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Long-term use of an injectable contraceptive: effect of depot-norethisterone oenanthate on carbohydrate metabolism.

In order to determine the metabolic effects of long-term use of the injectable contraceptive norethisterone oenanthate, plasma glucose and serum insulin concentrations were studied in two groups of women who had used the method continuously for at least five years. Group 1 comprised 24 subjects, from whom only fasting blood samples were taken. Despite similar plasma glucose concentrations to those of the controls, the subjects had significantly increased serum insulin concentrations (164.5 (39.9) v 120.3 (34.3) pmol/l, p less than 0.01). In addition the insulin:glucose ratios were also significantly increased (34.3 (8.5) v 24.6 (6.7), p less than 0.01), consistent with decreased insulin sensitivity. Group 2 comprised 13 of the original 24 subjects who also had an oral glucose tolerance test. Basal plasma glucose concentrations were similar in the subjects and their controls, whilst the significantly increased insulin:glucose ratios (35.0 (7.7) v 28.7 (5.6), p less than 0.05) were consistent with the results of the larger group. Following oral glucose challenge, plasma glucose concentrations, serum insulin concentrations and insulin:glucose ratios were similar in the subjects and their controls throughout the test. Thus, long-term use of norethisterone oenanthate injections is associated with a decrease in peripheral insulin sensitivity. However, these changes are not associated with any evidence of oral glucose intolerance.

Adult↗

Monthly combined injectable contraceptives and neoplasia.

Monthly injectable contraceptives, containing a combination of a long-acting progestogen and an estrogen, have been used in Latin America and China for many years. While knowledge about the effects of other hormonal contraceptives on cancer risk is relevant, close analogies with monthly injectables cannot be made. The relation between use of these preparations and cancers of the breast and cervix has been examined in case-control studies, but no firm conclusions can be drawn because of limitations in sample size. Adequate studies of the influence of monthly injectable contraceptives on risk of neoplasia need to be carried out.

Animals↗

A prospective, one-year study on the effects of two long acting injectable contraceptives (depot-medroxyprogesterone acetate and norethisterone oenanthate) on serum and lipoprotein lipids.

Two parenterally administered progestins (depot medroxyprogesterone acetate, DMPA, 150 mg/12 weeks and norethisterone oenanthate, NET, 200 mg/8 weeks respectively) were given to women seeking contraceptive advice. Before treatment and after 1, 6, 7, 12 and 13 months blood samples were taken. In serum and in the ultracentrifugally separated lipoprotein fractions the levels of total and free cholesterol, triglycerides and phospholipids were assayed, as were the apolipoprotein A1 and B levels in serum. At the end of the study NET had induced a decrease in all lipid components of the HDL (high density lipoprotein) fraction of approximately 30% and tended to increase LDL (low density lipoprotein) lipids. DMPA also decreased HDL-lipids, approximately 15%. There was also a transient decrease in apolipoprotein A1 after one month in both patient groups. From epidemiological studies it is inferred that low HDL-levels and high LDL-levels are independent risk factors for the development of atherosclerosis and cardiovascular disease. Thus our findings might indicate an adverse effect in this respect of long term treatment with these progestins, particularly with NET.

Adult↗

The influence of pharmaceutical compounds on male fertility.

1. Steroid hormones can affect spermatogenesis and thereby fertility directly and/or indirectly. All antigonadotropically active steroids inhibit spermatogenesis via inhibition of gonadotropin secretion, mainly that of H. Androgens and steroids occurring in the biosynthetic chain of testosterone synthesis have a direct promoting effect on spermatogenesis if applied in high doses. It has not been possible as yet to make clinical use of this positive effect since it is obviously not possible to achieve the necessary intratesticular androgen concentrations. 2. As concerns the different androgens and the steroids in the androgen biosynthetic chain, and also all synthetic anabolics, there is no parallelism between the direct spermatogenic activity, the androgenic activity and the antigonadotropic activity. 3. Estrogens and synthetic gestagens do not inhibit spermatogenesis directly at the testicular level. All effects of estrogens can be abolished experimentally by adequate substitution with gonadotropins or androgens, or a combination of androgens and gonadotropins. 4. Only those antiandrogens inhibit spermatogenesis with additional antigonadotropic properties (e.g. cyproterone acetate). Pure antiandrogens, like flutamide or cyproterone, have a slight and transient influence on spermatogenesis at the most. If at all, they merely cause transient subfertility. 5. Beside steroids and several centrally active pharmaceutics (e.g. psychotropic drugs and several antihypertensive compounds), only siloxanes and methallibur seem to affect spermatogenesis via inhibition of gonadotropin secretion. Other antispermatogenic agents act by inhibition of mitosis (Colchicine, alkylating agents) or presumably via damage of the Sertoli cells. 6. Based on present knowledge, contraception in men could be principally managed by administration of a) androgens alone, b) gestagen/androgen combinations, c) estrogen/androgen combinations, d) certain antiandrogens. 7. The difficulties of contraception in men by steroid hormones or steroid hormone combinations have been pointed out. As regards the usefulness of antiandrogens for contraception, no definite conclusions can be drawn at the moment. All non-steroidal inhibitors of spermatogenesis which have been found up to the present are not suitable because of toxic effects.

Androgen Antagonists↗

Vaginal bleeding disturbances associated with the discontinuation of long-acting injectable contraceptives. From the World Health Organization Special Programme for Research, Development, and Research Training in Human Reproduction; Task Force on Long-acting Systemic Agents for the Regulation of Fertility.

A randomized comparative trial of 832 women receiving norethisterone oenanthate (NET-OEN) and 846 women receiving depot medroxyprogesterone acetate (DMPA) injections at 12 week intervals was conducted in 10 centers. The pregnancy rate with NET-OEN was significantly higher than with DMPA. The termination rate for amenorrhoea was substantially lowe with NET-OEN than DMPA, whereas the discontinuation rates for bleeding problems were similar with the two drugs. Analysis of bleeding patterns among continuing and discontinuing users suggests that women tolerated frequent bleeding episodes, but found prolonged bleeding or prolonged bleeding-free intervals unacceptable. Bleeding for more than 30 days during an injection interval and complete amenorrhoea for a whole injection interval were jointly associated with 43.7% of all terminations among NET-OEN users and 64.5% of all terminations among DMPA users. In future efforts to improve the acceptability of long-acting injectable contraceptives, more attention should be given to the control of prolonged amenorrhoea and prolonged bleeding.

Amenorrhea↗

A prospective controlled study of the effect on blood pressure of contraceptive preparations containing different types and dosages of progestogen.

A prospective controlled study investigated the effects of oral contraceptives on blood pressure in 485 women who were between 17 and 46 years of age and had blood pressures of less than 140/90 mmHg at entry. The women were divided into seven groups depending on the chosen method of contraception: intrauterine device or barrier method (control group): ethinyl oestradiol 30 micrograms plus levonorgestrel 150 micrograms (Microgynon-30 or Ovranette); norethisterone 350 micrograms (Micronor); norgestrel 75 micrograms (Neogest); norethisterone oenanthate 200 mg intramuscularly every 2 months for the first 6 months, then every 3 months thereafter; ethinyl oestradiol 30 micrograms plus ethynodiol diacetate 2 mg (Conova-30); and ethynodiol diacetate 500 micrograms (Femulen). Blood pressures were measured every 3 months by the family planning clinic nurse under standardized conditions using an Elag-Köln automatic sphygmomanometer. After one year, blood pressure had risen significantly (P less than 0.05) in the 137 women taking ethinyl oestradiol plus levonorgestrel (mean systolic and diastolic rises 6.4 and 2.7 mmHg respectively) and in the 91 women taking ethinyl oestradiol plus ethynodiol diacetate (mean systolic and diastolic rises 6.2 and 3.0 mmHg respectively). The 94 women taking the progestogen-only preparations and the 143 women in the control group showed no increases in blood pressure. These data were confirmed after 2 years of follow-up.

Adolescent↗

Effects of seven low dose combined oral contraceptives on high density lipoprotein subfractions.

The effects on lipid metabolism of seven combined oral contraceptives were investigated, particularly the effects on high density lipoprotein (HDL) subfractions, which were separated by density gradient ultracentrifugation. There were no differences between the preparations in the effects on the LDL fraction, the so-called atherogenic particle, but there were marked differences in the effects on the anti-atherogenic HDL fraction, of which the effects on HDL-2 were most pronounced. After treatment with monophasic cyproterone acetate and biphasic desogestrel, the cholesterol and phospholipid contents of the HDL-2 fraction were significantly higher than those found after treatment with the other preparations. The lowest values were found after treatment with monophasic levonorgestrel, whereas monophasic desogestrel, triphasic levonorgestrel, monophasic norethisterone and triphasic gestoden induced intermediate values for these variables. The levels of HDL-2 reflect the intrinsic androgenicity of the various progestogens used in the preparations.

Adolescent↗