BRITISH MEDICAL JOURNAL

305

10 MAY 1975

Raised Serum Prolactin Levels in Amenorrhoea M. SEPPALA, E. HIRVONEN, T. RANTA, P. VIRKKUNEN, J. LEPPALUOTO British Medical Journal, 1975, 2, 305-306

Summary Serum prolactin levels measured by specific radioimmunoassay were over 30 ,tg/l in seven out of 25 women with amenorrhoea and in eight women with the amenorrhoea-galactorrhoea syndrome. There was no apparent relationship between these levels and levels of folliclestimulating hormone, luteinizing hormone, and thyroidstimulating hormone. Bromocriptine caused a transient fall in the prolactin levels in six out of seven cases, and in three menstruation and ovulation were restored. Estimation of serum prolactin may become important in assessing the degree of hypothalamic-pituitary dysfunction in amenorrhoea, and it may help in identifying a subgroup of patients at risk of developing a pituitary tumour or patients who may respond to specific treatment.

Introduction Raised circulating prolactin levels are usually associated with pregnancy and normal or inappropriate lactation. 15 As prolactin-secreting tumours constitute about 25 0 of all pituitary tumours 6 recent work has focused on the endocrine characterization of these lesions using prolactin measurements and stimulation tests.5 7 8 In the present study some cases of amenorrhoea without manifest galactorrhoea were found to be associated with raised serum prolactin levels.

25 jig LH/FSH-RH. The FSH and LH levels were expressed in ,ug/l (LER 907). Because there is an episodic fluctuation in serum LH and some interassay variation (up to 15 %) a net increase of at least 100 ,g LH/l was required for a positive response.

Results Of the 34 patients studied, 16 had raised serum prolactin levels. They included all eight women with the amenorrhoea-galactorrhoea syndrome and the one patient with galactorrhoea alone. Of the 25 women with amenorrhoea alone, 7 (28 0o) had raised serum polactin le'- 's (Fig. 1). Radiological examination including tomography showed no space-occupying lesions in the sella, and hypothyroidism was ruled out on the basis of normal protein-bound iodine concentrations (AutoAnalyzer method N-56), normal T-3 uptake,' 0 and normal T-4 levels.1' Of the 16 women with raised serum prolactin levels six had previously been using oral contraceptives and four had had a previous pregnancy (table I).

.

4001 200 0

0

E 100

Materials and Methods A total of 34 patients were studied, 25 with amenorrhoea alone, 8 with both amenorrhoea and galactorrhoea, and 1 with galactorrhoea alone. Blood samples were taken under basal conditions and after injections of synthetic luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH). The samples were allowed to clot at room temperature, and after centrifugation the serum was removed and stored at -20°C until assayed. Prolactin (National Pituitary Agency standard V.-L.-S.1), FSH and LH (National Pituitary Agency reference material LER 907), and thyroid-stimulating hormone (TSH; M.R.C. standard 68/38) were measured by specific radioimmunoassays. Prolactin levels were expressed in jig/l, the minimum level detectable being 4 tsg/l. The upper level in normal women was 30 ,ug/l. Seven women with raised prolactin levels were given bromocriptine (Sandoz; CB-154), a specific inhibitor of prolactin synthesis and release.2 3 9 The drug was given in a daily dose of 5 mg for two to six months. In 12 patients, serum levels were measured 60 minutes before and at 0, 10, 20, 40, 60, and 120 minutes after an intravenous injection of

Departments I and II of Obstetrics and Gynaecology, University Central Hospital, 00290 Helsinki 29, Finland M. SEPPALA, M.D., Senior Lecturer E. HIRVONEN, M.D., Consultant. Department of Physiology, University of Helsinki, Finland T. RANTA, Candidate in Medicine P. VIRKKUNEN, M.D. Department of Physiology, University of Oulu, Finland J. LEPPALUOTO, M.D., Associate Professor (Present address: The Salk Institute for Biological Studies, P.O. Box 1809, San Diego, California)

0

Amenorrhoea ga lactorr hoea

FIG. 1-Serum prolactin levels in patients with amenorrhoea and amenorrhoea-galactorrhoea syndrome. Dashed line indicates upper level in normal women.

There was no apparent relation between the levels of serum prolactin and those of FSH, LH, and TSH. The mean levels of LH and FSH in samples with raised prolactin levels were 82 5 ± S.E. 21 5 ,sg and 224 8 ± 26-8 ,g/l, respectively, while the corresponding levels in the samples with normal prolactin levels were 100 5 ± 22 0 ,ug and 238 i 13 7 ,ug/l, respectively. A more than 100 jug/l increment in LH in response to LH/FSH-RH occurred in eight of the 12 cases studied. A positive response occurred in four out of six women with normal prolactin levels and in four out of six women with raised levels. All four non-responders had low starting levels of LH (18, 20, 33, and 34 jtg/l), whereas patients with a positive response had mostly higher levels, ranging from 30 to 197 (median 86) ,ug/l. Bromocriptine caused a fall in serum prolactin levels in six out of seven patients studied (see table II). Menstruation and ovulation were restored in three of these patients but the effect of treatment was transient (fig. 2). Phenothiazine-related amenorrhoea and galactorrhoea were resistant to bromocriptine when both drugs were used together (see table I, case 8).

Discussion Our findings show that raised serum prolactin levels may be associated with amenorrhoea alone. This may be important,

BRITISH MEDICAL JOURNAL

306

TABLE I-Clinical Details of Patients with Raised Serum Prolactin Levels Case No.

Age (Years)

1

21

2

19

3 4

18 25

5

26

6

23

7

28

8

28

9

33

10

24

11

26

12

28

13

33

14

19

15

24

16

23

Serum Prolactin

Disorder and Clinical Data

(Rtg/l) 44

Secondary amenorrhoea for 36 months after use of oral contraceptives. No pregnancies Anorexia nervosa, secondary amenorrhoea for 12 months. No pregnancies Secondary amenorrhoea for one year. No pregnancies Secondary amenorrhoea and hirsutism. No pregnancies Secondary amenorrhoea for 60 months, hirsutism, previous oestrogen treatment. No pregnancies Hereditary primary amenorrhoea, also present in three sisters. Normal karyotype, 46 XX Galactorrhoea for five months after five years' use of oral contraceptives. Normal menses. No pregnancies Secondary amenorrhoea and galactorrhoea for 24 months. Long-term user of phenothiazines for psychiatric reasons. No response to bromocriptine Secondary amenorrhoea and galactorrhoea for 21 months, starting after normal delivery and lactation followed by divorce Secondary amenorrhoea and galactorrhoea for nine months following delivery and use of oral contraceptives Secondary amenorrhoea and galactorrhoea for 24 months after use of oral contraceptives. No pregnancies Secondary amenorrhoea and galactorrhoea for 12 months, starting after environmental change and adaptation difficulties. No pregnancies Secondary amenorrhoea and galactorrhoea for 36 months following delivery and use of oral contraceptives Secondary amenorrhoea for 20 months associated with weight loss. No pregnancies Secondary amenorrhoea for 12 months following delivery and use of oral contraceptives. Galactorrhoea for three months Secondary amenorrhoea and galactorrhoea for 24 months. No pregnancies

44

48 112

182 84 77

62 84

116 124 128 440 50

60 250

TABLE II-Clinical Responses of Seven Patients to Bromocriptine (No. of Positive Responses/total No. of Patients) Appreciable decrease in Serum Prolactin 6/7

Disappearance of Galactorrhoea 4/6t

Menstruation Restored

Ovulation*

3/6$

3/7

*Criteria for ovulation were an increase in basal body temperature and typical luteal changes in a vaginal smear. tOne patient with amenorrhoea alone is not included. tOne patient with galactorrhoea alone is not included.

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treatment. This study has been supported by a grant from the Association of the Finnish Life Insurance Companies and the Sigrid Juselius Foundation. We thank the National Pituitary Agency, N.I.A.M.D.D., Bethesda, Maryland, and the Medical Research Council, London, for prolactin, FSH, LH, and TSH reagents; Sandoz, Basle, for the bromocriptine; Hoechst-Denmark (Mr. K. Stubbe Teglbjaerg) for the LH/FSH-RH synthetic; and Miss Sirkka Soikkeli, Miss Aino Ala-Raisanen, Mrs. Kristiina Joki, and Mrs. Virpi Tiilikainen for technical help. Requests for reprints should be sent to Dr. M. Seppala.

1

-

Hwang, P., Guyda, H., and Friesen, H., Proceedings of the National Academy of Sciences, 1971, 68, 1902. Besser, G. M., et al., British Medical J7ournal, 1972, 3, 669. 3 Del Pozo, E., et al., J'ournal of Clinical Endocrinology and Metabolism, 1972, 35, 768. 4 Friesen, H., and Hwang, P., Annual Review of Medicine, 1973, 24, 251. 5 Del Pozo, E., et. al., J7ournal of Clinical Endocrinology and Metabolism 1974, 39, 18. 6 Friesen, H. G., Fournier, P., and Desjardins, P., Clinical Obstetrics and Gynaecology, 1973, 16, 25. 7 Frantz, A. G., et al., in International Symposium on Human Prolactin, ed. J. L. Pasteels and C. Robyn, p. 273. Amsterdam, Excerpta Medica, 1973. 8 Jacobs, L. S., and Daughaday, W., in International Symposium on Human Prolactin, ed. J. L. Pasteels and C. Robyn, p. 189. Amsterdam, Excerpta Medica, 1973. 9 Tashjian, A. H., jun., and Hoyt, R. F., in Molecular Genetics and Developmzental Biology, ed. M. Sussman, p. 353. Englewood Cliffs, N.J., Prentice Hall, 1972. 10 Hansen, H. H., Scandinavian Journal of Clinical and Laboratory Investigation, 1966, 18, 240. 1 Nobel, S., and Barnhart, F., Clinical Chemistry, 1969, 15, 509. 12 Murray, R. M. L., Mozaffarian, G., and Pearson, 0. H., in Prolactin and Carcinogenesis, ed. A. R. Boyns and K. Griffiths, p. 158. Cardiff, Alpha Omega Alpha, 1972. 13 Mittra, J., Hayward, J. L., and McNeilly, A. S., Lancet, 1974, 1, 889. 14 McNeilly, A. S., and Chard, T., Clinical Endocrinology, 1974, 3, 105. 2

Prolactin

E

menses

0 Months

because (1) it introduces a new measure of hypothalamicpituitary dysfunction in amenorrhoea; (2) it may help to identify a subgroup of patients at risk of developing pituitary tumours; and (3) it may identify amenorrhoeic patients who may respond to specific treatment. Present evidence indicates that women with raised prolactin levels are at greater risk of developing pituitary tumours.51 8 Some workers have found raised serum levels in postmenopausal women with breast cancer,12 whereas others have not.13 Though radiologica] studies, including tomography, showed a normal sella in all our patients with raised prolactin levels, the possibility of early pituitary adenomas cannot be ruled out completely. These patients are now being followed up to find whether their hyperprolactinaemia is persistent or transient; whether it is possible to identify by prolactin measurements and stimulation tests early pituitary tumours before they become radiologically apparent; and whether these women will develop breast tumours later in life. There was no apparent relation between the serum prolactin and serum gonadotrophin levels in our amenorrhoeic women. A similar finding in normal women was reported by McNeilly and Chard.14 The LH response to LH/FSH-RH also seemed to be independent of prolactin, since a positive response was found in four out of six women with normal prolactin levels and in four out of six women with raised ones. Instead, the LH response to small doses of LH/FSH-RH, such as 25 ,ag, was reJated to the pre-existing LH level. The part played by an increased prolactin level in the pathogenesis of amenorrhoea is not yet clear. An active role may be assumed since menses and ovulation retumed in several patients once the prolactin levels had decreased during bromocriptine

References

Bromocriptine Galactorrhoea

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FIG. 2-Typical response of serum prolactin levels and clinical symptoms to bromocriptine in patient with amenorrhoea and galactorrhoea. Note increase in serum prolactin and recurrence of symptoms when treatment was stopped.

Raised serum prolactin levels in amenorrhoea.

Serum prolactin levels measured by specific radio-immunoassay were over 30 mug/l in seven out of 25 women with amenorrhoea and in eight women with the...
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