Clinical presentation of PCOS following development of an insulinoma: Case Report

R.D. Murray1, R.M. Davison1, R.C. Russell2 and G.S. Conway1,3

1 Department of Endocrinology, and 2 Department of Surgery, The Middlesex Hospital, London WIN 8AA, UK


    Abstract
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
A 24 year old woman presented with a prolonged clinical history of fasting and exertional hypoglycaemia, and was subsequently diagnosed with an insulinoma. Concurrent symptoms of oligomenorrhoea and hyperandrogenism of similar duration were noted. Biochemically, hyperinsulinaemia was observed in association with a raised serum luteinizing hormone (LH), raised testosterone and androstendione concentrations. Surgical removal of the insulinoma resulted in resolution of the clinical and biochemical features of the polycystic ovarian syndrome (PCOS) but minimal change was observed in the ovarian ultrasound appearances. This case demonstrates the role of insulin in mediating the hypersecretion of both LH and androgens in women with polycystic ovaries. We suggest that hyperinsulinaemia converted occult `polycystic ovaries' to become clinically manifest as `polycystic ovary syndrome'. This paradigm has clear implications for women with insulin dependent diabetes mellitus who presumably have systemic hyperinsulinaemia.

Key words: hirsutism/hyperinsulinaemia/insulinoma/PCOS


    Introduction
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
Polycystic ovarian syndrome (PCOS) is likely to represent a heterogeneous group of disorders with varible clinical penetrance and multiple aetiological factors. PCOS is the `clinical' diagnosis for mild hyperandrogenism, when alternate pathologies have been excluded (Conway and Jacobs, 1990Go). The most prevalent biochemical observations are raised androgens, lutenizing hormone (LH) or prolactin concentrations although each of these are quite variable.

Evidence for insulin being an inherent part of PCOS is derived from both epidemiological and intervention studies. Hyperinsulinaemia has been reported to be present in 75 and 30% of obese and non-obese women diagnosed as having PCOS respectively (Conway et al., 1990Go). Fasting insulin concentrations have been shown to be correlated with obesity, amenorrhoea (Robinson et al., 1993Go) and serum androgen concentrations (Burghen et al., 1980Go). Therapeutic strategies aimed at reducing insulin concentrations in PCOS have consistently resulted in a reduction in serum androgen concentrations whether by diet (Kiddy et al., 1992Go; Holte et al., 1995Go) or drugs (Nestler et al., 1989Go; Velazquez et al., 1994Go; Dunaif et al., 1996Go). The role of insulin as an aetiological factor in PCOS remains controversial but accrued evidence leaves little doubt as to its importance in facilitating hyperandrogenism.

We describe a patient in whom PCOS presented clinically as a result of the hyperinsulinaemia from an insulinoma, and in whom, following curative surgery the clinical features resolved.


    Case report
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 Abstract
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 Case report
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A 24 year old woman was admitted for investigation following a grand-mal seizure during exercise. Further history revealed 6 months of excessive tiredness, tremors, and intermittent episodes of confusion, blurred vision and perioral paraesthesia. These symptoms were noted to resolved immediately following eating. Additional symptoms of acne, seborrhoea and mild hirsutism had developed concurrently. In the 12 months before presentation, the interval between menstrual periods increased with each cycle, cycle length at the time of presentation was 40–44 days. No history of weight gain over this period was elicited. Examination revealed acne, seborrhoea and mild hirsutism.

Investigations revealed a normal electroencephalogram (EEG) and magnetic resonsnce imaging (MRI) scan of the brain. Random glucose was 2.0 mmol/l, and following an overnight fast the patient was unrousable, sweaty and clammy. Plasma glucose was 1.6 mmol/l and clinical recovery quickly followed administration of i.v. glucose. Insulin and C-peptide were inappropriately elevated and a diagnosis of an insulinoma was made. Abdominal computerized tomography (CT) scan demonstated a solitary 2 cm nodule within the head of the pancreas (Figure 1Go). Pelvic ultrasonography showed enlarged polycystic ovaries with bilaterally increased stroma and >10 follicles per ovary, ranging in diameter from 4–9 mm. A reproductive endocrine profile revealed raised serum LH and androgen concentrations with normal serum follicle stimulating hormone (FSH), prolactin and sex hormone-binding globulin (SHBG) measurements.



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Figure 1. Computerized tomography (CT) scan demonstrating the insulinoma (arrows) in the head of the pancreas.

 
Surgical removal of the insulinoma was uneventful. Post-operatively plasma glucose concentrations remained within the normal range and symptoms of hypoglycaemia resolved completely. At re-assessment 4 months post-operatively her weight had reduced by 4 kg, symptoms of acne and seborrhoea had fully resolved and subjectively, her facial hair was finer and fairer. The patient's body mass index (BMI) changed minimally following removal of the insulinoma. Menstrual cycles were regular at 28 days. Biochemically serum insulin, LH, androgen, prolactin and leptin concentrations were lower than pre-operatively (Table IGo). A repeat pelvic ultrasound scan revealed no clinically significant change in ovarian appearances.


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Table I. Biochemical and ultrasound parameters before and after resection of the insulinoma
 

    Discussion
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 Case report
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This case provides an interesting insight into the effect of insulin on the reproductive axis. We have demonstrated clinical, biochemical and ultrasound features consistent with PCOS during the period of hyperinsulinaemia. We suggest that the ultrasound features of polycystic ovaries are likely to have been present, but occult, before the development of hyperinsulinaemia. The hormonal picture manifest by the insulinoma was of a markedly raised follicular phase serum LH, total testosterone, and androstendione concentrations. Resolution of the clinical and biochemical pictures occurred on removal of the insulinoma and thus the source of the hyperinsulinaemia. The ultrasound features remained unchanged 4 months following resolution of the hyperinsulinaemia.

Previous reports, with few exceptions, have failed to demonstrate an increase in serum androgen concentrations from short term exogenous insulin administration in vivo (Conway and Jacobs, 1993Go). The importance of hyperinsulinaemia in women with PCOS is suggested by the correlation of fasting insulin concentrations with amenorrhoea (Robinson et al., 1993Go) and serum androgen concentrations (Burghen et al., 1980Go). Further evidence of the importance of hyperinsulinaemia is derived from evidence that therapeutic strategies aimed at reducing insulin concentrations in PCOS have been associated with a reduction in circulating androgens and LH (Nestler et al., 1989Go; Kiddy et al., 1992Go; Velazquez et al., 1994Go; Dunaif et al., 1996Go; Nestler and Jakubowicz, 1996Go). Reduction of serum androgen concentrations in PCOS has been shown to enhance insulin sensitivity (Dahlgren et al., 1998Go), though this has not been a consistent finding in all studies (Geffner et al., 1986Go).

The mechanism by which insulin induces hyperandrogenism in PCOS remains controversial. Insulin acts directly to reduce hepatic SHBG production and thereby increase free testosterone (Nestler et al., 1991Go); however, this was not observed in our patient where a slight decrease in SHBG was observed following resolution of the hyperinsulinaemia. Other mechanisms are thus more likely to be important in this case. Insulin may act as a co-gonadotrophin; insulin has been observed to augment the androgen production of isolated ovarian theca cells of hirsute women in response to LH (Barbieri et al., 1986Go).

Hyperandrogenaemia might also have been the result of LH hypersecretion. In our patient, a marked increase in LH was observed in association with hyperinsulinaemia. This can be proposed to result from several mechanisms. The direct action of insulin on the pituitary might augment gonadotrophin-releasing hormone (GnRH)-stimulated LH release (Adashi et al., 1981Go), the consequent hyperandrogenism resulting from the increased LH secretion. Secondly, insulin acting as a co-gonadotrophin induces hyperandrogenism and anovulation, the resulting absence of progesterone negative feedback leading to LH hypersecretion. Finally, an increase in serum leptin was observed, resulting from weight gain and hyperinsulinaemia. Leptin in turn, acting as an intermediary, may stimulate its receptors present on GnRH neurones to promote LH synthesis (Conway and Jacobs, 1997Go).

The importance of LH as an intermediary in insulin augmented hyperandrogenism is further supported by the reduction in its concentration as a result of pharmacological reduction of hyperinsulinaemia (Nestler et al., 1989Go; Dunaif et al., 1996Go). Failure to show a relationship between insulin and LH in cross-sectional studies (Conway et al., 1992Go) probably resulted from the dominant effect of obesity. This case underlines the potential of antihyperinsulinaemic agents in the treatment of patients with PCOS, who are proven to be hyperinsulinaemic. However, the use of these agents as a new therapeutic approach requires further research into the efficacy and safety of the individual agents (van Montfrans et al., 1998Go). Despite many studies demonstrating improvements in insulin sensitivity, serum androgens, and menstrual cyclicity, the effect on the clinical end points of hirsutism, acne, seborrhoea and obesity for the most part remain unknown. In addition, their use in ovulation induction in women wishing to conceive assumes they are safe in this setting though the teratogenic potential of many of these agents has not been fully elucidated.

In summary, this case adds further weight to the important role of insulin in the clinical presentation of PCOS in those patients with occult polycystic ovaries. Furthermore, this case highlights the important interaction between insulin and LH in this syndrome. PCOS is a clinical diagnosis which is likely to represent a group of heterogeneous disease states. Insulin augmentation of LH and serum androgen production in PCOS is likely to be due to a combination of the mechanisms described with the relative importance of each being variable between individuals.


    Notes
 
To whom correspondence should be addressed at: The Cobbold Laboratories, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK Back


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 Abstract
 Introduction
 Case report
 Discussion
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Submitted on July 15, 1999; accepted on October 5, 1999.