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Neuroendocrine dysfunction in galactorrhea-amenorrhea after oral contraceptive use.

Nonpuerperal alactorrhea and amenorrhea have been reported following the use of oral contraceptives. Treatment of this condition with ergot alkaloids has proved to be of great therapeutic value. Pretreatment plasma hLH and hFSH concentrations in 13 women with postqill galactorrhea-amenorrhea (PPGA) were 6.6 plus or minus 0.6 (SE.) and 5.0 plus or minus 0.8 mlU/ml, respectively. The mean prolactin concentration was 80.7 plus or minus 13.2 ng/ml. After complete evaluation in which diagnostic evidence of pituitary tumor was absent, the patients were treated with ergocryptine (CB-154). The mean hPRL concentration at 14 days of therapy was 7.8 p;us or minus 1.9 ng/ml. Cyclic gonadotropin secretion resumed in all but one instance; ovulation was confirmed on the basis of a biphasic temperature chart and in 5 cases, endometrial biopsy. Measurement of serum dopamine-beta-hydroxylase (DBH) activity indicated a significant decline at the end of 8 weeks of CB-154 therapy. The fall in hPRL was not necessarily associated with a fall in DBH. The majority of women in this study exhibited a consistent personality suggesting varying degrees of anxiety unrelated to the PPGA and usually antedating the use of oral contraceptives. PPGA was found in women without hyperprolactinemia, but altered hPRL secretion was evident in all instances. The data suggest that the disorder of cyclic gonadotropin secretion is related to altered hPRL secretion, but the mechanism is possibly related to a catecholamine abnormality. The data support the presence of an inherent cyclic mechanism for the secretion of gonadotropins. CB-154 therapy does not affect conception, and no teratogenic effects were observed in 2 infants born to women who had received CB-154 during the first 40 days of gestation.

Abortion, Induced

The effect of metoclopramide, TRH and L-dopa on prolactin secretion in pituitary adenoma and in "functional" galactorrhoea syndrome.

The degree of autonomy in prolactin secreting pituitary adenomas and also prolactin secretory reserve in cases with suspected functional galactorrhea syndrome was evaluated with the use of metoclopramide, TRH and L-DOPA. It was found that in patients with pituitary adenoma the basal prolactin (PRL) level often exceeded 150 micrograms/l and the response to stimulation with TRH and/or metoclopramide was markedly diminished or even nonexistent, while the response to L-DOPA was usually retained. In patients with galactorrhoea and/or amenorrhoea, with normal skull X-ray the basal PRL level was either normal or moderately raised but the response to stimulation was various; mostly it was excessive, it was sometimes normal, but in some other cases it was markedly diminished as in patients with adenoma. In the author's opinion the so-called "functional disorder" of prolactin secretion is mainly hyperresponsiveness to stimulation, whereas the basal PRL level in those cases is usually normal or only intermittently raised. In the cases with a moderate hyperprolactinaemia, especially if it appears to be constant, and the response to stimulation is diminished or none at all, we suspect a pituitary microadenoma. Finally, there are rare cases of galactorrhoea with normal basal PRL and normal response to stimulation, in which the sensitivity of the mammary PRL receptor is probably increased. We suggest therefore that the above mentioned PRL stimulation tests may help in distinguishing between tumoural and functional hyperprolactinaemia.

Acromegaly

Hypothalamic pituitary disorders expressed by galactorrhea. A dynamic evaluation.

Physiologic and pathologic production of milk involves complex relations between the mammary glands, hormones, and the central nervous system. In all the galactorrhea syndromes there is a functional or mechanical problem at the pituitary level, with abnormal secretion or reserve of prolactin secretion. Stimulatory agents of prolactin, like thyrotropin releasing hormone (TRH), chlorpromazine, amnio acids, and insulin, can be helpful in the study of the hypothalamic pituitary functional reserve, while the osmotic tests seem to provide a clear distinction between functional and tumoral causes. The inhibitory agents of prolactin secretion, L-dopa and CB 154, permit the study of the negative control of the hormone. In addition, CB 154 appears to be an effective treatment for functional galactorrhea. Hyperprolactinemia appears to exert an inhibitory influence on gonadotropins. Clomiphene, acting on the hypothalamus, and LHRH, acting on the gonadotropes, permit the assessment of the gonadotropic hypothalamic-hypophyseal axis.

Amino Acids

Clinical and endocrinological analyses of patients with galactorrhea and menstrual disorders due to sulpiride or metoclopramide.

The clinical courses of galactorrhea and menstrual disorders were studied in 18 women with galactorrhea induced by sulpiride (SLP) or metoclopramide (MCP) given for the treatment of gastrointestinal diseases. The response of PRL and TSH to 500 micrograms iv TRH and the response of LH and FSH to 100 micrograms LRH were assessed by retrospective analysis during treatment in nine patients (six, SLP; three, MCP) and shortly after the end of treatment in nine patients (seven, SLP; two, MCP). The average time from the initiation of treatment to the onset of galactorrhea was 27.2 +/- 4.7 (mean +/- SE) days in the 13 SLP-treated patients and 23.2 +/- 5.8 days in the 5 MCP-treated patients. Five of the SLP-treated patients experienced amenorrhea, four had oligomenorrhea, and one had dysfunctional bleeding. In the MCP-treated patients, oligomenorrhea and dysfunctional bleeding occurred in one each. The average length of time from the end of treatment to disappearance of galactorrhea was 50.0 +/- 7.3 days in the SLP-treated patients and 56.6 +/- 12.1 days in the MCP-treated patients. Cyclic uterine bleeding returned within 2 months after treatment was stopped. Elevated PRL levels with good response to TRH were observed in four of six patients during SLP treatment, and in two of three patients during MCP treatment. Basal PRL levels and response to TRH were normal in almost all patients after the drugs were withdrawn. Normal HL and FSH levels with exaggerated responses of LH to LRH were observed in most patients during treatment, whereas the response of LH to LRH was normal in about half of the patients after treatment. Our findings suggest that hyperprolactinemia in patients treated with SLP or MCP may be in part the cause of both galactorrhea and menstrual abnormalities, and that these symptoms can be reversed by stopping treatment, provided the patients have not taken the drugs for longer than a year.

Adult

Clinical and hormonal response of patients with galactorrhea syndrome treated with bromergocryptine.

Tne patients with galactorrhea syndrome were treated with two different daily dosages (5 mg and 7.5 mg) of Bromergocryptine. The 5 mg daily dosage often did not produce the desired hormonal and clinical response. Five patients were treated with this regimen for 38 to 90 days, with treatment extending over more than one menstrual cycle. However, the 7.5 mg daily dosage resulted in complete cessation of galactorrhea in all patients, restoration of menstrual cycles in five patients, and pregnancies in four patients. Disappearance of lactation proved to be a very good indicator of the general responsiveness of patients. Nausea, vomiting, and occasional dizziness were side effects of the drug. The case histories and hormonal findings of four typical patients are reported.

Bromocriptine

Galactorrhea and the defective luteal phase of the menstrual cycle.

Twelve patients with primary infertility due to a defective luteal phase associated with hyperprolactinemia and galactorrhea are reported. All were treated with 2-bromoergocryptine. During the first cycle of therapy, the serum prolactin level decreased in all cases, and galactorrhea disappeared during the second cycle of therapy. Seven women responded to 2-bromoergocryptine, as was reflected in their endometrial biopsies. The remaining five were given clomiphene citrate on the second and sixth days of the next 2-bromoergocryptine cycle. Three of these patients responded favorably to this combined therapy. Six pregnancies were reported during therapy. The results of follow-up after labor or abortion suggested that these cases represent a latent stage of the amenorrhea-galactorrhea syndrome.

Adult

The borderline pituitary fossa in patients with amenorrhoea and/or galactorrhoea.

A retrospective clinicoradiological study of 80 patients with amenorrhoea and/or galactorrhoea showed: 1. Of 60 patients, in whom prolactin levels were estimated, 28 (47%) had hyperprolactinaemia (serum prolactin levels greater than 20 ng/ml). 2. Hyperprolactinaemia was present in 85% of patients with amenorrhoea and galactorrhoea, 35% of those with galactorrhoea only, and 12.5% of those with only amenorrhoea. 3. Pituitary adenomas were surgically removed from six patients; all but one had prolactin levels over 100 ng/ml. The level was 53 ng/ml in the sixth patient. 4. There is a considerable degree of observer variation in the interpretation of borderline sellar changes. 5. Minor abnormalities of the pituitary fossa were noted in 64% of patients with hyperprolactinaemia and 36% of those with normal prolactin levels. 6. The highest incidence of perfectly normal sellae was among patients with either amenorrhoea or galactorrhoea and normal serum prolactin.

Adenoma

[Pituitary adenomas of patients with galactorrhea. Light and electron microscopic studies (author's transl)].

A collection of 108 surgically removed pituitary adenomas was studied by histologic, immunohistochemical and electron microscopical methods. It included 7 predominantly chromophobe adenomas of patients whose clinical symptoms consisted of a pure galactorrhea. Ultrastructurally, 4 of these adenomas contained little endoplasmic reticulum so that an endocrine activity of the tumors could not be assumed. These cases represented inactive adenomas which probably led to a disturbance of the secretion of prolactin-inhibiting factor by suprasellar extension resulting in stimulation of the non-tumorous adenohypophysis and secondary hyperprolactinemia. Another 3 adenomas consisted of cells that showed histologic and immunocytochemical reactions of the same kind as normal prolactin cells. Electron microscopically, these adenoma cells exhibited a very well developed rough-surfaced endoplasmic reticulum, dilatation of the Golgi complexes, sparsely arranged pleomorphic secretory granules, an increased number of microtubules, and interdigitating microvilli formed by the cell membrane. These features resembled closely the characteristics of stimulated non-tumorous prolactin cells during lactation, and thus could be termed "prolactin cell adenomas". These tumors surely caused a hyperprolactinemia through their own hormone production. In addition 3 other adenomas were present which showed the same light and electron microscopic structures as the prolactin cell adenomas but did not cause galactorrhea. From the findings in these cases we assume that the tumors effected neither a clinically peculiar hyperprolactinemia nor produced an endocrinologically inactive polypeptide.

Adenoma, Chromophobe

Primary hypothyroidism and galactorrhea.

Ten of 16 women with primary hypothyroidism and high thyrotropin (TSH) concentrations had high serum prolactin (PRL) concentrations. A positive correlation was observed between the basal TSH and PRL levels in the hypothyroid patients. Five of these patients complained of persistent galactorrhea after delivery. After treatment with triiodothyronine (T3), the elevated TSH and PRL levels fell to within normal ranges, and the galactorrhea disappeared. It is suggested that the elevated serum PRL levels of patients with primary hypothyroidism are mediated by feedback-induced thyrotropin-releasing hormone (TRH) secretion or an enhanced response to endogenous TRH, and that the combination of delivery and the PRL excess may induce persistent galactorrhea in patients with primary hypothyroidism.

Adult

Nonpuerperal galactorrhea and hyperprolactinemia. Clinical findings, endocrine features and therapeutic responses in 56 cases.

The clinical and endocrine features, and the responses to different treatment modalities, were examined in 56 patients with galactorrhea and/or hyperprolactinemia after a two month to six year follow-up period. A pituitary adenoma was diagnosed in 17 patients. A prolactin-cell adenoma was identified histologically in eight patients. Other etiologic factors were myxedema (two patients), phenothiazine ingestion (six patients) and breast manipulation (four patients). In 27 patients, including three with abnormalities of the sella turcica, no causal factor was found, and their condition was labelled as dysfunctional in origin. Symptoms were preceded by childbirth in 11 patients and by estrogen-progestin contraception in 22; pituitary adenomas were discovered in both groups in approximately the same frequency (30%) as in the over-all study group. Aside from roentgenographic studies, as well as visual field perimetry in a few cases, a serum prolactin level above 100 ng/ml was the only indicator of a pituitary prolactin-cell adenoma. Prolactin-suppression tests (L-DOPA and 2alpha-Br-ergocryptine) were found to be of no value in discriminating between tumoral and dysfunctional conditions. No significant alterations in prolactin levels occurred after water loading irrespective of basal levels or the nature of the pathologic process. Selective pituitary tumor excision (eight patients) was followed by rapid normalization of prolactin levels and disappearance of clinical abnormalities. Conversely, after pituitary irradiation (eight patients), improvement tended to be slower. Treatment of infertility in those patients without an apparent organic lesion was more successful with 2alpha-Br-ergocryptine (three of three) than with clomiphene (two of seven). Pregnancies following the administration of drugs or after surgical treatment were uneventful. Since follow-up resulted in the early diagnosis of pituitary tumors from seven to 56 months after initial investigation, and since no diagnostic tools are currently available which help to discriminate between tumoral and dysfunctional conditions before abnormalities become evident on roentgenograms, prolonged observation of these patients remains essential.

Adenoma

Evaluation of Deladumone OB in the suppression of postpartum lactation.

Of 235 patients receiving Deladumone OB, more than 39 per cent complained of breast pain or swelling; 83 per cent were pleased with the medication. Of 215 patients receiving a placebo, more than 82 per cent complained of breast pain or swelling; 67.5 per cent were pleased with the medication.

Clinical Trials as Topic

Galactorrhea-amenorrhea: psychological interaction with neuroendocrine function.

Further substantiation of the interaction between psychological disease and the onset of galactorrhea-amenorrhea is presented in women who underwent intensive psychometric and neuroendocrine evaluation prior to the use of the dopamine against 2-Br-alpha-ergocryptine (CB-154). Normalization of a previously distorted psychometric test profile in each woman was accompanied by a profound decline in prolactin and an unexpected alteration in the peripheral concentrations of norepinephrine and dopamine-beta-hydroxylase. Cesation of galactorrhea and resumption of menses were observed in each instance.

Adult

Effects of alpha- and beta-adrenergic blocking agents on serum prolactin levels in women with hyperprolactinemia and galactorrhea.

The effects of alpha- and beta-adrenergic blocking agents on the serum prolactin levels of six women with hyperprolactinemia and galactorrhea were investigated. There was no indication that pituitary adenomas were etiologic agents for the hyperprolactinemia. Serum prolactin could be lowered with oral L-dopa. When intravenous phentolamine (an alpha-adrenergic blocking agent) or intravenous propranolol (a beta-adrenergic blocking agent) were administered for 1 hour, there was no significant change in serum prolactin levels.

Adenoma

Bromocryptine therapy in cases of amenorrhea-galactorrhea.

Of 28 patients presenting with amenorrhea-galactorrhea, pituitary tumors were confirmed in eight. Six patients had occult hypothyroidism and the rest had an endocrine profile suggestive of pituitary tumor or of an idiopathic etiology. Treatment with bromocryptine resulted in suppression of the inappropriate lactation and restoration of regular menstrual function. In five cases, however, the galactorrhea was only diminished and in four of these cases, normal ovarian function did not return. Of the 19 patients that were seeking fertility and continued the medication for at least 20 days, nine pregnancies resulted. A similar response to bromocryptine was observed regardless of the underlying cause of the amenorrhea-galactorrhea.

Adult