A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria.

Acute intermittent porphyria is a genetic disease in which endogenous hormones affect clinical expression. Premenstrual exacerbations can occur, sometimes often, in women with this disease. Gonadotropin releasing hormone analogues can prevent ovulation by reducing secretion of luteinizing hormone and follicle-stimulating hormone. In six patients with well-documented acute intermittent porphyria and frequent cyclical exacerbations, daily administration of an agonistic gonadotropin releasing hormone analogue, ([ImBzl]-D-His6,Pro9-NET)gonadotropin releasing hormone, intranasally or subcutaneously for as long as 26 months reduced or eliminated premenstrual attacks and caused only minor side effects. Adjustments in dosage or route of administration were sometimes needed. We conclude that endocrine manipulation by treatment with a gonadotropin releasing hormone agonist will prevent neurovisceral attacks of acute intermittent porphyria due to cyclical changes in endogenous hormones and is a safe alternative to exogenous steroids, which may induce attacks of this disease.

Growth and sexual development before and after sex steroid therapy in patients with thalassemia major.

Growth, sexual development, and hypothalamic-pituitary-gonadal function were evaluated in 23 patients with thalassemia major (14 female and nine male) aged 13 to 29 years. Five women (group 1) with hemoglobin levels of less than 7 g/dL, which were maintained by transfusions during childhood, did not spontaneously enter puberty. They had evidence of severe hypothalamic-pituitary dysfunction. Maintaining hemoglobin levels of about 8 g/dL resulted in spontaneous onset of puberty in seven of nine female patients (group 2), but had no such ameliorative effect on the nine male patients. In the latter, peak luteinizing hormone (LH) responses to gonadotropin releasing hormone correlated with bone age. Treatment with testosterone produced inconsistent partial inhibition of LH and follicle-stimulating hormone (FSH) responses to stimulation. After discontinuation of testosterone treatment, a rebound of basal testosterone, LH, and FSH levels was observed, but this was not sustained. These findings are compatible either with dysfunction of hypothalamic maturation or with partial pituitary dysfunction. Four of the group 1 females and six of the males treated with appropriate sex hormones showed satisfactory pubertal progression. Acceleration in linear growth was observed in four of the male patients whose epiphyses were still open. Treatment was well tolerated in all patients.

Gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists do not alter endogenous GnRH secretion in short-term castrated rams.

The administration of GnRH agonists and antagonists suppresses pituitary LH secretion. However little is known about their effects on endogenous GnRH secretion. To determine if GnRH analogs act on GnRH secretion through a short or ultrashort loop feedback mechanism, experiments were performed to analyze GnRH secretion in hypophyseal portal blood of conscious short-term castrated rams under both agonist or antagonist treatment. In Study 1, six rams were castrated and surgically prepared for portal blood collection on day -7. Portal and peripheral blood were collected simultaneously every 10 min for 14-15 h on day 0. Five hours after the beginning of the portal blood collection, animals were injected im with 5 mg potent GnRH antagonist (Nal-Glu). In Study 2, six rams were treated daily from day -11 to day 0 with the GnRH agonist D-Trp6 GnRH (0.5 mg im). Castration and surgical preparation for portal blood collection were performed on day -7. On day 0 portal and peripheral blood were collected simultaneously every 10 min for 10-11 h. In both studies, to determine whether an increase in GnRH concentration in hypophyseal portal blood can overcome the inhibitory effect of the GnRH analogs, between 5 and 5.5 h after the injection of the analogs, endogenous GnRH secretion was stimulated by Naloxone administration (3 x 100 mg, iv, at 30-min intervals) followed by a bolus of exogenous GnRH (2 x 10 micrograms, iv at 30-min intervals). In Study 1, Nal-Glu administration led to a rapid cessation of pulsatile LH secretion for the duration of blood collection while GnRH pulse frequency and amplitude were not affected. GnRH and LH pulse frequency before and after Nal-Glu administration were, 6.2 +/- 0.6 vs. 5.7 +/- 0.8 (NS) and 5.3 +/- 0.3 vs. 0.3 +/- 0.2 pulses/6 h (P less than 0.001) respectively. In Study 2, peripheral LH secretion was completely suppressed while GnRH secretion (portal blood) remained pulsatile. GnRH pulses frequency and pulse amplitude were 4.3 +/- 0.3 pulses/6 h and 43.0 +/- 4.7 pg/ml, respectively. In both experiments, neither stimulation of endogenous GnRH secretion by naloxone nor administration of exogenous GnRH allowed reinitiation of LH secretion. However, additional studies in two animals of each treatment group (study-III) showed that this was clearly a dose related effect in antagonist treated but not in agonist-treated animals since higher doses of exogenous GnRH (i.e. 100 micrograms or 1000 micrograms) can increase significantly LH levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Isolated deficiency of follicle-stimulating hormone: Further studies.

We record further studies over the past 2 yr on a unique female subject with isolated follicle-stimulating hormone (hFSH) deficiency, who developed human anti-gFSH antibodies after treatment with exogenous urinary gonadotropins. Administration of LRH resulted in a significant rise in serum hLH, but hFSH levels remained undetectable, "alpha Subunit" (the common alpha chain of the glycoprotein hormones) was detectable in basal samples obtained from our patient, and rose sharply after LRH. This is concordant with the hypothesis that the defect in our subject may be in the synthesis of the beta chain of hFSH, but it does not exclude other possibilities. The concentration of hFSH antibodies in the patient's serum has been monitored and her response to a further course of exogenous gonadotropins is recorded. The anti serum exhibits specificity for the hFSH molecule; the alpha and the beta chains of hFSH are virtually inert in competing with tracer 125-I-hFSH for binding to the antibody.

The exaggerated prolactin response to thyrotropin-releasing hormone and metoclopramide in 1,2-dibromo-3-chloropropane-induced azoospermia.

Twelve males with azoospermia secondary to exposure to the nematocide 1,2-dibromo-3-chloropropane were challenged to iv LRH (100 micrograms), TRH (200 micrograms), and metoclopramide (MET; 10 mg) administered 30 min apart. When compared to 24 male controls, both basal FSH and LH levels as well as peak gonadotropin responses to LRH were increased in the azoospermic group. The patients also had increased total estradiol (E2) and testosterone (T) as well as testosterone-binding globulins levels. Free T levels, however, were not significantly different from the controls. Basal PRL levels were similar in the two groups. However, the peak PRL responses to both TRH and MET were significantly increased in the azoospermia subjects (P < 0.001). In both groups, the PRL response to MET was greater than to TRH. In the individual control and azoospermic subjects, there was no correlation between the PRL response and E2, T, or the E2 to T ratio. However, a positive correlation did exist between testosterone-binding globulin levels and the PRL response to TRH and MET. Although the precise mechanism underlying the PRL hyperresponsiveness is unknown, it may be an estrogen-induced phenomenon.

Dissociation of prolactin response to thyrotropin-releasing hormone and metoclopramide in chronic renal failure.

PRL secretion was evaluated in 14 males with chronic renal failure on long term hemodialysis. Twelve had basal hyperprolactinemia. Ten subjects were challenged with TRH in doses ranging from 200--1000 micrograms. None of them responded to 200 or 500 micrograms TRH, although 2 of 4 subjects tested did respond to 1000 micrograms TRH. In contrast, all 4 subjects challenged with metoclopramide did have PRL responses which were indistinguishable from those of the controls. These results indicate that there is a dissociation in responsiveness to metoclopramide and TRH in chronic renal failure.

Late luteal phase administration of RU486 for three successive cycles does not disrupt bleeding patterns or ovulation.

RU486, a 19-nor steroid, binds with high affinity to the receptors for progesterone and glucocorticoids, blocking the actions of these hormones on their target tissues. We conducted studies to determine whether RU486 administered at the end of the luteal phase would disturb the menstrual rhythm, ovulation, or hormonal parameters in the treatment and post-treatment cycles. The first study was done in six surgically sterilized women during two consecutive cycles. RU486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(1-propynyl)estra-4,9-dien-3-one; 100 mg/day] was given for 4 consecutive days, commencing on days 23-27 of the first cycle. Menstrual bleeding occurred by the second day of RU486 administration in all women and was indistinguishable from their usual bleeding pattern. The onset of this bleeding was advanced by RU486 administration, since it entailed shortening of the luteal phase with prolongation of the following follicular phase. Serum LH, FSH, estradiol, and progesterone levels were normal in five of the six women in both the treatment and posttreatment cycles. The second study was conducted in 10 women who were not exposed to the risk of pregnancy. RU486 (100 mg/day) was given for 4 consecutive days, commencing 4 days before their expected menses for 3 successive cycles, preceded and followed by 2 placebo-treated cycles. Bleeding patterns were indistinguishable during the RU486 and placebo cycles. Late luteal phase administration of RU486 consistently produced menstrual bleeding within 1-3 days of drug administration. Daily early morning urinary LH excretion in 6 women and estrone glucuronide and pregnanediol glucuronide excretion in 5 women during both placebo and RU486 cycles were consistent with luteinization, suggesting ovulation and appropriate corpus luteum function. We conclude that RU486 has no major effect on menstrual cycle events if given at the time of the natural progesterone withdrawal that occurs before menses in nonpregnant women.

The thyrotropin (TSH) profile in isolated gonadotropin deficiency: a model to evaluate the effect of sex steroids on TSH secretion.

This study evaluated the effect of estrogens and androgens on TSH secretion in hypogonadal male and female patients with isolated gonadotropin deficiency (IGD). The IGD subjects were clinically euthyroid and had normal circulating levels of thyroid hormones and T4-binding globulin (TBG). The patients were challenged with TRH (200 micrograms) in the untreated state, during treatment, and 1 month after cessation of hormonal replacement therapy. For the study, five females were treated with ethinyl estradiol (0.05 mg twice daily) for 21 days; after stopping for 7 days, the treatment schedule was repeated for another two cycles. The remaining female was given a similar regimen with conjugated estrogens (0.625 mg daily). Five males were treated with hCG (5000 IU twice weekly) for 3 months; two were treated with hCG and Pergonal. The female patients had significantly decreased basal TSH levels as well as impaired TSH responses to TRH. After 3 months of ethinyl estradiol treatment, there was a rise in TBG, total serum T4 and T3 levels and a decrease in T3 resin uptake; the free T4 index was unchanged. During estrogen administration, there was no change in basal TSH, but there was an increase in the peak TSH response to TRH, which became identical to that of the controls. Cessation of estrogen was associated with a reduction in releasable TSH, and the profile reverted to the pretreatment state. In addition, serum TBG levels, with the associated changes in thyroid hormones, also returned to normal. The male patients had TSH responses to TRH identical to those of the male controls. After 3 months of hCG treatment, there was a marked rise in serum estradiol as well as testosterone. Serum T4 was reduced without a change in T3, T3 resin uptake, or TBG. Furthermore, there was no alteration in the TSH response to TRH. On the other hand, the administration of ethinyl estradiol (0.1 mg daily for 2 weeks) to two male IGD subjects produced an increase in TBG. This was associated with elevation of serum T4 and T3 levels and reduction of T3 resin uptake. During estradiol administration, there was an increase in the TSH response to TRH. These data are compatible with the hypothesis that estrogens are required to maintain a normal TSH response to TRH in the female. However, testosterone may counteract the effect of estradiol, which may explain why normal males tend to have a lower TSH response to TRH than females.

Elevtion of serum testosterone in ovarian hyperstimulation syndrome.

Serum testosterone levels were monitored in female subjects who received therapy with human gonadotropins of urinary origin (menotropins) and human chorionic gonadotropin (hCG). Serum testosterone levels were not elevated in those subjects who did not experience side effects with therapy (Group A); among the other 7 subjects (Group B) with either moderate or severe ovarian hyperstimulation, serum testoterone levels rose distinctly (range 1.4 minus 9.0 ng/ml). Total menotropin dosage and serum estradiol-17beta levels were higher in Group B than in Group A. Ovarian hyperstimulation and elevation of serum testosterone were not restricted to patients with the syndrome of polycystic ovaries.

Dissociation of prolactin responsiveness to TRH and chlorpromazine in women with isolated gonadotropin deficiency.

The hormonal response to luteinizing hormone releasing hormone (LHRH) thyrotropin releasing hormone (TRH) and chlorpromazine has been evaluated in eleven female subjects with the syndrome of isolated bihormonal gonadotropin deficiency (IGD). Following LHRH, all subjects had elevations of both LH and FSH, but the gonadotropin responses were attenuated relative to those observed in normal female subjects studied in the early proliferative phase of the cycle. Similarly, peak TSH levels after TRH were significantly less in subjects with IGD relative to normal controls. Basal prolactin levels were low in the patient group. Prolactin levels following TRH increased at least two-fold in control subjects and in the group with IGD. Conversely, chlorpromazine failed to induce elevations of prolactin in eight of nine females with IGD.

Effects of the antiglucocorticoid RU 486 on adrenal function in dogs.

We studied the antiglucocorticoid effects of RU 486 given orally in doses of 5 (low), 20 (intermediate), and 50 mg/kg (high) daily for 10 days to seven female mongrel dogs. No changes in plasma ACTH or cortisol levels were produced by the 5 mg/kg dose. Plasma ACTH levels increased 3-fold with both intermediate and high dosages. Plasma cortisol levels rose 4-fold (P less than 0.05) within 2 days of commencing the high dose schedule and within 3 days with the intermediate dosage. Plasma aldosterone concentrations increased significantly only with the highest dose schedule. Plasma RU 486 levels rose progressively during the 10 days of RU 486 administration and with the highest dose remained elevated for 7 days after it was stopped. Plasma RU 486 levels measured by RIA and high pressure liquid chromatography were comparable. The monodemethylated metabolite of RU 486 changed in parallel to the parent compound. During the high dose of RU 486, there was a 4% increase in body weight, with a reduction in hematocrit and plasma protein concentration. Plasma electrolyte levels and osmolality did not change. We conclude that in dogs a daily RU 486 dose of 5 mg/kg does not alter adrenal function, whereas higher doses (20 and 50 mg/kg) induce increases in plasma ACTH and cortisol concentrations. Despite the blockade of glucocorticoid receptors by RU 486, the presence of isotonic hypervolemia suggests that there was no functional deficiency of cortisol at the renal tubule or it was overshadowed by augmented mineralocorticoid production and action.

Diminished prolactin reserve: a case report.

A 17 year old male patient presented with short stature and delayed puberty. Investigations showed normal thyroid function and intact TSH response to TSH-releasing hormone (TRH). Although basal levels of LH were low, both LH and FSH rose following the administration of LH-releasing hormone (LHRH). ACTH secretion assessed indirectly by the cortisol response to insulin hypoglycemia was normal. Growth hormone levels increased following the onset of sleep, as well as after the administration of insulin, L-dopa and L-arginine. Basal levels of prolactin were low (2-5 ng/ml) compared with 5-12 ng/ml in controls. There was a markedly impaired prolactin response to TRH (maximum rise above basal values of 3 ng/ml compared to a rise of 12-29 ng/ml in controls). Prolactin levels did not rise after the administration of chlorpromazine or L-arginine. There was some suppression of prolactin levels after L-dopa. Similar patterns of prolactin are seen in panhypopituitarism, where they are usually associated with other hypophyseal hormonal deficiencies. The diminished prolactin reserve demonstrated in this subject in the presence of intact function of the remainder of the anterior pituitary is compatible with the diagnosis of diminished prolactin reserve.

Effect of administration of a gonadotropin-releasing hormone (GnRH) antagonist (Nal-Glu) during the periovulatory period: the luteinizing hormone surge requires secretion of GnRH.

In primates, the LH surge that triggers ovulation is induced by an increase in circulating estradiol (E2) levels. Although several studies suggest that E2 acts on the pituitary, it is still not clear whether GnRH is involved. We investigated the role of GnRH during the periovulatory period in normal women by treating them with the GnRH antagonist Nal-Glu ([Ac-D2Nal1,D4-ClPhe2,D3Pal3,Arg5,DGlu6 (AA),DAla10] when E2 levels exceeded 550 pmol/L. In the first study (A), Nal-Glu was administered in five regimens (n = 4 in each group): a single sc injection of 10 mg (group 1), a single injection of 20 mg (group 2), and an injection of 10 mg, sc, on 2 (group 3), 3 (group 4), and 5 consecutive days (group 5). In the second study (B; n = 4), Nal-Glu (10 mg, sc, on 3 consecutive days) was coadministered with E2 benzoate (EB; 0.5 mg, im, every 12 h on 3 consecutive days). Controls (n = 4) were treated with EB alone at the same stage of the cycle. In the third study (C), three women received 10 mg/day Nal-Glu, sc, on 3 consecutive days together with pulsatile GnRH therapy (25 micrograms/pulse, one pulse every 90 min, sc, for 3 days); the first pulse was given 12 h after the first Nal-Glu injection. In study A, gonadotropin suppression resulted in a transient decline in E2 in groups 1 and 2. Relative to control cycles, the LH surge occurred with a delay of 24-48 h in group 1 and 24-120 h in group 2. In groups 3, 4, and 5, Nal-Glu administration resulted in the demise of the dominant follicle in half of the women in each group. The remaining women showed a profile similar to that of groups 1 and 2, i.e. a transient decline in E2 levels followed by a recovery, and a LH surge occurring 4 +/- 0.3 days after the last Nal-Glu injection. In study B, simultaneous administration of Nal-Glu and EB induced a rise in E2 levels from 951.3 +/- 79.6 to 4000.1 +/- 772.5 pmol/L 24 h after the beginning of treatment. Serum LH and FSH levels both decreased and remained low throughout Nal-Glu treatment. None of the women showed a LH rise in response to the EB injection. In controls, however, EB administration was followed by a significant gonadotropin discharge 48 h after the first EB injection.(ABSTRACT TRUNCATED AT 400 WORDS)

Multiple abnormalities of anterior pituitary hormone secretion in association with pseudohypoparathyroidism.

A male with pseudohypoparathyroidism presented with several hormonal abnormalities. He was clinically euthyroid with no palpable goiter, His serum T4, total T3, T3 Sephadex retention, and 131I uptake were normal. However, elevated basal TSH levels and exaggerated TSH responses to TRH which normalized during the administration of thyroid extract suggested reduced thyroidal reserve. Despite these finding the 131I uptake increased after exogeneous TSH, and the T3 level rose after TRH. Basal testosterone levels and response to hCG were normal however, gonadotropins were elevated and there was an exaggerated response after LRH treatment. Both LH and FSH levels were suppressed by testosterone propionate. The patient demonstrated intermittent basal hyperprolactinemia and impaired PRL responsiveness after metolopramide, chlorpromazine, and insulin administration. There was, however, an intact response to TRH. Basal PRL, TSH, and LH levels decreased after the administration of L-dopa and bromocriptine. Although the precise mechanism underlying these finding is unknown, the elevated basal levels of TSH, LH, and FSH and the exaggerated responses to their respective releasing hormones suggest the presence of partial degree of end-organ resistance to these pituitary trophic hormones. Together with the resistance to PTH, this may imply a common defect, presumably at a postreceptor level. However, hyporesponsiveness of PRL to metoclopramide and chlorpromazine and normal responsiveness to TRH suggest that an abnormality of dopamine tone also exists in pseudohypoparathyroidism.

Acid-induced gastric inhibitory polypeptide secretion in man.

This study has assessed the effect of oral or intraduodenal HCl, administered alone or in combination with glucose, on gastric inhibitory polypeptide (GIP) and insulin secretion. Eight young males were given the following three oral tests: 30 g glucose, 150 cc 0.1 N HCl and the glucose-acid combination. Another group of eight controls received intraduodenal infusions of 20 g glucose, 75 cc 0.1 N HCl and their combination. All tests were performed in a random fashion at weekly intervals. When given alone, HCl did not influence glucose or insulin levels. However, HCl did produce an increase in GIP. The GIP response to acid was less than that to glucose and was delayed. The peak insulin and GIP responses with the glucose and glucose/acid combinations were similar with both the oral and intraduodenal routes. There was, however, a potentiation of both the GIP and insulin responses when intraduodenal acid was given with glucose. This effect on GIP and insulin was not evident with the oral glucose/acid load. It is concluded that HCl by itself is capable of stimulating GIP secretion. Since there was only a potentiation of insulin and GIP secretion when large doses of HCl were given together with glucose via the intraduodenal route, the physiological relevance of acid-induced GIP secretion remains to be resolved.

Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486.

A patient with Cushing's syndrome due to ectopic ACTH secretion was treated successfully with the new glucocorticoid antagonist RU 486 [17 beta-hydroxy-11 beta-(4-dimethylamino phenyl) 17 alpha-(1-propynyl)estra-4,9-dien-3-one]. This compound is a 19-nor steroid with substitutions at positions C11 and C17 which antagonizes cortisol action competitively at the receptor level. Oral RU 486 was given in increasing doses of 5, 10, 15, and 20 mg/kg . day for a 9-week period. Treatment efficacy was monitored by assessment of clinical status and by measuring several glucocorticoid-sensitive variables, including fasting blood sugar, blood sugar 120 min after oral glucose administration, and plasma concentrations of TSH, corticosteroid-binding globulin, LH, testosterone-estradiol-binding globulin, and total and free testosterone. With therapy, the somatic features of Cushing's syndrome (buffalo hump, central obesity, and moon facies) ameliorated, mean arterial blood pressure normalized, suicidal depression resolved, and libido returned. All biochemical glucocorticoid-sensitive parameters normalized. No side-effects of drug toxicity were observed. We conclude that RU 486 may provide a safe, well tolerated, and effective medical treatment for hypercortisolism.

Chromatin-positive Klinefelter's syndrome with undetectable peripheral FSH levels.

An 18 year old phenotypic man is described with chromatin-positive Klinefelter's syndrome and undetectable peripheral human follicle stimulating hormone levels. The subject manifested chromosomal mosaicism consisting of three stem cell lines (45X; 46XY; and 47XXY). Testicular biopsy specimen showed germinal cell aplasia: the tubules were lined by Sertoli cells only, whereas the Leydig cells appeared normal. Serum human follicle stimulating hormone levels were undetectable and rose to only 5 mIU/ml after the administration of luteinizing hormone releasing hormone. Serum human luteinizing hormone varied between normal and moderately elevated values, and serum testosterone was in the low normal range. We discuss the features which distinguish this syndrome from isolated gonadotropin deficiency and from classic germinal cell aplasia. We suggest that the patient represents a new variant of Klinefelter's syndrome, with failure of human follicle stimulating hormone release secondary to prolonged hypersecretion.

Gonadotrophin, testosterone and prolactin interrelationships in cadmium-treated rats.

We have investigated the long-term effect of a single subcutaneous injection of cadmium chloride on plasma testosterone and gonadotrophin levels and the prolactin response to the dopaminergic antagonist metoclopramide in the rat. Twelve days after treatment with cadmium there was testicular necrosis, associated with a decrease in testosterone concentration and atrophy of the accessory sexual glands. By 185 days, partial recovery of the accessory sexual glands indicated by Leydig cell regeneration and a slight rise in testosterone levels had occurred. There was, however, persistent damage to the germinal epithelium. Concentrations of LH increased eightfold above controls by day 12, remained raised until 60 days and then decreased to threefold above controls at 280 days. In contrast, FSH levels reached a maximum between 60 and 130 days and remained persistently raised. The peak prolactin response to metoclopramide in cadmium-treated rats was depressed 12 days after cadmium administration and levels remained low at 19 and 75 days. Normal prolactin responses to metoclopramide were obtained 130 days after cadmium treatment using 1:0 mg metoclopramide/kg or 280 days after treatment using 0.25 mg/kg. When control and cadmium-treated rats were castrated at 280 days and then given metoclopramide 10 days later, the prolactin response was significantly reduced. It is concluded that the impaired prolactin response to metoclopramide in cadmium-treated rats is reversible. Prolactin returns to normal in parallel with regeneration of the Leydig cells, partial restoration of the accessory sex organ weight, slight increase in plasma testosterone and decrease in LH levels. These results suggest that testosterone is not solely responsible for the maintenance of normal prolactin secretion in the male rat.

Diminished prolactin reserve in acromegaly.

Prolactin (PRL) secretion has been evaluated in twenty acromegalic patients. All had intact LH, FSH, and cortisol levels and normal thyroid function. Five patients had persistent hyperprolactinemia. The remainder had decreased basal PRL levels with impaired PRL responses to TRH and the dopaminergic antagonist metoclopramide (MET). Despite adequate hypoglycemia and an intact cortisol response, there was no PRL rise following insulin hypoglycemia. The imparied PRL response to TRH was evident in treated and untreated patients and was independent of GH levels. Basal hyperprolactinemia may be related to PRL secretion by the tumor cells or interference with the transport of PIF by the tumor. The decreased PRL reserve noted in the majority of the patients may be related to a decrease in lactotrope cell mass or, alternatively, to enhanced dopaminergic activity.