Current treatment issues in female hyperprolactinaemia

High prolactin levels can occur as a physiological condition in females who are pregnant or lactating. As a pathological condition, hyperprolactinaemia is associated with gonadal dysfunction, infertility and an increased risk of long-term complications including osteoporosis. The most frequent cause of persistent hyperprolactinaemia is the presence of a micro- (<10mm diameter) or macroprolactinoma (>/=10mm). These pituitary tumours may produce an excessive amount of prolactin or disrupt the normal delivery of dopamine from the hypothalamus to the pituitary; prolactin secretion from the pituitary is inhibited by dopamine released from neurones in the hypothalamus. Medications including anti-psychotics can induce hyperprolactinaemia, while idiopathic hyperprolactinaemia accounts for 30-40% of cases. The prevalence of hyperprolactinaemia is difficult to establish as not all sufferers are symptomatic or concerned by their symptoms and may remain undiagnosed. Symptoms of hyperprolactinaemia include signs of hypogonadism, with oligomenorrhoea, amenorrhoea and galactorrhoea frequently observed. Pharmacological intervention should be considered the first line therapy and involves the use of dopamine agonists to reduce tumour size and prolactin levels. Bromocriptine has the longest history of use and is a well-established, inexpensive, safe and effective therapy option. However, bromocriptine requires multiple daily dosing and some patients are resistant or intolerant to this therapy. The two newer dopamine agonists, quinagolide and cabergoline, provide more effective and better tolerated treatments compared with bromocriptine and may offer effective therapies for bromocriptine-resistant or intolerant patients. Quinagolide can be used until pregnancy is confirmed and may result in improved compliance in females wishing to become pregnant. For patients with hyperprolactinaemia, pregnancy is safe and can frequently be beneficial, inducing a decrease in prolactin levels. There does not appear to be any increased risk of abortion, malformations or multiple births in pregnancies achieved with bromocriptine and this dopamine agonist can be used safely during pregnancy. Surgery should be considered only in certain circumstances, and for the majority of patients, dopamine agonists will be sufficient to alleviate symptoms and restore normal prolactin levels.     

Hyperprolactinaemia: Diagnosis and Management

The patient with hyperprolactinaemia most commonly presents with infertility, menstrual irregularities, and/or gallactorrhoea. A complete history, physical examination, and measurement of prolactin and thyroid stimulating hormone (TSH) levels are the initial investigations. Hyperprolactinaemia can be physiologie, idiopathic, drug induced or secondary to numerous underlying disorders. When a cause cannot be found, radiological investigation with computed tomography (CT scan) or magnetic resonance imaging (MRI) of the hypothalamic pituitary area should be carried out. The choice of therapy depends on the pathological cause and the goals of the patient. When hypothyroidism is the cause, thyroid replacement therapy will correct the prolactin level. Treatment of pituitary micro-adenomas and idiopathic hyperprolactinaemia is aimed at the symptoms, Pituitary macro-adenomas should be treated for life with a dopamine agonist such as bramocriptine or pergolide. Two new drugs, quinagolide (CV205-502) a non-ergot dopamine agonist, and cabergoline, a long-acting dopamine agonist are currently undergoing clinical trials. They offer promising alternatives for the future treatment of hyperprolactinaemia. Surgery should be the second line of treatment if dopamine agonist therapy fails or is poorly tolerated. Macro-adenomas tend to regrow alter surgery and radio therapy may be warranted. Pregnancy can be achieved with dopamine agonist therapy. If this is not tolerated, administration of gonadotrophin releasing harmone (GnRH) by pump is effective. Therapy can be discontinued during pregnancy, although teratogenic effects have not been reported. Macro-adenomas should be kept under surveillance during pregnancy with routine history and physical examinations, and with bimonthly visual field examinations.     

Modern management of pituitary prolactinomas

Although any form of pituitary tumour, either hormone-producing or non-functioning, can occur in women of reproductive age the most important clinically, and by far the most prevalent, are prolactin secreting pituitary tumours — prolactinomas. It is a fascinating phenomenon that the identification of prolactin as a hormone distinct from pituitary growth hormone, the availability of reliable radioimmunoassays for serum prolactin and the development of effective medical treatment to control hyperprolactinaemia all occurred virtually simultaneously in the early 1970s. Since then much has been learned about the pathogenesis, natural history and management of prolactinomas although the aetiology of these tumours still remains obscure. In the following pages the management of pituitary prolactinomas will be discussed with particular reference to induction of ovulation in women with hyperprolactinaemic amenorrhoea. There is persuasive evidence that medical management of hyperprolactinaemia, even when associated with the presence of a large pituitary tumour, is, in most cases, both effective and safe.     

Physiologic concentrations of dopamine fail to suppress prolactin secretion in patients with idiopathic hyperprolactinemia or prolactinomas

Several investigators have suggested that normal responsiveness to dopamine is exhibited by pituitary lactotrophs in patients with idiopathic hyperprolactinemia and prolactinomas. These studies, however, have employed dopamine infusion rates that produced supraphysiologic serum dopamine concentrations. In order to further examine this issue, we infused graded doses of dopamine to normal men and women as well as to patients with idiopathic hyperprolactinemia and prolactinomas. Dopamine infusion rates as low as 0.004 micrograms/kg/min, which were associated with physiologic serum dopamine levels, produced significant (p less than 0.01) suppression of prolactin in normal women and in normal males (p less than 0.05). In contrast, a 10-fold increase in the dopamine infusion rate, 0.04 micrograms/kg/min, was required in the hyperprolactinemic subjects to produce prolactin suppression similar to that found in the control subjects. Hence, prolactin secretion in both tumors and other hyperprolactinemic states is associated with a resistance to suppression by dopamine.     

Hyperprolactinaemia

Hyperprolactinaemia is a frequent cause of reproductive problems encountered in clinical practice. A variety of pathophysiological conditions can lead to hyperprolactinaemia; therefore, pregnancy, drug effects, hypothyroidism and polycystic ovary syndrome should be excluded before investigating for prolactin-secreting pituitary tumours. Prolactinomas are mainly diagnosed in women aged 20-40 years. They present with clinical features of hyperprolactinaemia (galactorrhoea, gonadal dysfunction), and more rarely with large tumours, headache and visual field loss due to optic chiasm compression. Medical therapy with dopamine agonists is the treatment of choice for both micro- and macroprolactinomas. Tumour shrinkage and restoration of gonadal function are achieved in the majority of cases with dopamine agonists. A trial of withdrawal of medical therapy may be considered in many patients with close follow-up. Pituitary surgery and radiotherapy currently have very limited indications. Pregnancies in patients with prolactinomas need careful planning and close monitoring.     

Investigation and Management of Symptomatic Hyperprolactinaemia

Fifteen patients with infertility and hyperprolactinaemia have been investigated using tests of prolactin and LH secretion, and treated by prolactin suppression. In addition, 4 patients with hyperprolactinaemia not desiring fertility were also investigated. Of the total group, 16 had galactorrhoea and 15 had amenorrhoea. Pituitary tumours were present in 6 patients and 4 had pituitary microadenomas. Prolactin levels measured by both radioimmunoassay and radioreceptor assay were elevated before treatment and fell during therapy with bromoergocryptine (7.5 mg daily). Tests of prolactin release with TRH and chlorpromazine before treatment did not distinguish patients with functional hyperprolactinaemia from those with pituitary tumours. Basal plasma gonadotrophin concentrations were not elevated despite subnormal urinary oestrogen levels. The serum LH response to LRH was normal during hyperprolactinaemia, but LH release in response to oestrogen provocation was impaired in 14 of 17 patients. During prolactin suppression, mean oestrogen excretion rose significantly and the oestrogen provocation test became normal in all except 2 patients. Pregnancy occurred in all of the 15 patients desiring fertility. Abortion has occurred in 4 patients, all of whom are currently pregnant again. Nine pregnancies have reached term, with no complications from pituitary expansion. It appears that during hyperprolactinaemia there are defects in both positive and negative feedback of oestrogen on LH secretion, and that prolactin suppression in such patients is highly effective in restoring fertility.     

Dysfunction of dopaminergic regulation of prolactin in patients with functioning and nonfunctioning pituitary adenomas and craniopharyngiomas

The response to domperidone (a dopamine blocking agent) of serum prolactin (PRL) levels was compared in 3 patients with amenorrhea-galactorrhea without evidence of a pituitary tumor, 23 patients with prolactinomas (10 cases with histologic confirmation), 7 patients with histologically verified large nonfunctioning pituitary adenomas with normal or moderately elevated basal PRL levels, and 6 patients with histologically verified craniopharyngiomas (3 with normal basal PRL levels and 3 with elevated PRL levels). The response was compared with that of 10 patients with postpartum hyperprolactinemia and 14 normal women. Ten milligrams of intravenous domperidone induced a rapid rise in PRL that was maximal at 30 to 45 minutes in normal, postpartum, and amenorrhea-galactorrhea patients who had no sign of tumor. In contrast, domperidone failed to induce significant changes in PRL in cases of prolactinoma, nonfunctioning pituitary adenomas, and craniopharyngioma with or without elevated basal PRL levels. The results suggest that dopaminergic control on PRL secretion was impaired in all tumor cases. The mechanisms of this abnormal dopaminergic control, however, may be different. Whereas dopamine control in cases of prolactinoma is altered at the level of pituitary dopamine receptors, alternative explanations must be found for those tumors with normal basal PRL levels and lack of response to domperidone.     

CV 205-502, a new dopamine agonist, versus bromocriptine in the treatment of hyperprolactinaemia.

Forty-seven hyperprolactinaemic patients with serum prolactin (PRL) concentrations persistently above 1500 mU/l were treated with the new dopamine agonist CV 205-502 or bromocriptine in a prospective, randomized and double-blind fashion during a 24-week period. Two women had to be excluded because of poor compliance in the first month. Therefore 45 patients remained for evaluation. 81% of the patients in the CV 205-502 group and 70% of the patients in the bromocriptine group normalized their prolactin levels within the study period with a treatment dose as permitted in this protocol. In general serum prolactin normalized within 8 to 12 weeks of treatment. There were no differences between the two tested drugs regarding restoration of the menstrual cycle or disappearance of galactorrhoea. Both drugs gave rise to adverse reactions, especially during the initiation of therapy. However, the adverse reactions reported during CV 205-502 treatment were less severe and persistent than those attributed to bromocriptine. Patient acceptance of the new drug with regard to tolerability was judged by 90% of the women in that treatment group as very good or good, while 75% of those treated with bromocriptine evaluated its tolerability as very good or good. We conclude that CV 205-502 is highly effective in the treatment of hyperprolactinaemia with concomitant restoration of gonadal function and prevention of galactorrhoea. The tolerability of the drug seems better than of bromocriptine and therefore this drug is of value in the treatment of hyperprolactinaemic patients.     

Hyperprolactinaemia and the regular menstrual cycle in asymptomatic women: should it be treated during therapy for infertility?

It is known that hyperprolactinaemia can cause galactorrhoea and irregular cycles or even amenorrhoea. High serum prolactin (PRL) can disturb follicular maturation and corpus luteum function. Treatment of hyperprolactinaemia in patients with resulting bleeding anomalies is established, but the question is how to manage normal cyclic hyperprolactinaemic women? Studies have shown that in a subgroup of asymptomatic patients the serum contains mainly high molecular weight form (big big PRL), which has a low bioactivity, called macroprolactinaemia. It is evident that macroprolactin does not affect the control of pituitary PRL secretion via the short loop feedback mechanism or the secretion of gonadotrophins as does monomeric PRL. Identification of macroprolactinaemia is therefore clinically important to prevent unnecessary examinations and inappropriate treatment. Prolactinoma can be associated with macroprolactinaemia. Performance of pituitary imaging in asymptomatic patients with hyperprolactinaemia may therefore be justified, but further studies are needed to evaluate the relation of costs and benefit. An unsolved problem is the differentiation between inactive and PRL-secreting tumours. Caution should be exercised concerning medical treatment in unstimulated patients and also in patients during ovarian stimulation alone or in combination with intrauterine insemination or in-vitro fertilization. The potential clinical significance of hyperprolactinaemia/macroprolactinaemia in asymptomatic women must be further evaluated.     

The long-acting dopamine agonist pergolide mesylate for treatment of hyperprolactinaemia

Seven hyperprolactinaemic women were treated with the new, long-acting dopamine agonist pergolide mesylate. The treatment resulted in normalization of the prolactin secretion in four of the seven women and six of them experienced regular uterine bleedings. Four of the patients had previously discontinued bromocriptine because of adverse effects but had no problems to tolerate pergolide. One bromocriptine-resistant woman was unresponsive also to pergolide therapy. Reported side-effects in the seven women were mild and transient. Pergolide mesylate may be a valuable alternative to bromocriptine in the management of patients with hyperprolactinaemia.     

Hypothalamic-pituitary function following bromocriptine therapy in patients with prolactinomas

Bromocriptine in a dose of 5 mg daily was given to 18 patients with prolactinomas to promote resumption of menses, to overcome infertility and as a primary treatment for the tumor. Serum prolactin levels fell to within the normal range in 95% of the patients by 12 weeks of therapy. The prolactin response to TRH stimulation was significantly less than before treatment; however, the percent maximum increment was significantly higher. There was no significant change in pituitary reserve of the other hormones. Seven pregnancies occurred during treatment. All the pregnancies have been progressing normally. All patients have already been delivered of healthy babies, including one set of twins. It is suggested that follow-up studies of the various pituitary hormones be conducted on patients on maintenance bromocriptine treatment. In addition, bromocriptine treatment might be used to promote fertility in patients with prolactin-secreting microadenomas.     

Computed tomography of the brain in patients with serum prolactin levels over 200 ng/ml.

We reviewed the computed tomographic (CT) findings of the sella turcica in 26 patients with a serum prolactin level of over 200 ng/ml. The interval between the dates of CT examination and checking of the serum prolactin level were within 2 months. There were 24 nonpregnant women with a mean age of 30 years and 2 men with a mean age of 28.5 years. None of them were taking medication known to cause an elevation in serum prolactin levels. Surgery was performed on 8 patients with chromophobe adenomas of the pituitary gland: 6 of them were proven to have prolactin-secreting tumors (prolactinomas) after performing a special stain, and the remaining 2 patients, clinically diagnosed as prolactinomas, showed extremely high serum prolactin levels (3,200 and 2,251 ng/ml, respectively). CT studies showed that the height of the pituitary gland in the coronal sections were more than 7 mm in 15 cases (58%) and more than 10 mm in 13 cases (50%); focal bulging of the diaphragma sellae in 16 cases (62%); erosion of the sellar floor in 20 cases (77%); deviation of the pituitary stalk in 19 cases (73%); and abnormal attenuation or enhancement of the pituitary gland in 18 cases (69%). Three patients (12%) showed no evidence of any abnormal CT finding despite a hyperprolactinemic state of over 200 ng/ml. Six histologically proven cases (23%) of prolactinomas and chromophobe adenomas showed radiologic evidence of cavernous sinus invasion. We conclude that patients with a serum prolactin level higher than 200 ng/ml generally show significant changes in the sella turcica in CT.     

Review: Human Prolactin - Recent Advances in Physiology and Therapy

Summary: Human prolactin has been proven to exist as a unique hormone of the anterior pituitary gland. Use of sensitive bioassay and radioimmunoassay techniques has enabled it to be measured in serum and amniotic fluid. Serum prolactin values increase in some women during the luteal phase of the menstrual cycle, in all women during pregnancy and during postpartum suckling. High concentrations of this hormone are also found in amniotic fluid and in neonates for the first few weeks of life. Unlike most other pituitary hormones, prolactin is normally under inhibitory control from the hypothalamus and various stimulatory and inhibitory tests have been used to test the integrity of this hypo-thalamic-pituitary axis. Such tests have been used in clinical conditions where abnormally high serum prolactin levels, or hyperprolactinaemia, have been found in an attempt to localize the disorder and explain its pathogenesis. Hyperprolactinaemia is common in secondary amenorrhoea and galactorrhoea, or inappropriate lactation, and should be excluded in all patients presenting with these problems. It also occurs frequently in patients with pituitary tumours and may cause the reduced libido and impotence in some men complaining of infertility. Drug therapy is now available to suppress serum prolactin concentrations and has been used successfully to prevent or suppress puerperal lactation. Pathological states, such as hyperprolactinaemic secondary amenorrhoea and galactorrhoea have also been treated with these drugs with lowering of serum prolactin values to the normal range and subsequent restoration of ovulation and fertility, or cessation of lactation. A policy for the diagnosis, investigation and clinical management of such patients is presented.     

Outcome and long-term effects of pregnancy in women with hyperprolactinaemia.

Twenty-four women with high circulating prolactin became pregnant on 39 occasions, of which 32 ended in delivery. Sixteen patients showed radiological evidence of pituitary tumour, 6 exhibited a normal CT and 2 had an empty sella. The pregnancies were induced in 4 patients after successful pituitary surgery, in 3 after surgery and medical treatment, and in the rest by bromocriptine (16) long-acting repeatable bromocriptine (1) and methergoline (1). No major complications related to hyperprolactinaemia or its treatment were observed during pregnancy in the patients or offspring. Prolactin after pregnancy was lower than before (basal 95 micrograms/l, after 1st pregnancy 38 micrograms/l P < 0.002, after 2nd pregnancy 24 micrograms/l P < 0.005 compared to basal prolactin); this prolactin reduction tended to be greater in the 9 multiparous patients, but did not attain statistical significance, probably because the number of multiparous patients was too small. A new empty sella developed after delivery in 4 women and persisted in another 2, all of which were medically treated; prolactin fell in all 6 cases normalizing in 3; 4 of these patients had undergone two or more pregnancies. The mean period of follow-up from the last pregnancy was 41.6 months (8-101). These data suggest that pregnancy may hasten a tendency to spontaneous improvement of hyperprolactinaemia, and multiparity may be beneficial in this way.     

Polycystic ovary syndrome and hyperprolactinemia

Analysis of the evidence linking PCOS and hyperprolactinemia suggests that these conditions have independent origins. Elevated prolactin serum levels are documented in the early studies of patients with polycystic ovaries. However, recent investigators using serial serum sampling have excluded transient elevations of prolactin and have shown a less frequent association of these disorders. Treatment of individuals with both PCOS and hyperprolactinemia is distinct from the management of the individual with only one of these conditions. Upon evaluating the therapeutic alternatives for dysfunctional uterine bleeding and hirsutism in these patients, the effect of exogenous estrogen and progesterone on the secretion of prolactin must be considered. The addition of a dopamine agonist (e.g., bromocriptine or cabergoline) to a regimen of clomiphene citrate must also be considered as ovulation induction options for these women. Finally, future discoveries about the relationship between PCOS and hyperprolactinemia will require a better understanding of how the hypothalamus regulates the pituitary secretion of LH and prolactin.     

Prolactin response to thyrotropin-releasing hormone (TRH) in patients with hypothalamic-pituitary disease

The prolactin (PRL) response to thyrotropin-releasing hormone (TRH) was evaluated in 686 patients over a 4-year period. Of the 170 control subjects tested, none had a blunted PRL response to TRH. Eighty patients with prolactinomas documented by surgery were tested. Ninety-five percent (76 of 80) of these patients had an abnormally blunted PRL response to TRH. Of the 87 patients with a prolactinoma who did not undergo surgery, 98% (85 of 87) had a blunted PRL response to TRH. Many patients with other pituitary and hypothalamic diseases (pituitary tumors other than prolactinomas [Cushing's disease, acromegaly, chromophobe adenoma], craniopharyngioma) also had an abnormal PRL response to TRH (79 of 153, 52%). In the majority of patients with hyperprolactinemia due to dopamine antagonist medications, TRH stimulation did not produce a normal rise in PRL. The TRH test may be helpful in confirming the diagnosis of prolactinoma, but it is not a decisive factor in the diagnosis or management of this entity.     

Reduction in the size of prolactin-producing pituitary tumor after Cabergoline administration

Different weekly doses (400 to 3,000 micrograms) of the new, long-acting dopamine agonist Cabergoline (Farmitalia Carlo Erba, Milan, Italy) were given to 11 hyperprolactinemic women with pituitary tumor. Pituitary computerized tomography (CT) scans were performed before the start of treatment and after 3 (n = 5), 6 (n = 3), and 9 (n = 3) months of Cabergoline administration. Plasma prolactin (PRL) was determined in blood samples collected before and at weekly intervals during Cabergoline administration. Cabergoline induced marked inhibition of PRL secretion in conjunction with a CT demonstration of reduction in the pituitary tumor size in all patients. The potent, long-lasting PRL inhibitory effect of Cabergoline and the absence of side effects typical of dopaminergic compounds suggest that the use of this drug is advantageous over others in the medical treatment of hyperprolactinemia.     

Resistant cases of polycystic ovarian disease successfully treated with a combination of corticosteroids, clomiphene, and bromocriptine

Eight successively examined anovulatory women with polycystic ovarian disease (PCOD) who had remained resistant to treatment with clomiphene and dexamethasone (DEX) (and some to hMG/hCG) and had mildly elevated prolactin levels were treated with a combination of clomiphene, DEX, and bromocriptine. There was a decrease in the LH:FSH ratio and androgen and prolactin levels to normal values; within five to eleven treatment cycles, all were pregnant. These results were probably achieved because of the inhibition of prolactin secretion by the dopamine agonist, but may also be due to repletion of a suggested possible functional depletion of dopamine within hypothalamic nuclei in PCOD. This combination treatment is therefore highly recommended before resorting to hMG/hCG therapy or surgery, both of which have intrinsic disadvantages.     

Gynaecological Importance of Unusual Pituitary Tumours

Sixty-eight women with pituitary tumours exhibiting gynaecological symptoms have been reviewed. Fifty-two tumours were prolactinomas while 6 were growth hormone secreting, 6 ACTH secreting, 1 was a large 'inert' adenoma and 3 were late-presenting craniopharyngiomas. Several of the prolactinomas exhibited unusual features including excessively high prolactin secretion, a wide spectrum of sensitivity to bromocriptine, rapid expansion in pregnancy, association with the empty sella syndrome and even a secondary malignancy. The behaviour of tumours secreting other hormones but presenting with gynaecological symptoms is described.     

Clinical importance of antiprolactinaemic treatment of functional infertility (author's transl)]

Reported in this paper is the effectiveness of antiprolactinaemic treatment of 40 infertile women. All case histories revealed previous unsuccessful attempts to induce ovulation. Antiprolactinaemic treatment was in all cases preced by RIA determination of prolactin and gonadotrophin. Prolactin levels were found to be somewhat increase in 19 cases, while 21 women were normal. The gonadotrophin plasma levels usually were closer to the lower limits of normal values. The presence of hypophyseal adenoma had been ruled out beforehand. Long-time treatment was based on the administration of 5 mg Parlodel/die. The effect was excellent in all cases of hyperprolactinaemia, but response was recorded, as well, from a group of patients with normal prolactin levels. Galactorrhoea ceased to exist in all cases. Clomiphen was applied again to induce ovulation in those patients who had not responded at all or developed only bleeding without ovulation. That treatment proved to be effective in several cases.