The lipoprotein profile of women with hyperprolactinaemic amenorrhoea

U. Fahy1,3, M.I. Hopton2, M. Hartog2, C.H. Bolton2 and M.G.R. Hull1

1 University of Bristol, Division of Obstetrics and Gynaecology, St Michael's Hospital, Bristol and 2 Division of Medicine, Bristol Royal Infirmary, Bristol, UK


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The aim of this study was to evaluate the lipoprotein profile in women with hyperprolactinaemic amenorrhoea and to establish whether effective dopamine agonist therapy might have a beneficial effect. Blood samples were collected from women with hyperprolactinaemic amenorrhoea and from controls matched for age, body mass index and smoking. Follow-up blood samples were collected from women on dopamine agonist therapy as treatment for their hyperprolactinaemia. Plasma cholesterol, high density lipoprotein cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein cholesterol, triglycerides, serum oestradiol and prolactin were measured. No statistically significant differences were found in the lipoprotein profile of the patient (n = 15) and control (n = 15) groups. During treatment with the dopamine agonist, bromocriptine (n = 9), significant reduction in total cholesterol [4.87 (3.98–5.87) versus 5.60 (4.55–6.61) mmol/l, P = 0.024] and LDL cholesterol [3.22 (2.01–4.23) versus 3.72 (2.59–4.93) mmol/l, P = 0.033] was noted. We conclude that beneficial alterations in the lipoprotein profile may occur in response to effective dopamine agonist therapy, presumably as a consequence of return of ovarian function and alleviation of oestrogen deficiency. Women with hyperprolactinaemic amenorrhoea should be encouraged to take effective therapy to improve their lipoprotein profile and potentially reduce their cardiovascular risk.

Key words: hyperprolactinaemia/lipoprotein profile


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Women with hyperprolactinaemic amenorrhoea are at increased risk of osteoporosis (Klibanski et al., 1980Go; Schlechte et al., 1983Go; Cann et al., 1984Go) which appears to be due to oestrogen deficiency (Klibanski et al., 1988Go). It seems likely that oestrogen deficiency associated with hyperprolactinaemic amenorrhoea would also lead to adverse changes in the lipid profile and increased cardiovascular risk as occurs in postmenopausal and oophorectomized women (Oliver and Boyd, 1959Go; Sznajderman and Oliver, 1963Go; Gordon et al., 1978Go). This study was therefore designed to investigate the lipoprotein profile in women with hyperprolactinaemic amenorrhoea and to determine whether bromocriptine therapy to restore ovarian function has a beneficial effect.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects
Fifteen women with hyperprolactinaemic amenorrhoea (serum prolactin >1000 mU/l) were recruited together with 15 normal cycling controls. All patients had normal thyroid function. None of the patients had taken dopamine agonists or any oestrogen or progestogen therapy within the 2 months prior to the study. The controls were matched for age, body mass index (BMI) and smoking and none were using any medications. Ethical approval for the study was obtained from the local ethics committee.

Venous blood collection
All participants had fasting venous blood samples taken on two occasions, timed 7 days apart (during the follicular phase of the menstrual cycle, in the case of the controls) for measurement of plasma total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol and triglyceride concentrations. Mean values were calculated for each participant. Serum prolactin and oestradiol were assayed on the first sample only.

Nine of the patients were treated effectively with bromocriptine resulting in suppression of prolactin levels usually to normal and restoration of ovarian function and menstrual cycles. Blood sampling was repeated on two occasions during the follicular phase after at least 8 weeks of therapy. The other six patients declined bromocriptine therapy and did not have any further blood samples taken for this study.

Lipoprotein and hormone analysis
Lipoproteins were fractionated by a combination of precipitation and micro-ultracentrifugation (Fehily et al., 1988Go). Briefly, apoprotein-B containing lipoproteins were precipitated using sodium phosphotungstate/magnesium chloride, and high density lipoprotein (HDL) cholesterol in the supernatant was then measured. Very low density lipoprotein (VLDL) was isolated from plasma by ultracentrifugation in a Beckman Airfuge for 3.5 h at 150 000 g. Cholesterol and triglycerides were measured using Boehringer Mannheim kits (236691 and 644200 respectively) [Boehringer Mannheim (UK), Lewes, UK]. Low density lipoprotein (LDL) cholesterol was calculated by difference. All other chemicals were from Sigma Chemical Co., Poole, UK and BDH, Poole, UK. Interassay coefficients of variation were total cholesterol 1.7%, HDL cholesterol 3.1%, LDL cholesterol 2.5% and total triglycerides 7.6%.

Prolactin was assayed by a radio-immunometric method standardized against the WHO 3rd IRP 84/500 using a kit supplied by Medgenix Diagnostics (Fleurus, Belgium). Inter- and intra-assay coefficients of variation for the prolactin assay were 4 and 7% respectively. Oestradiol was estimated by DELFIA immunoassay system (UK distributor Wallac, Milton Keynes). The coefficient of variation was 5.9% at a level of 860 pmol/l, 5.0% at a level of 2500 pmol/l and 6.2% at a level of 5000 pmol/l. Within batch coefficient of variation was less than 5% at all levels.

Statistical analysis
Results were compared statistically by Wilcoxon matched pairs testing.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient characteristics are shown in Table IGo. Lipoprotein and hormone profile results are summarised in Table IIGo. Serum prolactin concentrations were significantly higher by definition and serum oestradiol concentrations were significantly lower in the patient group than in the control group. Total cholesterol, LDL and VLDL cholesterol appeared to be higher and HDL cholesterol appeared to be lower in the patients but the differences from the control group were not statistically significant. Total and LDL cholesterol concentrations in the patient group exceeded the concentrations of the matched control in 10 out of 15 (67%) and nine out of 15 (60%) of cases respectively. However, after treatment with bromocriptine the patients demonstrated significant reductions in total cholesterol and LDL cholesterol, an apparent reduction in VLDL cholesterol and triglycerides, and an apparent increase in HDL cholesterol. During treatment total and LDL cholesterol values decreased in eight out of nine (89%) patients. Serum oestradiol levels increased during treatment but the difference did not attain statistical significance (P = 0.108). One treated patient failed to achieve a normal prolactin level (<700 mIU/l) but menstruation was restored.


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Table I. Clinical characteristics of 15 women with hyperprolactinaemic amenorrhoea and 15 controls. Results are expressed as median (range)
 

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Table II. Lipoprotein and hormonal profile (median values and range) of 15 women with hyperprolactinaemic amenorrhoea compared with 15 normal controls and in a subgroup of women with hyperprolactinaemia before and during bromocriptine therapy
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Hyperprolactinaemia has been linked with hypercholesterolaemia and hypertriglyceridaemia (Pelkonen et al., 1982Go) in a study of 47 women with prolactinomas and 84 normal controls. Also, Hesmati et al. (1987) studied 15 hyperprolactinaemic women and found decreased HDL cholesterol levels although total serum cholesterol, LDL cholesterol and triglycerides were similar to controls. In our study, no statistically significant differences were found in the lipoprotein profile of hyperprolactinaemic patients and controls, although the observed values in the patient group tended to the abnormal.

However, in the hyperprolactinaemic patients who were effectively treated with bromocriptine there was a significant reduction in total cholesterol and LDL cholesterol levels and smaller changes in the other lipoprotein fractions, all towards the normal control values. We believe this to be the first report of such an effect. Pelkonen et al. (1982) reported no change in the lipoprotein profile in 12 hyperprolactinaemic women studied before and after pituitary surgery, but only seven of these subjects achieved normal or near normal prolactin levels with return of menstrual function.

It was important to establish normal thyroid function in the hyperprolactinaemic group. Hyperprolactinaemia is associated with primary and subclinical hypothyroidism (Semple et al., 1983Go; Olive and Hennessey, 1988Go) which are in turn associated with increased levels of total cholesterol, LDL cholesterol and HDL cholesterol (Muls et al., 1984Go; Friis et al., 1987; Kung et al., 1995Go). However, in this group of patients, the concentrations of thyroid stimulating hormone (TSH) were normal.

The most likely explanation for the beneficial alterations which we found in the lipoprotein profile following effective dopamine agonist therapy, is the alleviation of oestrogen deficiency as a consequence of return of ovarian function. Oestrogen deprivation, as occurs following bilateral oophorectomy or the natural menopause, is associated with increases in total cholesterol, LDL cholesterol and triglycerides and a reduction of HDL cholesterol (Matthews et al., 1989Go; Farish et al., 1990Go; Stevenson et al., 1993Go). Exogenous oestrogen therapy lowers plasma concentrations of total cholesterol and LDL cholesterol and raises HDL cholesterol (Bush et al., 1987Go; Walsh et al., 1991Go).

Surgical or natural menopause leads to an increased incidence of coronary heart disease (Oliver and Boyd 1959Go; Sznajderman and Oliver 1963Go; Gordon et al., 1978Go), which is markedly reduced by oestrogen replacement therapy (Hunt et al., 1990Go; Henderson et al., 1991Go; Stampfer et al., 1991Go). It is believed that changes in lipids and lipoproteins associated with the oestrogen deficient state are at least partially responsible for the increased cardiovascular risk. These changes may influence atheromatous plaque formation and regression. It is likely that hyperprolactinaemic amenorrhoeic women are also at increased cardiovascular risk because of their oestrogen deficiency. They should be encouraged to take effective dopamine agonist therapy, not only to protect them against osteoporosis but to improve their lipoprotein profile and potentially reduce their cardiovascular risk. Alternatively, oestrogen replacement therapy could be considered. Further studies to compare changes in the lipoprotein profile in response to dopamine agonist versus oestrogen replacement therapy would be of interest. However, one has to be mindful of the potential risks of stimulation of prolactin secretion (Fahy et al., 1992Go) and pituitary tumour growth (Gooren et al., 1988Go; Bevan et al., 1989Go; Fahy et al., 1992Go) when using oestrogen replacement therapy in such women.


    Acknowledgments
 
We are grateful to John Thompson, Leicester University for statistical advice and to the Departments of Clinical Chemistry, Bristol Royal Infirmary and Southmead Hospital, Bristol for the serum prolactin and serum oestradiol measurements.


    Notes
 
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Leicester Royal Infirmary NHS Trust, Infirmary Square, Leicester, LE1 5WW, UK Back


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 Introduction
 Materials and methods
 Results
 Discussion
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Submitted on March 12, 1998; accepted on October 27, 1998.





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