Edited by: Jennifer L. Miles-Chan, University of Auckland, New Zealand
Reviewed by: Caterina Conte, Vita-Salute San Raffaele University, Italy; Sarah M. Turpin-Nolan, Monash University, Australia
This article was submitted to Obesity, a section of the journal Frontiers in Endocrinology
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Obesity is one of the most serious worldwide epidemics of the twenty-first century according to the World Health Organization. Frequently associated with a number of comorbidities, obesity threatens and compromises individual health and quality of life. Bariatric surgery (BS) has been demonstrated to be an effective treatment to achieve not only sustained weight loss but also significant metabolic improvement that goes beyond mere weight loss. The beneficial effects of BS on metabolic traits are so widely recognized that some authors have proposed BS as metabolic surgery that could be prescribed even for moderate obesity. However, most of the BS procedures imply malabsorption and/or gastric acid reduction which lead to nutrient deficiency and, consequently, further complications could be developed in the long term. In fact, BS not only affects metabolic homeostasis but also has pronounced effects on endocrine systems other than those exclusively involved in metabolic function. The somatotropic, corticotropic, and gonadal axes as well as bone health have also been shown to be affected by the various BS procedures. Accordingly, further consequences and complications of BS in the long term in systems other than metabolic system need to be addressed in large cohorts, taking into account each bariatric procedure before making generalized recommendations for BS. In this review, current data regarding these issues are summarized, paying special attention to the somatotropic, corticotropic, gonadal axes, and bone post-operative health.
Obesity is a chronic, progressive, and multifactorial disease involving genetic, metabolic, psychological, and endocrinology-related factors, among others. Obesity-associated comorbidities are numerous and are also related to higher mortality. Obesity is a risk factor for a number of other chronic illnesses related to metabolic syndrome including type 2 diabetes mellitus (T2DM), high blood pressure, dyslipidemia, cardiovascular diseases (CVD), respiratory disorders, joint diseases, psychosocial disorders, and even several types of cancer (including esophagus, colon, pancreas, prostate, and breast) (
The World Health Organization (WHO) has defined the term “obesity” as excessive fat accumulation that is harmful to health. Considered the twenty-first century epidemic, obesity is the main health problem in developed countries, reducing life expectancy and presenting a challenge for the global economy. This is a disease with exponential growth, and its rise and prevalence is also affecting the child population. In the last 40 years the proportion of the population that is obese has tripled. In 2016, 39% of adults aged 18 years and over were overweight and about 13% were obese. If nothing changes, the growing trend will continue and these numbers will increase in the coming years (
From the point of view of therapeutics, proper dietary re-education, together with lifestyle modification and physical exercise as well as psychological specialized support for obesity treatment are needed. However, studies such as Look AHEAD showed that weight loss and glycemic control is difficult to maintain in the long term, even with intensive lifestyle intervention (
There are different effective surgical methods employed for obesity treatment and the majority of the most popular bariatric procedures such as Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), mini-gastric bypass, and biliopancreatic diversion (BPD) are considered safe procedures that are efficient regarding obesity-associated comorbidities and weight loss (
After BS, many aspects are modified and imply a reduction in the risk of obesity-associated disorders as well as of all-cause mortality (
Although there is extensive literature that claims beneficial health effects with BS, and the post-surgery mortality rate is <1%, these type of procedures are not exempt from long-term complications related to nutritional deficiencies. In general, mainly malabsorptive procedures, e.g., bypass procedures with duodenal exclusion of nutrients and a concomitant decrease in gastric acid, will have a higher risk of micronutrient and macronutrient deficiencies. Consequently, BS patients are at higher risk of developing nutrient deficiency-related disorders such as anemia, certain types of neuropathies or osteoporosis (
A number of studies have explored metabolic changes after BS, and the efficiency of BS for the treatment of T2DM is well-established. BS therefore offers a safe and more effective alternative to achieve sustained glycemic control in diabetic obese patients in comparison with intensive medical treatment (
The various surgical procedures usually employed in BS lead to partial or total T2DM remission of about 34–85.3% depending on the criteria applied to define T2DM remission, and 95% global success in glycemic control (
RYGB is also a highly effective option for T2DM remission. Most patients who underwent RYGB did not require hypoglycemic drugs 1 year post-surgery, and it has been reported 84–90% and 29–50% T2DM remission one and 5 years after RYGB, respectively (
Sleeve gastrectomy has gained popularity and appears to achieve glycemic control rates similar to RYGB but with fewer surgery-associated complications. The randomized controlled trial SMBOSS reported 60% T2DM remission rates after SG compared to 77% remission after RYGB 3 years after surgery (
Many explanations have been put forth for the metabolic improvements after BS. Early and pronounced improvement in hepatic insulin sensitivity after RYGB, which could be related to caloric restriction in the short-term post-operative period and the reduction in intrahepatic fat, has been reported. Moreover, an improvement in peripheral insulin sensitivity, which occurs later, and its relationship with the sustained weight loss has been described (
Nevertheless, it is well-known that the metabolic improvements after BS take place in the days or weeks after surgery even before significant weight loss occurs (
Several hypotheses have been put forth to explain the early improvement in carbohydrate metabolism after BS, but the precise mechanisms for T2DM resolution are not yet completely understood (
Mechanism for T2DM resolution. Mechanisms and modifications of main gastrointestinal hormones involved in T2DM resolution after bariatric surgery. Several mechanisms have been proposed to explain the metabolic improvement after bariatric surgery. However, due to the fact that each bariatric procedure does not involve the same gastrointestinal tract modifications, it has been suggested that each procedure acts by means of different mechanisms to achieve T2DM resolution, including differential shifts in gastrointestinal hormones levels. It has been proposed that the exclusion of the duodenum and proximal jejunum in bariatric procedures such as RYGB or BPD would inhibit the “anti-incretin” signaling (“foregut hypothesis”). This kind of remodeling would also reduce the time that nutrients take to reach distal jejunum which could imply an early activation of incretin-secreting L-cells in the distal ileum and proximal colon (“hindgut hypothesis”). Incretins such as GLP-1, PYY, or oxyntomodulin improve pancreatic insulin secretion and reduce glucagon release. By contrast, the main gastrointestinal hormonal shift expected after SG is the decrease in the levels of the orexigenic hormone ghrelin due to the removal of the gastric fundus and therefore, of the ghrelin-producing mucosa. However, it has also been described an increase in GLP-1 and PYY levels after SG likely due to a shorter intestinal transit after surgery. Apart from changes in gastrointestinal hormone patterns, alterations in bile acid metabolism, gut microbiota composition, modification in gastrointestinal vagal signaling or changes in adipokines levels described after the different bariatric procedures, could be also involved in the bariatric metabolic improvement and T2DM resolution after surgery. BPD, biliopancreatic diversion; GIP, gastric inhibitory polypeptide; GLP-1, Glucagon-like Peptide 1; PYY, Peptide YY; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy; T2DM, Type 2 diabetes mellitus.
Several hypotheses have been raised regarding the implication of the gastrointestinal system as a metabolically active organ:
- The “foregut hypothesis” is based on the exclusion of the duodenum and proximal jejunum from the nutrient traffic across the gastrointestinal tract, which may inhibit “anti-incretin” signal production such as gastric inhibitory polypeptide (GIP). The removal of this signaling would favor direct antidiabetic effects with a reduction in insulin resistance (
- The “hindgut hypothesis” posits that nutrients reach the distal jejunum quickly, ensuring optimal digestion and nutrient absorption as well as metabolic improvement and weight loss through stimulation of L cells in the distal ileum and proximal colon which secrete GLP-1, PYY, oxyntomodulin, and other hormones (
- Other possible mechanisms have been elucidated from the results of SG. Although it would initially be considered a purely restrictive bariatric procedure, evidence has highlighted that its effects cannot be explained by caloric restriction alone. SG also leads to complex hormonal changes such as diminished ghrelin levels, which enhance weight loss and improve post-prandial insulin response together with lower post-prandial glucose levels (
- The modulation of bile acid circulation has been postulated as a feasible mechanism to explain some of the metabolic effects of BS. Bile acids could be involved in both weight loss and the improvement in glycemic control by the stimulation of intestinal L-cell secretion of GLP-1, PYY, and oxyntomodulin which favors insulin response and the feeling of satiety (
- Another intestine-related effect of BS which could be involved in the BS metabolic effects is the modulation of gut microbiota. Gut microbiota composition has previously been associated with obesity, T2DM and other metabolic diseases (
- Changes in the neuroendocrine system have also been suggested to be involved in the beneficial effects of BS. As summarized above, the principal hypotheses about beneficial neuroendocrine effects of BS include the modification of gastrointestinal hormone release with well-recognized effects on food intake and energy equilibrium. Most of these hormones not only communicate with the brain in an endocrine manner, but they also act in a paracrine fashion by interacting with specific receptors located on vagal afferent nervous fibers which innervate the gastrointestinal tract and are in close proximity to gastrointestinal endocrine cells (
BS also alters hormone levels other than incretins such as glucagon. Patients who underwent RYGB had decreased glucagon levels (
Obestatin levels have also been described to be implicated not only in food intake and gastric emptying but also to have beneficial effects on pancreatic β cells by reducing apoptosis and promoting proliferation, increasing insulin secretion and decreasing insulin resistance, which have a positive effect on systemic glucose homeostasis. It has been suggested that obestatin may play a role in T2DM remission (
Increased adiponectin levels after BS have also been described. Adiponectin is an anti-inflammatory hormone that improves insulin sensitivity, and its rise after BS has been correlated with higher T2DM remission rates in patients who underwent BPD (
Despite the general overview that BS improves carbohydrate metabolism, there are also studies that have reported T2DM recurrence 5 years after surgery in 50–95% of patients who had achieved T2DM remission. This recurrence was associated with weight regain and a longer history of T2DM previous to the surgery (
Aside from the well-known metabolic effects of BS, these surgical procedures also induce changes in other systems with further endocrine consequences (
Endocrine consequences of bariatric surgery on somatotropic, corticotropic, and gonadal axes.
Mittempergher et al. ( |
BPD LAGB | Observational, prospective study | 1 year | 88 (34/54) | Obese patient (male/female) | GH IGF-1 | Higher effects of mainly malabsorptive techniques than restrictive techniques. | ||
Camastra et al. ( |
RYGB | Observational, prospective study | 6 months | 23 (16/7) | Severely obese and non-obese controls. | GH | Significant increase in GH secretion. | ||
De marinis et al. ( |
BPD | Observational prospective study | 16 and 24 months | 30 (15/15) | Obese females and non-obese females. | IGF-1 GH peak after GHRH | Slower IGF-1 secretion in response to BS possibly attributed to underlying catabolic status, as GH response to GHRH severely increased. | ||
Mancini et al. ( |
RYGB | Observational prospective study | 6 months | 10 | Non-diabetic premenopausal severely obese women | GH | Partial recovery of somatotropic axis. | ||
Britt Edén Engström et al. ( |
RYGB | Observational prospective study | 6 and 12 months | 63 (54/9) | Obese patients (female/male) | GH IGF-1 | Increase in GH and IGF-1 levels. | ||
Savastano et al. ( |
LAGB | Observational prospective study | 6 months | 254 (104/36) | Moderately and severely obese patients (female/male) | GH IGF-1 GH peak after GHRH plus arginine (ARG) test | Higher weight loss and improvement of body composition profile in subjects who recovered GH response to stimulus and with normal IGF-1 levels after surgery. | ||
Di somma et al. ( |
LAGB | Observational prospective study | 6 months | 72 | Severely obese females | GH peak after GHRH plus arginine test. IGF-1 IGFBP-3 | Postoperative IGF-1 levels were the strongest determinant of body composition profile. So, recovered GH axis is related with higher success of surgery. | ||
Manco et al. ( |
BPD | Observational prospective study | 2 years | 10 | Fertile non-diabetic obese women | CBG, Plasma cortisol suppression with dexamethasone suppression test | A significant decrease in circulating CBG levels and an increase in the free cortisol fraction in obese women. No difference was found in cortisol suppression after BS. | ||
Morrow et al. ( |
RYGB | Observational prospective study | 2 and 5 months | 24 (10/14) | Obese patients with presence or absence of night-eating syndrome undergoing BS | Fasting plasma cortisol | Decrease in fasting plasma cortisol in obese patients without night-eating syndrome after BS. | ||
Larsen et al. ( |
LAGB | Cross-sectional study | 34 (16/18) | Obese women with and without binge syndrome | Salivary cortisol | Lower salivary cortisol levels during the day in obese women with binge syndrome than without binge disorder. | |||
Guldstrand et al. ( |
LAGB | Observational prospective study | ~12 months (“After a stable body weight after BS”) | 8 (7/1) | Obese and non-diabetic patients (female/male) | Plasma cortisol | Reduction in cortisol levels in response to hypoglycemic clamp technique after BS-induced weight loss in comparison to the presurgical state characterized by exaggerated HPA axis activation. | ||
Ruíz-Tovar et al. ( |
SG | Observational prospective study | 6 and 12 months | 40 | Morbidly obese patients | Serum cortisol, CRP | Cortisol levels decreased from 6 months after BS. CRP levels decreased significantly 12 months after BS. | ||
Valentine et al. ( |
BPD RYGB LAGB SG | Observational prospective study | 6 and 12 months | 24 | Obese female participants | Salivary cortisol | A significant rise in morning salivary cortisol levels after BS, but no differences in nighttime salivary cortisol levels and the salivary cortisol awakening response. | ||
Hulme et al. ( |
RYGB LAGB SG | Observational prospective study | 3 and 6 months | 17 (14/3) | Obese patients (female/male) | Saliva Cortisol | No effect of BS on cortisol secretion daily patterns but morning cortisol showed a slightly non-significant increase. | ||
Sarwer et al. ( |
RYGB LAGB | Observational prospective study | 1 and 2 years | 106 | PCOS obese women | Total testosterone, estradiol, FSH, LH and SHGB levels | Significant improvements in general sexual quality, functioning and hormonal levels after BS. | ||
Jamal et al. ( |
RYGB | Observational prospective study | 46.7 months | 20 | Obese female with ≥ 2 of 3 diagnostic criteria for PCOS | Hormonal levels (Testosterone, SHBG, LH, FSH, estradiol levels), menstrual cycles, hirsutism | An improvement in gonadal dysfunction in 82% of patients with a recovery in menstrual irregularities, 89% hirsutism resolution, and 50% achieve conception. | ||
Eid et al. ( |
RYGB | Observational prospective study | 27.5 ± 16 months | 24 | PCOS obese women | Menstrual cycles, hirsutism, hormonal levels | Improvements in PCOS-associated symptoms including menstrual alteration resolution, and hirsutism. Successful conception was achieved by 5 patients. | ||
George and Azeez. ( |
SG | Retrospective analysis | 132 | PCOS Obese women | Clinical dates: menstrual cycles, hirsutism, hormonal levels and radiologic ovary pattern | Resolution of menstrual irregularities pattern in the majority of the cases, of hirsutism in 80% and of the radiologic pattern in PCOS in 81%. | |||
Skubleny et al. ( |
BPD RYGB LAGB SG | Meta-analysis | 1-year | 2130 | PCOS Obese women | Hormonal levels and clinical sequelae of PCOS: menstrual cycles, hirsutism, and infertility. | PCOS significantly decrease from 45.6% pre-operatively to 6.8% 1 year post-operatively. | ||
Shekelle et al. ( |
BPD RYGB LAGB SG | Meta-analysis of cohort studies, case series and individual case reports. | 57 articles analysis | Obese and reproductive age women | Fertility, contraception, pregnancy, weight management, and nutritional deficiencies. | Menstrual regularity was recovered in 71%; with an association between weight loss and ovulation recovery. Data suggest improvement fertility after BS with minimal nutritional deficiencies for mother and child and without higher complications in post-surgery pregnancies. | |||
Reis et al. ( |
RYGB | Prospective randomized controlled trial | 24 months | 20 (10/10) | Obese men in 2 groups with life style modification and RYGB | IIEF test, serum estradiol, PRL, LH, FSH, free and total testosterone | Improvements in sexual functioning and hormonal levels (total testosterone, FSH and PRL). | ||
Mora et al. ( |
RYGB SG | Prospective observational case series study | 1 year | 39 | Obese men | IIEF score, Testosterone, SHBG, estradiol, gonadotropins, inhibin B, PRL. | Improvement in sexual aspects (IIEF score and significant increment in testosterone level). | ||
Sarwer et al. ( |
RYGB | Prospective cohort study | 4 years | 32 | Obese men | SHBG, IIEF, Testosterone | Increase total testosterone and SHBG levels 4 years post-operatively, but improvements in sexual dysfunction were not significant during the follow-up. | ||
Facchiano et al. ( |
BPD RYGB LAGB | Prospective study | 6 months | 20 | Obese men | LH, FSH, Total and Free testosterone, SHBG, estradiol, | Increase in total testosterone, SHBG, LH and FSH levels with a relevant drop in estradiol levels. | ||
Luconi et al. ( |
BPD RYGB LAGB | Longitudinal study | 6 and 12 months | 24 | Morbidly obese male | Free-testosterone, SHBG, LH, FSH | Increase in total and free testosterone levels as well as SHBG and gonadotropins (simultaneous increases in LH and FSH). | ||
Aarts et al. ( |
RYGB LAGB | Observational study | 1-year | 24 (13/11) | MOSH and eugonadal Obese men | Free-testosterone | Increase in free-testosterone in both MOSH and eugonadal groups. | ||
Samavat et al. ( |
BPD RYGB LAGB SG | Cohort study | 55 (29/26) | Morbidly obese men (with MOSH and 26 without) | Total testosterone; Free testosterone; Gonadotropins. SHBG and estradiol levels. | Increase in androgen levels (total and free-testosterone) only in patients with hypogonadism. Decreased estradiol levels only in eugonadal patients. MOSH reversal that occurred early after surgery and was nearly complete. |
GH is mainly regulated by two hypothalamic peptide hormones: GH-releasing hormone (GHRH) and somatostatin. However, other brain signaling pathways such as those related to sleep regulation are also involved in the regulation of GH secretion (
Reports regarding serum IGF-1 levels in obesity have shown contradictory results with both normal (
Somatotropic axis alterations in obese subjects, similar to those in patients who have a GH deficit, are associated with a higher prevalence of cardiovascular risk factors and alterations in body composition (muscle mass and bone density reduction and rise in fat mass) (
Several studies have reported a restoration of somatotropic axis alterations in severely obese patients after BS. A significantly increased secretion of GH after BPD has been described (
Britt Edén Engström et al. determined that GH secretion and IGF-1 levels, previously compromised in severe obese subjects, were augmented at 6 months in women and at 12 months in both women and men after RYGB. A concomitant BMI reduction was reported in men and women at 6 months, which was further improved at 12 months after surgery (
Although some discrepancies have been found in the literature (
The HPA axis is a relevant pathway in the response to physiological stress which regulates cortisol secretion. Cortisol has a number of effects on the organism, including energy reserve mobilization to promote survival and to comply with metabolic requirements during stress. Cortisol is secreted by the suprarenal cortex after HPA axis activation in response to physiological or psychological stress and high cortisol levels are associated with intense emotional responses to stressful stimuli (
Very few studies have examined HPA axis regulation before and after BS in humans. The most commonly held idea is that weight loss tends to normalize cortisol levels and possible alterations in the HPA axis (
Morrow et al. studied HPA axis modulation in 24 severely obese participants (BMI = 40–70 Kg/m2) without associated comorbidities who underwent RYGB. Participants were classified according to the presence or absence of night-eating syndrome. A decrease in fasting plasma cortisol levels 5 months after surgery was reported in patients without night-eating syndrome, but an increase was seen in the subgroup of patients who had night-eating syndrome. However, the two groups did not differ in weight loss or waist circumference (
Valentine et al. also found a significant rise in morning saliva cortisol levels 6 and 12 months after BS (54.2% after SG; 16.7% after LAGB; 12.5% after RYGB, and 8.3% after duodenal switch) in 24 obese women, but no differences were found in nighttime saliva cortisol levels or in salivary cortisol awakening response (
Larsen et al. analyzed salivary cortisol levels in obese women after LAGB and found that neuroendocrine regulation after BS differs in these patients depending on the presence or absence of binge eating disorder. Obese women with binge eating disorder had significantly lower salivary cortisol levels during the day than patients without binge disorder. It is of note that a normal weight control group was not included in this study (
Manco et al. described a significant decrease in circulating corticosteroid-binding globulin (CBG) levels and a concomitant increase in the metabolically free cortisol fraction in obese women 2 years after BPD (
Guldstrand et al. studied HPA axis changes after LAGB in 8 non-diabetic severely obese patients. For this purpose, cortisol levels were analyzed in response to hypoglycemic clamp technique and a reduction in counter-regulatory hormone (cortisol among them) response was observed during the sustained hypoglycemic state after BS-induced weight loss in comparison to the pre-surgical state characterized by exaggerated HPA axis activation (
Ruiz-Tovar et al. reported sustained high serum cortisol levels up to 6 months after BS in 40 morbidly obese patients who underwent laparoscopic SG. However, cortisol levels decreased and were directly associated with the CVD risk predictor triglyceride/HDL ratio from 6 months after BS (
In view of these studies, obesity-induced corticotropic axis activation is reduced after BS and a normalization in HPA circadian rhythms might be also occurring. This effect has not been described for caloric restriction, which could add value to the use of BS for obesity treatment. However, although current evidence suggest that BS can affect HPA axis regulation with improvement in axis physiological health, controversial results have been found regarding the direction of this regulation. Therefore, more studies on this issue are needed to homogenize criteria concerning which variables should be used to monitor corticotropic axis status.
The incidence of sexual dysfunction, reproductive disorders, and infertility increase with age. The relationship between sexual dysfunction and other medical conditions such as obesity (
It is also well-known that adipose tissue plays a relevant role in the metabolism of hormones, including sex hormones, secreted by different glands (
It has been widely described that BS leads to an improvement in sex hormone and sexual hormone binding globulin (SHBG) levels in morbidly obese patients (
The main evidence found in this context are due to: (1) excess androgen in obese women, mainly associated with polycystic ovary syndrome (PCOS) (36%) and with idiopathic hyperandrogenism (
This improvement in gonadal profile occurs in parallel with insulin resistance improvement and metabolic disorder resolution (
Sex-specific changes induced by BS have been reported as described below.
Excess adipose tissue in obese women may contribute to excess androgens by stimulating both ovary and hormonal secretion by the suprarenal glands as secondary effects of insulin resistance and compensatory hyperinsulinism. Specifically, abdominal adiposity may feed a vicious circle in which excess androgens favors body fat deposition and this visceral fat promotes ovary and adrenal-derived excess androgens in PCOS. However, for PCOS to develop in response to obesity and visceral fat accumulation, women must have a primary defect in steroidogenesis that promotes excess androgen secretion, predisposing to androgen excess disorders (
Studies dealing with fertility recovery in women with PCOS that have assessed fertility before and after BS are scarce. The existing studies suggest that female fertility improves after bariatric procedures and intensive weight loss. However, most of these are observational studies with high variability in age, in the bariatric procedure employed and without a control group. This makes reach a consensus about the role of BS in fertility management difficult. Accordingly, smarter studies with a precise design comparing the different bariatric procedures are required (
George and Azeez carried out a study that included 132 women with PCOS who underwent SG in whom resolution was achieved in the majority of the cases of menstrual irregularities, hirsutism (80%) and radiologic irregularities (81%) (
Jamal et al. also observed improved gonadal dysfunction in 82% of RYGB PCOS patients, with decreased menstrual irregularities and resolution of hirsutism in 29% of the patients, and 50% of patients who were unable to conceive prior to surgery were successful after surgery (
Balen et al. based on low-quality evidence, recommended BS use in obese PCOS women with a BMI>35 kg/m2 and comorbidities such as gonadal dysfunction or BMI>40 kg/m2 who had infertility problems despite programmed intensive and structured treatment (based on dietary-hygienic habit changes) with no response for at least 6 months. They also recommended to avoiding pregnancy in the rapid post-operative weight loss period for at least 6–12 months after BS and at later times, recommended that these women should be attended in a specialized multidisciplinary unit due to the risk of BS-associated nutritional deficiencies (
Although PCOS is the most frequent reproductive disorder in obese women (
Bond et al. described that in 68% of obese women with sexual dysfunction (defined by the Female Sexual Function Index score), this condition resolved after BS. This improvement in sexual function was not dependent on type of surgery or amount of weight loss and appears to be an additional benefit for women undergoing BS (
As detailed above, weight loss after lifestyle modification, and particularly after BS, is associated with significant improvements in sexual functioning and resolution of both menstrual and ovulatory disorders that occur in nearly all patients. Thus, weight loss could also contribute to fertility restoration (
In obese men, excess adipose tissue appears to contribute to androgenic deficiency by means of pituitary gonadotropin inhibition. This suggests central production deterioration together with reduced gonadal sensitivity to LH and increased peripheral androgen degradation by their conversion to estrogens (
Thus, abdominal adiposity could favor a vicious cycle in MOSH development by inhibiting hypophyseal gonadotropin secretion (
Substantial fat mass loss after intensive weight loss will likely tend to reduce aromatase activity and regulate estradiol/testosterone equilibrium, resulting in decreased estradiol production, and will favor LH increase which contributes to stimulating testosterone production and substrate availability for estradiol production. It is thought that the differences between obese subjects with normal gonadal function and those with hypogonadism might be determined by aromatase expression levels: MOSH would be induced when aromatase gene expression is elevated. By contrast, testosterone levels would remain within the normal range when aromatase expression levels are low (
An increase in serum androgen levels (for both total testosterone and the free testosterone index), which was even higher than the increase in SHBG levels in men has been reported (
Chronic testosterone deficiency could reduce post-operative fat loss and enhance the catabolic effects of BS on muscle and bone. This would attenuate the positive effects of BS on insulin sensitivity. A number of recent studies dealing with the changes and benefits in gonadal dysfunction due to BS in obese men, are in agreement with BS-induced improvements in testosterone, SHBG and LH levels (
Reis et al. found significant improvements in sexual functioning and levels of hormones such as total testosterone, FSH and prolactin in 10 RYGB patients (
Mora et al. observed a pronounced weight loss (77.18% of excess weight), metabolic profile improvement together with improvements in sexual aspects such as an improved score on the International Index of Erectile Function and a significant increase in testosterone levels 1 year after surgery (RYGB and SG in 46.2 and 53.4%, respectively) in a prospective study carried out in 39 obese men (
In agreement, Sarwer et al. reported a concomitant decrease in patient weight by nearly one third and increase in total testosterone and SHBG levels 4 years after surgery in their cohort of 32 men who underwent RYGB and who showed deficient sexual functioning prior to surgery. Despite this finding and although improvements in sexual dysfunction were seen in the short term after surgery, these changes were not significant during the follow-up (
Facchiano et al. reported an increase in total testosterone, SHBG, LH, and FSH levels with a relevant drop in the initially elevated estradiol levels at 6 months after BS (10 with RYGB, 8 with LAGB and 2 with BPD) in 20 obese men (
The findings of Luconi et al. confirmed the already known relationship between excess adiposity and hypogonadism in morbidly obese men. In the same line as previous studies, patients showed increased total and free testosterone levels as well as gonadotropins (simultaneous increases in LH and FSH). The increased testosterone and SHBG levels induced by BS were higher than those expected for the weight loss alone. Likewise, the increase in total testosterone may be related to an SHBG rise and peripheral aromatization reduction that contributes to the observed fall in estradiol levels. Moreover, the direct effect of weight loss on Leydig cell function should not be discarded in the improvement of gonadal profile (
Aarts et al. included 24 severely obese men (BMI = 35–59 Kg/m2) in their study, 13 of them with MOSH and 11 eugonadal morbidly obese patients. One year after BS, an increase in free testosterone was observed in both MOSH and eugonadal groups. These levels were inversely related to weight loss. MOSH was a reversible situation in the majority of cases and this pre-operative condition was not adversely associated with BS efficiency in terms of weight, lipid and carbohydrate metabolism or with catabolic effects of surgery on muscle or bone mineral density (
Nevertheless, Samavat et al. in their study with morbidly obese BS patients (29 with hypogonadism and 26 eugonadal patients) observed that presurgery testosterone levels appear to moderate the BS effect on sex hormone recovery as an increase in androgen levels (total and free testosterone) only occurred in patients with hypogonadism. Preoperative estrogen levels were significantly lower in hypogonadal patients than in eugonadal patients. Moreover, estrogen levels only decreased after BS in eugonadal patients. Estradiol reduction in eugonadal patients was not related to testosterone level increment. As in the previous studies referenced above, Samavat et al. found a hypogonadism reversal that occurred early after surgery and was nearly complete. Taking into consideration these findings, the role of estradiol in obesity-related hypogonadism development might be limited (
All the revised studies, except for the study by Leenen et al. (
Few long-term studies have focused on the possible recurrence of gonadal dysfunction after weight regain. Rosenblatt et al. reported that patients who underwent RYGB from 6 to 16 years ago had high SHBG, total and free testosterone levels compared to non-surgical obese controls and these levels were comparable to those found in lean subjects. These findings agree with androgenic normalization in the long term. Nevertheless, the erectile function score was lower than in lean controls, which suggests incomplete functional restoration that may be related to weight gain and recurrent obesity comorbidities (
Recent research suggests reciprocal control between bone and testicles by means of osteocalcin (a peptide secreted by osteoblasts). It has been recently proposed that this peptide may be implicated in male fertility through direct stimulation of testosterone production by Leydig cells (
In view of these results, BS is an effective method to treat gonadal dysfunction including recovery of fertility in comparison with lifestyle changes and diet-induced weight loss (
It has been widely described that obese patients are at higher risk of vitamin D deficiency pre-operatively, although it is not clear whether this association is more closely related to obesity
The most common nutritional deficiencies after BS include folate, iron, vitamin B12, calcium, vitamin D and zinc. Therefore, post-surgical changes in calcium and vitamin D can lead to bone loss resulting in higher fracture risk (
BMD and BMC are determined by means of dual-energy X-ray absorptiometry (DXA), and technical limitations should be considered when data are interpreted. DXA are technically limited when applied to obese patients, particularly in severely obese subjects. Modifications in fat mass distribution due to drastic weight loss could influence measurement accuracy (
In addition, it is unclear whether the reported BMD and BMC decrease after BS, is clinically relevant regarding osteoporosis incidence and fracture risk. As recently reviewed by Ben-Porat et al. different studies have found controversial results (
The serum 25(OH)D form of vitamin D, calcium and parathyroid hormone (PTH) have also been measured to verify putative effects of BS on bone metabolism. As calcium is preferentially and actively absorbed in the proximal gut, and pancreatic secretion and bile acids are required for vitamin D absorption, bariatric procedures that bypass the duodenum and proximal jejunum could promote malabsorption of these micronutrients. Decreased stomach acid after SG and bypass of the proximal bowel would also reduce calcium absorption (
The tight regulation of serum calcium levels relies on PTH and the active form of Vitamin D (1,25(OH)2D). PTH stimulates osteoclast differentiation and survival and calcium release from the bone matrix when serum calcium levels are low. Negative feedback avoids uncontrolled PTH-induced bone loss, by stimulating 1,25(OH)2D synthesis. The active form of vitamin D inhibits PTH production and stimulates intestinal calcium absorption and FGF23 expression in bone (which leads to bone phosphorus loss) (
Vilarrasa et al. could not confirm these results when the administered doses of vitamin D were higher in the RYGB than in the SG group (
Taking into account the limitation mentioned above regarding bone health assessment, bone turnover markers may also be an accurate approach to verify bone resorption and formation rates after BS. N-terminal propeptide of type 1 procollagen (P1NP) (cleaved from type 1 procollagen for collagen fiber assembling when incorporated into the bone matrix), bone-specific alkaline phosphatase (BAP) (a specific marker of bone formation osteoblast activity) and osteocalcin (a bone-specific protein produced by mature osteoblasts during bone matrix synthesis) are used as bone formation biomarkers. C-terminal and N-terminal telopeptides of type I collagen (CTX-1 and NTX-1, respectively; produced as a secondary product of collagen proteolytic cleavage during bone matrix degradation by osteoclasts) and tartrate-resistant acid phosphatase (TRACP; an enzyme highly expressed by osteoclasts) are considered bone resorption biomarkers (
Although some authors have questioned the mechanical unloading hypothesis (
All in all, there is sufficient evidence to assume that BS has an effect on bone metabolism. However, due to the fact that multiple mechanisms affected by BS could affect bone health in opposite ways, further research is needed to elucidate the net effect of each bariatric procedure on bone metabolism. Consensus on the best way to estimate bone health, taking into account technical limitations, should also be reached to obtain clear conclusions about what is really happening to bones in obese patients before and after surgery. Long-term prospective studies evaluating fracture risk and bone disease prevalence after BS, with large sample sizes and considering the type of post-surgery vitamin D and calcium supplementation, are further required to confirm BS effects on bone metabolism and to provide patients with accurate recommendations following each bariatric procedure.
Effects on metabolism and gastrointestinal hormones of BS are widely recognized, but the precise mechanisms are not yet completely understood. Moreover, it has been suggested that the different bariatric procedures are not equally effective in T2DM remission. However, heterogeneity regarding the criteria to define T2DM remission after BS makes difficult to state which surgical procedure is the most recommendable. Furthermore, other aspects than those exclusively metabolic should be taken into consideration since many other endocrine effects, but less explored up to date, are produced secondarily by the different bariatric procedures affecting corticotropic, somatotropic and gonadal axes as well as bone metabolism. Nevertheless, study design and criteria to evaluate the secondary consequences of BS are also heterogeneous which complicates the characterization of the precise effects of each bariatric procedure on these aspects. In addition, only few studies have evaluated BS consequences in the very long-term finding nutrient deficiency-related disorders, particularly after mainly malabsoprtive procedures which are at the same time considered as the most effective regarding T2DM resolution. Thus, although it is generally considered that benefits counteract by far the drawbacks of BS, further studies with homogeneous criteria and design, considering other bariatric consequences than merely metabolic effects, as well as the performance of a close long-term follow-up, are necessary in order to have a wider comprehensive overview of the consequences of each bariatric procedure. This would be useful for individualized surgical intervention recommendations depending on the different obesity co-morbidities previous to surgery of each patient as well as for preventing health-derived complications of BS.
IC-P, MC-P, and FT contributed to the manuscript design, to researching the literature and to the discussion, drafted and wrote the manuscript, and approved the final version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors wish to thank FIMABIS and the help of Maria Repice for her language expertise in preparing this manuscript.