Medroxyprogesterone Acetate and Sleep Apnea

The Japanese Journal of Psychiatry and Neurology, Vol. 41, No. 4, 1987

Medroxyprogesterone Acetate and Sleep Apnea

Hiroharu Ohshima, M.D.

Department of Neuropsychiatry, Kurume University School of Medicine, Kurume

Abstract: Seven patients with sleep apnea DOES and one with sleep apnea DIMS were treated with medroxyprogesterone acetate (MPA). The therapeutic effect was confirmed in most of them by polysomnographic recording. A marked increase of TST was observed in two patients whose AI and/or %SAT remarkably decreased. Contrarily, three patients exhibited a considerable decrease in TST, and A1 and/or %SAT were reduced remarkably in two of them with MPA. After the MPA medication a few patients complained of disturbed nocturnal sleep. A significant positive correlation was observed between the decreased rate of TST and that of the mean duration of apneas. From these results, it was considered that MPA has a mild activating action on the arousal system in the CNS, and that the action may be partly responsible for the therapeutic effects of MPA on sleep apneas.

Key Words: sleep apnea, medroxyprogesterone acetate, arousal action

Jpn J Psychiatr Neurol 41: 645-650, 1987

INTRODUCTION

Both progesterone and medroxyprogesterone acetate (MPA), a synthetic progesterone, have been demonstrated to have a stimulant action on the respiratory system,l l4 l5 2o

and have been used in the treatment of patients with the sleep apnea syndrome.8 As of the present, the author has treated seven patients with sleep apnea DOES syndrome (SADOES) and one with sleep apnea DIMS syndrome (SADIMS) with MPA, and confirmed polysomnographically an obvious decrease in the apnea index (AI) and %time of sleep apnea (%SAT) in most of them.

It was of much interest, however, that two patients with SADOES exhibited a marked decrease in total sleep time (TST)

Received for publication March 3, 1987

even though considerable reductions were found in A1 and/or %SAT with MPA, and that a pronounced decrease was observed in the TST of another patient with SADOES whose A1 and %SAT were not affected by MPA. Moreover, a few patients with SADOES or SADIMS complained of a reduced time of nocturnal sleep or of early morning awakening during the MPA medication. These observations led the author to suppose that MPA might have a weak action as a stimulant on the arousal system in the CNS. In actual fact, a recent study by Kotorii et a1.9 experimentally revealed using normal healthy subjects that MPA has a stimulating action on the arousal system. Accordingly, it may be possible that MPA reduces the arousal threshold which would then lead to an early termination of each apneic episode, because a termination of the apneic episode is preceded by arousal

646 H. Ohshima

Table 1: Subjects

Patient Age Sex Diagnosis

1 43 M SADOES 2 43 M 0

3 62 M 0 4 48 M //

5 56 F 0

6 58 M 0

7 33 M 0 8 54 M SADIMS

- _ _ ~

~

from s l x i ~ . ~ '3 In

The present study, therefore, was retro- spectively carried out on patients with the sleep apnea syndrome to investigate whether the therapeutic effects of MPA on sleep apnea can bz partly attributable to its stimulating action on the arousal system.

jected to the present study. Their age and sex are presented in Table 1.

After a polysomnographic recording was performed for one night before medication, MPA (30-100 mg) was orally given to each patient (b.i.d.). One to four months later a second recording was conducted for one night during the MPA medication. Each recording lasted from between 1O:OO and 11 :O p.m. until the patient awoke sponta- neously the next morning. The sleep stage was scored at every 20-sec epoch during the recording, according to the criteria of Rechtschaffen and Kales.12 An apnea was defined as a cessation of the airflow at the nose and mouth lasting for more than 10 SW.7

The t-test or Mann-Whitney U-test was employed for the statistical analysis of two related samples.

SUBJECTS AND METHODS RESULTS

Seven patients with SADOES and one with SADIMS, all of whom were treated with MPA in the Sleep Disorders Clinic of Kurume University Hospital, were sub-

Tables 2 and 3 indicate TST, AI, %SAT, mean duration of apneas, percentage of each sleep stage and the total time spent for

Table 2: TST, AI, %SAT and Mean Duration of Apneas before and during MPA Medication

A1 Mean Duration of Apnea (sec)

C M Mean % SAT 0 C M Mean

I - 384 81.7 0 16.4 98.1 60.0 22 .o 0 22.1 22.0 MPA 60mg 452 43.4 0 3.7 47.1 24.1 18.6 0 16.4 18.4

2 - 397 42.3 1.1 0 43.4 18 .O 14.9 13.6 0 14.9 MPA 45mg 373 19.1 1.3 0 20.4 8.8 15.7 16.3 0 15.8

3 - 383 4.2 1.1 0.3 5.6 4.4 28.7 22.1 35.0 27.8 MPA 30mg 329 4.7 1.3 2.0 8.0 5.0 22.9 12.1 28.2 22.5

4 - 469 2.8 0.8 0.1 3.7 1.4 14.1 10.8 20.0 13.6 MPA 90mg 457 4.5 0 0.1 4.6 1.7 13.2 0 15.0 13.3

5 - 323 47.0 0.4 0.6 48.0 34.6 26.1 17.5 20.0 26.0 MPA 30mg 230 16.4 0.5 0.3 17.2 6.1 12.7 12.5 15.0 12.7

- 377 57.3 4.8 16.7 78.8 77.2 36.3 13.5 37.9 35.3 6 MPA 100mg 253 27.7 14.5 29.2 71.4 38.5 18.1 15.7 22.5 19.4

7 - 264 66.1 4.5 1.8 72.4 29.0 14.5 11.5 16.9 14.4 MPA 60mg 360 27.8 1.2 5.5 34.5 23.8 22.7 25.0 35.5 24.8

8 - 307 9.6 0.6 0.4 10.6 5 . 5 18.7 11.7 32.5 18.8

TST - Pt. Treatment (min) - ~ .~ __ _ ~~ ~-

0 ~- -- --___

MPA 45mg 333 4.1 0 0 4.1 2.6 22.2 0 0 22.2 - ~- ____ ~

0: obstructive, C: central, M: mixed.

Medroxyprogesterone Acetate and Sleep Apnea 6 47

Table 3: Stages of Sleep (%) and TIA before and during MPA Medication

Pt.

1

2

3

4

5

6

7

~ ~~

Treatment

- MPA COmg

MPA 45mg

MPA 30mg

MPA 90mg

MPA 30mg

MPA 100mg

MPA 60mg

-

-

-

-

-

-

St. 1 (%)

31.6 6.7

26.4 18.5 21.9 27.7 19.6 9.4

31.3 20.4 49.1 44.3 54.9 44.4

___ ~

St. 2 (%)

48.9 55.3 54.2 68.3 68.9 61.4 64.4 74 .o 57.3 68.7 38.5 51 .O 25 .O 45.3

8 - 14.7 MPA 45mg 15.3

intrasleep awakening (TIA) before and during the MPA medication for all the patients. The response range of these variables to the MPA medication was quite large among the patient group. With regard to TST, an increase of more than 50 min was noted in two patients (Pts. 1 and 7) while it decreased by more than 60 min in three others (Pts. 3, 5 and 6) with the MPA medication. The mean A1 was reduced by more than 50% in five patients (Pts. 1, 2, 5, 7 and 8) whereas no marked changes were noted in the remaining three (Pts. 3, 4 and 6). De- creases by more than 50% in %SAT were seen in five patients (Pts. 1, 2, 5, 6 and 8 ) . In four patients (Pts. 1, 3, 5 and 6), the mean duration of apneas was shortened by more than 3 sec, but was lengthened by more than 3 sec in the other two (Pts. 7 and 8). In the remaining two patients (Pts. 2 and 4), there was no alteration in the mean duration with MPA. TIA was reduced by more than 30% in five patients (Pts. 1, 2, 4, 5 and 7) and increased by a similar amount in two (Pts. 3 and 8). These results are displayed for each patient in Table 4.

It was considered noteworthy that a marked decrease in TST was exhibited by

St. sws (%I

REM (%)

0.5 11.9

0 0 0

0 . 6 0

0 .4 0 0 0

0 . 4 0

1.7

19.2 26 .O 19.4 17.7 9.1

10.3 16.0 16.2 11 .5 10.9 12.5 4 .3

20.1 8 .6

TIA (min)

100 12 68 27 81

171 39 15

124 71

112 117 96 64

71 .O 1 . 3 13 .O 91 70.3 0 . 3 14.1 132

~ ~

Table 4: Changes in TST, AI, %SAT, TIA and Duration of Apnea of all Patients

Pts. TST A1 % SAT TIA

1 T T 1 1 -11 .11 1 1 1 1 1 1 2

T T 3 1 1 - 1 1 4

5 11. 1 1 1.1 1 1 6 -11 - 1 1 - 7 T T 1 1 - 1

1 1 1 1 T

- -

- - -

- 8

Duration of apnea

1

1

1 1 t T

-

-

TST: .E+ or J.J. indicates an increase or decrease of more than SO min.

A1 and %SAT: &+ indicates a decrease of more than 50%.

TIA: .E+ or J.J. indicates an increase or decrease of more than SO%, and t or J. of more than 30% and less than 49%.

Duration of Apnea: 1. or J. indicates a lengthening or shortening of more than 3 sec.

three patients (Pts. 3, 5 and 6 ) . Pt. 3 presented a remarkable reduction in TST and an increase in TIA without showing any deterioration in A1 and %SAT, and Pt. 5 showed a marked decrease not only in TST but also in AI, %SAT and TIA. In Pt. 6, both TST and %SAT were considerably reduced with the MPA medication. Moreover,

648 H. Ohshima

c .- 0 %

Z 5 0 -

n

L =l

m W

c a 4

0

W

m E

'CI W

ul m W L

U W m

c

*

Table 5: Coefficients of Correlations between Decreased Rate of TST, and Decreased

Rates of Apneic Duration, AI, %SAT and TIA

Duration A1 % SAT TIA ~ .~

TST 0.9595* 0.3191 0.6456 -0.2009

p < 0.01

/ /

/ r . 0 . 9 5 9 5 , pe0 .01

Y - 1 . 8 X - 8 . 0 9

1 D e c r e a s e d R a t e o f T S T

Fig. 1: Correlation between a decreased rate in the mean duration of apneas and that of total sleep time in five patients who showed a decrease in total sleep time with MPA.

Pt. 5 frequently complained of a shortening of nocturnal sleep time in spite of improve- ments in A1 and %SAT. The fact that a remarkable decrease of TST was found to- gether with either an obvious improvement or without any deterioration at all in A1 and/or %SAT is seemingly beyond one's comprehension, for the simple reason that each apneic episode is almost always followed by an interruption of sleep and a decrease in A1 or %SAT will cause an increase in TST.

Accordingly, the author supposed that MPA has a stimulating action on the arousal

system in the CNS, and that this action may be partly responsible for its therapeutic effect on sleep apnea. Therefore, a relation between the decreased rate of TST and decreases of other variables of sleep apnea was examined. The results are presented in Table 5 and, as shown in Fig. 1, a significant positive correlation was observed only between the decreased rate of TST and that of the mean duration of apnea among the five patients whose TST had bzen reduced by MPA (Pts. 2, 3, 4, 5 and 6) .

DISCUSSION

The therapeutic effects of MPA on the sleep apnea syndrome have been exclusive- ly attributed to its stimulating action on the respiratory system by many researchers.l

'I l4 2o If this assumption is correct, TST, as estimated by polysomnographic re- cordings, should increase, not decrease, when apneas are reduced with MPA, because each apneic episode is followed by a disruption of sleep. Actually, in two patients (Pts. l and 7) of the present study, while in both an increase in TST and a decrease in TIA were found, they also exhibited reductions in the mean A1 and %SAT. The increase of TST and the decrease of TIA in these patients can be pre- sumed to have resulted from the reduction in the total number of apneas with MPA. However, a marked decrease was observed in TST of three patients (Pts. 3, 5 and 6) with MPA. In two of them (Pts. 5 and 6) , a decrease was also observed in AI, %SAT and mean duration of apneas. These observations led the author to suppose that MPA has an activating action on the arousal system in the CNS in addition to its stimulating action on the respiratory system.

It has been well established that the termination of each apneic episode and restora- tion of the upper airway patency are preceded by arousal from sleep.* Therefore, the decrease in the duration of apneas may

Medroxyprogesterone Acetate and Sleep Apnea 649

also be explained by the MPA action on the arousal system since a lowering of the arousal threshold will result in an early termination of apneic episode. In the present study, a relation between the decreased rate of TST and the decreases in the mean duration of apneas, AI, %SAT and TIA among patients whose TST was reduced with MPA administration was investigated. A significant positive correlation was found between the decreased rate of TST and that of the mean duration of apneas. These observations suggest that MPA has an activating action on the arousal system in the CNS, and that this action of MPA may be partly responsible for its therapeutic action on sleep apneas.

Pt. 5 frequently complained of a reduced time in nocturnal sleep after the MPA administration, and a reduction in TST was demonstrated polysomnographically even though AI, %SAT and TIA have all remarkably improved. Although Pt. 8 re- ported that he awoke earlier in the morning after the MPA medication, a reduction in TST was not confirmed by the polysomnographic recording. I t can be said, however, that the reports of these patients on their nocturnal sleep may indicate an activating action of MPA on the arousal system in the CNS.

Recently Kotorii et al.9 demonstrated that MPA given to normal healthy men resulted in a decrease of TST and Stage 4 sleep and an increase in TIA and Stage 1 sleep. From these results, they concluded that MPA has a mild activating action on human sleep, and the concluding remark of the present study is consistent with this. A further study, however, is necessary to elucidate the mechanism which induces the activating action of MPA on the arousal system in the CNS.

ACKNOWLEDGMENT

The author sincerely thanks Prof. K. Ina- naga and Associate Prof. Y. Nakazawa for their support and encouragement of the study.

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Medroxyprogesterone Acetate and Sleep Apnea