- Email: [email protected]
Normalization of Visual Fields Following Bromocriptine Treatment in Hyperprolactinemic Patients with Visual Field Constriction*
Vol. 29, No, 6, June 1978 Printed in U.SA.
FERTILITY AND STERILITY Copyright' 1978 The American Fertility Society
NORMALIZATION OF VISUAL FIELDS FOLLOWING BROMOCRIPTINE TREATMENT IN HYPERPROLACTINEMIC PATIENTS WITH VISUAL FIELD CONSTRICTION*
RAMA A. VAIDYA, M.D., D.G.O., D.F.P.t SAUDAMINI D. ALOORKAR, M.B., D.G.O., D.F.P. NAYANA R. REGE, B.Sc. BADRUDDIN T. MASKATI, M.S., D.O.M.S.:f: RUMI P. JAHANGIR, M.S., D.O.M.S.:f: ANIL R. SHETH, PH.D. SUNIL K. PANDYA, M.S.§ Institute for Research in Reproduction, Indian Council of Medical Research, Parel, Bombay 400 012, India
Two patients with galactorrhea-amenorrhea and bilateral visual field defects were studied. Routine radiologic examination of each patient revealed a normal sella turcica and no demineralization of the posterior clinoid process. Serum prolactin levels were elevated (patient V. G., 80 nglml; patient S. R., 204 nglml). Within 2 months of bromocriptine therapy, the serum prolactin levels were normal (patient V. G., 1221 nglml; patient S. R., 8.25 nglml) and the bilateral visual field defects were corrected. Bromocriptine has been shown to control prolactin secretion in patients with prolactin-secreting pituitary tumors. Normalization of restricted visual fields following bromocriptine therapy indicates the possibility of an anatomical regression ofpituitary hyperplasia or an underlying prolactin-producing microadenoma. It is speculated that the modality of functional galactorrhea reflects hyperplasia of the lactotrophs preceding a nodular and ultimately an adenomatous change. The continuous and prolonged administration of bromocriptine may prevent such a progressive sequence. Further experience is required to validate this possibility.
Enlargement of the pituitary gland secondary to target gland failure, as in primary hypothyroidism, 1-3 gonadal failure, 4-6 and Addison's disease,5 has been reported. Long-term d-eprivation of the target gland hormone leads to compensatory hyperplasia of the concerned tropic hormonesecreting cell. The mouse pituitary gland has been shown to undergo a progressive sequence
of hyperplasia, nodularity, and neoplastic changes following prolonged periods of thyroid deficiency.7,8 These changes can be prevented entirely by the administration of adequate amounts of thyroxine. 7. 8 There are several clinical reports indicating a similar possibility in patients with long-term primary hypothyroidism. Pituitary enlargement in primary hypothyroidism has been well documented both by radiologic 9 and autopsy studies. 1o However, Russfield 10 found that, at autopsy, pituitary glands from hypothyroid patients who had received replacement therapy were not enlarged. Obvious enlargement of the sella with regression following thyroid therapy has been observed in children with the syndrome of precocious menstruation and galactorrhea due to juvenile hypothyroidism. I Recently we reported that, after thyroid replacement, correction of the visual fields occurred concomitantly with nor.
Received May 11, 1977; revised January 31, 1978; accepted February 10, 1978. *Presented in part at the Ninth World Congress on Fertility and Sterility and the Thirty-Third Annual Meeting of' The American Fertility Society, April 12 to 16, 1977, Miami Beach, Fla. tReprint requests: Rama Vaidya, M.D., Institute for Research in Reproduction, Indian Council of Medical Research, Jehangir Merwanji Street, Parel, Bombay 400 012, India. :f:Department of Ophthalmology, K. E. M. Hospital, Bombay 400012. §Department of Neurosurgery, K. E. M. Hospital, Bombay 400012.
632
Vol. 29, No.6
BROMOCRIPl'INE IN HYPERPROLACTINEMIA
maliza tion of serum thyroid-stimulating hormone (TSH) and serum prolactin levels in a patient with galactorrhea-amenorrhea syndrome due to primary hypothyroidism. II The findings of regression of an enlarged sella I and normalization of the visual fields l l , 12 in these cases suggest reversibility of pituitary hyperplasia in primary hypothyroidism. The syndrome of galactorrhea-amenorrhea with its diverse causes provides a unique opportunity to test the concept of reversible pituitary hyperplasia. Such hyperplasia may be dependent on a decrease in negative feedback from the target glands, as in primary hypothyroidism, or on a decrease in hypothalamic prolactin-inhibiting factor, as in functional galactorrhea. This report describes two patients with galactorrhea-amenorrhea in whom visual field defects were corrected concomitantly with bromocriptine-induced normalization of elevated serum prolactin levels. METHODS
Serum prolactin levels were determined by radioimmunoassay using the kit supplied by the National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Md. Human prolactin was labeled with 120 1 (Radiochemical Centre, Amersham, England) according to the procedure described by Greenwood et al., 13 as modified by Midgley. 14 Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay using the double-antibody technique of Midgley.14 The results were expressed in nanograms per milliliter for serum prolactin and in milli-international units per milliliter for serum FSH and LH. CASE REPORTS
Patient 1. V. G., a 27-year-old female, had had primary infertility for 4 years and secondary amenorrhea for 6 months. She had had galactorrhea for 5 years which was particularly noticed during premenstrual periods. On inquiry she gave a history of headache and some visual disturbance for 1 year. Physical examination did not reveal any abnormality except for a moderate amount of milk secretion from both breasts: on several occasions prior to therapy the quantity of milk expressed manually from the left breast over 2 minutes ranged from 1 to 1.5 ml; from the right breast, 1.4 to 1.8 ml. The patient was clinically euthyroid, and thyroid function tests were
633
normal (serum TSH, 9 mIU/ml; 125I_T3 charcoal uptake rate, 96% [normal rate, 83% to 111% D.15 Serum FSH and LH levels were also within normal ranges (8.0 mIU/ml and 23.0 mIU/ml, respectively). The serum prolactin level was elevated (80.00 ng/ml). There was no evidence of pituitary tumor on plain radiography. Visual field examination revealed bitemporal hemianopia. Bromocryptine was started at a dose of 2.5 mg/day which was gradually increased to 7.5 mg/day. Menstruation started in 6 weeks and galactorrhea stopped completely within 8 weeks of therapy. The visual fields widened gradually and normalized along with a decline in serum prolactin to normal values (Fig. 1).
Patient 2. S. R., a 20-year-old female, consulted the clinic because of primary amenorrhea and galactorrhea. She had noticed a bilateral milk discharge for 2 years. She gave a history of headaches for 3 years. However, she did not complain of any visual disturbances. In the past, she had experienced withdrawal bleeding after taking combination hormone pills. Physical examination was normal except for the presence of obesity (body weight, 83 kg; height, 162 cm) and bilateral milk discharge. Thyroid function tests were normal (serum TSH, 10.6 p,U/ml; 125I_T3 charcoal uptake rate, 96% [normal rate; 83% to 111% D. The patient's glucose tolerance curve was normal. Growth hormone levels were· not determined, but the patient did not have acromegalic features. Her serum FSH and LH levels were normal (8.00 mIU/ml and 42.9 mIU/ml, respectively). Her serum prolactin level was markedly elevated (204 ng/ml). A lateral skull x-ray revealed a J-shaped sella. However, the size of the sella was normal and there was no demineralization of the clinoid processes. Bitemporal hemianopia was detected by visual field examination. Funduscopic findings were normal. The patient was scheduled for pneumoencephalography and carotid angiography to be followed by surgery, but she refused all of these procedures. Hence, bromocriptine was started at a dose of 2.5 mg/day which was gradually increased to 7.5 mg/ day. The visual fields normalized along with the serum prolactin levels (Fig. 2). Galactorrhea ceased, but the patient continues to have amenorrhea. The ranges for serum prolactin and TSH levels during the follicular phase in 10 normally menstruating women were 3 to 10 ng/ml and 4 to 10 p,U/ml, respectively, when the sera were assayed simultaneously with the patients' sera. The
V AIDYA ET AL.
634
June 1978 VISUAL FIELDS
S. PROLACTIN DATE
BASAL
80·0nQ/ml
BROME RGOCRYPTINE
2 WKS.
24'6nQlml
4 WKS.
14·0nQ/ml
8 WKS.
12·21nQ/ml
7· 5 mQ per day
FIG. 1. Patient V. G. Normalization of the visual fields and serum prolactin levels after bromocriptine therapy.
S. PROLACTIN
VISUAL FIELDS
DATE
BASAL
204'OnQ/ml
BROMERGOCRYPTINE
3 DAYS
56·1 ng/ml
2 WKS.
35·64 ng/ml
8 WKS.
8·25 nv/ml
7·5 mQ per day
FIG. 2. Patient S. R. Normalization of the visual fields and serum prolactin levels after bromocriptine therapy.
BROMOCRIPrINE IN HYPERPROLACTINEMIA
Vol. 29, No.6
ranges for serum FSH and LH levels in normally menstruating women were 1.8 to 16.8 mIU/ml and 7.4 to 54.4 mIU/ml, respectively.
DISCUSSION
The underlying pathology in these two cases of galactorrhea-amenorrhea with hyperprolactinemia remains obscure. In the absence of a history of use of psychotropic drugs, hormonal contraceptives, or antihypertensive agents, drug-induced hyperprolactinemia was ruled out. The finding of normal serum TSH levels ruled out primary hypothyroidism as an etiologic factor. Normal findings on routine radiologic examination of the sella turcica excluded the presence of a pituitary macroadenoma. The hyperprolactinemia in the patients reported here may have been caused by hyperplasia of the lactotrophs or the presence of a microadenoma. In the absence of facilities for hypocycloidal polytomography , the existence of a prolactin-secreting microadenoma cannot be ruled out as an etiologic factor. Child et al. 16 suggested that there was a linear relationship between the basal serum prolactin level and the lateral area of the pituitary fossa in patients with prolactin-secreting pituitary tumors. If this is so, then basal serum levels below 50 ng/ml will be associated with microadenomas which are undetectable using current diagnostic techniques. 17 However, the true incidence of microadenoma in women with galactorrhea and/or hyperprolactinemia and amenorrhea is unknown. The question of whether some of these patients may have mere hyperplasia of the lactotrophs is still not answered. Transsphenoidal microsurgical exploration of the sella on the basis of abnormal radiologic findings or hyperprolactinemia was reported in 34 patients by Chang et al. 18 A patient with an abnormal sellar poly tomograph showed a normal pituitary on transsphenoidal microsurgical exploration of the sella. In the same series, in three of the six patients without histologic evidence of adenoma (unidentified lesion), the histology of the surgical specimens was normal. IH These findings of unidentified lesions and negative explorations are suggestive of the possibility of a diffused lesion-hyperplasia of the lactotrophs. An abundance of prolactin cells in the nontumorous parts of human pituitaries harboring prolactin cell adenomas was reported recently. 19 The investigators proposed that the lack of regression of prolactin cells in the nontumorous portions of the anterior lobes may be
635
the cause of the persistence of clinical symptoms and hyperprolactinemia following surgery. 19 The synthesis and release of most of the tropic hormones of the pituitary gland are controlled and delicately balanced by the hormones of the target glands. A target gland deficiency or its surgical extirpation leads to hyperplasia and hyperfunction of the corresponding pituitary tropic cells. On the other hand, the control of prolactin secretion in mammals, including humans, is predominantly inhibitory and is provided by hypothalamic dopaminergic neurons. A functional aberration of the pituitary lactotrophhypothalamic dopamine system may be responsible for hyperprolactinemia. Pituitary enlargement secondary to primary hypothyroidism,I-3 gonadal failure,4-6 and Addison's disease 5 has been reported. Recently Yamada et al. 9 have shown that the magnitude of the increase in the volume of the sella turcica correlated well with the increase in circulating TSH levels. A regression of the size of the sella has been observed following thyroid replacement in juvenile hypothyroidism, resulting in normalization of the visual fields accompanied by a decline in serum TSH and prolactin to normal levels. These findings of regression of an enlarged sella and normalization of the visual fields I!, 12 suggest the reversibility of pituitary hyperplasia in primary hypothyroidism and emphasize the need for an early diagnosis and adequate replacement therapy in primary hypothyroidism. Such management would minimize the risk of irreversible pituitary adenomatous changes. The mouse pituitary gland undergoes a progressive sequence of hyperplasia, nodularity, and neoplastic changes following a long period of thyroid deficiency!' H In the first stage of adenomatous development these tumors are dependent and reversible if feedback is reinstituted by substitution therapy.2o Ergot-induced inhibition of prolactin secretion and galactorrhea by bromocriptine in a patient known to have a pituitary tumor was reported as early as 1972.21 A bromocriptine-induced decrease in serum prolactin to normal levels has also been reported by several investigators. 22 ,23 These studies indicate attenuation of the prolactin-secreting function of lactotrophs, Whether such a functional effect is accompanied by structural regression would be of interest, The complete normalization of the visual fields following bromocriptine therapy in two patients with galactorrhea suggests an anatomical regression of pituitary hyperplasia or
V AIDYA ET AL.
636
the presence of a microadenoma. Similar results have recently been reported by Wass et aJ.24 We would like to speculate that the modality of functional galactorrhea merely reflects hyperplasia of the lactotrophs preceding a nodular change (microadenoma) and ultimately an adenomatous change (macroadenoma). The continuous and prolonged administration of bromocriptine might prevent such a progressive sequence. Further experience is required to validate this possibility. REFERENCES 1. Van Wyck JJ, Grumbach MM: Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism. An example of hormonal overlap in pituitary feedback. J Pediatr 57:416, 1960 2. Patel YC, Kilpatrick JA: Pituitary enlargement with longstanding myxoedema. NZ Med J 70:21, 1969 3. Lawrence AM, Wilber JF, Hagen TC: The pituitary and primary hypothyroidism: enlargement and unusual growth hormone secretory responses. Arch Intern Med 132:327,1973 4. Caughey JE: The aetiology of pituitary tumours: the role of hypogonadism and hypothyroidism. Aust Ann Med 6:93,1957 5. Gordon SJ, Moses Am: Multiple endocrine organ refractoriness to tropic hormone stimulation. A patient with an enlarged sella turcica and increased FSH secretion. Ann Intern Med 63:313, 1965 6. Bower BF: Pituitary enlargement secondary to untreated primary hypogonadism. Ann Intern Med 69:107, 1968 7. Bielschowsky F: Neoplasia and internal environment. Br J Cancer 9:80, 1955 8. Clifton KH: Experimental hypophyseal neoplasia: a review of recent results. Unio Int Contra Cancrum Acta 18:293, 1962 9. Yamada T. Tsukui T, Ikejiri K, Yukimura Y, Kotani M: Volume of sella turcica in normal subjects and in patients with primary hypothyroidism and hyperthyroidism. J Clin Endocrinol Metab 42:817, 1976 10. RussfieldAB: Histology of the human hypophysis in thyroid disease-hypothyroidism, hyperthyroidism and cancer. J Clin Endocrinol Metab 15:1393, 1955
June 1978 11. Vaidya RA, Aloorkar SD, Raikar R, Pandya SK, Sheth AR: Functional pituitary hyperplasia in primary hypothyroidism: normalisation of visual field defects on thyroid replacement in a girl with galactorrhea-amenorrhea. J Assoc Physicians India 25:923, 1977 12. Vagenkis AG, Dole K, Braverman L: Pituitaryenlargement, pituitary failure, and primary hypothyroidism. Ann Intern Med 85:195, 1976 13. Greenwood FC, Hunter WMG, Glover JS: The preparation of 13lI-Iabelled human growth hormone of high specific radioactivity. Biochem J 89:114, 1963 14. Midgley AR Jr: Radioimmunoassay: a method for human chorionic gonadotropin and human luteinizing hormone. Endocrinology 79:10, 1966 15. Mehta MN, Desai KB, Mani LS, Ganatra RD: Uptake of labelled tri-iodothyronine by albumin coated charcoal as a test of thyroid function. Indian J Med Res 64:1235, 1976 16. Child DF, Gordon H, Mashiter K, Joplin GF: Pregnancy, prolactin, and pituitary tumours. Br Med J 4:87, 1975 17. Jacobs H, Franks S: Prolactin studies, Pituitary tumour and reproductive function (letter to the editor). Br Med J 2:141,1975 18. Chang RJ, Keye WR Jr, Young JR, Wilson CB, Jaffe RB: Detection, evaluation, and treatment of pituitary microadenomas in patients with galactorrhea and amenorrhea. Am J Obstet Gynecol 128:356, 1977 19. Kovacs K, Ryan M, Horvath E, Ezrin C, Penz G: Abundance of prolactin cells in the nontumorous parts of human pituitaries harbouring prolactin cell adenomas. IRCS Med Sci 5:37, 1977 20. Furth J: Experimental pituitary tumors. Recent Prog Horm Res 11:221, 1955. As cited in Leiba S, Landau B, Ber A: Target gland insufficiency and pituitary tumours. Acta Endocrinol (Kbh) 60:112, 1969 21. Quadri SK, Meites KHW: Ergot-induced inhibition of pituitary tumor growth in rats. Science 176:417, 1972 22. Child DF, Nader S, Mashiter K, Kjeld M, Banks L, Fraser TR: Prolactin studies in "functionless" pituitary tumors. Br Med J 1:604, 1975 23. Thorner MO, McNeilly AS, Hagan C, Besser GM: Longterm treatment of galactorrhea and hypogonadism with bromocryptine. Br Med J 2:419,1974 24. Wass JAH, Thorner MO, Morris DV, Rees LH, Mason AS, Jones AE; Besser GM: Long-term treatment of acromegaly with bromocryptine. Br Med J 1:875, 1977
FERTILITY AND STERILITY Copyright' 1978 The American Fertility Society
NORMALIZATION OF VISUAL FIELDS FOLLOWING BROMOCRIPTINE TREATMENT IN HYPERPROLACTINEMIC PATIENTS WITH VISUAL FIELD CONSTRICTION*
RAMA A. VAIDYA, M.D., D.G.O., D.F.P.t SAUDAMINI D. ALOORKAR, M.B., D.G.O., D.F.P. NAYANA R. REGE, B.Sc. BADRUDDIN T. MASKATI, M.S., D.O.M.S.:f: RUMI P. JAHANGIR, M.S., D.O.M.S.:f: ANIL R. SHETH, PH.D. SUNIL K. PANDYA, M.S.§ Institute for Research in Reproduction, Indian Council of Medical Research, Parel, Bombay 400 012, India
Two patients with galactorrhea-amenorrhea and bilateral visual field defects were studied. Routine radiologic examination of each patient revealed a normal sella turcica and no demineralization of the posterior clinoid process. Serum prolactin levels were elevated (patient V. G., 80 nglml; patient S. R., 204 nglml). Within 2 months of bromocriptine therapy, the serum prolactin levels were normal (patient V. G., 1221 nglml; patient S. R., 8.25 nglml) and the bilateral visual field defects were corrected. Bromocriptine has been shown to control prolactin secretion in patients with prolactin-secreting pituitary tumors. Normalization of restricted visual fields following bromocriptine therapy indicates the possibility of an anatomical regression ofpituitary hyperplasia or an underlying prolactin-producing microadenoma. It is speculated that the modality of functional galactorrhea reflects hyperplasia of the lactotrophs preceding a nodular and ultimately an adenomatous change. The continuous and prolonged administration of bromocriptine may prevent such a progressive sequence. Further experience is required to validate this possibility.
Enlargement of the pituitary gland secondary to target gland failure, as in primary hypothyroidism, 1-3 gonadal failure, 4-6 and Addison's disease,5 has been reported. Long-term d-eprivation of the target gland hormone leads to compensatory hyperplasia of the concerned tropic hormonesecreting cell. The mouse pituitary gland has been shown to undergo a progressive sequence
of hyperplasia, nodularity, and neoplastic changes following prolonged periods of thyroid deficiency.7,8 These changes can be prevented entirely by the administration of adequate amounts of thyroxine. 7. 8 There are several clinical reports indicating a similar possibility in patients with long-term primary hypothyroidism. Pituitary enlargement in primary hypothyroidism has been well documented both by radiologic 9 and autopsy studies. 1o However, Russfield 10 found that, at autopsy, pituitary glands from hypothyroid patients who had received replacement therapy were not enlarged. Obvious enlargement of the sella with regression following thyroid therapy has been observed in children with the syndrome of precocious menstruation and galactorrhea due to juvenile hypothyroidism. I Recently we reported that, after thyroid replacement, correction of the visual fields occurred concomitantly with nor.
Received May 11, 1977; revised January 31, 1978; accepted February 10, 1978. *Presented in part at the Ninth World Congress on Fertility and Sterility and the Thirty-Third Annual Meeting of' The American Fertility Society, April 12 to 16, 1977, Miami Beach, Fla. tReprint requests: Rama Vaidya, M.D., Institute for Research in Reproduction, Indian Council of Medical Research, Jehangir Merwanji Street, Parel, Bombay 400 012, India. :f:Department of Ophthalmology, K. E. M. Hospital, Bombay 400012. §Department of Neurosurgery, K. E. M. Hospital, Bombay 400012.
632
Vol. 29, No.6
BROMOCRIPl'INE IN HYPERPROLACTINEMIA
maliza tion of serum thyroid-stimulating hormone (TSH) and serum prolactin levels in a patient with galactorrhea-amenorrhea syndrome due to primary hypothyroidism. II The findings of regression of an enlarged sella I and normalization of the visual fields l l , 12 in these cases suggest reversibility of pituitary hyperplasia in primary hypothyroidism. The syndrome of galactorrhea-amenorrhea with its diverse causes provides a unique opportunity to test the concept of reversible pituitary hyperplasia. Such hyperplasia may be dependent on a decrease in negative feedback from the target glands, as in primary hypothyroidism, or on a decrease in hypothalamic prolactin-inhibiting factor, as in functional galactorrhea. This report describes two patients with galactorrhea-amenorrhea in whom visual field defects were corrected concomitantly with bromocriptine-induced normalization of elevated serum prolactin levels. METHODS
Serum prolactin levels were determined by radioimmunoassay using the kit supplied by the National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Md. Human prolactin was labeled with 120 1 (Radiochemical Centre, Amersham, England) according to the procedure described by Greenwood et al., 13 as modified by Midgley. 14 Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay using the double-antibody technique of Midgley.14 The results were expressed in nanograms per milliliter for serum prolactin and in milli-international units per milliliter for serum FSH and LH. CASE REPORTS
Patient 1. V. G., a 27-year-old female, had had primary infertility for 4 years and secondary amenorrhea for 6 months. She had had galactorrhea for 5 years which was particularly noticed during premenstrual periods. On inquiry she gave a history of headache and some visual disturbance for 1 year. Physical examination did not reveal any abnormality except for a moderate amount of milk secretion from both breasts: on several occasions prior to therapy the quantity of milk expressed manually from the left breast over 2 minutes ranged from 1 to 1.5 ml; from the right breast, 1.4 to 1.8 ml. The patient was clinically euthyroid, and thyroid function tests were
633
normal (serum TSH, 9 mIU/ml; 125I_T3 charcoal uptake rate, 96% [normal rate, 83% to 111% D.15 Serum FSH and LH levels were also within normal ranges (8.0 mIU/ml and 23.0 mIU/ml, respectively). The serum prolactin level was elevated (80.00 ng/ml). There was no evidence of pituitary tumor on plain radiography. Visual field examination revealed bitemporal hemianopia. Bromocryptine was started at a dose of 2.5 mg/day which was gradually increased to 7.5 mg/day. Menstruation started in 6 weeks and galactorrhea stopped completely within 8 weeks of therapy. The visual fields widened gradually and normalized along with a decline in serum prolactin to normal values (Fig. 1).
Patient 2. S. R., a 20-year-old female, consulted the clinic because of primary amenorrhea and galactorrhea. She had noticed a bilateral milk discharge for 2 years. She gave a history of headaches for 3 years. However, she did not complain of any visual disturbances. In the past, she had experienced withdrawal bleeding after taking combination hormone pills. Physical examination was normal except for the presence of obesity (body weight, 83 kg; height, 162 cm) and bilateral milk discharge. Thyroid function tests were normal (serum TSH, 10.6 p,U/ml; 125I_T3 charcoal uptake rate, 96% [normal rate; 83% to 111% D. The patient's glucose tolerance curve was normal. Growth hormone levels were· not determined, but the patient did not have acromegalic features. Her serum FSH and LH levels were normal (8.00 mIU/ml and 42.9 mIU/ml, respectively). Her serum prolactin level was markedly elevated (204 ng/ml). A lateral skull x-ray revealed a J-shaped sella. However, the size of the sella was normal and there was no demineralization of the clinoid processes. Bitemporal hemianopia was detected by visual field examination. Funduscopic findings were normal. The patient was scheduled for pneumoencephalography and carotid angiography to be followed by surgery, but she refused all of these procedures. Hence, bromocriptine was started at a dose of 2.5 mg/day which was gradually increased to 7.5 mg/ day. The visual fields normalized along with the serum prolactin levels (Fig. 2). Galactorrhea ceased, but the patient continues to have amenorrhea. The ranges for serum prolactin and TSH levels during the follicular phase in 10 normally menstruating women were 3 to 10 ng/ml and 4 to 10 p,U/ml, respectively, when the sera were assayed simultaneously with the patients' sera. The
V AIDYA ET AL.
634
June 1978 VISUAL FIELDS
S. PROLACTIN DATE
BASAL
80·0nQ/ml
BROME RGOCRYPTINE
2 WKS.
24'6nQlml
4 WKS.
14·0nQ/ml
8 WKS.
12·21nQ/ml
7· 5 mQ per day
FIG. 1. Patient V. G. Normalization of the visual fields and serum prolactin levels after bromocriptine therapy.
S. PROLACTIN
VISUAL FIELDS
DATE
BASAL
204'OnQ/ml
BROMERGOCRYPTINE
3 DAYS
56·1 ng/ml
2 WKS.
35·64 ng/ml
8 WKS.
8·25 nv/ml
7·5 mQ per day
FIG. 2. Patient S. R. Normalization of the visual fields and serum prolactin levels after bromocriptine therapy.
BROMOCRIPrINE IN HYPERPROLACTINEMIA
Vol. 29, No.6
ranges for serum FSH and LH levels in normally menstruating women were 1.8 to 16.8 mIU/ml and 7.4 to 54.4 mIU/ml, respectively.
DISCUSSION
The underlying pathology in these two cases of galactorrhea-amenorrhea with hyperprolactinemia remains obscure. In the absence of a history of use of psychotropic drugs, hormonal contraceptives, or antihypertensive agents, drug-induced hyperprolactinemia was ruled out. The finding of normal serum TSH levels ruled out primary hypothyroidism as an etiologic factor. Normal findings on routine radiologic examination of the sella turcica excluded the presence of a pituitary macroadenoma. The hyperprolactinemia in the patients reported here may have been caused by hyperplasia of the lactotrophs or the presence of a microadenoma. In the absence of facilities for hypocycloidal polytomography , the existence of a prolactin-secreting microadenoma cannot be ruled out as an etiologic factor. Child et al. 16 suggested that there was a linear relationship between the basal serum prolactin level and the lateral area of the pituitary fossa in patients with prolactin-secreting pituitary tumors. If this is so, then basal serum levels below 50 ng/ml will be associated with microadenomas which are undetectable using current diagnostic techniques. 17 However, the true incidence of microadenoma in women with galactorrhea and/or hyperprolactinemia and amenorrhea is unknown. The question of whether some of these patients may have mere hyperplasia of the lactotrophs is still not answered. Transsphenoidal microsurgical exploration of the sella on the basis of abnormal radiologic findings or hyperprolactinemia was reported in 34 patients by Chang et al. 18 A patient with an abnormal sellar poly tomograph showed a normal pituitary on transsphenoidal microsurgical exploration of the sella. In the same series, in three of the six patients without histologic evidence of adenoma (unidentified lesion), the histology of the surgical specimens was normal. IH These findings of unidentified lesions and negative explorations are suggestive of the possibility of a diffused lesion-hyperplasia of the lactotrophs. An abundance of prolactin cells in the nontumorous parts of human pituitaries harboring prolactin cell adenomas was reported recently. 19 The investigators proposed that the lack of regression of prolactin cells in the nontumorous portions of the anterior lobes may be
635
the cause of the persistence of clinical symptoms and hyperprolactinemia following surgery. 19 The synthesis and release of most of the tropic hormones of the pituitary gland are controlled and delicately balanced by the hormones of the target glands. A target gland deficiency or its surgical extirpation leads to hyperplasia and hyperfunction of the corresponding pituitary tropic cells. On the other hand, the control of prolactin secretion in mammals, including humans, is predominantly inhibitory and is provided by hypothalamic dopaminergic neurons. A functional aberration of the pituitary lactotrophhypothalamic dopamine system may be responsible for hyperprolactinemia. Pituitary enlargement secondary to primary hypothyroidism,I-3 gonadal failure,4-6 and Addison's disease 5 has been reported. Recently Yamada et al. 9 have shown that the magnitude of the increase in the volume of the sella turcica correlated well with the increase in circulating TSH levels. A regression of the size of the sella has been observed following thyroid replacement in juvenile hypothyroidism, resulting in normalization of the visual fields accompanied by a decline in serum TSH and prolactin to normal levels. These findings of regression of an enlarged sella and normalization of the visual fields I!, 12 suggest the reversibility of pituitary hyperplasia in primary hypothyroidism and emphasize the need for an early diagnosis and adequate replacement therapy in primary hypothyroidism. Such management would minimize the risk of irreversible pituitary adenomatous changes. The mouse pituitary gland undergoes a progressive sequence of hyperplasia, nodularity, and neoplastic changes following a long period of thyroid deficiency!' H In the first stage of adenomatous development these tumors are dependent and reversible if feedback is reinstituted by substitution therapy.2o Ergot-induced inhibition of prolactin secretion and galactorrhea by bromocriptine in a patient known to have a pituitary tumor was reported as early as 1972.21 A bromocriptine-induced decrease in serum prolactin to normal levels has also been reported by several investigators. 22 ,23 These studies indicate attenuation of the prolactin-secreting function of lactotrophs, Whether such a functional effect is accompanied by structural regression would be of interest, The complete normalization of the visual fields following bromocriptine therapy in two patients with galactorrhea suggests an anatomical regression of pituitary hyperplasia or
V AIDYA ET AL.
636
the presence of a microadenoma. Similar results have recently been reported by Wass et aJ.24 We would like to speculate that the modality of functional galactorrhea merely reflects hyperplasia of the lactotrophs preceding a nodular change (microadenoma) and ultimately an adenomatous change (macroadenoma). The continuous and prolonged administration of bromocriptine might prevent such a progressive sequence. Further experience is required to validate this possibility. REFERENCES 1. Van Wyck JJ, Grumbach MM: Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism. An example of hormonal overlap in pituitary feedback. J Pediatr 57:416, 1960 2. Patel YC, Kilpatrick JA: Pituitary enlargement with longstanding myxoedema. NZ Med J 70:21, 1969 3. Lawrence AM, Wilber JF, Hagen TC: The pituitary and primary hypothyroidism: enlargement and unusual growth hormone secretory responses. Arch Intern Med 132:327,1973 4. Caughey JE: The aetiology of pituitary tumours: the role of hypogonadism and hypothyroidism. Aust Ann Med 6:93,1957 5. Gordon SJ, Moses Am: Multiple endocrine organ refractoriness to tropic hormone stimulation. A patient with an enlarged sella turcica and increased FSH secretion. Ann Intern Med 63:313, 1965 6. Bower BF: Pituitary enlargement secondary to untreated primary hypogonadism. Ann Intern Med 69:107, 1968 7. Bielschowsky F: Neoplasia and internal environment. Br J Cancer 9:80, 1955 8. Clifton KH: Experimental hypophyseal neoplasia: a review of recent results. Unio Int Contra Cancrum Acta 18:293, 1962 9. Yamada T. Tsukui T, Ikejiri K, Yukimura Y, Kotani M: Volume of sella turcica in normal subjects and in patients with primary hypothyroidism and hyperthyroidism. J Clin Endocrinol Metab 42:817, 1976 10. RussfieldAB: Histology of the human hypophysis in thyroid disease-hypothyroidism, hyperthyroidism and cancer. J Clin Endocrinol Metab 15:1393, 1955
June 1978 11. Vaidya RA, Aloorkar SD, Raikar R, Pandya SK, Sheth AR: Functional pituitary hyperplasia in primary hypothyroidism: normalisation of visual field defects on thyroid replacement in a girl with galactorrhea-amenorrhea. J Assoc Physicians India 25:923, 1977 12. Vagenkis AG, Dole K, Braverman L: Pituitaryenlargement, pituitary failure, and primary hypothyroidism. Ann Intern Med 85:195, 1976 13. Greenwood FC, Hunter WMG, Glover JS: The preparation of 13lI-Iabelled human growth hormone of high specific radioactivity. Biochem J 89:114, 1963 14. Midgley AR Jr: Radioimmunoassay: a method for human chorionic gonadotropin and human luteinizing hormone. Endocrinology 79:10, 1966 15. Mehta MN, Desai KB, Mani LS, Ganatra RD: Uptake of labelled tri-iodothyronine by albumin coated charcoal as a test of thyroid function. Indian J Med Res 64:1235, 1976 16. Child DF, Gordon H, Mashiter K, Joplin GF: Pregnancy, prolactin, and pituitary tumours. Br Med J 4:87, 1975 17. Jacobs H, Franks S: Prolactin studies, Pituitary tumour and reproductive function (letter to the editor). Br Med J 2:141,1975 18. Chang RJ, Keye WR Jr, Young JR, Wilson CB, Jaffe RB: Detection, evaluation, and treatment of pituitary microadenomas in patients with galactorrhea and amenorrhea. Am J Obstet Gynecol 128:356, 1977 19. Kovacs K, Ryan M, Horvath E, Ezrin C, Penz G: Abundance of prolactin cells in the nontumorous parts of human pituitaries harbouring prolactin cell adenomas. IRCS Med Sci 5:37, 1977 20. Furth J: Experimental pituitary tumors. Recent Prog Horm Res 11:221, 1955. As cited in Leiba S, Landau B, Ber A: Target gland insufficiency and pituitary tumours. Acta Endocrinol (Kbh) 60:112, 1969 21. Quadri SK, Meites KHW: Ergot-induced inhibition of pituitary tumor growth in rats. Science 176:417, 1972 22. Child DF, Nader S, Mashiter K, Kjeld M, Banks L, Fraser TR: Prolactin studies in "functionless" pituitary tumors. Br Med J 1:604, 1975 23. Thorner MO, McNeilly AS, Hagan C, Besser GM: Longterm treatment of galactorrhea and hypogonadism with bromocryptine. Br Med J 2:419,1974 24. Wass JAH, Thorner MO, Morris DV, Rees LH, Mason AS, Jones AE; Besser GM: Long-term treatment of acromegaly with bromocryptine. Br Med J 1:875, 1977