Insulin Resistance in an Underweight Woman with Polycystic Ovary Syndrome: A Case Study

Introduction

Polycystic ovary syndrome (PCOS) is as a common endocrine disorder affecting women of reproductive age [1]. The prevalence ranges between 5% and 15%, depending on the diagnostic criteria applied [2]. The syndrome encompasses a spectrum of symptoms, including menstrual irregularities, hyperandrogenism manifestations, fertility problems, obesity, and psychological concerns [2–4].

The pathophysiology of this condition is affected by changes in several factors, including steroid production, ovarian follicle development, neuroendocrine function, metabolism, insulin production, insulin sensitivity, adipose cell activity, inflammatory factors, and sympathetic nerve function. According to Barre et al, the 4 main contributors to the pathophysiological changes in PCOS are high carbohydrate consumption, hyper-insulinemia, hyperandrogenemia, and persistent low-grade inflammation [2,4].

In 2003, the European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM) convened in Rotterdam to establish diagnostic criteria for PCOS. These criteria propose the diagnosis when 2 out of 3 conditions are met: the presence of clinical or biochemical signs of hyperandrogenism, oligo-ovulation or anovulation (reflecting menstrual cycle disturbance), and/or polycystic ovaries on ultrasound following exclusion of other causes [3,4].

The biochemical hallmark of PCOS is hyperandrogenemia, which manifests clinically as hirsutism, acne, and alopecia. High levels of androgens are observed in 75–90% of PCOS patients with oligomenorrhea, and their concentrations frequently increase with the severity of the phenotype. Excessive androgen synthesis by the ovaries and the adrenals contributes to hyperandrogenism [4,5].

There is a need for careful clinical assessment of women’s history, physical examination, and laboratory evaluation, emphasizing the accuracy and validity of the methodology used for both biochemical measurements and ovarian imaging [5].

Physical examination should be done to notice acne, hirsutism, and alopecia. Use of the Ferriman-Gallwey scoring system is important in establishing the diagnosis of hirsutism. The modified FG (mFG) score assesses hair growth across 9 body areas. Each area is rated on a scale from 0 (no terminal hair) to 4 (male pattern hair), with intermediate levels of hair growth represented by scores of 1, 2, and 3. The maximum possible score is 36. In contrast, the original method evaluates 11 body parts, with scores ranging from 0 to 4 for each part. A score of ≥8 typically indicates hirsutism [6].

Assessments of free testosterone (T) levels are more sensitive than the measurement of total testosterone for establishing the presence of excess androgen. It may be preferable to rely on calculated free T if the clinician is uncertain about the quality of the free T assay, which shows good concordance and correlation with free T as measured by equilibrium dialysis methods. Levels of dehydroepiandrosterone sulfate (DHEAS) are high in approximately 30% to 35% of PCOS patients [5]; however, its measurement does not significantly contribute to the diagnosis in most patients. Serum 17-hydroxyprogesterone and anti-Müllerian hormone are useful.

A patient with cycles shorter than 35 days can be assessed by measuring progesterone levels in the mid-luteal phase [7,8].

The best way to evaluate ovulation is the measurement of serum progesterone at the mid-luteal phase (days 21 to 22). Whereas progesterone levels >2.5 ng/mL may indicate ovulation, values ≥7 ng/mL are generally needed for regular luteal function [8].

Persistent hyperandrogenism in PCOS leads to disruptions in hypothalamic-pituitary feedback, resulting in LH hypersecretion, premature granulosa cell luteinization, aberrant oocyte maturation, and premature follicular arrest [9]. While the onset typically occurs during early puberty, the diagnosis is not solely reliant on hirsutism or elevated testosterone levels, as not all affected individuals display these features [9].

Androgen excess serves as a cornerstone in PCOS pathophysiology, hypothesized to underlie the diverse clinical manifestations of the disorder. Despite the heterogeneity in symptomatology, most adults (>80%) with PCOS exhibit high levels of male sex hormones.

Beyond menstrual irregularities and high levels of steroid hormones, PCOS presents metabolic and cardiovascular aberrations, along with psychological comorbidities like depression, anxiety, and social difficulties [10]. The syndrome is closely associated with obesity, and both obese and non-obese individuals demonstrate insulin resistance, often accompanied by compensatory hyperinsulinemia.

PCOS prevalence spans all BMI categories, with varying symptom severity observed among different groups [11]. Abdominal adiposity exacerbates insulin resistance due to elevated plasma non-esterified fatty acids, stemming from abdominal fat lipolysis [12].

Furthermore, body fat distribution strongly correlates with PCOS, as evidenced by studies comparing body composition between lean women with PCOS and healthy controls. One such study used DEXA scanning to compare these variables in women with PCOS and healthy women matched for age and weight. Such investigations reveal higher body fat content and lower lean body mass in lean PCOS individuals [13]. However, obesity is likely not a determinant of PCOS, as there are equal chances of lean and thin women getting diagnosed with PCOS [14]. Androgens have a substantial influence on insulin sensitivity and secretion.

Some authors report there is a primary lack of enzymatic default in adrenal and ovarian steroidogenesis and damage in gonadotropin-releasing hormone excretion that causes luteal hormone (LH) emission or alterations in insulin movements that produce insulin resistance [14]. Therefore, it is reasonable to use new therapy for PCOS with insulin-sensitizing drugs such as metformin [14–16]. Shigiyama et al presented a case of a 32-year-old lean woman with PCOS (polycystic ovary syndrome), with early-stage type 1 diabetes and moderate insulin resistance, which was successfully treated with metformin [16]. Low-dose dexamethasone treatment further reduces androgen levels in metformin-treated PCOS women [17].

This report presents the case of a 24-year-old underweight woman with a BMI of 15.9 kg/m2 with insulin resistance, hirsutism, and a diagnosis of PCOS.

Case Report

We present the case of a 24-year-old female patient with menstrual irregularity, acne, and hirsutism. Upon admission, she reported having started menarche at the age of 12, along with experiencing menstrual irregularities characterized by oligomenorrhea (cycles lasting 38 to 40 days) and anovulation (approximately 8 cycles per year). She denied any use of oral contraceptives, anabolic steroids, corticosteroids, testosterone supplements, or anxiolytic and antidepressant medications. She also reported a positive family history of diabetes and hirsutism.

During the clinical examination, acne vulgaris on the face was recorded, but no alopecia or acanthosis nigricans were observed on the skin. Clinical measurements recorded BP (blood pressure)=110/70 mmHg, and WHR (waist-to-hip ratio)=0.87, while the BMI of 15.9 indicated that the patient was under-weight. Ferriman-Gallwey’s scoring system was used to assess for hirsutism, and she scored 20 (on a scale of 0 to 36, with a score of 8 or higher indicating excess androgens). She had excessive hair growth on various body parts but was carefully shaving her sideburns (Figure 1A).

After receiving written informed consent, the patient was directed for hormonal laboratory analysis on the third day of the menstrual cycle, corresponding to the early follicular phase. The venous blood sample was taken at 8: 00 a.m. and again at 4: 00 p.m. for evening cortisol only. At the same time, other hormonal (Table 1), hematological (hemogram and leukocyte formula), and biochemical [urea, creatinine, HDL (high-density lipoprotein), triglycerides, LDL (low-density lipoprotein), AST (aspartate transaminase), ALT (alkaline aminotransferase), glycemia, insulin, and C-peptide] parameters were measured. The second sample was taken on the 25th day of the cycle to measure the progesterone level. Due to the positive family history of diabetes, an OGTT (oral glucose tolerance test) was performed according to the 3-hour procedure: in the morning and 2 hours after loading with 75 g of glucose. Hormonal analyses in our laboratory were done with RIA (radioimmune assay) and IRMA (immunoradiometric assay) methods.

All hematological and biochemical results were within normal values. In contrast, the hormonal tests showed increased testosterone, androstenedione, and 17-OH progesterone values. Accordingly, Cushing’s syndrome, hyperprolactinemia, and thyroid disorders [based on normal lab results of ACTH (adrenocorticotropic hormone) and cortisol, prolactin and T3 (triiodothyronine), T4 (thyroxine), and TSH (thyroid-stimulating hormone)] were excluded (Table 1).

The ratio between FSH (follicle-stimulating hormone) and LH (luteinizing hormone) was 1: 3. The ultrasound showed polycystic ovaries as described by the radiologist: “Ultrasound image of the right ovary shows the increased dimensions of the ovary measuring 41.5×25.2 mm. Many follicles of different sizes are present, with the biggest measuring up to 10 mm”, but without any ovarian tumor (Figure 1B).

The patient was diagnosed with PCOS and insulin resistance, which is rare in underweight patients, and based on the described pathology she was treated with metformin and dexamethasone for 6 months.

In the next follow-up, an extraordinary improvement of hirsutism and PCOS was observed: the points according to FG had dropped to 7, the level of total testosterone in the serum was 2.8 nmol/L, androstenedione was 9.9 nmol/L and 17-OH progesterone was 3 nmol/L. Also, the insulin level had decreased (at 0’=11.3 µIU/L, at 30’=78.6 µIU/L, and 60’=50.8 µIU/L) together with the glucose level, which in the 30th minute was 6.2 nmol/L). Anovulation, initially identified by low luteal phase progesterone levels upon admission, was successfully restored to normal ovulation after 6 months of treatment. This was evidenced by an increase in progesterone levels from 3.30 nmol/L to 18.3 nmol/L and was accompanied by approximately 12 menstrual cycles per year.

To date, the patient has been on metformin treatment only and did not report a relapse of the condition before treatment.

Discussion

We present a case of an underweight woman with menstrual irregularity, acne, and hirsutism, diagnosed as PCOS with insulin resistance. After treatment with metformin and dexasone, we observed significant improvement in menstrual cycle, acne, and hirsutism.

Many studies emphasize that PCOS is related to obesity and insulin resistance, but few works show the connection between PCOS, low weight, and insulin resistance.

She had not only clinical hyperandrogenism but also biochemical hyperandrogenism because the hormonal results showed increased testosterone, androstenedione, and 17-OH progesterone values. The ratio between FSH (follicle-stimulating hormone) and LH (luteinizing hormone) was 1: 3.

In differential diagnosis, Cushing syndrome, congenital adrenal hyperplasia, hyperprolactinemia, and thyroid disorders were excluded because of lack of typical symptoms and signs, low BMI, also based on normal lab results of ACTH (adrenocorticotropic hormone) and cortisol, prolactin and T3 (triiodothyronine), T4 (thyroxine), and TSH (thyroid-stimulating hormone).

Because of her positive family history of diabetes OGTT (oral glucose tolerance test) was performed and resulted in insulin resistance, but she had no hypertension, hyperlipidemia, or signs of metabolic syndrome. Ultrasound image of the right ovary showed the increased dimensions of the ovary measuring 41.5×25.2 mm. Many follicles of different sizes were present, with the biggest measuring up to 10 mm (Figure 1B). Based on her diagnosis of PCOS and insulin resistance, she was treated with metformin and dexamethasone for 6 months, with improved menstrual cycle, acne, and hirsutism. She continues with metformin treatment.

Shigijama et al presented the case of a lean, infertile, 34-year-old woman with acne, hirsutism, and menstrual irregularities. Her androgen levels were normal. Ultrasound revealed polycystic ovaries, and the ratio of LH to FSH was 3: 1. She was diagnosed with PCOS. Based on fasting and postprandial C-peptide levels and a positive islet autoantibody test for glutamic acid decarboxylase, another diagnosis of early-stage type 1 diabetes was made. A hyperinsulinemic-euglycemic clamp test (for evaluating insulin sensitivity) was performed and showed that she had moderate insulin sensitivity. She began treatment with low-dose insulin and low-dose metformin, which improved irregular ovulation, menstrual irregularities, and infertility. The authors concluded that her insulin resistance was likely due to PCOS [16].

In our case, similar to the one above, the patient had acne, hirsutism, menstrual irregularities, anovulation, a positive family history of diabetes, and an FSH: LH ratio of 3: 1. However, unlike that case, our patient presented with biochemical hyperandrogenism.

Moreover, considering the negative correlation between BMI and SHBG in overweight and obese women, as reported by the vast majority of referenced articles, the discrepancy between total and free testosterone in our patient could be attributed to low BMI. Hence, despite the high total testosterone levels, we speculated that SHBG levels within the normal range have caused the normal free testosterone levels, although the calculated free androgen index (cFAI=total testosterone/SHBG ×100) was 12.2, which is above the normal reference value of 7 to 10 for women [17].

Therefore, the basal level of 17 OHP of 4.7 nmol/L in our patient, although above normal level, is not indicative of NC-CAH based on reports by Chesover et al regarding basal 17OHP levels. They reported that the aforementioned hormonal levels greater or equal to >12 nmol/L (4 ng/mL) could identify patients with non-classical congenital adrenal hyperplasia in 96% and 97% of cases, respectively, with high sensitivity and specificity [18]. Also, according to Yesiladali et al, “a cut-off value of 5.4 ng/mL has been proposed in the differential diagnosis of NCAH and PCOS, dismissing the ACTH stimulation test” [19].

During an OGTT, we observed insulin resistance in our patient. At 30 minutes, glucose levels were 9 nmol/L, and insulin levels were elevated: 27.35 µIU/L at baseline, 82.81 µIU/L at 30 minutes, and 61.12 µIU/L at 60 minutes (Table 1). Given the risk of future diabetes, the patient was started on metformin and dexamethasone. Research suggests that 6 months of low-dose dexamethasone treatment can further reduce androgen levels in women with PCOS who are being treated with metformin [20].

Anastasiou et al analyzed 1269 consecutive patients with PCOS, identifying only 19 underweight patients (1.5%). Clinical and endocrine parameters were evaluated, and insulin resistance was assessed using a 3-hour oral glucose tolerance test (OGTT). They concluded that underweight PCOS patients are rare and exhibit higher postprandial insulin levels. Additionally, several underweight patients achieved regular menstrual cycles with metformin therapy [21].

While insulin resistance was traditionally thought to be strongly correlated with obesity, emerging evidence suggests it may serve as an intrinsic etiological factor for PCOS, irrespective of weight. Potential underlying mechanisms include genetic variations, defects in certain signaling pathways, and a vicious cycle involving hyperandrogenism [22]. Genes such as INSR and DENND1A have been implicated in IR among PCOS patients, highlighting a genetic component [23].

Tissue-specific defects in insulin signal transduction also contribute to IR in PCOS. Hyperinsulinemia can exacerbate hyper-androgenism through various mechanisms, including stimulating androgen production in ovarian theca cells [24].

Treatment with metformin in underweight patients with oligomenorrhea led to observed improvements in menstrual cycle regularity [4,25]. Also, metformin therapy has demonstrated efficacy in treating various aspects of PCOS, including endocrine, metabolic, and reproductive effects. It is particularly effective in improving ovulation in lean women with PCOS compared to obese women [26]. Additionally, dexamethasone has shown effectiveness in suppressing the secretion of androgens, thereby improving ovarian function in some PCOS patients, accompanied by reduction of hirsutism and acne due to decreasing elevated levels of 17-Oh progesterone and androstenedione [27,28].

It is necessary to conduct new research regarding the cases of patients with PCOS and insulin resistance, especially those with low weight, and to carry out clinical research regarding the efficacy of metformin in these patients.

Conclusions

This report highlights a patient with PCOS who, despite being underweight, had insulin resistance. This unique situation underscores the need for a multidisciplinary approach to diagnosis, treatment, and management, particularly given her elevated risk of developing type 2 diabetes mellitus.