Women with hypopituitarism have various degrees of androgen deficiency, which is marked among those with combined hypogonadotrophic hypogonadism and secondary adrenal insufficiency. The consequences of androgen deficiency and the effects of androgen replacement therapy have not been fully elucidated. While an impact of androgen deficiency on outcomes such as bone mineral density, quality of life, and sexual function is plausible, the available evidence is limited. There is currently no consensus on the definition of androgen deficiency in women and it is still controversial whether androgen substitution should be used in women with hypopituitarism and coexisting androgen deficiency. Some studies suggest beneficial clinical effects of androgen replacement but data on long-term benefits and risk are not available. Transdermal testosterone replacement therapy in hypopituitary women has shown some positive effects on bone metabolism and body composition. Studies of treatment with oral dehydroepiandrosterone have yielded mixed results, with some studies suggesting improvements in quality of life and sexual function. Further research is required to elucidate the impact of androgen deficiency and its replacement treatment on long-term outcomes in women with hypopituitarism. The lack of transdermal androgens for replacement in this patient population and limited outcome data limit its use. A cautious and personalized treatment approach in the clinical management of androgen deficiency in women with hypopituitarism is recommended while awaiting more efficacy and safety data.

BACKGROUND: Obesity-induced hypogonadism, which manifests as erectile dysfunction and a lack of libido, is a less visible and under-recognized obesity-related disorder in men.
OBJECTIVE: We examined the impact of weight loss on total (TT) and free testosterone (FT) levels, and constructed nomograms to provide an easy-to-use visual aid for clinicians.
METHODS: Meta-analysis was conducted using RevMan (v5.3) and expressed in standardized mean differences (SMD) for testosterone. Parallel-scale nomograms were constructed from baseline and target body mass index values to estimate the gain in testosterone.
RESULTS: In total, 44 studies were included, comprising 1,774 participants and 2,159 datasets, as some studies included several datasets at different time points. Weight loss was controlled by low calorie diet (LCD) in 19 studies (735 participants, 988 datasets), by bariatric surgery (BS) in 26 studies (1,039 participants, 1,171 datasets), and by both in one study. The median follow-up was 26 weeks (interquartile range = 12-52). The range of baseline mean age was 21-68 yr, BMI: 26.2-71.2 kg/m2 , TT: 7-20.2 nmol/L and FT: 140-583 pmol/L. TT levels increased after weight loss by LCD: SMD (95%CI) = 2.5 nmol/L (1.9-3.1) and by BS: SMD = 7.2 nmol/L (6.0-8.4); the combined TT gain was 4.8 nmol/L (3.9-5.6). FT levels increased after weight reduction by LCD: SMD = 19.9 pmol/L (7.3-32.5) and by BS: SMD = 58.0 pmol/L (44.3-71.7); the combined gain was 42.2 pmol/L (31.4-52.9). Greater amounts of total and free testosterone could be gained by weight loss in men with higher baseline BMI, or lower levels of SHBG, TT and FT, while gain in TT was relatively greater in older and FT in younger age. Age-stratified nomograms revealed that compared to older men (> 40 yr), younger men (≤ 40 yr) gained less TT but more FT for a given weight loss.
CONCLUSIONS: Both TT and FT levels increased after weight loss, relatively greater with higher baseline BMI, or lower levels of SHBG, TT and FT. Nomograms constructed from a large number of participants with a wide range of BMI and testosterone values provide an evidence-based and simple-to-use tool in clinical practice.

UNASSIGNED: Delayed puberty , usually affects psychosocial well-being. Patients and their parents show concern about genital development and stature. The condition is transient in most of the patients; nonetheless, the opportunity should not be missed to diagnose an underlying illness.
UNASSIGNED: The etiologies of pubertal delay in males and their specific pharmacological therapies are discussed in this review.
UNASSIGNED: High-quality evidence addressing the best pharmacological therapy approach for each etiology of delayed puberty in males is scarce, and most of the current practice is based on small case series or unpublished experience. Male teenagers seeking attention for pubertal delay most probably benefit from medical treatment to avoid psychosocial distress. While watchful waiting is appropriate in 12- to 14-year-old boys when constitutional delay of growth and puberty (CGDP) is suspected, hormone replacement should not be delayed beyond the age of 14 years . When hypogonadism is diagnosed, hormone replacement should be proposed by the age of 12 years . Testosterone replacement has been used for decades and is fairly standardized. Aromatase inhibitors have arisen as an interesting alternative . Gonadotrophin therapy seems more physiological in patients with central hypogonadism, but its efficacy and timing still need to be established.

NR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging.
The aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation.
We included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed.
Bilateral testicular volume increased from 8 ml (interquartile range, 6-9) to 12 ml (10-16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46-139) before and 91 ng/L (20-120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any.
We characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.

SOX3 is critical for the development of the pituitary, brain, and face, and SOX3 mutations may lead to hypopituitarism, intellectual disability, and craniofacial abnormalities. Common SOX3 mutations are duplications and deletions of the whole or part of SOX3, yet only a few cases with point mutations were reported by far. We present a case with growth retardation, small penis, and learning difficulty. Further assessment confirmed growth hormone deficiency, hypogonadotropic hypogonadism (HH), and borderline intellectual disability. He also responded well to gonadotropin-releasing hormone stimulation test, which suggests defects in the hypothalamus, contrary to previous studies that reported defects in the pituitary. A pathogenic frame-shift mutation of SOX3 was found. A heterogeneous missense mutation in SEMA3A was identified in this patient as well, which may also contribute to the development of HH. As far as we know, this is the first report that a frame-shift mutation of SOX3 constitutes rare genetic causes of HH and growth hormone deficiency. Whether mutations in these two genes act synergistically in the pathogenesis of the patient\'s phenotype remains to be further investigated. We believe that our case extends the phenotypic spectrum and genetic variability of SOX3 mutation.

The diagnostic suspicion of congenital central hypogonadism is based on clinical signs. Biochemical confirmation is challenging, especially after the postnatal activation stage of the hypothalamic-pituitary-testicular axis. Sertoli cell markers, like AMH and inhibin B, have become useful tools for the diagnosis of male central hypogonadism during childhood. Different mechanisms can participate in the aetiopathogenesis of central hypogonadism, leading to a deficiency in the production of gonadotrophins. Advances in genetic studies, mainly next generation sequencing techniques, have allowed the discovery of a large number of genes related to central hypogonadism. However, a causal variant is found in approximately half of the patients. Central hypogonadism has been classically described as a pathology with variable expressivity and incomplete penetrance. Currently, these characteristics are known to be partially explained by the presence of oligogenicity, that is the participation of variants in more than one gene in the aetiology of central hypogonadism in the same patient.

Pituitary stalk lesions can represent a wide range of pathologies. The exact cause is often unknown due to hesitancy to proceed with biopsy. We present a 16-year-old adolescent who presented with delayed puberty, short stature and bilateral cryptorchidism. He was found to have a thickened pituitary stalk of uncertain etiology with partial hypopituitarism (gonadotrophin and growth hormone deficiency) on further assessment. The presence of bilateral cryptorchidism and micropenis represents lack of \"mini puberty,\" a phenomenon of activation of the hypothalamic-pituitary-gonadal (HPG) axis in-utero or within the first few months of life.1 These key clinical features have been useful to establish an early temporal relationship and suggest a congenital origin of disease. This enabled a more conservative approach of surveillance to be employed as opposed to invasive pathological examination with pituitary stalk biopsy.

Puberty in children with Prader-Willi syndrome (PWS) is usually delayed and/or incomplete but in some patients premature/early adrenarche is observed. We assessed the premature adrenarche (PA) in PWS patients during the recombinant human growth hormone (rhGH) therapy and influence of PA on the course of central puberty (CP), rhGH efficacy and safety, and patients\' metabolic state. Forty-nine PWS patients were treated with rhGH, 11 presented with PA (group 1) and 14 had normal course of adrenarche (group 2). PA was observed in 22.5% of the PWS children treated with rhGH. The mean time between the rhGH start and the adrenarche, the rhGH dose, the growth velocity and the insulin-like growth factor 1 SD (IGF1 SD) during the treatment, as well as the time of CP, final height SD and BMI SD were similar in both groups. There were also no significant differences in the metabolic assessment-the oral glucose tolerance test (OGTT) and lipid profile results. PA may be a part of the clinical picture of PWS, apart from hypogonadotrophic hypogonadism and it seems to have no influence on CP in PWS patients. The rhGH efficacy and safety were comparable in the patients with PA and the normal course of adrenarche.

CONCLUSIONS: Lymphocytic hypophysitis is a rare neuroendocrine disease characterised by an autoimmune inflammatory disorder of the pituitary gland. We report a 50-year-old woman who presented with headaches and bilateral sixth cranial nerve palsies. MRI of the pituitary revealed extensive fibrosis involving the sellar and extending into both cavernous sinuses causing bilateral occlusion of the internal carotid arteries (ICA). Transphenoidal biopsy confirmed the diagnosis of infiltrative fibrotic lymphocytic hypophysitis. Symptoms resolved with high dose of oral steroids but relapsed on tapering, requiring several treatments of i.v. pulse steroids over 8 months. Rituximab combined with mycophenolate mofetil was required to achieve long-term symptom relief. Serial MRI pituitary imaging showed stabilisation of her disease without reduction in sellar mass or regression of ICA occlusion. The patient\'s brain remained perfused solely by her posterior circulation. This case demonstrates an unusual presentation of a rare disease and highlights a successful steroid-sparing regimen in a refractory setting.
CONCLUSIONS: Lymphocytic hypophysitis is a rare inflammatory disorder of the pituitary gland. In exceptional cases, there is infiltration of the cavernous sinus with subsequent occlusion of the internal carotid arteries. First-line treatment of lymphocytic hypophysitis is high-dose glucocorticoids. Relapse after tapering or discontinuation is common and its use is limited by long-term adverse effects. There is a paucity of data for treatment of refractory lymphocytic hypophysitis. Goals of treatment should include improvement in symptoms, correction of hormonal insufficiencies, reduction in lesion size and prevention of recurrence. Steroid-sparing immunosuppressive drugs such as rituximab and mycophenolate mofetil have been successful in case reports. This therapeutic combination represents a viable alternative treatment for refractory disease.

Kallmann-de Morsier syndrome (KS) is a genetic disease of the olfactory system characterized by the association of hypogonadotropic hypogonadism also referred to as gonadotropin-releasing hormone (GnRH) deficiency and anosmia or hyposmia (with hypoplasia or aplasia of the olfactory bulbs). Apart from sporadic cases that occur most often, familial Kallmann\'s syndrome is being described with increasing frequency. Diagnosis is mainly made in adolescents with absence of spontaneous puberty associated with smell disorders with hypoplasia or even aplasia of the bulbs and/or of the olfactory lobes on MRI. Sometimes, the diagnosis may be suspected in early childhood due to the association of cryptorchidism and micropénis. A mutation in one of known genes is only found in less than 30% of cases and, therefore, many other genes are still to be found. Hormone therapy allows pubertal growth in all cases and fertility can be obtained in most of the cases. We here report 3 cases of patients with this syndrome.