Frequency of Macroprolactin in Hyperprolactinemia.

OBJECTIVE: To determine the frequency of Macroprolactin (MaPRL) in patients with increased total prolactin and its clinical and financial impact. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from March to May 2015. METHODOLOGY: Patients with high total prolactin were screened by polyethylene glycol (PEG) precipitation for determination of MaPRL. Clinical history, imaging work-ups, and cost incurred in further investigations were collected by telephonic interview after verbal consent. Patients were stratified into true hyperprolactinemia and macroprolactinemia after PEG treatment, based on monomeric prolactin levels. Medical records of cases registered with AKUH were reviewed to confirm the diagnosis. RESULTS: Two hundred and thirty-nine patients were identified with high prolactin levels. Macroprolactinemia was identified in 145 (60.7%) and true hyperprolactinemia in 94 (39.3%) patients. Galactorrhea was significantly more in true hyperprolactinemic females (p=0.022), followed by visual disturbances (p=0.01) and headache (p=0.006). Moreover, as majority of population were females, the clinical features in the macroprolactinemia group as compared to true hyperprolactinemic group were mostly related to non-pituitary causes like drug intake [42.5% (54) vs. 37% (30)], heat intolerance due to thyroidal illness [41.7% (53) vs. 38.3% (31)] and surgery [26.8% (34) vs 22.2% (18)] in females. Further radiological workup (MRI, CT) were conducted in 35 (37.2%) patients with true hyperprolactinemia. Twenty-one (60%) of the patients were confirmed to have pituitary adenomas. In eight (5.5%) patients with MaPRL, only one had pituitary microadenoma on radiological workup. Total cost impact on the basis of investigations, was significantly higher in the group undergone imaging, despite 7 out of 8 individuals found to have normal imaging results. The median total cost in true hyperprolactinemic group undergone imaging was Rs. 4370 (IQR=2412.5, 22850) as compared to macroprolactinemic groups; Rs. 3,250 (IQR=2150, 4278). There was significant difference in the cost burden of both the groups (p <0.001). CONCLUSION: High frequency of MaPRL was identified in patients with hyperprolactinemia. Screening with PEG precipitation in hyperprolactinemic sera is simple and cost-effective.

Pituitary-ovarian axis during lactational amenorrhoea. II. Longitudinal assessment of serum FSH polymorphism before and after recovery of menstrual cycles.

BACKGROUND: The association of normal serum levels of immunoassayable gonadotrophins with anovulation during lactational amenorrhoea (LA) has not been fully explained. METHODS: Serum FSH polymorphism was analysed in 10 women during LA between days 60 and 70 post-partum and again, in the mid-follicular phase (MFP), after resuming menstrual cyclicity. FSH microheterogeneity was characterized according to charge, using preparative isoelectric focusing, and according to the inner structure of carbohydrate chains, using lectin chromatography. RESULTS: A significantly higher proportion of FSH charge isoforms isolated below pH 4.10 and a lower proportion of FSH isoforms bearing highly branched oligosaccharides were observed during LA when compared to MFP. Further analysis with higher resolution showed that FSH charge isoforms, isolated in the lower pH range in LA, corresponded to FSH molecules bearing highly branched and biantennary oligosaccharides. FSH isoforms bearing hybrid-type oligosaccharides were only present during LA. The circulating FSH isoform mix was significantly less bioactive in LA than in MFP. LA is characterized by a more acidic mix of FSH isoforms, containing hormone bearing less processed oligosaccharides, with decreased biopotency in comparison with the follicular phase. CONCLUSIONS: This FSH microheterogeneity may be one of the critical factors contributing to incomplete follicular development and anovulation during LA.

Pituitary-ovarian axis during lactational amenorrhoea. I. Longitudinal assessment of follicular growth, gonadotrophins, sex steroids and inhibin levels before and after recovery of menstrual cyclicity.

BACKGROUND: Comparisons of follicular development and hormonal profile in the same women during and after lactational amenorrhoea (LA) are scarce. We report follicular growth, pituitary and ovarian hormone serum levels in the same women during LA and in follicular phases after resumption of menstrual cyclicity. METHODS: Serum samples were obtained from 10 women during LA between days 60 and 89 post-partum and between days 1 and 4 (early follicular phase; EFP) and 7 and 10 (mid-follicular phase; MFP) of the second and third cycles after LA. RESULTS: The number of follicles >3 mm and diameter of the largest follicle were significantly higher during LA when compared to EFP and MFP. Serum levels of inhibin B were similar in LA and EFP and increased significantly in MFP. Pro-alphaC was significantly higher in EFP than in LA and MFP. Estradiol was similar during all stages. In comparison with EFP and MFP, LA is associated with higher prolactin levels, normal or slightly elevated gonadotrophins and increased number and size of follicles without a parallel increase in estradiol, inhibin B and Pro-alphaC. CONCLUSIONS: During LA, there is a profound dissociation between follicular growth and follicular endocrine activity, which suggests an alteration in the stimulus-response relationship at the follicular level.

Abnormal LH pulsatility in women with hyperprolactinaemic amenorrhoea normalizes after bromocriptine treatment: deconvolution-based assessment.

OBJECTIVE: The present study examines the LH secretory process in hyperprolactinaemic women before, during and after bromocriptine therapy, using restrictive clinical selection criteria as well as improved methodological tools. PATIENTS AND DESIGN: Six women (aged 20-40 years) with microprolactinomas (mean +/- SE prolactin, PRL: 2478 +/- 427 mU/l, range: 1370-3800 mU/l) and four age- and sex-matched healthy controls were admitted to the study. After an overnight fast, all patients and controls had blood samples withdrawn at 10 minute intervals for 6 h (during saline infusion) from 0800 h to 1400 h to determine serum LH and PRL concentrations. After baseline evaluation, patients were treated with bromocriptine, which was started at a daily dose of 1.25 mg for 7 days; the dose was then increased to 2.5 mg daily for the next 7 days and subsequently to 2.5 mg twice daily. PRL levels were evaluated at weekly intervals after the beginning of bromocriptine therapy for the duration of the study. The 6 h pulsatility study was repeated on four patients during treatment at a time when PRL levels were decreased, although not normalized (PRL range: 450-1350 mU/l) and, on four patients, with the attainment of normal serum PRL levels (PRL < 450 mU/l) in the early follicular phase of the menstrual cycle (days 2-5). The LH instantaneous secretion rate was reconstructed by a nonparametric deconvolution method. In addition to pulse analysis made using the program DETECT, the evaluation of the secretion rate yielded the pulse frequency as well as the pulse amplitude distribution. RESULTS: Each time series was submitted to deconvolution analysis using a nonparametric method in order to estimate the instantaneous secretion rate (ISR). Hyperprolactinaemic patients had very few high-amplitude LH pulses above 0.2 IU/(l minutes) before treatment (average frequency: 0.83 +/- 0.40 pulses/6 h) and at the intermediate evaluation (0.25 +/- 0.25 pulses/6 h). In both cases, the pulse frequency was significantly lower than in controls (P < 0.05 and P < 0.01, respectively). When PRL was normalized, the number of high-amplitude LH pulses (4.25 +/- 1.03 pulses/6 h), became statistically different from the pulse number before (P < 0.01) and during (P < 0.01) therapy; in particular the pulse frequency after therapy rose to a level not statistically different from that in controls. CONCLUSION: The present study shows the presence of reduced LH pulsatility in hyperprolactinaemic women that recovers completely to within the physiological distribution when PRL levels are normalized by bromocriptine therapy.

Ultrasonic assessment of the endometrium as a predictor of oestrogen status in amenorrhoeic patients.

Thirty consecutive amenorrhoeic patients were assessed with regard to the following: medical history, physical examination, pelvic ultrasonography, serum levels of 17-beta oestradiol (E2), other relevant serum hormones and the response to a progesterone challenge test. The results showed a correlation coefficient of 71% (P = 0.001) between the E2 levels and the endometrial width and of 52% (P = 0.03) between the testosterone levels and the E2 levels. Linear regression of endometrial width against E2 levels showed beta = 0.018 (R2 = 22%, P = 0.02). Patients with an endometrial width of 4 mm or less reported no bleeding or only scanty bleeding following progesterone and all the patients with an endometrial width of greater than 5 mm responded to progesterone with normal menstrual bleeding.

Hyperprolactinemia, amenorrhea, and galactorrhea. A retrospective assessment of twenty-five cases.

The syndrome of hyperprolactinemia, galactorrhea, and amenorrhea is frequently caused by a pituitary tumor. Transsphenoidal surgical removal is often advocated for microadenomas, tumors smaller than 10 mm, to prevent the progression of these small adenomas into large tumors. Because no strong evidence indicates that microadenomas naturally progress to macroadenomas, we studied 25 women who had had hyperprolactinemia, amenorrhea, or galactorrhea for a mean duration of 11.3 years. Their mean initial prolactin level was 225 ng/mL (normal, less than 36 ng/mL). Of 22 patients presenting with amenorrhea, 7 resumed menses spontaneously. Galactorrhea resolved completely in 6 of the 19 patients with this disorder. Only 1 patient had progression of a sellar abnormality, and this was slight. Visual fields remained full in all patients, and basal adrenal and thyroid functions remained normal. The mean prolactin level was 155 ng/mL at the reevaluation (p less than 0.01, initial versus reevaluation levels). Hyperprolactinemia apparently has a benign clinical course in most women, and we advocate a conservative approach to management of this disorder.

Endocrine assessment of post-pill amenorrhoea.

PIP: 24 cases of postpill amenorrhea are presented. The patients were 17-34 years of age and the length of amenorrhea was 6-60 months with a mean of 13.4 months. There was no relationship between the type of contraceptive pill, length of usage, and the incidence of amenorrhea which suggests that the mechanism of action is general rather than due to a specific combination of steroid hormones. The basal endocrine status of the thyroid and adrenal was normal. 14 of the patients had low estrogen and gonadotropins and of these only 4 had a positive clomiphene pituitary reserve test. These 4 patients subsequently restarted normal cycles and luteinizing hormone/follicle stimulating hormone-releasing hormone tests showed normal pituitary function, indicating that the others probably had some derangement of hypothalamic pituitary function.^ieng

Amenorrhoea in anorexia nervosa: assessment and treatment with clomiphene citrate.

Seven patients with anorexia nervosa were studied, three during the acute stages of the illness, and four in whom weight gain had been achieved, but who suffered from persistent amenorrhoea of 18 to 79 months' duration.In the acute stage all patients had low serum luteinizing hormone (LH) levels which were unresponsive to clomiphene citrate. In those who had regained weight the mean basal LH levels were normal, and they responded to clomiphene with an initial doubling of serum LH during administration of the drug, followed by a second peak of serum LH four to seven days after the drug was stopped. Menstruation occurred in these patients 13 to 19 days after the clomiphene was discontinued, and in two patients regular spontaneous menstruation was initiated.The low LH levels unresponsive to clomiphene in the acute stage provide evidence for a hypothalamic abnormality in anorexia nervosa. After regain of body weight the drug seems to be effective in treating the amenorrhoea which may be persistent.