The posterior nasoseptal flap: A novel technique for closure after endoscopic transsphenoidal resection of pituitary adenomas.

BACKGROUND: While effective for the repair of large skull base defects, the Hadad-Bassagasteguy nasoseptal flap increases operative time and can result in a several-week period of postoperative crusting during re-mucosalization of the denuded nasal septum. Endoscopic transsphenoidal surgery for pituitary adenoma resection is generally not associated with large dural defects and high-flow cerebrospinal fluid (CSF) leaks requiring extensive reconstruction. Here, we present the posterior nasoseptal flap as a novel technique for closure of skull defects following endoscopic resection of pituitary adenomas. This flap is raised in all surgeries during the transnasal exposure using septal mucoperiosteum that would otherwise be discarded during the posterior septectomy performed in binostril approaches. METHODS: We present a retrospective, consecutive case series of 43 patients undergoing endoscopic transsphenoidal resection of a pituitary adenoma followed by posterior nasoseptal flap placement and closure. Main outcome measures were extent of resection and postoperative CSF leak. RESULTS: The mean extent of resection was 97.16 ± 1.03%. Radiographic measurement showed flap length to be adequate. While a defect in the diaphragma sellae and CSF leak were identified in 21 patients during surgery, postoperative CSF leak occurred in only one patient. CONCLUSIONS: The posterior nasoseptal flap provides adequate coverage of the surgical defect and is nearly always successful in preventing postoperative CSF leak following endoscopic transsphenoidal resection of pituitary adenomas. The flap is raised from mucoperiosteum lining the posterior nasal septum, which is otherwise resected during posterior septectomy. Because the anterior septal cartilage is not denuded, raising such flaps avoids the postoperative morbidity associated with the larger Hadad-Bassagasteguy nasoseptal flap.

Surgical debulking of pituitary adenomas improves responsiveness to octreotide lar in the treatment of acromegaly.

BACKGROUND: Studies comparing primary medical treatment of acromegaly with surgery are often non-randomized, and not stratified by illness severity. We prospectively compared primary medical therapy with pituitary surgery in patients with acromegaly. All patients had macroadenomas, at least one random human growth hormone (GH) level ≥12.5 ng/mL, elevated IGF-I levels and failure to suppress GH to <1 ng/mL during an oral glucose tolerance test (oGTT). METHODS: Forty-one patients from seven centers were randomized to primary treatment with octreotide LAR, 30 mg every 4 weeks × 3 months (ARM A, N = 15), or pituitary surgery (ARM B, N = 26) using a 1:2 randomization design. Patients cured by surgery (defined as nadir GH during oGTT <1 ng/mL and normal IGF-I) received no subsequent treatment. Those not cured surgically were then treated with octreotide LAR (SubArm B1) for 3 months. RESULTS: Only one of the 15 patients in ARM A (6.7%) had normalization of both GH and IGF-I. In contrast, 13/26 patients had normalization of both GH and IGF-I after surgery alone (50%). Of the remaining 13 patients who did not normalize with surgery alone, treatment with octreotide LAR resulted in a normal nadir GH and normal serum IGF-I in 7 (53.9%). In total, 20/26 in ARM B (76.9%) experienced normalization of defined biochemical acromegaly parameters. CONCLUSIONS: Pituitary surgery alone was more effective than primary medical treatment (p = 0.006), and the combination of surgery followed by medical therapy was even more effective (p < 0.0001). Subjects treated with medical therapy after surgical debulking had a significant improvement in response rate compared to matched subjects treated with primary medical therapy.

Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial.

BACKGROUND: A novel oral octreotide formulation was tested for efficacy and safety in a phase III, multicenter, open-label, dose-titration, baseline-controlled study in patients with acromegaly. METHODS: We enrolled 155 complete or partially controlled patients (IGF-1 <1.3 × upper limit of normal [ULN], and 2-h integrated GH <2.5 ng/mL) receiving injectable somatostatin receptor ligand (SRL) for ≥ 3 months. Subjects were switched to 40 mg/d oral octreotide capsules (OOCs), and the dose escalated to 60 and then up to 80 mg/d to control IGF-1. Subsequent fixed doses were maintained for a 7-month core treatment, followed by a voluntary 6-month extension. RESULTS: Of 151 evaluable subjects initiating OOCs, 65% maintained response and achieved the primary endpoint of IGF-1 <1.3 × ULN and mean integrated GH <2.5 ng/mL at the end of the core treatment period and 62% at the end of treatment (up to 13 mo). The effect was durable, and 85 % of subjects initially controlled on OOCs maintained this response up to 13 months. When controlled on OOCs, GH levels were reduced compared to baseline, and acromegaly-related symptoms improved. Of 102 subjects completing the core treatment, 86% elected to enroll in the 6-month extension. Twenty-six subjects who were considered treatment failures (IGF-1 ≥ 1.3 × ULN) terminated early, and 23 withdrew for adverse events, consistent with those known for octreotide or disease related. CONCLUSIONS: OOC, an oral therapeutic peptide, achieves efficacy in controlling IGF-1 and GH after switching from injectable SRLs for up to 13 months, with a safety profile consistent with approved SRLs. OOC appears to be effective and safe as an acromegaly monotherapy.

Effects of low dose versus high dose human growth hormone on body composition and lipids in adults with GH deficiency: a meta-analysis of placebo-controlled randomized trials.

PURPOSE: Doses of growth hormone in adults with growth hormone deficiency are now lower than previously. However, it is not clear they are as effective as higher doses. The objective of this meta-analysis was to assess efficacy of low to moderate dose (LD) GH replacement on standard endpoints of GH compared to higher doses. METHODS: A meta-analysis was carried out using PubMed, Cochrane and Embase databases from 1960 to 9/23/12. Three reviewers identified randomized double-blind, placebo-controlled trials of 6 months duration. Of 173 publications, 28 representing 22 trials (591 GH-treated patients and 562 placebo) were included. Data were independently extracted by three reviewers. Endpoints were analyzed if ≥4 studies per dose group reported baseline and 6 month data. RESULTS: Mean lean body mass (LBM) increased by 2.61 kg in GH-treated subjects versus 0.04 in the placebo group (P < 0.0001). Fat mass (FM) was reduced by -2.19 kg versus 0.31 (GH vs. placebo) (P = 0.0002). Changes in LBM and FM were dose-related (P = 0.02 and 0.007, respectively), high dose (HD) being more effective than low dose (LBM P = 0.03 and FM P = 0.04). In contrast, treatment with GH reduced total cholesterol -0.38 mmol/L versus. 0.01 (placebo) (P < 0.0001), and low density lipoprotein cholesterol (LDL-C) -0.42 mmol/L versus -0.1 (P = 0.0009), but there were no differences between LD and HD GH. CONCLUSIONS: LDs of hGH improve total- and LDL-C, and body composition. Higher doses are more effective on body composition, but not lipids.

Insulin-like growth factor-I inhibition with pasireotide decreases cell proliferation and increases apoptosis in pre-malignant lesions of the breast: a phase 1 proof of principle trial.

INTRODUCTION: Estrogen inhibition is effective in preventing breast cancer in only up to 50% of women with precancerous lesions and many experience side effects that are poorly tolerated. As insulin-like growth factor I (IGF-I) underlies both estrogen and progesterone actions and has other direct effects on mammary development and carcinogenesis, we hypothesized that IGF-I inhibition might provide a novel approach for breast cancer chemoprevention. METHODS: In total, 13 women with core breast biopsies diagnostic of atypical hyperplasia (AH) were treated for 10 days with pasireotide, a somatostatin analog which uniquely inhibits IGF-I action in the mammary gland. They then had excision biopsies. 12 patients also had proliferative lesions and one a ductal carcinoma in situ (DCIS). Primary outcomes were changes in cell proliferation and apoptosis after treatment. Expression of estrogen receptor (ER), progesterone receptor (PR), and phosphorylated Insulin-like growth factor I receptor (IGF-1R), protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2) were also assessed. Core and excision biopsies from 14 untreated patients served as non-blinded controls. Hyperglycemia and other side effects were carefully monitored. RESULTS: Pasireotide decreased proliferation and increased apoptosis in all AH (from 3.6 ± 2.6% to 1.3 ± 1.2% and from 0.3 ± 0.2% to 1.5 ± 1.6%, respectively) and proliferative lesions (from 3.8 ± 2.5% to 1.8 ± 1.8% and from 0.3 ± 0.2% to 1.3 ± 0.6%, respectively). The DCIS responded similarly. ER and PR were not affected by pasireotide, while IGF-1R, ERK1/2 and AKT phosphorylation decreased significantly. In contrast, tissue from untreated controls showed no change in cell proliferation or phosphorylation of IGF-1R, AKT or ERK 1/2. Mild to moderate hyperglycemia associated with reduced insulin levels was found. Glucose fell into the normal range after discontinuing treatment. Pasireotide was well tolerated and did not cause symptoms of estrogen deprivation. CONCLUSIONS: IGF-I inhibition by pasireotide, acting through the IGF-1R, was associated with decreased proliferation and increased apoptosis in pre-malignant breast lesions and one DCIS. Assuming hyperglycemia can be controlled, these data suggest that inhibiting the IGF-I pathway may prove an effective alternative for breast cancer chemoprevention. TRIAL REGISTRATION: NCT01372644 Trial date: July 1, 2007.

Expert consensus document: A consensus on the medical treatment of acromegaly.

In March 2013, the Acromegaly Consensus Group met to revise and update guidelines for the medical treatment of acromegaly. The meeting comprised experts skilled in the medical management of acromegaly. The group considered treatment goals covering biochemical, clinical and tumour volume outcomes, and the place in guidelines of somatostatin receptor ligands, growth hormone receptor antagonists and dopamine agonists, and alternative modalities for treatment including combination therapy and novel treatments. This document represents the conclusions of the workshop consensus.

A panoramic view of the skull base: systematic review of open and endoscopic endonasal approaches to four tumors.

Endoscopic endonasal surgery has been established as the safest approach to pituitary tumors, yet its role in other common skull base lesions has not been established. To answer this question, we carried out a systematic review of reported series of open and endoscopic endonasal approaches to four major skull base tumors: olfactory groove meningiomas (OGM), tuberculum sellae meningiomas (TSM), craniopharyngiomas (CRA), and clival chordomas (CHO). Data from 162 studies containing 5,701 patients were combined and compared for differences in perioperative mortality, gross total resection (GTR), cerebrospinal fluid (CSF) leak, neurological morbidity, post-operative visual function, post-operative anosmia, post-operative diabetes insipidus (DI), and post-operative obesity/hyperphagia. Weighted average rates for each outcome were calculated using relative study size. Our findings indicate similar rates of GTR and perioperative mortality between open and endoscopic approaches for all tumor types. CSF leak was increased after endoscopic surgery. Visual function symptoms were more likely to improve after endoscopic surgery for TSM, CRA, and CHO. Post-operative DI and obesity/hyperphagia were significantly increased after open resection in CRA. Recurrence rates per 1,000 patient-years of follow-up were higher in endoscopy for OGM, TSM, and CHO. Trends for open and endoscopic surgery suggested modest improvement in all outcomes over time. Our observations suggest that endonasal endoscopy is a safe alternative to craniotomy and may be preferred for certain tumor types. However, endoscopic surgery is associated with higher rates of CSF leak, and possibly increased recurrence rates. Prospective study with long-term follow-up is required to verify these preliminary observations.

Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension study.

Pasireotide has a broader somatostatin receptor binding profile than other somatostatin analogues. A 16-week, Phase II trial showed that pasireotide may be an effective treatment for acromegaly. An extension to this trial assessed the long-term efficacy and safety of pasireotide. This study was an open-label, single-arm, open-ended extension study (primary efficacy and safety evaluated at month 6). Patients could enter the extension if they achieved biochemical control (GH ≤ 2.5 µg/L and normal IGF-1) or showed clinically relevant improvements during the core study. Thirty of the 60 patients who received pasireotide (200-900 µg bid) in the core study entered the extension. At extension month 6, of the 26 evaluable patients, six were biochemically controlled, of whom five had achieved control during the core study. Normal IGF-1 was achieved by 13/26 patients and GH ≤ 2.5 µg/L by 12/26 at month 6. Nine patients received pasireotide for ≥24 months in the extension; three who were biochemically controlled at month 24 had achieved control during the core study. Of 29 patients with MRI data, nine had significant (≥20%) tumor volume reduction during the core study; an additional eight had significant reduction during the extension. The most common adverse events were transient gastrointestinal disturbances; hyperglycemia-related events occurred in 14 patients. Twenty patients had fasting plasma glucose shifted to a higher category during the extension. However, last available glucose measurements were normal for 17 patients. Pasireotide has the potential to be an effective, long-term medical treatment for acromegaly, providing sustained biochemical control and significant reductions in tumor volume.

Prospective safety surveillance of GH-deficient adults: comparison of GH-treated vs untreated patients.

CONTEXT: In clinical practice, the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown. OBJECTIVE: The objective of this study was to compare adverse events (AEs) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement. DESIGN AND SETTING: This was a prospective observational study in the setting of US clinical practices. PATIENTS AND OUTCOME MEASURES: AEs were compared between GH-treated (n = 1988) and untreated (n = 442) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate. The standardized mortality ratio was calculated using US mortality rates. RESULTS: After a mean follow-up of 2.3 years, there was no significant difference in rates of death, cancer, intracranial tumor growth or recurrence, diabetes, or cardiovascular events in GH-treated compared with untreated patients. The standardized mortality ratio was not increased in either group. Unexpected AEs (GH-treated vs untreated, P ≤ .05) included insomnia (6.4% vs 2.7%), dyspnea (4.2% vs 2.0%), anxiety (3.4% vs 0.9%), sleep apnea (3.3% vs 0.9%), and decreased libido (2.1% vs 0.2%). Some of these AEs were related to baseline risk factors (including obesity and cardiopulmonary disease), higher GH dose, or concomitant GH side effects. CONCLUSIONS: In GH-deficient adults, there was no evidence for a GH treatment effect on death, cancer, intracranial tumor recurrence, diabetes, or cardiovascular events, although the follow-up period was of insufficient duration to be conclusive for these long-term events. The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement.

The pivotal role of insulin-like growth factor I in normal mammary development.

Mammary development begins in puberty in response to an estrogen (E(2)) surge. E(2) does not act alone. It relies on pituitary growth hormone (GH) to induce insulin-like growth factor I (IGF-I) production in the mammary stromal compartment. In turn, IGF-I permits E(2) (and progesterone) action. During puberty, E(2) and IGF-I synergize for ductal morphogenesis. During pregnancy, progesterone joins IGF-I and E(2) to stimulate secretory differentiation necessary to produce milk. Prolactin stimulates milk production, while transforming growth factor-ß inhibits proliferation. The orchestrated action of hormones, growth factors, and receptors necessary for mammary development and function are also critical in breast cancer.

Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline.

OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia. PARTICIPANTS: The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented.

Moderate doses of hGH (0.64 mg/d) improve lipids but not cardiovascular function in GH-deficient adults with normal baseline cardiac function.

CONTEXT: Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient (GHD) adults are limited. OBJECTIVES: The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults. DESIGN: The study was a 6-month double-blind, placebo-controlled randomized trial. SETTING: The study was conducted at the General Clinical Research Center. PARTICIPANTS: Thirty hypopituitary adults with GHD were studied. INTERVENTION: Subjects were randomized to recombinant human GH or placebo for 6 months, followed by open-label recombinant human GH for 12 months. MAIN OUTCOME MEASURES: Primary endpoints were exercise duration, maximal oxygen consumption, and left ventricular ejection fraction. Secondary endpoints were echocardiographic indices of systolic and diastolic function, left ventricular mass, lipids, and body composition. RESULTS: In the 6-month double-blind phase, mean GH dose was 0.64 mg/d. Mean IGF-I sd score increased from -4.5 to -1.0. Exercise duration, maximal oxygen consumption, left ventricular ejection fraction, and other echocardiographic parameters were normal at baseline and did not change. GH decreased total and low-density lipoprotein cholesterol by 7.5% (P = 0.016) and 14.7% (P = 0.002) (P = 0.04 vs. placebo). Mean lean body mass increased by 2.2 kg (P = 0.004), fat mass decreased by 1.7 kg (P = 0.21), and percent body fat decreased by 2.5% (P = 0.018), although between-group changes were not significant. CONCLUSIONS: Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol, increased IGF-I, and increased lean body mass. These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment.

Pasireotide, an IGF-I action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia.

Mammary hyperplasia increases breast cancer risk. Tamoxifen prevents breast cancer in women with atypical hyperplasia, but has serious side effects. As estradiol action requires IGF-I, direct inhibition of IGF-I action theoretically might be an efficacious alternative to tamoxifen. After hypophysectomy and oophorectomy, 21-day-old female rats were treated with GH and E2. After 7 days all terminal end buds (TEBs) and 75% of ducts became hyperplastic. Co-treatment with pasireotide, a somatostatin analog that blocks GH secretion and IGF-I action in the mammary gland, prevented hormone-induced hyperplasia. The number and size of TEBs and moderately or floridly hyperplastic ducts was reduced by pasireotide (P < 0.01). In contrast, the same concentration of octreotide, which has a more selective somatostatin receptor subtype binding profile, was less effective than pasireotide. Tamoxifen inhibited hyperplasia when used alone with GH + E2, but did not add to the inhibitory effect of pasireotide when the two treatments were combined. Both pasireotide and tamoxifen acted via the IGF-I receptor signaling pathway and both were found to inhibit mammary cell proliferation and stimulate apoptosis. The number of epithelial cells expressing phosphorylated insulin receptor substrate (IRS)-1 in response to GH and E2 was reduced by pasireotide, as was staining intensity. These results support the concept that IGF-I inhibition, in this case by pasireotide, inhibits E2 and GH-induced mammary hyperplasia. As tamoxifen did not further increase the inhibitory effect of pasireotide, the peptide appears to be at least as effective as tamoxifen in preventing GH + E2-induced mammary hyperplasia.

Prevalence of metabolic syndrome in adult hypopituitary growth hormone (GH)-deficient patients before and after GH replacement.

CONTEXT AND OBJECTIVE: Metabolic and body compositional consequences of GH deficiency (GHD) in adults are associated with a phenotype similar to the metabolic syndrome (MetS). PATIENTS: We assessed MetS prevalence in adult GHD patients (n = 2531) enrolled in the Hypopituitary Control and Complications Study. Prevalence was assessed at baseline and after 3 yr of GH replacement in a subset of 346 adult-onset patients. RESULTS: Baseline MetS crude prevalence was 42.3%; age-adjusted prevalence in the United States and Europe was 51.8 and 28.6% (P < 0.001), respectively. In the United States, age-adjusted prevalence was significantly higher (P < 0.001) than in a general population survey. Increased MetS risk at baseline was observed for age 40 yr or older (adjusted relative risk 1.34, 95% confidence interval 1.17-1.53, P < 0.001), females (1.15, 1.05-1.25, P = 0.002), and adult onset (1.77, 1.44-2.18, P < 0.001). In GH-treated adult-onset patients, MetS prevalence was not changed after 3 yr (42.5-45.7%, P = 0.172), but significant changes were seen for waist circumference (62.1-56.9%, P = 0.008), fasting glucose (26.0-32.4%, P < 0.001), and blood pressure (59.8-69.7%, P < 0.001). Significantly increased risk of MetS at yr 3 was associated with baseline MetS (adjusted relative risk 4.09, 95% confidence interval 3.02-5.53, P < 0.001) and body mass index 30 kg/m(2) or greater (1.53, 1.17-1.99, P = 0.002) and increased risk (with a P value < 0.1) for GH dose 600 microg/d or greater (1.18, 95% confidence interval 0.98-1.44, P = 0.088). CONCLUSION: MetS prevalence in GHD patients was higher than in the general population in the United States and higher in the United States than Europe. Prevalence was unaffected by GH replacement, but baseline MetS status and obesity were strong predictors of MetS after GH treatment.

Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions.

Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer chemoprevention by preventing actions of both estrogen and progesterone, especially in women at extremely high risk for developing breast cancer such as BRCA gene 1 or 2 mutations.

IGF-I, GH, and sex steroid effects in normal mammary gland development.

Although the pubertal surge of estrogen is the immediate stimulus to mammary development, the action of estrogen depends upon the presence of pituitary growth hormone and the ability of GH to stimulate production of IGF-I in the mammary gland. Growth hormone binds to its receptor in the mammary fat pad, after which production of IGF-I mRNA and IGF-I protein occurs. It is likely that IGF-I then works through paracrine means to stimulate formation of TEBs, which then form ducts by bifurcating or trifurcating and extending through the mammary fat pad. By the time pubertal development is complete a tree-like structure of branching ducts fills the rodent mammary fat pad. In addition to requiring IGF-I in order to act, estradiol also directly synergizes with IGF-I to enhance formation of TEBs and ductal morphogenesis. Together they increase IRS-1 phosphorylation and cell proliferation, and inhibit apoptosis. In fact, the entire process of ductal morphogenesis, in oophorectomized IGF-I(-/-) knockout female mice, can occur as a result of the combined actions of estradiol and IGF-I. IGF-I also permits progesterone action in the mammary gland. Together they have been shown to stimulate a form of ductal morphogenesis, which is anatomically different from the kind induced by IGF-I and estradiol. Although both progesterone and estradiol synergize with IGF-I by increasing IGF-I action parameters, there must be other, as yet unknown mechanisms that account for the anatomical differences in the different forms of ductal morphogenesis observed (hyperplasia in response to IGF-I plus estradiol and single layered ducts in response to IGF-I plus progesterone).

Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study.

OBJECTIVE: Cabergoline is a dopamine agonist used to treat hyperprolactinaemia. Because hyperprolactinaemia is a significant cause of infertility in women, cabergoline and other dopamine agonists are frequently prescribed to reduce prolactin levels and restore normal menses. They are usually discontinued shortly after the patient becomes pregnant. Although cabergoline has been used to treat hyperprolactinaemia since the mid-1990s, safety data related to maternal and foetal exposure to this agent are still limited. DESIGN: The current prospective, observational study reports on a total of 380 pregnancies. This extends by 154 pregnancies the results of a previously published interim report on the outcomes of 226 pregnancies in women treated with cabergoline up to 1994. MAIN OUTCOME MEASURES: Outcomes examined include the incidence of abortions and premature delivery and the number and types of foetal malformations or abnormalities. RESULTS: Follow-up data were available for 329 pregnancies, including 258 (78%) deliveries and 71 (22%) abortions. Of the 71 reported abortions, 31 (44%) were voluntary, 30 (42%) were spontaneous miscarriages, and nine (13%) were therapeutic. Of the 258 deliveries, 250 (97%) were live deliveries, four (2%) were stillbirths, and the status of delivery was unknown for the remaining four (2%). Of the 250 live deliveries, 193 (77%) were term deliveries (gestational period > 37 weeks), 45 (18%) were preterm deliveries (gestational period < or = 37 weeks), and 62% of the infants had normal birthweights (i.e. 3-4 kg). Neonatal abnormalities were recorded for 23 (9%) of the infants with no apparent pattern in type or severity. CONCLUSION: The results of this study suggest that foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation.