David L. Kleinberg

Guidelines for acromegaly management: An update

OBJECTIVE The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. PARTICIPANTS The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. CONCLUSIONS The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.

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.

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

INSULIN-LIKE GROWTH FACTOR I IS ESSENTIAL FOR TERMINAL END BUD FORMATION AND DUCTAL MORPHOGENESIS DURING MAMMARY DEVELOPMENT

Previous studies from this laboratory have emphasized the essential role of GH in pubertal mammary development and shown that insulin-like growth factor I (IGF-I) was capable of substituting for GH in this process in rats and mice. The present study shows that, even when GH is present, no mammary development is possible unless IGF-I is present. IGF-I(−/−) null female animals were found to have significantly less mammary development than age matched wild-type controls (P <0.006) using several endpoints including the number of terminal end buds or TEBs (1.3 vs. 7.3), percent of the fat pad occupied by glandular elements (6.5 vs. 100), and number of ducts (15 vs. too numerous to count). That the deficiency in mammary gland development was related to the absence of IGF-I was underscored by the observation that des (1–3) IGF-I administration to IGF-I(−/−) null animals for 5 days caused significant mammary gland development as measured by TEB formation and branching of ducts. The number of TEBs rose from a mean...

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.

IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis.

Growth hormone (GH)3 is essential for rodent mammary gland development during puberty.It binds to GH receptors in the stromal compartment of the mammary gland and stimulatesIGF-I mRNA expression. These findings lead to the hypothesis that GH acts through locallyproduced IGF-I, which in turn, causes development of terminal end buds (TEBs), the structuresthat lead the process of mammary gland development during puberty. Subsequent studieshave in large measure proven this hypothesis. They include the observations that mammarydevelopment was grossly impaired in female mice deficient in IGF-I (IGF-I(−/−) knockoutmice), and treatment of these mice with IGF-I plus estradiol (E2) restored pubertal mammarydevelopment while treatment with GH + E2 did not. Thus, the full phenotypic action of GHin mammary gland development is mediated by IGF-I. We have demonstrated one effect ofGH on the mammary gland that does not appear to be mediated by the action of IGF-I. GHincreased the level of estrogen receptor (ER) mRNA and protein in the nuclei of mammaryfat pad cells, but IGF-I did not. In addition to the critical role of the GH/IGF-I axis duringpubertal mammary development, other data suggest that IGF-I might also be of importanceduring pregnancy and lactation. In summary, the earliest phase of pubertal mammarydevelopment (formation of TEBs) requires IGF-I or GH in IGF-I sufficient animals. No other hormoneshave been shown to stimulate formation of TEBs unless GH or IGF-I is present. GH-inducedIGF-I is of major importance in ductal morphogenesis, and may, in fact, be necessary for laterstages of mammary development, as well.

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.

Visual Loss in Pregnant Women with Pituitary Adenomas

Pituitary adenomas in women of childbearing age present a potential contraindication to pregnancy because of the risk for developing visual loss during pregnancy as a result of tumor expansion. Earlier reports have not resolved whether patients with macroadenomas are at greater risk than those with microadenomas [1, 2]. Enlargement of an adenoma can be caused by tumor growth or an infarction or hemorrhage of the tumor. In addition, the 70% increase in the volume of the pituitary gland that normally occurs during pregnancy may contribute to the mass effect on the optic apparatus in the suprasellar region [3, 4]. Also, prolactinomas, previously reduced in size by treatment with bromocriptine (a dopamine agonist), may enlarge as soon as the drug is withdrawn, which is frequently done during pregnancy [5]. The advent of high-resolution computed tomography and magnetic resonance imaging made it possible to accurately assess tumor size and study its relation to visual loss during pregnancy [2, 6-11]. Only two previous studies [6, 7] have correlated visual performance with abnormal radiologic test results, using sellar radiograph or tomography findings. We tried to determine whether factors such as tumor size, secretory characteristics, or other clinical features could be used to predict those women with pituitary adenomas who were at risk for developing visual loss during pregnancy. Methods Patients We examined the records of all women with pituitary adenomas who had been evaluated by the New York University neuro-ophthalmology service between 1982 and 1992 and who became pregnant. Sixty-six patients became pregnant who had not had previous surgery or radiation therapy directed at the adenoma (mean age at pregnancy, 30.6 years; range, 21 to 38 years). Except for one patient (patient 3), a diagnosis of pituitary adenoma had been established before referral by endocrinologists or gynecologists for consultation and baseline visual function testing (see vision analysis) during the first trimester or before conception. During pregnancy, a neuro-ophthalmologist (MJK) prospectively repeated visual testing at least once, usually in the third trimester. Missing endocrine data and neuroimaging studies for review were sought by mail and telephone inquiries with the assistance and consent of the patients and referring physicians for all patients. Neuroimaging Analysis High-resolution computed tomography or magnetic resonance imaging (or both) were done in all but two patients before the first pregnancy. Coronal- and axial-oriented images (2.5- to 5.0-mm thick) for computed tomography studies and coronal-, axial-, and sagittal-oriented images (3-mm thick) for magnetic resonance imaging were all evaluated for the presence of an adenoma. On the coronal images, the maximum vertical height (the direction of growth toward the optic chiasm and typically the largest dimension) of the tumor mass was measured. Eight patients had adenomas that were smaller than 0.3 cm and difficult to distinguish from the surrounding pituitary gland. These patients were considered to have an adenoma because of abnormal tilting of the pituitary stalk, asymmetric fullness of a pituitary hemisphere, amenorrhea, infertility, and high levels of serum prolactin. The tumor height in these patients was considered to be zero for the purpose of data analysis. In general, patients with adenomas of 1.0 cm or larger and no visual loss were counseled to avoid pregnancy unless they had previous treatment to decrease the probability of optic structure compression. This may partially explain the small number (eight) of patients with adenomas larger than 1.1 cm in this series. Vision Analysis We prospectively collected data on the visual and ocular motor systems. Before pregnancy, 55 patients had a normal baseline neuro-ophthalmologic examination. Within 3 weeks of the calculated conception date, 10 additional patients were found to have normal vision. Only 1 patient was not examined until the end of the second trimester (patient 3). This patient was included because she had a normal ophthalmologic examination, done by the referring ophthalmologist, 1 year before her pregnancy. The evaluation included the best corrected visual acuity; color vision testing using pseudoisochromatic plates; the evaluation of lid, pupil, and ocular motility functions; and ophthalmoscopy. Visual field measurement was done with tangent or Goldmann perimetry in 52 patients and, in later years (after 1987), with computerized threshold perimetry in 14 patients. Table 1. Cases of Pituitary Adenoma That Were 1.2 cm or Larger Each patient was encouraged to return at yearly intervals if she was not pregnant and during the first trimester if she was pregnant. Patients were examined at least one other time, usually in the last trimester, or more often if a potential problem occurred (such as frequent headaches, visual loss, or concern by the patient or referring doctor). Patients were also instructed to be examined before having a subsequent pregnancy. Visual loss was diagnosed when visual field defects typical of optic nerve or chiasm compression occurred (Figure 1)not when minor degrees of nonspecific threshold elevation were presentwith or without a decrease in acuity or color vision. Figure 1. Visual fields measured by tangent perimetry of patients 1 to 6 are listed (top to bottom) at the time that visual loss occurred during pregnancy. R L Endocrine Studies The patients had no other disorders and were receiving no drugs known to influence prolactin levels at the time of diagnosis [12]. Serum prolactin levels were measured in all 65 patients in the analysis and were increased in 58 (range, 40 g/L to 2000 g/L; normal, 0 to 25 g/L). The prolactin level was greater than 100 g/L in 27 patients. Two patients had acromegaly with serum growth hormone levels of 55.2 g/L and 81.2 g/L (normal <8 g/L) and prolactin levels of 7.8 g/L and 69.8 g/L (patients 6 and 8, respectively). Five patients had data consistent with nonsecretory tumors. In patients diagnosed as having a prolactinoma, bromocriptine mesylate (Parlodel; Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey), 2.5 mg one to three times daily, was prescribed. Although some patients admitted to not taking the bromocriptine, an accurate rate of compliance was not determined. Bromocriptine was stopped at a mean of 4.45 weeks from the calculated date of conception in 56 pregnancies (range, 2 days to 23 weeks). Neither patient with acromegaly received medication before or during pregnancy. The presence of a clinical pregnancy reported by each patient was confirmed by a conventional laboratory pregnancy test [13]. Failure to sustain the pregnancy to term was considered a spontaneous abortion. Examination for fetal tissue was not uniformly done. Data Analysis One patient with a 2.0-cm tumor conceived three times and immediately had medical abortions each time because of her fear of visual loss. Because all her pregnancies were terminated, we omitted data from this patient, leaving 65 patients in the final data analysis. Data were analyzed using simple logistic regression analysis for yes-no outcomes and using simple regression analysis for continuous outcomes. The small sample size precluded the use of any multiple regression procedures. Linear regression [14] data were interpreted by the size and significance of their -coefficients, whereas the logistic regression data [15] were assessed by examination of odds ratios. The odds ratio in such patients was obtained using the -coefficients (an exponential calculation). Confidence intervals (95% CI) accompanied the odds ratio or -coefficient for each condition. A two-tailed Fisher exact test was used to calculate exact P values. All statistical calculations were done using SAS [16]. Results A total of 111 pregnancies was noted. The neuro-ophthalmologic examination showed visual field defects from tumor compression of the anterior visual pathway in six patients during pregnancy (Table 1); five of these patients were in their first pregnancy (patient 3 was first seen during the second trimester). The visual field defects occurred in one eye in one patient and in both eyes in five patients (Figure 1). An incomplete superior temporal quadrantanopia was found in eight eyes of six patients. A complete superior temporal quadrantanopia was found in two eyes of two patients. An incomplete temporal hemianopia (progressed from a partial quadrantanopia) was found in the one patient (patient 3) with decreased visual acuity in one eye. Concomitant with the field loss, the visual acuity was 20/30 or better in eyes from all patients except for one eye of one patient (patient 3), which was 20/80. When patient 3 was first examined by the neuro-ophthalmologist (MJK), the acuity of this eye was 20/30. The color vision was normal in all the eyes except in the 1 patient with decreased acuity in one eye. All of the patients having visual loss had adenomas of 1.2 cm or more. No women developed dysfunction of cranial nerves III, IV, V, or VI, clinical signs of an infarction, or hemorrhage in the pituitary gland or adenoma. No patients had any other signs of central nervous system dysfunction or increased intracranial pressure. Treatment was individualized for each patient with visual loss (Table 1). When treated postpartum with bromocriptine, two patients had normal visual examinations within 3 months. Bromocriptine administered during the last 5 months of pregnancy normalized the vision in one patient (within 3 months). Bromocriptine therapy combined with a therapeutic abortion in one patient led to a return of normal vision (within 1 month). Trans-sphenoidal adenomectomy, done in the third trimester in patient 3 and done postpartum in a second patient, resulted in normal visual function (visual acuity > 20/30, normal color vision, full visual fields) within 4 months. Eight patients had adenomas with a vertical height of 1.2

Early Mammary Development: Growth Hormone and IGF-1

The first step in pubertal mammary development is the appearance of terminal end buds arising from pleuropotent stem cells present in the immature ductal tree of the prepubertal animal. Work from this laboratory indicates that growth hormone is the pituitary hormone responsible for terminal end bud development. Growth hormone likely acts through the production of IGF-1.3 This minireview focuses on the hormonal control of early mammary development with special emphasis on the roles of growth hormone and IGF-1.

Diagnosis and treatment of acromegaly complications

The Pituitary Society in conjunction with the European Neuroendocrine Association held a consensus workshop to develop guidelines for diagnosis and treatment of the co-morbid complications of acromegaly. Fifty nine pituitary specialists (endocrinologists, neurosurgeons and cardiologists) assessed the current published literature on acromegaly complications in light of recent advances in maintaining tight therapeutic control of GH hypersecretion. The impact of elevated GH levels on cardiovascular disease, hypertension, diabetes, sleep apnea, colon polyps, bone disease, reproductive disorders, and neuropsychologic complications were considered. Guidelines are proposed for effective management of these complications in the context of overall acromegaly control. When appropriate, requirements for prospective evidence-based studies and surveillance database development are enunciated. Effective management of co-morbid acromegaly complications will lead to improved morbidity and mortality in acromegaly.