Thrombocyte function in relation to the long term application of medroxyprogesterone acetate as a female contraceptive agentL Mettler, D Shirwani, FJ Brunnberg
Department of Obetetrics and Gynaecology, University of kiel
In two hundred and twenty eight parous women between thirty and forty years o f age, Medroxyprogesterone acetate 150 mg depot injection every three months proved to be a one hundred per cent contraceptive agent. Minimal side effects were noted with some spotting and amenorrhoea. No significant increase in blood coagulation and tendency to thrombosis was noted as tested by the platelet aggregation test during medication.
Since 1969, medroxyprogesterone acetate has been used clinically as a female contraceptive agent.  It is slowly absorbed from the injection site and has a prolonged activity which should therefore make it an ideal long acting contraceptive drug. It appears to act as a powerful inhibitor of gonadotrophins, ,, and the hormone response to it of gonadotrophins and estrogens have been well documented in dogs by Bryan  and in man by Laron et al. 
Little is, however, known about the blood clotting or thrombogenic effects of medroxyprogesterone acetate and although Robinson  in 1970, found no adverse effects of the drug on clotting factors, Mettler and Meseck-Selchow.  in 1972 found an increase in platelet aggregation and therefore a predisposition to thrombosis when the drug was used in monophasic combination with estrogens.
This study was therefore designed to report on the thrombogenic potential of medroxyprogesterone acetate administered intramuscularly at 3 monthly intervals.
Two hundred and twenty eight women with an age range of twenty to forty five years volunteered to participate in the study. All had completed their families. Patients were seen and examined clinically every three months and a full menstrual history was taken and twelve ml fresh blood collected directly into a polyestrol plastic tube containing 1.5 ml of a 3.8% aqueous sodium citrate solution.
At each visit the patient was administered 150 mgs (3.0 ml) Medroxyprogesterone acetate* as a single intramuscular injection. The number of injections ranged from one to twelve with the shortest treatment of three months and the longest, of thirty six months, The majority of patients discontinued medroxyprogesterone acetate after three to four treatment cycles.
(c) Laboratory investigations
The blood samples were centrifuged for one to three minutes at 500 to 700 x g. The supernatant thrombocyte rich plasma was then separated and rotated in a 20 ml siliconized glass container at 37°C with a velocity of 20 rotations per minute for 10 minutes. The rotated plasma was then diluted 1: 10 with a citrate sodium physiological saline solution.
Plastic slides were over-layered with 1.5 ml of the diluted plasma and by decanting and rinsing with the same solution 20 times in 30 minutes the majority of erythrocytes and leucocytes were washed away.
Specimens were then fixed for 5 minutes in 40%% formalin, oxidated for 5 minutes in 0.1 N Potassium permanganate solution and rinsed again in distilled water. The preparations were stained for 60 minutes in a 1/5 diluted and filtered Giemsa solution, and air dried and evaluated with the phase contrast microscope.
Following 3 degrees only were distinguished according to the method of Breddin.1 See [Figure 1] below.
Platelet Aggregation Test Degree I demonstrated solitary platelets and a few reversible aggregations. Platelet Aggregation Test Degree II consisted of an increasing number of reversible platelet aggregations. Solitary platelets were decreased. Platelet Aggregation Test Degree III showed a growing number of irreversible platelet aggregations and solitary platelets were severely diminished.
In the 228 patients no pregnancies resulted. From [Table 1] it can be seen that as the course continued intra-menstrual bleeding and spotting decreased but amenorrhoea developed in 68. cases, Many patients had symptoms of anxiety associated with taking the drug and twenty seven patients experienced some degree of diminished libido.
As can be seen from [Figure 2] (see on page ) no statistical alteration in the degree of platelet aggregation was found during the period of maximal twelve injections of medroxyprogesterone,
In this series of 228 women, medroxyprogesterone acetate proved one hundred per cent effective as a contraceptive agent. The patients tolerated the drugs well and apart from minimul spotting and some cases of amenorrhoea no severe clinical side effects were observed. A number of women, however, discontinued the treatment early although they did not desire to have any more children. This may be in part due to the psychological symptoms of anxiety and diminished libido they experienced which may also have had a degree of effect on menstrual cycle regularity.
The drug appears to be free from thrombotic potential for, unlike ingested estrogen - gestagen - compounds, ,,,, the platelet aggregation was not altered under medroxyprogesterone acetate contraceptive intake during the three to thirty six months of treatment.
Therefore, medroxyprogesterone acetate would appear to be a safe useful alternative to the application of intrauterine devices and laparoscopic sterilisation  for the group of women between thirty and forty five years of age who do not desire to have any more children.
Mr. R. F. Harrison for his help with the text.
[Figure 1], [Figure 2]