Iatrogenic panhypopituitarism: how many puzzles you need to solve on your way to pregnancy: a clinical case

Introduction. Iatrogenic panhypopituitarism requires specific approaches to infertility treatment, prenatal care and childbearing. Aim: to show difficulties and peculiarities of infertility treatment of a patient with iatrogenic panhypopituitarism. Methods and materials. We present a clinical case of an infertile patient with panhypopituitarism followed the operation for a chromophobe pituitary adenoma. Results. The 31-year old infertile patient was operated at the age of 21 for pituitary adenoma, the surgery was followed by the hormone replacement therapy. At examination: Anti-Mullerian hormone - 0,28 ng/mL., uterine hypoplasia by ultrasound, hysterosalpingography showed that fallopian tubes were passable, normospermia. Three ovulation stimulations were performed: the first one - Menopur®, the "step up" protocol (after 44-day period one dominant follicle developed); the second - Menopur® "step up" (after 26-day period 4 follicles developed), both times - biochemical pregnancy; the third stimulation - 20 days using Gonal-F® 150 ME and Pregnyl 70 M.E., 4 follicles developed, childbirth went after pregnancy. During the stimulation, growth hormone, cortisol and low molecular weight heparin were added, with the extension of the growth hormone administration to the 36th week of gestation. Conclusion. Patients with hypogonadotropic hypogonadism are a population in which ovulation stimulation leads to folliculogenesis in 80 % of cases. The following questions remain debatable: Is the corresponding function achieved when solving the problem of uterine hypoplasia? Should we add growth hormone and for how long? How to evaluate the follicular reserve, and is Anti-Mullerian hormone accurate in such patients? What is the best compensation for luteinizing hormone activity? Is human chorionic gonadotropin the key to pregnancy

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.

Background: Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients. Subjects and methods: Insulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP. Results: Serum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT. Conclusions: Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.Serbian Ministry of Science (Project number 175033)MS from Society for Endocrinology (Practical Skills Grant)MS from Society for Endocrinology (Practical Skills Grant)British Society for Neuroendocrinology (Research Visit Grant)European Society of Endocrinology (Short Term Fellowship)Wellcome Clinical Training Fellowship (Grant no 097970/Z/11/Z)

Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures

Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. Exome sequencing data were used to identify rare variants in known genes in CHH ( <i>n</i>  = 116), CDGP ( <i>n</i>  = 72) and control cohorts ( <i>n</i>  = 36 874 ExAC and <i>n</i>  = 405 CoLaus). Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, <i>P</i>  = 7.6 × 10 <sup>-11</sup> ) or controls (18%, <i>P</i>  = 5.5 × 10 <sup>-12</sup> ). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, <i>P</i>  = 0.002) and controls (2%, <i>P</i>  = 6.4 × 10 <sup>-7</sup> ). Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder

An updated view of hypothalamic-vascular-pituitary unit function and plasticity

The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic–pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment

Specific Design Features of Solid Propellant Rocket Motors for Shoulder-Launched Weapon Systems

Solid propellant rocket motors for Shoulder Launched Infantry Weapon Systems (SLWS) are characterized with a very short burning time, high-pressure combustion and a wide spectrum of design solutions for rocket motor structure. Interior ballistic behaviour of such rocket motors depends on many factors such as design structure, propellant grain shape, propellant grain joint to the rocket motor case, type and location of the igniter, spinning mode and nozzle design. Erosive burning also plays important role due to high combustion gases mass flow rate. Numerical simulation of the igniter combustion gases flow through the hollow of the propellant grain tubes with gas temperature distribution was carried out in this paper. Results confirmed assumptions that igniter interior gas flow affected duration of the pressure rise. A mathematical model approach for prediction of the curve p = f(t) which was included in a model of the corrected propellant grain burning surface for two types of short-time rocket motors has been presented. A good agreement with measured curves was achieved