Amenorrhoea,Galactorrhoea, and Primary Hypothyroidism with High Circulating Levels of Prolactin

A 22-year-old woman with primary hypothyroidism developed amenorrhoea and galactorrhoea during oral contraceptive therapy. Investigation showed high levels of circulating prolactin which rose in response to insulin-induced hypoglycaemia and were suppressed by an oral glucose load. After treatment with thyroxine normal periods returned, the galactorrhoea improved, and the prolactin levels fell to undetectable levels. The results of the prolactin and human growth hormone assays confirm that it is possible to distinguish between human growth hormone and human prolactin.     

Prolactin levels in pregnancy: comparison of normal subjects with patients having micro- or macroadenomas after early bromocriptine withdrawal

14 previously infertile patients, 11 with radiologically abnormal fossae, and a mean prolactin level of 761 ng/ml (range 49-4,500 ng/ml) conceived on 19 occasions during bromocriptine treatment. So far, 15 healthy infants have been delivered. Treatment was withdrawn soon after conception and the subsequent prolactin changes compared with those of 44 normal subjects. Prolactin levels returned to pretreatment values in 7, but stayed within our normal range (less than 350 ng/ml) in the 6 remaining patients studied. No patient developed signs or symptoms of tumor enlargement. 2 patients, 1 of them with the largest tumor, have now normal prolactin levels and can be considered as cured. Bromocriptine treatment can restore fertility and be safely withdrawn during pregnancy even in patients presenting with large tumors. Nevertheless, patients should be carefully monitored and treatment with bromocriptine re-introduced if necessary.     

溴隐亭不同给药方案治疗高泌乳素血症女性性腺激素促排卵临床研究

目的:研究溴隐亭不同给药方案在治疗高泌乳素血症(HPRL)女性不育症中的临床疗效,关注其对女性促性腺激素诱导排卵的影响。方法:本研究共纳入60例就诊于我院的确诊为高泌乳素血症不孕不育患者,随机分为两组。分为研究组与对照组:研究组采取先口服溴隐亭调整血清泌乳素水平至正常后予以促性腺激素诱导排卵;对照组采取促性腺激素与溴隐亭同步治疗方案。结果:观察两组患者的促排卵周期数、平均用药天数、雌二醇水平及妊娠率,两组治疗前后的血清泌乳素都显著改善(P0.05);但是两组之间相比,采取溴隐亭药物治疗后诱导排卵的研究组在促排卵、雌二醇水平和妊娠率方面具有显著优势(P0.05)。结论:采用溴隐亭治疗高泌乳素血症患者,调整至正常后再使用促卵泡激素药物促排卵治疗不孕不育具为较优的治疗方案。     

Prolactin studies in "functionless" pituitary tumours.

Hyperprolactinaemia was found in all 17 women and in one out of six men who presented with hypogonadism and a radiologically enlarged sella turcica but no other clinical endocrine dysfunction. Some of the women also had galactorrhoea. The greater the level of hyperprolactinaemia in these 18 patients the larger their sellae turcica except in two patients with unusual features. The sella turcica was usually asymmetrically enlarged and there was rearly an upward extension of tumour, though the sella floor often showed some erosion on tomography. An oral dose of bromocriptine suppressed the hyperprolactinaemia in mose patients at the same rate as in normal post-partum women. Nine of the 18 patients with hyperprolactinaemia had low basal luteinizing hormone (LH) levels. The LH responsiveness to 100 mug of LH-releasing hormone (LHRH) was tested in 12, and eight showed subnormal values. Of eight biopsy specimens obtained four showed acidophil granules on light microscopy, and in five granules of various sizes were seen on electron microscopy.     

Extrasellar prolactinomas: successful management of 24 patients using bromocriptine

24 patients with an extrasellar prolactinoma (mean prolactin 4,722 ng/ml), 8 of whom had previously had surgery, received 5-40 mg bromocriptine daily for 13-252 weeks. The mean prolactin level had fallen 89% at 2 days, 95% at 6 weeks, and 15 patients achieved normal values. Tumor shrinkage occurred in all 9 patients rescanned within 2 weeks and later was documented in 23; in 18 the extrasellar tumour disappeared. 12 patients had visual abnormalities; 7, including 2 who had been completely blind, improved within 1 week. 2 patients had normal prolactin levels after withdrawal of bromocriptine, 1 following radiotherapy and the other during two uncomplicated pregnancies. Bromocriptine is safe and effective. We conclude that medical treatment should always precede surgery unless pituitary apoplexy causes sudden deterioration of vision. Most patients will subsequently require radiotherapy or surgery for permanent cure.     

Treatment of prolactinomas with megavoltage radiotherapy.

The outcome of treatment of 36 women with prolactinomas using megavoltage radiotherapy combined with interim dopamine agonists (bromocriptine, lysuride, pergolide) was reviewed; 16 of the women showed radiological evidence of a macroadenoma. The most common presenting symptom was secondary amenorrhoea; 26 of the patients had galactorrhoea. In 29 patients who wished to conceive the ovulation rate (as indicated by circulating progesterone concentrations) was 97% and the successful fertility rate 86%. No patient had enlargement of the tumour during pregnancy and there were no complications of radiotherapy. No further tumour enlargement was detected in serial skull radiographs, and an improvement in size of the fossa was noted in 45% of those assessed. When medical treatment was withdrawn a mean of 4.2 years (range 1-11) after radiotherapy in the 27 patients who had completed their families the serum prolactin concentration had fallen appreciably in 26 of them and later became normal in eight. The incidence of growth hormone deficiency rose from 24% of the whole group before radiotherapy to 79% afterwards. Only one patient required thyroxine, and one was receiving gonadotrophin. No patient became deficient in adrenocorticotrophic hormone. A regimen of megavoltage radiotherapy and interim bromocriptine allows women with prolactinomas safely to undergo pregnancy and results in the long term prospect of tumour shrinkage and control of hyperprolactinaemia.     

Hyperiodotyrosinemia-induced hyperprolactinemia and hyperaldosteronism

A 21-year-old goitrous hypothyroid Chinese woman had elevated serum iodotyrosines with a monoiodotyrosine level of 85.9 nmol/l (normal 0.49-0.89 nmol/l) and a diiodotyrosine level of 25.3 nmol/l (normal 0.023-0.53 nmol/l). She was amenorrheic with low luteinizing hormone and follicle-stimulating hormone levels at 5.8 and 2.8 U/l, respectively. The hypogonadotropic hypogonadism was due to an elevated prolactin level of 8.8 nmol/l. She also had a low potassium level of 3.2 mmol/l, and a high urinary aldosterone level of 158 nmol/day. The hyperprolactinemia, hypogonadotropic hypogonadism, hyperaldosteronism and hypokalemia subsided with the administration of bromocriptine 5 mg/day. However, bromocriptine accentuated the hyperiodotyrosinemia, and the patient remained hypothyroid. Levothyroxine therapy lowered the monoiodotyrosine and diiodotyrosine levels, ameliorated all her endocrinopathies, started her periods, and shrank the goiter. She probably had a deiodinase defect which permitted the discharge of accumulated iodotyrosines from the thyroid gland. Since iodotyrosines are tyrosine hydroxylase inhibitors, the hyperiodotyrosinemia causes dopamine synthesis inhibition, and induces the hyperprolactinemia and hyperaldosteronism.     

Achievement of Fertility in an Infertile Man With Resistant Macroprolactinoma Using High-Dose Bromocriptine and a Combination of Human Chorionic Gonadotropin and an Aromatase Inhibitor

ObjectiveTo describe the achievement of fertility in an infertile man with a resistant macroprolactinoma by using high-dose bromocriptine and a combination of human chorionic gonadotropin (hCG) and an aromatase inhibitor.MethodsWe present historical features and results of clinical, laboratory, and imaging evaluation in a man with secondary infertility attributable to a resistant macroprolactinoma.ResultsWe report a case of macroprolactinoma in a 36-year-old infertile man who failed to attain a normal serum testosterone level and fertility with use of either bromocriptine or cabergoline treatment. Testosterone replacement or hCG therapy in this patient resulted in an increase in serum prolactin levels, which declined after discontinuation of this therapy. The combination of high doses of bromocriptine, hCG, and an aromatase inhibitor facilitated near-normalization of serum prolactin levels, shrinkage of the macroprolactinoma, recovery of serum testosterone levels, sexual function, and sperm count, and achievement of fertility.ConclusionAn aromatase inhibitor may facilitate successful testosterone replacement therapy in male patients with prolactinoma. (Endocr Pract. 2010;16:669-672)     

Effectiveness of pergolide mesylate in long term treatment of hyperprolactinaemia.

Twenty five patients with hyperprolactinaemia were treated with pergolide mesylate, a new dopamine receptor agonist. Twenty three received treatment for six to 20 months, and in all serum prolactin concentrations were considerably reduced. In most patients prolactin concentrations were maintained in the normal range by a low, once daily dose of pergolide and reversal of associated reproductive disorders was observed. Tumour volume as assessed by computed tomography decreased considerably during treatment in three out of four patients with a pituitary tumour. The drug was well tolerated. Side effects were similar to those of bromocriptine, but four out of eight patients who had been forced to stop taking bromocriptine because of untoward effects were subsequently able to tolerate treatment with pergolide. Pergolide mesylate promises to be a useful addition to the currently available long acting dopamine agonists in the management of hyperprolactinaemia.     

Analyse de l’algorithme décisionnel basé sur la testostérone totale et recommandé pour le diagnostic de l’hypogonadisme acquis

Introduction

The diagnosis of acquired hypogonadism is still an important issue for laboratory medicine. Hypogonadism is defined as a sustained decrease of total testosterone confirmed by the biochemistry laboratory and total testosterone measurement is proposed as the initial step in the investigation of hypogonadism. If TT is over 12 nmol/l, the probability of hypogonadism is considered low and it is suggested that patients be referred to others methods of investigation. Only a small percentage of men aged 50 and over are treated for hypogonadism. Seventy percent of men investigated for hypogonadism have a TT of over 12 nmol/l and there is an unpredictable increase of SHBG during this period, reducing the bioavailability of circulating testosterone. The hypothalamic-pituitary gonadal axis is modified with age and contributes to hypogonadism. The efficacy of biochemical investigation of hypogonadism needs to be reassessed.

Materials and methods

Total testosterone and LH were measured on the Centaur immunoanalyser (Siemens) and SHBG was analysed on the Immulite 2000 (Siemens). Bioavailable testosterone was calculated using the formula provided by ISSAM.

Results

Using the algorithm based on TT, only 27.9% of men would have been investigated for hypogonadism. Of the 638 patients considered as normal, 325 showed an index of hypothalamic-pituitary gonadal axis stimulation and possible hypogonadism, revealed by an elevated LH. In these patients with TT superior to 12 nmol/l and a LH superior to 7 UI/l, SHBG level was at the upper limit of or over the reference range. No correlation was observed between calculated BT and the abnormal LH level found in these patients. Calculated BT was not considered a good marker of hypogonadism for these patients.

Conclusion

Elevated LH is a biochemical marker of hypogonadism and should be interpreted in the context of stimulation of the hypothalamic-pituitary gonadal axis. Based on our data, an initial step in the investigation of hypogonadism based only on TT does not seem suitable for the identification of all patients who might experience hypogonadism. A complete investigation should be offered to all patients with clinical evidence of hypogonadism whatever their TT level. In patients who might benefit from hormonal treatment, calculated BT should be interpreted with caution. A definition of hypogonadism based on TT does not seem appropriate and a new definition based on bioavailable testosterone and the hypothalamopituitary gonadal axis should be considered.     

Restoration of fertility with gonadotropin and bromocriptine in a hypogonadal man after removal of macroprolactinoma

A case of male hypogonadism after removal of macroprolactinoma was successfully treated with gonadotropin. A 35-year-old man treated surgically for pituitary adenoma had elevated plasma prolactin and impaired pituitary function after the operation. He was on replacement of hydrocortisone, levothyroxine and testosterone depot along with bromocriptine. Normal plasma testosterone levels were achieved with HCG, 3,000 IU three times a week. The addition of 75 IU of FSH daily restored spermatogenesis and the sperm count reached the fertile range at the 11th month. Doses of HCG and FSH were cut in half at the 10th month without affecting the plasma testosterone levels. His wife was impregnated at the 12th month and gave birth to a normal baby girl.     

Plasma Prolactin Activity in Inappropriate Lactation

Using a bioassay dependent on the development of a lactogenic response in rabbit mammary tissue cultured in vitro, prolactin distinct from immunoreactive growth hormone has been found in the plasma of patients of both sexes with inappropriate lactation with and without evidence of pituitary tumours. It has also been found in one patient with primary hypothyroidism and galactorrhoea, and in another during chlorpromazine therapy, but not in nine patients with gynaecomastia without galactorrhoea. Plasma prolactin levels were examined in seven patients during oral glucose tolerance tests: no change occurred in the four patients with pituitary tumours, but the levels were suppressed in the three patients with normal pituitary fossae. Prolactin appears to be a distinct pituitary hormone in man, as in animals, and also to be aetiologically related to states of inappropriate lactation.     

Positive Prolactin Response to Bromocriptine in 2 Patients with Cabergoline-Resistant Prolactinomas

ObjectiveTo describe a positive prolactin response to bromocriptine treatment in 2 patients with cabergolineresistant prolactinomas.MethodsWe report the patients’ clinical presentations, laboratory test results, imaging findings, and clinical courses.ResultsPatient 1 had a 5-mm pituitary microadenoma that was initially diagnosed at age 30 years. After initial diagnosis, she was treated with transvaginal bromocriptine for 9 years and then subsequently went untreated for 2 years. After developing symptoms of amenorrhea, decreased libido, and hyperprolactinemia, oral cabergoline, 0.5 mg twice weekly, was initiated. Her prolactin concentration remained elevated at 80 ng/mL while taking cabergoline. Her prolactin concentration decreased to 13 ng/mL after her regimen was switched to bromocriptine, 5 mg daily. Patient 2 had a 17-mm pituitary macroadenoma that was initially diagnosed at age 15 years. Oral cabergoline was started at 0.5 mg twice weekly and increased to 1 mg 3 times weekly when prolactin levels continued to rise to 340 ng/mL over 18 months. After visual field defects developed, transsphenoidal surgery was performed. One year after surgery, magnetic resonance imaging showed a 6-to 7-mm pituitary adenoma, and there was a gradual rise in serum prolactin. Her serum prolactin concentration continued to rise to 212 ng/mL with increasing tumor size over 3 years. Cabergoline was discontinued and oral bromocriptine was initiated at a dosage of 10 mg daily. After 4.5 months of bromocriptine therapy, her serum prolactin concentration decreased to 133 ng/mL. However, after 2 months, the macroadenoma continued to increase in size and a visual field defect developed, so another transsphenoidal operation was performed.ConclusionsAlthough cabergoline is generally preferred to bromocriptine for the treatment of patients with prolactinomas because of its better tolerance profile and greater effectiveness, in patients with cabergoline-resistant prolactinomas, a bromocriptine trial should be considered a safe, relatively inexpensive, and well-tolerated alternative. (Endocr Pract. 2011;17:e55-e58)     

Prolactinomas and resistance to dopamine agonists.

Among 288 patients with prolactinoma (aged 12-62 years; 242 women), 27 were diagnosed as resistant to bromocriptine as their plasma prolactin (PRL) levels remained elevated despite long-term (3 months or more) treatment at high doses (> or = 15 mg daily). These 18 women and 9 men, aged 29 +/- 9 years (mean +/- SD, range 13-50), followed-up for 8 +/- 4 years, had microadenomas (n = 6) or macroadenomas. They were treated by dopamine agonists alone (n = 6) or associated with surgical or radiation therapy. In 8 cases repetitive surgical treatments were necessary. Among the 24 patients who were treated with the nonergot dopamine agonist CV 205-502 after unsuccessful bromocriptine treatment, half of them (9 women, 3 men) resumed normal PRL levels on doses ranging from 0.15 to 0.45 mg/day. Despite daily doses of CV 205-502 from 0.3 to 0.525 mg, the remaining patients were not normalized by this drug which did not prevent tumor growth in 4 of them. Two patients died from invasive cerebral extensions of their tumor and a third had vertebral metastases with positive anti-PRL immunostaining. It is concluded that bromocriptine-resistant prolactinomas represent the most severe aspect of this disease and that a more powerful dopamine agonist like CV 205-502 is effective in only a fraction of these patients.     

Increased MIB-1/Ki-67 labeling index as a predictor of an aggressive course in a case of prolactinoma

Secondary resistance to dopamine agonists is a rare phenomenon in patients with a prolactinoma. We describe a 55-year-old male with a macroprolactinoma initially responding favorably to bromocriptine treatment with normalization of prolactin levels and tumor shrinkage. Two years later, he developed resistance to bromocriptine treatment and subsequently to cabergoline. The aggressive course of the disease necessitated three surgical interventions. Staining of the pituitary tissue revealed a very high MIB/Ki-67 labeling index that increased further in specimens derived from repeated surgery. This case demonstrates that high and increasing levels of the MIB/Ki-67 labeling index may indicate an aggressive course associated with secondary dopamine resistance.     

Bromocriptine administration lowers serum prolactin and disrupts parental responsiveness in common marmosets (Callithrix j. jacchus)

The influence of prolactin on parental responsiveness was investigated in eight unpaired, parentally inexperienced common marmosets (Callithrix jacchus; 6 female, 2 male). The marmosets were prescreened with infants (1-10 days of age) and required to exhibit short latency retrieval and infant carrying in at least three consecutive pretests as criterion for inclusion in this study. The marmosets were then administered the dopamine agonist bromocriptine (0.5 mg/0.5ml vehicle subcutaneously) and the vehicle alone (0.5 ml 10% ethanol solution) twice daily for 3 consecutive days in random order. Bromocriptine treatment reduced circulating prolactin to nondetectable levels. Bromocriptine treatment eliminated infant retrieval in four of the eight marmosets and was associated with significantly increased retrieval latencies and significantly reduced carrying durations in the four monkeys that continued to retrieve following bromocriptine treatment. When given the vehicle alone, the marmosets retrieved infants significantly faster than during pretests, suggesting a handling effect of the injection series. Bromocriptine treatments were associated with significantly increased movement during the tests. The results of this study indicate that prolactin and/or its regulatory neurotransmitters are involved in the control of the spontaneous display of parental responsiveness in common marmosets.     

Immunohistochemical, electron microscopic and morphometric studies of estrogen-induced rat prolactinomas after bromocriptine treatment

To clarify the effects of bromocriptine on prolactinoma cells in vivo, immunohistochemical, ultrastructural and morphometrical analyses were applied to estrogen-induced rat prolactinoma cells 1 h and 6 h after injection of bromocriptine (3 mg/kg of body weight). One h after treatment, serum prolactin levels decreased markedly. Electron microscopy disclosed many secretory granules, slightly distorted rough endoplasmic reticulum, and partially dilated Golgi cisternae in the prolactinoma cells. Morphometric analysis revealed that the volume density of secretory granules increased, while the volume density of cytoplasmic microtubules decreased. These findings suggest that lowered serum prolactin levels in the early phase of bromocriptine treatment may result from an impaired secretion of prolactin due to decreasing numbers of cytoplasmic microtubules. At 6 h after injection, serum prolactin levels were still considerably lower than in controls. The prolactinoma cells at this time were well granulated, with vesiculated rough endoplasmic reticulum and markedly dilated Golgi cisternae. Electron microscopical immunohistochemistry revealed positive reaction products noted on the secretory granules, Golgi cisternae, and endoplasmic reticulum of the untreated rat prolactinoma cells. However, only secretory granules showed the positive reaction products for prolactin 6 h after bromocriptine treatment of the adenoma cells. An increase in the volume density of secretory granules and a decrease in the volume densities of rough endoplasmic reticulum and microtubules was determined by morphometric analysis, suggesting that bromocriptine inhibits protein synthesis as well as bringing about a disturbance of the prolactin secretion.     

Hypothalamic hypogonadism in congenital adrenal hypoplasia

Congenital adrenal hypoplasia (CAHP) in its X-linked form is associated with hypogonadotropic hypogonadism (HH). A 23 year old man with this disorder received substitution therapy with gluco- and mineralocorticoids starting one week after birth and, recently, pulsatile subcutaneous GnRH treatment via a miniature infusion pump with stepwise increasing doses from 50 to 200 ng/kg body weight/2 hours for a total of 394 days. Testosterone levels increased from prepubertal levels to 409 ng/dl after 2 weeks and to 626 ng/dl after 3 months of treatment. The results of pulsatile GnRH therapy in our patient prove the hypogonadotropic hypogonadism to be of hypothalamic origin. Pulsatile GnRH substitution is a successful therapeutic regimen in patients with CAHP leading to pituitary and gonadal maturation.     

Neuroendocrine function in Huntington's disease: dopaminergic regulation of prolactin release.

Plasma prolactin levels were measured in 7 patients with Huntington's disease (HD) and 8 age matched controls after the random, oral administration of 1) placebo, 2) chlorpromazine 100 mg, 3) carbidopa 50 mg followed by levodopa 200 mg, and 4) bromocriptine 1 mg. After placebo, HD patients had significantly higher prolactin levels than controls at all times except 180, 240, and 360 minutes. Controls showed a significant suppression of prolactin release at 180 and 240 minutes after levodopa/carbidopa and at 180, 240, and 360 minutes after bromocriptine. In contrast, HD patients demonstrated no change after both levodopa/carbidopa and bromocriptine. Both groups showed a sustained elevation after CPZ, but despite having an initially higher baseline and an earlier response, the maximum prolactin levels of HD patients were significantly less than those of controls.This data suggest that HD patients may have a diminished number of hypothalamic-pituitary dopamine receptors for the regulation PRL secretion.     

Effects of hypersecretion of growth hormone and prolactin on plasma levels of glucagon and insulin in GH3-cell-tumor-bearing rats, and the influence of bromocriptine treatment

Plasma levels of prolactin, growth hormone, glucagon insulin and glucose were measured in non-treated control rats, bromocriptine-treated control rats and GH3-cell-tumor-bearing rats with and without bromocriptine treatment. Bromocriptine treatment increased plasma levels of glucagon, insulin and glucose in control rats. Tumor-bearing rats had increased body weight and increased plasma levels of prolactin, growth hormone, glucagon, insulin and glucose. Bromocriptine treatment reduced body weight and decreased the plasma levels of prolactin, glucagon and insulin, as compared to non-treated tumor-bearing rats. The drug had no effect on plasma levels of growth hormone and glucose. These results indicate that, in GH3-cell-tumor-bearing rats, prolactin, glucagon and insulin are more sensitive to the action of bromocriptine than growth hormone.