Edition 69 - 2018, July-August / Bibliographic Reviews

Bibliographic Reviews – Ed. 69

Marco A. Rivarola y Alicia Belgorosky

Servicio de Endocrinología, Hospital de Pediatria Garrahan, Buenos Aires, Argentina

For this issue of Endocrinologia Pediatrica On line, we have selected the following publications: 

340

J Clin Endocrinol Metab. 2018 Mar 15. Bilateral Adrenalectomy in Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis. MacKay D1, Nordenström A2,3, Falhammar H1,4,5,6. 1 Department of Endocrinology, Royal Darwin Hospital, Darwin, NT, Australia. 2 Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden. 3 Department of Pediatric Endocrinology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden. 4 Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden. 5 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 6 Menzies School of Health Research, Darwin, NT, Australia.

Abstract

CONTEXT: Management of congenital adrenal hyperplasia (CAH) involves suppression of the hypothalamic-pituitary-adrenal (HPA) axis using supra physiological doses of exogenous glucocorticoids. This can pose a challenge, with Cushing’s syndrome being a frequent complication of adequate suppression. Bilateral adrenalectomy, with subsequent replacement of glucocorticoids and mineralocorticoids at physiological doses, has been proposed as an alternative therapeutic strategy. OBJECTIVE: To review the outcomes following bilateral adrenalectomy for CAH. Data Sources: A systematic search of PubMed/MEDLINE and Web of Science, identifying relevant reports published up to January 10, 2018. Study Selection: Case reports or case series were included if they reported individual patient data in patients with CAH who had undergone bilateral adrenalectomy. Data Extraction: Information regarding the following was extracted: first author, country, sex, age at adrenalectomy, year of adrenalectomy, diagnosis, molecular abnormality, pre- and post-operative biochemistry, pre- and post-operative medications, pre- and post-operative body mass index (BMI), indication for adrenalectomy, surgical technique, gross and microscopic adrenal characteristics, follow-up duration, and short-term as well as long-term post-operative outcomes. Data Synthesis: Forty-eight cases of bilateral adrenalectomy in CAH were identified, with patients aged from four months to 56 years at time of surgery. The most common indication for surgery was inability to control hyper-androgenism/virilization and/or Cushing’s syndrome (n=30, 62%). Most patients (n=34, 71%) reported symptomatic improvement post-operatively, with some cases of short-term (n=5, 10%) and long-term (n=13, 27%) adverse outcomes. Conclusions: Bilateral adrenalectomy in CAH appears to be a reasonable therapeutic option in carefully selected patients who have had unsatisfactory outcomes with conventional medical management.

Comments.

The “CONTEXT” of this Abstract inappropriately states that “Management of congenital adrenal hyperplasia (CAH) involves suppression of the hypothalamic-pituitary-adrenal (HPA) axis using supra-physiological doses of exogenous glucocorticoids”. It is true that exogenous medications can never exactly reproduce “in vivo” physiologic secretions (timing and metabolism of adrenal secretions), but this is much more complex that merely a “supra-physiological dose”. Management can prove frustrating for clinicians and patients, because the glucocorticoid doses required for adequate HPA axis suppression might lead to iatrogenic Cushing syndrome. The aim of the present systematic review and meta-analysis was to clarify the outcomes of bilateral adrenalectomy in the management of CAH.

A systematic search of PubMed/MEDLINE and Web of Science was conducted to identify relevant reports published up to 10 January 2018. Patient age at bilateral adrenalectomy ranged from 4 months to 56 years, with fairly even numbers undergoing surgery in childhood or adolescence (age

Iatrogenic Cushing syndrome was also a common primary indication (n = 10; 21%), with 14 patients (29%) having both hyperandrogenism and Cushing syndrome listed as indications for surgery. These indications accounted for a greater proportion of children and adolescents undergoing bilateral adrenalectomy (n = 21; 81%) compared with adults (n = 9; 41%; P = 0.004).

Infertility was the indication for bilateral adrenalectomy in three women (6%). Eight patients (17%) underwent adrenalectomy because of bilateral adrenal enlargements causing mass symptoms or concern for tumor formation; five of these patients had a history of nonadherence with medical therapy. Five patients (10%), all with 11OHD, had undergone bilateral adrenalectomy for management of refractory hypertension. The mean daily HCE was reduced by 12 mg (from 38mg to 26 mg; 32%; P = 0.02) after adrenalectomy. The mean daily fludrocortisone dose was unchanged.

The median 17OHP was reduced by 91% after bilateral adrenalectomy.  Androstenedione was 96% lower postoperatively, and testosterone was reduced by 87%. No substantial change was found in adrenocorticotropic hormone, dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEAS) levels postoperatively. Most patients (74%) reported symptomatic improvement after adrenalectomy. This included improvements in features of hyperandrogenism, recommencement of menses or onset of menarche, increased growth velocity, and improvements in Cushingoid features, in particular, weight loss. The mean body mass index was reduced from 29 kg/m2 preoperatively to 27 kg/m2 postoperatively (P = 0.01). Ten case reports specifically reported patient or parental satisfaction and/or improvements in body image.

Adrenal crises. Eight patients (17%) developed adrenal crises after adrenalectomy. This corresponded to 14.8 adrenal crises per 100 patient-years. Five of the eight patients were children or adolescents). The adrenal crises in four patients were precipitated by infection, and one patient developed an adrenal crisis after extraction of a wisdom tooth. Most of the affected patients experienced a single episode in the reported follow-up period, with no subsequent crises after adjustment of the glucocorticoid dosage and emphasis on sick day management. Two girls, aged 1.3 and 8.1 years at bilateral adrenalectomy, experienced adrenal crises complicated by hypoglycemic seizures. Both instances occurred in the setting of infection, with the younger girl having a nonspecific febrile illness and the elder having acute gastroenteritis. Neither child had any further reported episodes of crisis. The elder subsequently developed epilepsy with an ongoing need for antiepileptic therapy. Five patients required subsequent surgery to remove ectopic adrenal rest tumors. Four cases occurred in girls aged 10 to 16 years at adrenalectomy, presenting with recurrence of hyperpigmentation and features of hyperandrogenism and/or amenorrhea. The interval to presentation ranged from 1 to 16 years after adrenalectomy. One case occurred in a boy with 11OHD (karyotype 46XX) who had undergone bilateral adrenalectomy at age 15 years for management of refractory hypertension; five adrenal rest tumors in the abdomen and pelvis were removed 1 year after adrenalectomy.

The results of this systematic review have confirmed the safety of the procedure, with low rates of perioperative morbidity for both open and laparoscopic approaches. With advances in perioperative management in recent decades, it appears that the risk of mortality is very low. Perioperative morbidity was also low, with no evidence of long-term sequelae. The present systematic review and meta-analysis have demonstrated improvement in clinical and biochemical. parameters after bilateral adrenalectomy for CAH, along with the safety of the procedure, indicating this is a reasonable therapeutic option for appropriately selected patients with unsatisfactory outcomes with conventional medical therapy. Care must be taken to emphasize the importance of appropriate management of glucocorticoid therapy, especially in the setting of intercurrent illness. Long-term monitoring for the recurrence of features of hyperandrogenism is essential, with their occurrence indicating possible activation of ectopic adrenal rest tissue, which should prompt appropriate biochemical and imaging assessments.

341

J Clin Endocrinol Metab. 2018 May 1;103(5):1985-1996. doi: 10.1210/jc.2017-02585.

Altered MicroRNA Profile in Osteoporosis Caused by Impaired WNT Signaling. Riikka E. Makitie,1 Matthias Hackl,2 Riitta Niinimaki,3 Sakari Kakko,4 Johannes Grillari5 and Outi Makitie1,6,7

1Folkha lsan Institute of Genetics and University of Helsinki, FI-00290 Helsinki, Finland; 2TAmiRNA GmbH, 1190 Vienna, Austria; 3Department of Children and Adolescents, Oulu University Hospital, and PEDEGO Research Unit, University of Oulu, FI-90220 Oulu, Finland; 4Internal Medicine and Clinical Research Center, University of Oulu, FI-90220 Oulu, Finland; 5Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, University of Natural Resources and Life Sciences Vienna, 1190 Vienna, Austria;  Children’s Hospital, University of Helsinki and Helsinki University Hospital, FI-00290 Helsinki, Finland; and 7Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.

Abstract

CONTEXT: WNT signaling is fundamental to bone health, and its aberrant activation leads to skeletal pathologies. The heterozygous missense mutation p.C218G in WNT1, a key WNT pathway ligand, leads to severe early-onset and progressive osteoporosis with multiple peripheral and spinal fractures. Despite the severe skeletal manifestations, conventional bone turnover markers are normal in mutation-positive patients. OBJECTIVE: This study sought to explore the circulating microRNA (miRNA) pattern in patients with impaired WNT signaling.

DESIGN AND SETTING: A cross-sectional cohort study at a University Hospital.

PARTICIPANTS: Altogether, 12 mutation-positive (MP) subjects (median age, 39 years; range, 11 to 76 years) and 12 mutation-negative (MN) subjects (35 years; range, 9 to 59 years) from two Finnish families with WNT1 osteoporosis due to the heterozygous p.C218G WNT1 mutation. METHODS AND MAIN OUTCOME MEASURE: Serum samples were screened for 192 miRNAs using quantitative polymerase chain reaction. Findings were compared between WNT1 MP and MN subjects. RESULTS: The pattern of circulating miRNAs was significantly different in the MP subjects compared with the MN subjects, with two upregulated (miR-18a-3p and miR-223-3p) and six downregulated miRNAs (miR-22-3p, miR-31-5p, miR-34a-5p, miR-143-5p, miR-423-5p, and miR-423-3p). Three of these (miR-22-3p, miR-34a-5p, and miR-31-5p) are known inhibitors of WNT signaling: miR-22-3p and miR-34a-5p target WNT1 messenger RNA, and miR-31-5p is predicted to bind to WNT1 30 UTR. CONCLUSIONS: The circulating miRNA pattern reflects WNT1 mutation status. The findings suggest that the WNT1 mutation disrupts feedback regulation between these miRNAs and WNT1, providing insights into the pathogenesis of WNT-related bone disorders. These miRNAs may have potential use in the diagnosis and treatment of osteoporosis.

Comments

In addition to key regulatory pathways and endocrine factors, microRNAs (miRNAs) have recently emerged as integral modulators of bone metabolism. The canonical WNT/b-catenin pathway is a key regulator of bone metabolism, and defective WNT signaling underlies several monogenic skeletal disorders with low or high bone mass. In 2013, authors research group identified WNT1 as a major regulator of bone mass, as the heterozygous missense mutation p.C218G in WNT1 was shown to decrease activity of the WNT/b-catenin pathway in bone; this resulted in low bone turnover with a decreased number of bone cells and impaired bone formation and consequently low bone mass and skeletal fragility.

The mutation was first reported in a large Finnish family exhibiting severe early onset osteoporosis, multiple peripheral and spinal compression fractures, and subsequent loss in adult height. Despite the low BMD and major skeletal pathology, the conventional bone biomarkers currently in clinical use, such as alkaline phosphatase, the bone formation marker N terminal propeptide of type I procollagen, and the bone resorption marker type I collagen cross-linked N-telopeptide, did not differ between WNT1 mutation-positive and mutation-negative individuals.

Recent research found that circulating miRNAs are promising new markers in various diseases, including malignancies, as many conventional biomarkers have shown limitations in diagnostics and in evaluating treatment outcomes. Regarding bone health and disease, current conventional metabolic bone markers are inadequate in reflecting bone health status, predicting future fracture risk, or monitoring treatment efficacy. Circulating miRNAs show promise as future bone markers, as specific miRNAs that discriminate [e.g., patients with manifest osteoporosis have also influenced bone metabolism in vitro and in vivo. This suggests that circulating miRNA based biomarkers might have causal links to the disease phenotype, as miRNAs packaged in extracellular vesicles or in protein particles can be taken up by recipient cells in an auto-, para-, or even endocrine manner.

Authors concluded that a unique miRNA profile was observed in WNT1 mutation-positive individuals compared with healthy individuals. These observations provide valuable information about the molecular pathways involved in WNT1 osteoporosis and the effect of aberrant WNT signaling on miRNA expression. These data also support an association between WNT1 and miR-31-5p and miR-423-3p expression. The specific miRNAs highlighted in this study could serve as circulating metabolic bone markers in WNT1 osteoporosis to evaluate bone health, fracture healing, and treatment efficacy in affected individuals. Authors finally state that additional, studies are necessary to explore these specific miRNAs in other WNT pathway-related skeletal diseases, their response to anti-osteoporosis treatment, and their potential utilization in the development of osteoporosis treatment.

341

J Clin Endocrinol Metab. 2018 May 1;103(5):1985-1996. doi: 10.1210/jc.2017-02585.

Altered MicroRNA Profile in Osteoporosis Caused by Impaired WNT Signaling. Mäkitie RE1Hackl M2Niinimäki R3Kakko S4Grillari J5Mäkitie O1,6,7. 1 Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland. 2 TAmiRNA GmbH, Vienna, Austria. 3 Department of Children and Adolescents, Oulu University Hospital, and PEDEGO Research Unit, University of Oulu, Oulu, Finland. 4 Internal Medicine and Clinical Research Center, University of Oulu, Oulu, Finland. 5 Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, University of Natural Resources and Life Sciences Vienna, Vienna, Austria. 6 Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 7 Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Abstract

CONTEXT: WNT signaling is fundamental to bone health, and its aberrant activation leads to skeletal pathologies. The heterozygous missense mutation p.C218G in WNT1, a key WNT pathway ligand, leads to severe early-onset and progressive osteoporosis with multiple peripheral and spinal fractures. Despite the severe skeletal manifestations, conventional bone turnover markers are normal in mutation-positive patients. OBJECTIVE: This study sought to explore the circulating microRNA (miRNA) pattern in patients with impaired WNT signaling.

DESIGN AND SETTING: A cross-sectional cohort study at a university hospital.

PARTICIPANTS: Altogether, 12 mutation-positive (MP) subjects (median age, 39 years; range, 11 to 76 years) and 12 mutation-negative (MN) subjects (35 years; range, 9 to 59 years) from two Finnish families with WNT1 osteoporosis due to the heterozygous p.C218G WNT1 mutation. METHODS AND MAIN OUTCOME MEASURE: Serum samples were screened for 192 miRNAs using quantitative polymerase chain reaction. Findings were compared between WNT1 MP and MN subjects. RESULTS: The pattern of circulating miRNAs was significantly different in the MP subjects compared with the MN subjects, with two upregulated (miR-18a-3p and miR-223-3p) and six downregulated miRNAs (miR-22-3p, miR-31-5p, miR-34a-5p, miR-143-5p, miR-423-5p, and miR-423-3p). Three of these (miR-22-3p, miR-34a-5p, and miR-31-5p) are known inhibitors of WNT signaling: miR-22-3p and miR-34a-5p target WNT1 messenger RNA, and miR-31-5p is predicted to bind to WNT1 3’UTR. CONCLUSIONS: The circulating miRNA pattern reflects WNT1 mutation status. The findings suggest that the WNT1 mutation disrupts feedback regulation between these miRNAs and WNT1, providing insights into the pathogenesis of WNT-related bone disorders. These miRNAs may have potential in the diagnosis and treatment of osteoporosis.

Comments.

In bone, miRNAs regulate both osteogenesis during fetal development and maintenance of bone health postnatally. In vitro studies further demonstrated their direct role in the regulation of osteoblast and osteoclast development, maturation, and function. Furthermore, some clinical studies suggest that expression levels of different miRNAs are associated with idiopathic and postmenopausal osteoporosis, correlate with bone mineral density (BMD), and differentiate between patient cohorts. The canonical WNT/b-catenin pathway is a key regulator of bone metabolism, and defective WNT signaling underlies several monogenic skeletal disorders with low or high bone mass. In 2013, authors´ research group identified WNT1 as a major regulator of bone mass, as the heterozygous missense mutation p.C218G in WNT1 was shown to decrease activity of the WNT/b-catenin pathway in bone; this resulted in low bone turnover with a decreased number of bone cells and impaired bone formation and consequently low bone mass and skeletal fragility.

Data on miRNA expression and circulating miRNA levels in genetic bone diseases are scarce. In patients with altered WNT signaling, the miRNA profiles, the potential roles of the miRNAs in disease pathogenesis, the clinical diagnostics, and the follow-up remain unknown and unexplored. To gain more insight into the clinical relevance of miRNAs in inherited bone diseases with defective WNT signaling, authors assessed miRNA profiles in subjects with a heterozygous WNT1 mutation and their mutation-negative family members.

They previously identified two large Finnish families with autosomal dominant WNT1 osteoporosis. The first family (Family A) was identified in 2013 when the heterozygous missense mutation p.C218G in WNT1 was determined by linkage analysis and targeted sequencing to be the cause of severe early-onset osteoporosis in 10 affected family members. Subsequently they offered genetic screening to all first-degree relatives at risk, and, since then, 21 additional mutation-positive individuals in Family A have thus far been identified.

When the whole WNT1 gene was Sanger sequenced for 250 other Finnish index patients with osteoporosis, a second family (Family B) was found to harbor the exact same point mutation. In this family, four subjects have so far been found to harbor the same mutation. Hence, to date, altogether 25 mutation-positive subjects with the heterozygous p.C218G have been identified in Finland.

For this study, a control group with similar age and sex distributions was formed by also offering the mutation-negative subjects in Family A (n = 29) and Family B (n = 3) the opportunity to participate. Altogether, 17 mutation-positive and 18 mutation negative individuals consented miRNA analysis:

Clinical and biochemical characteristics: They recruited study subjects from two families with autosomal dominant WNT1 osteoporosis. They screened a custom-designed panel of 192 miRNAs and compared the results from 12 mutation positive (MP) subjects with those from 12 mutation negative (MN) subjects. Results show that a unique profile of eight miRNAs differentiated between MP and MN subjects, and that three of these miRNAs, miR-22-3p, miR-34a-5p, and miR-31-5p, were downregulated in the serum of MP subjects. All three miRNAs were known inhibitors of WNT signaling, and miR-22-3p and miR-34a-5p have been shown to target WNT1 specifically.

Authors concluded that a unique miRNA profile was observed in WNT1 mutation-positive individuals compared with healthy individuals. These observations provide valuable information about the molecular pathways involved in WNT1 osteoporosis and the effect of aberrant WNT signaling on miRNA expression. These data also support an association between WNT1 and miR-31-5p and miR-423-3p expression. The specific miRNAs highlighted in this study could serve as circulating metabolic bone markers in WNT1 osteoporosis to evaluate bone health, fracture healing, and treatment efficacy in affected individuals.

 

 

342

Pituitary. 2017 Aug; 20(4):430-440. doi: 10.1007/s11102-017-0802-1.

Surgical outcomes in patients with Cushing’s disease: the Cleveland Clinic experience. Johnston PC1,2Kennedy L3, Hamrahian AH3,4Sandouk Z3, Bena J5, Hatipoglu B3, Weil RJ6,7. 1 Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, 9500 Euclid Avenue Desk F20, Cleveland, OH, 2 Regional Center for Endocrinology and Diabetes, Royal Victoria Hospital, Grosvenor Road, Belfast, UK. 3 Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, 9500 Euclid Avenue Desk F20, Cleveland, OH, Department of Endocrinology, Cleveland Clinic, Abu Dhabi, Abu Dhabi, United Arab Emirates. 5 Department of Biostatistics, Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA. 6 Department of Neurosurgery, the Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. 7 National Clinical Enterprise, Catholic Health Initiatives, Englewood, CO, USA.

Abstract

CONTEXT: Trans-sphenoidal surgery (TSS), to resect a pituitary adenoma, is considered a first-line treatment for patients with Cushing’s disease (CD). Early, post-operative remission rates >80% are expected for patients with a micro-adenoma (≤ 10 mm) visible on magnetic resonance (MR) imaging. OBJECTIVE: To report surgical outcomes and predictors of remission in a specialist center for patients with CD. PATIENTS AND METHODS: Clinical data were obtained from a prospective CD database in addition to review all electronic medical, laboratory and surgical patient records. Patients who underwent their first TSS by one neurosurgeon between 2004 and 2013, and had a minimum of 1 year follow up, were evaluated. RESULTS: One hundred and one consecutive patients with CD (73F, 28M) underwent TSS. Median (range) age and follow-up were 47 (15-87) and 4.33 (1-9.8) years, respectively. At surgery, 74 (73.2%) patients had a microadenoma, 27 a macroadenoma; six of the latter patients had a planned, subtotal resection to control neurological signs due to mass effect. Initial remission rates were: microadenoma, 89% (66/74); macroadenoma, 63% (17/27); and 81% (17/21) in those macroadenomas where complete surgical removal was anticipated. Initial non-remission occurred in 18 patients, ten macro- and eight microadenoma; six of 18 had residual disease on most recent follow up. Six (2 macro, 4 micro) of the 83 patients with initial remission have had late (>12 months) recurrence of hypercortisolism that required either repeat TSS or adjunctive therapy, three of whom have persistent hypercortisolism. Macroadenoma (p = 0.003) and tumor invasion beyond the pituitary and sella (p < 0.001) were associated with failure to obtain remission with the initial TSS and greater likelihood of late recurrence. Patients in whom no lesion was seen on neuroimaging, had rates of initial remission (21/25 or 84%) and a similar late recurrence rate of 4% (1/25) in comparison with those with MR-visible microadenomas (3/49, or 6%). CONCLUSIONS: A team-based approach, in a specialized pituitary center, can lead to initial and durable, long-term remission in patients with CD. The presence of a macroadenoma and tumor extension beyond the pituitary and sella were predictive of initial non-remission as well as risk of late recurrence.

Comments

Cushing’s disease (CD) is uncommon and results from excess cortisol due to hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary gland tumor.

This is a report of trans-sphenoidal surgical outcomes and predictors of remission in the Cleveland Clinic for 101 patients with Cushing disease (74 micro-adenomas), aged 15-87 years. Patients were followed up for 1-9.8 years after pituitary adenoma resection. Authors reported that pituitary imaging revealed that median pituitary adenoma size was 7 mm (range 2–43 mm). Pre-operative magnetic resonance (MR) imaging identified a pituitary adenoma in 76/101 patients (75%); 49 of the 74 microadenomas identified at surgery were visualized on MR.

Five patients had an ectopic ACTH-secreting pituitary adenoma: two were located wholly within the anterior or lateral aspect of the sphenoid sinus, without connection to the sella; one was located wholly above the diaphragm sella without connection to the adenohypophysis; and two were located completely in the neurohypophysis. Inferior petrosal sinus sampling (IPSS) was performed in 53 of the 74 patients with microadenomas; a central/peripheral (C/P) ACTH gradient was present in 51. The two patients with no gradient on IPSS had ectopic ACTH secreting pituitary adenomas located within the sphenoid sinus.

Of the 18 with persistent disease after first TSS, 12 were in remission at most recent follow up and six had residual disease (3 macroadenomas, 3 microadenomas). In contrast, among 83 patients with initial remission, six (2 macroadenomas, 4 microadenomas) have had recurrence of signs and symptoms of CD, with biochemical confirmation of recrudescent disease. In these six patients, the following have been done subsequently: three had repeat TSS (2 microadenomas at 35 and 91 months, respectively, after initial TSS; 1 with a macroadenoma had a second surgery 16 months after initial TSS, but at a different center). The two patients with microadenomas in whom the re-operation was done at Cliveland Center, are currently in remission. The third patient with a macroadenoma received the second surgery elsewhere and had subsequent radiotherapy for persistent disease. Finally, three out of six patients had initial remission followed by disease recurrence. but did not have repeat TSS: one patient with a macroadenoma had SRS radiotherapy at 58 months after initial TSS (now in remission, at most recent follow up, 81 months later); one had bilateral adrenalectomy, 18 months after initial TSS, with remission; and the last patient remains on medical therapy, with control of hypercortisolism.

343.

J Clin Endocrinol Metab 103: 1258–1264, 2018

Treatment Options for Hirsutism: A Systematic Review and Network Meta-Analysis. Patricia Barrionuevo,1,2* Mohammed Nabhan,1,3* Osama Altayar,1,4* Zhen Wang,1 Patricia J. Erwin,1,5 Noor Asi,1,6 Kathryn A. Martin,7 and M. Hassan Murad1

1 Mayo Clinic Evidence-based Practice Center, Mayo Clinic, Rochester, Minnesota 55905; 2 Unidad de Conocimiento y Evidencia, Universidad Peruana Cayetano Heredia, 15102 Lima, Peru; 3 Internal Medicine Department, Saint Joseph Mercy Health System, Ypsilanti, Michigan 48197; 4 Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri 63110; 5 Mayo Clinic Libraries, Mayo Clinic, Rochester, Minnesota 55905; 6 Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut 1107 2020, Lebanon; and 7 Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.

Abstract

BACKGROUND: Several pharmacologic treatments for hirsutism are used in practice; however, their relative efficacy is unclear. METHODS: Authors searched MEDLINE, EMBASE, and CENTRAL through January 2017 for randomized controlled trials (RCTs) with follow-up of at least 6 months that evaluated antiandrogens, insulin sensitizers, and oral contraceptives in women with hirsutism. Independent pairs of reviewers selected and appraised trials. Random-effects network meta-analysis was used to compare individual drugs and classes. RESULTS: They included 43 trials. Estrogen-progestin oral contraceptives pills (OCPs), antiandrogens, and insulin sensitizers were superior to placebo, with standardized mean reductions (95% confidence intervals) of 20.94 (21.49 to 20.38), 21.29 (21.80 to 20.79), and 20.62 (21.00 to 20.23), respectively. Antiandrogen monotherapy, the combination of OCP and antiandrogen, the combination of OCPs and insulin sensitizer, and the combination of antiandrogen and insulin sensitizer were superior to insulin sensitizer monotherapy. The combination of OCPs and antiandrogen was superior to OCPs. Antiandrogen monotherapy with flutamide, finasteride, and spironolactone were each superior to placebo but similar to each other in efficacy. OCPs containing levonorgestrel, cyproterone acetate, or drospirenone were similar in effectiveness to other OCPs or had trivial differences. The certainty in comparisons with placebo was moderate and for head-to-head comparisons was low. CONCLUSIONS: Estrogen-progestin OCPs, antiandrogens, and insulin sensitizers are superior to placebo for the treatment of hirsutism.

Practical implications

Women with mild hirsutism and no evidence of an endocrine disorder may not necessarily require treatment. However, when hirsutism is sufficiently important to women and they seek treatment, several pharmacological therapies are available. OCPs appear to be the first-line therapy, particularly when contraception is desired.

Antiandrogens are effective, but because of their teratogenic potential, they may be more suited for women who are not sexually active, have undergone permanent sterilization, or use long-acting reversible contraception. Combination therapies can be used when women do not respond to a particular agent. Evidence is insufficient to recommend one OCP over another. Women at high risk for venous thromboembolism because of age, obesity, or smoking should consider a non-OCP therapy or use OCPs with the lowest effective dose of ethinyl estradiol and a low-risk progestin. When additional cosmetic benefit is desired, direct hair removal methods (e.g., laser therapy) are additional options.

344

Hum Mutat. 2015 Apr;36(4):474-81. doi: 10.1002/humu.22773.

Heterozygous Mutations in Natriuretic Peptide Receptor-B (NPR2) Gene as a Cause of Short Stature. Wang SR1, Jacobsen CM, Carmichael H, Edmund AB, Robinson JW, Olney RC, Miller TC, Moon JE, Mericq V, Potter LR, Warman ML, Hirschhorn JN, Dauber A. 1Genome Institute of Singapore, Singapore.

Abstract

Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor-B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). Authors enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family. Nine additional rare nonsynonymous NPR2 variants were found in three additional cohorts. Functional studies identified eight loss-of-function mutations in short individuals and one gain-of-function mutation in tall individuals. With these data, they were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature. They estimate a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in people with ISS. They also suggest that NPR2 gain of function may be a more common cause of tall stature than previously recognized.

Comments

C-type natriuretic peptide (CNP, gene natriuretic peptide precursor C, NPPC; MIM# 123830) is a small, secreted peptide and a member of the natriuretic peptide family. CNP binds to a homodimeric transmembrane receptor named natriuretic peptide receptor-B (NPR-B, gene NPR2), which functions as a guanylyl cyclase to generate cGMP in chondrocytes, female reproductive organs, and endothelial cells. In the growth plate chondrocytes, binding of CNP to NPR-B stimulates chondrocyte differentiation and hypertrophy as well as increases matrix synthesis. This occurs in part through NPR-B signaling, inhibiting MAP kinase signaling by FGFR3. Several lines of evidence indicate that CNP/NPR-B signaling is an important regulator of skeletal growth.

NPR2 loss-of-function variants likely account for approximately 0.4–4% of all patients with short stature (height < −2 SD), and should be considered in the diagnostic evaluation of patients presenting with ISS. Interestingly, authors identified NPR2 loss-of-function variants in 13.6% of familial cases, suggesting that such variants will provide a frequent explanation for patients with familial ISS.

 

345

Clin Endocrinol (Oxf). 2018 Jul;89(1):56-64. doi: 10.1111/cen.13722.

Growth hormone-Insulin-hyperactivity on bone fibrous dysplasia in McCune-Albright Syndrome. Tessaris D1, Boyce AM2, Zacharin M3, Matarazzo P1, Lala R1, De Sanctis L1, Collins MT2.

1 Department of Pediatric Endocrinology, Regina Margherita Children’s Hospital, University of Torino, Torino, Italy. 2 Section on Skeletal Disorders and Mineral Homeostasis, NIDCR, NIH, Bethesda, MD, USA. 3 Department of Endocrinology, Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia.

Abstract

CONTEXT: In bone fibrous dysplasia (BFD), normal bone and bone marrow are replaced by fibro-osseous tissue, leading to fracture, deformity and pain. BFD may be isolated, or in association with cutaneous hyperpigmentation and/or hyper-functioning endocrinopathies, termed McCune-Albright  syndrome (MAS). GH hypersecretion has been described in 10%-20% of MAS-BFD patients. An aim of the study was to determine the impact of GH-insulin-like growth factor 1 (IGF-1) axis hyperactivity on MAS-BFD morbidities and the efficacy of GH excess therapy.

DESIGN AND PATIENTS: A multicentric cross-sectional analysis was conducted on three MAS cohorts. From 195 MAS patients, 37 subjects (19%) with GH excess were identified and compared with 34 MAS controls without GH hypersecretion on three different MAS cohorts. RESULTS: Mean head circumference SDS was significantly higher in GH excess: 4.025 SDS vs 0.683 SDS (P < .0001). The risk of optic neuropathy (Odds ratio 4.231; P = .039), hearing deficit (Odds ratio 2.961; P = .0481), facial asymmetry (Odds ratio 6.563; P = .0192), malignancies (Odds ratio 15.24; P = .0173) were higher in GH excess group. Overall, pharmacotherapy (octreotide alone 10-30 mg/mo or with pegvisomant 10-20 mg/d) was effective in IGF1 normalization (IGF1 Z-score between -2 and +2 SDS) in 21/29 patients (72.4%) with good compliance to the regimen. Late diagnosis and GH excess treatment after 16 years old of age was associated with an increased risk of optic neuropathy (Odds ratio 4.500; P = .0491) and growth of pituitary adenomas (Odds ratio 7.846; P = .050). CONCLUSIONS: GH-IGF1 hyperactivity increases risk of morbidities in MAS. Medical therapy is effective in normalizing IGF1 in most patients, and early treatment during pediatric age is associated with a decreased risk of optic neuropathy and GH-secreting adenomas growth.

Comments

Bone fibrous dysplasia/MAS arises from activating mutations in the GNAS gene, which encodes for the α-subunit of the Gs stimulatory protein (Gsα). Mutations occur post-zygotically, leading to mosaic disease with wide variability between individuals. Disease burden is determined by the embryonic stage during which the mutation occurs, and the locations to which mutated progenitors subsequently migrate. Endocrinopathies include gonadotropin-independent precocious puberty resulting from recurrent ovarian cysts in girls and autonomous testosterone production in boys; testicular lesions with or without associated gonadotropin-independent precocious puberty; thyroid lesions with or without non-autoimmune hyperthyroidism; growth hormone (GH) excess; FGF23-mediated phosphate wasting with or without hypophosphatemia; and neonatal hypercortisolism.

The GNAS complex locus [Homo sapiens (human)] has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5′ exons. Approximately 10%-20% of individuals with Bone Fibrous Dysplasia/MAS harbour GNAS mutations in the anterior pituitary that can lead to autonomous GH secretion, typically accompanied by hyperprolactinemia. GH excess in MAS is reported to be associated with possible vision loss, macrocephaly and increased post-operative regrowth after craniofacial surgery. Medical therapy is the preferred first-line treatment: options include (alone or in combination) the somatostatin analog octreotide and the growth hormone receptor antagonist pegvisomant.

A retrospective, multicentric cross-sectional analysis was conducted at National Institutes of Health, NIH, NIDCR, Bethesda, USA; at the Department of Pediatric Endocrinology, Regina Margherita Children Hospital, University of Torino, Italy; and at Pediatric Endocrinology and Diabetology; Royal Children’s Hospital; Parkville, Australia. Three large cohorts affected by MAS were analyzed: 131 patients (50 males and 81 females) from the American cohort, 34 subjects (10 males and 24 females) from the Italian cohort, and 30 patients from the Australian cohort (18 males and 12 females). Treatment embraced octreotide, pegvisomant, transphenoidal surgery and radiotherapy.

In these three cohorts, 37 patients with GH excess were identified (19% of the whole MAS population): 27/131 cases identified from the American cohort (20.6 %), 3/34 cases identified from the Italian cohort (8.8 %), 7/30 from the Australian cohort (23.3 %). Females constituted 37.8% of subjects with GH excess and 56% of the total cases.

Eighteen patients were placed in Group A (Early intervention) while 19 patients in the Group B (Late Intervention). There was a significant difference in age at start of therapy between the 2 groups: 8.000 ± 0.6777 yrs., n=18 vs 20.92 ± 2.445 yrs, n=19 (R squared 0.4138; p < 0.0001).

Authors proposed that, unlike isolated acromegaly, increased height is not a reliable predictive sign, and final height is generally normal, because it is the result of multiple endocrinopathies, in particular precocious puberty and hyperthyroidism, and it depends on the involvement of long bones and vertebral column by fibrous dysplasia.

In these cohorts, patients with GH excess were significantly taller compared to MAS without GH excess, although the mean height was under 2 SDS. Fibrous displasia involving the skull base was present in all patients with GH-IGF axis hyperactivity, so it is an important predictive sign of GH excess, nevertheless it is very common in MAS.

The MAS control group included 33 MAS patients without GH excess (19 males and 14 females) matched for sex, age (mean age at evaluation 20.44 ± 1.852 yrs, n=33, vs 22.52 ± 1.759 yrs, n=37) (p= 0.4184) and total BSS (+-7 scores). Mean height SDS of patients with GH excess was 0.5866 ± 0.3993 SDS (range from -4.86 to 4.85 SDS), which was higher than in MAS controls (mean -1.412 ± 0.3236 SDS, range from -5.29 to 2.41 SDS; p= 0.0003).

Overall, pharmacotherapy (ocreotide 10-30 mg/month or with pegvisomant 10-20 mg/day) was effective in IGF1 normalization (-2SDS<IGF1< +2SDS) in 21/29 patients (72.4%) with good compliance with the regimen. Post-treatment IGF1 SDS were significantly reduced: mean pre-therapy 4.260 ± 0.9246 SDS (n=29) vs mean post-therapy 0.7264 ± 0.3370 SDS (n=29) (p=0.0009).

They analyzed impact of early medical therapy for GH hypersecretion in the paediatric age group (under 16 years of age) respect to late treatment group. Odds ratio of optic neuropathy for late treatment was 4.5: 9/19 patients (47.36%) in the late intervention group compared with 3/18 patients (16.66%) in early intervention group (p= 0.0491). In the late treatment group there was a trend toward increased risk for hearing deficit (Odds ratio 1.746; p=0.5148), facial asymmetry (Odds ratio 7.00, p= 0.2342), dental malocclusion (Odds ratio 2.857, p= 0.4048) and tumour development (Odds ratio 3.692, p= 0.2320), however this did not reach statistical significance.

Medical therapy appeared to be effective at preventing growth of pituitary adenomas growth: macroadenomas were identified in 6/19 subjects in the late therapy group compared with 1/18 subjects in early therapy group (Odds ratio 7.846; p= 0.050).

GH hypersecretion diagnosis, random GH and basal IGF1 investigations are mandatory and are used for routine screening; however, when the basal tests are not conclusive and the clinical suspicion is high, overall in patients with progressive craniofacial asymmetry, GH suppression test and frequent overnight GH sampling can be utilized as confirmatory tests. Pituitary MRI is not useful for the diagnosis because the absence of adenomas does not exclude diffuse somatolactotroph hyperplasia: in half of cases imaging was normal or diffuse enhancement on T1 weighted was identified.

The pathogenesis of bone fibrous dysplasia (BFD) expansion is related to stromal cell proliferation and osteoclast invasion of normal areas of bone. In acromegalic patients without MAS, GH excess leads to linear growth of bones, including craniofacial bones, through IGF1 effects on bone forming mesenchymal cells. Expansion of BFD in MAS has got an exponential growth because is the result of a combination of Gs-alpha hyperactivation and IGF1 overproduction.

Octreotide alone was effective in IGF1 normalization in half of the patients, while combined therapy with octreotide and pegvisomant was effective in two third of patients. Medical therapy significantly decreases risk of optic neuropathy and growth of pituitary adenomas, when it was performed during pediatric age, demonstrating that somatostatin analogs with or without GH receptor antagonist represent an effective first line treatment for MAS GH excess. Pituitary surgery is technically difficult in patients with MAS, due to thickness of the cranial dysplasia of the skull base, particularly for sphenoid sinus obliteration with a high risk of hemorrhage given the high vascularity of BFD.

Medical therapy significantly decreases risk of optic neuropathy and growth of pituitary adenomas, when it was performed during paediatric age, demonstrating that somatostatin analogs with or without GH receptor antagonist represent an effective first line treatment for MAS GH excess. Pituitary surgery is technically difficult in patients with MAS, due to thickness of the cranial dysplasia of the skull base, particularly for sphenoid sinus obliteration with a high risk of hemorrhage given the high vascularity of BFD.

This study further points out that GH-IGF1 hyperactivity increases risk of morbidities in MAS. The medical therapy in such condition is effective in normalizing IGF1 in most patients, and the early treatment during paediatric age seems to decrease optic neuropathy and GH adenomas growth.


Posted in Edition 69 - 2018, July-August, Bibliographic Reviews
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