ENDOCRINE OBESITY: Pituitary dysfunction in obesity

in European Journal of Endocrinology
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  • 1 Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital and Research Institute, Badalona, Catalonia, Spain

Correspondence should be addressed to M Puig-Domingo; Email: mpuigd@igtp.cat

*(S Pellitero and M Puig-Domingo contributed equally as senior authors)

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Obesity, the growing pandemic of the 21st century, is associated with multiple organ dysfunction, either by a direct increase in fatty organ content or by indirect modifications related to general metabolic changes driven by a specific increase in biologic products. The pituitary gland is not protected against such a situation. Different hypothalamic–pituitary axes experience functional modifications initially oriented to an adaptive situation that, with years of obesity, turn to maladaptive dynamics that contribute to perpetuating obesity and specific symptoms of their hormonal nature. This paper reviews the recent knowledge on obesity-related pituitary dysfunction and its pathogenic mechanisms and discusses potential therapeutic actions aimed at contributing to ameliorating the complex treatment of severe cases of obesity.

Abstract

Obesity, the growing pandemic of the 21st century, is associated with multiple organ dysfunction, either by a direct increase in fatty organ content or by indirect modifications related to general metabolic changes driven by a specific increase in biologic products. The pituitary gland is not protected against such a situation. Different hypothalamic–pituitary axes experience functional modifications initially oriented to an adaptive situation that, with years of obesity, turn to maladaptive dynamics that contribute to perpetuating obesity and specific symptoms of their hormonal nature. This paper reviews the recent knowledge on obesity-related pituitary dysfunction and its pathogenic mechanisms and discusses potential therapeutic actions aimed at contributing to ameliorating the complex treatment of severe cases of obesity.

Invited Author’s profile

Manel Puig-Domingo MD, PhD is currently Head of Endocrinology and Nutrition Department at the Germans Trias University Hospital and former Director of the Germans Trias Research Institute. He is also a Professor of Endocrinology at the Autonomous University of Barcelona. He currently serves as the representative of the European Society of Endocrinology (ESE) to the European Agency of Medicines and member of the ESE Clinical Committee. He has previously been President of the Spanish Society of Endocrinology and Nutrition and Visiting Professor at UCLA-Cedars Sinai Medical Center. His main research interests are pituitary and thyroid disorders and diabetes mellitus.

Introduction

Obesity is a worldwide growing pandemic with a current prevalence in most European countries of approximately 20% (1). It is associated with chronic comorbidities such as type 2 diabetes mellitus (T2DM), dyslipidaemia, hypertension, cardiovascular and respiratory disease, and cancer (2). In addition, obesity leads to endocrine abnormalities and virtually all endocrine organs and systems may be damaged by excess adipose content, either directly or indirectly. Thus, any endocrine organ may present alterations in its function because of the general metabolic obese dysbiology or because of the specific excess of fatty organ content. Although less known, this also includes the pituitary gland and, as a matter of fact, thyrotrophic, gonadotropic, somatotropic, and corticotropic dysfunctions may occur as a consequence of obesity-related abnormalities in the hypothalamic–pituitary axis (3, 4, 5). In addition, obesity is considered both a cause and consequence of endocrine dysfunction (3, 4), thus establishing a vicious cycle that perpetuates this altered functional biologic scenario. This bidirectional relationship is complex and not completely understood (4, 6). In addition, hormonal function assessment in people with obesity may be difficult to interpret. The European Society of Endocrinology has recently published a clinical practice guideline with some recommendations on endocrine testing and replacement treatment for this group of patients (3). As an example, thyroid function screening is recommended in all patients with obesity, given the apparent high prevalence of subclinical hypothyroidism. However, the extent to which these patients have ‘true’ primary thyroid dysfunction or functional thyrotropin dysregulation, which is ameliorated after substantial weight loss, will be further discussed. This situation may account for other endocrine organ systems.

Bariatric surgery is, for a substantial part of patients with serious obese conditions, the most effective treatment and can lead to remission or amelioration of most of the associated classic comorbidities, such as T2DM, sleep apnoea, hypertension, dyslipidaemia, and coronary artery disease and can decrease overall mortality (7, 8). At the same time, different studies have highlighted the improvement in obesity-related endocrine dysfunctions after bariatric surgery (9, 10, 11, 12, 13, 14, 15). For this reason, it has been suggested that patients should not be treated until weight amelioration is obtained and the abnormal endocrine parameters persist over time.

As the topic of obesity-related pituitary dysfunction is not fully understood and, to some extent, is a relatively controversial issue, we aimed to review the prevalence, associated mechanisms, and clinical approach regarding thyrotropic, gonadotropic, somatotropic, and corticotropic axis dysfunctions related to obesity. Finally, we will review the current replacement treatment recommendations suggested in these situations.

Thyrotropic axis dysregulation in obesity

There is a reciprocal relationship between obesity and thyroid function. Thyroid function is involved in the control of thermogenesis and appetite, among other universal biological effects that play a crucial role. Therefore, its dysfunction is associated with secondary changes in body weight and composition (16). On the other hand, obesity has been associated with modifications in the hypothalamic–pituitary–thyroid (HPT) axis leading to changes in thyroid function (17). It is not clear to what extent the anomalies observed in thyroid function are due to primary gland involvement, related to hypothalamic–pituitary dysfunction, or both.

A recent meta-analysis showed a prevalence of overt hypothyroidism among patients with obesity that ranged from 1.7 to 43.7%, with a pooled prevalence that was 14.0% (6), which is consistently higher than the figures found for the general population.

There is compelling evidence of a positive correlation between serum thyroid-stimulating hormone (TSH) levels and higher BMI, regardless of the presence of hypothyroidism (18, 19). However, thyroid hormone level data in patients with obesity are discordant between studies. In the Danish DanThyr 1997–1998 population cohort, the authors described that BMI was negatively associated with serum-free thyroxine (T4) and was not associated with total or free triiodothyronine (T3) levels (19). Later studies showed similar results (20, 21), whereas others found opposite results or no association (22, 23).

The mechanism or mechanisms underlying the changes observed in the hypothalamic-pituitary-thyroid (HPT) axis in obesity are not completely understood, and different hypotheses have been proposed. One of the most accepted explanations suggests that hyperthyrotropinaemia could be an adaptation response to increase thermogenesis and energy expenditure and to minimize weight gain (16). Leptin seems to play an important role in the interaction between adipose tissue and thyroid function at the pituitary level (16). As a hormone that is predominantly released from subcutaneous adipocytes, leptin enhances thyrotropin-releasing hormone (TRH) expression and synthesis in the paraventricular nucleus of the hypothalamus and arcuate nuclei and stimulates TSH secretion by the pituitary gland (16, 22, 24, 25) (Fig. 1A). Thus, a positive correlation has been identified between serum leptin and serum TSH levels in patients with obesity (24, 26). In this regard, leptin secreted by excess subcutaneous adipose tissue would lead to increased activation of the hypothalamus–pituitary–thyroid axis as an adaptive mechanism (16). As elegantly demonstrated by Fontenelle et al. (16), the main leptin effect on TRH occurs through the paraventricular hypothalamic nucleus in which leptin, through its ObRb receptor, activates phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3). It favours the binding of STAT3 to the promoter region of the gene coding for TRH. Additionally, in the arcuate nucleus, leptin is able to activate a subpopulation of neurons expressing proopiomelanocortin while inhibiting neurons that synthesize agouti-related protein and neuropeptide Y. This action also leads to increased production of α-melanocyte-stimulating hormone, which contributes to stimulating TRH expression by hypothalamic neurons through binding to the melanocortin 4 receptor. However, due to the presence of a selective leptin resistance state in the arcuate nucleus in obesity, the main route of modulation of the thyrotropic axis is through the direct action of leptin on the paraventricular nucleus (16, 27, 28). Furthermore, leptin affects the activity of deiodinase enzymes in different tissues. In obesity, changes in the activity of these enzymes may occur with an increase in type 1 deiodinase in the thyroid activating T4 to T3 conversion, but with the opposite effect on type 2 deiodinase in the pituitary gland (16). This decrease in the activity of type 2 deiodinase at the pituitary level may be involved in the upregulation of TSH at the pituitary level in addition to the leptin-enhanced TRH effect.

Figure 1
Figure 1

Pathogenic mechanisms implicated in pituitary dysfunction in obesity. (A) Thyrotropic dysfunction. Leptin secreted by excess adipose tissue enhances thyrotropin-releasing hormone (TRH) expression and synthesis in the hypothalamus and stimulates serum thyroid-stimulating hormone (TSH) secretion by the pituitary gland. Leptin affects the activity of thyroid deiodinases with activation of thyroxine (T4) to triiodothyronine (T3) conversion. (B) Somatotropic dyshomeostasis. Altered ghrelin secretion contributes to reduced growth hormone (GH) levels. The dysmetabolic combination of high circulating free fatty acids (FFAs) and the inflammatory milieu negatively influences GH release by the hypothalamus. This inflammatory profile contributes to the induction of liver GH resistance, accounting for a decrease in insulin-like growth factor (IGF-1) production. GH clearance is significantly higher. The decreased GH and IGF-1 levels contribute to an increase in adipogenesis, as well as a decrease in muscle mass. (C) Gonadotropic function impairment. Insulin resistance, inflammation, increased leptin concentrations, and decreased endogenous kisspeptin secretion have an inhibitory effect on the hypothalamic–pituitary–testicular (HPT) axis. Leptin inhibits the production of testosterone by Leydig cells. The high levels of oestradiol from excessive peripheral conversion of testosterone in the adipose tissue have a negative feedback effect on gonadotropin secretion. Testosterone deficiency facilitates increased adipogenesis and visceral obesity.

Citation: European Journal of Endocrinology 186, 6; 10.1530/EJE-21-0899

In addition to these central mechanisms, peripheral mechanisms may also play a relevant role in HPT axis changes in obesity. In accordance with that, Nannipieri et al. showed that weight loss was associated with increased expression of thyroid hormone receptors in subcutaneous adipose tissue (29).

The hyperthyrotropinaemia of people with obesity reverts after weight loss induced by a hypocaloric diet (30, 31, 32). A cross-sectional study including 246 children with obesity found that substantial weight loss after a 1-year intervention programme based on exercise, behaviour therapy, and nutrition education was associated with a significant decrease in TSH and T3 levels (30). Bariatric surgery is also associated with a decrease in TSH levels (9, 10), even in those subjects with previous values within the normal range, thus confirming the relationship between excess adipose mass and thyrotropic dysregulation. In addition, the magnitude of TSH reduction after surgery positively correlates with baseline TSH levels but not with the percentage of excess weight loss (10). The mechanisms underlying the improvement in thyroid function have been, again, mostly related to leptin but also to ghrelin changes through a reduction in the stimulatory effect on the hypothalamo-thyrotropic axis (10, 33). Ghrelin receptors exist at the hypothalamic level, and clinical studies in humans have shown that ghrelin injection causes a decline in TSH levels (34, 35). In general, bariatric surgery is associated with the resolution of ‘subclinical hypothyroidism’ in almost 90% of patients but also with a decrease in levothyroxine dose requirements in those treated, thus confirming the adequacy of ‘wait and see’ criteria and the reversible nature of the ‘apparent’ thyrotropic dysfunction (10). In parallel with the decrease in TSH, FT3, and T3 also decrease significantly, with nonsignificant changes in FT4, T4, and reverse T3 levels, also indicating an effect on deiodinase activity, including the pituitary deiodinase system (9).

There is a paucity of data regarding which type of bariatric surgery has a greater impact on TSH level normalization, although in the end, it will depend on the success achieved in weight loss. A retrospective study comparing thyrotropin changes in patients with obesity undergoing laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass showed that both techniques normalized TSH similarly (36). A subanalysis from the meta-analysis conducted by Guan et al. found that RYGB, but not biliopancreatic diversion (BPD) or adjustable gastric band (AGB), had a significant effect on TSH reduction. Regarding FT3 reduction, RYGB and BPD were superior to SG. In addition to weight loss, this could also be explained by the fact that, after RYGB and BPD, the enterohepatic circulation diminishes, altering the reabsorption of FT3 excreted through the bile. However, the heterogeneity between studies and the relatively small number of subjects included in some subgroups imply that these results should be interpreted with caution (9). Muraca et al. showed that patients with obesity with lower TSH levels achieved higher weight loss after AGB than those with normal or high-normal TSH levels. These associations were not observed after SG, and the authors speculate that this could be explained by the greater effect of caloric restriction than baseline endocrine factors (37).

According to the Clinical Practice Guideline of the European Society of Endocrinology, all patients with obesity should be tested for thyroid function (3). Instead, the latest guidelines by the American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, and the American Society for Metabolic & Bariatric Surgery do not recommend routine screening for TSH levels since the higher upper limit with obesity may result in an overdiagnosis of hypothyroidism (38).

Somatotropic axis dysfunction in people with obesity

It is well established that growth hormone (GH) secretion is blunted in adult patients with obesity compared to lean subjects. Both basal and stimulated concentrations of GH levels have been described to be markedly reduced in adults with morbid obesity (39). Studies regarding insulin-like growth factor (IGF-1) levels in obesity have reported discordant results, with most showing a decrease in free IGF-1 levels (14, 15, 40, 41). Our group retrospectively studied 109 patients with morbid obesity treated with bariatric surgery and found an overall prevalence of low total IGF-1 levels of 22% before surgery (14). However, normal (42) or even increased serum levels of IGF-I have been described (43). These discrepancies could be attributed to methodological differences in the assays used to determine free IGF-1 throughout the studies, since in the last study mentioned, the researchers used a recently developed ultrafiltration method that allowed free fractions to be isolated under in vivo conditions (39, 43). The differences could also be due to diurnally induced variations in free IGF-1, IGFBP-1, fasting-induced, or other hour-to-hour factors influencing the amount of free IGF-1. Another possible explanation for the different levels of free IGF-I described in obesity could be the type of fat distribution, as it has been reported that visceral fat mass, rather than adiposity per se, correlates inversely with circulating IGF-I levels. Therefore, it appears that obesity, and especially visceral obesity, correlates with a decrease in free IGF-1 levels (39), as shown by the results of the study of Rasmussen et al. in which circulating free IGF-I determined by ultrafiltration was markedly decreased in women with severe obesity (40).

GH and IGF-1 play an important role in the regulation of metabolism and body composition homeostasis (44). GH has both anabolic and catabolic actions on different tissues, stimulating lipolysis in adipose tissue and protein synthesis in muscle (45). Thus, decreased GH levels contribute to an increase in weight gain and abdominal adiposity accumulation, as well as a decrease in muscle mass. Moreover, it has been suggested that GH deficiency modulates adipokine and cytokine protein expression patterns, which might predispose to adipose tissue growth and differentiation (46). Altogether, these factors enhance the establishment of a vicious cycle that may be difficult to break (47). Moreover, if a low IGF-1 concentration is present, it might contribute to the impaired cardiometabolic risk profile of patients with obesity (48). Although obesity in general is related to insulin resistance, in patients with GH deficiency, this relationship may be altered. The results regarding insulin resistance in patients with GH deficiency are controversial in the literature (49, 50). Considering studies involving euglycaemic–hyperinsulinaemic clamp in patients with GH deficiency, six out of ten studies found no alteration of insulin sensitivity in these patients (49).

The mechanism underlying the modifications of GH regulation in people with obesity remains incompletely understood and several hypotheses have been proposed. It has been demonstrated that abdominal visceral fat and fasting insulin are major determinants of GH secretion in healthy nonobese adults (51, 52). Data from previous studies showed an inhibitory role of insulin on pituitary GH secretion by reducing the mRNA expression of GH, GHRH receptor, and GH secretagogue receptor, as well as GH production in cultured pituitary cells (53). Moreover, the dysmetabolic combination of hyperinsulinaemia, high circulating free fatty acids (FFAs) and the inflammatory milieu may negatively influence GH processing and release (14, 39, 54, 55). The elevation of plasma FFAs inhibits GHRH-mediated GH secretion (56). Proinflammatory cytokines determine dysregulation of the somatotropic axis, altering GH secretion from the pituitary gland and inducing liver GH resistance due to a decrease in GH receptors, leading to a decrease in IGF-1 production (54, 57). On the other hand, ghrelin physiologically increases circulating GH, and since ghrelin secretion is impaired in obesity, this could also contribute to the reduced GH levels observed in subjects with obesity (54). Furthermore, Langendonk et al. showed that GH clearance was significantly higher in women with obesity (58) (Fig. 1B). Moreover, GH and IGF-1 inhibit the expression and activity of 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme expressed in liver and adipose tissue that converts inactive glucocorticoids to active glucocorticoids (59, 60). 11β-HSD1 expression and activity are increased in subcutaneous abdominal adipose tissue of people with obesity, with a consequent impact on cortisol metabolism (59, 61). It has been suggested that in patients with GH deficiency, enhanced activity of 11β-HSD1 results in an increase in regeneration of cortisol locally in liver and visceral fat (60), thus closing the vicious cycle of functional depression of the somatotropic axis in these patients.

Another point worth mentioning is the relationship between nickel allergy and obesity and its association with GH–IGF1 axis impairment. Nickel allergy is much more prevalent in patients with obesity than in the general population (62, 63), and its association with impaired function of the GH–IGF1 axis has been reported in human subjects (63). A recent study demonstrated that patients with overweight/obesity with nickel allergy had lower IGF-1 levels and blunted GH response upon dynamic testing and that nickel allergy also correlates with morphological abnormalities in the pituitary gland. The authors suggest that this detrimental effect could be due to increased inflammation of the pituitary gland (64).

Different studies have demonstrated that weight loss after a hypocaloric diet and after bariatric surgery drives the recovery of the somatotropic axis (14, 15, 19, 36, 41, 54, 65). Rasmussen et al. showed that 24-h GH release profiles, IGF-1 levels, and the IGF-1/IGFBP-3 ratio increased after a massive weight loss induced by a hypocaloric diet (65). Regarding bariatric surgery, a recent study that included 116 patients with severe obesity showed an increase in GH and IGF-1 levels 12 months after bariatric surgery (sleeve gastric (SG) and Roux-en-Y gastric bypass (RYGBP)) (54). In line with these results, Galli et al. studied 80 women with obesity with BMI >34 kg/m2 and showed an increase in IGF-1 levels after 2 years of follow-up, which was proportional to the amount of weight loss (15). Engström et al. studied 63 patients with obesity and described that GH and IGF-1 increased 6 and 12 months, respectively, after RYGBP (41). In our experience, with 119 patients with morbid obesity treated with bariatric surgery, we observed that total IGF-1 levels increased significantly 1 year after SG but not after RYGBP (14). According to the surgical treatment modality, these different results could be explained by the different functional nutritional consequences induced by both bariatric surgery procedures. Thus, changes in the albumin concentration after bariatric surgery were the only independent variable associated with the percentage total IGF-1 change. This scenario suggests that IGF-1 recovery after bariatric surgery is mostly related to the nutritional modifications induced by the specific surgical procedure. Free IGF-1 levels assessed by the IGF-1:IGFBP3 ratio showed an increase after 1 year of follow-up with both SG and RYGBP, mostly due to a decrease in IGFBP3 (14).

According to the European Society of Endocrinology’s Clinical Practice Guideline, measuring IGF-1 and GH is not generally recommended when evaluating people with obesity. It would only be necessary for patients with suspected structural anatomical lesions of the pituitary gland that may cause hypopituitarism (3). Assessment of somatotropic function is challenging in people with obesity and is even more challenging in those with morbid obesity since, as mentioned above, the levels of stimulated GH decrease with increasing BMI. Thus, previous studies have reported BMI-specific cut-off values for the GHRH-arginine test (66) and glucagon stimulation test (67). The Macimorelin test has been proposed as a diagnostic test for adult GH deficiency. This test has demonstrated a diagnostic accuracy similar to that of the insulin tolerance test, is well tolerated, and has a more favourable safety profile (68). Moreover, the results of a post hoc analysis of macimorelin for the diagnosis of adult GH deficiency showed that the performance of the macimorelin test is not affected by BMI, so it could be a more appropriate stimulation test for patients with obesity (69).

Gonadotropic axis dysfunction in obesity

The impact of obesity on the gonadal axis shows a sexual dimorphism, generally recognized as hypogonadism in men but hyperandrogenism in women, and affects fertility in both sexes (13, 70, 71).

Male obesity-related secondary hypogonadism

In men, obesity, particularly high visceral adipose tissue, induces androgen deficiency. This condition is now referred to as male obesity-related secondary hypogonadism (MOSH) (13, 72). The prevalence of MOSH in men with obesity based on free testosterone measurements has been reported to be approximately 30% (6). A systematic review and meta-analysis in patients with morbid obesity who underwent bariatric surgery indicated even higher figures, with a MOSH prevalence of 64% (13). MOSH is characterized by low free and total testosterone levels, together with reduced sex hormone-binding globulin (SHBG) and increased oestradiol (12, 73). Gonadotropins are low or inappropriately normal (72), thus confirming its central nature. Furthermore, the association between obesity and infertility in men has also been reported, with a negative correlation between obesity and semen quality and a reduction in the pregnancy rate after in vitro fertilization (74).

The pathophysiology of MOSH involves a vicious cycle whereby testosterone deficiency facilitates increased adipogenesis and visceral obesity, and abdominal adiposity further induces hypogonadism (71, 75). The underlying mechanisms are complex and multifactorial. First, the high levels of oestradiol from excessive peripheral conversion of testosterone in the adipose tissue exert a negative feedback effect on gonadotropin secretion (72). Secondly, it has been suggested that kisspeptins also play a central role in the modulation of gonadotropin-releasing hormone (GnRH) secretion in people with obesity (76). The kisspeptin peptide family regulates the HPT axis by stimulating its receptor KISS1R on GnRH neurons, thereby enhancing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion (77) (Fig. 1C). George et al. postulated that decreased endogenous kisspeptin secretion is the common pathway that links obesity-related metabolic and endocrine effectors at the central level in the pathophysiology of hypogonadotropic hypogonadism seen in men with obesity and T2DM (76). Insulin resistance and consequent hyperinsulinaemia and the inflammatory mediators secreted by adipose tissue, including increased leptin concentrations, act on kisspeptin neurons to decrease kisspeptin signalling, thereby also decreasing GnRH release and contributing to the pathophysiology of MOSH (13, 71, 72, 75). Leptin, in addition to its central effect, has been demonstrated to directly inhibit the production of testosterone by Leydig cells, contributing to impaired gonadal function (78).

Several studies have shown that weight loss obtained by both a hypocaloric diet and surgery leads to an improvement in MOSH and semen quality (12, 13, 74, 79, 80, 81), with bariatric surgery being more effective since it achieves greater weight loss (12). A systematic review and meta-analysis described a complete resolution of MOSH in 87% of men with obesity after bariatric surgery (13). These results are in accordance with a previous report stating that bariatric surgery induces an increase in both total testosterone and free testosterone levels, which is greater in those who lose more body weight (12). Moreover, body weight loss is also associated with an increase in SHBG and gonadotropin levels and a decrease in oestradiol (12). Together, these studies support that the inhibition of the HPT axis by factors derived from adipose tissue plays a central role in the development of MOSH (13). Calderón et al. carried out a study in 35 men undergoing bariatric surgery and showed no differences between laparoscopic gastric bypass and restrictive procedures in achieving remission of MOSH (80). Regarding fertility, there is little evidence to determine the effectiveness of weight loss on fertility outcomes. A recent systematic review on the effects of bariatric surgery on fertility showed inconsistent results on seminal outcomes; four studies evaluated the quality of semen or sperm, and only two of them reported some positive results (82).

Recent guidelines of the European Society of Endocrinology on the diagnosis of hypogonadism in obesity recommend testing for hypogonadism only in male patients with obesity with clinical features of hypogonadism and measuring testosterone, free testosterone, SHBG, FSH, and LH in these subjects (3). Since testosterone secretion has a circadian rhythm, it is recommended that the sample be taken between 7:00 and 11:00 h in the morning or within 3 h after waking up. Low testosterone concentrations must be confirmed by taking morning samples on two separate days in the fasting state. It is recommended that free testosterone levels be measured when total testosterone is in the lower limit of the normal range. However, since equilibrium dialysis, the gold standard procedure to measure free testosterone, is not widely available, it may be advised to calculate bioavailable testosterone by using testosterone, SHBG, and albumin concentrations. This recommendation applies especially to patients with obesity, as they usually have low SHBG circulating values (3). Once hypogonadotropic hypogonadism has been diagnosed, it is important to exclude hyperprolactinaemia as another cause of secondary hypogonadism (3).

Functional female hypogonadism

It is well known that obesity may also directly affect fertility in women, but the predominant mechanisms of such effects are more related to peripheral ovary hyperandrogenism than to central mechanisms (70). However, in women without hyperandrogenism, obesity may also be associated with a decrease in gonadotropin and sexual steroids, although from a clinical point of view, this effect is less obvious in women than in men. Quennell et al. showed for the first time that a high-fat diet was able to reduce Kiss1 gene expression in female rats, indicating that this biologic pathway is also a player in disrupting gonadotropic function in females with obesity (83). However, experimental models have shown that when a high-fat diet is administered, male rats are more susceptible to central hypogonadism than females (84). There is no sufficient reported information on replacement treatment of central hypogonadism in women with obesity, as most of the hormonal problems found in these subjects deal with a hyperandrogenic state. In the case of nonhyperandrogenic obese women with amenorrhea of central origin, as in other similar situations, hormonal substitution may be beneficial for the patient.

Several studies have reported an increased risk of premature mortality in patients with hypopituitarism, and this risk is especially higher in women, mainly due to the higher risk of cardiovascular events (85, 86). It has been suggested that the underdiagnosed and undertreated hormonal deficiencies could explain, at least in part, this increased mortality (87, 88), and some studies have suggested that hypogonadism is a key factor behind this increased mortality in hypopituitary women (85, 86).

Regarding fertility, more studies are needed to understand the impact of weight loss on fertility outcomes (82, 89, 90). A recent meta-analysis showed that fertility parameters, including sex hormone parameters and menstrual cycle irregularity, improved after bariatric surgery (82). Nevertheless, more studies are needed to report direct pregnancy outcomes after bariatric surgery as a specific improvement in fertility outcomes. A recent retrospective study of 872 women who underwent bariatric surgery showed that even though menstrual irregularity improved, it was not related to an improvement in fertility outcomes (89).

Lactation initiation and maintenance may also be affected by excess body fat. A reduced prolactin response to suckling and a higher-than-normal progesterone concentration in the first week after delivery have also been observed among mothers with obesity, thus compromising neonatal feeding in the first days after delivery (91). It has been observed that the normal decrease in progesterone concentration early after delivery does not take place in these mothers due to potential obesity-related hyperprogesteronaemia. Consequently, it has been proposed that the appropriate low concentrations of this sex steroid that would allow the initiation of active lactogenesis are not produced, although the results of current studies are inconsistent with such a pathogenic mechanism (91). Therefore, the normal neurogenic suckling stimulus is unable to trigger the physiological response at the central level with a disturbed lactogenic response. This has been confirmed by the clinical observation of an excess of breastfeeding failures in obese women in comparison to the lean population (92).

Corticotropic axis dysregulation in obesity

Abdominal obesity is associated with dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis (93). Data accumulated in the last decade suggest that obesity is characterized by an overstimulation of the HPA axis (94). Nevertheless, the prevalence of Cushing syndrome in obesity is low, ranging from 0 to 0.7% (3). Although basal concentrations of cortisol and adrenocorticotrophic hormone (ACTH) do not appear to be different in people with obesity compared to lean individuals (95), dynamic testing using corticotrophin and arginine vasopressin in combination shows an enhanced ACTH response in obesity (96). In addition, the declining curve of daily cortisol secretion is usually less pronounced in obesity (97). Basal adrenal parameters may differ according to whether obesity has a strong abdominal component; thus, in the former, early-morning salivary cortisol is lower, while the meal response is higher (98). Moreover, obesity is associated with increased cortisol clearance, which in fact would preclude a compensatory modification at the central level and would explain the hyperresponsiveness to stimulatory tests (99).

Another very well-known effect of obesity on the HPA axis is a relatively blunted response to the dexamethasone screening test leading to false-positive results, which adds more difficulties in the endocrine work-up in the case of suspicion of Cushing syndrome in a patient with obesity. Nevertheless, 1 mg late-night dexamethasone suppression is the screening method recommended to detect Cushing syndrome in obesity. Moreover, urinary-free cortisol and late-night salivary cortisol measurements are recommended after 1 mg late-night dexamethasone suppression to establish or rule out the diagnosis of Cushing syndrome (3).

Weight loss tends to normalize alterations in the HPA axis (94, 100). Immediately after bariatric surgery, cortisol increases due to the acute stress by the surgery itself. However, current evidence regarding the long-term effects of bariatric surgery on the HPA axis suggests that the overstimulation of the HPA axis in obesity is reduced after bariatric surgery and that circadian rhythms might be normalized (94, 101, 102). Nevertheless, these studies use different methodologies for assessing the HPA axis, which makes it difficult to compare the data and to have clear conclusions, and controversial results have been found regarding the direction of this regulation (94).

The Clinical Practice Guideline of the European Society of Endocrinology recommends testing for hypercortisolism in the presence of clinically suspicious features of hypercortisolism in patients with obesity, with special attention to ruling out Cushing syndrome in those patients who are candidates for bariatric surgery (3).

Other hypothalamic–pituitary alterations related to obesity

Idiopathic intracranial hypertension

Obesity and weight gain are known risk factors for idiopathic intracranial hypertension (IIH), also known as pseudotumour cerebri. The cause of IIH is unknown, but one theory linking obesity and IIH suggests that the increased intraabdominal pressure that occurs in obesity raises cardiac and pleural pressures, which in turn impedes venous return in the brain and results in elevated intracranial pressure (103).

Weight loss is an essential part of the treatment for IIH, and it has been demonstrated that weight loss after a low-energy diet or after bariatric surgery is associated with complete remission or considerable improvement in the signs and symptoms associated with IIH (103, 104, 105, 106). A recent randomized clinical trial with 66 women with obesity with IIH demonstrated that bariatric surgery was more effective than community weight management intervention in reducing intracranial pressure because of the greater sustained weight loss (107).

Primary empty sella

An increase in intracranial pressure is proposed to be one of the pathogenic mechanisms involved in primary empty sella (PES) (108). More than 94% of patients with IIH already carry an empty sella (109). The prevalence of obesity in patients with PES is high. Specifically, between 50 and 80% of women with PES are overweight or obese (108, 110). Interestingly, the results of a cross-sectional study of 906 patients showed that among 70 individuals with obesity with GH deficiency, 98% showed a complete or partial ES (111). This close relationship between ES and GH deficiency points out the possibility of the organic nature of GH deficiency in a portion of people with obesity (111).

Morphologic abnormalities of the pituitary gland

Obesity is also associated with changes in the morphology of the pituitary gland. In individuals with Prader–Willi syndrome, a syndromic case of morbid obesity, pituitary abnormalities have been reported, including empty sella, absent or small posterior pituitary gland, and marked pituitary gland hypoplasia (112). A case–control study that included 27 patients with Prader–Willi syndrome and 16 patients with unknown causes of early-onset morbid obesity showed that both had a high prevalence of morphological and functional pituitary gland abnormalities compared to those of the control groups (112).

Hypothalamic dysfunction

The hypothalamus regulates whole-body energy homeostasis, as well as pituitary function. A recent study has suggested that structural and functional hypothalamic dysregulation can be involved in the development and progression of obesity (113). Moreover, it is well known that hypothalamic tumours, such as craniopharyngiomas, are frequently associated with excessive weight gain and hypothalamic obesity (114). On the other hand, as previously mentioned in this review, hypothalamic function itself could be compromised by excess peripheral fat accumulation. In experimental models, overnutrition has been followed by hypothalamic inflammation and local impaired neurogenesis, with increased neuron apoptosis and synaptic defects, loss of plasticity, and dysfunction of the blood–brain barrier (115). In this regard, potential modifications of leptin permeability might be part of the pathophysiologic mechanisms involved in leptin resistance at the central level, in part originating from diminished transport of leptin into the brain (116). Moreover, it has been radiologically demonstrated that hypothalamic gliosis is improved in women with obesity and type 2 diabetes after bariatric surgery (117).

Implications of obesity treatment for hypothalamic pituitary function

The treatment of hypothalamic obesity remains a challenge. Different drugs targeting the hypothalamus have been used in the last 20 years. In this regard, amphetamine-like compounds such as fenproporex or the beta-phenethylamine derivative compound sibutramine, which affects the reuptake of noradrenaline and serotonin, may strongly modulate pituitary function at different levels, either directly or through activating or deactivating different hypothalamic nuclei. Thus, it has been shown that these two drugs used for obesity treatment for years with central actions have different effects upon modification of central leptin resistance when compared with orlistat, a compound with intestinal effects but without known central actions (118).

Glucagon‐like peptide‐1 receptor agonist (GLP-1 RA) agents have been proposed as a recent novel approach for patients with obesity (119). Different hypothalamic nuclei are enriched in GLP-1 receptors; the hypothalamus is a target for drugs that decrease appetite, such as GLP-1 RA. A randomized clinical trial conducted with adolescents and young adults with a diagnosis of hypothalamic obesity following treatment for craniopharyngioma showed that GLP‐1 RA therapy led to a reduction or stabilization in BMI and adiposity, supporting the potential benefit of these drugs not only for general obesity but also for the type that is more resistant to therapy, which is hypothalamic obesity (119). In addition, GLP-1RA has a potential direct impact on the HPT axis, as reported in animal models, while in humans, it is not clear if a direct action is present or if the improvement in gonadal function is a consequence of weight loss rather than the compound itself (120). Little is known regarding the potential direct effect of the different anti-obesity compounds, but those with known action at the hypothalamic level may be of relevance in the amelioration of pituitary function in people with obesity, thus gaining justification for their use even before an insufficient effect of lifestyle changes is observed.

Should replacement treatment of pituitary defects be considered in people with obesity?

Recommendations regarding thyroid hormone replacement treatment are not easy to formulate, and as a consequence, most guidelines indicate that patients with obesity with hyperthyrotropinaemia and normal FT4 levels should not be systematically treated with the aim of losing weight (3, 17).

Regarding the somatotropic axis, many studies have shown that GH treatment in obese adults has favourable effects on body composition, leading to a decrease in visceral adiposity and an increase in lean body mass. Moreover, these studies also showed a beneficial effect on lipid profiles and glucose metabolism (55, 121, 122). However, the dose of GH replacement treatment in many of them was supraphysiological and its impact on cardiovascular morbidity is not known (121). Therefore, the clinical use of GH replacement in obesity still remains controversial, as clinical practice guidelines state that GH treatment is not indicated unless there is clear evidence of organic GH deficiency but not in dysfunctional situations (3, 4). However, an important aspect to have in mind is the potential benefit of GH replacement treatment during the early post-operative period after bariatric surgery to prevent sarcopenia and excess muscle loss while losing weight. In this regard, a prospective study in women with morbid obesity with persistently low GH/IGF-1 levels after bariatric surgery showed that GH treatment reduces the loss of lean body mass and improves the lipid profile (123).

Regarding the treatment of MOSH, weight loss is a very effective therapeutic measure. However, if symptoms of hypogonadism do not improve or androgen levels do not recover at the same time as weight loss, testosterone replacement treatment could be considered (3, 4). A prospective study of 261 hypogonadal men who received testosterone replacement treatment showed that increasing the levels of testosterone to normal physiological levels was associated with a decrease in body weight, waist circumference, and BMI (124), and in some subjects with obesity, full testosterone recovery was not observed despite active weight loss.

Given that excess adipose tissue is the common biologic origin of changes in pituitary function described above, it seems reasonable to conceptualize that, to reverse the changes, a weight loss treatment is necessary. Whenever possible, ‘wait and lose weight’ is the cardinal goal in these patients. However, some of these patients will not achieve sufficient weight loss, or surgical treatment may not be indicated. Therefore, a personalized approach would be applied in these cases, with a very cautious management of hormonal substitution, while taking into account that pituitary hormonal dysregulation clearly observed in severely affected obese patients may also be operative in less severe obese patients. An active debate is ongoing on whether a combination of small doses of the missing hormones might be justified for these patients or whether this would be an aberration. Clinical studies that address and answer this question are lacking, and it would likely be informative to perform such studies.

Conclusions

The impact of obesity at the pituitary level leads to endocrine dysfunction involving the thyrotropic, gonadotropic, somatotropic, and corticotropic axes. Moreover, these abnormalities per se also induce changes in body composition, further increasing weight and adipose tissue, which perpetuate a biological vicious cycle. Obesity-related pituitary dysfunction is considered a potentially reversible situation and, in most cases, could be ameliorated or completely reverted with medical- or surgery-induced weight loss.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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     European Society of Endocrinology

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    Pathogenic mechanisms implicated in pituitary dysfunction in obesity. (A) Thyrotropic dysfunction. Leptin secreted by excess adipose tissue enhances thyrotropin-releasing hormone (TRH) expression and synthesis in the hypothalamus and stimulates serum thyroid-stimulating hormone (TSH) secretion by the pituitary gland. Leptin affects the activity of thyroid deiodinases with activation of thyroxine (T4) to triiodothyronine (T3) conversion. (B) Somatotropic dyshomeostasis. Altered ghrelin secretion contributes to reduced growth hormone (GH) levels. The dysmetabolic combination of high circulating free fatty acids (FFAs) and the inflammatory milieu negatively influences GH release by the hypothalamus. This inflammatory profile contributes to the induction of liver GH resistance, accounting for a decrease in insulin-like growth factor (IGF-1) production. GH clearance is significantly higher. The decreased GH and IGF-1 levels contribute to an increase in adipogenesis, as well as a decrease in muscle mass. (C) Gonadotropic function impairment. Insulin resistance, inflammation, increased leptin concentrations, and decreased endogenous kisspeptin secretion have an inhibitory effect on the hypothalamic–pituitary–testicular (HPT) axis. Leptin inhibits the production of testosterone by Leydig cells. The high levels of oestradiol from excessive peripheral conversion of testosterone in the adipose tissue have a negative feedback effect on gonadotropin secretion. Testosterone deficiency facilitates increased adipogenesis and visceral obesity.

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