Comparison of Short and Long-Term Outcomes of Metabolic and Bariatric Surgery in Adolescents and Adults.

Objective: We sought to compare the short and long-term outcomes of MBS in adolescents vs. adults who have undergone a Roux-en-Y gastric bypass (RYGB) or Sleeve gastrectomy (SG). Design: Retrospective cohort study. Setting: Single tertiary care academic referral center. Participants: One hundred fifty adolescent (≤ 21-years) and adult (>21-years) subjects with severe obesity between 15 and 70 years of age who underwent RYGB or SG. Outcomes: Metabolic parameters, weight and height measures were obtained pre-and post-surgery (at 3 and 6 months, and then annually for 4 years). Results: Median pre-surgical body mass index (BMI) was higher in adolescents (n = 76) vs. adults (n = 74): 50 (45-57) vs. 44 (40-51) kg/m2 (p < 0.0001). However, obesity related complications were greater in adults vs. adolescents: 66 vs. 21% had hypertension, 68 vs. 28% had dyslipidemia, and 42 vs. 21% had type 2 diabetes mellitus (all p < 0.010). % BMI reduction and % weight loss (WL) were greater in adolescents vs. adults at all time points (p < 0.050). %WL was higher in adolescents who underwent SG at each time point (p < 0.050), and trended higher among adolescents who underwent RYGB (p = 0.060), compared to adults with the respective procedure. Follow-up data showed greater resolution of type 2 diabetes and hypertension in adolescents than adults (87.5 vs. 54.8%; p = 0.04, and 68.7 vs. 35.4%; p = 0.040). Conclusion: Adolescents compared to adults had greater reductions in BMI and weight, even at 4 years, and greater resolution of type 2 diabetes and hypertension. Earlier intervention in the treatment of severe obesity with MBS may lead to better outcomes.

Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital hypogonadotropic hypogonadism.

CONTEXT AND OBJECTIVE: The optimal strategy for inducing fertility in men with congenital hypogonadotropic hypogonadism (CHH) is equivocal. Albeit a biologically plausible approach, pretreatment with recombinant FSH (rFSH) before GnRH/human chorionic gonadotropin administration has not been sufficiently assessed. The objective of the study was to test this method. DESIGN AND SETTING: This was a randomized, open-label treatment protocol at an academic medical center. PATIENTS AND INTERVENTIONS: GnRH-deficient men (CHH) with prepubertal testes (<4 mL), no cryptorchidism, and no prior gonadotropin therapy were randomly assigned to either 24 months of pulsatile GnRH therapy alone (inducing endogenous LH and FSH release) or 4 months of rFSH pretreatment followed by 24 months of GnRH therapy. Patients underwent serial testicular biopsies, ultrasound assessments of testicular volume, serum hormone measurements, and seminal fluid analyses. RESULTS: rFSH treatment increased inhibin B levels into the normal range (from 29 ± 9 to 107 ± 41 pg/mL, P < .05) and doubled testicular volume (from 1.1 ± 0.2 to 2.2 ± 0.3 mL, P < .005). Histological analysis showed proliferation of both Sertoli cells (SCs) and spermatogonia, a decreased SC to germ cell ratio (from 0.74 to 0.35), and SC cytoskeletal rearrangements. With pulsatile GnRH, the groups had similar hormonal responses and exhibited significant testicular growth. All men receiving rFSH pretreatment developed sperm in their ejaculate (7 of 7 vs 4 of 6 in the GnRH-only group) and showed trends toward higher maximal sperm counts. CONCLUSIONS: rFSH pretreatment followed by GnRH is successful in inducing testicular growth and fertility in men with CHH with prepubertal testes. rFSH not only appears to maximize the SC population but also induces morphologic changes, suggesting broader developmental roles.

Metabolic effects of Roux-en-Y gastric bypass in obese adolescents and young adults.

Weight loss surgery is an increasingly common treatment option for obese adolescents, but data are limited regarding the metabolic effects of surgical weight loss procedures. We performed a retrospective review of the electronic medical record to determine metabolic outcomes for 24 adolescents and young adults ages 15 to 22 years undergoing Roux-en-Y gastric bypass from 2009 to 2011 as well as 24 age-, sex-, and BMI-matched controls. During a median follow-up of 6 months after Roux-en-Y gastric bypass, fasting glucose, hemoglobin A1c, low-density lipoprotein, triglyceride, and high-sensitivity C-reactive protein decreased significantly. Changes in these measures were not significantly associated with age or extent of weight loss.

A genetic basis for functional hypothalamic amenorrhea.

BACKGROUND: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. METHODS: We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. RESULTS: Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. CONCLUSIONS: Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.).

Rathke's cleft cysts in children and adolescents: association with female puberty.

There are few pediatric data regarding manifestations and outcomes of Rathke's cleft cysts (RCC). We retrospectively reviewed 13 cases treated at Massachusetts General Hospital over 10 years. Age at presentation was 12-17 years, except for one 7-year-old who presented with sexual precocity. There was a female preponderance [11 females, 2 males, p = 0.01], and all were pubertal at diagnosis. Common features at presentation were headaches (11/13), endocrine abnormalities (5/13) and visual disturbances (2/13). Four patients underwent transsphenoidal surgery. Symptoms improved in all but one, in whom headaches persisted. Recurrent growth in one patient was treated successfully by excision. For conservatively treated patients, cyst size was unchanged over follow-up (6 months-5 years). Female preponderance and pubertal presentation suggest a possible link between sex hormones and RCC pathogenesis. Although estrogen and progesterone receptor immunostaining was negative in the cyst lining, estrogen receptor immunostaining was positive in adjacent pituitary cells. Further investigations regarding this issue are warranted.

Role of seminiferous tubular development in determining the FSH versus LH responsiveness to GnRH in early sexual maturation.

BACKGROUND: The onset of sexual maturation at puberty is a unique developmental period from a neuroendocrine perspective in that it is characterized by enhanced FSH secretion and FSH responsiveness to exogenous GnRH (vs. LH) from the gonadotrope, yet the mechanism of these dynamics remains unclear. This study aimed to elucidate this phenomenon using a human disease model of GnRH deficiency (idiopathic hypogonadotropic hypogonadism, IHH) in which GnRH input can be experimentally controlled. METHODS: 25 GnRH-deficient men were selected for study based upon their baseline testicular volumes (TV) and serum inhibin B (I(B)) levels to represent a spectrum of pubertal/testicular development. Subjects underwent: (i) a 12-hour overnight neuroendocrine evaluation for hormonal profiling and determination of endogenous LH secretion pattern, and (ii) a 7-day exposure to a physiologic regimen of exogenous pulsatile GnRH (25 ng/kg every 2 h). Daily measurements of serum testosterone (T) and I(B) levels were made and a 2-hour window of frequent blood sampling was monitored to measure LH and FSH following a single i.v. GnRH bolus (25 ng/kg). All subjects were screened for known loci underlying GnRH deficiency and the response to GnRH was tracked according to genotype. RESULTS: Among the entire cohort, no changes were noted in serum T or I(B) during the 7 days, thus keeping gonadal feedback relatively constant. However, serum LH and FSH levels increased significantly (p < 0.0001) in the entire cohort. When analyzed by degree of pubertal/testicular development, men with no evidence of prior spontaneous pubertal development (TV 3 ml, Group II, p < 0.0001). Group I exhibited a decreased LH response to GnRH on day 2 compared to day 1 (p < 0.01), which did not recover until day 5 (1-4 vs. 5-7 days, p < 0.0001). Group II displayed robust and equivalent LH responses to GnRH throughout the 7-day study. Genetic studies identified 8 mutations in 4 different loci (DAX1, KAL1, GNRHR, and FGFR1) in this cohort. CONCLUSIONS: GnRH-deficient men undergoing GnRH-induced sexual maturation display an inverse relationship between FSH responsiveness to GnRH and baseline testicular size and I(B) levels. This observation implies that increasing seminiferous tubule maturity represents the major constraint on FSH responsiveness to GnRH in early puberty. In contrast, LH responsiveness to GnRH correlates directly with duration of GnRH exposure. Attenuated pituitary gonadotropin responses were noted in subjects harboring DAX1 mutations, consistent with known pituitary defects.

Adolescent obesity and bariatric surgery.

PURPOSE OF REVIEW: Examines the effects of bariatric surgery on adolescent obesity. RECENT FINDINGS: The risks and outcomes of bariatric surgery in adolescence are presently being defined and may be somewhat different from those in adults. Adolescents may have a greater risk of weight regain, and greater risk of noncompliance to treatment after surgery. However, long-term outcomes are not yet available, and the underlying metabolic benefits appear to be substantial and similar to those of adults. SUMMARY: Morbid obesity in adolescents has severe acute and chronic complications. Bariatric surgery in adolescents seems as well tolerated as in adults when performed in centers with appropriate experience and adequate surgical volume. The pathophysiologic implications of bariatric surgery are profound. A better understanding of the mechanisms leading to postsurgical improvement in insulin resistance and weight loss could lead to the development of other therapies to achieve the same effects with lesser morbidities.

The relative role of gonadal sex steroids and gonadotropin-releasing hormone pulse frequency in the regulation of follicle-stimulating hormone secretion in men.

OBJECTIVE: Our objective was to determine the importance of testosterone (T), estradiol (E(2)), and GnRH pulse frequency to FSH regulation in men. DESIGN: This was a prospective study with four arms. SETTING: The study was performed at the General Clinical Research Center. PATIENTS OR OTHER PARTICIPANTS: There were 20 normal (NL) men and 15 men with idiopathic hypogonadotropic hypogonadism (IHH) who completed the study. INTERVENTION: Medical castration and inhibition of aromatase were achieved using ketoconazole x 7 d with: 1) no sex steroid addback, 2) T addback starting on d 4, and 3) E(2) addback starting on d 4. IHH men in these arms received GnRH every 120 min. In a further six IHH men receiving ketoconazole with no addback, GnRH frequency was increased to 35 min for d 4-7. Blood was drawn every 10 min x 12 h at baseline, overnight on d 3-4 and 6-7. MAIN OUTCOME MEASURES: Mean FSH was calculated from the pool of each frequent sampling study. RESULTS: In NL men FSH levels increased from 5.1 +/- 0.7 to 8.7 +/- 1.3 and 9.7 +/- 1.5 IU/liter (P < 0.0001). T caused no suppression of FSH. E(2) reduced FSH from 12.4 +/- 1.8 to 9.3 +/- 1.3 IU/liter (P < 0.05). In IHH men on GnRH every 120 min, FSH levels went from 6.0 +/- 1.6 to 9.0 +/- 3.0 and 11.9 +/- 4.3 (P = 0.07). T caused no suppression of FSH. E(2) decreased FSH such that levels on d 6-7 were similar to baseline. Increasing GnRH frequency to 35 min had no impact on FSH. CONCLUSIONS: The sex steroid component of FSH negative feedback in men is mediated by E(2). Increasing GnRH frequency to castrate levels has no impact on FSH in the absence of sex steroids. When inhibin B levels are NL, sex steroids exert a modest effect on FSH.

Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men.

CONTEXT: Studies on the regulation of LH secretion by sex steroids in men are conflicting. OBJECTIVE: Our aims were to determine the relative contributions of testosterone (T) and estradiol (E2) to LH regulation and localize their sites of negative feedback. DESIGN: This was a prospective study with three arms. SETTING: The study was conducted at a General Clinical Research Center. PATIENTS OR OTHER PARTICIPANTS: Twenty-two normal (NL) men and 11 men with GnRH deficiency due to idiopathic hypogonadotropic hypogonadism (IHH) participated. INTERVENTION: Medical castration and inhibition of aromatase were achieved using high-dose ketoconazole (KC) for 7 d with 1) no sex steroid add-back; 2) T enanthate 125 mg im starting on d 4; or 3) E2 patch 37.5 microg/d starting on d 4. Blood sampling was performed every 10 min for 12 h at baseline, overnight on d 3-4 and d 6-7. MAIN OUTCOME MEASURES: Mean LH levels, LH pulse amplitude, and GnRH pulse frequency were assessed at baseline, d 3-4, and d 6-7. RESULTS: In NL men, KC caused a 3-fold increase in mean LH on d 3-4, which was stable on d 6-7 with no add-back. Addition of T reduced LH levels (34.6+/-3.9 to 17.4+/-3.6 IU/liter, P<0.05) by slowing GnRH pulse frequency (13.3+/-0.4 to 6.7+/-1.0 pulses/12 h, P<0.005). LH amplitude increased (6.9+/-1.0 to 12.1+/-1.4 IU/liter, P<0.005). E2 add-back suppressed LH levels (36.4+/-5.6 to 19.0+/-2.4 IU/liter, P<0.005), by slowing GnRH pulse frequency (11.4+/-0.2 to 8.6+/-0.4 pulses/12 h, P<0.05) and had no impact on LH pulse amplitude. In IHH men, restoring normal T levels caused no suppression of mean LH levels or LH amplitude. E2 add-back normalized mean LH levels and decreased LH amplitude from 14.7+/-1.7 to 12+/-1.5 IU/liter (P<0.05). CONCLUSIONS: 1) T and E2 have independent effects on LH. 2) Inhibition of LH by T requires aromatization for its pituitary, but not hypothalamic effects. 3) E2 negative feedback on LH occurs at the hypothalamus.

Interplay between dose and frequency of GnRH administration in determining pituitary gonadotropin responsiveness.

BACKGROUND/AIMS: The dose, frequency and contour of GnRH stimulation of the pituitary gonadotrope have been shown to be independent variables influencing pituitary LH secretion. The dynamic interaction between these variables during physiological and pathophysiological states has yet to be examined. METHODS: Twelve men with GnRH deficiency and idiopathic hypogonadotropic hypogonadism undergoing GnRH therapy participated in a series of studies in which 2 log orders of GnRH doses (2.5-250 ng/kg) were administered at frequencies varying from 0.5 to 8 hourly. Pituitary responses were characterized by pulse amplitudes and nadirs. The relative sensitivity of the gonadotrope to GnRH was defined as that dose of GnRH capable of eliciting an LH pulse amplitude equal to the mean LH amplitude in normal men. RESULTS: As GnRH stimulation of the gonadotrope slowed from 0.5 to 8 hourly, pulse amplitudes of LH increased whereas mean nadirs decreased (p < 0.05). Unique, curvilinear dose-response curves were found for each frequency that demonstrated an increasing slope (p < 0.03) as the frequency of GnRH stimulation slowed. Thus, the relative sensitivity of the gonadotrope increased as the frequency of GnRH stimulation decreased over the range of physiological frequencies tested. CONCLUSIONS: We conclude that a delicate interplay exists between the dose and frequency of GnRH stimulation of the gonadotrope that determines pituitary LH gonadotropin responsiveness in the human. Slower frequencies favor increased LH release largely due to decreasing LH nadirs and improved sensitivity of the gonadotropes to GnRH stimulation.

Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism.

GnRH treatment is successful in inducing virilization and spermatogenesis in men with idiopathic hypogonadotropic hypogonadism (IHH). However, a small subset of IHH men, poorly characterized to date, fail to reach a normal testicular volume (TV) and produce sperm on this therapy. To determine predictors of outcome in terms of TV and sperm count, we studied 76 IHH men (38% with anosmia) undergoing GnRH therapy for 12-24 months. The population was stratified according to the baseline degree of prior pubertal development: absent (group 1, n = 52), partial (group 2, n = 18), or complete (adult onset HH; group 3, n = 6). Cryptorchidism was recorded in 40% of group 1, 5% of group 2, and none in group 3. Pulsatile GnRH therapy was initiated at 5-25 ng/kg per pulse sc and titrated to attain normal adult male testosterone (T) levels. LH, FSH, T, and inhibin B (I(B)) levels were measured serially, and maximum sperm count was recorded. A longitudinal mixed effects model was used to determine predictors of final TV. LH (97%) and T (93%) levels were normalized in the majority of IHH men. Groups 2 and 3 achieved a normal adult testicular size (92%), FSH (96%), I(B) levels (93%), and sperm in their ejaculate (100%). However, given their prior complete puberty and thus primed gonadotropes and testes, group 3 responded faster, normalizing androgen production by 2 months and completing spermatogenesis by 6 months. In contrast, group 1 failed to normalize TV (11 +/- 0.4 ml) and I(B) levels (92 +/- 6 pg/ml) by 24 months, despite normalization of their FSH levels (11 +/- 2 IU/liter). Similarly, sperm counts of group 1 plateaued well below the normal range (median of 3 x 10(6)/ml) with 18% remaining azoospermic. The independent predictors of outcome of long-term GnRH therapy were: 1) the presence of some prior pubertal development (positive predictor; group effect (beta) = 4.3; P = 0.003); 2) a baseline I(B) less than 60 pg/ml (negative predictor; beta = -3.7; P = 0.009); and 3) prior cryptorchidism (negative predictor; beta = -1.8; P = 0.05). Notably, anosmia was not an independent predictor of outcome when adjusted for other baseline variables. Our conclusions are: 1) pulsatile GnRH therapy in IHH men is very successful in inducing androgen production and spermatogenesis; 2) normalization of the LH-Leydig cell-T axis is achieved more uniformly than the FSH-Sertoli cell-I(B) axis during GnRH therapy; and 3) favorable predictors for achieving an adult testicular size and consequently optimizing spermatogenesis are prior history of sexual maturation, a baseline I(B) greater than 60 pg/ml, and absence of cryptorchidism.

The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism.

As our knowledge of the molecular mechanisms underlying idiopathic hypogonadotropic hypogonadism (IHH) expands, it becomes increasingly important to define the phenotypic spectrum of IHH. In this study we examined historical, clinical, biochemical, histological, and genetic features in 78 men with IHH to gain further insight into the phenotypic heterogeneity of the syndrome. We hypothesized that at least some of the spectrum of phenotypes could be explained by placing the disorder into a developmental and genetic context. Thirty-eight percent of the population had Kallmann syndrome (KS; IHH with anosmia), 54% had normosmic IHH, and 8% had acquired IHH after completion of puberty. Phenotypically, KS represented the most severe subtype (87% with complete absence of any history or signs of spontaneous pubertal development), normosmic IHH displayed the most heterogeneity (41% with some evidence of spontaneous puberty), and acquired IHH after completion of puberty clustered at the mildest end (all had complete puberty). Classification based on historical or clinical evidence of prior pubertal development, rather than the presence or absence of sense of smell, served to distinguish the population more clearly with respect to other clinical and biochemical features. Comparing IHH patients according to the absence (68%) or presence (24%) of some prior pubertal development revealed significant differences in testicular size (3.3 +/- 0.2 vs. 11.8 +/- 1.2 ml; P < 0.001), incidence of cryptorchidism (40% vs. 5%; P < 0.05), microphallus (21% vs. 0%; P < 0.05), inhibin B levels (45 +/- 4 vs. 144 +/- 20 pg/ml; P < 0.0001), and Mullerian inhibitory substance levels (9.8 +/- 1.4 vs. 2 +/- 0.5 ng/ml). Most familial cases had no pubertal development (95% vs. 5%; P < 0.001); males with mutations in the KAL gene displayed the most severe phenotype. Mean gonadotropins levels (LH, 1.8 +/- 0.1 vs. 2.9 +/- 0.4 IU/liter; FSH, 2.2 +/- 0.2 vs. 3.3 +/- 0.3 IU/liter; P < 0.05) and the finding of apulsatile LH secretion based on frequent sampling (80% vs. 55%; P < 0.05) were statistically different between patients lacking and those exhibiting partial pubertal development, but the overlap was extensive. The use of clinical parameters (presence or absence of some evidence of prior pubertal development, cryptorchidism, and microphallus), biochemical markers of testicular growth and differentiation (inhibin B and Mullerian inhibitory substance), and genetic evidence provides insight into the time of onset and the severity of GnRH deficiency. Viewing IHH in the full context of its developmental, genetic, and biochemical complexity permits greatest insight into its phenotypic variability.