Ocular Effects of Oral Contraceptives. I. Studies in the Dog

Vol. 26. No.9. September 1975 Printed in U.s.A.

FERTILITY AND STERILITY Copyright © 1975 The American Fertility Society

OCULAR EFFECTS OF ORAL CONTRACEPTIVES. I. STUDIES IN THE DOG VICTOR A. DRILL, PH.D., M.D.,* K. S. RAO, PH.D., ROBERT G. McCONNELL, PH.D., ELIAS N. SOURI, V.M.D.

AND

Research Laboratories, G. D. Searle & Co., Skokie, Illinois 60076

The case reports collected by Walsh et aLl and similar reports in the literature have raised the possibility that ophthalmic side effects may occur in women using oral contraceptives. In contrast to the case reports,. several clinical studies have demonstrated that there is no difference in the frequency of ocular changes observed between a control group and women receiving oral contraceptives,2-5 and in prospective clinical studies the use of oral contraceptives did not induce ocular pathology.6-12 Only limited experimental data on contraceptive steroids and the eye have appeared, norethynodrel with mestranol being administered parenterally to rabbits for 4 to 10 weeksY The present study reports the ophthalmologic findings in groups of dogs receiving low, medium, and high doses of norethynodrel with mestranol (Enovid-E) and ethynodiol diacetate with mestranol (Ovulen) orally and cyclically for 5 consecutive years.

three groups of 16 dogs received respectively a low, medium, or high dose of the oral contraceptive. The animals used were kennel-reared, adult virgin female beagle dogs which were 20 ± 6 months of age at initiation of drug administration. Treatment Schedule. Enovid-E or Ovulen was administered orally and cyclically to the treated groups of dogs at dosage multiples of 1, 10, and 25 times the average human dose. Enovid-E is a combination of 2.5 mg of norethynodrel and 0.1 mg of mestranol, and the daily human contraceptive dose is 2.6 mg; for a 50-kg woman this represents a dose of 0.052 mglkg of body weight. Ovulen is a combination of 1.0 mg of ethynodiol diacetate and 0.1 mg of mestranol. The daily contraceptive dose of Ovulen is 1.1 mg; for a 50-kg woman this represents a dose of 0.022 mglkg of body weight. The dose of Enovid-E or Ovulen administered to each group of dogs and its relationship to the clinical dose is listed in Table 1.

Each oral contraceptive was administered as compressed tablets of various Experimental Design. Sixty-four female strengths, the tablets containing the exdogs were used in the study with Enovid-E cipients and other ingredients used in and 64 in the study with Ovulen. For each commercial tablets. Placebo tablets constudy the 64 dogs were divided into taining all ingredients except the drug groups of16 and assigned individual cages components were also prepared. Treataccording to a predetermined randomiza- ment was given cyclically; treated dogs tion procedure. One group of 16 animals received the tablets ofEnovid-E or Ovulen served as untreated controls and the other orally once daily 7 times per week for 3 consecutive weeks and control animals Received December 27,1974. *To whom reprint requests should be addressed: received the placebo tablet once daily 7 times per week for 3 consecutive weeks. 1620 Meadow Lane, Glenview, Ill. 60025. MATERIALS AND METHODS

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TABLE 1. Doses of Erwvid-E and Ovulen Administered to Dogs Oral contraceptive and group" Progestin (dosage level)

Total

Multiple of human dose

Dose Estrogen mglkg body wt

Enovid-E 1 (control) 2 (low) 3 (medium) 4 (high)

0.050 0.50 1.25

0.002 0.02 0.05

Placebo 0.052 0.52 1.30

0 1 10 25

Ovulen 1 (control) 2 (low) 3 (medium) 4 (high)

0.020 0.20 0.50

0.002 0.02 0.05

Placebo 0.022 0.22 0.55

0 1 10 25

aSixteen animals per group.

Neither drug nor placebo was administered to any animal during the 4th week of the cycle. All animals were weighed monthly and the drug dosage was adjusted each month to the nearest kilogram of body weight. Ophthalmoscopic Examination. Ophthalmoscopic examination of each dog in each group was performed once pretreatment and once during treatment cycles 6, 16, 44, and 67. Additional ophthalmologic examination was made in all dogs in the high-dose group during cycle 10 and in the medium- and high-dose treatment groups during cycle 30. Also, selected animals were examined and reexamined periodically as deemed necessary for various reasons. Tropicamide (Mydriacyl, 1%) was used to facilitate the examinations, which were made by William G. Magrane, D.V.M., and Eugene J. Youkilis, Ph.D., and later by Elias N. Souri, V.M.D. Animal Care. Appropriate veterinary care was provided by staff veterinarians. All dogs were parasite-free and immunized against infectious hepatitis, distemper, leptospirosis, and rabies. The animals were housed individually in stainless steel cages and fed a balanced diet of prepared dog food once daily with water ad libitum via an automatic watering device. Good dental hygiene was maintained by the procedure of Brown and

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Park.14 The animal quarters were airconditioned, with thermostats set to maintain room temperature at 70° F, and artificial fluorescent lighting was provided on a 12-hour daily cycle. In addition to a daily general inspection of the animals for appearance, behavior, appetite, and the nature of any vaginal discharge, a physical examination was performed on each dog every 3 months. It is generally recognized that the dog is peculiarly susceptible to the development of pyometra, particularly when progestins are administered. IS. 16 Several of the treated dogs died of pyometra and subsequent septicemia during the study, and, to prevent similar recurrences, all remaining animals in the medium- and high-dose groups were hysterectomized during cycles 49 to 51. Additional hysterectomies were performed as necessary in other animals from the control and low-dose groups when severe pymetra was evident. RESULTS

Treatment with oral contraceptives produced the expected hormonal effects on the external genitalia, the mediumand high-dose groups exhibiting notable vulvar enlargement, compared with the controls. Slight enlargement of the mammary papilla also occurred in some of the dogs in these two groups. The hormonal actions of the steroids also produced pyometra, particularly in the medium- and high-dose-treated groups, necessitating hysterectomies as discussed under "Materials and Methods." Body Weight. Treatment with EnovidE had a slight effect on body weight. At the start of the study the average body weights were: control group, 7.3 kg; group 2,7.6 kg; group 3, 7.7 kg; group 4,8.1 kg. After 5 years of study, the average increases in body weight were 0.9 kg in the controls, 1.0 kg in group 2, 0.4 kg in group 3, and 0.5 kg in group 4.

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DRILLET AL.

The administration of Ovulen had a slight effect on weight gain. The average body weights at the start of the study were 7.4 kg for the controls, 7.7 kg for group 2, 7.5 kg for group 3, and 7.4 kg for group 4. After 5 years of treatment, the average gains in body weight were: controls, 2.0 kg; group 2, 1.1 kg; group 3, 0.2 kg; and group 4, 0.3 kg. Survival of Animals. During the first 4 years of study with Enovid there was one death in the low-dose group, two in the medium-dose group, and six in the high-dose group. Pyometra occurred as expected, and two dogs in the high-dose group died during cycles 23 and 31, respectively, of pyometra and its complications. In one medium-dose dog and two high-dose dogs, death was due to complications following the hysterectomy performed during cycles 50 and 51. The other four deaths occurred at random as follows: malignant lymphoma Clow-dose group, cycle 45); probable septicemia (mediumdose group, cycle 53); pneumonia (highdose group, cycle 47); septicemia and anemia (high-dose group, cycle 52). No deaths occurred during the 5th year of study. In the study with Ovulen there was one death in the medium-dose group and four deaths in the high-dose group, occurring as follows: acute pulmonary disease (medium-dose group, cycle 20; high-dose group, cycle 49); interstitial nephritis and uremia (high-dose group, cycle 28); pyometra and complications (high-dose group, cycle 30); post-hysterectomy (high-dose group, cycle 50). There were no deaths during the 5th year of the study. Corneal Opacities. Pretreatment corneal opacities were present in three dogs, but the change was not present in two of the animals (control dog, Ovulen study; low-dose dog, Enovid-E study) at subsequent examinations. In the third dog (medium-dose, Enovid-E study) an initial triangular haze and later development of corneal scars were observed; at the 67th

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cycle a slight corneal scar was present. The number of opacities present at the end of 5 years of treatment in dogs receiving low, medium, or high doses of Enovid-E or Ovulen did not differ from the control values as judged either by the number of dogs or number of eyes affected (Table 2). TABLE 2. Corneal and Lens Opacities Present after 5 Years of Treatment Corneal opacities

Study and dosage group

Lens opacities

No. of dogs No.ofeyes No. of dogs No. of eyes affected" affected affected" affected

Enovid-E 1 (control) 2 (low) 3 (medium) 4 (high)

1116 3/15 3/14 2/10

1132 3/30 3/28b 2/20

8/16 6/15 6/14 3/10

10/32 7/30 6/28 6/20

Ovulen 1 (control) 2 (low) 3 (medium) 4 (high)

2/16 2/16 2/15 1/12

3/32 2/32 2/30 1124

5/16 6/16 c 5/15c

8/32 9/32c 9/30c 10/24

5/12

a Denominator indicates number of dogs per group at end of 5th year. bNot including one eye with pretreatment lesion. cNot including one dog with pretreatment lesion.

Lenticular Opacities. Pretreatment changes were not present in the lenses of any of 64 dogs in the Enovid-E study. In the Ovulen study pretreatment changes were observed in two dogs. One dog in the low-dose group demonstrated translucent lenticular spokes in the posterior cortical region, and one medium-dose animal had a lens-streak opacity in the center of the posterior cortical region; neither lesion changed during the 5-year period of treatment. Lenticular opacities developed in both control and treated dogs during the 5 years of study. The changes varied from a minimal streak opacity, "scratch" opacity, cloudy or opaque areas, whisp or filamentous opacity, to the more established and typical opacity. In several dogs a minor whisp opacity observed at one examination was not present at subsequent ophthalmic examinations. In general, the opacities became evident on examination

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during the 44th cycle of the study; the maximal number observed was during the 67th cycle. All lens opacities of any degree of severity that developed during the study and that were present at the end of 5 years of treatment are tabulated in Table 2. The number of control dogs developing opacities varied from eight in the Enovid study to five in the Ovulen study. Treatment with low, medium, or high doses of oral contraceptives did not significantly affect the occurrence of lenticular opacities (Table 2).

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tachment inferiorally was evident in the same eye during cycles 44 and 67. In the study with Ovulen, the optic discs of the right and left eyes of a dog in the high-dose group were more elevated than normal on examination at cycle 6; the same elevation was present unchanged on examination at cycles 10, 16, 30, 44, and 67. Ophthalmoscopic examination at cycle 67 revealed areas of increased reflectivity around the optic disc in three control dogs, two medium-dose dogs, and one dog in the high-dose group. Miscellaneous Findings. Miscellaneous ophthalmic changes of various types ocFundus. Fundic changes were present curred at random in both the control and in three dogs prior to treatment. One contreated groups of dogs. trol dog in the Enovid-E study had areas of retinal thinning pretreatment and in In the Enovid-E study, vitreous strands cycles 6 and 16. At cycle 44 the fundus were observed unilaterally pretreatment was unremarkable, but at cycle 67 an area in one control dog, and persisted throughof thinning was observed in the tapetum out the study; in one medium-dose animal, nigrum of the right eye, and there were the finding was observed only in the two areas of thinning in the tapetum pretreatment period. Vitreous strands lucidum of the left eye. In the Ovulen were observed at times during the study study, one control dog showed an area of in one low-d'lse, two medium-dose, and one chorioretinitis in the left eye pretreat- high-dose dog. At the end of 5 years of ment; the lesion was "quiet" and did not treatment, vitreous strands or bodies were change during the 5 years of study. Prior present in the right eye of one low-dose to treatment, a low-dose dog in the Ovulen and one high-dose dog. One high-dose study showed a lack of pigment in the dog had an excessive mucous discharge tapetum nigrum resulting in an exposed and slight to moderate swelling of the choroidal circulation; this congenital palpebrae of both eyes on examination lesion persisted unaltered during the at cycles 57 and 67. Another dog in this group had a unilateral subconjunctival study. Fundic changes were observed in two hemorrhage and a small hemorrhagic dogs concomitant with the use ofEnovid-E. area lateral to the cornea; this was present One low-dose dog had three small areas of for only several days during the 32nd quiescent chorioretinitis at cycle 44; the cycle. One low-dose dog showed evidence fundus was unremarkable at cycle 67. of an old vascularization in the medial In the medium-dose group, the right eye of periphery of the cornea of the left eye at one dog had an area of pigment clumping cycle 67. In the study with Ovulen, one control in the non-tapetal fundus, suggestive of a retinal scar, and also a cloudy vitreous animal showed at the pretreatment exon examination initially at cycle 6 which amination a transparent band in the anpersisted unchanged through cycles 16 terior chamber of the right eye just posand 30. During this period, no progres- terior to the corneal endothelium; the sion of the lesion, characteristic of drug same finding persisted on examination induction, was apparent. A retinal de- at cycles 6, 16, 44, and 67. A low-dose

DRILLETAL.

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dog had a small corneal scar in the right eye at cycle 6, which remained unchanged on each examination through cycle 67. Another animal in this group showed a pigmented posterior capsular filamentous fibrous adhesion in the left eye at cycle 67. One medium-dose dog had excessive tears and mucinous discharge, without inflammation, in both eyes on examination at cycles 57 and 67. A high-dose dog was observed at cycle 67 to have a lower palpebral growth at the medial canthus of the left eye. Hypertrophy of the nictitating membrane (with attending hyperemia of inflammation in two dogs) was observed in one eye occasionally during the studies as follows: Enovid-E study, one mediumdose and one high-dose dog; Ovulen study, one low-dose and one high-dose dog. The occurrence of scleral hyperemia or keratitis in several animals during the study was of no significance. Peripheral cystoid degeneration, a change associated with age, was also seen in some control and treated dogs. DISCUSSION

The effect of norethynodrel with mestranol on the rabbit eye has been reported,13 but the study presents problems in design and in the inadequacy of controls. A group of six control rabbits given corn oil for 4 weeks was intended to match the eight rabbits given steroid for 4 weeks, but the duration of observation after treatment was 6 months for controls and 12 months for the treated animals. The six rabbits that received injections of steroid 7 days per week for 10 weeks were matched with only two control rabbits that received injections 7 days per week; none of the other treated groups was matched with a control group. Also, five treated rabbits, but no controls, were autopsied 8 months after cessation of treatment. The wide variation in initial body weight, from 1.9 to

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5.6 kg (4.18 to 12.32 pounds), indicates that animals of varying age, from weanling rabbits to old does, were used. The data of Lee et aI. 13 show that among the various groups of rabbits the incidence of lens opacities before treatment ranged from 0% to 58.4% in group 3. Since the eyes were examined under general anesthesia, the depth of anesthesia was a variable that would have affected venous dilatation; for examination, "the rabbits' heads were held upright" to avoid mechanically induced retinal vein congestion. Other complicating factors were infections causing diarrhea, decreased water intake, dehydration, and poor general condition in 23% of the animals. This may have been due to mucoid diarrhea, which is a common disease in this species, or to coccidiosis, a disease found at autopsy in many rabbits. 17-19 Pasteurellosis is enzootic in rabbits and may cause chronic disease characterized by a variety of signs, among them being various neurologic findings such as middle ear disease, tilting of the head, and walking in circles. 17-19 It is obvious from the variables and problems discussed that valid conclusions cannot be drawn from the study cited. 13 In the present study, young adult female dogs were treated with Enovid-E or Ovulen in doses of 1, 10, or 25 times the human dose for 5 years. Ophthalmoscopic examination did not reveal any drug-induced effects. Corneal opacities and opacities of the lens were the most common findings, the opacities occurring with equal frequency in the control and treated groups. In general, the corneal opacities were small and superficial and in some cases transient, which would indicate that most, if not all, of the findings in the control and treated dogs represent the end result of a mechanical injury or an inflammation. Drug-induced changes in the fundus were not observed; treatment with oral contraceptives did not induce venous dilatation, papilledema, thrombosis of the ophthalmic artery or vein, or thrombosis

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5. Andelman MB, Zackler J, Slutsky HL, Jacob- . of retinal arterioles or venules. son MM: Family planning and public health. The pattern of the retinal vasculature Int J Fertil 13:405, 1968 varies among vertebrates. The rabbit 6. Diddle AW, Watts GF, Gardner WH, Williamdoes not possess a true retinal vascular son PJ: Control of fertility with oral medication. system, and Wise et al.2° state that the West J Surg Obstet Gyhecol 72:222, 1964 7. Strade HA: Lyndiol: evaluation of safety and ((rabbit fundus is a poor choice for the efficacy as an oral contraceptive. Curr Ther Res study of retinal vascular disease and 8:265,1966 other experimental animals should be 8. Kanitkar SD: Four years' experience of oral used whenever possible." Circulation in contraception in Bombay. Clin Trials J 5:205, the dog more closely resembles that of 1968 man, since the dog possesses a holangiotic 9. Rovinsky JJ: Clinical effectiveness of a low-dose progestin-estrogen combination. Obstet retinal vascular supply. Thus, data obGynecol 23:840, 1964 tained in the dog may correlate better 10. Laurie RE, Lewis ET: Fertility control with with the results obtained in man. HowOvral: a clinical review. J Reprod Fertil [Suppl] ever, of all commonly used experimental 5:95,1968 animals, the rhesus monkey has a fundus 11. Moses LE, Godzieher JW, Moses IG: Evaluation of a new combination oral contraceptive: lynesmost closely resembling that of man; the trenol-mestranol (Lyndiol). Fertil Steril 20: effects of oral contraceptives on the eye 715,1969 of this species are described separately.21 12. Rice-Wray E, de Ferrer SA, Perez-Huerta I, Gorodovsky J: Clinical evaluation of a new combined oral contraceptive. Contraception 1: 389, 1970 SUMMARY 13. Lee PF, Donovan RH, Mukai N: Effects of norethynodrel with mestranol on the rabbit eye. The administration of two oral contraArch Ophthalmo181:89, 1969 ceptives to female dogs for 5 years did not 14. Brown MG, Park JF: Control of dental calculus produce ocular lesions. Corneal and lenin experimental beagles. Lab Anim Care 18: ticular opacities occurred with equal fre527, 1968 quency in control and treated groups, and 15. Dow C: The cystic hyperplasia-pyometra complex in the bitch. J Comp Pathol 69:267, 1959 fundic lesions, including papilledema, 16. Tucker MJ: Some effects of prolonged adminisvenous dilatation, and venous or arterial tration of a progestin to dogs. Proc Eur Soc Stud retinal thrombosis, were not produced by Drug Tox 12:228, 1971 doses of Enovid-E or Ovulen 1, 10, and 25 17. The UFAW Handbook on the Care and Managetimes the human dose. ment of Laboratory Animals. Baltimore, Williams & Wilkins Co, 1967, p 419 18. Committee on Laboratory Animal Diseases: A REFERENCES guide to infectious diseases of guinea pigs, gerbils, hamsters, and rabbits. ILAR News (Inst 1. Walsh FB, Clark DB, Thompson RS, Nicholson Lab Anim Resources, Nat! Acad Sci) 17:ID8, DH: Oral contraceptives and neuro-ophthalmo1974 scopic interest. Arch Ophthalmol 74:628, 1965 2. Faust JM, Tyler ET: Ophthalmologic findings 19. Weisbroth SH, Flatt RE, Kraus AL: The Biology of the Laboratory Rabbit. New York, Academic in patients using oral contraception. Fertil Press, 1974 Steril 17:1, 1966 3. Connell EB, Kelman CD: Ophthalmologic find- 20. Wise GN, Dollery CT, Henkind P: The Retinal Circulation. New York, Harper and Row, 1971, ings with oral contraceptives. Obstet Gynecol p 80 31:456, 1968 4. Connell EB, Kelman CD: Eye examinations in 21. Drill V A, Martin DP, Golway PL, Hart ER: Ocular effects of oral contraceptives. II. Studies patients taking oral contraceptives. Fertil Steril in the rhesus monkey. Fertil Steril26:914, 1975 20:67,1969