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In summarizing their study, Suliman et al recommended that in the screening of macroprolactinaemia using the PEG precipitation method, prolactin values obtained after PEG precipitation should be compared with the reference interval derived by treating the sera from healthy individuals in an identical manner. This is totally different from the traditional method of using < 40%

prolactin recovery after PEG precipitation which has been used in the previous studies ^4,5,11,70.

The reference interval for serum prolactin in adult premenopausal women as established and provided by the commercially available immunoassay kit (BIOTEC Laboratories Ltd, 32, Anson Road, Martlesham Heath, Ipswich, Suffolk, IP5 3RG, UK) in common use in Clinical Pathology laboratory of the Lagos University Teaching Hospital is 118-555mIU/L. This, somewhat varies from the reference interval of serum prolactin (before PEG precipitation) established by this study using the 120 apparently healthy premenopausal adult females (76.6-856.4mIU/L). The relative difference may also stem from the factors alluded to previously. As usual, it is recommended that each local laboratory establish its own reference interval from the population it serves using a particular commercially available prolactin test kit.^9,70,78.

Previous studies have revealed a wide variation in the prevalence of macroprolactinaemia. Macroprolactinaemia has been noted to occur in the general population at a prevalence rate of 0.1-0.2% ^19,52,58

Different studies have reported different prevalence rates for macroprolactinaemia in hyperprolactinaemic individuals as: 20 to 30% ^5,54. 26% ^4.11, 22% ⁶² and 46% ⁶⁷.

This present study, in contrast to the above studies found the prevalence macroprolactinaemia in 60 hyperprolactinaemic Nigerian women with infertility to be 76.4%. This is rather on the high side when compared with values of the previous studies. The higher prevalence rate may be explained by the following reasons: (i) relatively small sample size (n=60) (ii) different types of immunoassay method (ELISA as opposed to fluoroimmunoassay) used by most of the previous studies (iii) over-precipitation of monomeric prolactin together with macroprolactin in the sera. Nevertheless, no study in this environment to the knowledge of the author has previously established prevalence of macroprolactinaemia in hyperprolactinaemic patients.

The studies carried out by Olukoga and associates were done in the United Kingdom ^11,53,55. Thus, this study is in the position to serve as a reference point and further studies are needed to confirm, corroborate or disagree with the findings.

The variation of reference intervals of serum prolactin and prevalence of macroprolactinaemia could also be explained by the varying immunoreactivity of macroprolactin and/or monomeric prolactin to various immunoassay methods used. Prolactin immunoassays commonly used in various

laboratories have been observed to exhibit varying degree of immunoreactivity to macroprolactin^59,70,72. The procedure manual for the prolactin ELISA method used in this study has no specification as regards the immunoreactivity with macroprolactin.

From this study, the mean (SD) of serum IgG concentration in the 60 subjects is 2485.7 (863.4)mg/dl while that of the normal controls is 1903.0 (460.1) mg/dl. In other words, serum total IgG is relatively higher in hyperprolactinaemic individuals than normo prolactinaemic individuals. Also the increase in total srum IgG in macroprolactinaemic subjects when compared to those of true hyperprolactinaemic patients support the assertion that macroprolactin is chiefly a heteropolymeric complex of monomeric prolactin and IgG^8,25,31-38.

CONCLUSION

This study has been able to establish the reference intervals of serum prolactin in apparently healthy Nigerian women before and after PEG precipitation of samples.

Also the prevalence of macroprolactinaemia in hyperprolactinaemic Nigerian women with infertility has been determined. This study showed a net increase in total serum IgG levels in hyperprolactinaemic patients when compared with normoprolactinaemic individuals.

PRECISION STUDIES

Precision studies were carried out using immunoassay control sera from Fortress Diagnostics Limited, Antrim BT41 1QS, UK. Three levels of control sera: Level 1 (Lot no. IC3003, Expiry date: 2010/06), Level 2 (Lot no: IC3002 Expiry date 2010/06) and Level 3 (Lot No: IC 3001, Expiry date 2010/06) were used.

The intra-assay precisions for Levels 1, 2 and 3 controls at the level of 121.4mIU/L, 405.9 mIU/L and 1320.2mIU/L were 9.8%, 6.1%, and 5.9%

respectively between run precision. while the between-run precisions at the same levels of concentrations were 5.1%, 7.0% and 10.0% respectively. The between-day precisions at the same levels of prolactin concentration were 9.3%, 10.1% and 13.1% respectively.

LIMITATIONS OF THE STUDY

i. Cost of procurement of reagents and materials used for the study.

ii. High non-compliance rate of subjects approached to consent for the study.

iii. Relatively small sample size for determination of prevalence of macroprolactinaemia in hyperprolactinaemic patients with infertility.

iv. Use of semi-automated immunoassay (ELISA) method different from the fully automated fluoroimmunoassay techniques used mostly by cited authors.

v. Inability to follow-up the hyperprolactinaemic patients with macroprolactinaemia to determine their clinical outcome with or without treatment.

vi. Inability to determine a local laboratory established cut off value for defining hyperprolactinaemia based on indigenous laboratory- established reference interval. However a cut off value of 700mIU/L has been used by other studies^5,10,64.

vii. The need to carry out radiodiagnostic and imaging techniques e.g. magnetic resonance imaging (MRI) and computerized tomography (CT) scanning to exclude the co-existence of prolactinoma with macroprolactinaemia¹⁹.

RECOMMENDATIONS

i. There is need to create the clinical awareness about the concept of contribution of macroprolactin/macroprolactinaemia as a cause of

“false” hyperprolactinaemia.

ii. Macroprolactinaemia should be recognised by clinical endocrinologist and gynecologists as a relatively common phenomenon and a frequent cause of misdiagnosis, inappropriate investigations and unnecessary treatment.

iii. There is need to establish a cost effective and viable screening protocol for macroprolactinaemia in all hyperprolactinaemic serum samples.

iv. The polyethylene glycol precipitation method well-known for its cost-effectiveness, simplicity and amenability to routine laboratory usage should be validated by each clinical laboratory intending to screen for macroprolactinaemia.

v. Manufacturers of commercially available immunoassay kits should specify if their serum prolactin immunoassay method is equally immunoreactive to macroprolactin or not.

vi. Any serum sample with intermediate serum monomeric prolactin recovery that falls between 40% and 50% must be confirmed by the gel filtration chromatography (the gold standard) method for macroprolactin detection.