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Spontaneous regression of prolactin-producing pituitary adenomas
Spontaneous regression of prolactin-producing pituitary adenomas THOMAS A.
C. VAUGHN,
F, HANEY.
R. HE,RBERT
M.D. WIEBE,
RICHARD
S. KRAMER,
CHARLES
B. HAMMOND.
Dzuhnm.
North
M.D. M.D. M.D. M.D.
Caroli;atr
women evaluated for amenorrhea, gafactorrhee, end hyparprolectinemia had radiographic changes of the sella turcice (focaiitsd erosion on trispiral tomography) suggestive of a pituitary tumor. Both patients experienced sponteneous regression of apparent prolactin-secreting edenomes with a merked decrease in the quantity of gefactorrhee and a reduction of serum prolectin concentrations to the normal renge. One patient noted e marked improvement of heedeches end spontaneous menses resumed in the other patient. (AM. J. OBSTET. GYNECOL. 136:980, 1980.) Two
RECEST DEVELOPMENT ofradioimmunoassays for determination of circulating prolactin (PRL) concentrations’ along with the advent of thin-section tomographic evaluation of the sella turcica* has allowed the identification of patients with very small prolactinsecreting pituitary adenomas (microadenomas < 1 cm in diameter). Since pituitary microadenomas have the potential for further growth, treatment has usually been initiated after the identification of these tumors, particularly if pregnancy is desired. Consequently, the natural history of this disease is unknown. Two patients are presented who, by current criteria? probably had prolactin-producing pituitary tumors which underwent apparent spontaneous regression. One patient has been previously included in limited detail in a paper from this institution which discussed etiologies of the empty sella syndrome.l THE
caee report Case 1. Patient M. C., a 39-year-old, black woman referred in 1970 for para 2-O-O-Z was originally oligomenorrhea and galactorrhea of 2 years’ duration. After normal menarche and two uncomplicated
980
pregnancies in 1959 and 1964, the patient began Ortho-Novum-2 for contraception. When she discontinued the medication in 1968, she experienced spontaneous menses at monthly intervals for 1 year but subsequently developed amenorrhea. After 6 months of amenorrhea the patient restarted Ortho-Novum-2 and developed bilateral galactorrhea. The medication was then discontinued but galactorrhea persisted and menses became irregular (every 1 to 3 months). At the time of the patient’s original evaluation at this institution she also gave a l-year history of right periorbital headaches. Evaluation revealed massive obesity, mild glucose intolerance, low gonadotropin levels (by urinary assay), and an “upper limit of normal size” sella turcica on routine anteroposterior and lateral skull x-ray films without other specific radiographic abnormality. Visual fields were normal. Insulin tolerance testing demonstrated a normal growth hormone reserve and follow-up was recommended. Because of continued amenorrhea, galactorrhea, and headaches, she was re-evaluated in 1972. Normal growth hormone reserve was again demonstrated with insulin tolerance testing. as welt as adequate adrenocorticotropic hormone reserve with metyrapone testing. On a lateral x-ray film. the stella had marginally increased in size and standard tomograms (0.5 cm sections) demonstrated “localized areas of’ absence of lamina clura in the posterior portion.” Spinal Huid study and pneumoencephalography were normal. Based on preliminary data (serum PRL concentrations >5f) rig/ml), hromocriptine, 2.5 mg 1~) mouth three times a day. was begun in ,January, 197.5, for an experimental protocol but had to be discontinued after only 2 weeks because of nausea and vomiting. Repeat testtng revealed no response of low normal gonado000%9378/80/080980+03$00.30/0
0
1980
The
C:. V. Moshy
Co.
Volume Number
136 8
Prolactin-producing
tropin levels to luteinizing hormone-releasing hormone* (LH-RH) testing (100 pg subcutaneously). L-Dopa ( 10 mgikg orally) failed to produce a rise in the serum growth hormone concentration; however, the PRL concentration was suppressed from a baseline value of 1,170 to 250 rig/ml. Although thyroid function studies (thyronine and tri-iodothyronine resin uptake) were normal, the serum thyroid-stimulating hormone (TSH) was minimally elevated to 14 pIU/mI (normal 0 to IO). Because of the markedly elevated serum PRL concentration and the abnormal tomography of the pituitary sella, a presumptive diagnosis of a PRL-producing pituitary microadenoma was advanced. Transsphenoida1 extirpation of the suspected tumor was recommended in the summer of 1975; however, the patient declined. In January, 1976, the patient was admitted to another hospital for aseptic meningitis which resolved in a few days without specific therapy. Although the amenorrhea and galactorrhea had persisted unchanged since her last examination, the previously noted headaches had resolved. In July, 1976, she was admitted for transsphenoidal pituitary exploration. Pertinent physical findings included a blood pressure of 120190 mm Hg and a weight of 130 kg. Milky discharge from both breasts was Sudan IV positive. Trispiral (thin-section) tomography revealed “obvious destruction of the posterior floor of the sella turcica as well as the dorsum with the obvious deformity of the postkrior clinoids.” A repeat pneumoencephalogram was normal. Transsphenoidal exploration of the pituitary fossa revealed a small pituitary remnant only 2 mm in thickness found displaced to one side with no prominence in any portion of the gland to suggest a microadenoma. Although the area was thoroughly explored, no pathologic tissue was found, only a partially empty sella with many very delicate adhesions randomly bridging the sella in multiple directions. The patient’s postoperative course was benign and she was discharged on a regimen of cortisone acetate. A serum PRL concentration determined one day before operation (but not available until after the operation) was 64.7 rig/ml, markedly reduced from the prior value. Postoperative pituitary testing (on cortisone) failed to demonstrate any reserve in gonadotropins, No response in growth hormone was noted with 1,300 mg of L-dopa orally (10 mg/kg). Simultaneously measured serum PRL concentrations were suppressed from a baseline of 52.1 to 33 rig/ml. Five months following the surgical exploration, a serum PRL concentration was 19.8 rig/ml. Mild hypothyroidism was noted and confirmed bt thyroid function studies. Serum TSH ‘level was 3 kIU/ml (normal 0 to 10) and the patient was begun on a regimen of thyroid replacement. Glucocorticoid replacement has
*AY-24031,
provided by Ayerst Laboratories.
pituitary
adenomas
981
been continued. The galactorrhea has persisted and she has not had any spontaneous vaginal bleeding. Case 2. Patient D. D., a 25-year-old, married, white, nulliparous woman, was referred in January, 1978, for evaluation of “postpill” oligomenorrhea (intervals of 30 to 90 days) and galactorrhea of 4 years’ duration. After 2 years of involuntary infertility a diagnostic evaluation was begun. A flat basal body temperature and proliferative endometrium on biopsy confirmed suspected anovulation. Clomiphene citrate (50 mg orally for 5 days) was begun to induce ovulation but was unsuccessful even when the dosage was increased to 150 mg and supplemented with two injections (5,000 U each) of human chorionic gonadotropin. As a consequence additional laboratory data were obtained. The serum PRL concentration was 140 rig/ml on two occasions (normal for that laboratory 0 to 40 rig/ml). Polytomography of the sella was reported as diagnostic of a small pituitary adenoma. After the above studies (2 to 3 months prior to referral to this institution), the patient noted decreasing breast size and a reduction in the amount of galactorrhea. She had a spontaneous menses and 26 days later responded to a progesterone challenge test. She had received no other medications. Physical examination was normal except for a milky discharge from both breasts that was Sudan IV positive. Trispiral thin-section tomography demonstrated 3 mm of thinning of the dorsum of the anterior wall consistent with erosion’from tumor with enlargement of the hemisella. Visual field testing was normal. The initial serum PRL concentration in our laboratory was IO.2 rig/ml and a repeat determination was 12.5 rig/ml. Insulin tolerance testing demonstrated adequate growth hormone reserve (65.3 rig/ml at 60 minutes) as well as adequate cortisol reserve (baseline 8.9 pg% with an increase to 21.3 pg%). LH-RH testing (100 pg subcutaneously) produced a normal rise of both gonadotropins, and L-dopa (10 mg/kg) suppressed a baseline PRL concentration of 8.8 to 4.5 ngiml. Serum progesterone concentration was 3.5 rig/ml. The patient has continued to experience only minimal galactorrhea and has spontaneous menses at intervals of 24 to 38 days. In September, 1978 (8 months after her initial evaluation at this institution) a repeat serum PRL concentration was 22.9 ngiml. Selected tomographic views of the sella were unchanged. Although no contraception has been utilized, she has failed to conceive to date.
Comment Two cases are presented in which, by current criteria, a PRL-secreting pituitary tumor was suspected. Patient M. C.‘s operative findings of a partially empty sella were initiaily surprising since she had previously had a massively elevated PRL concentration, tomographic evidence of a pituitary tumor (erosion), and two negative pneumoencephalograms. The pituitary gland
982
Vaughn
et al. Am.
was inspected thoroughly for evidence of tumor since it has been rcpcnted that microadenornas mav coexist with an empty sella”: however. no microadenoma was found. The hnding of trabeculations and adhesions within the srll,~ and the atrophic-appearing pituitary displaced to one side strongly suggest that a spaceoccupying lesion had been present and had resorbed. Because of the magnitude of the initial elevations ot serum PRI, concentrations (>l,OOO rig/ml), it is improbable that a hypothalamic dysfunction could be impIicated as the etiology of the hyperprolactinemia. Thus. the dramatic fall in the PRL concentration from I, 170 to 64 ngiml most likely represents a spontaneous infarction and/or necrosis of a PRL-secreting pituitary adenoma. With subsequent resorption it is not surprising retrospectively that an “empty sella” was found at operation. L’nfortunatelythe preoperative PRL level was not available in time to avoid sellar exploration. Pituitarv hemorrhage might produce the same clinical findings as those of nerrosis: however, most cases ot pituitary apoplexy usually involve extensive hemorrhage and produce altered consciousness and other central nervous system symptoms (i.e., acute headaches, ocular palsies, hyperpyrexia. visual loss, etc.6). In early reports dearh was not uncommon with mortality rates reported as high as 60s.’ However, the majority of cases were not microtumors (
April J. Obstet.
15. 1980 Gynecol.
spontaneous remissions of the process by a reduction in serum growth hormone concentrations. The sequela of the spontaneous resolution of at least one of the cases was an empty sella syndrome.” The authors of this report speculated that the tumor had undergone selective silent infarction that led to the creation of an “empty” sella. D. D. most likely represents a case of asymptomatic selective tumor infarction. Hypothalamic dysfunction with hyperprolactinemia rather than microadenoma might be implicated as the cause of the galactorrheaoligomenorrhea. and spontaneous resolution of this dysfunction could create a similar clinical situation. However, the magnitude of the serum PRL elevation and the changes noted on polytomographic evaluation of the sella make a PRL-producing tumor a more likely possibility-. Without treatment the serum PRL concentration subsequently fell to a normal value and she experienced spontaneous menses. The patient noted a decrease in the quantity of galactorrhea and a decrease in breast size. Pituitary testing was normal, suggesting adequate reserve of other pituitary trophic hormones, and the serum progesterone value of 5.5 ngiml may represent a return of spontaneous ovulation. Several patients who have recently undergone transsphenoidal extirpation of PRL-producing pituitary tumors at this institution were found to have tumors with significant central necrosis.” This surgical finding possibly represents a microadenoma in the early process of spontaneous regression. Patients M. (I;. and D. D. may represent cases of infarction of the majority of galactotrophit cells since PRL concentrations returned to normal values in both. Attention is drawn to the phenomenon of spontaneous regression since the natural history of PRL-secreting pituitary adenomas is poorly understood and the clinical course of these two patients suggests that spontaneous remission may be a more frequent outcome than currently appreciated.
REFERENCES
I. Sinha. A. S., Selby, F. W.. Lewis, V. J., and Vanderlaan. W. I’ : A homologous radioimmunoassay for human prolactin, J. Clin. Endocrinol. Metab. 36:509, 1973. 2. Vezina, J. L., and Sutton. T. J.: Prolactin-secreting pituitary microadenomas, Am. J. Roentgenol. 120:46, 1974. 3. Wiebe, R. H., Hammond, C. B., and Handwerger, S.: Prolactin-secreting pituitary microadenoma: detection and evaluation, Fertil. Steril. 29:282, 1978. 4. Haney, A. F., Kramer, R. S., Wiehe, R. H., and Hammend, C. B.: Hypothalamic-pituitary function and radiographic evaluation of women with hyperprolactinemia and an “empty” sella turcica, AM. ,J. OBSTET. GYNECOI.. 134:917, 1979. .i. Dominque, J. N., Wing, S. D., and Wilson, C. B.: Coexisting pituitary adenomas and partially empty sellas, J. Neurosurg. 48:‘23, 1978.
6. Locke, W., and Schally, A. V.: The Hypothalamus and Pituitary in Health and Disease, Springfield. Illinois, 1972, C Thomas, Publisher. 7. Uihlein, A., Balfour, W. M., and Donovan, P. F.: Acute hemorrhage into pituitary adenomas, J. Neurosurg. 14:140, 1957. 8. Ewer, R. H., and Kotheimer, T. G.: Spontaneous burned-out acromegaly with preservation of normal growth hormone responses: diagnostic, historical, theoretical, and treatment aspects, Johns Hopkins Med. J. 127: 199, 1970. 9. Login, I., and Sante, R. J.: Empty sella syndrome. Sequela of the spontaneous remission of acromegaly, Arch. Intern. Med. 135:1519, 1975. 10. Kramer, R. S.: Unpublished data.
C. VAUGHN,
F, HANEY.
R. HE,RBERT
M.D. WIEBE,
RICHARD
S. KRAMER,
CHARLES
B. HAMMOND.
Dzuhnm.
North
M.D. M.D. M.D. M.D.
Caroli;atr
women evaluated for amenorrhea, gafactorrhee, end hyparprolectinemia had radiographic changes of the sella turcice (focaiitsd erosion on trispiral tomography) suggestive of a pituitary tumor. Both patients experienced sponteneous regression of apparent prolactin-secreting edenomes with a merked decrease in the quantity of gefactorrhee and a reduction of serum prolectin concentrations to the normal renge. One patient noted e marked improvement of heedeches end spontaneous menses resumed in the other patient. (AM. J. OBSTET. GYNECOL. 136:980, 1980.) Two
RECEST DEVELOPMENT ofradioimmunoassays for determination of circulating prolactin (PRL) concentrations’ along with the advent of thin-section tomographic evaluation of the sella turcica* has allowed the identification of patients with very small prolactinsecreting pituitary adenomas (microadenomas < 1 cm in diameter). Since pituitary microadenomas have the potential for further growth, treatment has usually been initiated after the identification of these tumors, particularly if pregnancy is desired. Consequently, the natural history of this disease is unknown. Two patients are presented who, by current criteria? probably had prolactin-producing pituitary tumors which underwent apparent spontaneous regression. One patient has been previously included in limited detail in a paper from this institution which discussed etiologies of the empty sella syndrome.l THE
caee report Case 1. Patient M. C., a 39-year-old, black woman referred in 1970 for para 2-O-O-Z was originally oligomenorrhea and galactorrhea of 2 years’ duration. After normal menarche and two uncomplicated
980
pregnancies in 1959 and 1964, the patient began Ortho-Novum-2 for contraception. When she discontinued the medication in 1968, she experienced spontaneous menses at monthly intervals for 1 year but subsequently developed amenorrhea. After 6 months of amenorrhea the patient restarted Ortho-Novum-2 and developed bilateral galactorrhea. The medication was then discontinued but galactorrhea persisted and menses became irregular (every 1 to 3 months). At the time of the patient’s original evaluation at this institution she also gave a l-year history of right periorbital headaches. Evaluation revealed massive obesity, mild glucose intolerance, low gonadotropin levels (by urinary assay), and an “upper limit of normal size” sella turcica on routine anteroposterior and lateral skull x-ray films without other specific radiographic abnormality. Visual fields were normal. Insulin tolerance testing demonstrated a normal growth hormone reserve and follow-up was recommended. Because of continued amenorrhea, galactorrhea, and headaches, she was re-evaluated in 1972. Normal growth hormone reserve was again demonstrated with insulin tolerance testing. as welt as adequate adrenocorticotropic hormone reserve with metyrapone testing. On a lateral x-ray film. the stella had marginally increased in size and standard tomograms (0.5 cm sections) demonstrated “localized areas of’ absence of lamina clura in the posterior portion.” Spinal Huid study and pneumoencephalography were normal. Based on preliminary data (serum PRL concentrations >5f) rig/ml), hromocriptine, 2.5 mg 1~) mouth three times a day. was begun in ,January, 197.5, for an experimental protocol but had to be discontinued after only 2 weeks because of nausea and vomiting. Repeat testtng revealed no response of low normal gonado000%9378/80/080980+03$00.30/0
0
1980
The
C:. V. Moshy
Co.
Volume Number
136 8
Prolactin-producing
tropin levels to luteinizing hormone-releasing hormone* (LH-RH) testing (100 pg subcutaneously). L-Dopa ( 10 mgikg orally) failed to produce a rise in the serum growth hormone concentration; however, the PRL concentration was suppressed from a baseline value of 1,170 to 250 rig/ml. Although thyroid function studies (thyronine and tri-iodothyronine resin uptake) were normal, the serum thyroid-stimulating hormone (TSH) was minimally elevated to 14 pIU/mI (normal 0 to IO). Because of the markedly elevated serum PRL concentration and the abnormal tomography of the pituitary sella, a presumptive diagnosis of a PRL-producing pituitary microadenoma was advanced. Transsphenoida1 extirpation of the suspected tumor was recommended in the summer of 1975; however, the patient declined. In January, 1976, the patient was admitted to another hospital for aseptic meningitis which resolved in a few days without specific therapy. Although the amenorrhea and galactorrhea had persisted unchanged since her last examination, the previously noted headaches had resolved. In July, 1976, she was admitted for transsphenoidal pituitary exploration. Pertinent physical findings included a blood pressure of 120190 mm Hg and a weight of 130 kg. Milky discharge from both breasts was Sudan IV positive. Trispiral (thin-section) tomography revealed “obvious destruction of the posterior floor of the sella turcica as well as the dorsum with the obvious deformity of the postkrior clinoids.” A repeat pneumoencephalogram was normal. Transsphenoidal exploration of the pituitary fossa revealed a small pituitary remnant only 2 mm in thickness found displaced to one side with no prominence in any portion of the gland to suggest a microadenoma. Although the area was thoroughly explored, no pathologic tissue was found, only a partially empty sella with many very delicate adhesions randomly bridging the sella in multiple directions. The patient’s postoperative course was benign and she was discharged on a regimen of cortisone acetate. A serum PRL concentration determined one day before operation (but not available until after the operation) was 64.7 rig/ml, markedly reduced from the prior value. Postoperative pituitary testing (on cortisone) failed to demonstrate any reserve in gonadotropins, No response in growth hormone was noted with 1,300 mg of L-dopa orally (10 mg/kg). Simultaneously measured serum PRL concentrations were suppressed from a baseline of 52.1 to 33 rig/ml. Five months following the surgical exploration, a serum PRL concentration was 19.8 rig/ml. Mild hypothyroidism was noted and confirmed bt thyroid function studies. Serum TSH ‘level was 3 kIU/ml (normal 0 to 10) and the patient was begun on a regimen of thyroid replacement. Glucocorticoid replacement has
*AY-24031,
provided by Ayerst Laboratories.
pituitary
adenomas
981
been continued. The galactorrhea has persisted and she has not had any spontaneous vaginal bleeding. Case 2. Patient D. D., a 25-year-old, married, white, nulliparous woman, was referred in January, 1978, for evaluation of “postpill” oligomenorrhea (intervals of 30 to 90 days) and galactorrhea of 4 years’ duration. After 2 years of involuntary infertility a diagnostic evaluation was begun. A flat basal body temperature and proliferative endometrium on biopsy confirmed suspected anovulation. Clomiphene citrate (50 mg orally for 5 days) was begun to induce ovulation but was unsuccessful even when the dosage was increased to 150 mg and supplemented with two injections (5,000 U each) of human chorionic gonadotropin. As a consequence additional laboratory data were obtained. The serum PRL concentration was 140 rig/ml on two occasions (normal for that laboratory 0 to 40 rig/ml). Polytomography of the sella was reported as diagnostic of a small pituitary adenoma. After the above studies (2 to 3 months prior to referral to this institution), the patient noted decreasing breast size and a reduction in the amount of galactorrhea. She had a spontaneous menses and 26 days later responded to a progesterone challenge test. She had received no other medications. Physical examination was normal except for a milky discharge from both breasts that was Sudan IV positive. Trispiral thin-section tomography demonstrated 3 mm of thinning of the dorsum of the anterior wall consistent with erosion’from tumor with enlargement of the hemisella. Visual field testing was normal. The initial serum PRL concentration in our laboratory was IO.2 rig/ml and a repeat determination was 12.5 rig/ml. Insulin tolerance testing demonstrated adequate growth hormone reserve (65.3 rig/ml at 60 minutes) as well as adequate cortisol reserve (baseline 8.9 pg% with an increase to 21.3 pg%). LH-RH testing (100 pg subcutaneously) produced a normal rise of both gonadotropins, and L-dopa (10 mg/kg) suppressed a baseline PRL concentration of 8.8 to 4.5 ngiml. Serum progesterone concentration was 3.5 rig/ml. The patient has continued to experience only minimal galactorrhea and has spontaneous menses at intervals of 24 to 38 days. In September, 1978 (8 months after her initial evaluation at this institution) a repeat serum PRL concentration was 22.9 ngiml. Selected tomographic views of the sella were unchanged. Although no contraception has been utilized, she has failed to conceive to date.
Comment Two cases are presented in which, by current criteria, a PRL-secreting pituitary tumor was suspected. Patient M. C.‘s operative findings of a partially empty sella were initiaily surprising since she had previously had a massively elevated PRL concentration, tomographic evidence of a pituitary tumor (erosion), and two negative pneumoencephalograms. The pituitary gland
982
Vaughn
et al. Am.
was inspected thoroughly for evidence of tumor since it has been rcpcnted that microadenornas mav coexist with an empty sella”: however. no microadenoma was found. The hnding of trabeculations and adhesions within the srll,~ and the atrophic-appearing pituitary displaced to one side strongly suggest that a spaceoccupying lesion had been present and had resorbed. Because of the magnitude of the initial elevations ot serum PRI, concentrations (>l,OOO rig/ml), it is improbable that a hypothalamic dysfunction could be impIicated as the etiology of the hyperprolactinemia. Thus. the dramatic fall in the PRL concentration from I, 170 to 64 ngiml most likely represents a spontaneous infarction and/or necrosis of a PRL-secreting pituitary adenoma. With subsequent resorption it is not surprising retrospectively that an “empty sella” was found at operation. L’nfortunatelythe preoperative PRL level was not available in time to avoid sellar exploration. Pituitarv hemorrhage might produce the same clinical findings as those of nerrosis: however, most cases ot pituitary apoplexy usually involve extensive hemorrhage and produce altered consciousness and other central nervous system symptoms (i.e., acute headaches, ocular palsies, hyperpyrexia. visual loss, etc.6). In early reports dearh was not uncommon with mortality rates reported as high as 60s.’ However, the majority of cases were not microtumors (
April J. Obstet.
15. 1980 Gynecol.
spontaneous remissions of the process by a reduction in serum growth hormone concentrations. The sequela of the spontaneous resolution of at least one of the cases was an empty sella syndrome.” The authors of this report speculated that the tumor had undergone selective silent infarction that led to the creation of an “empty” sella. D. D. most likely represents a case of asymptomatic selective tumor infarction. Hypothalamic dysfunction with hyperprolactinemia rather than microadenoma might be implicated as the cause of the galactorrheaoligomenorrhea. and spontaneous resolution of this dysfunction could create a similar clinical situation. However, the magnitude of the serum PRL elevation and the changes noted on polytomographic evaluation of the sella make a PRL-producing tumor a more likely possibility-. Without treatment the serum PRL concentration subsequently fell to a normal value and she experienced spontaneous menses. The patient noted a decrease in the quantity of galactorrhea and a decrease in breast size. Pituitary testing was normal, suggesting adequate reserve of other pituitary trophic hormones, and the serum progesterone value of 5.5 ngiml may represent a return of spontaneous ovulation. Several patients who have recently undergone transsphenoidal extirpation of PRL-producing pituitary tumors at this institution were found to have tumors with significant central necrosis.” This surgical finding possibly represents a microadenoma in the early process of spontaneous regression. Patients M. (I;. and D. D. may represent cases of infarction of the majority of galactotrophit cells since PRL concentrations returned to normal values in both. Attention is drawn to the phenomenon of spontaneous regression since the natural history of PRL-secreting pituitary adenomas is poorly understood and the clinical course of these two patients suggests that spontaneous remission may be a more frequent outcome than currently appreciated.
REFERENCES
I. Sinha. A. S., Selby, F. W.. Lewis, V. J., and Vanderlaan. W. I’ : A homologous radioimmunoassay for human prolactin, J. Clin. Endocrinol. Metab. 36:509, 1973. 2. Vezina, J. L., and Sutton. T. J.: Prolactin-secreting pituitary microadenomas, Am. J. Roentgenol. 120:46, 1974. 3. Wiebe, R. H., Hammond, C. B., and Handwerger, S.: Prolactin-secreting pituitary microadenoma: detection and evaluation, Fertil. Steril. 29:282, 1978. 4. Haney, A. F., Kramer, R. S., Wiehe, R. H., and Hammend, C. B.: Hypothalamic-pituitary function and radiographic evaluation of women with hyperprolactinemia and an “empty” sella turcica, AM. ,J. OBSTET. GYNECOI.. 134:917, 1979. .i. Dominque, J. N., Wing, S. D., and Wilson, C. B.: Coexisting pituitary adenomas and partially empty sellas, J. Neurosurg. 48:‘23, 1978.
6. Locke, W., and Schally, A. V.: The Hypothalamus and Pituitary in Health and Disease, Springfield. Illinois, 1972, C Thomas, Publisher. 7. Uihlein, A., Balfour, W. M., and Donovan, P. F.: Acute hemorrhage into pituitary adenomas, J. Neurosurg. 14:140, 1957. 8. Ewer, R. H., and Kotheimer, T. G.: Spontaneous burned-out acromegaly with preservation of normal growth hormone responses: diagnostic, historical, theoretical, and treatment aspects, Johns Hopkins Med. J. 127: 199, 1970. 9. Login, I., and Sante, R. J.: Empty sella syndrome. Sequela of the spontaneous remission of acromegaly, Arch. Intern. Med. 135:1519, 1975. 10. Kramer, R. S.: Unpublished data.