Polycystic Ovary Syndrome (PCO Syndrome, Stein-Leventhal Syndrome) is the most common endocrine disturbance in women of reproductive age (Sozen and Arici, 2000; Dewailly, 2000). The condition is a complex functional disturbance that may be associated with virilization, oligomenorrhea or amenorrhea, infertility, metabolic disturbances, hyperinsulinism, and obesity in about 50% of the cases (Dewailly, 2000; Goudas and Dumesic, 1997) (Table 1). In the majority of patients, the disease has its onset prior to puberty, and obesity appears to play a major role (Sozen and Arici, 2000; Goudas and Dumesic, 1997; Geisthövel, 1995). Besides hypertestosteronemia (Dexter and Dovre, 1998; Cistulli et al., 1994), obesity is a factor that predisposes patients with PCO Syndrome to develop sleep-related breathing disorders as well—a point that has, so far, hardly found mention in the literature. On the basis of two cases, the relationships will be described and discussed.

CASE I (G.R., 33 years old)

History

Massive obesity since early childhood. Repeated failed attempts to lose weight. Menarche at age 13, irregular menses, periods of amenorrhea up to a six-month duration. No children, despite all attempts to conceive. Ovulation inhibitors for the past 12 months, with complete amenorrhea for the past nine months. Hypertension and hypercholesterolemia of six years standing, the former treated with amlodipine.

Over many years, progressive loud snoring, reportedly with periods of cessation of breathing. For the past two years, progressive loss of vigilance and diurnal sleepiness, associated with decreased physical performance.

Results of Physical Examination

Height 162 cm, weight 122.6 kg, body mass index 64.5 kg/m², waist-hip ratio 1.12. General state of health normal, virile alopecia, otherwise no pathological findings affecting the head and neck, in particular no pathology in the throat. Percussion and auscultation of heart and lungs unremarkable. Evaluation of the abdomen impossible due to massive obesity. Congestive dermatosis affecting both calves. Sparse pubic hair, otherwise typical female phenotype. No further abnormalities.

Normal Examination Findings

Laboratory Investigations: blood count, electrolytes, creatinine, urea, CK, GOT, GPT, LDH, gamma-GT, TSH basal, blood sugar daily profile, HbA1c, urinary status, catecholamines in 24-hour urine, dexamethasone suppression test, arterial blood gas analysis and acid-base balance. Exercise and resting ECG, two-dimensional echocardiography and whole body plethysmography.

Pathological Findings

Laboratory Investigations: Cholesterol 258 mg/dL; HDL 42.9 mg/dL, LDL 182 mg/dL; triglycerides 296 mg/dL; testosterone 74 ng/dL.

24-hour Blood Pressure Monitoring: Mean pressure 145/92 mmHg, loss of night dipping.

Ultrasonography of the Abdomen: Hepatic steatosis; evaluation of the ovaries not possible due to massive obesity. No other pathological findings.

Epworth Sleepiness Scale: 16 points, indicating high-grade diurnal sleepiness.

Computer Vigilance Test (fly catching, 3×20 minutes): Correct reactions in 82% (normal value >90%), no reactions in 18% (<10%). Thirty-four inappropriate reactions (<10). Reaction time (250-400 msec) minimum 285 msec, maximum 896 msec, average 419 msec (standard deviation 79.9%). Overall, signs of considerably reduced vigilance and rapid tiring.

Cardiorespiratory Polysomnography: Sleep-onset latency six minutes, sleep efficiency 81%, one complete and three incomplete sleep cycles. REM sleep and slow-wave sleep considerably shortened with increase in the wake time. Considerably disrupted sleep architecture with massive sleep fragmentation caused by 297 arousals and awakenings with an index of 56.3/h. Loud snoring, overall 76 apneas and hypopneas, one central and 75 obstructive. RDI 15.2/h. Mean oxygen saturation in the wake state 95%, during sleep 92%, in part prolonged oxygen desaturations, minimum 84%. For 34.8% of the sleep time, oxygen saturation below 90%. No increase in motoric events.

Assessment: Combined sleep-related breathing disorder with obstructive sleep apnea and obesity-hypoventilation syndrome.

Diagnoses

Overlap syndrome with obstructive sleep apnea and obesity-hypoventilation syndrome, PCO Syndrome with hypertestosteronemia and metabolic syndrome (massive obesity, arterial hypertension, hypercholesterolemia).

Treatment and Course

On the basis of the clinical symptoms and the polysomnographic findings, the patient was fitted out with a respiratory aid for use at night. With nCPAP treatment, adequate suppression of the respiratory disturbances could not be achieved. Under nBiPAP treatment with a pressure of 17/5 mbar, breathing during sleep was regular, snoring suppressed, and sleep quality considerably improved. Diurnal well-being was also considerably improved. Despite comprehensive counseling, a weight reduction in the first three months after initiation of nBiPAP treatment was not achievable. The PCO Syndrome was treated with an estrogen/gestagen combination (ethinylestradiol 0.05 mg, norethisteronacetate 1 mg=Non-Ovlon^® 1/day), and hypertension treatment supplemented by an ACE inhibitor.

CASE II (J.F., 25 years old)

History

Overweight since childhood. Weight reduction of 10 kg over the past two years. Menarche at age 18, irregular menses, approximately one menstruation a year. Single, no sexual partner, childless.

Since the age of 12, progressive snoring and diurnal somnolence with an irresistible urge to sleep during the day. Currently, repeated episodes of falling asleep during the day in quiet situations. Total sleep time 16-18/24 hours. Occupation not possible because of tiredness.

Results of Physical Examination

Height 170 cm, weight 118.4 kg. Body mass index 40.9 kg/m², waist-hip ratio 0.98. Normal general state of health. Hirsutism. No pathological findings affecting the head, neck or throat. Heart and lungs unremarkable on percussion and auscultation. Abdomen soft with no pathological resistances, striae present. Sparse pubic hair, otherwise typical female phenotype. No other pathological findings.

Normal Examination Findings

Laboratory Investigations: Blood count, electrolytes, creatinine, urea, CK, GOT, GPT, LDH, gamma-GT, TSH basal, blood sugar daily profile, HbA1c, urinary status, ferritin, dexamethasone suppression test, 17-beta-estradiol, progesterone, LH. ECG, two-dimensional echocardiography, body plethysmography, computer tomography of the head, abdomen, and pelvis.

Pathological Findings

Laboratory Investigations: Cholesterol 276 mg/dL; HDL 44.1 mg/dL; LDL 203 mg/dL; testosterone 134.2 ng/dL; oral glucose tolerance test: 120 minutes after 75 g oral glucose blood sugar 135 mg/dL, insulin 489 mU/L, C-peptide >14 ng/mL. HLA status: HLA-DR 12, HLA-DR 15(2), HLA-DQ 7, HLA-DQ 6(1).

Epworth Sleepiness Scale: 19 points, evidencing high-grade daytime somnolence.

Multiple Sleep Latency Test: In all five naps, sleep latency between 0 and 2 minutes, in four naps, REM sleep with a latency of between 1.5 and 20 minutes. Consequently, pronounced diurnal sleepiness and sleep onset REM.

Cardiorespiratory Polysomnography: Sleep latency three minutes; sleep onset REM after five minutes. Sleep efficiency 64%. Multiple awakenings. Arousal/awake index 66.5/hour. REM sleep and slow wave sleep considerably shortened with increase in wake episodes. Continuous loud snoring with a total of 88 apneas and hypopneas, RDI 15.4/hour. Mean oxygen saturation in the wake 96%, during sleep 93%, with, in part, long-duration desaturations to a minimum of 81%. For 24% of the total sleep time, O₂ saturation was less than 90%. No relevantly increased motoric events.

Assessment: Combined sleep-related breathing disorder with obstructive sleep apnea and obesity-hypoventilation syndrome.

Diagnoses

Overlap syndrome with obstructive sleep apnea and obesity-related hypoventilation syndrome, indicative of narcolepsy. PCO Syndrome with hypertestosteronemia and metabolic syndrome (massive obesity, hypercholesterolemia, insulin resistance).

Treatment and Course

With the aid of a nCPAP device, the sleep-related respiratory disorder was well suppressed and the quality of sleep appreciably improved. Nevertheless, an irresistible desire to sleep persisted during the day. Since concomitant narcolepsy was suspected, the patient was referred to a neurological sleep laboratory, where the diagnosis could be clarified and a successful treatment with modafinil (Vigil^® 2/day) was initiated. The PCO Syndrome was treated with an estrogen/gestagen combination (ethinylestradiol 0.05 mg, norethisteronacetate 1 mg=Non-Ovlon^® 1/day), but there was no influence on the patient's body weight and the severity of nocturnal breathing disorder in the first six months.

DISCUSSION

The syndrome of polycystic ovaries is associated with a wide range of manifestations, which can be very burdensome and carry an unfavourable prognosis for those affected (Table 1). Obesity, virilization and infertility together represent a powerful psychological stress which, in turn, may cause a psychoreactive disturbance of eating habits and thus perpetuate the obesity (Gortmaker et al., 1993). Hypertension, hypercholesterolaemia, hyperinsulinaemia and, again, obesity, are factors that negatively affect the morbidity and mortality of the patients (Wild et al., 2000 ; Lerner and Kannel, 1986).

Our two cases show that sleep-related breathing disorders, which in turn worsen the prognosis (He et al., 1988; Young et al., 1993), may also commonly occur, a point which, so far, has been described only once in the literature (Cistulli et al., 1994).

Obesity, in particular the android form with a waist-hip ratio >0.8, appears to be one of the major factors for comorbidity of the PCO syndrome and sleep-related respiratory disturbances. An increased incidence of sleep-related respiratory disorders in obesity is well-known. Sixty to eighty percent of patients with obstructive sleep apnea are overweight which, although not the sole causal factor for this condition, is nevertheless of substantial importance (Kopelman, 1992; Borys and Boute, 1994). But, there are no data about the prevalence of sleep related breathing disorders in PCO-patients without obesity.

Furthermore, as in our first case, massive overweight results in nocturnal alveolar hypoventilation, formerly known as the Pickwickian Syndrome, but now referred to as obesity-hypoventilation syndrome (Kopelman, 1992; Borys and Boute, 1994). Those affected suffer, in common with patients with sleep apnea, from appreciable diurnal somnolence and concomittant or consecutive cardiovascular diseases (Konermann et al., 1995).

For the onset and perpetuation of the PCO syndrome, the patient's weight also plays an important role (Sozen and Arici, 2000; Goudas and Dumesic, 1997; Geisthövel, 1995). The fat is an endocrine organ in which C19 steroids are converted from less to more strong acting androgens (androstendione), and C18 steroids (estrone) are synthesized (Geisthövel, 1995). Via these mechanisms the prepubertal obesity has a decisive influence on the development of the PCO syndrome (Goudas and Dumesic, 1997; Geisthövel, 1995). Figure 1 shows some of the known underlying endocrinological pathways.

The elevation of the serum androgen concentration in the PCO syndrome, which was also detectable in our patients, apparently has a role to play in the genesis of the sleep-related respiratory disorders. Men are much more frequently afflicted by obstructive sleep-related breathing disorders than are women, and it is only after the menopause that the ratio of the sexes becomes more equal (He et al., 1988; Young et al., 1993; Ferini-Strambi at al., 1994). In the sole publication on the topic PCO syndrome and sleep-related respiratory disorders, ovarectomy performed in a slim patient with severe obstructive sleep apnea successfully eliminated the hypertestosteronaemia, and also the respiratory disorder (Dexter and Dovre, 1998).

The frequent coexistence of the PCO syndrome, obesity, hypertension, hyperlipidaemia, hyperinsulinaemia and Type 2 diabetes suggests that the PCO syndrome might be one component of a metabolic/endocrine syndrome. The obesity-associated sleep-related respiratory disturbances are also considered by some authors to be a component of the metabolic syndrome (Grunstein, 1996; Strohl, 1996). Indeed, positive correlations and synergistic effects of insulin, androgens and android obesity have been demonstrated (Sozen and Arici, 2000; Geisthövel, 1995; Wang et al., 1998).

The PCO syndrome can be treated surgically by ovarectomy or ovarotomy, but this is rarely curative (Dewailly, 2000; Goudas and Dumesic, 1997; Geisthövel, 1995). Otherwise, treatment is, as in our own patients, symptomatic by the administration of ethinyloestradiol and cyproterone acetate, which inhibit the secretion of gonadotropins by the hypophysis and suppress ovarial production of testosterone (Dewailly, 2000; Geisthövel, 1995; Creatsas et al., 2000;). Modern alternatives are the use of LH-RH antagonists and anti-androgens (Dewailly, 2000; Goudas and Dumesic, 1997; Geisthövel, 1995; Diamanti-Kandarakis and Zapanti, 2000). With this approach, however, adequate treatment of the concomitant components of the metabolic syndrome (hypertension, hyperinsulinaemia, hyperlipidaemia, obesity) cannot be achieved, so that, in addition to hormone therapy, a holistic-internistic treatment concept should be applied. Here, treatment of hyperinsulinaemia with insulin sensitizers, is simultaneously treatment for hyperandrogenism, on account of the synthesis interactions (Sozen and Arici, 2000; Wang et al., 1998; Diamanti-Kandarakis and Zapanti, 2000; De Leo et al., 2000). When the internistic treatment concept is being considered, however, it is imperative that sleep-related breathing disorders also be taken into account.

The treatment of the sleep-related respiratory disorders is oriented to the usual therapeutic guidelines. Apart from the consideration of the general rules of sleep hygiene and, if possible, weight reduction, treatment of severe obstructive sleep apnea consists in the nocturnal application of nCPAP or nBiPAP. Treatment of obesity-related hypoventilation requires—occasionally in combination with nCPAP or nBiPAP—nocturnal O₂ insufflation of 2 - 4 litres /min (Sampol et al., 1996). Using this approach, an appreciable improvement in ventilation during sleep and daytime vigilance can be achieved in almost all cases.

In our second patient, the medical history together with the results of the sleep-laboratory examination and HLA typing, aroused suspicion of narcolepsy, with which HLA-DR 15 and HLA-DQ 6 are associated. The diagnosis was clarified and a successful treatment was initiated.

Conclusion

The PCO syndrome is an endocrine/metabolic disease comprised of the complex of symptoms: virilization, oligomenorrhea/amenorrhea, infertility, obesity, hypertension, hyperlipidemia, and hyperinsulinemia. Our two cases also indicate that sleep-related breathing disorders may also form part of the Syndrome, and thus need to be taken into account for the diagnostic work-up and treatment.

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ACKNOWLEDGMENTS

The authors do not wish to include any acknowledgments.