September 1990, Volume 40, Issue 9

Review Articles

BROMOCRIPTINE IN OBSTETRICS AND GYNAECOLOGY

Parveen Haider  ( Department of Obstetrics and Gynaecology, Jinnah Postgraduate Medical Centre, Karachi. )

Bromocriptine, the active ingredient of Parlodel is a specific dopamine receptor agonist available for use in clinical practice. It has been successfully used in the treatment of hyperprolactinemia with associated amenor­rhea, galactorrhea and infertility; in the inhibition of postpartum lactation; acromegaly and in Parkinson’s dis­ease. Its role in obstetrics and gynaecology is strategic since it restores gonadal function and fertility. It decreases the size of prolactin secreting pituitary tumors, and has been used with varying degrees of success in the treatment of menstrual disorders, premenstrual syndrome and polycystic ovarian disease. Its role in the treatment of carcinoma cervix is beneficial, but not proven. Withdrawal of bromocriptine therapy however is associated with reversal of its beneficial effects and return of hyperprolac­tinemia. In this article the current knowledge about the pharmacologic effects and individual clinical applications oLbromocriptine pertaining to obstetrics and gynaecology have been reviewed.
Pharmacology
2 Br - alpha - ergokryptine mesylate (Bromocriptine) is a semisynthetic ergot alkaloid, that was specifically developed in 1967, as an inhibitor of prolactin secretion. It was introduced into clinical research in 1969 and was shown to directly stimulate neuronal dopamine recep­tors1-3. Since prolactin is undertonic inhibition of dopamine4,5 bromocriptine acting as a receptor agonist markedly inhibits its secretion6. After oral administration, 28% is absorbed from gastrointestinal tract, and peak plasma concentration. is achieved 1 to 3 hours after ingestion2,3. First pass metabo­lism of the absorbed dose is extensive (94%) and only 6% reaches the systemic circulation unchanged. Excretion occurs exclusively in faeces (98%) and only 2% of the dose appears in urine1-3.  Serum prolactin levels remain sup­pressed for about 14 hours after a single dose and after that no bromocriptine is detectable in circulation2. Side effects can be separated into two major groups, those noticed with initiation of therapy and those as­sociated with long term treatment. Initial effects include nausea, vomiting and orthostatic hypotension, that can be minimized by starting therapy with alow dose given at bed time with food, and gradually increasing it until a therapeutic response is achieved ,3 With long term treat­ment headache, fatigue, abdominal cramps, constipation, nasal congestion and digital vasospasm may be noted. Intense visual hallucinations, erythromelalgia, reversible, pleuropulmonary changes including pleural thickening and effusion and even urinary incontinence have been described2,3,7. The therapeutic role of bromocriptine in different disorders is discussed below.
Hyperprolactinemia
Hyperprolactinemia is an increasingly recognized cause of amenorrhea, galactorrhea and infertility in females and impotence and infertility in males2,8. Its incidence ranges from 13 to 50% (mean 24%) in women with amenorrhea. Galactorrhea is present in 30-79% of hyperprolactinemic women, although it is less common in men8. The commonest cause is a pituitary tumor2. This may be a macroadenoma (greater than 10mm diameter) or a microadenoma (less than 10mm diameter) 9. In general serum prolactin levels may reflect tumor size. In patients with levels less than 100ng/ml, often no discrete tumour is identifiable at surgery. Patients with prolactin levels of 100-250ng/ml usually have microadenomas, and those with levels greater than 250ng/ml have macroadenomas2. It has been shown that about 12% non-pregnant women with amenorrhea during their reproductive life have ‘pituitary prolactinoma syndrome’ and this proportion rises to 50% if galactorrhea is also present10. Hyperprolactinemia may also result from hypo­thalamic damage due to infection, tumor, trauma or irradiation; or may be drug induced (reserpine, methyl­dopa, phenothiazines, metoclopramide). It may be seen in hypothyroidism, renal or liver diseases, following physical or psychological stress, breast stimulation, chest wall lesions and with the use of oral contraceptives2,8,10. In the absence of any other cause, it is usually considered that hyperprolactinemia is due to pituitary disease, even if the lesion is not demonstrable radiographically11. Since its introduction into clinical practice, ‘bro­mocriptine’ has been shown to reduce circulating prolactin levels irrespective of the cause12,13. Many studies have shown the efficacy of bromocriptine in decreasing prolac­tin levels, suppressing galactorrhea and restoring cyclic menses in women8,14,15. Reviewing the literature Vance et al2 have shown that within a month of beginning, of bromocriptine therapy, 73 - 100% women will attain normal menstrual function and documented ovulation in 57 to 100% cases. Whereas most patients have a lowering of prolactin levels to normal range, afewmaynot achieve this response. However these patients may also attain gonadal function despite the lack of complete suppression of prolactin12. Additionally, bromocriptine is also effective in restoring fertility in normoprolactinemic women with unexplained infertility and galactorrhea16. Bromocriptine is now proposed as the first line of treatment for prolactinomas13. In patients with macro­adenomas, there have been many reports of the efficacy of bromocriptine in suppressing prolactin levels, reducing tumor size, improving visual fields and restoring gonadal function2,8,17-20. Dramatic clinical improvement and reduction in tumor size without the risk of hypopituitarism is compelling evidence for recommending bromocriptine in treatment of macroadenomas2,8. Bromocriptine also has a beneficial effect in reducing serum prolactin levels and decreasing the size of prolactin secreting micro­adenomas with cessation of galactorrhea and return of cyclic menses21. Non- functioning pituitary tumors may also be responsive to bromocriptine therapy, 22but this suggestion is controversial and requires further evalua­tion. The beneficial effect of bromocriptine on pituitary tumors is achieved by various mechanisms. Other than lowering prolactin levels, it has been shown to have a specific antimitotic action on pituitary tumors in animal models22. The reduction in tumor size is also accomplished by a direct necrosing or a cytocidal effect on tumor cells20. Nevertheless, bromocriptine therapy does not result in a permanent cure, for withdrawal results in return of hyperprolactinemia and tumor re-expansion2’8’23.
Hyperprolactinemia and pregnancy
When a woman with hyperprolactinemia is success­fully treated, her chances of becoming pregnaat are the same as those of a normal woman2. In bromocriptine treated hyperprolactinemic women with pituitary tumors, conception rate varies from 37.5 to 81%2. The main problem encountered during pregnancy is the risk of pituitary tumor expansion10. Genizel and Wang9 have estimated this risk to be 35% in women with macro­adenomas; but in women with microadenomas, the risk of pregnancy induced tumor expansion is much less. Bromocriptine not only restores fertility, but it has been observed that in bromocriptine induced pregnancies, the risk of tumor related complication is much smaller24,25. Bergh et al25 reported the clinical course and outcothe of 19 bromocriptine induced term pregnancies and found severe pituitary tumor related complication in one patient only. Mornex et al24 did not report any complication in 7 pregnant women with clear cut adenomas. This can be attributed to the anti-mitotic action of bromocriptine22 that can possibly shrink pituitary tumors. Pregnancy does not have any long term adverse effect on hyperprolactinemic state. Fifty eight women with at least one bromocriptine induced pregnancy were fol­lowed up for 13 to 108 months. Following pregnancy, prolactin levels decreased by more than 50% in 20 women. Only 2 women shoWed an increase in prolactin levels, during long term follow up. This suggests that pregnancy does not make prolactin hypersecretion worse26. Teratogenicity and outcome of pregnancy have been carefully assessed. Turkalj et al27 reporting the outcome of 1410 pregnancies, found no associated increased risk to the fetus. The incidence of spoutaneous abortion, extra uterine pregnancy and malformations in offsprings of women treated with bromocriptine during a portion of pregnancy were comparable to normal population. Even continuous administration of bromocriptine throughout pregnancy resulted in the birth of children whose sub­sequent mental and physical development observed upto the age of 6 years. was normal28. Nevertheless it is recommended that bromocriptine therapy should be dis­continued soon after conception on general principle that unnecessary medication should be avoided during preg­nancy. Furthermore bromocriptine crosses placenta and suppresses fetal qrolactin levels, and long term effects of this are unknown2.
Puerperal lactation
Although several hormones interact at the breast for puerperal lactation to occur, prolactin secretion is needed for initiation and maintenance of galactopoiesis4,5. There­fore a logical method to suppress lactation is to reduce prolactin secretion. Treatment of puerperal women with bromocriptine inhibits both basal and suckling induced prolactin secretion and provides a more physiological method of suppressing lactation2,29. Within 24 to 48 hours after beginning treatment, bromocriptine lowers prolactin levels to normal, blocks initiation of lactation and prevents breast engorgement and mastodynia2. Controlled trial of bromocriptine com­pared with placebo has proved its superiority in preventing breast congestion and engorgement. However 25% in­cidence of rebound breast engorgement was observed when bromocriptine was given for 8 days only30. Cook and associates31 found a 14 day course of 2.5mg twice daily effective in lowering prolactin levels, reducing milk production, breast congestion and pain as compared to placebo. Comparing bromocriptine and estrogen treat­ment, bromocriptine has been found to be more effective in preventing rebound mammary engorgement, although both agents effectively suppress lactation30,32. Moreover there is no risk of thromboembolic disease with bromo­criptine, and this is a distinct advantage over estrogen preparation2. Bromocriptine has been equally effective in sup­pressing lactation once it is established32 and in reducing milk yield in puerperae with polygalactia33. The most effective dose schedule is 2.5mg twice daily during the first two weeks followed by 2.5mg once daily for the third week2.
Luteal phase insufficiency
Menstrual cycle with a short luteal phase may be a distinct entity occurring in 3 to 11% of infertile women34,35. The syndrome is characterized by inadequate secretion of progesterone and early regression and degeneration of corpus luteum with menses occurring 6 to 9 days after the mid cycle peak of lutenizing hormone2. The etiology is unknown but subnormal levels of 17 estradiol and FSH suggest an inadequate replication & follicular cells with delayed development of a small follicle and consequent evolution of a defective corpusiuteum. Alternately the cause could he attributed to a primary ovarian defect34. Prolactin directly appears to influence steroid secre­tion36 and the function of corpus luteum2. Mild hyper­prolactincmia has been found in 40-47% women with luteal insufficiency37,38. Bromocriptine 2.5mg daily, resulted in reduction of serum progesterone levels and prolongation of luteal phase. It was also effective in prolonging luteal phase in normoprolactinemic women. 37 Using the same dose, Lehtovirta et al38 also demonstrated the beneficial effect of bromocriptine in luteal insufficien­cy. Luteal phase was significantly prolonged but plasma proçsterone levels remained unchanged. However Smith et al39 failed to demonstrate lengthening of luteal phase with bromocriptine therapy. But because a significant percentage of women have responded to bromoeriptine, a trial of 2.5mg twice daily may. be worth while; success however may not be absolute2.
Idiopathic edema
It is a poorly understood disorder occurring pre­dominantly in women of reproductive age, and involves fluid retention in absence of any cardiac, hepatie or renal pathology2. A gain in excess of 1.4kg during the day is an essential clement in the diagnosis2. The cause is not fully understood, but there appears to be an alteration of peripheral dopaminergie function as evidenced by de­creased urinary excretion of dopamine40 Norbiato et al41 have suggested a dopaminergic control of renin and aldosterone and an alteration of this control may play a role in the pathogenesis of idiopathic edema. Dopamine agonists therefore have a place in the treatment of this condition. Dent and Edwards42 reported beneficial effect of bromoeriptine in a study of 5 women with idiopathic edema. Three had a significant decrease in diurnal weight gain and 2 reported symptomatic improve­ment. Sowers and colleagues43 examined the effect of bromoeriptine therapy (2.5mg three times a day) in patients with idiopathic edema and found a favourable response. Bromocriptine therefore appears to be benefi­cial in the treatment of this subgroup of patients.
Premenstrual syndrome
It is characterized by mental symptoms, headache, mastodynia, peripheral edema and abdominal distension2. The etiology remains unknown, however suggestions have ranged from cyclic fluctuation of sex steroids to psycho genie influences, but no theory has gained general accep­tance2. Horrobin (1974) and Halbriech et al (1976) have reported an association between elevated levels of prolac­tin and premenstrual tension syndrome44. Bromoeriptine can therefore play an important role in alleviating premenstrual symptoms. Anderson and collegues,44 comparing the effect of placebo and bromocriptine, showed that medication con­siderably improved all the premenstrual symptoms, but mastodynia was the only one where bromocriptine was better than placebo. Elsner et al45 reported significant improvement in breast tenderness, bloating and depres­sion on bromocriptine therapy. Durning and Sellwood46 also proved the superiority of bromocriptine over placebo in reducing cyclical breast pain, tenderness and nodu­larity. Comparing bromocriptine and norethisterone Ylos­tab et al47 proved the effectiveness of bromoeriptine with regards to premenstrual symptoms. However nore thisterone was better tolerated. Anderscb et al48 com­pared bromocriptine and diuretic bumetanide in 19 women. Overall11 of the 19 women thought that bro­mocriptine was more effective. The dose in all these studies was 2.5mg twice daily. Although the results of these studies are provocative yet bromocriptine does not appear to be consistently effective in the treatment of premenstrual syndrome.
Polycystic ovarian syndrome
The syndrome of polycystic ovarian disease results from excessive androgen production stimulated by eleva­ted levels of lutenizing hormone. These elevated LH levels can be reduced by dopamine infusion49 suggesting a relative dopamine deficiency in women with polycystic ovarian syndrome. Gonzalez50 and Buvat et al51 have suggested that women with polycystic ovarian syndrome may have a defect in central dopaminergic tone. There are therefore theoretical reasons for bromocriptine to become a therapeutic option in these patients50. Adrenal involvement in PCOS has also been proved and bromocriptine is known to decrease the adrenal contribution to androgenic pool in these patients52. This could be another mechanism whereby bromocriptine exerts its beneficial effect. Spruce et al53 reported favourable response in 20 patients with PCOS treated with 7.5mg bromocriptine daily for upto 1 year. and found a significant reduction in LHlevels, LH/FSH ratios and plasma testosterone leading to restoration of cyclic ovarian function and a subjective improvement in hirsutism. However Murdoch et al54  unable to find any evidence to support a therapeutic role for bromocriptine in these patients. There were no sig­nificant changes in biochemical parameters; no improve­ment in hirsutism54,55. and the ovulatory response was disappointingly low55. Nevertheless to ascertain the role of bromocriptine in PCOS, further trials are required.
Carcinoma cervix
In 1981, Guthrie et al56 reported a case of advanced carcinoma cervix that achieved remission lasting more than 7 years when treated with a combination of bromo­criptine and aprotinin. In a subsequent trial, on bromocriptine alone, out of 18 patients with Ca cervix all having received primary treatment, he reported tumor stasis in three and very long remissions in five cases. 57 Encouraged by thise results Donath and Schindler58 began a trial of bromocriptine in women with persistent cervical intra epithelial neoplasia and reported a positive influence. In all these trials, bromocriptine was given in a dose of 2.5mg twice daily for prolonged periods. However Praest and Klem59 using the same dose failed to demon­strate a beneficial effect of the drug on reôurrent squamous cell Ca of cervix. The rationale for treating cancer patients with bromocriptine was that prolactin may depress certain anticancer defense mechanism, but precisely how this effect is achieved is still a matter of debate. Elevated levels of prolactin reduce cell mediated and enhance bumorally mediated responses. Hence bromocriptine by modulating immune responses can achieve favourable results. Alter­nately cervix could be a hormone target organ in relation to prolactin. If this is so,it is possible that certain carcinomas of cervix may be prolactin dependent and hence bromo­criptine therapy could be effective in the same wçç as hormone therapy in Ca of breast and endometrium56,57
Breast cancer
Prolactin is a known mammary epithelial growth promoter. It is an important, perhaps anessentialhormone in the development phases of mouse mammary tumo­rigenesis60 but its role in human breast cancers has to be ascertained. Bromocriptine has a beneficial effect on mammary tumors in mice, 0 but in patients with breast cancer it has been used with little success61. However used as an adjuvant perioperative therapy in a trial, bromocriptine has exerted a positive effect on primary tumor and can therefore modify the clinical course of the disease62. Larger trials are however required before bromocriptine can be accepted for adjuvant therapy in breast tancers.
Adenomyosis
Endocrine mechanisms for the geneses of adenom­yosis are not clearlyunderstood. Based on an animal model Mori et al63 have suggested that prolactin plays an important role in the development of this pathological state. Huseby and Thurlow64 have also attributed chronic hyperprolactinemia as an etiologic factor in genesis of lesions resembling adenomyosis in a strain of mice. Consequently bromocriptine has been shown to exert a beneficial effect by completely inhibiting the development of experimental adenomyosis in animals65. However its role in human beings remains undetermined.
Other uses of bromocriptine
The beneficial effects of bromocriptine are not merely confined to obstetrics and gynaecology. There is documented evidence regarding its efficacy in Parkinson’s disease and as adjuvant therapy in acromegaly2. It has been used in the management of various psychiatric disorders, hepatic encephalopathy, neuroleptic malignant syndrome. Huntington’s chorea and tardive dyskinesia2,66. There have been reports of its use in benign prostatic byper­trophy, 67 in prostatic cancers, 68 in dermatological condi­lions like psoriasis69 and in the prevention of cocaine craving70 and alcohol withdrawal syndrome71.

CONCLUSION

Bromocriptine hq been in clinical use for over 20 years. Although it was initially approved for the treatment of byperprolactinemia, suppiession of lactation and Parkinson’s disease, the spectrum of its usefulness has now extended considerably. As more and more dilemmas about prolactin are being revealed, more and more indications for its use are coming up. Till safer and more effective dopamine agonists are available, bromocriptine will con­tinue to enjoy the existing position it has in obstetrics and gynaecology.

ACKNOWLEDGEMENT

My sincere gratitude and thanks to Prof. S. Jafarey, Head of Department of Obstetrics and Gynaecology (JPMC) for the encouragement and help in the prepara­tion of this paper.

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