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Progesterone treatment of the obesity hypoventilation syndrome in a child
March 1977 The Journal o f P E D l A T R I C S
477
Progesterone treatment of the obesity hypoventilation syndrome in a child David M. Orenstein, M.D.,* Thomas F. Boat, M.D., Robert C. Stern, M.D., Carl F. Doershuk, M.D., and Morton S. L i g h t , M . D . , C l e v e l a n d , O h i o
THE OBESITY HYPOVENTILATION SYNDROME, consisting of extreme obesity, somnolence, plethora, and edema,' is u n c o m m o n but life-threatening in children? -'~ Vital capacity is decreased, the cardiac silhouette is enlarged, and hypoxemia and hypercapnea are present, especially during sleep. Weight reduction may help correct ventilation/. '-' but weight reduction is difficult to achieve, nearly impossible to maintain, and alone may not completely correct the ventilatory abnormality. 1 ~ ~ Progesterone, whether endogenous (as in pregnancy and the luteal phase o f the menstrual cycle "-*~) or exogenous (in healthy male and female volunteers 1~ ~), increases minute ventilation and reduces alveolar Pco2, probably by increasing the sensitivity of the respiratory center to carbon dioxide?' Intramuscularly 7 and sublingually 1:' administered progesterone correct alveolar hypoventilation in adults with OHS. The use of orally administered progesterone in this condition or progesterone treatment by any route of administration in children with OHS has not been reported. We document here the correction of alveolar hypoventilation by parenteral, and subsequently oral, administration of progesterone in a child with OHS complicating the Prader-Willi syndrome.'
CASE REPORT A 4V2-year-old white girl with the Prader-Willi syndrome was hospitalized for treatment of orthopnea and edema. OxytriphylFrom the Department of Pediatrics, Case Western Reserve University, and Rainbow Babies and Childrens Hospital. Supported in part by grant HL 06009from the United States Public Health Service, the Cleveland Foundation, Cystic Fibrosis Foundation, Health Fund o f Greater Cleveland, and United Torch Services. *Reprint address: Rainbow Babies and Childrens Hospital, '2101 Adelbert Rd, Cleveland, OH 44106.
line had been given for several months because of occasional mild wheezing. Hypercapnia and electrocardiographic evidence of right ventricular hypertrophy were present. Oxytriphylline was continued. She was treated with furosemide, improved, and was discharged after 10 days. Eight days later she was readmitted because of dyspnea, orthopnea, and somnolence. There was marked pedal edema. Weight on admission was 50 kg (weightage = 13% years) and height was 105 cm (height-age = 4% years). Physical examination was limited by obesity. A chest roentgenogram revealed cardiac enlargement, and an echocardiogram showed a dilated right ventricle. An oral glucose tolerance test and serum electrolyte values were normal. The venous Pcoz was 54 mm Hg, while the patient was awake; it was 67 mm Hg during sleep (Table I). After eight days of oral diuretic therapy (40 mg of furosemide and 50 mg of spironolactone daily) she lost 3 kg and most of the edema. The Pvco.~ during sleep remained elevated (Table I), and somnolence and orthopnea Abbreviations used OHS: obesity hypoventilation syndrome Pco~: partial pressure of carbon dioxide Pvco: venous Pco2 MPA: medroxyprogesterone acetate Paco: arterial Pcoz persisted. Treatment with intramuscular medroxyprogesterone acetate, 50 mg each morning, was instituted. Somnolence and orthopnea disappeared promptly. The Pvco._,during sleep fell to 24 mm Hg. The daily dose was decreased to 25 mg, and the Pvco ~ value during sleep then rose to 40 mm Hg. Intramuscular treatment was discontinued and oral MPA was begun (10 mg three times a day). Thereafter Pvco.~ values during sleep were approximately 40 mm Hg. There was no change in respiratory rate during sleep or waking with the MPA treatment. The glucose tolerance test was unchanged, the cardiac silhouette returned to normal, and the patient was discharged on Day 38 to continue therapy with oral MPA and a 400 calorie/day diet. Symmetrical ecchymoses developed on the lateral aspects of her upper arms after 96 days of therapy. There was no other evidence of bleeding diathesis or trauma. The platelet count, prothrombin time, partial Vol. 90, No. 3, pp. 477-479
47g
Orenstein et al.
The Journal qf' Pediatrics March 1977
T a b l e i. Clinical information Day of progesterone treatment
11
Weight (kg) Diuretics MPA rag/day (single dose, intramuscularly) MPA rag/day (by mouth)* Blood gases during sleep pH Pco._, (mm Hg) Po~ (ram Hg) H C O (mEq/I)
50 +
-4
0
7
11
13
20
27
47 +
46 + 50
46 + 50
46 + 25
46 + 25
45
45 .
-
. . . . . .
7.4(v) 7.4(v) 67(v) 52(v) . 41(v) 33(v)
.
7.4(v) 24(v) . 14(v)
--
25
119
129
130
-
37
37
38 .
.
.
30
30 "~,0"~
7.4(v) 7.4(v) 7.4(v) 40(v) 40(v) 38(v)
. -
131
. . . . 30
-
31
25(v) 25(v) 23(v)
-
7.4(a) 66(a) 92(a) 40(a)
30
30
--
7.4(a) 36(a) 104(a) 22(a)
Abbreviations used: MPA = medroxyprogesterone acetate: (v) = venous blood sample, from indwelling cannula, v.ithoul tourniquet: (a) = arterial blt~od sample, from indwelling cannula. *Divided into three equal doses. ~lndicates gradual reduction of dose over I7 days.
thromboplastin time, and Lee White clotting time were normal. A small amount of coarse pubic hair was now present. The MPA dosage was reduced and then discontinued on Day 119. Daytime somnolence gradually reappeared, and she was rehospitalized on Day 129, Weight was 36.5 kg (weight-age = 11 years). There was no edema. The arterial P(o, during sleep was 66 mm Hg; the Pao._,was 74 mm Hg (Table l). Oral MPA (10 mg three times a day) was reinstituted, and alter one day she was again alert and playful. The Paco ~ during sleep was 36 and the Pao., was 104 mm Hg, Oral MPA (10 mg three times a day') has been continued. There has been an additional 6 kg weight loss, and cardiorespiratory symptoms have nol recurred by Day 200. Ketosis has never been observed. DISCUSSION Both i n t r a m u s c u l a r and oral progesterone have been effective a n d apparently safe in treating life-threatening OHS in this 4-year-old girl with the Prader-Willi syndrome. I n t r a m u s c u l a r t r e a t m e n t initially resulted in hyperventilation and hypocapnea. With decreased dosage the ventilatory status improved, and then was m a i n t a i n e d with oral administration. Oral progesterone for O H S has been avoided previously because of the uncertainty of absorption. '~' In this child, in w h o m the sublingual route would have been impractical, oral t r e a t m e n t has been effective. The total daily oral and i n t r a m u s c u l a r doses were lJ/2 to 2 m g / k g of ideal weight for her height. The dosage did not need a d j u s t m e n t for weight loss because progesterone is not stored in body fat in substantial amounts. ~' W h e n progesterone was stopped, her ventilatory status quickly deteriorated, even though she had lost 28% of her original weight. Hypoventilation despite
substantial weight loss has also been reported in adults,: implicating factors other than weight in the pathogenesis of OHS. In our patient, reinstitution o f oral progesterone therapy resulted in p r o m p t ventilatory i m p r o v e m e n t . Fasting ketosis corrects hypoventilation in obese adults who have decreased respiratory sensitivity to c a r b o n dioxide,'" but ketosis has never been present in our patient despite her 400 c a l o r i e / d a y diet. Undesirable effects of progesterone are not well defined. In this patient the a p p e a r a n c e of pubic hair may be the result of a n d r o g e n i c activity of M P A or its metabolites: hirsutism has been associated with M P A treatment of other disorders. ~ The disadvantages o f this side effect are far outweighed by the m a i n t e n a n c e of n o r m a l cardiorespiratory function. Bleeding disorders have been reported with estrogen-progesterone c o m b i n a tions but not with progesterone alone. We feel that this patient's ecchymoses were not caused by the medication. No o t h e r side effects have been evident d u r i n g the six m o n t h s of t r e a t m e n t to date. We are not aware o f any successful appetite-decreasing t r e a t m e n t for patients with Prader-Willi syndrome. A l t h o u g h decreased appetite has not previously been reported with progesterone, this patient's formerly uncontrollable eating has been m u c h more m a n a g e a b l e during progesterone treatment. Progesterone has been safe a n d effective in treating the obesity hypoventilation s y n d r o m e in this child with Prader-Willi syndrome. Its use in O H S from other causes and in alveolar hypoventilation not associated with obesity should be studied.
Volume 90 Number 3
Progesterone treatment of obesitv h)poventilation syndrome
REFERENCES
1. Rochester DF, and Enson Y: Current concepts in the pathogenesis of the obesity-hypoventilation syndrome, Am J Med 57:402, 1974. 2. Finkelstein JW, and Avery ME: The pickwickian syndrome: Studies on ventilation and carbohydrate metabolism. A case report of a child who recovered, Am J Dis Child 106:251, 1963. 3. Jenab M, et al.: Cardiorespiratory syndrome of obesity in a child. Case report and necropsy finding, Pediatrics 24:23, 1959. 4. Cayler GG, Mays J, and Riley HO: Cardiorespiratory syndrome of obesity (Pickwickian syndrome) in children, Pediatrics 27:237, 1961. 5. Cayler GG, Riley HO, and Mays J: Pickwickian syndrome in children, Am J Dis Child 98:663, 1958. 6. Spier N, and Karelitz S: The Pickwickian syndrome, Am J Dis Child 99:822, 1960. 7. Lyons HA, and Huang CT: Therapeutic use of progesterone in alveolar hypoventilation associated with obesity, Am J Med 44:881, 1968. 8. Estes EH, et al.: Reversible cardiopulmonary syndrome with extreme obesity, Circulation 16:179, 1957. 9. Lyons, HA, and Antonio R: The sensitivity of the respira-
10. 11.
12.
13. 14.
15.
16. 17.
479
tory center in pregnancy and after the administration of progesterone, Trans Assoc Am Physicians 52:173, 1959. Prowse CM, and Gaensler EA: Respiratory and acid-base changes during pregnancy, Anesthesiology 26:381, 1965. Doting GK, et al.: Weitere Untersuchungen fiber die Wirkung der Sexualhormone auf die Atmung, Pflugers Arch 252:216, 1950. Goodland RL, et al.: Respiratory and electrolyte effects induced by estrogen and progesterone, Fertil Steril 4:300, 1953. Sutton FD, et al,: Progesterone for outpatient treatment of Pickwickian syndrome. Ann Intern Med 83:476, 1975. Zellweger H, and Schneider HJ: Syndrome of hypotoniahypomentia-hypogonadism-obesity (HHHO) or PraderWilli syndrome, Am J Dis Child 115:558, 1968. Murad F.. and Gilman AG: Estrogens and progestins, in Goodman LS, and Gilman AG, editors: The pharmacological basis of therapeutics, ed 5, New York, 1975, The MacMillan Company, p 1439. Fried Pl, et al.: Effect of ketosis on respiratory sensitivity to carbon dioxide in obesity, N Engl J Med 294:1081, 1976. Richman RA, et al.: Adverse effects of large doses of medroxyprogesterone acetate (MPA) in idiopathic isosexual precocity, J PEDIATR79:963, 1971.
477
Progesterone treatment of the obesity hypoventilation syndrome in a child David M. Orenstein, M.D.,* Thomas F. Boat, M.D., Robert C. Stern, M.D., Carl F. Doershuk, M.D., and Morton S. L i g h t , M . D . , C l e v e l a n d , O h i o
THE OBESITY HYPOVENTILATION SYNDROME, consisting of extreme obesity, somnolence, plethora, and edema,' is u n c o m m o n but life-threatening in children? -'~ Vital capacity is decreased, the cardiac silhouette is enlarged, and hypoxemia and hypercapnea are present, especially during sleep. Weight reduction may help correct ventilation/. '-' but weight reduction is difficult to achieve, nearly impossible to maintain, and alone may not completely correct the ventilatory abnormality. 1 ~ ~ Progesterone, whether endogenous (as in pregnancy and the luteal phase o f the menstrual cycle "-*~) or exogenous (in healthy male and female volunteers 1~ ~), increases minute ventilation and reduces alveolar Pco2, probably by increasing the sensitivity of the respiratory center to carbon dioxide?' Intramuscularly 7 and sublingually 1:' administered progesterone correct alveolar hypoventilation in adults with OHS. The use of orally administered progesterone in this condition or progesterone treatment by any route of administration in children with OHS has not been reported. We document here the correction of alveolar hypoventilation by parenteral, and subsequently oral, administration of progesterone in a child with OHS complicating the Prader-Willi syndrome.'
CASE REPORT A 4V2-year-old white girl with the Prader-Willi syndrome was hospitalized for treatment of orthopnea and edema. OxytriphylFrom the Department of Pediatrics, Case Western Reserve University, and Rainbow Babies and Childrens Hospital. Supported in part by grant HL 06009from the United States Public Health Service, the Cleveland Foundation, Cystic Fibrosis Foundation, Health Fund o f Greater Cleveland, and United Torch Services. *Reprint address: Rainbow Babies and Childrens Hospital, '2101 Adelbert Rd, Cleveland, OH 44106.
line had been given for several months because of occasional mild wheezing. Hypercapnia and electrocardiographic evidence of right ventricular hypertrophy were present. Oxytriphylline was continued. She was treated with furosemide, improved, and was discharged after 10 days. Eight days later she was readmitted because of dyspnea, orthopnea, and somnolence. There was marked pedal edema. Weight on admission was 50 kg (weightage = 13% years) and height was 105 cm (height-age = 4% years). Physical examination was limited by obesity. A chest roentgenogram revealed cardiac enlargement, and an echocardiogram showed a dilated right ventricle. An oral glucose tolerance test and serum electrolyte values were normal. The venous Pcoz was 54 mm Hg, while the patient was awake; it was 67 mm Hg during sleep (Table I). After eight days of oral diuretic therapy (40 mg of furosemide and 50 mg of spironolactone daily) she lost 3 kg and most of the edema. The Pvco.~ during sleep remained elevated (Table I), and somnolence and orthopnea Abbreviations used OHS: obesity hypoventilation syndrome Pco~: partial pressure of carbon dioxide Pvco: venous Pco2 MPA: medroxyprogesterone acetate Paco: arterial Pcoz persisted. Treatment with intramuscular medroxyprogesterone acetate, 50 mg each morning, was instituted. Somnolence and orthopnea disappeared promptly. The Pvco._,during sleep fell to 24 mm Hg. The daily dose was decreased to 25 mg, and the Pvco ~ value during sleep then rose to 40 mm Hg. Intramuscular treatment was discontinued and oral MPA was begun (10 mg three times a day). Thereafter Pvco.~ values during sleep were approximately 40 mm Hg. There was no change in respiratory rate during sleep or waking with the MPA treatment. The glucose tolerance test was unchanged, the cardiac silhouette returned to normal, and the patient was discharged on Day 38 to continue therapy with oral MPA and a 400 calorie/day diet. Symmetrical ecchymoses developed on the lateral aspects of her upper arms after 96 days of therapy. There was no other evidence of bleeding diathesis or trauma. The platelet count, prothrombin time, partial Vol. 90, No. 3, pp. 477-479
47g
Orenstein et al.
The Journal qf' Pediatrics March 1977
T a b l e i. Clinical information Day of progesterone treatment
11
Weight (kg) Diuretics MPA rag/day (single dose, intramuscularly) MPA rag/day (by mouth)* Blood gases during sleep pH Pco._, (mm Hg) Po~ (ram Hg) H C O (mEq/I)
50 +
-4
0
7
11
13
20
27
47 +
46 + 50
46 + 50
46 + 25
46 + 25
45
45 .
-
. . . . . .
7.4(v) 7.4(v) 67(v) 52(v) . 41(v) 33(v)
.
7.4(v) 24(v) . 14(v)
--
25
119
129
130
-
37
37
38 .
.
.
30
30 "~,0"~
7.4(v) 7.4(v) 7.4(v) 40(v) 40(v) 38(v)
. -
131
. . . . 30
-
31
25(v) 25(v) 23(v)
-
7.4(a) 66(a) 92(a) 40(a)
30
30
--
7.4(a) 36(a) 104(a) 22(a)
Abbreviations used: MPA = medroxyprogesterone acetate: (v) = venous blood sample, from indwelling cannula, v.ithoul tourniquet: (a) = arterial blt~od sample, from indwelling cannula. *Divided into three equal doses. ~lndicates gradual reduction of dose over I7 days.
thromboplastin time, and Lee White clotting time were normal. A small amount of coarse pubic hair was now present. The MPA dosage was reduced and then discontinued on Day 119. Daytime somnolence gradually reappeared, and she was rehospitalized on Day 129, Weight was 36.5 kg (weight-age = 11 years). There was no edema. The arterial P(o, during sleep was 66 mm Hg; the Pao._,was 74 mm Hg (Table l). Oral MPA (10 mg three times a day) was reinstituted, and alter one day she was again alert and playful. The Paco ~ during sleep was 36 and the Pao., was 104 mm Hg, Oral MPA (10 mg three times a day') has been continued. There has been an additional 6 kg weight loss, and cardiorespiratory symptoms have nol recurred by Day 200. Ketosis has never been observed. DISCUSSION Both i n t r a m u s c u l a r and oral progesterone have been effective a n d apparently safe in treating life-threatening OHS in this 4-year-old girl with the Prader-Willi syndrome. I n t r a m u s c u l a r t r e a t m e n t initially resulted in hyperventilation and hypocapnea. With decreased dosage the ventilatory status improved, and then was m a i n t a i n e d with oral administration. Oral progesterone for O H S has been avoided previously because of the uncertainty of absorption. '~' In this child, in w h o m the sublingual route would have been impractical, oral t r e a t m e n t has been effective. The total daily oral and i n t r a m u s c u l a r doses were lJ/2 to 2 m g / k g of ideal weight for her height. The dosage did not need a d j u s t m e n t for weight loss because progesterone is not stored in body fat in substantial amounts. ~' W h e n progesterone was stopped, her ventilatory status quickly deteriorated, even though she had lost 28% of her original weight. Hypoventilation despite
substantial weight loss has also been reported in adults,: implicating factors other than weight in the pathogenesis of OHS. In our patient, reinstitution o f oral progesterone therapy resulted in p r o m p t ventilatory i m p r o v e m e n t . Fasting ketosis corrects hypoventilation in obese adults who have decreased respiratory sensitivity to c a r b o n dioxide,'" but ketosis has never been present in our patient despite her 400 c a l o r i e / d a y diet. Undesirable effects of progesterone are not well defined. In this patient the a p p e a r a n c e of pubic hair may be the result of a n d r o g e n i c activity of M P A or its metabolites: hirsutism has been associated with M P A treatment of other disorders. ~ The disadvantages o f this side effect are far outweighed by the m a i n t e n a n c e of n o r m a l cardiorespiratory function. Bleeding disorders have been reported with estrogen-progesterone c o m b i n a tions but not with progesterone alone. We feel that this patient's ecchymoses were not caused by the medication. No o t h e r side effects have been evident d u r i n g the six m o n t h s of t r e a t m e n t to date. We are not aware o f any successful appetite-decreasing t r e a t m e n t for patients with Prader-Willi syndrome. A l t h o u g h decreased appetite has not previously been reported with progesterone, this patient's formerly uncontrollable eating has been m u c h more m a n a g e a b l e during progesterone treatment. Progesterone has been safe a n d effective in treating the obesity hypoventilation s y n d r o m e in this child with Prader-Willi syndrome. Its use in O H S from other causes and in alveolar hypoventilation not associated with obesity should be studied.
Volume 90 Number 3
Progesterone treatment of obesitv h)poventilation syndrome
REFERENCES
1. Rochester DF, and Enson Y: Current concepts in the pathogenesis of the obesity-hypoventilation syndrome, Am J Med 57:402, 1974. 2. Finkelstein JW, and Avery ME: The pickwickian syndrome: Studies on ventilation and carbohydrate metabolism. A case report of a child who recovered, Am J Dis Child 106:251, 1963. 3. Jenab M, et al.: Cardiorespiratory syndrome of obesity in a child. Case report and necropsy finding, Pediatrics 24:23, 1959. 4. Cayler GG, Mays J, and Riley HO: Cardiorespiratory syndrome of obesity (Pickwickian syndrome) in children, Pediatrics 27:237, 1961. 5. Cayler GG, Riley HO, and Mays J: Pickwickian syndrome in children, Am J Dis Child 98:663, 1958. 6. Spier N, and Karelitz S: The Pickwickian syndrome, Am J Dis Child 99:822, 1960. 7. Lyons HA, and Huang CT: Therapeutic use of progesterone in alveolar hypoventilation associated with obesity, Am J Med 44:881, 1968. 8. Estes EH, et al.: Reversible cardiopulmonary syndrome with extreme obesity, Circulation 16:179, 1957. 9. Lyons, HA, and Antonio R: The sensitivity of the respira-
10. 11.
12.
13. 14.
15.
16. 17.
479
tory center in pregnancy and after the administration of progesterone, Trans Assoc Am Physicians 52:173, 1959. Prowse CM, and Gaensler EA: Respiratory and acid-base changes during pregnancy, Anesthesiology 26:381, 1965. Doting GK, et al.: Weitere Untersuchungen fiber die Wirkung der Sexualhormone auf die Atmung, Pflugers Arch 252:216, 1950. Goodland RL, et al.: Respiratory and electrolyte effects induced by estrogen and progesterone, Fertil Steril 4:300, 1953. Sutton FD, et al,: Progesterone for outpatient treatment of Pickwickian syndrome. Ann Intern Med 83:476, 1975. Zellweger H, and Schneider HJ: Syndrome of hypotoniahypomentia-hypogonadism-obesity (HHHO) or PraderWilli syndrome, Am J Dis Child 115:558, 1968. Murad F.. and Gilman AG: Estrogens and progestins, in Goodman LS, and Gilman AG, editors: The pharmacological basis of therapeutics, ed 5, New York, 1975, The MacMillan Company, p 1439. Fried Pl, et al.: Effect of ketosis on respiratory sensitivity to carbon dioxide in obesity, N Engl J Med 294:1081, 1976. Richman RA, et al.: Adverse effects of large doses of medroxyprogesterone acetate (MPA) in idiopathic isosexual precocity, J PEDIATR79:963, 1971.