Pituitary Hormones

The design and methodology of NordiNet IOS and ANSWER have been reported previously (16 (link)). Key points are summarized below and in Table 1.
NordiNet IOS was a multicenter, longitudinal, observational cohort study based on systematic collection of data using the NordiNet IOS Web-based system. ANSWER was originally a postmarketing registry of adults and pediatric patients in the United States treated with Norditropin, and it was developed into a noninterventional, observational study. The two studies were complementary, with similar aims, using the same electronic platform for data management. Results of the studies are presented side by side, rather than pooled, because the reporting of effectiveness and safety endpoints differed.
In both studies, Norditropin was administered as directed by the treating physician and according to routine practice and local regulations. Approval was obtained from relevant ethics committees, written consent was obtained, and all data were pseudonymized. The studies were conducted in accordance with the Declaration of Helsinki, Guideline for Good Pharmacoepidemiology Practices, and regulatory requirements.
Pediatric patients were eligible for inclusion when they had an appropriate diagnostic condition and when treatment with Norditropin was initiated before 18 years of age. Diagnoses were determined by the participating physicians. For study purposes, patients with more than one diagnosis recorded were classified as follows: patients with a syndrome and coexisting GHD were classified by syndrome; patients recorded as both SGA and GHD (isolated or multiple pituitary hormone deficiency) were classified as GHD.
Baseline data were collected according to routine clinical practice (16 (link)). Follow-up time on GH treatment during childhood with known dose (mg/kg/d) was recorded.
In both studies, numerous effectiveness endpoints were assessed (16 (link)), with change from baseline in height SD score (SDS) as a key outcome. Data on IGF-I SDS were reported in both studies (NordiNet IOS and ANSWER).
Safety data were based on physicians’ reporting of adverse events (AEs). Adverse reactions (ARs; AEs deemed related to product), classed as serious (SARs) or nonserious (NSARs), were recorded. In NordiNet IOS, serious AEs (SAEs) not related to GH therapy were also recorded throughout the study. (For SAEs in both studies, an SAE was defined as an experience that resulted in any of the following: death, a life-threatening experience, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that might not result in death, be life-threatening, or require hospitalization could be considered as SAEs if, based on appropriate medical judgement, they might jeopardize the patient and might require medical or surgical intervention to prevent one of the outcomes listed. The term “life-threatening” in the definition of an SAE referred to an event in which the patient was at risk for death at the time of the event. It did not refer to an event that hypothetically might have caused death if it had been more severe.) In ANSWER, however, it was not mandatory to report SAEs that were not related to GH therapy until 9 November 2011, when the protocol was amended. Fewer than 20 SAEs had been reported prior to this amendment, but subsequently the number increased. Only SAEs reported after that date were included in the analysis. In both studies, a double assessment of causality was used to identify any causal relationship to GH therapy: causality was reported by the treating physician, and all SAEs, including SARs, were also reviewed by the study sponsor. When either the original reporter or the study sponsor considered the relationship as possible or probable, the event was considered as an AR.

The Massachusetts General Hospital IHH cohort consisted of a total of 1,453 IHH (KS and nIHH) patients enrolled in a research study within the Massachusetts General Hospital (MGH) Harvard Center for Reproductive Medicine. This cohort was clinically defined by (i) absent or incomplete puberty by age 18 years, (ii) serum testosterone < 100 ng/dL in men or estradiol < 20 pg/mL in women with low or normal levels of serum gonadotropins, (iii) otherwise normal anterior pituitary function, (iv) normal serum ferritin concentrations, and (v) normal MRI of the hypothalamic-pituitary region (4 (link)). These stringent clinical criteria allowed us to infer a hypothalamic site defect in these patients. In addition, since hypothalamic GnRH deficiency is often intertwined with olfactory dysfunction (KS form of IHH), both self-reported olfaction as well as University of Pennsylvania Smell Identification Test scores were used to classify patients as either KS (when olfaction was abnormal: anosmia/hyposmia) or nIHH (normal smell) (48 (link), 49 (link)). For male patients who were evaluated at prepubertal age, other signs of neonatal hypogonadism were evaluated, including hypospadias, micropenis, and cryptorchidism. Clinical charts and patient questionnaires were reviewed for phenotypic evaluation for both reproductive and nonreproductive phenotypes.
The diagnosis of SOX2 disorder was established in IHH probands in whom molecular genetic testing identified a heterozygous intragenic SOX2 pathogenic variant, a deletion that is intragenic, or a deletion of 3q26.33 involving SOX2 (1 ). Eye defects were classified as severe or mild as previously described (3 (link)). Severe eye defects were defined as bilateral ocular malformations including anophthalmia and microphthalmia. Mild eye defects were defined as unilateral anophthalmia or microphthalmia, coloboma, optic nerve hypoplasia/aplasia, strabismus, hypertelorism, nystagmus, small palpebral fissures, and myopia. Patients were evaluated for other nonocular features that have been associated with the syndrome, including neurocognitive developmental delay, seizures, hearing loss, and esophageal abnormalities, as well as genital anomalies including hypospadias, micropenis, and cryptorchidism. Patients’ pituitary function was assessed by detailed laboratory evaluation of all pituitary hormones, including thyroid-stimulating hormone, free thyroxine, prolactin, IGF1, adrenocorticotropic hormone, and morning cortisol, and pituitary anatomy was evaluated with pituitary MRIs.

This meta-analysis was performed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two independent investigators (Nie and Fang) conducted literature (from inception to May 15, 2022), using the following databases: PubMed, Cochrane, and Ovid MEDLINE. Search strategy based on keywords is as follows: “pituitary adenoma,” “growth hormone pituitary adenoma,” “growth hormone-producing pituitary adenoma,” “somatotroph tumor,” “acromegaly,” “endoscopic surgery,” “endoscopic transsphenoidal surgery,” “anterior pituitary function,” “pituitary insufficiency,” “hypothyroidism,” “thyroid insufficiency,” “adrenal insufficiency,” “hypoadrenalism,” and “endoscopic.”
Two researchers (Nie and Fang) independently conducted literature screening, data extraction, and quality evaluation. If there is any disagreement, another researcher will help mediate it (Zhang). The inclusion criteria were English original research articles. Case reports, conference abstracts, meta-analyses, and reviews were excluded. This article should describe the pituitary hormone before and after endoscopic transsphenoidal pituitary tumor surgery in patients with somatotroph tumors. References to all selected articles are reviewed.