Acta Medica Scandinnvicr. Vol. CLV, fnsc. V, 1956.

From the Medical Out-Patient Clinic, University Hospital, Copenhagen.

Clinical Endocrine Disturbances in Diabetics; their Relation to Late Diabetic Lesions.

BY

ARNE P. SKOUBY.

(Submitted for publication July 3, 1956.)

A variety of clinical endocrine disorders is inconstantly found in diabetics, whether coincidentally or in relation to the diabetic metabolic disorder has not been settled. However, such differences in endocrine function may contribute to the varying predisposition to late diabetic lesions in patients of uniform age a t onset, duration of diabetes and management in a series analysed especially with regard to the influence of treatment (Skouby 1956).

Therefore the incidence of clinical endocrine disorders in the series was also examined. Their relation to diabetes and the influence on the development of late lesions were estimated as was the influence of chorionic gonadotropin from urine administered to a number of the patients.

Material nitd Method.

The series studied comprised 124 women and 101 men with an onset of diabetes before the age of 40. They were questioned with special reference to endocrine disorders in the family (comprising descendants from the patients grandparents) and to endocrine disorders before and after the onset of diabetes. A planned exam- ination of the incidence of impotence and similar sexual disturbances was not carried out, as no reliable information could be obtained for several cases. A thorough description of patient selection and of the detailed follow-up study of the series is given elsewhere (Skouby 1956).

B e d ts. Apart from one case of adiposo-genital dystrophy family histories were known

only of diabetes, obesity and goiter.

402 ARNE P. SKOUBY.

Incidence of diabetes, other endocrine disorders and obesity i n the family.

A family history of diabetes was given by 51 per cent of the women and by 40 per cent of the men, corresponding fairly well to the figures found by previous investigators. In the patients predisposed to diabetes a family history of obesity was given by 19 per cent of the women and by 9 per cent of the men, while an incidence of 4-5 per cent was found in patients not predisposed to diabetes. The incidence of predisposition to endocrine disorders apart from diabetes was 4 per cent for women and 2 per cent for men in patients with predisposition and 2 and 0 per cent in patients without predisposition to diabetes (table 1).

No correlation was demonstrated between predisposition to one or several of the disturbances mentioned above and the occurrence of late lesions.

Obesity, goiter with or without hyperthyroidism, delayed maturity and abnormal growth were the only disturbances found to occur before or after the onset of diabetes in all but two patients in whom diabetes occurred after hormonal treat- ment for irregular uterine hyperplasia and for eunuchoidism respectively.

Incidence of prediabetic obesity.

Prediabetic obesity occurred in approximately 50 per cent of the female and in 40 per cent of the male patients predisposed to obesity but independent of predis- position to diabetes. I n the groups with no predispositions or a predisposition to diabetes only the incidence was approximately 20 per cent for women and 6 per cent for men.

No correlation was demonstrated between prediabetic obesity and the occurrence of late lesions.

Incidence of goiter.

An incidence of hyperthyroidism in diabetics of approximately 1 per cent was found by the Joslin group (Root 1952). Aarseth (1952) found similar figures for toxic and nontoxic goiter, while a 5 per cent incidence of goiter was found in women by Horstmann (1949). The incidence may partly depend on the over-all incidence of goiter in the areas concerned.

I n Denmark the incidence varies from one place to another and in a narrow area with sex and age. As the gland can be outlined by palpation in most Danish individuals and is visible in approximately 90 per cent of the women, the term goiter is used only when the gland is distinctly larger than usual or when an adenoma can be demonstrated. Ih a rural district assumed to be free of endemic goiter the incidence was 2.3 per cent in females and 0.4 per cent in males. For individuals 10-35 years of age the incidence was 5.1 and 1.2 per cent (Rosen- quist 1943). Similar values have been found for Copenhagen (Trier pers. comm.).

I n the present series of diabetics a distinct goiter was demonstrated in 12 women (10 per cent) and 1 man (1 per cent) (table 1). The man and 4 of the women had been treated for hyperthyroidism. The goiter was detected after diabetes in all cases but one. The family history of diabetes was the same as for the total series, but five were predisposed to both diabetes and goiter. One was predisposed to

CLINICAL EKDOCRINE DISTURBANCES I N DIABETICS. 403

Table 1.

Per cent incidence of predisposition to diabetes, obesity and other endocrine disorders. F. M.

Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 40 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 13 Diabetes and obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 9 Other endocrine disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2 Diabetes and other endocrine disorders. .................... 4 2

Per cent incidence of goiter, delayed menarche and abnormal growth. F. M.

Goiter .................................................. 10 1 Delayed menarche ....................................... 13 Retardation of growth ................................... 2 6 Acceleration of growth ................................... < 1 3

obesity. I n one the menarche appeared late, while no endocrine disturbances apart from diabetes and goiter were found in the other patients.

The incidence of late diabetic lesions corresponded to that found for the total series.

Incidence of early and of late menarche.

The menarche occurs usually between 13 and 15 years of age. It may occur earlier without endocrine disorder, while an appearance later than 16 years of age is suspicious for endocrine disease.

I n the present series of 124 women the first menstruation occurred a t 11-12 years of age in 6 and a t the age of 17 or later in 16 women.

I n the group with an early menarche diabetes was detected a t 13-36 years of age. A family history of diabetes was given by five and predisposition to obesity by three. Two were obese before and four after the onset of diabetes. None was predisposed to endocrine disorders apart from diabetes and no endocrine dis- orders apart from the early menarche were detected in these cases. Only one had an adult height below the average level. Diabetes appeared a t 36 years of age in this patient.

The incidence of late lesions in this group was probably less than for the total series, but cannot be safely settled due to the small number of cases.

Sixteen women (13 per cent) had their first menstruation after 17 years of age (table 1). As for those with an early menarche the incidence of predisposition to diabetes was greater than for the total series (70 per cent). This was not due to the early onset of diabetes and a secondarily retarded maturity in predisposed girls, as the incidence was even greater for the 8 women in whom diabetes appeared after the first but retarded menstruation. Two of the women were predisposed to obesity and none to endocrine disorders apart from diabetes. Three were fat before but only one after the onset of diabetes. An atoxic goiter was found in one and in another amenorrhoea persisted to 23 years of age, when menstruation was provoked by the administration of gonadotropin from urine. I n one case the adult height

404 ARNE P. SKOUBY.

Table 2.

Retinopathy and aIhninur ia in patients with transient or permanent growth retardation.

, 1 Type of Age at I Duration ’ Retino- Albumin- ’ Final height

Sex I diet onset ofdiabetes pathy uria , in cm ~

M M M M M M F P F

~

F . D . . . . . . ‘C .D . . . . . . . . F . D . . . . . . . . C.D . . . . . . . . . F . D . . . . . . . .

1C. D. . . . . . . . . F . D . . . . . . . .

. C . D . . . . . . . . $ . D . . . . . . . . .

4 1 21 5 ~ 24 8 “3

11 1 30

39 ’ 20 14 25 19 2 28 12

19 I 12

IV + 1G4 I1 0 ‘ 161 I v + 160 0 0 ~ 169

111 + ~ 163 IV 0 141 1V 0 152 0 0 160

I1 + 1 166

For each case the type of diet, the age at onset of diabetes, the duration of the disease and the final height are given. The degree of retinopathy is given according to previous definitions (Skouby 1956).

F. D. Free diet without sugar. C. D. Classical diet.

was definitely below the average. Ten married when adult and 7 were pregnant one or several times.

The incidence of late complications in these patients with late menarche did not differ from the figures found for the total series.

Incidence of abnormal growth.

Transitory or permanent retardation of growth occurred in three females and 6 males. Transitory acceleration of growth was stated by one female and three males (table 1). Four patients were small before diabetes onset. Predisposition to diabetes was stated by one woman and one man with retarded growth and predis- position to obesity in one woman with this anomaly. None were predisposed to endocrine disorders apart from diabetes.

Slight retinopathy (I) was found in one of 4 patients with transient rapid growth (after 6 years diabetes duration). 7 of 9 patients with retarded growth had retino- pathy II-IV a t the afterexamination, but five had suffered from diabetes for 20-30 years. The incidence of severe lesions is higher than for the total series, also when the duration of the disease is considered, but the small number of cases permits no definite conclusions (table 2).

Four of these patients had been treated with chorionic gonadotropin from urine. Three are dealt with in more detail below in connection with other patients devel- oping diabetes or severe retinopathy after this therapy.

Occurrence of diabetes or late complications in patients given chorionic gonadotropin from urine.

Three patients got diabetes after therapy with gonadotropic hormone for endocrine disturbances.

CLINICAL ENDOCRINE DISTURBANCES IN DIABETICS. 405

Case 1. Female with no predisposition to diabetes or endocrine disorders. Irregular menstruation from the age of 12, treated several times with abrasio uteri due to irregular hyperplasia of the uterine mucosa. At the age of 19 she was given 5 injections of 1,500 i. u. gonadotropic hormone over a fortnight and then Lutocyclin (Ciba) 10 mg daily for 5 days. The following weeks she complained of thirst, polyuria and an abnormally&large appetite. Glucose was demonstrated in the urine and her doctor referred her to us, as he believed her diabetes to be caused by the injections of gonadotropic hormone. Her diabetes was fairly mild and was treated by diet only, not by insulin. No late complica- tions were detected after two years.

At the afterexamination she looked a little infantile but growth of sexual hair was normal for the age and her breasts well developed. Her menstruation was still irregular.

Case 2. Male with a family history of diabetes. A cousin has adiposo-genital dys- trophy. When the patient was six his parents were divorced and he was then brought up by his grandmother. Due to rich food he soon became fat. Because of obesity and (apparently?) small reproductive organs he was given a total of 20,000 i. u. of gonadotro- pic hormone from pregnant mare serum and 17,000 i. u. of chorionic gonadotropin from urine over a 2-year period from 12 to 14 years of age. During this treatment he com- plained of thirst and polyuria. Nothing is stated concerning his bodyweight. When examined two years later diabetes was detected. His physical development has since been fairly normal under treatment with the classical diet and 80 i. u. insulin daily. No late complications could be demonstrated after a diabetes duration of 14 years.

Case 3. Eunuchoid male with no familiar predisposition, but ))the only boy in the whole family)). When he was ten orchidopexia was performed for cryptorchidism. Due to this disorder and hypogonadism he was given several series of gonadotropic hormone from 24 years of age. Under the first series transient edema occurred. Half a year after a final series given a t 32 years of age (to a total amount of 164,000 i. u.) diabetes occurred. No late complications were detected a t the afterexamination seven years a€ter the onset of diabetes. His epiphyses were closed. Excretion of 17-ketosteroids in urine was normal (13.7 mg/24 h.). Due to osteoporosis of the spine a fractionated 17-ketosteroidanalysis was performed, reflecting testicular insufficiency (decreased androsterone) and a simul- taneous adrenal hyperfunction (increased dehydroisoandrosterone) (Johnsen 1956). He needs 56 i. u. of insulin daily.

Two patients developed severe retinopathy after treatment with gonadotropic hor- mone from urine.

Case 4. Female with a family history of diabetes and with diabetes from 11 years of age. Due to hypogonadism and primary amenorrhoea she had 5 injections of serum gonadotropin and three injections of Urine gonadotropin when 20 years old Fever and pains in the abdomen occurred but no menstruation. ilnother series of gonadotropin from urine was given two years later. The following year menstruation appeared after 13 injections of gonadotropin from urine.

Microaneurysms and a single exudate was detected when she was 19 years old. Visual acuity decreased slightly during the second series of hormone injections and after the last treatment i t decreased rapidly so that she was nearly blind half a year later. X-ray treatment was given on the eyes with little effect.

At the afterexamination she was of normal height and developnient and menstruation was still normal. Her insulin needs are 56 i. u. a day.

Case 5. Male with no predisposition to diabetes or endocrine disorders. Diabetes from 4 years of age and always stunted and infantile on free diet and insulin. His reproduc- tive organs were always within normal limits in size. When 17 years old ophthalmoscopy was normal.

At 16 year3 of age he was given a total of 13,000 i. u. gonadotropin from urine. The following year he had another series of 16 injections followed by 30 injections containing 15,000 i. u. plus 2 ml phyol (a preparation of somatotropin from anterior lobe). When 18, 20 injections of phyol(2 ml) were given. During a series of 22 injections of gonadotropin

29 -5fi35.37. .4cltr m r d . Scctndintro. I ’ o I . CI.1’.

406 ARNE P. SKOUBY.

from urine at 23 years of age his visual acuity decreased and several microaneurysms, small hemorrhages and exudates were detected. His vision decreased during the fol- lowing months and X-ray on the pituitary produced no changes. He is now nearly blind. He needs 88 i. u. of insulin daily.

In an obese male patient dead before the present investigation a slight diabetes not needing insulin was worsened during treatment with chorionic gonadotropin for impo- tence. Diet alone was insufficient as therapy and insulin in daily amounts of up to 96 i. u. had to be given. Two years after stopping the treatment with gonadotropic hormones the insulin needs were reduced to zero in spite of unchanged body weight.

Total incidence of cases with definite endocrine disorders.

Sixteen women had menarche after 17 years of age. One of them had also a goiter as was the case for 11 women with normal menarche. Retardation of growth was claimed by three women but only one of these had a definite endocrine disturbance apart from a late menarche. This was the diabetic woman with diabetes occurring just after hormonal treatment. Thus 28 of 124 women (23 per cent) had definite endocrine disturbances apart from diabetes.

Among the diabetic males five had definite endocrine disturbances apart from diabetes (5 per cent). One had a toxic goiter, one was small (141 cm) before diabetes appeared a t 39 years of age, one suffered from eunuchoidism before diabetes and in 2 with diabetes from 4-5 years of age stunting of growth and delayed maturity were the main complaints.

As one female and three males were sent to us because of other disturbances than diabetes the incidence of definite endocrine disturbances casually found in the series is approximately 22 per cent for women and 2 per cent for men.

Discussion.

From the figures found for prediabetic obesity and for predisposition to obesity and diabetes a genetical relationship between obesity and diabetes may be sug- gested for some of the patients as between goiter and diabetes in others.

The incidence of goiter in the present series is higher than in any series hitherto published. This may be due to the limited number of cases examined but more likely to the long standing of diabetes in several cases before the follow-up study. However, the incidence certainly exceeds by far that to be expected from accidental coincidence.

The high incidence of delayed menarche preceding diabetes indicates that in diabetics delayed maturity often is independent of the diabetic metabolic disorder as was probahly the case for the group of patients reported by Gibson and Fowler (1936). In their cases infantilism in girls was manifested by amenorrhoea and com- plete or partial failure of development of the secondary sex characteristics. A cs ta in degree of dwarfism was present in all. No growth disturbances were demon- strated in our patients with a late menarche, but their height a t puberty is un- known and a prolonged period of growth and development as demonstrated for immature, stunted diabetics (Beal 1948) cannot be excluded.

CLINICAL ENDOCRINE DISTURBANCES I N DIAHETICS. 407

Retardation of growth in the present series was often slight and occurred Ilefore the onset of diabetes in 4 of 9 cases suggesting again an independence of the diabetic metabolic disorder. This is in agreement with the findings in series of diabetic children examined for disturbances of growth and development. In such groups with an onset of diabetes before 15-16 years of age a definitely delayed menarchc cannot be demonstrated before diabetes. Stunting, however, is often detected early in life. When the height a t the onset of the disease is given for stunted children with well controlled diabetes, it is nearly always below average and often below the normal range a t that time (Boyd and Nelson 1928, Priesel and Wagner 1930, Boyd and Kantrow 1938, Greene et al. 1941, Jackson and Kelly 1946).

These findings do not exclude that delayed maturity and growth can he clue to insufficient treatment as similar disturbances are frequently seen in non-diabetic children due to undernutrition or severe illness. Hepatomcgaly indicating mal- adjustment (Hanssen 1936) was demonstrated in more than 50 per cent of tlicl ))dwarfs)) of Wagner et al. (1942) and in nearly all cases reported by Engel (1947, 1950) and Bergquist (1954). Insufficient therapy was probably of importance for the final degree of stunting produced in these patients in spite of the fact that such disturbances are found in a minority of patients with insufficient medical treatment. However, other factors played a role as well. In the series of Wagner et al. the prediabetic height was below average in $0 per cent of the cases whosc height a t the onset of diabetes was known and in nearly all reported by Engel and Bergquist. Small size in other family members was reported by 30 per cent of the total series of Wagner et al. and by 8 of 11 ))dwarfs)) published by Bergquist. Whether delayed maturity also occurred in the families was not investigated.

Thus delayed growth and development in several cases are demonstrated before the diabetic metabolic disturbances, which are never shown to be of decisive importance for delayed growth and development in diabetics.

Endocrine function tests have revealed abnormalities in diabetic ))dwarfso (for references: Bergquist 1954) but not different from those generally demonstrated in ))mature)) adult diabetics (for references: Horstmann 1950. Becker et al. 1954). Thus the only difference between the two groups of patients may be the time for the onset of the same endocrine disorder responsible for the delayed maturity and growth in the )dwarfs)), for the limited sexual activity in the ))mature)) and for the low excretion in urine of 17-ketosteroids and gonadal hormones in them all. Whether a pituitary dysfunction is of importance for the disturbances remains to be demonstrated. In diabetic ))dwarfs)) the needs of insulin are often large, glycosuria and ketosis common findings and adrenal function tests normal. A normal or increased liberation of growth hormone is not inconsistent with diabetic ))dwarfism)) and might explain the occurrence of diabetes in genetically small individuals with a reduced demand for protein. Furthermore retardation of growth in spite of a normal or increased liberation of growth hormone may occur before diabetes due to an insufficient output of insulin. When also corticotropin in the blood is increased a diabetic state occurs because of an enhanced formation of carbo- hydrate precursors and an intensified inhibition of glucose utilization. Hepato- megaly so frequently seen in diabetic ))dwarfs)) may partly be due to the mobiliza-

408 ARNE P. SKOURY.

tiori of depot fat arid its transportation to the liver caused by growth hormone (for references concerning the action of growth hormone: Weil 1955).

The disturbances discussed above are not the only endocrine disorders frequently detected in diabetics. Russi et al. (1945) reported an incidence of adenomas of the adrenal cortex of 1.45 per cent in a series of 9,000 consecutive autopsies. Among 270 diabetics in the same series, however, the incidence was 8 per cent. Becker and Friedenwald found the incidence of adenomas to be correlated with the occur- rence of Kimmelstiel- Wilson renal disease. The incidence of simultaneous abnor- malities of other endocrine glands was not examined. Whether diabetes or adenomas are the primary disorder cannot be settled in these cases, no more than for the cases with goiter in the present series. However, disturbances in function or mor- phology of nearly all endocrine glands seem to occur more frequently in diabetics than in non-diabetics.

Most of the endocrine disturbances discussed ahovc may be explained by a pituitary overactivity in individuals suffering from hypogonadism. Treatment with gonadal hormones, however, is of little influence on the diabetic disorder, indicating that the disease is not caused by but associated with the other hormonal disturbances. Whether diabetes usually is part of a general endocrine disease with a symptomatology dependent of the weakest links of the chain cannot he settled.

The appearance of permanent diabetes in three patients after the adniinistra- tion of gonadotropin from urine may be accidental or due to the diabetogenio properties of the extracts in predisposed individuals. During the years covered by the present investigation choriongonadotropin was very extensively used in our clinic in the treatment of hypogonadism in young persons. On the other hand the assumption of a diabetogenic action is supported by the fact that a decreased carbohydrate tolerance occurred in 2 of 3 stunted diabetics given chorionic gonadotropin from urine by Gibson and Fowler (1936) and in a case of the present author. From the apparent influence of the extract on the progression rate of retinopathy in two cases of the present series it seems wise to avoid this thera- peutic measure in the treatment of diabetics a t least until its mechanism is better understood. From the results i t may be suggested that the increased insulin sen- sitivity in pregnant women in periods with an increased excretion in urine of chorionic gonadotropin (Keltz et al. 1950) may be due to other factors than the excess production of this hormone. An increased demand for protein and any additional outlets for the surplus short chain elements which accumulate under the influence of growth hormone would reduce the requirement for insulin as well.

It is interesting that the incidence of late lesions in the series exceeded the expect- ed rate only in the group of stunted patients often treated with chorionic gonado- tropin. I n diabetic ))dwarfs)) examined by Wagner et a]., and carefully treated, arteriosclerosis and cataract occurred more frequently and ocular changes as frequently as in groops of poorly controlled children without retardation of growth and development. The incidence of late lesions in the vdwarfso published by Berg- quist was remarkable too. This may partly be due to the factors responsible for the retardation or to an influence of the procedures instituted in these cases such

CLINICAL ENDOCRINE DISTURBANCES IN DIABETICS. 409

as administration of chorionic gonadotropin, pituitary extracts, thyroid and testosterone all found t o increase the needs for insulin in these patients.

Se m mary.

A series of 124 female arid 101 male diabetics was examined for endocrine tlis- turhances apart from diabetes. In 23 per cent of the females aiid in 5 per cent of the male patients such definite endocrine disorders occurred.

Goiter was found in 12 women (10 per cent) and 1 man. Delayed menarche (after the age of 17) occurred in 16 women (13 per cent)

and before the onset of diabetes in 8 of them. Growth c~isturbances occurred in 4 female aiid 8 male patients. 4 were small

Iwfore the onset of the disease. One patient suffercd also from irregular liyper- plasia of the uterine mucosa and another from eunuchoidism.

Therapy with chorionic gonadotropin from urinc was followed by diabetes in 3 cascs arid by severe retinopathy in two diabetics.

I n patients with retarded growth the incidence of late diahctic lesions was greater than t o be expected.

The results are discussed.

References.

Aarseth, S.: Cardiovascular-Renal Disease in Uiabetes Mellitus. Oslo 1953. - Heal, C. J.: Pediat. 32, 170, 1948. - Becker, B. and Friedenwald, J. S.: cit. - Becker, B., Maegwyn-Davies, G. D., Rosen, I)., Friedenwald, J. D. and Winter, F. C.: Diabetes 3 , 175, 1954. - Hergquist, N.: ilcta Endocrinol. If5, 133, 1954. - Boyd, J. I). and Nelson, M. V.: Am. J. Dis. Child. 35, 753, 1928. - Boyd, J. D. and Kantrow, A. H.: Am. J. Dis. Child. 55, 460, 1938. - Engel, A.: Nord. Med. 33, 25, 1947. - Engel, A.: Nord. Med. 43, 902, 1950. - Gibson, R. R. and Fowler, W. M.: Arch. Int. Med. 57, 695, 1936. - Green?, J. A., January, L. E. and Rwanson, L. W.: J. Clin. Endocrinol. I , 538, 1941. -- Hanssen, P. J.: Am. Med. Ass. 106, 914, 1936. ~- Horstmann, P.: Acta Endocrinol. 5, 261, 1950. - Jackson, R. L. and Kelly, H. G.: J. Pediat. 29, 316, 1946. - Johnsen, S. G.: Acta Endocrinol. 21, 157, 1956. - Keltz, B. F., Keaty, E. C. and Hellbaum, A. A.: South Med. J. 43, 803, 1950. - Priesel, R. and Wagner, R.: Ztschr. f. Kinderh. 49, 419, 1930. - Russi, S., Blumenthal, H. T. and Gray, S. H.: Arch. Int. Med. 76, 284, 1945. - Root, H. F. in J o s h : Treatment of Diabetes Mellitus p. 626, 1952. - Rosenquist, K.: Om Strumaproblemet. Copenhagen 1943. - Skouby, A. P.: Acta Med. Scand. Suppl. 317, 1056. - Trier, E.: pers. comm. - Wagner, H., White, P. and Bogan, .J.: A. J. Dis. Child. 63, 667, 1942. - Wed, R.: Arch. Int. Med. 95, 739, 1955.