Clinical evaluation of two monthly injectable contraceptives and their effects on some metabolic parameters

CONTRACEPTION

CLINICAL EVALUATION OF TWO MONTHLY INJECTABLE CONTRACEPTIVES AND THEIR EFFECTS ON SOME METABOLIC PARAMETERS A. Darwish', N.A. Haiba', M.A. El-Habashy',2S.A. Said' ’ FW.S. Abdel-Sayed , S.E. Nayel 1. Department of Obstetrics and Gynecology, Faculty of Medicine, Alexandria University 2. Director, Clinical Chemistry Laboratory, Shatby University Hospital

ABSTRACT One-hundred-and-thirty normally menstruating females were subgrouped equally and enrolled from the family planning clinic to study the clinical performance of the monthly injectable contraceptives medroxyprogesterone acetate 25mg + estradiol cypionate 5mg (Cycloprovera) and norethisterone enanthate 50mg + estradiol valerate 5mg (HRP-102) and their effects on some metabolic parameters. The contraceptive efficacy after 6 months of use for both drugs was 100%. No change in menstrual pattern occurred in 74% of Cycloprovera users and 67.3% of HRP-102 users. A statistically significant decrease (P< 0.01) occurred in HDLcholestrol and total serum protein values and a statistically significant increase (P< 0.01) was observed in hematocCit va%ue of Cycloprovera users only. Body weight and blood pressure values after 6 months of drug use showed no statistically significant changes in both groups. Also, no statistically significant changes were noticed in both groups for hemoglobin, post+prandial blood glucose, cholesterol, A/G ratio, SGOT and SGPT values following 6 months of injectable contraceptive use. None of the injectable users developed cervical dysplastic changes cytologically.

This work was partially supported by WHO. Author for correspondence: Dr. Nasr A. Haiba Dept. of Ob/Gyn Shatby Universitv Hospital Alexandria - Egypt. Submitted for publication September 9, 1988 Accepted for publication March 6, 1989

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INTRODUCTION The presence of a wide variety of fertility control methods provides different alternatives to cope with the diversity in human customs and preferences, so up until now there is no method to be termed "idealV1for contraception. A major approach to improve the effectiveness, safety and acceptability of steroid contraception is to develop long-acting preparations and delivery systems that can provide continuous medication at minimal daily doses sufficient to obtain a therapeutically adequate blood level to maintain their effectiveness. These systems have assumed a variety of forms, as injectable depot formulations, subdermal implants and also included intravaginal, intrauterine, and intracervical devices (1). Oral administration of steroids results in rapid high blood levels that decrease with time, and repetitive doses must be given at frequent intervals to keep the blood level within the effective zone. Steroid doses in excess of the optimal therapeutic range constitute over-medication with the possibility of appearance of dose-dependent side effects; while doses below the effective range can result in contraceptive failure. Therefore, controlled release from injection site allows reduction of the total dose of the administered steroid for a prolonged period of time, and reduces the chance of human errors by eliminating the need for repetitive selfadministration (2). The aim of this work is to study the efficacy and clinical side effects of medroxyprogesterone acetate 25mg + estradiol cypionate 5mg (Cycloprovera) and norethisterone enanthate 50mg + estradiol valerate 5mg (HRP-102) and their effects on some metabolic parameters. MATERIAL AND METHODS One-hundred-and-thirty normally menstruating females were selected from the family planning clinic of Shatby University Hospital. They were not lactating or had stopped lactation at least 70 days prior. For post-partum and postabortive subjects, despite knowing that this duration does not ensure return of the metabolic parameters to the prepregnancy values, the cases were enrolled at least 70 days

JUNE 1969 VOL. 39 NO. 6

CONTRACEPTION

post-partum or post-abortive and had at least one normal cycle since labour or abortion and were regularly menstruating for 6 months prior to pregnancy or abortion. They had to be willing to use injectable contraceptives and able to return at the prescribed intervals for follow-Up. Women with contra-indications to steroid contraceptives were excluded from the study. The studied cases were divided of sixty-five women:

into two groups, each

Group I used Cycloprovera, formulated as an aqueous microcrystalline suspension, whichwasinjectedbydeepgluteal/ intramuscular route between days l-5 of the first treatment cycle and subsequently every 30 days for 6 months. Group given route every

II used HRP 102, supplied in an oily solution. It was in one ml of solution by deep gluteal intramuscular between days l-5 of the first treatment cycle and then 30 days for 6 months.

On admission, a full medical, obstetric and gynecological history was taken. A thorough medical and gynecological examination was performed including measurement of blood pressure and weight. Breast examination was done. Speculum examination of the vagina was done; a cervical smear was taken by Ayre's spatula and sent for cytological examination. Cases with glycosuria on urinalysis were excluded. A venous blood sample was taken and the following laboratory tests were done: a) Hemoglobin concentration; b) Hematocrit (PCV); c)' Two hours post-prandial blood glucose level; d) Cholesterol; e) High density lipoprotein (HDL) cholesterol; f) Total serum protein; g) Albumin/Globulin (A/G) ratio; h) Serum glutamic oxaloacetic transaminase (SCOT); and i) Serum glutamic pyruvic transaminase (SCPT). After that, the drug was given and each subject was followed-up monthly with blood pressure, body weight and development of any complaints. Breast and vaginal examinations were repeated at the third and the sixth month of the study. Cervical smear and a blood sample for the selected metabolic parameters were repeated after six months for cases who completed the planned follow-up period and the drop-out cases were excluded from the study.

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RESULTS The age of women in the first group ranged between 18-35 years with a mean of 26.5 years while it ranged between 20-35 years with a mean of 28.8 years for those in the second group. CONTINUATION RATE (Table I) In the first group, out of sixty-five cases, fifty cases (76.9%) completed the planned six months of followup. Four cases were dropped from the study and 11 cases did not complete the desired follow-up period. The causes were amenorrhea (18.2%), weight and backache in

of discontinuation in Cycloprovera users in 5 cases (45.5%), headache 2 cases gain 2 cases (18.2%), prolonged bleeding one case (9.1%).

In the second group, out of sixty-five cases, fortynine cases (75.4%) completed the planned follow-up period. Three cases dropped out of the study and 13 cases did not complete the proposed follow-up period. The causes of discontinuation in HRP-102 users were amenorrhea in 5 cases (38.5%), prolonged bleeding in 4 cases (30.8%), polymenorrhea, headache, low backache and weight gain in one case (7.7%). CONTRACEPTIVE EFFICACY None of the cases in either group became pregnant during the proposed six months of follow-up. MENSTRUAL PATTERN No change in menstrual pattern occurred in 37 cases (74%) out of the 50 cases of the Cycloprovera group while only 33 cases (67.3%) out of 49 cases of the HRP-102 group showed no change in their menstrual pattern. At the end of the planned period of follow-up, it was found that the incidence of amenorrhea in the first group was 24% (12 cases); only 7 cases completed the scheduled follow-up while the remaining 5 cases discontinued use because of amenorrhea. In the second group, amenorrhea occurred in 12.2% (6 cases); only one case completed the scheduled follow-up and 5 cases discontinued use of drug because of amenorrhea.

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CONTRACEPTION

r.

.

P-

N .

2

N

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Irregular pattern of menstruation was found in 2 cases (4%) of the first group; one of them discontinued due to prolonged bleeding. In the second group, 8 cases (16.3%) developed menstrual irregularities; three cases discontinued the use of the drug for this reason. BODY WEIGHT (Table II) The changes in body weight in either group were not statistically significant from the pre-injection weight despite a slight increase in the second group (P>O.O5). BLOOD PRESSURE (Table III) The blood pressure values following 6 months of injectable use compared to the pre-injection data showed no statistically significant readings in both groups despite a slight increase noted in the second group for both the systolic and diastolic values. METABOLIC PARAMETERS (Table IV) In both groups, only the cases that completed the planned 6-month follow-up period were included in studying the metabolic parameters (50 and 49 cases in the first and second group, respectively) and those who dropped out from the study or discontinued use of the drugs were excluded. No statistically significant changes were noted in both groups following 6 months of injectable use for hemoglobin, post-prandial blood glucose, A/G ratio, SGOT and SGPT values. No changes occurred in cholesterol values following injectable use for 6 months despite an observed increase which occurred in the second group which was statistically insignificant. A statistically significant decrease (P< 0.01) occurred in HDL-cholesterol and total serum protein values following 6 months of Cycloprovera use. This change was not statistically significant in HRP-102 users. A statistically significant increase occurred after 6 months of Cycloprovera use in hematocrit values compared

to the pre-injection value (P
624

This change was not

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CONTRACEPTION

Table

II:

Changes

in

body

weight

in

Cycloprovera

and

llRP-102

users

kc-injection

Cycloprovera

group

IIRP-102 group

Table

III:

Blood

Mean

70.9

S.D+

14.4

After 6

70.6 14.1

t

0.123

I'

> 0.05

Mean

73.8

74.4

S.D+

15.7

15.9

t

0.318

P

> 0.05

pressure

IIRP-102

changes

months

in Cycloprovera

hf Lcr 6 lwntlls

Pm-iujcction

Cycloprovera

group

I.1 ean S.Dk

llRP-102

group

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and

acceptors

119.7f78.7

119.5/7Y.l

6.8715.1

8.817.1

t

0.347

P

> 0.05

Mean

118.9/78.9

119.4/79.4

S.D?

9.9/7.1

7.416.1

t

0.348

I'

> 0.05

625

c C

and IIRP-102 groups

27.9* 7.3

8. SGOT (U/L)

*P < 0.01

19.4+ 6.6

1.9f 0.5

7. A/G ratio

9. SGPT (U/L)

7.5f 0.6

5. HDL-cholesterol(gm/dL)

6. Total serum protein (g/dL)

37.6+-5.2

19.1 + 4.8

29.1 f 0.9

23.3 f 6.4

29.1 + 6.9

1.7 * 0.4

2

f;0.6

7.9 * 0.6

46.3 + 13.9

174.2 f 31.1

7.1 t 0.4s

34.4 +-5.3s

160.4 f 21.7

4. Serum cholesterol(mg/dL) 165.9+ 28

35.6 t 2.3 136.4 f 28.2

37.9 f 4.4"

12.1 f 1.2

118.8 f 23.2

11.6 + 0.9

23.1 f 5.7

29.8 f 7.4

1.6 +-0.3

7.5 + 0.5

45.7 f 14.3

175.8 f 32.6

129.9 f 27.5

36.2 2 2.5

12.2 + 0.9

HRP-102 group Pre-injection After 6 months

(mean -+ SD)

35.E 3.4 3. Two-hour P.P. blood glucose (mg/dL) 135.8-c27.2

12 + 1.8

Cycloprovcra group Pre-injection After 6 months

changes in Cycloprovera

2. Hematocritvalue (%)

1. Hb (g/dL)

Table IV: Metabolic

CONTRACEPTION

CYTOLOGICAL

CHANGES (Table 'f)

As shown, following 6 months of injectable use in both groups 9 none of the cases developed dysplastic changes and

the incidence of an inflammatory smear pattern showed some decrease. DISCUSSION The contraceptive efficacy of Cycloorovera and HRP-102 was 100% at the end of the proposed 6 months of use. This data is in agreement with the pregnancy rates reported with various monthly injectable formulations (3,4). Compared with the two long-acting progestins, DMPA and NET-EN, Cycloprovera and HRP-102 showed better contraceptive efficacy. DMPA had a failure rate ranging from O-l.2 per 100 womenyears, whereas NET-EN showed a Pearl index of 0.66-3.6 per 100 women-years when used every 12 weeks (5). The continuation rates of Cycloprovera and HRP-102 users were found favourable (76.9% and 75.4%, respectively) at the end of the study. These continuation rates were better than for DMPA (6) and oral contraceptives but lower than that of IUD users (7). The overall incidence of menstrual disorders was 26% for Cycloprovera users and 32.7% for HRP-102 users. Extensive studies suggested that monthly injectables do offer a significant advantage in terms of bleeding irregularities when compared to long-acting injectables (8) or implants (9) of the progestogen-only type. There was no effect on body weight for both Cycloprovera and HRP-102 users. On the contrary, weight gain has been a regularly observed side effect in DMPA studies (10) and to a lesser extent in NET-EN studies (11). As regards the blood pressure, Cycloprovera and HRP-102 had no effect while other studies (12) reported a significant rise in the diastolic pressure in 10% of DMPA-treated women, and occasionally NET-EN caused a significant rise in blood pressure (13). No statistically significant changes occurred in hemoglobin concentration after 6 months of Cycloprovera and HRP-102 use. This is in agreement with other studies on longacting hormonal contraceptives including injectables (14) and subdermal implants (15).

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Cytological

Dysplasia

14

Non-specific inflammatorysmear 28%

16% 24%

8

12

Trichomonas

32%

16

12

12

6

20

No.

24%

24%

12%

40%

%

After 6 months

%

No.

and HRP-102

Pre-injection

group

in Cycloprovera

Cycloprovera

changes

Moniliasis

Normal smears

Table V:

groups

10

9

11

19

No.

20.4%

18.4%

22.4%

38.8%

%

Pre-injection

HRP-102

6

12

9

22

NO.

12.2%

24.5%

18.4%

44.9%

%

After 6 months

group

CONTRACEPTION

A statistically significant increase in hematocrit value was noted in Cycloprovera users compared to the preinjection value but such an increase was not observed for HRP-102 users. Also no change was noted in other studies for injectables (16) or subdermal implants (15). Regarding the study of the metabolic effects, the post-partum and post-abortive subjects were enrolled at least TO days following delivery or abortion despite knowing that this duration did not ensure return of the metabolic parameters to the pre-pregnancy values. The two-hour postprandial blood glucose level, despite the limitations of this test to ascertain the impact on carbohydrate intolerance, showed no statistically significant changes in both groups. This agreed with the studies carried out on NET-EN (17) and are in contrast to those on DMPA (6) which showed a definite, although slight, diabetogenic effect. Cholesterol and HRP-102 use, This agreed with compounds, DMPA

levels, following 6 months of Cycloprovera showed no statistically significant changes. studies done on long-acting progestational (18) and NET-EN (4).

As regards the HDL-cholesterol, the baseline value was significantly different between the two treatment groups at admission. Following injectable use, no statistically significant change was noted for HRP-102 users but an additional lowering of HDL-cholesterol was observed for Cycloprovera users after 6 months which might be associated with some intrinsic difference in this group and not solely to the different drug given to it. However, this reduction in HDL-chol.esterol agreed with other studies on long-acting progestational injectables, DMPA and NET-EN (191, an effect that is linked to an increase in theincidenceof ischemic heart disease (20). In the present study, no statistically significant changes were observed in liver function tests except for a decrease in total serum proteins in the first group (Cycloprovera users), but no changes in A/G ratio, SCOT and SGPT values. Our findings of no impairment of liver function are in agreement with other studies on DMPA, NET-EN (21) and subdermal implants (22). In the present study, there was no evidence of dysplastic changes in the studied smears for both groups after 6 months. This is in agreement with other studies which showed no evidence of the effect of injectables on the developmeht of cervical carcinoma in situ (2O,23), breast cancer (24) or endometrial carcinoma (25).

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Zatuchni GI. Contraceptive development for the future. Papers presented at the symposium on long-acting contraception. Alexandria, Egypt. Nov 3-4, 1983. Goldsmith A, Toppozada M, ed. pp 8-23, 1983.

2.

Beck LR. Pharmacological aspects of slow release in steroidal systems. Papers presented at the symposium on long-acting contraception. Alexandria, Egypt. Nov. 3-4, 1983. Goldsmith A, Toppozada M, ed. pp 24-35,1983.

3.

Koetsawang S, Srisupandit S, Kiriwat 0. The monthly injectable contraceptive: A two-year clinical trial. Int J Gynecol Obstet 16: 61-4, 1978.

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Coutinho EM, ED Souza JC. Conception control by monthly injections of medroxyprogesterone suspension and a longacting estrogen. J Reprod Fertil 15: 209-14, 1968.

5.

World Health Organisation (WHO). Special programme of research, development and research training in human reproduction. Multinational comparative clinical trial of long-acting injectable contraceptives: norethisterone enanthate given in two dosage regimens, and depot-medroxyprogesterone acetate: a preliminary report. Contraception 25: l-11, 1982.

6.

Nash H. Depo-provera: A review. Contraception 12:377-93, 1975.

7.

Population Reports. Long-acting progestins-promise and prospects. Population reports. Series K, No. 2, Washington DC, Population Information Program, May pp 17-55,1983.

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Faundes A, Sivin I, Stern J. Long-acting contraceptive implants: an analysis of menstrual bleeding patterns. Contraception 18: 355-65, 1978.

10.

Fraser IS, Weisberg E. A comparative review of injectable contraception with special emphasis on depot-medroxyprogesterone acetate. Med M Aust 1: 19, 1981.

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World Health Organisation (WHO). Expanded programme of research, development and research training in human reproduction. Task force on long-acting systemic agents for the regulation of fertility. Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids, norethisterone enanthate and medroxyprogesterone acetate. I. Use-effectiveness. Contraception 15: 513-33, 1977.

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Giwa-Osagie OF, Sagage J, Newton JR. Norethisterone enanthate as an injectable contraceptive. A study of patients discontinuing treatment. Contraception i8: 517-26, 1978.

14. Aznar-Romas R, Giner-Velasquez J, Lara-Ricalde A: Incidence of side effects with contraceptive placebo. Am J Obstet Gynecol 105: 1144-52, 1969. 15. Shaaban MM, Salah M, Zarzour A, Abdallah SA. A prospective study of Norplant implants and TCu 380 Ag IUD in Assiut, Egypt. Stud Fam Plann 14:163-g, 1983. 16. Howard G, Blair M, Davis H, Treaty M. The effect of norethisterone enanthate on the full blood count. Brit J Fam Plann 8: 125-9, 1983. 17. Gillich KH, Kruchemper G, Hermann J. Observations under treatment with norethisterone.oenanthate. Acta Endocrinol 152:64, 1971. 18.

Toppozada HK, Khowessah M, Youssef HA, Saleh FM. A study of injectable contraceptives. Bull Alex Fat Med IX: 35-41, 1973.

19. Kremer J, De Bruijin HWA, Hindriks FR. Serum high density lipoprotein cholesterol levels in women using a contraceptive injection of depot-medroxyprogesterone acetate. Contraception 22: 359-67, 1980. 20. World Health Organisation (WHO). Injectable hormonal contraceptives. Technical and safety aspects. WHO Offset Pub., Geneva, No.65: 16-23, 1982.

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Garcia CR, Wallach EE. Liver function studies and progestogen contraception. Fertil Steril 19: 172-85, 1968.

22. Croxatto HB, Diaz S, Robertson DN, Paves M. Clinical chemistry in women treated with levonorgestrel implants (Norplant) or a TCu 200 IUD. Contraception 27:281-8, 1983. 23. El-Mahgoub SE, Karim M, Ammar R. Long-term use of depotmedroxyprogesterone acetate as a contraceptive. Acta Obstet Gynecol Stand 51: 251-5, 1972. 24. Creenspan AR, Hatcher RA, Moore M, Rosenberg MJ, Ory HW. The association of depo-medroxyprogesterone acetate and breast cancer. Contraception 21:563-g, 1980. 25. MC Daniel EB, Potts M. Depo-medroxyprogesterone acetate and endometrial carcinoma. Int J Gynecol 17:297-9,1979.

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