Vaginal cabergoline in the treatment of hyperprolactinemic patients intolerant to oral dopaminergics.

OBJECTIVE: To evaluate the effectiveness and tolerance of vaginal cabergoline in hyperprolactinemic patients intolerant to oral dopaminergics. DESIGN: Case reports. SETTING: University hospital endocrinological outpatient clinic. PATIENTS: A 35-year-old primipara woman with idiopathic hyperprolactinemia and a 22-year-old female with primary amenorrhea harboring macroprolactinoma. INTERVENTIONS: Treatment with vaginal cabergoline (0.5 mg two and five times a week). MAIN OUTCOME MEASURES: The serum PRL levels and side effects were assessed before and during treatment. RESULTS: A single vaginal dose of 0.5 mg cabergoline reduced serum PRL levels by approximately 50% to 85% of basal values over a period of 4 to 5 hours. In the patients with idiopathic hyperprolactinemia, serum PRL levels normalized during long-term treatment, whereas in the one with macroprolactinoma they remained above the normal values (79 ng/mL [conversion factor to SI unit, 3.180]) despite resumption of menses and marked tumor shrinkage (70% reduction). No side effects were reported. CONCLUSIONS: Vaginal cabergoline is a safe and effective method of therapy for hyperprolactinemia and it avoids the adverse events of oral administration.

The efficacy and tolerability of long-term cabergoline therapy in hyperprolactinaemic disorders: an open, uncontrolled, multicentre study. European Multicentre Cabergoline Study Group.

OBJECTIVE: We assessed the efficacy and safety of the new, long-acting dopamine agonist drug cabergoline during long-term therapy of hyperprolactinaemia. DESIGN: Open, prospective, multicentre study. PATIENTS: One hundred and sixty-two females with either a microprolactinoma (n = 100), idiopathic hyperprolactinaemia (n = 54), empty sella syndrome (n = 7) or residual hyperprolactinaemia after surgery for a macroprolactinoma (n = 1). All had previously been treated with cabergoline or placebo for 4 weeks as part of a dose-finding study. MEASUREMENTS: Menstrual pattern, adverse symptoms, blood pressure and pulse, serum PRL, blood count, liver and renal function were assessed after one month and subsequently at two-monthly intervals. RESULTS: Treatment was started at doses of 0.25 mg (n = 3), 0.5 mg (n = 8), 1 mg (n = 150) or 2 mg (n = 1) per week, given either as a single weekly dose (n = 8) or divided into twice-weekly doses (n = 154), and was continued for at least 49 weeks in 123 patients. Final treatment doses ranged from 0.25 mg fortnightly to 2 mg twice weekly: most patients finished the study taking 0.5 mg once (n = 31) or twice (n = 77) weekly. Stable normalization of PRL levels was achieved in 138 subjects (85%), in 129 of whom the effective dose was < 1 mg per week. In the subset of 114 patients completing 49 weeks of therapy and having dose adjustments according to the protocol, the biochemical success rate was 92%. Fifty-nine of the 65 previously amenorrhoeic women (91%) and 44 of the 49 (90%) who were previously oligomenorrhoeic resumed regular menses and/or became pregnant during the study. Adverse events were reported in 64 patients (39.5%). In 84% of cases with adverse events, the symptoms were of mild or moderate severity and most occurred during the first few weeks of therapy; five patients (3%) discontinued treatment because of poor tolerance. The most frequent symptoms were dizziness (13% of patients), headache (13%), nausea (10%) and weakness and/or fatigue (10%). Of 27 patients who had previously been poorly tolerant of other dopamine agonists, 17 (63%) did not experience any side-effects and only one was intolerant of cabergoline. No adverse haematological or biochemical effects were detected except for a slight downward trend in haemoglobin which may have been related to the resumption of regular menses in previously amenorrhoeic or oligomenorrhoeic women. A mild hypotensive effect was observed, mean systolic and diastolic blood pressures falling by 5 and 4 mmHg respectively during treatment. CONCLUSIONS: The results provide evidence for the long-term effectiveness and safety of cabergoline in the treatment of hyperprolactinaemia. Its ability to normalize PRL and restore gonadal function compares favourably with reported data on reference compounds while its tolerability profile and simple administration schedule offer potential advantages in terms of patient acceptability.

Successive transperitoneal migration of ova in a woman with extensive pelvic adhesions.

Our case report describes three conceptions after transperitoneal migration of the ovum in a woman with only one ovary, the contralateral oviduct, and extensive postoperative pelvic adhesions obliterating the Douglas cul-de-sac. This suggests that anatomic integrity of the pelvis is not always essential for ovum pick-up.

Dose-dependent suppression of serum prolactin by cabergoline in hyperprolactinaemia: a placebo controlled, double blind, multicentre study. European Multicentre Cabergoline Dose-finding Study Group.

OBJECTIVE: Dopamine agonists have a well established place in the treatment of hyperprolactinaemic disorders but their use is associated with a high incidence of adverse effects. We have investigated the biochemical efficacy and side-effect profile of a range of doses of the novel, long-acting dopamine agonist, cabergoline, in suppressing prolactin (PRL) in hyperprolactinaemic women. DESIGN: Multicentre, prospective, randomized, placebo controlled and double blind. PATIENTS: One hundred and eighty-eight women with hyperprolactinaemia secondary to microprolactinoma (n = 113), idiopathic disease (n = 67), empty sella syndrome (n = 7) or following failed surgery for a macroprolactinoma (n = 1). MEASUREMENTS: Weekly assessment of adverse symptoms, blood pressure and pulse, serum PRL, blood count, liver and renal function. RESULTS: Patients received either placebo (n = 20) or cabergoline 0.125 (n = 43), 0.5 (n = 42), 0.75 (n = 42) or 1.0 mg (n = 41) twice weekly for 4 weeks. The five treatment groups were comparable in age (mean 31.8, range 16-46 years), diagnosis, previous therapy, and pretreatment serum PRL. PRL was suppressed to below half the pretreatment level in 5, 60, 90, 95 and 98% and normalized in 0, 30, 74, 74 and 95% of patients taking placebo or cabergoline 0.125, 0.5, 0.75 or 1.0 mg twice weekly respectively (Armitage's test, chi 2 = 39.3, P < 0.01). Cabergoline therapy (all doses) restored menses in 82% of the amenorrhoeic women not previously treated with dopamine agonists. Adverse events were recorded in 45% of patients in the placebo group and in 44, 50, 50 and 58% of those taking 0.125, 0.5, 0.75 and 1.0 mg cabergoline twice weekly (Armitage's test, P > 0.05). Over 95% of reported symptoms were relatively trivial, most frequently transient nausea, headache, dizziness, fatigue and constipation. More severe adverse events, interfering significantly with the patients' lifestyle, occurred in 13 (7.7%) patients taking cabergoline; treatment withdrawal was necessary in only one case. No adverse effects were detected on blood pressure or haematological or biochemical parameters. CONCLUSIONS: We have shown a linear dose-response relationship for cabergoline in the treatment of hyperprolactinaemia in the range 0.125-1.0 mg twice weekly, with normalization of PRL in up to 95% of cases and acceptable tolerability throughout the dose range.

Gonadotropin releasing hormone agonist treatment for severe menorrhagia in patients with contraindications to surgery.

Four patients with heavy menorrhagia, severe iron-deficiency anemia and contraindications to surgery were treated with a gonadotropin-releasing hormone agonist in a depot formulation. At 2 months of therapy they were all amenorrheic, and at 6 months the hematologic values had improved markedly. Gonadotropin-releasing hormone agonists may obviate emergency surgery in patients at high surgical risk or could constitute the first line of sequential therapeutic regimens, once general health conditions have improved.

Cabergoline in the long-term therapy of hyperprolactinemic disorders.

The efficacy and safety of the new long-acting dopamine agonist cabergoline were evaluated in 127 hyperprolactinemic patients (124F and 3M; 71 with microprolactinoma, 14 with macroprolactinoma, 5 with operated macroprolactinoma and 37 with idiopathic disorder) who were treated with the drug for from 3 to 52 months (median, 14 months). Cabergoline was administered orally at dose levels ranging between 0.2 and 3.5 mg per week, given once weekly in 92 patients, twice weekly in 22, thrice weekly in 9 and daily in 4. Serum prolactin and progesterone levels, hematology, blood chemistry and electrocardiograms were frequently evaluated throughout treatment. CT or MR imaging of the pituitary was repeated during treatment in patients with macroprolactinoma and in 38 with microprolactinoma. After drug discontinuation, serum prolactin and gonadal function were evaluated monthly for three months in 65 patients and for up to two years in 12. Serum prolactin levels were normalized in 114 patients (90%). Of 56 women with amenorrhea, 52 resumed menses (with presumptive evidence of ovulation in 49); 17 women became pregnant; and sexual potency was restored in the 3 men. Evidence of tumor shrinkage was obtained in 13 of the 14 patients with macroprolactinoma and in 28 of 38 with microprolactinoma; complete disappearance of the tumor image was achieved in 2 macro and 14 microprolactinomas. A total of 48 adverse events was reported by 29 patients (23%), almost all typical of the pharmacological class and mild to moderate; no patient withdrew from treatment due to adverse events. Safety parameters did not change. Following cabergoline discontinuation, prolactin levels increased slowly, being still markedly lower than pretreatment values after three months; 10 patients out of 32 had persistently normal prolactin levels during one year of follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pregnancy in "older" women: biologic limit or social prejudice? Bibliographic review]. / La gravida "attempata": limite biologico o preconcetto sociale? Rassegna bibliografica.

The number of women undertaking a pregnancy in late reproductive age is increasing. It is unclear if age of 35 to 40 years constitutes a real biologic limit to reproduction or if unfounded social prejudices play a role. Many publications present advanced age as a significant risk factor for the mother and fetus. Only recent data can be considered because of constant advances in perinatal medicine. Furthermore, many studies are limited by the small sample size and by the lack of control groups and correct statistical analysis. Reproductive outcome is influenced by obstetric, maternal, social and psychological factors. The most recent data obtained on large series of women after control for confounding variables have demonstrated that advanced maternal age is a risk factor for fewer complications than generally believed, such as probability of conception, frequency of chromosomal anomalies, occurrence and consequences of hypertension and diabetes, type of delivery, and maternal and fetal mortality. In the absence of preexisting maternal disease and if correct care is provided by health personnel the prognosis for a pregnancy in an older woman is not greatly different from that of a younger one. By adopting an appropriate attitude the physician can reduce the mother's excessive preconceived concerns, thus allowing the delivery of correct prenatal care and a serene pregnancy.

Flutamide in the treatment of hirsutism.

Ten hirsute women were treated with flutamide (250 mg/day) for 6 months to evaluate its effect. Hair growth as assessed by the Ferriman and Gallwey hair score was significantly reduced in all patients (P less than 0.01). The only significant change in endocrine levels was an increase in serum androstenedione (P less than 0.01). Acne and seborrhea improved markedly. No side effects were noted during the treatment. Our data suggest that the antiandrogenic properties of flutamide render it a suitable single agent in the treatment of hirsutism.

Gonads and genital ducts in a case of male pseudohermaphroditism.

We describe a patient with a 46,XY karyotype, ambiguous external genitalia and partial 17a-hydroxylase deficiency in whom we performed a light microscopic study of the gonads and genital ducts. The right and left testes and epididymides were hypoplastic whereas the right vas deferens was normal, the left one was atretic and a left infundibular remnant was also present, which could be due to a concomitant deficiency in testicular secretions in the early stages of embryonic development or to the possibility of receptor insensitivity for testicular hormones or to a concomitant gonadal dysgenesis.

Cabergoline versus bromocriptine in suppression of lactation after cesarean delivery.

We evaluated the efficacy of cabergoline, a new ergoline derivative, in blocking puerperal lactation in a group of women delivered by cesarean section. In a single-blind controlled trial 36 women were randomly allocated to treatment with cabergoline 1 mg in a single dose p.o. (n = 18) or bromocriptine 5 mg/day p.o. for 14 days (n = 18). Treatment was started about 50 h after delivery. Clinical assessment of breast signs and determination of serum prolactin were performed just before treatment and at 3, 5, 7 and 14 days. In the cabergoline-treated group milk secretion was inhibited in 17 women (94.4%). Maximum decrease of serum prolactin was -89.7% at 5 days, and the prolactin-lowering effect of cabergoline was still present at 14 days. In the bromocriptine group milk secretion was inhibited in 16 women (88.9%). Maximum prolactin decrease (-86.9%) was reached at 3 days. Persistent side effects were comparable in the two groups. This study demonstrates that a single oral dose of 1 mg cabergoline is as effective in suppressing puerperal lactation as a full treatment with bromocriptine, even in women delivered by cesarean section.

Maternal thyroid function in early and late pregnancy.

Thyroid function was investigated during and after pregnancy in 12 healthy euthyroid women. During pregnancy, serum total T4 (TT4) levels were significantly elevated and nearly stable, while thyroxine-binding globulin (TBG) levels progressively increased till the 7th month. A slight elevation, though not significant, of free T4 (fT4) was recorded in early pregnancy. In the following months, fT4, free T3 (fT3) and the T4/TBG ratio progressively diminished, reaching a plateau at the 7th month. Serum TSH levels, measured by an ultrasensitive immunofluorometric assay, were comparable to postpartum values during the first trimester and showed a moderate upward trend with the progression of pregnancy. The evaluation of 24-hour TSH profiles was performed in 5 women during the first trimester of pregnancy. In all women, the circadian rhythm of TSH was present with a normal nocturnal surge, though anticipated in 1 case. In summary (1) during the first trimester of pregnancy, the increased thyroid activity does not seem to be only sustained by pituitary TSH which remains unmodified; the negative correlation between TSH and hCG levels might suggest that hCG also stimulates the gland to increase thyroid hormone output, and the presence of a normal TSH circadian rhythm indicates that the central mechanism of neuroregulation of the pituitary-thyroid axis is preserved in early pregnancy, and (2) in late pregnancy, a marked decrease in free thyroid hormone fractions is accompanied by serum TSH levels still in the normal range, indicating a modification of thyroid homeostasis which might recognize various etiological factors.

Growth hormone and ACTH secretory dynamics in Turner's syndrome.

The secretory dynamics of GH and ACTH were studied in 14 patients with Turner's syndrome. The parameters investigated were plasma GH and cortisol responses to hypoglycemia, plasma cortisol circadian rhythm and suppressibility by dexamethasone, and response of urinary Porter-Silber chromogens to metyrapone. The results were mostly normal. These data do not support the hypothesis suggesting an abnormality of hypothalamic-pituitary function in Turner's syndrome.

Male pseudohermaphroditism due to 17-hydroxylase deficiency.

A 27-year-old phenotypic female presented with primary amenorrhea, severe hypertension, and hypokalemia. At the age of puberty sexual development had not occurred; in particular, sexual hair had not grown. Past history revealed an episode of subarachnoid hemorrhage and several episodes of ventricular tachyarrhythmia. Karyotype was 46, XY. The steroids requiring 17-hydroxylation (cortisol, testosterone, pregnanetriol, 17-ketosteroids, 17-hydroxycorticosteroids) were low, while those not requiring 17-hydroxylation (progesterone, deoxycorticosterone, corticosterone) were high, demonstrating 17-hydroxylase deficiency. The corticosterone/deoxycorticosterone ratio was relatively low, suggesting an associated partial deficiency of 11-hydroxylase.

Gestational aspects of uterus didelphys.

The reproductive history was analyzed of 13 women with a laparoscopic or laparotomy diagnosis of uterus didelphys and followed for two to six years. Two patients (15.4%) presented with primary infertility; the other 11 had a total of 27 pregnancies, the outcome of which was spontaneous abortion in 20 cases (74%), premature labor in 6 (22.2%) and term birth in 1 (3.7%), with a live birth rate of 18.5%. Metroplasty was performed in five cases, with live birth in three, spontaneous abortion in 1 and no postoperative conceptions in one. Cervical cerclage was performed in only one case and bilateral ovarian resection in one. The live birth rate, considering all pregnancies before and after treatment, was 35%. The compromised fertility of the uterus didelphys is probably attributable to congenital alterations in vascularization that may have a negative influence on developmental phases following implantation, particularly the structuralization of the fetomaternal relations that precede placentation.

Localization of cationic proteins derived from platelets and polymorphonuclear neutrophils and local loss of anionic sites in glomeruli of rabbits with experimentally-induced acute serum sickness.

The localization of cationic proteins (CP) derived from platelets and from polymorphonuclear neutrophils (PMN) in glomeruli of 42 rabbits injected i.v. with a large amount of bovine serum albumin, was investigated in sequential biopsies by immunofluorescence, using goat-anti-platelet CP and anti-PMN CP sera. Platelet CP deposits became detectable within 7 to 8 days after the i.v. injection of bovine serum albumin, before or coincident with the onset of proteinuria. The intensity and the extent of linear and segmental deposits of platelet CP along the glomerular capillary walls reached a peak at day 9 to 10, when proteinuria was maximal. The anti PMN-CP serum stained the cytoplasm of the few PMN present in glomeruli and only occasionally at day 11 and 12 identified focal deposits of PMN-CP along the glomerular capillary walls. The kinetic study of glomerular immune deposits showed that the first appearance of immune deposits in antigen excess was preceded by, or was concomitant, with the detection of platelet-CP in glomeruli. In the later stages of serum sickness, the immune deposits showed a progressive increase in rabbit IgG and C3. The glomerular polyanions were studied by light microscopy, using the colloidal iron technique, and by electron microscopy using polyethyleneimine as a cationic probe. The glomerular deposits of platelet-CP were associated with a reduction of colloidal iron staining, which was maximal 9 to 11 days after the i.v. injection of bovine serum albumin. At day 15, colloidal iron staining was almost completely restored. At day 9 in rabbits with acute serum sickness the anionic sites of glomerular basement membrane evidenced by polyethyleneimine, were segmentally decreased, mainly in the lamina rara interna. In rabbit studied at day 15 the anionic sites were decreased only at the base of the subepithelial electron dense deposits (humps). These results suggest that in rabbits with experimentally-induced acute serum sickness, during the early stages of glomerular immune deposit formation endogenous CP, released mainly from platelets, bind to glomerular capillary walls and possibly contribute to the neutralization of glomerular polyanions.