Maledon, Anne R.

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The Linacre QuarterlyVolume 33 | Number 4 Article 18November 1966Oral Contraceptives: Nature, Use and PhysiologicalEffectsAnne R. MaledonFollow this and additional works at: http://epublications.marquette.edu/lnqRecommended CitationMaledon, Anne R. (1966) "Oral Contraceptives: Nature, Use and Physiological Effects," The Linacre Quarterly: Vol. 33 : No. 4 , Article18.Available at: http://epublications.marquette.edu/lnq/vol33/iss4/18OraJ ontraceptives: Nature, Use And Physiological Effects* ANNE R. MALEDON, B.S. "Within a few years 80 million women on this continent alone will be taking 'the pill'!" John Gillies, Medical World Approximately 5,000,000 Ameri­can women are now using oral contraceptives. "Never have so many people taken such potent drugs vol­untarily over such a protracted pe­riod for an objective other than the control of disease. "1 So spoke a spe­cial advisory committee of the U.S. Food and Drug Administration. But is "the pill" safe to take? To this question came the answer: "The committee finds no adequate scien­tific data, at this time, proving these compounds unsafe for human use."2 The tone of reservation implicit in the double negative of the statement is not surprising. Even without reading the Time magazine report, a non-professional layman knows that medicines "cannot be certified as completely safe until after years of detailed study on tens of thou­sands of patients."3 And even then certification can be valid only if large scale, careful reporting is adhered to. As "the pill" moves into its second decade of consumption, however, * Revision of a student paper directed by Sister M. Stanislaus Huddleston, I.H.M., Professor of biology, Marygrove College, Detroit. Miss Maledon is a graduate of Marygrove College. 360interest in it grows apace. b er of aspects, particul£ moral and socio-economic, triguing. But this paper c elusively with the natl and physiological effects contraceptives. NATURE num­,, the :e in­ls ex­' use, , oral All oral contraceptives consist basically of two synthetic .eroids, an estrogen and a progestc 'n. Se-lection of one of two rithetic estrogens and one of ten gesto-gens accounts for the trad names. If the two steroids are adrr 1istered together for twenty days, · e ther­apy is called combinatior If an estrogen is given for fiftE. 1 days, then a progestogen for the tst five, the therapy is called sequen· il.4 The combined steroids are Jld as Enovid ( the original "pill" Ortho­N ovum, Norinyl, Prov, .t, and Norlestin. The estrogen-pr< ;estogen composite goes by the r· :mes of Oracon and C-Quens, br h more recently developed drugs. 1 ,e diff�r­ence? Theoretically, the s-·quenual therapy resembles the secr..:tion se­quence as it occurs in t,1e body. Practically, however, neithLr type of therapy replicates the natvral proc­ess of secretion of the sex hormones, nor are all the synthetic steroids chemically identical with the natural steroid hormones of either class. In efficacy and general side effects, none the less, the combined and sequential forms are similar. LINACRE QuARTERL1' USES "The pill," composed of synthetic steroids, has several uses. Paradoxi­cally, it is employed for both con­ceptive and contraceptive purposes. As a contraceptive agent, it is un­questionably effective. In fact, its 99+% efficiency rate is becoming a dictum. Over and above their effi­cacy as contraceptives, "the pills" have proved remedial for gyneco­logical orders. Irregular menses, amenorrhea, dysmenorrhea, endo­metrios.is, and menopausal complaints are some of these. Obviously, it will be some time before the overall ther­apeutic value of "the pills" is estab­lished. Even so, oral contraceptives to date have been an important medical tool. PHYSIOLOGICAL EFFECTS Ironically, despite their 99+% effectiveness when taken as directed the mode of action of oral contra� ceptives is littl� understood. Author­ities are certain of only the obvious: · that administered daily from thefifth through the twenty-fourth dayof the menstrual cycle, "the pill"will prevent conception and producean artificial menstrual period re­sembling the natural one in bothduration and quantity of flow.Many authorities believe that ovu­lation is prevented. In support ofthis view, Edwin DeCosta, writingin ].A.M.A., postulates that the twohormones in "the pill" suppress ovu­lation by acting on the pituitary�land.5 "The pill" inhibits the pitu­itary from secreting the gonado­trophic hormones, FSH and LH.Since these two hormones are notsecreted, the egg is not "prepared"for ovulation, and the process doesNOVEMBER, 1966not occur. R L. Holmes in the journal Lancet, states a different opinion, namely, that LH release is not blocked, and that suppression of FSH has neither been proved nor disproved.6 Experiments with ani­mals do indicate that ovulation is suppressed, but since ovulation in animals is not identical with that of women, what may be true of animals is not necessarily true of humans, in this regard. Other investigators .have suggested other mechanisms by which oral con­traceptives may produce functional sterility (There is some evidence of permanent sterility, incidentally, which may work a hardship for those women who plan to have children after a year or two on "the pill"). These mechanisms may be either a direct influence on the ovary, or a deleterious action on the germ cells themselves.7, 8 Whatever the uncertainty regard­ing the mode of action of "the pills," their influence on the body's natural hormone balance is well known. The estrogen-progestogen combina­tions taken daily lead also to altera­tions of the harmonics of several other systems including the neuro­logical, which are concerned in reproductive and behavioral physi­ology.9 Experiments with estrogen­progestogen i n  animals a l so  demonstrate that pituitary tumors are frequently found after prolonged treatment. The most obvious effects of these contraceptive agents, however, is a local one, i.e., the radical change produced in the endometrium. In contrast to a normal endometrium, characterized by vascular tissue 361 supplied with many glands, the progestogen-treated endometrium ex­h i  b i t s  only a f ew  i nvolute d  glands, poor vascularity, and stromal edema.1° Collectively, these changes produce the appearance of aging of the endometrium.11 Although neo­plastic relationships as such will be dealt with later on in this paper, attention should be called here to the observation that "in predisposed individuals, the unopposed action of estrogenic substances - and all oral contraceptives are estrogenic- for considerable periods of time will re­sult in endometrial adenomatous hyperplasfa, carcinoma in situ, and eventually in carcinoma."12Over and above the influence of oral contraceptives on the endocrine and other systems in · general, and the uterine lining in particular, their action is associated with liver dam­age. The estrogen component of "the pill" is known to impair the excre­tory function of the liver; it may damage liver cells directly.rn Tests generally employed in medical prac­tice to detect hepatic impairment are I) serum transaminase level, 2) bromsulphthalein retention, 3)serum alkaline phosphatase levels.Abnormally high serum transami­nase levels and bromsulphthaleinretention appear in almost every tested user of "the pill."14,15 ,16,11Stroll noted an increase in serum transaminase from the normal I 0-40units to 200 units, and in serum iso­citric dehydrogenase levels from thenormal 3-10 units to 77-165 units.tsBromsulphthalein retention has been known to increase to pathologicallevels within two weeks during "pill" use. Hepatic malfunction may de-362 velop in as few as 28 days, )ne cycle of treatment. In 1963, Enovid was bn ght under criticism for its susf �ted relationship with thromboembc ;sm. This is not astonishing, for thrc 1bo­embolism has been associate vith pregnancy, during which time 1igh concentrations of estrogens an, pro­gestins appear in the blood. lhat brought "the pill" to mm idity headlines, however, was the �port that more than 350 cases of t rom­boembolism had occurred in I 10vid users in little over a twelve .onth period. At this point, the FI \ ap­pointed the Wright Commi 2e to investigate these cases; the c, ,1mit­tee reported its findings l; �r in 1963. Wright and his work1 s tal­lied a 12.1 % incidence r fatal thromboemboli among Enovi users, as compared with the 8.4% ate in the general population.19 1 ,e fig­ures became statistically rn1 e sig­nificant when age group were considered. In women use s who were over thirty-five, there was a disproportionately greater ir ;idence of thromboembolism. Usi.:g the same statistics as Wright, � assouf calculated fatality rates on ,, differ­ent basis. He used "woma1,-years" (twelve women taking the drug for one month each) as the unit of exposure. This was the basis on which most of the favorable statistics on Enovid had been calculated. According to Kassouf's calculations, the death rate from thromboembo­lism was 22.3 per million per year, nearly three times as high as that in the population at large.20Not w i t hs tanding, the Wright Committee concluded that a defi-LINACRE QUARTERLY nite cause-effect relationship between "the pill" and thromboemboli is yet to be statistically demonstrated. Still to be demonstrated, however, is the absence of cause and effect correla­tion between "pill" and clot. In the interim, though, it is not irrelevant to note that oral progestins are being used in the treatment of hemorrhagicdisorders.2lA second circulatory phenomenon observed in "the pill" users is an increased venous distensibility simi­lar to that observed in pregnancy. Over a period of time, the valves which prevent the backflow of blood become incompetent, and allow the blood to stagnate in the vessels, thereby providing opportune envi­ronment for thrombophlebitis and/or thromboemboli. As Eugene F. Dia­mond points out, even those who disagree on the association between "the pill" and thromboemboli, "fairly uniformly admit the associa­tion between oral progestins and thrombophlebitis."22 And how many cardiovascular specialists would deny that thrombophlebitis at least pre­disposes vessels to the formation of clots? Finally, estrogenic agents, even naturally occurring ones, have been known since the turn of the century to be associated with malignancies. To what extent malignant neo­plasms are effected or affected by estrogens depends in part upon· the type of neoplasm23 ·24 and the amount of estrogen administered. 2;; In certain predisposed humans and research animals, estrogen has been known to "cause" cancer. This is usually a gradual process, which begins with the alteration of the NOVEMBER, 1966 hormone balance, which in turn produces cellular changes in the ovary or other parts of the body, and eventually ends with tumors.26 A much more common concomitant of estrogen therapy, however, is a pronounced growth of already exist­ing tumors. Very small breast car­cinomas have developed with great rapidity during oral contraceptive use, according to Shipman.27 More­over, the progestogen component of "the pill" ma,y increase metastasis of an initially localized malignancy.28Above and beyond the major ill­effects so far mentioned, oral con­traceptives may induce so-called minor side-effects:29 ,30,31 ,32 l) break­through bleeding or "spotting," 2) nausea; 3) weight-gain - up to ten pounds, 4) breast soreness and en­largement, 5) acne, 6) headache, 7) dizziness, 8) depression and fatigue, 9) irritability, IO) edema, 11) aug­mented pre-menstrual tension, 12)stoppage of lactation, 13) insomnia,14) increased facial pigmentation,IS) leg cramping, 16) rash/itching,17) amenorrhe'a, 18) loss or growthof body hair, 19) 'growth of uterinefibroids, 20) virilization of the fe­male infant. Many of these are, ad­mittedly, more disagreeable thandangerous. A few, however, carrya subtle threat. Two of these onlywill be treated here.First, break-through or intermens­trual bleeding. Under ordinary con­ditions, unusual bleeding may be symptomatic of malignancy. Since, however, spotting is to be expected during oral contraceptive use, both patient and doctor may dismiss such bleeding as unimportant. G. H. Green highlights the danger latent 363 in such a dismissal: a young woman of thirty had complained of spotting while taking "the pill." The attend­ing physician had attached no sig­nificance to the event, because the woman had had a cervical smear within the year. That six months later she was found to have a far advanced malignancy33 would seemto be somewhat alarming. The second side-effect deserving special comment is virilization of the female infant. Not always, but fre­quently enough, oral contraceptives taken during the early months of pregnancy affect the female foetus. The masculinizing effect is usually in the form of an enlarged clitoris, of which the implications for the child's future may be more than incidental. Having come this far, let us take a backward glance at these data on "the pills." They are effective as contraceptives to the extent of almost 100%. They are useful as gyneco­logical tools. Such is medical con­sensus about their efficacy. About their safety, however, there is not such unanimity. Even so, suppose that all the side-effects, major and minor, are later obviated. What will be the results of long term - a pos­sible thirty years34 - alteration of human female metabolic rhythms? Of the disruption of the delicate and dynamic body equilibrium which physiologists have so long sought to understand and to pre­serve? Perhaps not even time will tell. REFERENCES I. U.S. Food and Drug Administration Committee on Oral Contraceptives. Time, 88:59, Aug. 19, 1966. 2. Ibid. 364 3. Ibid. 4. Goldzieher, J. W.: New oral cc tra­ceptive: sequential estrogen-prof ;tin. Amer.]. Obstet. and Gynec., 90:4 -11, Oct.!, 1964. 5. DeCosta, E. J.: Those deceptive c, tra-ceptives. J.A.M.A., 181: 122-5, Ju 14, 1962. 6. Holmes, R. L. and Mandi, A. M. Jral contraceptives: an assessment of heir mode of action. Lancet, 1:1174 June 2, 1962. 7. Morris, N.: Oral contraceptives. 'rac­titioner, 194:498, April 1965. 8. Groseclose, E. S.: Present sta s of endocrine therapy in obstetric and gynecology. Va. Med. Month., r l:473, Oct. 1963. 9. Brennan, M. J., Pres. Mich. ' :mcer Foundation: Personal Commun' ,tion. March 1966 IO. Maqueo, M.: Endometrial histok ; and vaginal cytology during oral con ·acep­tion with sequential estrogen ar pro­gestogen. Amer. J. Obstet. and ( :1nec., 90:395, Oct. 1, 1964. 11. Goldfarb, A. F.: Uterine utiliz,, on of steroids. Its role in contraception. Ietab­olism, 14:341, March 1965, supy . 12. Steiner, G. J. and Kistner, R.: Histo­logical effects of progestins . '1 hy­perplasia and carcinoma in ,,tu of the endometrium. Metabolism, 14:380, March 1965, suppl. 13. Aldercreutz, H.: Oral contraceptives and liver damage. Brit. Med. / .. 5417: 1133, Oct. 31, 1964. 14. Eisalo, A. et al: Liver function tests during intake of contraceptive tablets in pre-menopausal women. Brit. Med. /.; 5447:1416, May 29, 1965. 15. Stroll, B. A. et al: Oral contraceptives and liver damage. Brit. Med. J., 5436: 723, March 13, 1965. 16. Paiva, I. P. and Mustata, 0. 0.: Oral contraceptives and liver damage. Brit. Med. J., 5410:688, Sept. 12, 1964. LINACRE QUAHTERLY 17. Tyler, E. T.: Eight. years . experience with oral contraception. Brit. Med. ]., 5413:844, Oct. 3, 1964. 18. Stroll et al, 723. 19. Wright Committee: Final report on Enovid. (HEW document) Sept. 12, 1963. 20. Langer, Elinor: Enovid: contrac:ptiv_e pill and recent FDA report _clearmg it stirs continued research. Science, 141: 892, Sept. 6, 1963. 21. Diamond, E. F.: Oral progestins and the Catholic physician. Linacre Quar­terly, 33:193, May 1966. 22. Langer, 893. 23. Jabora, A.: Induction of canine ovarian tumors. Aust. ]our. Exptl: Biol., 40:151, . April 1962. 24. Shipman, J. J.: Oral contraceptives andbreast cancer. Brit. Med. ]., 5409:629, Sept. 5, 1964. 25. Brennan, M. J.: Oral contraception andbreast cancer. Brit. Med. ]., 5434:587, Feb. 27, I96S. No·n::r.r�::r:., 1966 26. Lipschutz, A_ and Ceriosol�,-·H.:._Ovar­ian tumors due to a funct10nal 1mbal­.ance of the hypophysi5,,. Nature, 193: 145, Jan. 13, 1964. .27. Shipman, 629. 28. Mills, W.: The difficulties and dangers of oral contraceptives, Proc. Royal Soc. Med., 57:210, March 1964. 29. Bacher, V.: The contraceptive pill: a clinical evaluation of its long term use. Med. J. Aust., 50:809, June l, 1963. 30. Drill, V. A.: Endocrine properties _and long term safety of oral contraceptives. Metabolism, 14:296, March 1965, suppl. 31. Eichner, E.: Clinical uses of 1700 -hydroxy - 600 - methyl progesterone ac:­tate in gynecologic and obstetric practice. Amer. J. Obstet. and Gynec., 86:174, May IS, 1963. 32. Langer, 622. 33. Green, G. H.: Break-thro�gh bleeding and cervical cancer. Bnt. Med. J.,5440:997, April 10, 1965. 34. Dodds, C.: The pill. Trans. Med. Soc. London, 80:171, 1964.365 

Oral Contraceptives: Nature, Use and Physiological Effects

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Oral Contraceptives: Nature, Use and Physiological Effects

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