2023 Volume 70 Issue 10 Pages 1015-1021
Polycystic ovary syndrome (PCOS) frequently exhibits hyperinsulinemia due to insulin resistance, but there are many unknown aspects of this disease. This report presents the case of a 31-year-old woman with PCOS and type B insulin resistance syndrome (TBIRS). The patient had repeated hyperglycemia and hypoglycemia, and prominent hyperinsulinemia. The insulin receptor antibody was positive, leading to a diagnosis of TBIRS. She also had amenorrhea during the previous 3 months, high blood testosterone levels, and enlarged polycystic ovaries, leading to a diagnosis of PCOS at the same time. The patient was treated with glucocorticoid for TBIRS. The insulin receptor antibody eliminated at 8 weeks after initiation of glucocorticoid treatment, and the blood glucose levels and hyperinsulinemia improved at 9 weeks. Then, the enlargement of both ovaries diminished at 32 weeks, and the menstruation had normalized since 36 weeks. The blood testosterone level normalized at 41 weeks. To the best of our knowledge, this is the first report to demonstrate that enlarged polycystic ovaries and a menstrual disorder in TBIRS improved after glucocorticoid treatment. It is possible that elimination of insulin receptor antibodies by glucocorticoid treatment attenuated insulin resistance and subsequently improved PCOS in TBIRS.
POLYCYSTIC OVARY SYNDROME (PCOS) is a disease characterized by menstrual disorders and hyperandrogenemia, with the basic characteristics being polycystic changes in the ovaries. Although there are many unknown aspects of PCOS pathogenesis, it is frequently recognized as involving insulin resistance, and it is known that menstrual disorders can be improved by weight loss and metformin [1].
By contrast, type B insulin resistance syndrome (TBIRS) is an acquired disorder characterized by marked insulin resistance due to antibodies against insulin receptors. In TBIRS, insulin can hardly bind to insulin receptors, resulting in high blood insulin levels. TBIRS is frequently associated with autoimmune diseases, such as systemic lupus erythematosus, and is normally treated with glucocorticoids and other immunosuppressive agents. Because the insulin receptor antibodies are removed on treatment, insulin functions normally and blood insulin levels decrease.
In the current case, PCOS was also present at the onset of TBIRS; however, over time, her menstrual disorder, enlargement of both ovaries, and high blood testosterone levels improved after glucocorticoid treatment. The glucocorticoid treatment for TBIRS can have resulted in elimination of the insulin receptor antibody and subsequent improvement of insulin resistance and hyperinsulinemia. The fact that PCOS in TBIRS improved after blood insulin levels decreased is of great interest in considering the relationship between PCOS, insulin resistance and hyperinsulinemia.
A 31-year-old woman presented with complaints of fatigue, weight loss, and irregular menstruation at Kyushu Medical Center. She had been healthy but had experienced irregular menstruation during the previous 6 months and weight loss during the previous 5 months. She had noticed darkening of the skin (acanthosis nigricans) in her axillae and both inguinal regions during the previous 4 months. She had fatigue and amenorrhea during the previous 3 months. On examination, she was found to have a lean body with a body mass index of 18.1 kg/m2 (body weight 39.7 kg). Blood tests showed a hemoglobin A1C level of 9.4 %, a fasting glucose level of 133 mg/dL, and a 2-hour blood glucose level of 463 mg/dL on a 75 g oral glucose tolerance test, leading to a diagnosis of diabetes (Table 1). A fasting blood test before breakfast during hospitalization showed a low blood glucose level of 42 mg/dL and a low serum C-peptide level of 0.07 ng/mL, but a high serum insulin level of 25.3 μU/mL. Continuous subcutaneous glucose monitoring showed repeated daytime hyperglycemia and dawn hypoglycemia. The anti-insulin antibody was negative at 0.8 U/mL, whereas the insulin receptor antibody was positive (inhibition rate 79.5%), leading to a diagnosis of TBIRS. In addition, there was a menstrual disorder and a high blood testosterone level of 3.29 ng/mL, and magnetic resonance imaging showed enlarged polycystic ovaries, leading to a diagnosis of PCOS (Fig. 1). Moreover, swelling of the fingers, back of the hands, and cervical lymph nodes were observed, and a positive anti-U1-RNP antibody led to a diagnosis of mixed connective tissue disease.
Laboratory findings on admission
| Parameter | Value | Reference range | ||
|---|---|---|---|---|
| General | ||||
| White-cell count (/μL) | 4,000 | 3,500–8,500 | ||
| Neutrophils (%) | 39.9 | 38.0–71.8 | ||
| Lymphocytes (%) | 51.5 | 18.9–49.7 | ||
| Monocytes (%) | 6.3 | 4.1–11.3 | ||
| Eosinophils (%) | 1.8 | 0.5–9.6 | ||
| Basophils (%) | 0.5 | 0.2–3.6 | ||
| Hemoglobin (g/dL) | 15.3 | 11.5–15.0 | ||
| Platelet count (/μL) | 81,000 | 150,000–350,000 | ||
| Albumin (g/dL) | 4.6 | 4.0–5.0 | ||
| Creatinine (mg/dL) | 0.44 | 0.40–0.70 | ||
| Alanine aminotransferase (IU/L) | 33 | 6–27 | ||
| Lactate dehydrogenase (IU/L) | 175 | 119–229 | ||
| Alkaline phosphatase (IU/L) | 377 | 115–359 | ||
| Creatine kinase (IU/L) | 31 | 45–163 | ||
| Endocrinological | ||||
| Thyroid stimulating hormone (μIU/mL) | 0.974 | 0.500–5.000 | ||
| Free thyroxine (ng/dL) | 1.19 | 0.90–1.70 | ||
| Adrenocorticotropic hormone (pg/mL) | 54.2 | 7.2–63.3 | ||
| Cortisol (μg/dL) | 20.1 | 6.2–18.0 | ||
| Dehydroepiandrosterone sulfate (μg/dL) | 149 | 23–266 | ||
| Growth hormone (ng/mL) | 1.3 | 0.13–9.88 | ||
| Insulin-like growth factor 1 (ng/mL) | 28.0 | 126–297 | ||
| Prolactin (ng/mL) | 15.83 | 4.91–29.32 | ||
| Luteinizing hormone (mIU/mL) | 4.81 | 1.76–10.24 | ||
| Follicle stimulating hormone (mIU/mL) | 1.09 | 3.01–14.72 | ||
| Testosterone (ng/mL) | 3.29 | 0.11–0.47 | ||
| Estradiol (pg/mL) | 106 | 28.8–196.8 | ||
| Diabetes-related | ||||
| Glucose (mg/dL) | 42 | 80–112 | ||
| Hemoglobin A1C (%) | 9.4 | 4.6–6.2 | ||
| Glycated albumin (%) | 34.5 | 12.4–16.3 | ||
| Immunoreactive insulin (IRI) (μU/mL) | 25.3 | 5.0–10.0 | ||
| C-peptide immunoreactivity (CPR) (ng/mL) | 0.07 | 0.78–5.19 | ||
| Urine CPR (μg/day) | 480 | 23.7–207.0 | ||
| Anti-insulin antibody (U/mL) | 0.8 | — | ||
| Anti-insulin receptor antibody (Inhibition rate (%)) | Positive (79.5) | — | ||
| 75 g oral glucose tolerance test | ||||
| Time (minutes) | 0 | 30 | 60 | 120 |
| Glucose (mg/dL) | 133 | 299 | 382 | 463 |
| IRI (μU/mL) | 170.3 | 251.9 | 276.5 | 495.6 |
| CPR (ng/mL) | 1.73 | 3.34 | 3.57 | 6.45 |
T2-weighted magnetic resonance images of the ovaries
Magnetic resonance imaging showed enlarged polycystic changes in both ovaries before treatment. The enlarged ovaries improved at 32 weeks after initiation of glucocorticoid treatment.
The treatment for TBIRS was initiated with 40 mg prednisolone/day (Fig. 2). To treat hyperglycemia, insulin preparations were administered in addition to metformin (1,500 mg/day) during the early period. The blood glucose levels elevated after initiating glucocorticoid treatment, and insulin preparations were used to a maximum dose of 482 U/day. The blood glucose levels had gradually improved since 3 weeks of the treatment, with cessation of insulin therapy at 6 weeks. The insulin receptor antibody became negative at 8 weeks after initiation of glucocorticoid treatment. At 9 weeks, a fasting blood glucose was normal at 100 mg/dL, and the hyperinsulinemia improved, with a serum insulin level of 5.9 μU/mL. The prednisolone dosage was gradually reduced, and had kept at 5 mg/day since 26 weeks, with no worsening of the blood glucose levels.
Clinical course and laboratory findings
Type B insulin resistance syndrome was treated with prednisolone. The hyperglycemia worsened for the first 3 weeks of the treatment, but then gradually improved, with cessation of insulin therapy at 6 weeks. The dosage of prednisolone was gradually reduced, with no deterioration in blood glucose management. The serum C-peptide levels decreased and the blood testosterone levels subsequently normalized. The menstruation had normalized since 36 weeks of glucocorticoid treatment.
T, testosterone; CPR, C-peptide immunoreactivity; HbA1c, hemoglobin A1C; IGF-1, insulin-like growth factor 1; PSL, prednisolone.
While no specific treatment except for glucocorticoid treatment was given for PCOS, the blood testosterone levels gradually decreased and normalized to 0.44 ng/mL at 41 weeks. The magnetic resonance imaging at 32 weeks showed improvement of the enlarged polycystic ovaries, and the menstruation had normalized since 36 weeks. The luteinizing hormone (LH)-releasing hormone loading test performed before the treatment showed an excessive response with the peak LH value of 63.8 mIU/mL after the load, whereas at 26 months, the peak LH value after the load was reduced to 23.4 mIU/mL, a normal response in the LH-releasing hormone loading test.
TBIRS is a rare disease caused by insulin receptor antibody that leads to hyperglycemia and hypoglycemia. The patient exhibited hyperglycemia during the daytime and repeated hypoglycemia at dawn. After having an evening snack every day, the hypoglycemia was resolved without any drugs. It cannot be proven whether the patient’s insulin receptor antibody acted as a partial agonist. In Chinese hamster ovary cells expressing human insulin receptor, immunoglobin G from the serum of a patient with type B insulin resistance inhibited insulin binding to the insulin receptor and insulin-induced phosphorylation of the insulin receptor [2]. Considering that the hyperglycemia was difficult to treat and the hypoglycemia was rarely a problem, it is likely that the patient’s insulin receptor antibody mainly acted as an antagonist of the insulin receptor.
At the time of diagnosis of TBIRS, there was no indication for glucocorticoid treatment for the patient’s mixed connective tissue disease, as there was no evidence of vital organ involvement. The patient’s TBIRS was treated with glucocorticoid in addition to insulin and metformin. TBIRS is generally treated primarily with glucocorticoids, while immunosuppressants, rituximab, and plasmapheresis can be used in combination. We selected glucocorticoid for the initial treatment considering the patient’s employee insurance and economic aspect. Although the glucocorticoid took more than 3 weeks to exert its therapeutic effect on the hyperglycemia, this may have been the time required for the antibody to become absent in the blood. After 7 weeks of glucocorticoid treatment, diabetes drugs such as insulin and metformin were discontinued, however, glycemic control did not worsen. Immunosuppressive treatment with glucocorticoid can have been effective for glycemic control of TBIRS, with elimination of insulin receptor antibodies.
PCOS is a disease characterized by menstrual disorders, hyperandrogenemia, and the presence of numerous follicles in both ovaries. It is known that insulin resistance and obesity are frequently associated with PCOS, but the exact cause of this syndrome is unclear. While glucocorticoid treatment can have been effective for TBIRS, its treatment may have worsened PCOS, because glucocorticoids can generally exacerbate insulin resistance and promote hyperinsulinemia. Indeed, hyperinsulinemia worsened during the initial period of glucocorticoid treatment, however, the blood insulin level was within the normal range at 9 weeks after the treatment. Although the glucocorticoid administration had continued since 9 weeks, the improvement of insulin resistance would have maintained from the fact that the serum C-peptide remained at low levels. These findings are probably because the reduction of insulin resistance due to the elimination of insulin receptor antibodies exceeded the exacerbation of insulin resistance due to glucocorticoid. The exact mechanism by which elevated blood testosterone levels and enlarged polycystic ovaries attenuated after 32 weeks of glucocorticoid treatment is unknown. However, because improving insulin resistance through weight loss or treatment with metformin is often effective in common PCOS, it is possible that attenuation of insulin resistance and hyperinsulinemia by glucocorticoid treatment involves in improvement of PCOS in TBIRS [3, 4]. In this case, metformin was administered early in the treatment for diabetes mellitus with marked insulin resistance. It is possible that metformin had a therapeutic effect for PCOS. Considering that the menstruation had normalized since 29 weeks after cessation of metformin, however, its effect for PCOS may be negligible.
In TBIRS, despite hyperinsulinemia, the action of insulin through the insulin receptor may be suppressed due to the presence of insulin receptor antibodies. Therefore, it was assumed that the hyperinsulinemia may have induced PCOS by acting on something other than the insulin receptor. Insulin in the blood exerts its effect by binding to the insulin receptor, but it also weakly binds to the insulin-like growth factor 1 (IGF-1) receptor [5]. By contrast, the effect of insulin receptor antibody is specific for the insulin receptor, with no effect on the IGF-1 receptor [2]. In the present case, when the patient displayed PCOS, insulin receptor antibodies were present, but the insulin, while being at a high blood concentration, may not have bound to the insulin receptor; rather, it may have bound to the IGF-1 receptor and exerted its effect through this receptor.
There have been some clinical studies on PCOS and abnormal IGF-1 excess (Table 2). Of 14 women with acromegaly who had increased growth hormone (GH) and IGF-1, 7 were diagnosed with PCOS [6]. In another study, 33% of 97 patients with acromegaly met the diagnostic criteria for PCOS before their diagnosis of acromegaly [7]. Additionally, when IGF-1 treatment was performed on women with Laron syndrome, which involves a GH receptor abnormality, an increase in LH and testosterone was observed, and some cases exhibited polycystic ovaries [8]. Furthermore, there were case reports of improved PCOS in patients with acromegaly after pituitary surgery [9] or the administration of dopamine agonists [10]. On the basis of these results, it is possible that an increase in blood IGF-1 can lead to PCOS.
List of literatures suggesting that abnormal insulin-like growth factor 1 (IGF-1) excess is involved in the pathogenesis of polycystic ovary syndrome (PCOS)
| Reference | Subject | Treatment | Result |
|---|---|---|---|
| Kaltsas et al. [6] | Women with acromegaly | — | 7 of 14 patients were diagnosed with PCOS. |
| Khiyami et al. [7] | Women with acromegaly | — | 32 of 97 patients met the diagnostic criteria for PCOS before their diagnosis of acromegaly. |
| Klinger et al. [8] | Women with Laron syndrome | IGF-1 injection | 4 of 6 patients presented with hyperandrogenism, 2 of whom were diagnosed with PCOS. |
| Goto et al. [9] | Woman with acromegaly and PCOS | Pituitary surgery | IGF-1 decreased from 804 ng/mL to 309 ng/mL and PCOS improved thereafter. |
| Hashimoto et al. [10] | Woman with acromegaly and PCOS | Dopaminergic agents | IGF-1 decreased from 463 ng/mL to 283 ng/mL and PCOS improved thereafter. |
The results of basic research also suggested that IGF-1 receptor-mediated actions can induce high LH and androgen levels. IGF-1 receptors are present in pituitary anterior lobe cells, and IGF-1 administration to goat pituitary anterior lobe cells increased LH secretion [11]. Additionally, both insulin receptors and IGF-1 receptors are expressed in granulosa cells from follicular pre-ovulatory follicles in the ovary [12], and IGF-1 administration in the presence of LH to granulosa cells increased androgen production [13]. These results suggested that when the intracellular signaling through the IGF-1 receptors present in granulosa cells or pituitary anterior lobe cells is activated by IGF-1, a hormone profile similar to PCOS may be obtained.
By contrast, it is known that intracellular signaling mediated by the insulin receptor and that mediated by the IGF-1 receptor are interrelated in the cell [14, 15]. For example, it has been reported that in ovarian follicle cells, activation of the serine/threonine kinase Akt through the IGF-1 receptor is further enhanced by the reduction of action through the insulin receptor [16]. In PCOS, insulin resistance is frequently observed and hyperinsulinemia is present, but intracellular insulin signaling is suppressed [17]. Additionally, in ovarian follicle cells and theca cells of PCOS patients with hyperinsulinemia, insulin receptor downregulation was reported [12]. Therefore, in patients with PCOS, reduced insulin action through the insulin receptor itself in turn may affect IGF-1 signaling.
Consequently, in TBIRS, intracellular signaling through the insulin receptor may be blocked by insulin receptor antibodies, while the intracellular signaling through the IGF-1 receptor may be enhanced by hyperinsulinemia. Although the mechanism of PCOS is not well understood, it is possible that the initial cause is the suppression of intracellular signaling through the insulin receptor, such as in obesity, and with insulin receptor antibodies, that is, the induction of insulin resistance. In a patient whose insulin secretion capacity is adequately maintained, when insulin resistance occurs, hyperinsulinemia will be induced. In a pathological state where insulin signaling is suppressed, that is, in the presence of insulin resistance, hyperinsulinemia is likely to play a significant role in PCOS development by enhancing IGF-1 signaling. The imbalance between suppressed insulin signaling and activated IGF-1 signaling may be important in PCOS pathogenesis (IGF-1/insulin signaling balance hypothesis) (Fig. 3). The reason why PCOS does not occur in all patients with acromegaly may be that PCOS onset is affected not only by IGF-1 excess but also by the degree of attenuation of insulin signaling.
IGF-1/insulin signaling balance hypothesis
In healthy individuals, serum insulin primarily activates intracellular insulin signaling through insulin receptors, which in turn inhibits intracellular insulin-like growth factor 1 (IGF-1) signaling (Fig. 3A). In insulin-resistant diabetic patients, despite high insulin levels, intracellular insulin signaling through insulin receptors is suppressed and intracellular IGF-1 signaling is slightly activated (Fig. 3B). In type B insulin resistance syndrome, there is a marked hyperinsulinemia, but intracellular insulin signaling is blocked by insulin receptor antibodies, leading to a release of the inhibition of intracellular IGF-1 signaling. Furthermore, high levels of insulin in the blood activate intracellular IGF-1 signaling through IGF-1 receptors, leading to highly activated intracellular IGF-1 signaling (Fig. 3C). Polycystic ovary syndrome may be induced by the activation of IGF-1 signaling and the inhibition of insulin signaling.
Interestingly, in the present case, the IGF-1 level before treatment was 28 ng/mL, lower than the reference value. The peak GH value after the growth hormone-releasing peptide 2 load before glucocorticoid treatment was 62.8 ng/mL, a normal response in this loading test. The IGF-1 level improved to 187 ng/dL after 9 weeks of glucocorticoid treatment, and remained within the standard range thereafter (Fig. 2). These findings suggested that the low IGF-1 level before treatment was not due to irreversible damage to the pituitary gland. It appears that low IGF-1 levels are common in TBIRS, given the report showing that IGF-1 levels were significantly lower in TBIRS (mean IGF-1: 25.0 ng/mL, mean age: 58.7 years) than in insulin autoimmune syndrome (mean IGF-1: 132 ng/mL, mean age: 54.7 years) [18]. Although the molecular mechanism is unknown, there is a clinical report that insulin resistance is associated with lower circulating GH concentrations [19]. The patient’s IGF-1 level appears to have improved together with a decrease in insulin resistance, based on the change in serum C-peptide levels. Therefore, attenuation of intracellular insulin signaling may be involved in the reduction of GH-stimulated IGF-1 synthesis or secretion. Because the patient’s IGF-1 level was low at the onset of PCOS, the high level of insulin, but not IGF-1, may have mainly stimulated the IGF-1 receptor.
Arioglu et al. reported that the patients with TBIRS had cystic enlargement of ovaries in most of 20 women and elevated testosterone levels in 7 of 13 women [20]. Brown et al. reported that a woman with TBIRS had bilaterally enlarged ovaries and her elevated testosterone level normalized after insulin resistance improvement [21]. However, to the best of our knowledge, this is the first report to demonstrate that enlarged polycystic ovaries and a menstrual disorder in TBIRS improved after glucocorticoid treatment (Fig. 1).
We hope that the pathophysiology of PCOS will be further elucidated through the rare disease of TBIRS.
We thank Robert Blakytny, DPhil, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
The authors have no conflict of interests to disclose.
