while off cortisone therapy, she developed menometrorrhagia, and a curettage revealed proliferative endometrium. The patient was restarted on steroids because of an elevated 24 hour urinary ketosteroid excretion. Regular
rt'l'Urrred and endometrial hiopsil's p.roved that thPsc cycles wrn· o\ulatory. At present. the urinary 17-ketost('J'oids arc lU.:l mt;. and tlw patient is being maintained 1.1J1 2.0 rm;. methylprednisolone (Mcdrol)·)f twice a clay. Hn .t;''neral health is satisfartorv. cvclcs
Comment
ThP nccurn'nce of 0\ ulation aml./or prn!nancy following active acromegaly is <"'-· tremdy rare. ' 7 - 111 1ndeecl. rnost of the fl'mak patit-nts de\Tlop anwnorrlwa aml a dinicd picture (lf secondary m·arian fa iltm'. Tl w ovaries usually diminish considerably in si;e and there is failure of graal1an follicle dt'n·loprnent.'· ""Two of our l·ases han~ dcrnonstratcd that ('VCil after ll!any ,·,:ars of ilractivity, the ovary is ca pabk of responcliug '~ith ovulation, tr11der favorahk conditiorh. The nranag(~meut of thC' female pati(·lll in whorn it is desirable to maintain n·producti,,· function n·quires :1 COJISl'JTativf' approaclr. Surgical intcrn'ntion with l'l'TIW\ al of tlw pituitary gland should he n·st'nrd for tlm:>t: cas1•s vvith rapidlv pro!.it'('ssive l'isual distHrbances, lit thost' who fail lu rt'spond tn radiation thnapy or hormonal Jllanagenw1rt. The patient who shows little or no visual field impairment, may be treated with ~"The
Upjohn Company. Kalamalon,
1\ficl·i~~u~.
Volume 96 \'umber 2
methylated androgens ( methylandrostenediol 25 mg-. twice a day) and estrogens (0.2 mg. of ethinyl estradiol, or 5.0 mg. of conjugated estrogens (equine) per day. 9 Periodic deciduation of the endometrium can be accomplislwd with ont> of the progestational agents. The experimental basis for this treatment program may be attributed to the work of Zondek. 21 He gave high doses of estrogen to immature chickens and noted a decrease rate of .e:rowth. which resulted in dwarfism. It appeared that these steroids decreased pituitary eosinophilic activity and inhibited secretion of growth hormone. Such therapy is rcst'rYt>d for the patient who is in the early phase of the disease, in whom enlargcmt'nt of the sella turcica is not evident, and who is willing to submit to very close supervision. Radiation therapy is the most common form of treatmenL:' 2 Current methods utilizing high encrgy radiation from the betatron or alpha. particle radiation from the cyclotron allow the therapist to give a larger localized dose to the tumor. During the course of the radiation therapy, the visual fields should he closely followed. Further visual field impairment may occur due to post radiation edema. An additional decrease of ont' third of the visual fields points toward a need for rapid smgical intervention. Yittrium-90 implants have also been used with some success,":' but a number of complication>. such as t>rosion of the ethmoid sinus,
REFERENCES
1. Marie. Pierre: Rev. med. 6: 297, 1886. '' Davidoff, L. M.: Endocrinology 10: 461, 1926. :1. Da\·idoff, L. M.: Bull. !\ew York Acad. Med. 16: 227. 1940. 4-. Putnan. T. J., and DaYidoff, L. M.: Proc. A. Res. ~erv. & Ment. Dis. 17: 714, 1938. 5. Hamwi, G. J., Skillman, T. G., and Tufts, K. C., .Jr.: Am. J. Med. 29: 690, 1960. 6. Lohlein: Monatsschr. Geburtsh. u. Gyn~ik., 65: 129, 1924. 7. Shimkin. N.: Folia ophth. orient. 1: 90, 1932. 8. William~, R. H.: Textbook of Endocrinology, Philadelphia, 1962, W. B. S:!Unders Company, p. 69. . 9. Kupp~rman, H. S.: Human Endocrmology, Philadelphia, 1963, F. A. Davis Company, p. 168.
Acromegaly
179
with spinal fluid leakage, and subsequent meningitis, have been noted. Radiation therapy may arrest progression of the acromegalic process however, other vital functiom of the pituitary may also be diminished, particularly gonadotropic function. Replacrment therapy, according to the deficiency of trw end organ hom10ne, may then be instituted. That this pituitary insufficiency may be reversible is illustrated by the 2 cases presentee!. One must postulate that while there is art arrest of pituitary function, there is not a complete destruction of the secretol)' cells and eventually th(•se may regenerate and n·sume normal function. Surgical removal of the pituitary would preclude any restoration of pituitary function. It is conceivable that in the future, with the purification and availability of human anterior pituitary hormones, pituitary function may be simulat(•d (even in the hypophysectomized individual I by exogenous administration of purified hllman or synthetic tropic hormones. Summary
Clinical and laboratory features of acmmegaly have been reviewed. Two patients with resumption of ovulatory cycl<·s, and one successful pregnancy following radiation therapy for acromegaly have been describPd. The concepts of therapy have been discussed particularly in relation to maintenance of r('productive function.
10. :Fraser, R., Albright, F., and Smith, P. H.: J. Clin. Endocrinol. 1: 297, 1911. 11. Fraser. R.: Brit. M. Bull. 16: 2~2, 1962. 1') Almgvist, S., Ikkos, D., and Luft, R.: Acta endocrinol. 37: 138, 1961. 13. Daughaday, W. H., Salmon, W. D., Jr .. and Alexander, F.: J. Clin. Endocrinol. 19: 74-3, 1959. 1+. Read, C. H., and Bryan, G. T.: Ciba Found. Col!. Endocrinol. 13: 89, 1960. 15. Yalow, R. S., and Berson, S. A.: Diabetes 10: ~39, 1961. 16. Parker, M. L., l;tiger, R. D., and Dau~ha day, W. H.: J. Clin. Invest. 41: 251, 1962. 17. Abelove, W. A., Rupp, J. J., and Pasrhkis, K. E.: J. Clin. Endocrinol. 14: 32, 1954. 18. Greenblatt, R. B., Vasquez, E., and McLendon, I. C.: Fertil. & Steril. 7: 499, 19.i6.
180 Truchly et al.
:'\1 :\Ill.
19. Finkler, R. S.:
!9.H.
J.
Clin. Endocrinol. 14: 1245,
20. Tandler, J., and Grosz, S.: Klin. Wchnschr. 21: 277, 1908. 21. Zondek, B.: Clinical and experimental in\'estigations on th<' genital function and tht'ir hormonal regulation, Baltimorr, 1941, \Villiams & Wilkins Company, pp. 29-48.
plt·mbn L-l.
J
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!~It,{·
& C-..rwc
Sheline, G. E .. Goldberg. lvL B.. ;wd hid m~n. R.: Radiology 76: 70. I gt) 1 :.'3. Molinatt. G. M., c~manni. F ..\1as;ar;r. :-.1 Olivrcth. M., Pizzini. :\ .. and (;iuliani. (; J C!in. Endocrinol. 22: c)
~~.
550 Fint ANnue Neu• }'ork, New York IOOJii
associatcd with acromegaly. as \\!'II as o11r concept of treatment of the acromegalic female in the childbearing age.
I N 1886, Marie 1 described the clinical entity which we know now as acromegaly. The clinical state that ensues is due to an excessive production of growth hormone at a time when the epiphyses are already closed. In the initial sta,ges of the disease, the modification in the general appearance of the patient may be insidious and is neither readily apparent to the patient. nor to the people with whom he is in close continuous contact. The classical clinical picture pn·~·ents acral enlargement, prognathism, frontal bossing and coarsening of the facial features, including thickenin.g of the lips and enlargenwnt of the nose. ThPre is great \·ariability in the progression of the disease and at times even spontaneous remission may occur. Hypopituitarism may eventually develop either due to advancement of the disease i tsdf or to therapy, resulting in multiglandular defioenctes. In the female, following therapeutic radiation, secondary ovarian failure due to pituitary gonadotropic insufficiency is common. Thl' cases presented in this paper will illustrate that pituitary gonadotropic insufficiency is not always permanent, as menses, ovulation, and even pregnancy may occur. The report herein will briefly summarize the clinical picture and laboratory flndin~s
Manifestations of acromegaly
Enlargement of the sella turcica has bv<'ll reported in as high as 93 per C('tlt and as low as 25 Pf'r cf'nt of these patients." Hcadaclw is a frequent ntanifestation but the so-called typical retrobulbar lwadaclw of pituitan tumor is not common."· ., Hamwi. Skilltnan, ancl Tufts'' obsen·ed 2 patients wlto had ,.i,twl Jicld impairment without gross enlargl'llWilt of the sella turcica, as wcJI as matt\· patit•nV; with normal visual fields accompanil·cl h: massive enlar~ement of the sella. The di1 nsity of the ftndings depends on the direction of the ,growth of the tumor, and pn·ssure ext'rted on surrounding structures.'' The most common visual field impairrnent not1~d i-: ;t hilt'rnporal 11f'mianopsia, with tfw u ppcr nu tn quadrants being; most frequ!'ntly aJlcctecl.' Enlargement of thr ramus of tlw mandihlt• and the frontal sinuses arc cbaractcrist ic fittdings of the changes of tlte sktdl Enbr~t· rncnt of the nw.ndible usually re-;ults in Jmlc:·nathism and widening of the span·s het\\"l'l'rt the spacings of tht' teeth. The l)(lllV changt•., in the vertebral column that !lM,. IH: seen aJ•· those of ltypertrophv and incn·
From the Department of Therapeutic.r, New York University Medical Center. *Present address: Presbyterian-St. Luke's Hospital, Chicago, Illinois. **Present address: The Brookdale Hospital Center, Brooklyn, New r ork.
174
Volume 9ti ~uwlwr ~
of the pores and exaggeration of the skin markings along with the oiliness and excessive sweating are frequent complaints during the actiYe disease state. An increased incidence of lipomas, multiple nevi, or papillomatous skin tags may be encountered. Hirsutism may be another manifestation. Enlargement of the viscera is a common occurrence. The tongue may at times show considerable enlargement with furrowing. Lactorrhea may be present although it is relatively infrequent. 9 The thrust of the enlarged tongue against the teeth of the mandible may contribute further to the diastasis between the teeth. A more recent observation of diagnostic importance has been the increase in thickness of the soft tissue of the heel. Normally, the measurement from the calcaneum to the bottom of the foot is about 16 mm; in acromegaly the same area measures some 22 mm. or more. Laboratory findings
A decrease in glucose tolerance is noted in about 60 per cent of the patients during the active phase of the disease. 10 Some of these patients1 " will show evidence of insulin resistance, and this may be demonstrated by the insulin tolerance testY The most typical finding during the active phase of the disease is the retention of phosphorus, so that the serum phosphorus is usually above 4.5 mg. per cent. Multiple determinations are advisable because of spontaneous fluctuations in serum phosphorus level. Elevation of the 17hydroxysteroids and 17 -ketosteroids also may be observed during the active phase. Assays for growth hormone have been developed more recently, and while such tests are most specific for the detection of active acromegaly, their use is limited, since they are still not readily available to most laboratories. Another assay that has been reviewed is an indirect procedure which use~ the fact that the cartilage of hypophysectomized rats has a reduced ability to incorporate sulfate into chondroitin sulfate. This may be corrected by giving growth horrnone. 12 This principle is used in the assay described by Daughaday, Salmon, and Alcxander/ 3 and is known as the sulfation factor. An immunologic assay
Acromegaly
175
was developed by Read and Bryant/1 usiug the hemagglutination inhibition technique. An ingenious assay similar to the radioisotopic immunoassay of insulin as developed by Yalow and Berson15 has been adapted to the assay of growth hormone. 1 " Case reports Case 1. Mrs. 0. G., a 48-year-old married woman of Czechoslovakian origin, was in good health until 1938, when she noted the onset of severe headaches, weight gain, and, subsequently, increasing facial and general body hair. The patient not<'d a marked change in her regular cyclic menstrual pattern. At first hypomenorrhea ensued, but this progressed to complr~te amenorrhea by 1941. Over the next year she noted enlargement of her hands and feet and changes in her facial features. At that time she sought medical attention and was informed that she had acromegaly. She received x-ray treatment directed to the pituitary in 1943, and again in 1944. During the following year she noted symptomatic improvement. In 1954 -;he was hospitalized because of generalized convnlsions and subsequently was maintained on anticonvulsive therapy. She was later seen in the endocrine clinic of Bellevue Hospital whrre she has since b<'en followed. Physical examination in 1955 revealed an obese 38-year-old woman with coarsened facial features, moderate prognathism, increased spacing of the teeth, and enlarged spadelike hands. Blood pressure was 130/80, weight 193 pounds, height 63 im·hes. There was mild facial hirsutism and hair on the areolae of the breasts. Examination of the heart, lungs, and abdomen was unremarkable as was the pelvic examination, except for a slightly enlarged clitoris. Neurologic examination showed a constriction of the right upper temporal visual field and increased deep tendon reflexes in the right <"Xtn·mities. Laboratory findings revealed a normal blood count and urinalysis. The serum calcium was 9.0 mg. per cent, phosphorus 3.4 mg. per cent, and the alkaline phosphatase 2.8 Bodansky units. There was decreased glucose tolerance accompanied by insulin resistance (Fig. 1). The protein-bound iodine was 5.0 gamma per rent, cholesterol 225 mg. per cent, 17-hydroxysteroids 7.1 mg. per 24 hour urine (normal 4 to 8), 17ketosteroids 27.8 mg. per 24 hours (normal 8 to 12 mg.), and the FSH was less than 6.6
176
:-,,·· p tt' ml.tt' l' t."'' · l ~ll)t
Truc hl y et al.
160 "0 ~
::;:
140
l
.\Ill .
J. Ob ~ T .
\li{ (;\'I WI
GLUCOSE AND INSULIN TOLERANCE TE ST - - - - N ORMAL GT T PATIENT 'S GTT "" " " "'"' NORMAL iTT · - · - • • PATIENT 'S I T T
a: 120 <(
:::>
100
0
0 0
80
Ill
60
rJl
...J
40
1------ - - ,-----------,--------- r0
30
60 TIME
r ·-
90 IN
---- ---
12 0
_ T __ _
150
--- - , lBO
MINUTE S
Fig. 1. Giucose and insulin tolerance tes ts of Case I. Mrs. 0. G.
Fig. 2. Enlargement and ir reg ularity of scll
:M. U. (norma l 6.6 to 52.8
~'vi. U. ). X-ray of the skull shm..-ed an enlargement of the sella turcica (Fig. 2) , and prognathism. X-ray of the hands revealed tufting of the distal phalanges (Fig. 3). Spinal fl uid ana lysis, pneumoencepha logram, and left carotid arteriogram were normal. The electroencephalogram showed a focal abnormality of the left frontotemporal motor area. The vaginal smear revealed estrogen defi ciency. C ourse. Over the n ext several months she lost weight on a low calorie diet. Because of th e elevation of 17-ketosteroids along with h ir-
_,uiti sJJJ and an enlarged clitoris. ;Jdreua l sup JH''s.. ; ion th c r~lj>}' \vi th prednisone :2 .:.• 111g. thrv!'· tinu·.s a day w as initiated. After Ollt: month of therapy, the 17-ketosteroids were depressed to R. 'l mg. per 2 - ~ hours, substantiating the diagnosis uf the acquired adrcnogen ital syml rOIJl ('. M cnsvs, ho\\'l' l'cr, did not return . Prcgn::ltlt lll are S<'l'lllll was indft·rt il · ~ in ind ucing m cnsc:;. She subs"quenlly rccciwd cydic therapy with chlorutrian iscnc (Tace*) and progesterone and menstruated in n:sponse to this treatment. During tlw nex t '*Tl1e Wm. S.
Mcr r~ll
Company, Cincilluati, Ohiu.
Volume 9G \'umbt:r 2
Acromegaly
177
Fig. 3. Tufting of th e terminal phalanges, Case 1. years, the patient showed a response with menses to progesterone without exogenous estrogen. This indicated rrsumption of some pituitary gonadotropic secretion associated with endogt•nous release of estrogen from the ovary. In 1959, intravem>us Prema rin* induced ovulation as don•mented by basa l b(Jdy temperature chart and pregnanediol determination . Subsequently, the patient showed evidence of spontaneous ovulation and finally becam e pregnant. This pregnancy terminated in a spontaneous abortion at 6 wt~eks' gestation. In the postabortion period she was amenorrheic again for a period of several months and cyclic treatment with progesterone was reinstituted. Spontaneous menses an d ovulation eventually re~umed , and in July, 1963, she repo rtt ~d that hrr last nH·nstrual period was June 12 to 17. A pn.:gnancy test was positive on .July 17, and the pregnanediol level was 2.0 mg. per 24 hour urine. A pre-gnanediol level on July 3 1, was 8.3 mg., which was relatively low and, therdon~, the patient was st:~rted on I ,000 mg. of oral progesterone daily. She had an uneventful pre
March 20, and a normal 5 pound, 5 ounce female infant was delivered. The patient's postpartum course was uneventful and she and her baby were discharged from the hospital in goPd condition. Case 2. Mrs. L. P ., a 48-year-old white femak , was well until 1944, when she noted a coarsenin~ of her facial features, enlargement of the nos t~, acne, facial and body hirsutism, and, finally, enlargement of her hands and feet. She also complained of headaches but reported no visual diffi culties. Menarche occurred at the age of l.">Y2 years and cycles occurrt>d at regubr monthlv intervals. With the onset of disease hn periods, became very irregular and reased entirely by 1949. She was a gravida ii, para ii (first pregnancy in 1940, second in 1942 ) . In 1951, when she sought medical attention, a diag-nosis of acromegaly wa$ made and radiation the;apy was initiated. She received a total of 3,400 r to the pituitary, and subsequently not•·d a decrease in headaches and reg ression of the initial findings. In 1955, she had two spontaneous menstrual periods. Endometrial biopsies revcakd proliferat ive endometrium. She was seen in the Endocrine Clinic of the University H ospital in December 1955, where she presented as a '!> 7vear-old woman with acromegalic facies and enlarged spadelike hands. The blood pressure was 140/ 100, pulse rate 80, RR 12. Eyes: pupils were r qual, reacted to light, the fundi were normal. Thyroid was palpable but not enlarged. The
178
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lungs were clear and the heart had a regular VE'ntricular beat of 80, no murmurs were heard. The liver, spleen, kidneys, and abdomen \vere not palpably enlarged. Extremities showed no edema. Skin was unremarkable except for some coarsening. There was increased facial and hodv hair. Neurological examination was within normal limits except for a bitf'mporal \'isual field defect. Laboratory findings revealed normal blood count and urinalysis. The serum calcium was 10.5 mg. per cent, phosphorus 4.2 mg. per cent, alkaline phosphatase 3..1 Bodansky units, and cholesterol 190 mg. ]Wr rent. The glucose tolerance test is noted in Fig. J. The 24· hour urinary excretion of 17-ketostC'roids was 30.2 mg., 17 -hydroxysteroids 7.3 mg., pn•g11;mrdio1 0.6 mg., and pregnanetriol 1.3 mg. Vaginal smear revealed estrogen defirienr:y. Skull x-rays .showed a markedly enlarged sella turcica.
Course. Due to the elevated 17-ketosteroids. suppression therapy with glucocorticoids was instituted (prednisone 2.::l mg. three times a day) . On this regime the 17ketosteroids suppressed to 10.3 mg. and was accompanied by resumption of regular menses. In 195 7, an endometrial biopsy revealed a secertory endometrium. In .1960, while off cortisone therapy, she developed menometrorrhagia, and a curettage revealed proliferative endometrium. The patient was restarted on steroids because of an elevated 24 hour urinary ketosteroid excretion. Regular
rt'l'Urrred and endometrial hiopsil's p.roved that thPsc cycles wrn· o\ulatory. At present. the urinary 17-ketost('J'oids arc lU.:l mt;. and tlw patient is being maintained 1.1J1 2.0 rm;. methylprednisolone (Mcdrol)·)f twice a clay. Hn .t;''neral health is satisfartorv. cvclcs
Comment
ThP nccurn'nce of 0\ ulation aml./or prn!nancy following active acromegaly is <"'-· tremdy rare. ' 7 - 111 1ndeecl. rnost of the fl'mak patit-nts de\Tlop anwnorrlwa aml a dinicd picture (lf secondary m·arian fa iltm'. Tl w ovaries usually diminish considerably in si;e and there is failure of graal1an follicle dt'n·loprnent.'· ""Two of our l·ases han~ dcrnonstratcd that ('VCil after ll!any ,·,:ars of ilractivity, the ovary is ca pabk of responcliug '~ith ovulation, tr11der favorahk conditiorh. The nranag(~meut of thC' female pati(·lll in whorn it is desirable to maintain n·producti,,· function n·quires :1 COJISl'JTativf' approaclr. Surgical intcrn'ntion with l'l'TIW\ al of tlw pituitary gland should he n·st'nrd for tlm:>t: cas1•s vvith rapidlv pro!.it'('ssive l'isual distHrbances, lit thost' who fail lu rt'spond tn radiation thnapy or hormonal Jllanagenw1rt. The patient who shows little or no visual field impairment, may be treated with ~"The
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methylated androgens ( methylandrostenediol 25 mg-. twice a day) and estrogens (0.2 mg. of ethinyl estradiol, or 5.0 mg. of conjugated estrogens (equine) per day. 9 Periodic deciduation of the endometrium can be accomplislwd with ont> of the progestational agents. The experimental basis for this treatment program may be attributed to the work of Zondek. 21 He gave high doses of estrogen to immature chickens and noted a decrease rate of .e:rowth. which resulted in dwarfism. It appeared that these steroids decreased pituitary eosinophilic activity and inhibited secretion of growth hormone. Such therapy is rcst'rYt>d for the patient who is in the early phase of the disease, in whom enlargcmt'nt of the sella turcica is not evident, and who is willing to submit to very close supervision. Radiation therapy is the most common form of treatmenL:' 2 Current methods utilizing high encrgy radiation from the betatron or alpha. particle radiation from the cyclotron allow the therapist to give a larger localized dose to the tumor. During the course of the radiation therapy, the visual fields should he closely followed. Further visual field impairment may occur due to post radiation edema. An additional decrease of ont' third of the visual fields points toward a need for rapid smgical intervention. Yittrium-90 implants have also been used with some success,":' but a number of complication>. such as t>rosion of the ethmoid sinus,
REFERENCES
1. Marie. Pierre: Rev. med. 6: 297, 1886. '' Davidoff, L. M.: Endocrinology 10: 461, 1926. :1. Da\·idoff, L. M.: Bull. !\ew York Acad. Med. 16: 227. 1940. 4-. Putnan. T. J., and DaYidoff, L. M.: Proc. A. Res. ~erv. & Ment. Dis. 17: 714, 1938. 5. Hamwi, G. J., Skillman, T. G., and Tufts, K. C., .Jr.: Am. J. Med. 29: 690, 1960. 6. Lohlein: Monatsschr. Geburtsh. u. Gyn~ik., 65: 129, 1924. 7. Shimkin. N.: Folia ophth. orient. 1: 90, 1932. 8. William~, R. H.: Textbook of Endocrinology, Philadelphia, 1962, W. B. S:!Unders Company, p. 69. . 9. Kupp~rman, H. S.: Human Endocrmology, Philadelphia, 1963, F. A. Davis Company, p. 168.
Acromegaly
179
with spinal fluid leakage, and subsequent meningitis, have been noted. Radiation therapy may arrest progression of the acromegalic process however, other vital functiom of the pituitary may also be diminished, particularly gonadotropic function. Replacrment therapy, according to the deficiency of trw end organ hom10ne, may then be instituted. That this pituitary insufficiency may be reversible is illustrated by the 2 cases presentee!. One must postulate that while there is art arrest of pituitary function, there is not a complete destruction of the secretol)' cells and eventually th(•se may regenerate and n·sume normal function. Surgical removal of the pituitary would preclude any restoration of pituitary function. It is conceivable that in the future, with the purification and availability of human anterior pituitary hormones, pituitary function may be simulat(•d (even in the hypophysectomized individual I by exogenous administration of purified hllman or synthetic tropic hormones. Summary
Clinical and laboratory features of acmmegaly have been reviewed. Two patients with resumption of ovulatory cycl<·s, and one successful pregnancy following radiation therapy for acromegaly have been describPd. The concepts of therapy have been discussed particularly in relation to maintenance of r('productive function.
10. :Fraser, R., Albright, F., and Smith, P. H.: J. Clin. Endocrinol. 1: 297, 1911. 11. Fraser. R.: Brit. M. Bull. 16: 2~2, 1962. 1') Almgvist, S., Ikkos, D., and Luft, R.: Acta endocrinol. 37: 138, 1961. 13. Daughaday, W. H., Salmon, W. D., Jr .. and Alexander, F.: J. Clin. Endocrinol. 19: 74-3, 1959. 1+. Read, C. H., and Bryan, G. T.: Ciba Found. Col!. Endocrinol. 13: 89, 1960. 15. Yalow, R. S., and Berson, S. A.: Diabetes 10: ~39, 1961. 16. Parker, M. L., l;tiger, R. D., and Dau~ha day, W. H.: J. Clin. Invest. 41: 251, 1962. 17. Abelove, W. A., Rupp, J. J., and Pasrhkis, K. E.: J. Clin. Endocrinol. 14: 32, 1954. 18. Greenblatt, R. B., Vasquez, E., and McLendon, I. C.: Fertil. & Steril. 7: 499, 19.i6.
180 Truchly et al.
:'\1 :\Ill.
19. Finkler, R. S.:
!9.H.
J.
Clin. Endocrinol. 14: 1245,
20. Tandler, J., and Grosz, S.: Klin. Wchnschr. 21: 277, 1908. 21. Zondek, B.: Clinical and experimental in\'estigations on th<' genital function and tht'ir hormonal regulation, Baltimorr, 1941, \Villiams & Wilkins Company, pp. 29-48.
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Sheline, G. E .. Goldberg. lvL B.. ;wd hid m~n. R.: Radiology 76: 70. I gt) 1 :.'3. Molinatt. G. M., c~manni. F ..\1as;ar;r. :-.1 Olivrcth. M., Pizzini. :\ .. and (;iuliani. (; J C!in. Endocrinol. 22: c)
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