, Population Reports SERIES K . ~ . NUMBER 1 MARCH 1975 -.~. : I ' .. .. , ' .. Department of Medical and Public Affairs, The George Washington University Medical Center, 2001 S Street, N.W. Washington, D .C. 20009 -Injectable Progestogens­ This Population Report on injectable proges­ togen contraceptives was prepared by Ward Officials Debate Rinehart and Jane Winter on the basis of pub­ lished and unpublished papers, personal But Use Increases interviews, and correspondence, The assistance of the following reviewers is ap­ The place of the injectable progestogen in family planning preciated: Ridgely C, Bennett, Victor R. Berliner, remains uncertain. Although some compounds have been Elizabeth Connell, Hanni Levi Ellis, Suporn used as injectable contraceptives for over a decade and are Koetsawang, Richard Lincoln, Edwin B, McDaniel. both popular and effective, controversy still surrounds Malcolm Potts, Allan G, Rosenfield, Paul C, them , Schwallie, J , J, Speidel, Andrew Wiley, and Nicholas Wright Frances G, Conn is Executive Editor. Comments and additional updated ma­ Depo-Provera ® (depot medroxyprogesterone acetate), a terial are welcome. product of the Upjohn Company, USA, is currently the only injectable progestogen in widespread use; it is available commercially for contraceptive purposes in 64 countries, Another will be available soon, Schering AG of the Federal The injectable progestogens are not without problems. Republic of Germany is now registering an injectable Over the short run, they disturb menstrual patterns in progestogen, norethindrone enanthate (also known as many women and cannot be immediately withdrawn if norethisterone enanthate) in some 70 countries, It will be other problems arise. Over the long run, the return of marketed commercially under the brand name Norigest ® fertility after discontinuation may be delayed, especially and available for family planning organizations under the with Depo-Provera, brand name Noristerat ®, Because of suspicions about other long-term effects, the use of Depo-Provera has been limited, In some countries Injectable progestogens offer many advantages that may concern about permanent infertility after injections has be of special importance in developing countries, They are: caused it to be restricted to older women with completed • highly effective in preventing pregnancy, on a par families, In other countries Depo-Provera has not yet won with oral contraceptives, regulatory approval for general use. A controversy in the • independent of coitus, USA over the interpretation of statistical data on cervical • simple to administer, carcinoma in situ has prevented approval specifically for • long-lasting, with injections required only two or contraception. The US Food and Drug Administration four times a year, (USFDA) is reanalyzing the raw data on cervical carcinoma • not lactation suppressors and thus, unlike combina­ in situ, a possible precursor of invasive cancer. A report is tion oral contraceptives, can be offered to nursing expected in 1975, mothers without danger of reducing the supply of milk, • popular in developing countries where injections are CONTENTS associated with safe, effective, modern medicine, History . ...... ... .. , ..... ... .. .. .. ..... K- 2 Mechanism of Action . .. ... ... , .. .. .. , . K- 3 An estimated 1 million women now depend on injectable Effectiveness . ... .... .. .. , ... ... ... K- 3 progestogens for contraception, That number is small com­ Short-Term Side Effects .. ... .. .. ... .. K- 4 pared with the 50 million who use oral contraceptives and Continuation .... ....... , . ... , .. ... .... .. K- 7 the 15 million who use intrauterine devices (IUDs), but the Fertility-Related Effects ... .. .. .. .. .. .. .. .. K- 8 use of injectables appears to be gradually increasing. In Debate over Cancer Risks. , . .... ... .. .. K- 9 recent years international donors of contraceptive supplies Program Issues, ......... ...... .. ..... .. K-11 have received a growing number of requests for injectables Distribution . .. , . ..... , . ....... ' . .. ... .. .K-14 and several countries have added Depo-Provera to their Bibliography .. ....... .. .. .. , . ... ... .. .K-14 national family planning programs, Part 1 of 2 parts· March 1975 mailing K-1 place in Egypt, Europe, and elsewhere. In 1967 Norigest Population Reports are published bi-monthly was first marketed in Peru, but in 1971 it was withdrawn at 2001 S Street, N.W., Washington, D.C. and field trials suspended pending further analysis of 20009, USA, by the Population Information toxicologic findings in rats. Some researchers have since Program, Science Communication Division, concluded that the findings in rats are not applicable to Department of Medical and Public Affairs of humans, and Schering AG is now registering Norigest in the George Washington University Medical some 70 countries. The brand name Noristerat will be Center and are supported by the United States used when the drug is sold to international donor organi­ Agency for International Development, P. T. zations in order to make it readily identifiable if it should be Piotrow, Ph.D., Director. diverted from intended channels (25). In 1958 the Upjohn Company began clinical trials of Second class postage paid at Washington, D.C. medroxyprogesterone acetate (Depo-Provera) as a treat­ ment for threatened or habitual abortion and for endome­ triosis. In 1960, the USFDA approved it for these uses on the basis of its safety, but without assessing its effective­ An injectable contraceptive is a welcome addition to family ness. In February 1974, after the agency concluded that planning methods. But the present progestogen injec­ Depo-Provera had not been proved effective for either of tables, troubled as they are by menstrual side effects and these uses and after steroids administered during preg­ unresolved questions about long-term effects, have not yet nancy had been associated with congenital defects (69, won the unqualified approval of clinicians. Nevertheless, if 117). the USFDA withdrew its approval for use of Depo­ further research can dispel fears about carcinogenicity and Provera during pregnancy or to treat endometriosis (33, disprove or define the risk of infertility after Depo-Provera 34, 35). use, the injectable progestogens may yet become an important component of family planning programs, espe­ The first clinical trials of Depo-Provera as a human contra­ cially in areas where treatment by injection is popular. ceptive began in 1963 and established a standard regimen of 150 mg every three months. Field trials began in 1965 and have since been conducted in 61 countries (48). Since the late 1960s regimens of 300 or 400 mg every six HISTORY months have also been studied. The first systemic contraceptives, developed in the mid­ Upjohn applied to the USFDA in 1967 for permission to 1950s, were Short-acting progestogens administered orally market Depo-Provera as a contraceptive in the USA (173), (128). With the development of longer-acting proges­ but, at first, questions about reversibility and relationship togens shortly thereafter, injectable contraceptives also to breast cancer in beagle dogs and, more recently, ques­ became possible. Over the past 20 years a number of tions about cervical carcinoma in situ in humans have compounds have been tested as injectable contraceptives, blocked USFDA approval. but only one-Depo'-Provera-is currently being produced for international distribution and is widely used. In the In 1972 Depo-Provera received USFDA approval as a USA, Depo-Provera has a checkered history of regulation palliative treatment ofadvanced endometrial cancer. Cur­ and at present is not approved for contraception. rently this is the only approved use in the USA (168). Depo­ Provera has also been studied as a treatment for idiopathic The development of progestogens (synthetic compounds precocious puberty (64, 83, 106), but its effectiveness and with the effects of the natural hormone progesterone) safety for this purpose have not been established. grew out of the post-World War II competition among drug companies to create synthetic hormones for a variety of Several combinations of a progestogen and an estrogen therapeutic purposes. These early progestogens are me­ are being distributed in a few countries as monthly injec­ tabolized quickly and therefore have to be administered in tables. Promeco markets the combination of algestone frequent small doses in order to maintain their effect. As a acetophenide and estradiol enanthate in Mexico and Argen­ result, when in the early 1950s Dr. Gregory Pincus and his tina under the brand name Perlutal® and in Spain under associates set about utilizing the powerful ovulation­ the brand name Topasel®. In Chile, Recalcine Labora­ inhibiting properties of these progestogens for fertility tories produces Aguria ®, and Silesia Laboratories control, they concentrated on developing a contraceptive produces Unalmes®. Both are combinations of dihy­ which could be administered orally. droxyprogesterone acetophenide and estradiol enanthate. Dr. Karl Junkmann in 1953 discovered that esterifying a Other steroids have also been tested as injectable contra­ progestogen alcohol created a drug with long lasting ceptives, but are not being pursued because of the ex­ effects when injected (20, 62). (Esters are formed from a pense of clinical trials needed to prove safety (130) and/ or free alcohol and an acid by the removal of water.) Junk­ the severe disturbances of the menstrual cycle which