Ernesto Sosa

Clinical and Biochemical Impact of the d3 Growth Hormone Receptor Genotype in Acromegaly

CONTEXT Lack of exon 3 of the GH receptor (d3-GHR) has been associated with increased responsiveness to GH therapy. By analogy, we hypothesized that patients with acromegaly bearing the d3-GHR genotype may have a more morbid clinical and biochemical picture. OBJECTIVE Our objective was to determine whether the GHR genotype, by modifying tissue sensitivity to GH, influences the clinical/biochemical expression of acromegaly and its outcome after treatment. SETTING The study was conducted at a specialized clinic at a tertiary care hospital. DESIGN, PATIENTS, AND METHODS We conducted a prospective genotype investigation and retrospective analysis and correlation with clinical, biochemical, and outcome data from a group of 148 patients. Samples from 175 healthy blood donors were used as controls. GHR genotyping was performed by real-time PCR. MAIN OUTCOME MEASURES We assessed prevalence of the three GHR genotypes (fl/fl, d3/d3, and d3/fl), associations between the genotypes, and baseline as well as post-therapeutic characteristics. RESULTS Prevalence of the fl/fl, d3/d3, and d3/fl genotypes was 45, 22, and 32%, respectively, similar to what was found in the controls. Baseline characteristics were similar in carriers of the three genotypes. A positive correlation between IGF-I and log GH concentrations was significant only in homo- or heterozygous d3 carriers. Among d3-GHR carriers, diabetes, but no other comorbidities, was more prevalent (odds ratio = 2.02; 95% confidence interval = 0.96-4.2). d3-GHR carriers had significantly higher IGF-I concentrations after treatment. Multiple regression analysis revealed that the homo- or heterozygous lack of exon 3 was the strongest predictor of persistent biochemical activity (odds ratio = 1.29; 95% confidence interval = 0.65-2.58). CONCLUSIONS The absence of exon 3 of the GHR may be associated with a more morbid acromegalic clinical and biochemical picture and a lower chance of achieving IGF-I normalization after therapy.

Successful Mortality Reduction and Control of Comorbidities in Patients With Acromegaly Followed at a Highly Specialized Multidisciplinary Clinic

CONTEXT Acromegaly is usually due to the excessive secretion of GH by a pituitary adenoma. It is frequently accompanied by comorbidities that compromise quality of life and results in elevated mortality rates. OBJECTIVE To evaluate mortality and morbidity in patients with acromegaly receiving multimodal care. SETTING Tertiary care center. DESIGN, PATIENTS, AND METHODS Retrospective evaluation of 442 patients (65.4% women; mean age, 43.5 ± 13.1 y) followed for a median of 6 years (interquartile range [IQR], 3-10). RESULTS Twenty-two patients died during the study period (4.9%), representing a total standardized mortality ratio (SMR) of 0.72 (95% confidence interval [CI], 0.41-1.03). Standardized mortality ratios were 1.5 and 0.44 for patients whose last GH was above and below 2.5 ng/mL, respectively; 1.17 and 0.16 for those whose last GH was above and below 1 ng/mL, respectively; and 0.94 and 0.46 for those whose last IGF-1 was above and below 1.2 times the upper limit of normal (ULN), respectively. The prevalence of diabetes mellitus, hypertension, heart disease, and cancer was 30%, 35%, 8%, and 4.7%, respectively. The most common cause of death was cancer. On multivariate analysis, diabetes, heart disease, and cancer were related to a baseline GH > 10 ng/mL; the presence of cancer and the last IGF-1 were significant predictors of mortality. Survival decreased as the latest GH levels increased from < 1 ng/mL to > 5 ng/mL and as IGF-1 increased from < 1.2 to > 2 times the ULN. CONCLUSIONS Mortality in acromegaly can be successfully reduced, provided patients are treated using a multimodal approach with careful management of comorbidities.

Clinical-Biochemical Correlations in Acromegaly at Diagnosis and the Real Prevalence of Biochemically Discordant Disease

Objective: To analyze clinical-biochemical correlations in newly diagnosed acromegaly, focusing in particular on patients with discrepant parameters. Design: Retrospective study. Methods: Data from 164 patients with acromegaly seen between 1995 and 2003. Patients were reviewed for the presence of headaches, arthralgias, hypertension, menstrual abnormalities, impotence, glucose intolerance or diabetes. Biochemical evaluation consisted of age- and gender-adjusted IGF-I levels and glucose-suppressed GH. Results: Magnetic resonance imaging (MRI) revealed macroadenoma in 127 patients and microadenoma in 37. Patients with macroadenomas were younger than those with microadenomas and the disease was more frequent in females. Excluding acral enlargement, which was present in all the patients, the most commonly reported complaints were headaches (66%) and arthralgias (52%). Hypertension was present in 37% of patients, whereas the prevalence of glucose intolerance and diabetes was 27 and 32%, respectively. Hyperprolactinemia was present in 20% of patients with microadenomas and in 40% of patients with macroadenomas. Hypogonadism was demonstrated in more than half of the patients and was not related to tumor size or prolactin level. Of all the clinical and metabolic abnormalities of acromegaly, only the presence of diabetes correlated with both basal and nadir post-glucose GH levels. Only 4 patients (2.4%) had glucose-suppressed GH values of <1 ng/ml in the presence of clinical evidence of acromegaly, an elevated IGF-I level and a pituitary adenoma on MRI. Conclusions: Clinical features of acromegaly correlate poorly with indices of biochemical activity. The prevalence of biochemically discordant acromegaly is considerably lower than recently reported.

Biochemical evaluation of disease activity after pituitary surgery in acromegaly: a critical analysis of patients who spontaneously change disease status.

Background  The definition of biochemical cure in acromegaly involves both the normalization of IGF‐1 and a glucose‐suppressed GH level of < 1 ng/ml. These criteria were reached by several consensus meetings, although no evidence‐based recommendations as to the optimal time to perform biochemical evaluations were made, nor was the fact that several patients may change biochemically upon long‐term follow‐up taken into consideration.

Discontinuation of octreotide LAR after long term, successful treatment of patients with acromegaly: is it worth trying?

BACKGROUND Somatostatin analogs (SA) have been used for over 25 years in the treatment of acromegaly. A major disadvantage is the need to continue therapy indefinitely. OBJECTIVE To evaluate the feasibility of discontinuing therapy in well-controlled patients with acromegaly treated chronically with SA. DESIGN AND METHODS Of the 205 subjects on octreotide LAR, we selected those who met the following criteria: two or more years of treatment, a stable dose and injection interval of 20  mg every 8 weeks or longer for the previous year, no history of radiation, no cabergoline for the previous 6 months, a GH <1.5  ng/ml, and an IGF1 <1.2×upper limit of normal (ULN). Octreotide LAR was stopped and both GH and IGF1 were measured monthly for 4 months; a glucose-suppressed GH value and magnetic resonance imaging were obtained at the 4th month, thereafter, basal GH and IGF1 were measured q. 3 months, for 12-18 months. Patients were removed from the study if GH or IGF1 rose to 1.5  ng/ml or 1.2×ULN respectively. RESULTS Twelve patients (ten women, mean age 48±13 years) were studied. Seven patients (58.3%) relapsed biochemically within 1 year of having stopped the SA; two patients relapsed by GH and IGF1 criteria, the remaining five patients kept GH levels within target. Five patients (41.7%) remain in remission after 12 months of follow-up. Non-recurring patients were on longer injection intervals but no other characteristic was associated with a successful withdrawal. CONCLUSION Withdrawal of SA is possible in a small but distinct subset of patients, particularly in those who are very well controlled on relatively low doses administered at long intervals.

Adequate Thyroid-Stimulating Hormone Levels After Levothyroxine Discontinuation in the Follow-Up of Patients with Well-Differentiated Thyroid Carcinoma

BACKGROUND In the follow-up of patients with well-differentiated thyroid carcinomas (WTC), a thyroid-stimulating hormone (TSH) >or=30 micro U/mL is generally accepted as adequate to perform whole body scans (WBS), determine thyroglobulin (Tg), and administer radioiodine therapeutically. These patients, inevitably rendered hypothyroid, are traditionally switched to T3 for 3-4 weeks prior to withdrawing all thyroid hormones for an additional 2-3 weeks. Neither TSH and Tg elevation dynamics nor WBS characteristics after simply interrupting L-T4 treatment without T3 administration have been evaluated. METHODS TSH, total T4 and T3, as well as FT4 were measured weekly after discontinuing L-T4 in 21 subjects (group I) and after thyroidectomy in 10 subjects (group II). WBS and Tg determination was performed upon achievement of TSH >or=30 micro U/mL. RESULTS By the second week, 42% of group I patients and 70% of group II patients had TSH >or=30 micro U/mL. By the third week, 90% in group I and 100% in group II had achieved this target. Group I patients who needed 4 weeks to increase TSH received a greater cumulative radioiodine dose and had higher Tg levels. Positive WBS were found in eight cases and the incidence of a negative WBS with elevated Tg was significantly higher when evaluation occurred at the second week of L-T4 withdrawal compared to the fourth week. CONCLUSIONS L-T4 interruption is a reasonable alternative to temporary T3 in preparation for radioiodine scanning and treatment.

Efficacy and Safety of Radiotherapy in Acromegaly

BACKGROUND AND AIMS Transsphenoidal surgery remains the treatment of choice in acromegaly, yet 40-50% of patients require secondary forms of therapy such as radiation therapy (RT) and somatostatin analogues (SA). We undertook this study to evaluate the efficacy and safety of RT in acromegaly. METHODS Forty patients with acromegaly treated with RT (mean dose, 52 Gy) after failed pituitary surgery between 1993 and 2007 were analyzed; all were clinically and biochemically active. Patients were evaluated with yearly hormonal measurements [basal and glucose-suppressed growth hormone (GH), IGF-1, thyroid-stimulating hormone (TSH), free T4, cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone or estradiol and prolactin (PRL)] and with magnetic resonance imaging every 2 years. RESULTS Mean age of patients was 52.9 ± 12.1 years and 85% were female. All subjects had been followed for 1 year, 75% for 3 years, 70% for 5 years and 35% for 10 years. The median basal GH level fell from a baseline of 8.8 ng/mL to 2.27 ng/mL at 5 years (p = 0.001) and to 1.88 ng/mL at 10 years (p = 0.001). A GH <1 ng/mL was achieved by 46% and 57% of the patients at 5 and 10 years of follow-up, respectively. The proportion of patients achieving a normal IGF-1 was 36% at 5 years and 43% at 10 years. Before RT, hypothyroidism, hypocortisolism and hypogonadism were present in 44%, 26% and 74% of patients, respectively. After 5 years of follow-up (n = 28), these figures increased to 51%, 41% and 79% and over a third of the group had panhypopituitarism. One patient developed optic neuritis and another patient was diagnosed with a meningioma 10 years after RT. No cerebrovascular events or deaths occurred. CONCLUSIONS RT is an effective, low-cost and reasonably safe means of controlling acromegalic activity, particularly useful in parts of the world where SA are not readily available.

Men with Acquired Hypogonadotropic Hypogonadism Treated with Testosterone may be Fertile

Men with acquired hypogonadotropic hypogonadism treated with testosterone are generally assumed to be infertile. The finding of two such patients with unexpected fertility and normal sperm counts prompted an evaluation of spermatogenesis in additional men with this condition. Case records were initially searched and one similar case with fertility was found. Subsequently, 12 consecutive men with acquired hypogonadotropic hypogonadism were evaluated for gonadal function and sperm production while receiving testosterone. In five of the cases with proven spermatogenesis, exon 10 of the FSH receptor was sequenced to look for activating mutations.The original three cases and four of the subsequent 12 men had sperm concentrations ≥15 million/ml. Two additional men had concentrations of 1 million/ml and six were azoospermic. Residual LH and FSH levels were slightly higher in those with maintained spermatogenesis prior to testosterone replacement. No activating mutations were found in exon 10 of the FSH receptor in the five cases studied.We conclude that men with acquired hypogonadotropic hypogonadism being treated with testosterone should not be assumed to be sterile, as we have found that more than half have been shown to have persistent spermatogenesis with more than one-third having sperm concentrations ≥15 million/ml. This may be related to fact that gonadotropin levels in such patients are present, albeit low. Semen analyses in such men should be routinely carried out so that they can be appropriately counseled regarding potential fertility.

Persistence of Cushing's disease symptoms and comorbidities after surgical cure: a long-term, integral evaluation.

OBJECTIVES Successful surgery does not always resolve all the clinical consequences of hypercortisolism in patients with Cushings disease (CD). Our purpose was to integrally evaluate a group of CD patients cured by pituitary surgery and look for the persistence of CD symptoms, signs, and comorbidities. METHODS We performed clinical and biochemical evaluations of 29 CD patients (2 males) cured by pituitary surgery. All patients underwent early (median 12 months) and late (median 58 months) postoperative evaluations. We sought information regarding hypercortisolism-related symptoms and signs, as well as metabolic, cardiovascular, reproductive, and psychologic comorbidities. RESULTS The prevalence of obesity dropped from 72.4% at diagnosis to 31% at early evaluation but increased again to 44.8% at the late evaluation. Diabetes was present in 14 patients (48.3%) at diagnosis and persisted in 9 at the late evaluation. Hypertriglyceridemia was present in 58.6% and 55.1% of patients at diagnosis and at the late follow-up, respectively. The prevalence of hypercholesterolemia was 79.3% at diagnosis, decreased to 55.1% at the early evaluation, and increased to 65.5% at the late evaluation. Menstrual abnormalities were originally present in 15 of 20 women, and 8 of the 15 had recovered normal periods when seen at the last evaluation. Among the 24 patients with depression at diagnosis, 11 and 6 still exhibited mood abnormalities at the early and late evaluations, respectively. CONCLUSIONS In a variable proportion of patients, the cardiovascular, metabolic, and emotional comorbidities of CD persist after long-term remission, irrespective of the initial degree of hypercortisolism.

SURGICAL REINTERVENTION IN ACROMEGALY: IS IT STILL WORTH TRYING?

BACKGROUND AND OBJECTIVE There has not been a formal evaluation of how frequently and to what extent surgical reintervention in patients with persistently active acromegaly may achieve significant, albeit incomplete, reductions in growth hormone (GH) and insulinlike growth factor-I (IGF-I) levels. Of importance, recent studies suggest that the response to radiotherapy and pharmacotherapy is better with lower degrees of hypersomatotropism. The objective of this study was to evaluate the outcome of surgical reintervention in patients with active acromegaly at our institution between 1995 and 2005. METHODS We retrospectively evaluated the outcome in 53 patients with active acromegaly (49 with macroadenomas) who underwent a second operation a mean of 24.1 +/- 25.2 months after the first intervention. Basal and postglucose GH as well as IGF-I levels were analyzed at diagnosis and after the first and second pituitary procedures. RESULTS Basal GH decreased in 38 patients (72%): to <10 ng/mL in 17 and to <2.5 ng/mL in 11. The mean IGF-I index and basal GH decreased significantly after surgical reintervention: 1.7 +/- 0.4 to 1.4 +/- 0.4 (P = .0001) and 13.0 +/- 12.8 to 8.3 +/- 11.3 ng/mL (P = .0001), respectively. Some decrement in IGF-I was observed after surgical reintervention in 30 patients (57%), being greater than 30% in 9 (17%). Only 5 patients (9%) achieved complete biochemical cure (normal IGF-I and a postglucose GH level of <1 ng/mL). Reoperation achieved a significant decline in basal and postglucose GH levels as well as in IGF-I index only in patients with noninvasive macroadenomas. CONCLUSION Pituitary surgical reintervention in patients with acromegaly results in a low percentage of biochemical cure. If a remnant of a noninvasive macroadenoma is visible and accessible, however, such a procedure may significantly reduce GH and IGF-I levels.