Differential loss of fat in polycystic ovary syndrome: A welcome or warning sign?

INTRODUCTION

Lipodystrophy syndromes are a group of rare acquired or genetic disorders characterized by selective deficiency of adipose tissue. Its presentation as polycystic ovary syndrome (PCOS) is even rarer. This is categorized based on aetiology (genetic or acquired) and distribution of disease (generalized or partial). It is associated with metabolic complications such as diabetes mellitus (DM), dyslipidaemia, PCOS and non-alcoholic steato-hepatitis.¹ Cardiovascular diseases (myocardial infarction and arrhythmia) are important causes of mortality in them, so timely diagnosis and preventive measures are needed.^2,3 Patients need lifelong follow-up due to the association of PCOS with metabolic syndromes. We present a woman with PCOS who was subsequently diagnosed with lipodystrophy.

THE CASE

A 23-year-old woman presented to the outpatient department of endocrinology with complaints of secondary amenorrhoea for 3 years and hirsutism for 2 years. Initially, she had oligomenorrhoea which progressed to amenorrhoea over 2 years. She also had complaints of excess hair growth over her face, arms and legs for the past 2 years. She noticed loss of scalp hair and darkening of skin at the back of the neck for the past 1 year. On being asked specifically about any change in body composition, she said there was decreased fat mass on her cheeks, upper arms, buttocks and thighs. Her cousin sister had complaints of irregular periods and hirsutism but not of fat loss. There was no history of diabetes or metabolic disorder in her family. Her height was 138 cm and weight 41 kg with a body mass index (BMI) of 21.5. She had decreased subcutaneous fat in the arms, thighs, buccal and gluteal area; and abdominal obesity (Fig. 1) along with acanthosis nigricans on the back of her neck. She had frontal recession, temporal balding and a masculine body. Her modified Ferriman–Gallwey score for hirsutism was 18.

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FIG 1.

Loss of fat from the gluteal region and thigh, with abdominal obesity

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Her ultrasound of the pelvis showed the right and left ovary volume to be 10 ml and 14 ml, respectively with multiple peripherally arranged follicles and thick stroma. Ultrasound of the upper abdomen showed a fatty liver. She was assigned a diagnosis of PCOS with phenotype A as per the consensus of the National Institutes of Health (NIH).⁴ Further work-up suggested diabetes mellitus. The cause of deranged liver function tests (LFT) was non-alcoholic steatohepatitis as viral markers and markers of autoimmune hepatitis were negative. Fat composition measurement (done by Dual energy X-ray absorptiometry) showed loss of fat from the lower limbs and increased ratio of trunk-to-leg fat. Autoimmune work-up ruled out acquired causes of lipodystrophy (Table I).

With a history of fat loss from cheeks and buttocks, investigations showing abnormal body fat distribution along with deranged LFT and blood sugars, we made a diagnosis of partial lipodystrophy with metabolic complications of dyslipidaemia, diabetes, non-alcoholic steatohepatitis and PCOS. The patient was advised lifestyle modifications in the form of dietary restriction and physical activity. Metformin 500 mg twice a day was started, which was gradually increased to 1000 mg twice a day. For her deranged LFT, ursodeoxycholic acid and for dyslipidaemia, statins were started. Over a period of 6 months, her LFT, blood sugar and dyslipidaemia improved. She resumed spontaneous menstrual cycles at an interval of 40– 50 days, but her balding did not improve.

DISCUSSION

Weight gain is generally seen in PCOS, but a proportion of patients present as lean variants. In all lean PCOS, the pattern of fat distribution should be noted, and if there is any suspicion, metabolic screening should be done. Lipodystrophy syndrome can be a possibility in them. As in our patient, diagnosing her as lean polycystic ovary disease (PCOD) only would have been incomplete and missing out on the underlying lipodystrophy would have been important due to the long-term complications associated with this pathology. A diagnosis of lipodystrophy can be made on detailed work-up of PCOD.^5,6 It is a rare condition⁷ due to which most clinicians are not familiar with the diagnosis and management. The diagnosis of lipodystrophy is based on history and presentation. Although serum leptin level has been proposed as a marker, it is not diagnostic as there is considerable overlap with the general population.⁸ There are four main varieties of lipodystrophy (Table II).⁸ However, due to heterogeneity of the condition, all subtypes cannot be classified into these categories.³ Autoimmune markers in acquired causes and genetic testing in familial cases help in the classification. Genetic testing has implications in family members of the proband. Mutation in lamin A/C (LMNA) gene is seen in familial cases.^5,9 Other causes of lipodystrophy should be ruled out such as retrovirus positivity, diabetes on insulin therapy, etc.

Severe insulin resistance is a feature of lipodystrophy which leads to endogenous hyperinsulinaemia having leutenizing hormone-like activity on ovarian theca cells producing increased androgen. Further, hyperinsulinaemia leads to decreased sex hormone-binding globulin increasing bioavailable androgens, leading to hirsutism and menstrual irregularity. Due to non-availability of adipose tissue, dietary fat accumulates in nonadipose tissue such as the liver leading to lipotoxicity, for example, steatohepatitis. Although we did not do a genetic analysis of our patient, we came to the diagnosis of acquired partial lipodystrophy due to the absence of positive family history. Our patient had all the above-mentioned manifestations of metabolic syndrome such as diabetes, dyslipidaemia, PCOS and non-alcoholic steatohepatitis.

There is no curative treatment for lipodystrophy syndrome. Management is directed towards metabolic complications and mitigating morbidity of the condition.⁷ Dietary management and exercise is the mainstay of treatment, to prevent accumulation of fat in non-adipose tissue. At present, metreleptin, a synthetic analogue of the hormone leptin, is the only medical treatment approved for this condition.⁷ Lipodystrophy also affects the physical appearance of patients, leading to psychological distress in some. Hence, appropriate mental health counselling is needed.

To conclude, in patients with lean PCOS, lipodystrophy becomes a differential diagnosis, so attention should be paid to body fat distribution in these patients. Despite normal BMI, they tend to develop metabolic complications as in our patient (BMI 21.5). This diagnosis has long-term implications in view of its association with metabolic complications.