The role of triphasic levonorgestrel in oral contraception: a review of metabolic and hemostatic effects.

Epidemiological studies suggesting a possible association between the use of combined oral contraceptives and an increased risk of cardiovascular disease have led to extensive investigations into the effect of oral contraceptives on lipid and carbohydrate metabolism, and on hemostasis. Since this association was originally suggested, the steroid dose in oral contraceptives has been significantly reduced and new progestogens have been developed. Also, triphasic formulations have been introduced which offer a well-balanced estrogen/progestogen ratio, allowing a further reduction in the progestogen dose per cycle, and thus helping to minimize unwanted metabolic and hemostatic effects. The metabolic interactions of triphasic levonorgestrel, the first triphasic formulation to be introduced, have received particular attention. Lipid metabolism appears to be largely unaffected by triphasic levonorgestrel, most studies reporting no significant change in high- (HDL-C) or low-density lipoprotein-cholesterol (LDL-C) levels. Several studies have reported a decrease in the lipoprotein subfraction HDL2-C levels, but in most cases measurements of the LDL-C/HDL-C and apolipoprotein A-1/B ratios reveal no clinically significant effects. Concerning lipids, most studies suggest that triphasic levonorgestrel has less metabolic impact than the monophasic formulation. In common with all currently available oral contraceptives, triphasic levonorgestrel appears to have some effect on carbohydrate metabolism. The study results vary, however; some investigators have found an impairment of glucose tolerance, whereas others have not detected any significant effect. Compared with lipid and carbohydrate metabolism, fewer studies have investigated the effect of triphasic levonorgestrel on hemostasis. In common with all estrogen-containing oral contraceptives, levonorgestrel appears to stimulate some procoagulant activity, elevating the levels of factors VII and X, and fibrinogen. However, the effect of triphasic levonorgestrel appears to be balanced, with most studies reporting a corresponding increase in anti-coagulant-fibrinolytic activity. Although most of the studies reviewed here reported some statistically significant metabolic interactions, many authors comment that the changes are probably not clinically relevant in terms of an altered risk of cardiovascular disease. The true risk of vascular disease associated with modern low-dose oral contraceptives remains to be confirmed when sufficient epidemiological data eventually become available.

PIP: This review of studies published since 1985 on the metabolic effects of triphasic levonorgestrel in oral contraceptives (OCs) reveals that triphasic levonorgestrel tends not to affect lipid metabolism. Specifically, it does not significantly change the level of the lipids associated with increased vascular risk (low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and lipid ratios). Overall, triphasic levonorgestrel OCs do not affect triglycerides, while other OCs increase the level of triglycerides. They also have a lower effect on lipid metabolism than do monophasic levonorgestrel OCs. About 50% of the studies suggest that triphasic levonorgestrel OCs do not affect carbohydrate metabolism, while the remaining studies suggest that they cause a significant increase in carbohydrates. Some studies found that triphasic levonorgestrel OCs impair glucose tolerance. Studies on the effect of triphasic levonorgestrel on hemostasis are less numerous than those on lipid and carbohydrate metabolism. Unlike all combined monophasic OCs, triphasic levonorgestrel OCs appear to have a balanced effect on hemostasis. In fact, they stimulate both the coagulant and anti-coagulant-fibrinolytic pathways. Many of the researchers who found statistically significant metabolic interactions found that the changes fell within the normal clinical range and therefore did not increase the risk of cardiovascular disease. Triphasic levonorgestrel OCs tend to have less of a metabolic effect than its monophasic counterpart and a metabolic effect similar to other low-dose OCs.

Inhibition of ovulation by a triphasic gestodene-containing oral contraceptive.

The minimal effective dose of gestodene for inhibition of ovulation was studied in 30 female volunteers. Daily doses of 10 micrograms to 50 micrograms gestodene were given orally for 21 days. A control cycle prior to treatment and a treatment cycle were monitored for LH, FSH, estradiol, progesterone and cervical score. At a daily dose of 40 micrograms of gestodene, 6/7 volunteers exhibited inhibition of ovulation and 1/7 had a cycle with luteal insufficiency. Ovulation was inhibited in all volunteers on 50 micrograms gestodene, suggesting that the minimum dose required to inhibit ovulation was 40 micrograms gestodene. Cervical score was blunted even at 10 micrograms gestodene. Similarly, 20 volunteers were treated with coated tablets containing ethinylestradiol/gestodene at 30/50 micrograms for 6 days, 40/70 micrograms for 5 days and 30/100 micrograms for 10 days. This triphasic gestodene-containing preparation inhibited ovulation in all 20 females. In one cycle in which follicle development was observed only 43 pg estradiol/ml was secreted. Data from this investigation suggest that this triphasic gestodene-containing OC has a high contraceptive efficacy.

[New approaches to interception--postcoital use of a gestagen/estrogen combination]. / Neue Wege zur Interzeption--postkoitale Anwendung einer Gestagen-/Ostrogen-Kombination.

Postcoital application of high doses of ethenyloestradiol (EE) over a period of 5-6 days can, in the majority of cases, prevent pregnancy if therapy is initiated early enough (failure rate 1%), but such doses are attended by a high rate of side effects. Yuzpe et al. have tested an alternative formulation for interception: in a series of studies conducted in Canada and USA they administered a total dose of only 0.2 mg EE in combination with 2.0 mg DL-norgestrel (potency equivalent to a dose of 1.0 mg D-norgestrel) which was given in 2 portions separated by a 12-hour interval. The results of these studies and, in particular, those of a double-blind study (high doses of EE versus EE/norgestrel combination) in the Netherlands appear to indicate that the interceptive efficacy of the oestrogen-gestagen combination is equivalent to that of the high-dose oestrogen formulation. Distinct advantages are: the much lower active substance content, the shorter period of therapy (12 hours as opposed to 5 days), which is important as regards patient compliance, the limited duration of concomitant gastro-intestinal effects which can no longer be responsible for premature termination of therapy, the absence of breast tension and menstrual disorders. However, even application of the new method, which is facilitated by the commercial preparation Tetragynon, is intended for emergencies only.

[Progress in oral contraception. Advantages of a levonorgestrel-containing 3-stage preparation over low-dose levonorgestrel and desogestrel containing monophasic combination preparations]. / Fortschritte in der oralen Kontrazeption. Vorteile eines Levonorgestrel-haltigen Dreistufenpräparates gegenüber niedrigdosierten Levonorgestrel- und Desogestrel-haltigen monophasischen Kombinationspräparaten.

The three-phase preparation, which contains levonorgestrel, has a number of advantages compared to the traditional monophase combination preparations. With the same contraceptive reliability its cycle stability is very much better than the monophase preparations, which are 40% high dosed in the progestin proportion (levonorgestrel and desogestrel). The dose relations of the new preparation agree with the most recent scientific knowledge on the metabolism aspects of hormonal contraceptives. The hormone dosage in the various phases of the menstrual cycle is largely adapted to the plasma level course of beta-oestradiol and progesterone in the corresponding phases of the normal cycle.

[The first three-stage preparation for hormonal contraception. Clinical results (author's transl)]. / Erstes Dreistufenpräparat zur hormonalen Konzeptionsverhütung. Klinische Ergebnisse.

The controlled clinical trial is reported of a new three-stage oral contraceptive which has meanwhile been introduced on to the market under the trade name Triquilar. Triquilar has a reliable contraceptive action: no pregnancy occurred in 8068 treatment cycles. In spite of the very low doses of estrogen and gestagen--Triquilar contains the lowest total quantity of steroids of all available preparations--the multistage structure guarantees an outstanding cycle control and a particularly good general tolerance. The reasons are discussed which today support the use of an oral contraceptive with the lowest possible amounts of the two hormone components.

PIP: A study comparing 2 triphasic hormonal contraceptive preparations (combinations of ethinyl estradiol and levonorgestrel) is reported. SH B 264 AB was used by 594 women for 6628 cycles with no pregnancies, while 634 women used SH B 261 AB for 6025 cycles with 1 pregnancy. A lower incidence of breakthrough bleeding and spotting was observed among SH B 264 AB users, and this preparation ("Triquilon") is preferred to the other. Triquilon users had a menstrual cycle length of 26-30 days and an amenorrhea rate of .4%. There was a low rate of breakthrough bleedings and spottings, which was higher when patients forgot to take their pills. In the vast majority of Triquilar users, body weight and blood pressure remained constant. Subjective side effects (e.g. nausea, dizziness, headache) were infrequent and decreased as the length of Triquilar use increased. A separate study of 1440 cycles of Triquilar use and 1343 cycles of Microgynon use showed that, while the contraceptive effectiveness was the same, the incidence of breakthrough bleeding and spotting was significantly less frequent among Triquilar users.

[Oestrogens during the menopause and the risk of endometrial carcinoma (author's transl)]. / Ostrogene im Klimakterium und Endometriumkarzinomrisiko.

PIP: A review of the literature concerning the relationship between menopausal estrogen treatment and endometrial carcinoma is presented. Results from animal studies indicate that estrogens may work in conjunction with carcinogenic substances to stimulate proliferation of cancerous growths. Since estrone is produced by fatty tissue, obesity and certain correlated diseases, such as hypertension or diabetes, may be predisposing factors to developing endometrial cancer. Other risk factors are a hereditary predisposition and age. Several American epidemiologica studies showed an increased risk of developing endometrial cancer among women who undergo hormone treatments during menopause. It must be remembered, however, that such studies cannot establish causal relationships. Also, in the American studies, several biases complicate evaluation of the data, e.g. a disregard for social factors, the uncertainty of the state of the endometrium before the beginning of the study, and the inclusion of the problematic "stage 0" into the study. Furthermore, in America there is a tendency to proscribe estrogens alone in high dosages for menopausal treatment over long periods of time. It is concluded that individually determined low-dosage cyclical estrogen therapy during menopause does not increase the risk of endometrial cancer.^ieng

The development and evaluation of an ovulation inhibitor (DIAne) containing an antiandrogen.

The combination of 2 mg cyproterone acetate, a pronounced antiandrogenic substance, in combination with 0.05 mg ethinyl estradiol has undergone intensive multiphasic clinical evaluation. The preparation with the trade name Diane has proven to be not only a reliable contraceptive, but also a very potent drug for the treatment of both acne and seborrhea, and of milder cases of hirsutism. The effect of Diane on markedly increased hair growth was not so pronounced. In addition to the presentation of the most pertinent steps of the clinical investigation of Diane, the possible mode of actions of antiandrogens alone and in combination with an estrogen is discussed.

[Contraceptive efficiency of triphasic inhibitors (author's transl)]. / Zur kontrazeptiven Wirksamkeit von Dreistufenpräparaten.

The effects of two newly developed triphasic preparations with a sequence of 6/5/10 and a reduced content of the total dose of oestrogen per cycle on the parameters of cycle function were studied in 10 young women with normal phasic cycles using a randomized trial design. Cervical function, spinnbarkeit and crystallisation of cervical secretion and the karyopyknotic index were monitored and LH,E2 and progesterone levels in serum radioimmunologically determined in a pretreatment control cycle, the immediately following 1st treatment cycle, the 3rd treatment cycle and a subsequent treatment-free cycle. Both preparations brought about suppression of ovulation already in the 1st treatment cycle with the periphery (cervical barrier) greatly reduced but still reactive. The results of the study show that by adapting the ratio of active substances to the phases of the normal cycle, not only good cycle control and tolerance are achieved but also inhibition of ovulation.

[Therapy of androgenization symptoms: double blind study of an antiandrogen preparation (SH B 209 AB) against neogynon (author's transl)]. / Zur Beeinflussung von Androgenisierungserscheinungen. Doppelblindstudie eines cyproteronacetathaltigen Präparats (SH B 209 AB) gegen Neogynom.

The antiandrogen-containing preparation SH B 209 AB was tested in comparison with an ovulation inhibitor with no antiandrogenic effect (Neogynon) in a randomized, double blind study conducted to determine the effects of both on androgenization symptoms. 88 patients took part in the study. In the majority of cases the duration of the treatment period was more than 6 months. It was shown that the therapy with the combination preparation containing cyproterone acetate was distinctly more successful in cases of acne and seborrhoea: not only acne in its various locations but also all forms of seborrhoea were more favourably influenced by the trial preparation. This difference was statistically significant (p less than 0.05). It was not possible to establish a significant difference between the two preparations in the case of hirsutism in its various locations from the limited number of cases observed. There were also no differences detected in hepatic tolerance. During treatment with both preparations all values measured were within the normal range.

[Comparative studies on oral glucose tolerance and serum lipids under the influence of a new oral contraceptive (SH B 209 AB: 2 mg cyproterone acetate + 0.05 mg ethinyl estradiol), the combination D-norgestrel/ethinyl estradiol and in a control group (author's transl)]. / Vergleichende Untersuchungen der oralen Glukosetoleranz und der Serumlipide unter Anwendung eines neuen oralen Kontrazeptivums (SH B 209 AB: 2 mg Cyproteronacetat + 0,05 mg Athinylöstradiol), der Kombination D-Norgestrol/Athinylöstradiol und bei einer Kontrollgruppe

24 healthy women given the combination of cyproterone acetate (2 mg) + ethynyl estradiol (0.05 mg) [SH B 209 AB] and D-norgestrel (0.25 mg) + ethinyl estradiol (0.05 mg) [Neogynon] were compared with a control group in oral glucose tolerance tests. The volunteers were divided into three groups. Two received alternately both preparations with each treatment cycle preceded by one cycle without medication. The third group served as an independent control. On the 25th day of each cycle blood was withdrawn before and 15, 30, 45, 60, 90 and 120 min after the carbohydrate load. Blood glucose and insulin and free fatty acids in serum were determined. Fasting values of triglycerides and cholesterol in serum were determined. The following results were obtained: 1. The mean fasting levels of blood glucose, serum insulin and free fatty acids were unchanged. 2. The total area under the blood glucose curve over the initial value was not altered 2 h after treatment with SH B 209 AB or Neogynon. The total area under the insulin and free fatty acids curves were also unchanged after the oral glucose load. 3. There was no change in serum cholesterol. 4. Serum triglycerides were significantly increased after SH B 209 AB. 5. The implications of the structural differences between both gestagens are discussed.