Effect of medroxyprogesterone on inspiratory flow shapes during sleep in postmenopausal women

https://doi.org/10.1016/S1569-9048(02)00208-2Get rights and content

Abstract

We previously showed that medroxyprogesterone acetate (MPA) effectively decreases the arterial CO2 levels in postmenopausal women with partial upper airway obstruction. The aim of the present study was to analyze the effects of MPA on the inspiratory flow shapes during sleep. Eight postmenopausal women with hypoxemia and partial upper airway obstruction during sleep (patients) received MPA 60 mg daily for 14 days. Four matched postmenopausal women without MPA treatment served as controls. Sleep and nasal pressure were recorded on each visit. Each breath was analyzed for duration, volume and inspiratory flow shape class. MPA shortened inspiration and prolonged expiration. The inspiratory volumes increased consistently in all flow shape classes. The inspiratory shapes with single late peak were transformed to those with double peak. MPA also decreased shapes with mid-peak or mid-plateau. MPA did not have an effect on sleep. Sleep modified the flow shape distribution only in patients but in a similar fashion in stages S2, SWS and REM. The results suggest that postmenopausal women present with a significant proportion breaths with poor initial inspiratory flow, which is reversed with MPA-induced respiratory stimulation.

Introduction

Despite many efforts there are no established pharmacologic treatments available for sleep-disordered breathing. Several respiratory stimulants have been suggested (Hudgel and Thanakitcharu, 1998) but in general they have proved inefficient or side effects have limited their usage. Electrical stimulation of the diaphragm causes secondary upper airway obstruction if the upper airway dilator muscles are not synchronously activated during inspiration. Certain pharmacologic respiratory stimulants have been suspected to do the same, resulting in worsening rather than improvement of upper airway obstruction.

Progestins are female hormones that stimulate ventilation (Skatrud et al., 1978; Zwillich et al., 1978; Saaresranta et al., 1999). Medroxyprogesterone acetate (MPA) has been a disappointment as a treatment of sleep apnea in men. Although MPA could be more efficient and better tolerated in females, only two studies (Block et al., 1981; Saaresranta et al., 2001) have evaluated MPA alone and few studies in combination with estrogen in controlling sleep-disordered breathing in postmenopausal women (Pickett et al., 1989; Cistulli et al., 1994; Keefe et al., 1999). During luteal phase of the menstrual cycle or on MPA therapy the upper airway muscle activity increases but the airway resistance does not change while awake (Popovic and White, 1998). The effect of MPA on the flow dynamics in the upper airway has not been studied during sleep.

Analysis of the nasal flow profile recorded with nasal prongs is a non-invasive method to monitor upper airway behavior during sleep. Flow profile analysis is particularly useful in studying partial upper airway obstruction where increase in the upper airway dilator muscle activity is still transformed into decreased collapsibility of the airway (Aittokallio et al., 1999, Aittokallio et al., 2001). Partial collapse of the upper airway during inspiration is identified as a plateau flow on the inspiratory flow signal (Condos et al., 1994; Montserrat et al., 1995; Hosselet et al., 1998). Nasal flow profile has been successfully applied to feed-back control the appropriate CPAP pressure during treatment of sleep apnea (Berthon-Jones, 1993). To evaluate whether MPA therapy improves or worsens the upper airway flow dynamics in women we analyzed the inspiratory flow shape changes on MPA.

Section snippets

Subjects

Initially, 71 healthy previously hysterectomized postmenopausal women were enrolled in the study evaluating the effect of short-term estrogen replacement therapy on sleep (Polo-Kantola et al., 1999). They were recruited from the city of Turku and the neighbourhood through announcements in local newspapers. Sixty-three out of 71 subjects completed the trial with two full polygraphic sleep recordings on and off estrogen replacement therapy (Polo-Kantola et al., 1999). Eleven out of the remaining

Results

All patients had normal flow-volume spirometry curves. Two of ten patients had marked sinus bradycardia (<50 BPM) without any other abnormal findings in their ECG. Eight of ten patients completed the study. The total number of respiratory cycles analyzed was 119 769, of which 94 417 in patients (51 054 or 54.1% during treatment nights) and 25 352 in controls. The mean proportion of wakefulness of the total recording time did not differ between controls (6.5%, range 1.0–14.6%) and patients at

Discussion

Our study shows that MPA 60 mg daily for 14 days significantly alters the inspiratory waveforms during sleep. Because MPA is a respiratory stimulant, increasing respiratory drive with MPA could lead to increased flow limitation and collapsibility in the upper airway if the upper airway dilators do not respond appropriately. MPA shortened inspiration, prolonged expiration, and tended to increase the maximum inspiratory slope during sleep. MPA decreased flow shape classes 5, 6 and 7, and

Acknowledgements

This work was supported by grants from The Finnish Anti-Tuberculosis Association Foundation, Finnish Sleep Research Society, The Research Foundation for Respiratory Diseases, The Väinö and Laina Kivi Foundation and The Turku University Foundation. Dr. Polo was supported by Paulo Foundation. MPA assessments were done and medication supplied by the drug company Orion Pharma, Espoo, Finland. The authors also thank Esa Wallius, BSc, for statistical assistance.

References (36)

  • S.A Clark et al.

    Assessment of inspiratory flow limitation invasively and noninvasively durind sleep

    Am. J. Respir. Crit. Care Med.

    (1998)
  • R Condos et al.

    Flow limitation as a noninvasive assessment of residual upper-airway resistance during continuous positive airway pressure therapy of obstructive sleep apnea

    Am. J. Respir. Crit. Care Med.

    (1994)
  • R Farre et al.

    Relevance of linearizing nasal prongs for assessing hypopneas and flow limitation during sleep

    Am. J. Respir. Crit. Care Med.

    (2001)
  • S.J Heitman et al.

    Validation of nasal pressure for the identification of apneas/hypopneas during sleep

    Am. J. Respir. Crit. Care Med.

    (2002)
  • M.J Hensley et al.

    Medroxyprogesterone treatment of obstructive sleep apnea

    Sleep

    (1980)
  • J.-J Hosselet et al.

    Detection of flow limitation with a nasal cannula/pressure transducer system

    Am. J. Respir. Crit. Care Med.

    (1998)
  • D.W Hudgel et al.

    Pharmacologic treatment of sleep-disordered breathing

    Am. J. Respir. Crit. Care Med.

    (1998)
  • E.D.B Johansson et al.

    Medroxyprogesterone acetate pharmacokinetics following oral high-dose administration in humans: a bioavailability evaluation of a new MPA tablet formulation

    Acta Pharmacol. Toxicol.

    (1986)
  • Cited by (28)

    • Understanding sleep-disordered breathing through mathematical modelling

      2009, Sleep Medicine Reviews
      Citation Excerpt :

      Although much of the clinical attention has been directed towards a rather limited spectrum of the events (e.g., no airflow, reduced airflow, normal airflow), the shape of the airflow curve can provide additional information on the upper airway behaviour throughout the respiratory cycle. Descriptive flow shape analysis has successfully been exploited to automatically adjust and test therapeutic devices such as the CPAP titration,38 distinguish subject with different degrees of SDB,39 or to monitor the treatment effects on the upper airway dynamics during sleep.40 Each particular flow profile is a result of a composite of forces that either promote a collapse or support the airway (Fig. 1A).

    • Progesterone reduces wakefulness in sleep EEG and has no effect on cognition in healthy postmenopausal women

      2008, Psychoneuroendocrinology
      Citation Excerpt :

      After 6 months of treatment time spent awake after sleep onset was significantly decreased in the estrogen/micronized progesterone group but not in the estrogen/medroxyprogesterone acetate group. Studies by Saaresranta et al. (2003, 2005) demonstrated that medroxyprogesterone, a synthetic progestin that binds at the progesterone receptor, is capable to stimulate ventilation during sleep in postmenopausal women, but did not have an effect on sleep pattern. The occurrence of hot flashes in 5 of the 10 subjects had no negative influence on sleep efficiency index, and subjects, who reported a reduction of hot flashes during progesterone treatment did not improve in sleep EEG parameters more than subjects without hot flashes.

    • Sleep Apnea and Neuroendocrine Function

      2007, Sleep Medicine Clinics
      Citation Excerpt :

      Small uncontrolled pilot reports of estrogen alone, progesterone alone, cyclical (ie, estrogen with addition of progesterone for 2 weeks each month) HRT, and continuous combined (ie, estrogen with progesterone continuously coadministered) HRT for 1 to 2 months in 5 [39], 6 [40], 10 [41,42], and 15 [43] postmenopausal women show modest decreases in apnea-hypopnea index, variable effects on hypoxic or hypercapnic ventilatory responsiveness, respiratory patterns and inspiratory flow, and no clinically meaningful effect on sleep. Importantly all of these studies recruited women with clinically defined OSA, except one where women were diagnosed with partial upper airway obstruction [41,42]. In contrast, all the available randomized studies discussed below have examined the effect of HRT in postmenopausal women without OSA.

    View all citing articles on Scopus
    View full text