Macroprolactinemia in Patients Presenting with Hyperandrogenic Symptoms and Hyperprolactinemia

This Article


Article Information:

Group: 2008
Subgroup: Volume 6, Issue 3, Summer
Date: September 2008
Type: Original Article
Start Page: 140
End Page: 143


  • M Taghavi
  • Endocrine Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, IR.Iran
  • F Sedigheh
  • Endocrine Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, IR.Iran


      Affiliation: Endocrine Research Center, Ghaem Hospital, Mashhad University of Medical Sciences
      City, Province: Mashhad,
      Country: IR.Iran


Macroprolactinemia may account for a signifi-cant number of hyperprolactinemic sera includ-ing hyperandrogenemic women and this may lead to unnecessary diagnostic and therapeutic procedures and false exclusion of PCOS. The aim of this study was to evaluate macroprolactinemia in women with hyperandrogenemic symptoms and hyperprola-ctinemia. Materials and Methods: In a series of 200 hyper-androgenemic women aged 14-40 year, present-ing to the endocrine clinic of Ghaem Hospital between 2004-2006, serum prolactin was meas-ured. Those with hyperprolactinemia (prolactin >35μg/L), were studied for the presence of ma-croprolactinemia using the by polyethylenegly-col precipitation test (PEG). Results: Mean age of hyperandrogenic women was 24.0±5.6 years; 38 (19%) of the patients had serum prolactin >30 µg/L and in 9 of them the rise was >35 µg/L. Macroprolactinemia was de-tected in 5 of those with serum prolactin >35 µg/L who also carried the diagnosis of PCOS. In the remaining 4 patients there was true hyper-prolactinemia and prolactin remained elevated after PEG precipitation test (52±10, vs 48±9 µg/L, respectively). Conclusion: It is necessary to rule out macropr-olactinemia in women presenting with hyperan-drogenemic symptoms and hyperprolactinemia to prevent false exclusion of PCOS. This may help to avoid expensive and unnecessary diag-nostic procedures and inappropriate use of do-paminergic agonists.

Keywords: Macroprolactinemia;Hyperprolactinemia;Hyperandrogenism;polyethyleneglycol precipitation test

Manuscript Body:


Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy in women during their reproductive years. Oligomenorrhea and clinical or biochemical hyperandrogenism are two main diagnostic criteria, but for confirmation of diagnosis other causes such as hyperprolactinemia should be ruled out.1-4 Hyperprolactinemia is common in women presenting with hyperandrogenic symptoms and menstrual disturbances,4–6 and the diagnosis of PCOS cannot be substantiated in these women.Prolactin exists in three different molecular sizes in human serum: small or monomeric (90% of serum prolactin), big and big big (macroprolactin).7-9 In most studies10,11 macroprolactin is defined as a complex of monomeric prolactin and immunoglobulin G, but in some of them it is referred to as a complex of prolactin and glucose or aggregation of prolactin molecules.10-13 Macroprolactin has lesser clearance12-16 and bioactivity8,10,17,18 than monomeric prolactin and may constitute the dominant form (more than 80%) of serum prolactin in some people.7Association of macroprolactinemia in hyperandrogenic women can result in unnecessary and expensive diagnostic procedures and inappropriate treatment. The standard test for diagnosis of macroprolactinemia is Gel Filtration Chromatography. However the procedure is expensive and time consuming,19 whereas acceptable results can be achieved by Polyethyleneglycol (PEG) precipitation that is a rapid and non expensive test.20,21 The aim of this study was to answer to this question if macroprolactinemia or true monomeric hyperprolactinemia may be the cause of hyperprolactinemia in women with hyperandrogenic symptoms and hyperprolactinemia.

Materials and Methods

We evaluated 200 hyperandrogenemic women aged 14-40 years, presenting to the endocrine clinic of Ghaem Hospital from September 2004 to September 2006. Hyperandrogenism was defined as acne and hirsutism (Ferriman-Gallway score >7) or androgenic hair loss. After taking history and physical examination, serum prolactin was measured in all patients using the immunoradiometric assay. Hyperprolactinemia was diagnosed if serum prolactin level was more than normal (>30 μg/L). It has been shown in previous studies that in serum prolactin <35 μg/L (700 mu/L), macroprolactin does not constitute a significant proportion of serum prolactin.22 Therefore, when serum prolactin was >35 μg/L, serum prolactin was measured again in fasting state, by immunoradiometric assay (IRMA), with Kavoshyar kit using Gamma Counter (Gammatic 1, Swiss). In addition, 200 μL of patient serum was incubated with similar volume of PEG for 10 minutes at room temperature in pH=7.4 and centrifuged at 1800 G for 15 minutes. After precipitation, prolactin was measured again in patient serum treated with PEG by IRMA method and the difference was determined and expressed as recovery rate. Macroprolactinemia was diagnosed if the serum prolactin after PEG was equal or less than 40% of initial serum prolactin or in other words if precipitation after PEG was more than 60%.21,22


The patients were 200 women aged 24.0±5.6 years (range 14-40), serum prolactin was higher than 30 μg/L in 38 (19%) patients. In 9 women (4.5%), hyperprolactinemia was significant (>35 μg/L). In these patients evaluation for macroprolactin was performed with PEG precipitation test. Serum prolactin decreased more than 60% in 5 patients and macroprolactinemia was confirmed. Serum prolactin was within normal limits in these women after PEG precipitation (Table 1).Mean serum prolactin in these women was 89±61 and decreased to 17.6±6.2 μg/L after precipitation with PEG (80% precipitation on average). Mean body mass index (BMI) in these patients was 28.6±2.9 kg/m2. All of these patients have diagnostic criteria for PCOS.In 4 patients there was true hyperprolactinemia. Mean serum prolactin in these patients was 52±10 and decreased to 48±9 μg/L after PEG precipitation; therefore, less than 7% precipitation occurred after PEG. Mean BMI in these patients was 31.7±8.3 kg/m2. Hypophyseal micoadenoma was seen in one patient in imaging studies and she was diagnosed as microprolactinoma. Three other patients had normal imaging of hypophysis and were diagnosed as idiopathic hyperprolactinemia. Clinical and paraclinical findings of patients are summarized in Table 1.

Table 1. Clinical and paraclinical findings of patients with hyperandrogenism and hyperprolactinemia


Acne Hair



Diagnosis of
1 20 28 -  +  +
 -  35  10  +
2 19 23 +  -  +  +  190  12  +
3 27 26 -  -  +  +  56  24  +
4 22 26 +  -  +  +  64  20  +
5 22 31 +  +  +  +  100  22  +
6 24 32 +  +  +  -  56  50  -
7 37 37 -  -  +  +  40  38  -
8 19 28 +  -  +  +  64  60  -
9 25 30 -  +  +  +  48  46  -



In spite of many studies having been performed about the cause of hyperprolactinemia in hyperandrogenic women, there is not enough information available on this association. Increased serum estron4 and change in dopaminergic and opioid tone of hypothalamus may be the cause of this association. Evaluation of the patients presented with hyperandrogenism and hyperpprolactinemia is difficult because there is no accepted protocol for this diagnosis.23 Hyperprolactinemia caused by macroprolactinoma, may impose expensive, unnecessary diagnostic procedures and inappropriate treatment and it may delay the diagnosis and treatment of the main background disease.
Recently the PEG precipitation test has been used for determination of macroprolactinemia with good results and reasonable prices. In this study, we used this test for determination of macroprolactinemia in women
with hyperandrogenic symptoms and significant hyperprolactinemia. Evaluation of 200 women with hyperandrogenism showed that 19% of patients had hyperprolactinemia, which was significant in 9 (4.5%). In 5 patients (55%), macroprolactinemia was confirmed with the PEG precipitation test. These patients had diagnostic criteria of PCOS; in 4 patients, there was true hyperprolactinemia. In a similar study performed in Spain,24 hyperprolactiemia was present in 8 of 109 women with hyperandrogenic symptoms and 4 had macroprolactinemia.
In conclusion, macroprolactinemia may be the cause of hyperprolactinemia in women with hyperandogenic symptoms. Screening for macroprolactin with the inexpensive and simple PEG precipitation with PEG is recommended for prevention of expensive and unnecessary diagnostic procedures and inappropriate treatment in such patients.

References: (24)

  1. Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. Boston: Blackwell Scientific Publications; 1992.p. 377– 84.
  2. Homburg R. What is polycystic ovarian syndrome? A proposal for a consensus on the definition and diagnosis of polycystic ovarian syndrome. Hum Reprod 2002; 17: 2495-9.
  3. The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41–7.
  4. Carmina E, Rosato F, Maggiore M, Gagliano AM, Indovina D, Janni A. Prolactin secretion in polycystic ovary syndrome (PCO): correlation with the steroid pattern. Acta Endocrinol (Copenh) 1984; 105: 99-104.
  5. Luciano AA, Chapler FK, Sherman BM. Hyperprolactinemia in polycystic ovary syndrome. Fertil Steril 1984; 41: 719-25.
  6. Milewicz A. Prolactin levels in the polycystic ovary syndrome. J Reprod Med 1984; 29: 193-6.
  7. Luciano AA. Clinical presentation of hyperprolactinemia. J Reprod Med 1999; 44: 1085-90
  8. Suliman AM, Smith TP, Gibney J, McKenna TJ. Frequent misdiagnosis and mismanagement of hyperprolactinemic patients before the introduction of macroprolactin screening: Application of a new strict laboratory definition of macroprolactinemia. Clin Chem 2003; 49: 1504-9.
  9. Fahie-Wilson MN, John R, Ellis AR. Macroprolactin; high molecular mass forms of circulating prolactin. Ann Clin Biochem 2005; 42: 175-92.
  10. Leite V, Cosby H, Sobrinho LG, Fresnoza MA, Santos MA, Friesen HG. Characterization of big, big prolactin in patients with hyperprolactinaemia. Clin Endocrinol (Oxf) 1992; 37: 365-72.
  11. Bonhoff A, Vuille JC, Gomez F, Gellersen B. Identification of macroprolactin in a patient with asymptomatic hyperprolactinemia as a stable PRL-IgG complex. Exp Clin Endocrinol Diabetes 1995; 103: 252-5.
  12. Carlson HE, Markoff E, Lee DW. On the nature of serum prolactin in two patients with macroprolactinemia. Fertil Steril 1992; 58: 78-87.
  13. Cavaco B, Leite V, Amparo Santos M, Arranhado E, Sobrinho LG. Some forms of big big prolactin behave as a complex of monomeric prolactin with an immunoglobulin G in patients with macroprolactinaemia or prolactinoma. J Clin Endocrinol Metab 1995; 80: 2342-6
  14. Hattori N, Ikekubo K, Ishihara T, Moridera K, Hino M, Kurahachi H. A normal ovulatory woman with hyperprolactinaemia: presence of anti-prolactin autoantibody and the regulation of prolactin secretion. Acta Endocrinol 1992; 126: 497-500.
  15. Hattori N, lkekubo K, lshihara T, Moridera K, Hino M, Kurahachi H. Correlation of antibody titers with serum prolactin levels and their clinical course in patients with anti-prolactin auto antibody. Eur J Endocrinol 1994; 130: 438-45.
  16. Heaney AP, Laing I, Walton L, Self MW, Beardwell CG, Davis JRE. Misleading hyperprolactinaemia in pregnancy. Lancet 1999; 353: 720.
  17. Andersen AN, Pedersen H, Djursing H, Andersen BN, Friesen HG. Bioactivity of prolactin in a woman with an excess of large molecular size prolactin, persistent hyperprolactinaemia and spontaneous conception. Fertil Steril 1982; 38: 625-8.
  18. Hattori N, lnagaki C. Anti-prolactin autoantibodies cause asymptomatic hyperprolactinaemia: bioassay and clearance studies of PRL-immunoglobulin G complex. J Clin Endocrinol Metab 1997; 82: 3107-10.
  19. Freeman ME, Kanyicska B, Levant A, Nabgy G. Prolactin: structure, function and regulation of secretion. Physiol Rev 2000; 80: 1523-631.
  20. Bjøro T, Johansen E, Frey HH, Turter A, Torjesen PA. Different responses in little and bigbig prolactin to metoclopramide in subjects with hyperprolactinemia due to 150-170 kD (bigbig) prolactin. Acta Endocrinol (Copenh). 1993; 128: 308-12.
  21. Atha DH, lngham KC. Mechanism of precipitation of proteins by polyethylene glycols. J Biol Chem 1981; 256: 12108-7.
  22. Toldy E, Locsei Z, Szabolcs I, Kneffel P, Goth M, Szoke D, Kovacs LG. Macroprolactinemia in the differential diagnosis of hyperprolactinemia. Orv Hetil. 2003; 144: 2121-7 (Hungarian).
  23. Bracero N, Zacur HA. Polycystic ovary syndrome and hyperprolactinemia. Obstet Gynecol Clin North Am 2001; 28: 77-84.
  24. Escobar-Morreale HF. Macroprolactinemia in women presenting with hyperandrogenic symptoms: Implications for the management of polycystic ovary syndrome. Fertil Steril 2004; 82: 1697-9.