Endocrinopathies and Infertility

Endocrinopathies and Infertility I.

Acromegaly and Pregnancy

Robert B. Greenblatt, M.D., Efrain Vazquez, M.D., and Irwin C. Mclendon, M.D.

PREGNANCY associated with acromegaly is a relatively rare combination, only 35 cases having been reported to this time. Abelove, Rupp, and Paschkis 1 reviewed the literature in 1953 and found only 33 reported cases, to which they added one more. Finkler2 reported another case in 1954. A number of these cases did not show signs of acromegaly until their pregnancies or afterward. Few patients with true acromegaly have subsequently become pregnant, although several with two or more children have been reported. It is now generally accepted that the pituitary gland enlarges to almost twice its normal size during pregnancy. The acidophilic cells are believed to become larger and more active during pregnancy, regressing to normal size and activity within a few months postpartum. Many pregnant women are observed to undergo an increase in size with coarsening of the facial features resembling acromegaly, and this has been termed C
From the Deparbnent of Endocrinology, Medical College of Georgia, Augusta, Ga. Grateful acknowledgment for supplies of medications used in this study is made to the following: Ciba Pharmaceutical Products, Inc., Summit, N. J.-Ethinyl estradiol (Estinyl), Ethisterone (Lutocylol) • Schering Corp., Bloomfield, N. J.-Pellets of progesterone. Ayerst Laboratories, New York, N. Y.-Conjugated estrogens (Premarin). The Wm. S. Merrell Co., Cincinnati, Ohio-Chlorotrianisene (TACE). 498

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common findings in acromegaly in the female. Approximately 85 per cent of patients will have some disturbance in menstruation, 75 per cent complete amenorrhea. Acromegalic women can have children if cyclic menses continue, but pregnancy in an acromegalic woman practically never occurs after the development of amenorrhea, although it did in the case under consideration. The following study, the thirty-sixth case to be reported, is presented because of many unusual features; to wit, the emphasis on the tests that led to early diagnosis and the purely endocrine approach in therapy. CASE REPORT Mrs. D. R., a white female 28 years of age, married for 9 years, was referred to us in December, 1949, because of sterility and functional amenorrhea. The menarche occurred at age 11, menses were 40-42 days apart, lasting 4-5 days, in moderate amount with mild pain. Her periods became irregular and scanty after the age of 18 years and finally she developed functional amenorrhea. When first seen for this study she had been amenorrheic for 6 months. During this time there was diminution of libido, some hypertrichosis of the extremities, and deepening of the voice. Her husband was 34 years old, apparently in good health, and his seminal fluid examination proved satisfactory. Physical Examination The patient was 5 ft. 6 in. tall and weighed 130 pounds. The facial tissues, nares, and lips were thickened, and the skin was somewhat rough and coarse (Fig. 1A). The lower eyelids were baggy, the frontal bosses were prominent, the tongue large, and there was a moderate prognathism with increased spacing of the teeth. Fundoscopic examination and visual fields were found normal. The thyrOid was not palpable. Rather pronounced dorsal scoliosis was noted. The breasts were small. No enlargement of the heart was found. Lungs were clear to percussion and auscultation. The blood pressure and pulse rate were normal. A male escutcheon was present. Pelvic examination revealed a small uterus and apparently normal adnexa. The hands were stubby and spadelike (Fig. 2). Other Pertinent Findings. Upon direct questioning information was obtained that it had been necessary to increase her shoe and glove size from ~ to 8~ and her rings had to be enlarged. Some backache and myalgias were also disclosed. She denied headache, loss of vision, or any other neurologic symptom. Laboratory and Roentgen Studies Serum phosphorus was 5.6 mg., calcium 10.5 mg., urinary creatine 170 mg./24 hr., creatinine 970 mg./24 hr., urinary 17-ketosteroids 18.5 mg./24 hr., "cortins" 1.4

A

B

Fig. 1. A, patient in 1949 at time of first visit. Note coarse facial features with baggy eyelids, prominent nares and frontal sinuses, and slight prognathism. B, patient in 1956. Note degree of regression in acromegalic features.

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mg./24 hr. (Talbot's method). Luteinizing hormone (LH) excretion was 12.6 m.u./24 hr. Vaginal smear: hypoestrogenic. Glucose tolerance test: decreased glucose tolerance. Insulin tolerance test: insulin resistance (Fig. 3). The Thorn ACTH test showed a drop in the eosinophil count from 150/cu.mm. to 55/cu.mm.

Fig. 2.

Note spadelike hands and hypertrichosis of forearms.

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80 60 40

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90

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150

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TIME IN MINUTES

Fig. 3.

Glucose and insulin tolerance tests. Note decreased glucose tolerance and increased insulin resistance.

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Lateral view of the skull showed a slight irregular enlargement of the sella turcica, measuring 10 x 14 mm. The hands revealed no tufting of the terminal phalanges. Diagnosis

A diagnosis of early acromegaly was made because of the following positive findings: 1. Elevated serum phosphorus 2. Increased urinary creatine 3. Decreased glucose tolerance 4. Insulin resistance 5. Increased urinary 17-ketosteroid excretion 6. Increased urinary "cortins" 7. Enlarged sella turcica 8. Increase in shoe and glove size Therapy and Course

Radiation therapy to the pituitary was purposely avoided in the management of this patient in order to learn what might be accomplished with hormonal treatment alone. She was placed on moderate daily doses of conjugated estrogens as shown in Fig. 4, and ethisterone, 10 mg. twice a day for 5 days in cyclic fashion was added to give her withdrawal periods at monthly intervals. Her physical appearance, symptomatology, and psychologic improvement were remarkable,

Fig. 4.

Summary of hormonal therapy, 17-ketosteroid levels, and serum phosphorus levels.

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although she continued to have considerable chest and back pain. The changes in her serum phosphorus, which were taken as a guide for the effectiveness of the therapy, may be followed through Fig. 4, which shows an initial increase, then a drop, a new peak when the dosage of estrogen was lowered, and a new drop after administration of high doses of estrogens. The 17-ketosteroid excretion showed a similar pattern. In August, 1950, the estrogen therapy 'Yas changed to ethinyl estradiol, 0.5 mg. per day. On cessation of ethinyl estradiol therapy, the breasts became engorged and milk could be expressed from the nipples.

Fig. 5.

Irregularly enlarged sella turcica with thinning of the dorsum sellae.

Roentgen studies of the chest in September, 1950, revealed a tumor located in the middle lobe of the right lung. A right middle lobectomy was performed. The patient responded remarkably well and had no postoperative complications. The lesion was found to be a large hamartoma. Ethinyl estradiol was stopped on November 17, 1950, and eight 50-mg. pellets of progesterone were implanted subcutaneously. Thereafter, pellets of progesterone were implanted at intervals of three to five months and no more estrogens were given. Again the serum phosphorus and urinary 17-ketosteroids showed a rise which reverted to normal in 4 months. Menses soon became regular and after 10 months the basal temperature records showed evidence of ovulatory cycles.

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Endometrial biopsies performed on several occasions revealed a secretory endometrium. The back pain improved remarkably. Lactation also stopped under progesterone therapy. Menses continued regularly every five weeks, lasting five days. Temperature charts had shown ovulatory cycles for three consecutive periods. The last implantation of pellets was performed in September, 1951. The patient became pregnant in April, 1952. She did well throughout pregnancy and did not exhibit exacerbation of symptoms or much change in her physical appearance. There was a slight increase in her serum phosphorus during the third trimester. She

Fig. 6.

Early tufting of the terminal phalanges, which was not present when the patient was first seen.

delivered a normal full-term 7}~-pound male infant after four hours of labor in January, 1953, without complication. She nursed her baby for four months and lactation was stopped with TACE ®, 12.5 mg. 4 times a day for seven days. Her menses returned seven months postpartum, and after a few months she had two normal ovulatory cycles and became pregnant for the second time. She again had an uneventful pregnancy and delivered a female infant in November, 1954. She nursed this child for five months. In May, 1955, at which time milk could still be expressed from her breasts, her serum phosphorus and urinary 17-ketosteroids were normal. However, x-rays of the skull showed further enlargement of the sella turcica (Fig. 5), measuring 17 x 18 mm., with some thinning of the dorsum sellae

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and posterior clinoids; x-rays of the hands showed some tufting of the terminal phalanges (Fig. 6). The patient felt well and her general appearance was good (Fig. 1B).

Further Laboratory Studies Besides the serum phosphorus and 17-ketosteroid variations, which have been referred to, blood calcium and cholesterol levels were within normal limits throughout the entire time of observation. Urinary creatine excretion was eleTABLE 1.

Laboratory Determinations During Active Phase and After Control

Laboratory determinations

During active phase

After control

3.0-3.5 mg. % 9.2-10.4 mg. % 5.8-10.4 mg./24 hr. 2.7-3.2 mg./24 hr.a

Serum phosphorus Serum calcium Urinary 17-ketosteroids Urinary corticoids

4.9-6.4 mg. % 8.9-10.8 mg. % 13.0-27.6 mg'/24 hr. 1.09-1.94 mg./24 hr.a

Urinary creatinine Urinary creatine

FSH

830-1551 mg. % 122-640 mg. % 106-212 m.u./24 hr.b

816-1011 mg. % 47-185 mg. % 6-32 m.u./24 hr.

LH (?)c

Positive

Positive

(Talbot method)

(Reddy method)

Normal values in our laboratory: Talbot method for ll-hydroxycorticoids = 0.2-0.6 mg./24 hr. Reddy method for 17-hydroxycorticoids 2-9 mg./24 hr. b Normal 6.6-52 m.u. /24 hr. c Both LH and prolactin induce ovarian hyperemia in the test animal. a

=

=

vated and remained between 122 and 640 mg./24 hr. until 1951, then decreased to less than 100 mg./24 hr. and remained normal thereafter. Urinary creatinine levels were constantly within normal limits. Her fasting eOSinophile counts during the period of observation varied from 48 per cU.mm. to 150 per cU.mm. LH determinations became elevated to between 16 and 32 m.u. per 24 hrs. in 1952, and then returned to normal. Urinary follicle-stimulating hormone (FSH) excretion first reported in 1952 was more than 106 m.u./24 hr. but less than 212 m.u./24 hr. By 1953 they had decreased to between 6.6 and 13.2 m.u./24 hr. Urinary cortins were elevated on several occasions, but have been normal since October, 1952. Qualitative tests for dehydroisoandrosterone were negative throughout the study.

Follow-up Follow-up examination on the patient was done in March, 1956. No symptoms were volunteered. Menses remain regular at 40-day intervals, lasting 5 days. Eye grounds and visual fields were normal; blood pressure was 100/60. The serum

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phosphorus was 3 mg., serum calcium 9.5 mg., 17-ketosteroids (Drekter method) 5.8 mg., 17-hydroxycorticoids (Reddy method) 3.2 mg., creatinine 816 mg., creatine 185 mg. Roentgen studies of the sella turcica did not show any further enlargement and the hands did not reveal any advancement in the tufting of the phalanges. Endometrial biopsy taken on the first day of menstruation showed a secretory endometrium. The FSH assay showed more than 6.6, less than 13.2/ m.u. per 24 hours. A summary of the laboratory findings is presented in Table 1.

DISCUSSION

Endocrine therapy proved successful in that it modified the physical and chemical changes associated with acromegaly. Estrogens were given because of their known pituitary-inhibiting effect, and the arrest in the clinical evolution and control of blood serum phosphorus levels were in accordance with the experience of other investigators.s After nine months of estrogen therapy along with cyclic administration of progesterone, estrogens were stopped, at which time the breasts became full and lactation occurred, a phenomenon which was interpreted as indicative of prolaCtin release. Assuming that progesterone inhibits LH release, it was postulated that it could also inhibit the production of growth hormone. Accordingly, it was deemed advisable to try progesterone alone in treatment. Pellets of progesterone were implanted several times and the improvement previously obtained was sustained and, most important of all, spontaneous cyclic menstruation began under this therapy with ovulatory cycles and the advent of two normal pregnancies with full-term deliveries. The return of menstruation has been considered by some as one of the best signs of the control of acromegaly,4 and others state that pregnancy in acromegaly is possible only in the first stages while the patient still menstruates, and not after the development of amenorrhea. 5 Serum phosphorus levels may be considered as an index of growth hormone activity,S. 6.1 and according to this criteria the hormonal therapy was also successful; the remission obtained has been sustained even five years after the last implantation of pellets of progesterone. In spite of the clinical improvement and arrest of the progress of acromegalic features and normal serum phosphorus levels, the pituitary continued to enlarge and some tufting of the terminal phalanges has appeared, which may indicate that the acromegaly has not completely "burned out" but remains quiescent.

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SUMMARY The thirty-sixth case of pregnancy occurring in acromegaly is reported. The patient had had symptoms for about 5 years when she was first seen for this study. She had already developed amenorrhea and some of her features were suggestive of acromegaly. Roentgen studies, hormonal assays, and chemical studies verified the diagnosis. Steroid hormone therapy was the only form of medication employed, irradiation to the pituitary being purposely avoided. Two years and four months after institution of treatment the patient became pregnant for the first time. After an uneventful delivery of a normal child she became pregnant again ten months later and again carried successfully to term. At the present time, twenty months after the birth of the second child, studies suggest that the acromegalic process is quiescent. REFERENCES 1. ABELOVE, W. A., Rupp, J. J., and PASCHKIS, K. E. Acromegaly and pregnancy. ]. Clin. Endocrinol. & Metab. 14:32, 1954. 2. FINKLER, R. S. Acromegaly and pregnancy: Case report. ]. Clin. Endocrinol. & Metab. 14:1245,1954. 3. REIFENSTEIN, E. C., JR., KINSELL, L. W., and ALBRIGHT, F. Observations on the use of the serum phosphorus level as an index of pituitary growth hormone activity: The effect of estrogen therapy in acromegaly. ]. Clin. Endocrinol. 6:470, 1946. 4. HURXTHAL, L. M., et al. The treatment of acromegaly. J. Clin. Endocrinol. & Metab. 9:126, 1949. 5. ALBRIGHT, F. Quoted from REIFENSTEIN, E. C., JR., in REIFENSTEIN, E. c., JR.:

Conference on Metabolic Aspects of Convalescence, Transactions of Fourteenth Meeting, Nov. 12-13, 1946. New York, Macy, pp. 122-125. 6. KINSELL, L. W., et al. Metabolic effects of "pituitary growth hormone preparations" in human subjects. ]. Clin. Endocrinol. & Metab. 14:110, 1954. 7. KINSELL, L. W. "Human Studies with Purified Pituitary Growth Hormone Preparations." In SMITH, R. W., GAEBLER, O. H., and LONG, C. N. H.: The Hypophyseal Growth Hormone: Nature and Actions. New York, McGraw-Hill, 1955.