Barocrinology: The Endocrinology of Obesity from Bench to Bedside

Obesity has reached pandemic proportions. Hormonal and metabolic imbalances are the key factors that lead to obesity. South Asian populations have a unique phenotype, peculiar dietary practices, and a high prevalence of consanguinity. Moreover, many lower middle-income countries lack appropriate resources, super-specialists, and affordability to manage this complex disorder. Of late, there has been a substantial increase in both obesity and diabesity in India. Thus, many more patients are being managed by different types of bariatric procedures today than ever before. These patients have many types of endocrine and metabolic disturbances before and after bariatric surgery. Therefore, these patients should be managed by experts who have knowledge of both bariatric surgery and endocrinology. The authors propose “Barocrinology”, a novel terminology in medical literature, to comprehensively describe the field of obesity medicine highlighting the role of knowing endocrine physiology for understating its evolution, insights into its complications and appreciating the changes in the hormonal milieu following weight loss therapies including bariatric surgery. Barocrinology, coined as a portmanteau of “baro” (weight) and endocrinology, focuses upon the endocrine and metabolic domains of weight physiology and pathology. This review summarizes the key pointers of bariatric management from an endocrine perspective.


Introduction
Obesity has become a global pandemic, with numbers nearly tripling since 1975 [1]. Initially thought to be a disease of the developed world, it has now shown to be a rapidly increasing trend even in the Indian subcontinent [2]. The World Health Organization (WHO) defines obesity and overweight as an "abnormal or excessive fat accumulation that presents a risk to health" [3].
Obesity is characterized by several hormonal disturbances. These can be primary abnormalities which can contribute to the development of obesity. Alternatively, there can be secondary abnormalities which can often be reversed by weight loss. Obesity is also the symptom of many endocrine disorders, and treating these disorders can cause weight loss.
Obesity has conventionally been managed as a disease that results from an imbalance between energy intake and energy expenditure. However, it is now understood as a "neurohormobehavioral" Table 1. Syndromic obesity [6,9].

Endocrine Hormone Levels in Obesity and Weight Loss
Endocrine hormone changes in obesity and after achieving weight loss are shown in Table 2 [12][13][14]. Table 2. Hormonal changes in obesity and after weight loss [12,13,15].

Anthropometric Evaluation in Endocrinopathy
Anthropometric evaluation is a part of detailed clinical and systemic examination of a patient presenting with obesity. Body mass index (BMI) is the most commonly utilized tool for measuring obesity. It is a measure of a person's weight in kilograms divided by the square of the height in meters. The BMI classification obesity for adults by the World Health Organization and in Asian sub-continents is given in Table 4. Though BMI is more accurate than skin-fold measurements in community settings, and provides a reasonable estimate of body fat, it has certain limitations. BMI does not distinguish between lean mass and fat mass, nor throws light on fat distribution. The literature shows that body fat distribution and not excess weight is associated with many obesity-related risk factors [21][22][23][24]. Accurate body fat estimation techniques like computed tomography or magnetic resonance imaging are very costly and require sophisticated equipment [25]. Hence, these cannot be routinely used in community settings. Therefore, along with BMI assessments for classifying obesity, waist circumference (WC) and waist-hip ratios (WHR) can be measured to assess body fat distribution (subcutaneous vs. visceral) [13,24,26,27]. Visceral fat, and not the subcutaneous fat ( Figure 1) is comparatively more significantly linked with metabolic syndrome [24]. Table 5 shows the predictive value of BMI, WC, and WHR in capturing subcutaneous fat [13,28]. Though BMI is more accurate than skin-fold measurements in community settings, and provides a reasonable estimate of body fat, it has certain limitations. BMI does not distinguish between lean mass and fat mass, nor throws light on fat distribution. The literature shows that body fat distribution and not excess weight is associated with many obesity-related risk factors [21][22][23][24]. Accurate body fat estimation techniques like computed tomography or magnetic resonance imaging are very costly and require sophisticated equipment [25]. Hence, these cannot be routinely used in community settings. Therefore, along with BMI assessments for classifying obesity, waist circumference (WC) and waisthip ratios (WHR) can be measured to assess body fat distribution (subcutaneous vs. visceral) [13,24,26,27]. Visceral fat, and not the subcutaneous fat ( Figure 1) is comparatively more significantly linked with metabolic syndrome [24]. Table 5 shows the predictive value of BMI, WC, and WHR in capturing subcutaneous fat [13,28].    Moreover, a recent study in the Indian population revealed that WC, WHR, and waist:height ratio (WHtR) were the most appropriate obesity indicators that predict T2DM. WC, WHR, and WHtR values were significantly higher in patients with T2DM than in those without (p < 0.001). The receiver-operating characteristic (ROC) curve analyses showed that these three obesity indicators identified well with T2DM. The ROC for WHR was 0.67 (95% confidence interval [CI] 0.59, 0.75), WHtR was 0.66 (95% CI 0.57, 0.75), and for WC, was 0.64 (95% CI 0.55, 0.73) [30].
Furthermore, certain surrogate measures of visceral adipose tissue estimation, like METS-VF, have also been validated, and can be useful adjuncts to predict VAT content in resource-limited settings [31].

Approach to Evaluating Syndromic Obesity
Since patients with syndromic obesity have characteristic dysmorphic features, a detailed family history and clinical examination is the starting point of evaluation of syndromic obesity. Endocrine abnormality and genetic defects are tested in cases highly suspicious of a particular syndrome ( Figure 2) [32]. Moreover, a recent study in the Indian population revealed that WC, WHR, and waist:height ratio (WHtR) were the most appropriate obesity indicators that predict T2DM. WC, WHR, and WHtR values were significantly higher in patients with T2DM than in those without (p < 0⋅001). The receiveroperating characteristic (ROC) curve analyses showed that these three obesity indicators identified well with T2DM. The ROC for WHR was 0⋅67 (95% confidence interval [CI] 0⋅59, 0⋅75), WHtR was 0⋅66 (95% CI 0⋅57, 0⋅75), and for WC, was 0⋅64 (95% CI 0⋅55, 0⋅73) [30].
Furthermore, certain surrogate measures of visceral adipose tissue estimation, like METS-VF, have also been validated, and can be useful adjuncts to predict VAT content in resource-limited settings [31].

Approach to Evaluating Syndromic Obesity
Since patients with syndromic obesity have characteristic dysmorphic features, a detailed family history and clinical examination is the starting point of evaluation of syndromic obesity. Endocrine abnormality and genetic defects are tested in cases highly suspicious of a particular syndrome ( Figure  2) [32].  [32]. Abbreviations: BDNF, brain derived neurotrophic factor; MC4R, melanocortin-4 receptor; POMC, proopiomelanocortin; SIM1, single-minded homolog 1; TrKB, tyrosine kinase B.

Endocrine Impact of Non-Pharmacological Management of Obesity
Non-pharmacological management of obesity includes lifestyle changes, such as diet and exercise. Stress in everyday life is known to be associated with endocrine responses that contribute to obesity. Hence, stress management is an important factor in the endocrine management of obesity.  [32]. Abbreviations: BDNF, brain derived neurotrophic factor; MC4R, melanocortin-4 receptor; POMC, proopiomelanocortin; SIM1, single-minded homolog 1; TrKB, tyrosine kinase B.

Endocrine Impact of Non-Pharmacological Management of Obesity
Non-pharmacological management of obesity includes lifestyle changes, such as diet and exercise. Stress in everyday life is known to be associated with endocrine responses that contribute to obesity. Hence, stress management is an important factor in the endocrine management of obesity.

Potential Endocrine/Metabolic Impact of Exercise
Exercise impacts all the endocrine glands. During exercise, the pituitary releases growth hormones, the thyroid releases T4, and the adrenals release cortisol and aldosterone. All these hormones increase the body's capacity to exercise, stay alert, focus on the high-intensity task, provide energy for the exercise, and prevent dehydration (especially aldosterone). Exercise releases endorphins which help reduce anxiety and stress. Exercise also increases release of testosterone [33].
The level and type of hormone differs with the type and stage of exercise. Together, the hormones increase lipolysis, peripheral utilization of glucose, increase protein synthesis and muscle-building (in strength training exercises), and bring about the beneficial effects of increased body energy and weight loss, especially in individuals with obesity [34,35].
Exercise also increases insulin sensitivity, which helps in utilization of glucose and reduces postprandial insulinemia. Timing of nutrients is important for bringing out the best results of an exercise. A study found that whole-body and skeletal-muscle lipid utilization increased if an exercise was done before a mixed-macronutrient meal, including 65% of kcal carbohydrate versus exercise, was performed after taking the meal. The lipid utilization increased two-fold when this exercise was continued for six weeks [36].
Hence, all patients undergoing bariatric surgery should be encouraged to take up physical activity. A proper exercise plan should be built into their routine as per their capability. Exercise should include both aerobic exercises and strength training. Exercise also helps release endorphins, which help combat stress. The various endocrine and metabolic benefits of exercise are shown in Figure 3. Exercise impacts all the endocrine glands. During exercise, the pituitary releases growth hormones, the thyroid releases T4, and the adrenals release cortisol and aldosterone. All these hormones increase the body's capacity to exercise, stay alert, focus on the high-intensity task, provide energy for the exercise, and prevent dehydration (especially aldosterone). Exercise releases endorphins which help reduce anxiety and stress. Exercise also increases release of testosterone [33].
The level and type of hormone differs with the type and stage of exercise. Together, the hormones increase lipolysis, peripheral utilization of glucose, increase protein synthesis and musclebuilding (in strength training exercises), and bring about the beneficial effects of increased body energy and weight loss, especially in individuals with obesity [34,35].
Exercise also increases insulin sensitivity, which helps in utilization of glucose and reduces postprandial insulinemia. Timing of nutrients is important for bringing out the best results of an exercise. A study found that whole-body and skeletal-muscle lipid utilization increased if an exercise was done before a mixed-macronutrient meal, including 65% of kcal carbohydrate versus exercise, was performed after taking the meal. The lipid utilization increased two-fold when this exercise was continued for six weeks [36].
Hence, all patients undergoing bariatric surgery should be encouraged to take up physical activity. A proper exercise plan should be built into their routine as per their capability. Exercise should include both aerobic exercises and strength training. Exercise also helps release endorphins, which help combat stress. The various endocrine and metabolic benefits of exercise are shown in Figure 3. More recently, emerging literature has also highlighted the role of skeletal muscle as a secretory organ and its role in the regulation of body fat metabolism. Myokines induced by physical activity and muscle contraction have paracrine effects on the muscle. They promote myogeneisis and muscle hypertrophy in the individual. Beyond the muscle, they also assist in promoting glucose uptake, More recently, emerging literature has also highlighted the role of skeletal muscle as a secretory organ and its role in the regulation of body fat metabolism. Myokines induced by physical activity and muscle contraction have paracrine effects on the muscle. They promote myogeneisis and muscle hypertrophy in the individual. Beyond the muscle, they also assist in promoting glucose uptake, lipolysis, β-oxidation of fat, angiogenesis, and revascularization. Muscular irisin, β-aminoisobutyric acid (BAIBA), and fibroblast growth factor 21 (FGF21) may also lead to conversion of white adipose tissue to brown adipose tissue. Overall, they improve lipid and glucose profiles in the individual [37], a potential endocrine/metabolic of impact of stress management A patient going for bariatric surgery is under a lot of stress. Bariatric surgery, like any other surgery, induces stress in the body. Any stressful situation triggers the hypothalamic-pituitary-adrenal (HPA) axis to release hormones to combat this stress. The corticotrophin-releasing hormone (CRH) is then released from the hypothalamus, which activates the anterior pituitary to release ACTH, which in turn stimulates the adrenal cortex to release glucocorticoids. Stimulation of the HPA also releases catecholamines and vasopressin [38]. There is downregulation and thus a decrease in circulating gonadotropins and gonadal steroid hormones, T3 and T4. Growth hormone release increases, the prolactin level can either increase or decrease, and the insulin level may decrease [38].
As a net result, there is poor glycemic control and preponderance of central fat deposition. The secretion of orexogenic hormone ghrelin increases, resulting in increased appetite and food intake [39]. Therefore, proper stress management is important to avoid these obesity-contributing factors before and after bariatric surgery. Proper counseling and an addressing of ways to combat stress should be sought from a trained psychologist.

Potential Endocrine/Metabolic Impact of Diet
Calorie restriction is the main component of weight-loss dieting. This calorie restriction impacts the endocrine system. There is a fall in T 3 and gonadal function, and an increase in cortisol secretion [40]. Low-calorie diets aid T2DM reversal and improve the lipid profile [41].
A ketogenic diet (high-fat, low-carbohydrate, with adequate proteins) results in higher glucagon and cortisol levels before, during, and after aerobic exercise. Glucagon levels and, to a lesser extent, cortisol levels were associated with a more than two-fold increased peak fat oxidation rate [43].

Medical Nutrition Therapy (MNT)
Diet therapy in obesity may include MNT/formula MNT. The metabolic goals of MNT can vary, and include the lowering of blood pressure, serum cholesterol, and/or fasting blood glucose [44]. In patients with obesity who have an endocrine disease, planned diet restrictions are aimed at improving the gland function.
The landmark Diabetes Remission Clinical Trial (DiRECT) included patients with T2DM and BMIs of 27-45 kg/m 2 in intervention and control groups (n = 149 each; intent to treat). In the intervention group, the total diet was replaced with a formula diet of 825-853 kcal/day for 3-5 months. Their antidiabetic and antihypertensive drugs were withdrawn, and food was carefully stepped up and reintroduced over a period of 2-8 weeks. The control group did not receive formula MNT. All patients received structured support for maintaining long-term weight loss. At 12 months, weight loss of 15 kg or more was recorded in 24% and 0% of participants in the intervention and control groups, respectively (Fisher's exact p < 0.0001). Diabetes remission was achieved in 46% and 4% of participants in the intervention and control groups, respectively (odds ratio 19.7, 95% CI 7.8-49.8; p < 0.0001) [45]. Since the DiRECT trial included patients with T2DM with characteristics similar to patients in routine practice, the results of the trial can be generalized to a wider population [46].
Another trial showed that structured MNT improves glycemic and cardiovascular parameters. Three groups of patients received MNT from a registered nutritionist (RDN). Group A received an individualized eating plan, and Groups B and C received a structured meal plan; Group C also received weekly phone support from RDN. After 16 weeks, there was no change in HbA1c from baseline in Group A, but HbA1c decreased significantly in Groups B and C (−0.66%, 95% CI -1.03 to −0.30 and −0.61%, 95% CI −1.0 to −0.23, respectively; p < 0.001). Groups B and C also showed significant reductions in body weight and cardiovascular parameters, such as body fat percentage and waist circumference [47].
The effect of long-term calorie-restricted diets (CR) with adequate protein and micronutrient intake on thyroid function was compared with age-and sex-matched sedentary (WD), and body-fat-matched exercising (EX) subjects (n = 28 each; all subjects were healthy lean and weight-stable). The CR group had lower serum T3 concentration than the WD and EX groups (p ≤ 0.001). However, serum TSH, total and free T4 (fT4), and reverse T3 concentrations were similar among groups [48]. Another study showed that a low-calorie diet program was associated with a significant increase in free T3, fT4, and significant decrease in TSH, leptin, and BMI compared to baseline [49].
Moderate dietary restrictions in 47 subjects with BMIs of 25-45 kg/m 2 resulted in weight loss of 6.3 ± 0.9 kg (6.5 ± 1.0%). TSH and T3 concentrations correlated significantly with fat mass (p = 0.024 and p = 0.005, respectively) at baseline. T3 decreased significantly after weight loss (p < 0.001) but there were no significant changes in TSH or fT4. There was a significant correlation between decrease in serum T3 and decrease in weight (p < 0.001). There was a significant decrease in T3:fT4 ratio (p = 0.02) in subjects who lost >5% of body weight [50].

Endocrine Impact of Weight-Reducing Drugs
There are six major anti-obesity medications approved by the U.S. Food and Drug Administration (FDA): orlistat, phentermine, phentermine-/topiramate-extended release (ER), lorcaserin-, liraglutide-, and naltrexone-sustained release (SR)/bupropion SR (only injectable) ( Table 6). Most of these drugs either reduce appetite or enhance satiety, except orlistat, which works by decreasing fat absorption [51]. In patients with obesity with T2DM, glucagon-like peptide-1 receptor agonists (GLP-1 RA), like semaglutide and dulaglutide, help control hyperglycemia and reduce weight. GLP-1 RAs act on alpha cells of the pancreas to inhibit glucagon secretion, and have extra-pancreatic effects, such as increased satiety and delayed gastric emptying [52]. Thus, their impact is mainly on the gut endocrine system, and is similar to but less than that achieved by bariatric surgery. Further details are covered under bariatric surgery. Table 6. Pharmacotherapy of obesity [51].

Weight Impact of Endocrinotropic Drugs
Many medications used to treat comorbidities have an endocrinotropic effect, which means they act on the endocrine system. Hence, these drugs can contribute to hyperglycemia, and thus T2DM [53], dyslipidemia, and body fat redistribution that favors central and visceral obesity with or without subcutaneous fat atrophy (lipodystrophy) [54], non-alcoholic steatohepatitis (NASH), and metabolic syndrome [55].
For treating co-morbid conditions during the pre-and post-bariatric surgery period, clinicians should cautiously choose medications that will be used over a long period and have weight gain as a side-effect. Common medications likely to cause weight gain include antipsychotics, antidiabetics, antihypertensives, antidepressants, and antihistaminics. Medications for co-morbid conditions that are either weight-neutral or have weight loss as a side effect should be preferred over medications that have weight gain as a side effect (Table 7) [56,57]. However, these medications prescribed for co-morbid conditions that have weight loss as a side effect should not be solely prescribed with the intention of losing weight. Table 7. Medications prescribed and their treatment profile [56,57].

Endocrine Impact of Bariatric Surgery
The anatomic changes post-bariatric surgery result in reduced appetite, reduced food consumption, and change in gut hormone secretion. Together, these changes profoundly improve the overall systemic metabolic profile [58]. Apart from dramatic weight loss benefits, bariatric surgery significantly improves insulin resistance and leads to resolution of type 2 diabetes in many cases [59]. Other benefits of bariatric surgery include reduction in other comorbidities, such as osteoarthritis, obstructive sleep apnea, respiratory dysfunction, gonadal dysfunction, and improvement in symptoms of polycystic ovarian syndrome (PCOS) in women and androgen deficiency in men, known as male obesity-associated secondary hypogonadism (MOSH) [60][61][62][63], improvement in physical function and quality of life [64], as well as the lowering of triglyceride levels, improvement in HDL-C levels, and resolution of cardiovascular risk factors [65][66][67][68][69][70][71][72].

Impact of Bariatric Surgery on Islet Function, Insulin Secretion, and Glucose Control
All bariatric surgery procedures modify the gastrointestinal tract in different ways, but all procedures improve the status of T2DM. This reduction in hyperglycemia that is achieved post-surgery is superior to that achieved through medical and lifestyle management [73].
Of the various bariatric procedures (Figure 4), studies show that biliopancreatic diversion (BPD) gives the most benefits in T2DM remission, sustained weight loss, and improved lipid profile. However, this is a complex procedure and has more post-operative complications than other procedures, and hence, is less used. Of the commonly used procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) provide similar benefits for T2DM remission, metabolic profile, and weight loss [74]. The glucose control post-BPD, -RYGB, and -SG is independent of weight loss, but improves significantly with loss of weight. The glucose control after laparoscopic adjustable gastric banding (LAGB) is similar to that achieved through dietary restrictions, and is less than that achieved through BPD, RYGB, and SG [73].
Enteral signals after bariatric surgery stimulate the islet β-cells to secrete insulin. Additionally, postprandial GLP-1 secretion increases after RYGB or SG (Table 6), which in turn further enhances insulin secretion [73]. In addition, insulin sensitivity improves after RYGB, SG, BPD, and LAGB. procedures, and hence, is less used. Of the commonly used procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) provide similar benefits for T2DM remission, metabolic profile, and weight loss [74]. The glucose control post-BPD, -RYGB, and -SG is independent of weight loss, but improves significantly with loss of weight. The glucose control after laparoscopic adjustable gastric banding (LAGB) is similar to that achieved through dietary restrictions, and is less than that achieved through BPD, RYGB, and SG [73].

Hormonal Impact of Bariatric Surgery on Hypoglycemia
Hypoglycemia is a serious complication after bariatric surgery. After gastric bypass, there is a marked decrease in levels of glucagon, cortisol, and catecholamine in response to hypoglycemia. The sympathetic nerve response to hypoglycemia also decreases. The growth hormone response is delayed, but its peak level is higher than seen pre-surgery. Though GLP-1 and gastric inhibitory polypeptide levels rise during hypoglycemia, the response is lower compared to the pre-surgery level. Therefore, gastric bypass results in re-wiring of glucose homeostasis, which reduces neurohormonal responses to hypoglycemia, and therefore, the symptoms of hypoglycemia [75]. Post-bariatric surgery hypoglycemia is therefore difficult to diagnose, and clinicians should remain alert about its possibilities.

Impact of Bariatric Surgery on Gut Hormones: Hunger and Satiety
Significant changes in gut hormones are brought about by RYGB, SG, BPD, duodenal switch (DS), LAGB, and jejunoileal bypass. These changes in gut hormones positively stimulate satiety and reduce hunger, and are thought to be responsible for the metabolic improvements seen post-bariatric surgery (Table 8) [73,[76][77][78]. Table 8. Gut hormones and their actions and effects; three common bariatric procedures on gut hormone regulation [77].

Hormone
Organ

Impact of Bariatric Surgery on Energy Expenditure
Bariatric surgery induces weight loss. However, this weight loss may disproportionately reduce the resting energy expenditure (REE) and fat-free mass (FFM; trunk organ mass, skeletal mass) which may predispose these patients to weight regain and sarcopenia. A study showed significant REE (mean ± standard error) differences between patients who had RYGB versus controls were 43.2 ± 34 kcal/day (p = 0.20) at one year; (−)27.9 ± 37.3 kcal/day (p = 0.46) at the second year; and 114.6 ± 42.3 kcal/day (p = 0.008) at year five. Compared to controls, patients who had RYGB had greater trunk organ mass (~0.4 kg) and less skeletal mass (~1.34 kg) at each visit [79].
Another study compared the REE and thermic effect of food (TEF) between adolescent females who underwent SG versus controls. The study found that fasting REE and post-meal TEF did not differ between the groups. However, compared to controls, patients who underwent SG consumed less daily energy during their usual food intake, had lower postprandial glucose, but higher insulin and C-peptide [80]. The literature shows that obesity-related alterations in the somatotropic axis (Table 1) are restored after bariatric surgery. GH secretion has been found to increase significantly after BPD [81]. Partial recovery of the somatotropic axis has been reported after RYGB (a procedure with both malabsorptive and restrictive components) [82,83]. There is about a 2.7-fold increase in GH after malabsorptive procedures (BPD, DS), as compared to a 1.4-fold increase after restrictive procedures (LAGB), with similar benefits in cardiovascular profile and BMI reduction. Hence, malabsorptive procedures may be better suited for patients with somatotropic deficiencies [82,84]. However, further research involving large trials is necessary to confirm this benefit.
Another study showed that the GH and IGF-1 levels that were compromised in patients with severe obesity were increased after RYG at 6 months in women, and at 12 months in both men and women. BMI reduced for both men and women at 6 months, and the reduction improved by 12 months post-surgery [85].
In patients with obesity who underwent LAGB, the GH response to stimulus (GHRH with arginine) before and after surgery was found to be significantly associated with body composition. Weight loss and improvement in body composition was higher in patients with somatotropic axis alterations who recovered their GH response to stimuli after surgery [86,87]. These benefits were also seen in patients who had no somatotropic axis alterations. Hence, alterations in the somatotropic axis may be a useful tool to assess the patient's response to bariatric surgery [87]. However, GH should not be used to treat obesity in patients with normal GH levels.
IGF-1 secretion usually shows a slower response after bariatric surgery, even though conflicting reports have been published [84,88]. The response is similar to that seen in weight loss achieved through non-surgical means. This could be due to the catabolic status induced by bariatric surgery because of the malabsorptive and diet-/calorie-restrictive effects [85,89].

Impact of Bariatric Surgery on Hypothalamic/Pituitary/Gonadal Axes in Women
Women with obesity can have sub-fertility, or infertility. Though PCOS is the most common gonadal dysfunction in women with obesity, idiopathic hypogonadotropic hypogonadism is also associated with increased prevalence of obesity [63,90].
A study showed that sexual dysfunction, as assessed by the Female Sexual Function Index score, improved in about 68% of women with obesity, but this improvement was not dependent on surgery type or amount of weight loss achieved [91]. Bariatric surgery helps restore the disturbed levels of gonadotropin-releasing hormones (GnRH)/follicle-stimulating hormones (FSH), luteinizing hormones (LH)/testosterone, and estradiol (Table 1) to near normal levels.
Abdominal adiposity in women with PCOS results in a vicious circle where visceral fat promotes formation of excess androgen from the ovaries and adrenals, and the excess androgens in turn favor body fat deposition. Women who have excess androgen secretion due to a primary defect in steroidogenesis are predisposed to androgen excess disorders. These women are also predisposed to developing PCOS in response to visceral fat accumulation and obesity [92]. Therefore, women who do not have this primary defect in steroidogenesis do not develop PCOS, even if they have extreme obesity or insulin resistance [93].
Gonadal dysfunction in women with PCOS improves, and may even resolve with weight loss [94]. A meta-analysis showed that the pre-to post-operative PCOS status improved from 45.6% to 6.8% at one year post-bariatric surgery [95]. This improvement in PCOS status is brought about by weight loss achieved through bariatric surgery, and maintained through medication and lifestyle modification. Studies show that this improvement post-bariatric surgery correlates with a decrease in serum total testosterone, androsterone, and sulfate dehydroepiandrosterone (DHEA) with resolution of menstrual irregularities and hirsutism. Serum estradiol, FSH, and SHBG levels also improve (Table 1) [14,[96][97][98]. In the study by Sarwer et al. (2014), women who underwent RYGB or LAGB showed significant improvement in sexual desire and function, along with improvement in body image and decrease in depressive symptoms. However, results from these studies should be weighed cautiously as the definition of PCOS varies from study to study, making comparisons difficult.
Women who have PCOS also face issues of sub-fertility or infertility. However, studies looking into the improvement in fertility with bariatric surgery are scarce. In a study, 24 women with PCOS and obesity who achieved weight loss post-RYGB saw an improvement in menstrual irregularities and hirsutism. Additionally, five patients who could not conceive pre-RYGB, conceived after surgery [99].
In 20 women with PCOS and gonadal dysfunction who underwent RYGB, 82% saw an improvement in gonadal dysfunction with decrease in menstrual irregularities in most patients, and resolution of hirsutism (29%). About half the patients who could not conceive before RYGB, could conceive post-surgery [100].
In female patients with PCOS and metabolic features, metformin should be started. Metformin should not be started with the sole aim to reduce body weight. Similarly, estrogen should not be started in postmenopausal obese women with the sole aim to reduce body weight [94].
Hence, women with grade II or III obesity, who face infertility despite going through a structured weight loss program for six months, may benefit from bariatric surgery. However, pregnancy should be avoided preferably for a year post-surgery and at least six months post-surgery, as this is the time for rapid weight loss and significant changes in the endocrine hormones. Patients who have undergone bariatric surgery are also prone to nutritional deficiencies. Hence, pregnancy should be carefully monitored by a specialized multidisciplinary team that should include a Barocraniologist/Endocrinologist [101].

Impact of Bariatric Surgery on Hypothalamic/Pituitary/Gonadal Axes in Men
Excess adipose tissue in obese men is likely to contribute to androgenic deficiency through inhibition of pituitary gonadotropin. MOSH is characterized by low serum testosterone, inappropriately low or normal LH and FSH, and high relative estradiol levels [102]. Abdominal adiposity confers a vicious cycle in the development of MOSH by inhibiting hypophyseal gonadotropin secretion, with the resulting androgen deficiency promoting body fat accumulation with a decrease in muscle and lean mass [103,104].
Weight loss after bariatric surgery, such as RYBG and SG, improves sexual function, as depicted by an improved score on the International Index of Erectile Function. The levels of total testosterone, FSH, and prolactin also improve [105,106].
In patients with obesity who have biochemical and clinical hypogonadism, weight loss should be encouraged to restore eugonadism. Testosterone may be tried if features of clinical and biochemical hypogonadism persist despite weight loss. However, testosterone should be started after other causes of hypogonadism are ruled out. Testosterone should also never be offered as the first therapeutic measure in a male patient seeking fertility treatment. Testosterone should not be started with the sole purpose of losing weight. Efforts should be made to monitor testosterone levels to keep them in the normal age related range. If even after 6-12 months of testosterone therapy, there are biochemical benefits but no clinical benefit, then testosterone should be stopped [94].

Impact of Bariatric Surgery on Bone Metabolism
Bone metabolism in obesity is quite complex. Vitamin D deficiency in obesity has been linked to secondary hyperparathyroidism [107].) Paradoxically, patients with obesity have higher bone mineral content (BMC) and bone mineral density (BMD), and these therefore may have a protective role in osteoporosis [107].
Similarly, contradictory hormonal effects are seen after bariatric surgery. PYY deficiency is associated with low BMD [108]. However, PPY levels increase after RYGB, LAGB, SG, and BPD. GLP-1 levels rise after BS procedures such as BPD, but this procedure is less used. Exogenous administration of GLP-1 and GLP-2 after bariatric surgery may improve BMD [109]. Adipokines, such as leptin, decrease after bariatric surgery, and positively affect bone metabolism [110]. On the contrary, adiponectin, which increases after bariatric surgery, has been negatively correlated with BMD [111].
However, nutritional deficiencies after bariatric surgery play a major role in bone metabolism. Deficiency of vitamin B 12 , folate, iron, calcium, vitamin D, and zinc are commonly seen. Further bariatric surgery further reduces vitamin D levels and BMD, enhancing bone resorption and hyperparathyroidism [112]. Therefore, patients undergoing bariatric surgery have higher post-surgical risk of fracture [113].
Adequate calcium and vitamin D supplementation should be ensured in patients before and after bariatric surgery. Exercise as per capacity and exposure to sunlight also helps improve vitamin D levels.

Impact of Bariatric Surgery on Thyroid Function
Bariatric surgery improves the thyroid function in patients with obesity and hypothyroidism. This improvement of thyroid function is accompanied by a reduction in dosages of thyroid medication. The mean TSH decline is directly related to the baseline TSH value and does not correlate with BMI reduction. This shows that the improvement in thyroid function has a hormonal component and is not related to weight loss [114,115]. A study from China showed that decrease in leptin levels was associated with improved thyroid function in patients with obesity, T2DM, and euthyroidism [116].
In 83 patients with obesity and hypothyroidism treated with laparoscopic SG (LSG; >80%) or RYGB, there was a significant decrease in mean BMI and thyroid-stimulating hormones (TSH) in the 6 and 12 months post-surgery period. The fT4 levels remained stable. A year after surgery, 13.2% of patients did not require thyroid hormone replacement (THR) therapy. THR doses were reduced significantly in the rest of the patients (p < 0.02) [114]. Rudnicki et al. (2018) reported similar results in 90 patients treated with either LSG or RYGB. In their observational study of 1581 patients with hypothyroidism and obesity mainly treated with LSG and RYGB, Matute et al. (2018) also observed a significant reduction in BMI (p < 0.0001) and THR doses (p = 0.071) after one year post-surgery. The mean TSH measurement (p = 0.153) and the mean thyroxine measurement (p = 0.021) improved after one year post-surgery [117].
Overt hypothyroidism (elevated TSH and decreased FT4) in patients with obesity is treated irrespective of the antibodies' status. However, thyroid hormones should not be used for treating obesity if the thyroid function is normal. Hyperthyrotropinaemia (elevated TSH and normal FT4) in obesity should not be treated with the sole aim of reducing body weight. The TSH level (Table 9), thyroid antibodies, and age should be considered when deciding whether or not to treat hyperthyrotropinaemia in obesity [13]. Table 9. Normative range of TSH cut-offs proposed on the basis of body mass index [118].

Impact of Bariatric Surgery on Adrenal Function
Adrenal insufficiency is a common complication after bariatric surgery. Therefore, clinicians should be very vigilant about symptoms and signs of adrenal insufficiency after bariatric surgery, such as anxiety, sweating, transient loss of consciousness, hypoglycaemia, and conflicting symptoms of profound weight loss or weight regain [119,120]. However, in patients who have rapid weight loss after bariatric surgery, these symptoms are often masked.
The possible cause of post-bariatric surgery adrenal insufficiency could be malabsorption of factors that help in steroid biosynthesis such as bile, and therefore cholesterol levels, selenium, and other trace elements, and vitamin B5 and other vitamins. Additionally, weight loss causes re-setting of the hypothalamo-pituitary-adrenal axis [119,120].
The plasma cortisol profiles in patients with adrenal insufficiency can be almost similar before and after bariatric surgery. However, individual variations may exist [121]. However, in patients having persisting symptoms of adrenal insufficiency despite oral hydrocortisone treatment, the cortisol day curve may be abnormal due to malabsorption of oral hydrocortisone [119].

Summary
This review highlighted the importance of involving a Barocraniologist, or at least an Endocrinologist as part of the bariatric team in all stages of management of a patient who is a candidate for bariatric surgery. Both obesity and weight loss after bariatric surgery are associated with important metabolic and endocrine changes. Additionally, obesity is often the result of endocrine and metabolic imbalances. Hence, proper management of obesity is only possible when these endocrine and metabolic imbalances are appropriately managed. With changing lifestyles and growing cases of obesity and diabetes in countries like India, there is a felt need to incorporate a proper endocrine evaluation in obese patients.
Author Contributions: Conceptualization, S.K. and N.K., Review and Editing, S.K., N.K., S.B., H.A., A.C., Original draft preparation, S.K., N.K., S.B., H.A., A.C. All named authors for this manuscript meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship. All authors take full responsibility for the integrity of the work and have given final approval for the published version. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.