Clinical Endocrinology (1976) 5, 439-454.

CLINICAL A N D E N D O C R I N E F E A T U R E S OF HYPERPROLACTINAEMIC A M E N O R R H O E A H. S . JACOBS, S . F R A N K S , * M. A. F. M U R R A Y , M . G . R . H U L L , S . J. STEELE" A N D J . D. N . N A B A R R O " Department of Obstetrics and Gynaecology, St Mary's Hospital Medical School, London, and * The Middlesex Hospital, London (Received 3 December 1975; revised 16 February 1976; accepted 15 April 1976)

SUMMARY

The clinical, radiological and endocrine findings in thirty-five women with hyperprolactinaemia and amenorrhoea are described. Twelve patients had radiological evidence of a pituitary tumour and six were tested after pituitary ablation. Seventeen patients with hyperprolactinaemia and normal pituitary X-rays were also studied. None was on any drug known to increase prolactin secretion and all patients were euthyroid when tested. Basal serum prolactin concentrations were high in the group with untreated pituitary tumours and in those with normal X-rays. The levels were variable in the post-ablation cases. The increase of prolactin after TRH was subnormal in all of the groups. Serum oestradiol concentrations were low in most patients and nineteen of twenty-one patients tested had no withdrawal bleeding after treatment with a progestogen. Mean serum gonadotrophin concentrations (basal and after LHRH) were normal in twenty-nine patients but subnormal in four post-ablative cases. Anovulatory responses to clomiphene were obtained in nineteen of twenty patients tested. Fifteen patients were treated with bromocriptine; twelve ovulated and eight became pregnant; two not responding had impaired LH and FSH production. Hyperprolactinaemic amenorrhoea is a common disorder with characteristic endocrine features. Galactorrhoea is unusual (30%). Treatment with bromocriptine lowers prolactin concentrations and rapidly repairs the reproductive defect. INTRODUCTION Patients with galactorrhoea and amenorrhoea may have raised serum prolactin concentrations, and when these are reduced, cyclical hormone secretion, ovulation and fertility may return (Del Pozo et al., 1974). In a retrospective study we reported that twenty-six of 106 Correspondence: Dr H. S. Jacobs, Department of Obstetrics and Gynaecology, St Mary's Hospital Medical School, London, W.2.

439

440

H . S. Jacobs et nl.

women with amenorrhoea had hyperprolactinaemia (Franks et al., 1975). Only six patients in the entire series had galactorrhoea, in each case associated with a raised serum prolactin concentration. Thirteen of the 106 patients had radiological evidence of a pituitary tumour and twelve of these were hyperprolactinaemic. The functional significance of the disturbance of prolactin secretion was demonstrated in two patients without galactorrhoea by induction of ovulation following suppression of hyperprolactinaemia by treatment with bromocriptine (2-cr bromergocryptine, CB 154, Sandoz Products Ltd). We now report the results of more detailed investigations in fourteen patients from that series together with those of an additional twenty-one patients with this syndrome. The results indicate a characteristic pattern of reproductive disturbance in these patients. The mechanism underlying their failure to ovulate appears to involve both disordered regulation of gonadotrophin secretion and an impairment of ovarian function by the excessive amounts of prolactin. PATIENTS AND METHODS The clinical, radiological and endocrine findings in thirty-five women with amenorrhoea associated with serum prolactin concentrations which were elevated on at least two occasions form the basis of this report. None of the patients was taking any drug known to increase prolactin secretion at the time of investigation. Secondary amenorrhoea was diagnosed when the time elapsing since the last spontaneous menstrual period exceeded 120 days (Hull et al., 1976). The diagnosis of galactorrhoea was based in all cases on history and careful examination of the breasts. All patients had antero-posterior (AP) and lateral skull X-rays, as well as coned views and lateral tomography of the pituitary fossa. Lumbar air encephalography (AEG) was performed in nineteen patients. Progestogen withdrawal tests were performed by administering oral medroxy-progesterone acetate (Provera, Upjohn, 5 mg/day) for 5 days. The results were classified according to the degree of vaginal bleeding that occurred after treatment was discontinued. A positive response was defined as bleeding consistent with the patient’s own menstrual loss, a negative response as no bleeding, and an impaired response as bleeding for less than 2 days in the week following withdrawal of the progestogen (Hull et al., 1975). Clomiphene tests were performed by administering clomiphene citrate 100 mg/day for 5 days, 1 week after the progestogen was withdrawn. The index used for a positive response was ovulation, judged either by the occurrence of pregnancy or inferred from a serum progesterone concentration of 25 nmol/l or more, measured during the putative luteal phase. An impaired response was defined by a progesterone concentration of less than 25 nmol/l measured 12 days after stopping clomiphene, despite subsequent vaginal bleeding or a shift of the basal body temperature. A negative response was defined by a progesterone concentration below 3.1 nmol/l, a monophasic temperature chart and no subsequent vaginal bleeding (Hull et al., 1975). Combined luteinizing hormone releasing hormone (LHRH, 100 pg, Hoechst Pharmaceuticals) and thyrotrophin releasing hormone (TRH 200 pg, eighteen cases Hoechst, fifteen cases Roche Products Ltd) tests were performed by obtaining samples before and at 20 min intervals for an hour after an intravenous injection of the mixed hormones. The techniques and details of the radioimmunoassays used for the measurement of serum

Features of hyperprolactinaemic amenorrhoea

441

prolactin (VLS No. l), luteinizing hormone (LH, MRC 68/40), follicle stimulating hormone (FSH, MRC 68/39) and thyrotrophin (TSH, MRC 'A') concentrations, have been described previously (Franks et al., 1975). Serum oestradiol concentrations were measured in duplicate by radioimmunoassay, using a modification of the method described by Hotchkiss et al. (1971). Recovery was monitored in all samples by an internal standard and the results corrected accordingly. Using 0.5 ml samples the detection limit of this assay was 0.03 nmol/l. Serum thyroxine concentrations were measured by competitive protein binding, by the Tetralute method in seventeen cases and by radioimmunoassay (Corcoran et al., 1973) in eighteen cases. Within the range of thyroxine concentrations encountered in these subjects, there is no systematic difference between the two methods (Burke & Eastman, 1974). In all patients the T3 resin uptake was determined and a free thyroxine index calculated. RESULTS Based upon the radiological findings and on surgical exploration of the pituitary, the results have been divided into three groups. Group 1 (Table 1) consisted of seventeen patients in whom there was no radiological evidence (including AEG in four cases) of a pituitary tumour. Group 2 (Table 2) consisted of twelve patients with radiological evidence of an intrasellar expanding lesion. An empty sella was excluded by AEG in nine patients in this group and suprasellar extension of a pituitary tumour was demonstrated in four. In the remaining three patients in this group who had not had AEGs the diagnosis of pituitary tumour was necessarily presumptive. The six patients in Group 3 (Table 3) were studied after treatment for a pituitary tumour. All had previously had AEGs. Four had been treated surgically and the presence of a chromophobe adenoma had been demonstrated histologically. The remaining two patients had been treated with external irradiation. Amenorrhoea was a presenting symptom in all cases: five had primary amenorrhoea and in the remaining thirty the duration varied from less than 1 to 19 years. There was no difference between Groups 1 and 2 in the duration of amenorrhoea but four of the patients in Group 3 had never menstruated spontaneously. Galactorrhoea was a relatively uncommon finding, being present at the time of these investigations in only twelve of the thirty-five women. Two patients (M.B. and C.E., Table 3) had persisting hyperprolactinaemia after galactorrhoea had been abolished by pituitary ablative treatment. However, even when these cases were included there was no significant difference in the incidence of galactorrhoea between those with and without pituitary tumours. Clinical hypothyroidism was not present in any of these patients at the time of review and all the serum thyroxine concentrations were normal. (Group 1, mean thyroxine ( fSE) concentration 91.8+3-6 nmol/l, n = 17, Group 2, 92.2f6.3, n = 12, Group 3, 106f3.4, n = 6 , normal range 52-138 nmol/l.) Two patients were on replacement treatment (200pg of L-thyroxine per day) following hypophysectomy (J.F. and E.L., Table 3). One patient (J.B., Table l), who had a normal serum thyroxine concentration (106 nmol/l) and free thyroxine index (1 12), had an elevated serum TSH concentration (22 u/l) and exaggerated response of TSH to TRH. Neither her galactorrhoea nor the hyperprolactinaemia resolved on medication with L-thyroxine (200 pg/day for 6 months) but the addition of bromocriptine (2-5 mg three times a day for 3 months) led to cessation of lactation, reduction of the scrum prolactin concentration to 6 pg/l and a resumption of ovulatory cycles. In the remaining

S.S.

S.L. C.C. M.C. Y.U. B.S. J.Cr.

R.P.

Neg. Pos. Neg. Neg. Pos. Neg. Neg. Neg. Neg. Neg. Pos. Neg. Neg. POS. Neg. Neg. Pos.

29 36 27 29 33 25 25 34 28 29 28 29 35 28 33 30 22

J.D. J.B. J.M. M.G.I. D.G. B.M. A.C. A.W. J.C.

3 4 9 7 5 4 2 7 0.4 2 4 7 1 4 9 2 7

Age Amen. Galact. (yr)

Patient

18 37

-

21 35

-

52 50 46 61 62 100 56 45 58 78 20 39 30 1.5 1.6 0.7 0.4 0.8 1.0 0.3 1.2 0.5 1.8 1.1

0.1

1.9 1.3 2.2 1.0 -

59 16 58 72 65 16 51 51 < 16

Clinical and endocrine features of hyperprolactinaemic amenorrhoea.

Clinical Endocrinology (1976) 5, 439-454. CLINICAL A N D E N D O C R I N E F E A T U R E S OF HYPERPROLACTINAEMIC A M E N O R R H O E A H. S . JACOBS...
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