Progestogen-only Preparations Research Articles

The Thromboembolism Risk with Combined Hormonal Contraceptives: Current Status and Prescribing Practice

The Thromboembolism Risk with Combined Hormonal Contraceptives: Current Status and Prescribing Practice Abstract. The use of combined hormonal contraceptives (CHC) increases not only the risk for venous thromboembolism, but also for arterial thromboembolism. The risk for thromboembolism is the same for non-oral CHC (patches, vaginal rings) as for oral CHC. Risk factors such as age >35, obesity, smoking and a positive family history need to be recognized and considered in contraceptive counselling. Elaborate information concerning risks and benefits is mandatory. This applies to first-time as well as long-term users. Careful investigation of the history is required, and the risk factors need to be re-evaluated at yearly prescription. It is also very important to inform the patients about the early symptoms of thrombosis or pulmonary embolism, so that therapy can be started immediately. Apart from these risks, CHC may have beneficial effects on organs such as the ovaries, the endometrium and the general well-being for many women. When prescribing a CHC for the first time or when changing to another preparation, one should always weigh up whether certain benefits justify prescribing a preparation with a slightly higher risk of thrombosis compared to the second-generation pill or preparations with Estradiol/Nomegestrolacetat. Women who are already using a third-generation pill or a pill with drospirenone or cyproterone acetate and feel comfortable with it do not need to switch to another preparation (provided no new risk factors have arisen). For women with increased risks, i.e. several relative contraindications or one absolute contraindication, safe alternatives to CHC include progestogen-only preparations, intrauterine devices containing copper or levonorgestrel or, after family planning has been completed, surgical methods (sterilisation/vasectomy).

Association between contraceptive use and risk of lower urinary tract infection (LUTI): A case-control study.

The aim of this study was to analyze the association between widely used contraceptive methods and the manifestation of lower urinary tract infections (LUTI) in patients treated in gynecological practices in Germany. This study was based on IQVIA Disease Analyzer database and includes a total of 133,638 females aged between 16 and 50 years who received an initial diagnosis of LUTI including cystitis (ICD-10: N39.0, N30.0) between January 2011 and December 2020 (index date). 1 : 1 matching of LUTI cases to non-LUTI controls was used to investigate the association between predefined criteria and LUTI. A greedy nearest neighbor propensity score method was used to balance cases and controls with respect to age, pregnancy, visit frequency during the observation period, and comorbidities including cancer, diabetes mellitus, and urolithiasis. Univariate logistic regression models were used to assess the association between contraceptive prescriptions and LUTI. The general use of any contraceptive method was negatively associated with subsequent LUTI. Injectable contraceptives and pills were negatively associated with LUTI manifestation. There was a significant negative association between monophasic preparations containing <50µg estrogen, triphasic preparations, and progestogen-only preparations and LUTI. By contrast, we found a significant positive association between emergency contraceptives and LUTI. The general application of birth control methods as well as the use of injectable contraceptives and oral contraceptives were negatively associated with LUTI manifestation. In contrast to other birth control methods, the intake of emergency contraception was positively associated with a manifestation of LUTI.

Ovulation Inhibition With A New Vaginal Ring Containing Trimegestone

(Abstracted from Contraception 2020;102:237–242) Women receiving combined hormonal contraceptives (CHCs) are at increased risk of stroke, myocardial infarction, or venous thromboembolism, whereas those receiving progestogen-only preparations for contraception have little or no increased risk of these complications. However, the progestogen-only pills (POPs) currently marketed in the United States all have drawbacks.

Endogenous thrombin potential is higher during the luteal phase than during the follicular phase of a normal menstrual cycle

Do thrombin generation and haemostatic parameters differ during the two phases of the menstrual cycle? Total thrombin concentration is higher during the luteal phase compared with the follicular phase of the menstrual cycle. The coagulation cascade is affected by many variables, such as fluctuations in the levels of sex hormones. The studies on the variations in haemostatic parameters during the menstrual cycle have produced diverse results. Thrombin generation and selected haemostatic parameters (fibrinogen, factor II, factor VII, factor VIII, factor X, von Willebrand factor, antithrombin and D-dimer) were measured during the two phases of a normal menstrual cycle in 102 healthy women not taking any form of hormone medication. The study cohort consisted of 102 healthy women with regular menstrual cycles. Thrombin generation was measured by the calibrated automated thrombogram method. Progesterone and sex hormone-binding globulin were measured by chemiluminescence enzyme immunoassays. Estradiol was measured by a sensitive radioimmunoassay. Fibrinogen was measured by a clotting method, antithrombin was measured by a chromogenic method and factor II, factor VII, factor VIII, factor X, von Willebrand factor and D-dimer were measured by photometric methods. It was shown that the total amount of generated thrombin (Endogenous Thrombin Potential) was significantly higher during the luteal compared with the follicular phase (P = 0.027). Factor X was significantly higher during the follicular phase (P = 0.028). Progesterone exhibited significant associations (measured by the least squares regression analysis) with fibrinogen and factor X during the follicular phase (P = 0.043 and P = 0.033, respectively) and with factors II and VII during the luteal phase (P = 0.034 and P = 0.024, respectively). The validity of the results from the regression analysis was further confirmed by performing correlation analyses (Pearson correlation matrix) for haemostatic markers for the luteal and follicular phases (accepted correlation level >0.8). The wide confidence interval for the differences in endogenous thrombin potential during the two phases could imply that the size of the cohort may not be sufficient to fully evaluate the biological variations. Additionally, the haemostatic markers were not shown to have significant associations with thrombin generation, suggesting that the increased thrombin concentration during the luteal phase would be mediated by another mechanism, as yet unidentified. The associations between progesterone and the haemostatic markers, as shown for both phases of the menstrual cycle, suggest a previously unknown or undefined yet potentially significant role for progesterone in the coagulation system. However, it has been shown that the use of progestogen-only preparations does not affect the coagulation system, which is partly the reason why they are considered safe for women with thrombophilia or previous thrombotic event. Further studies are required in order to demonstrate whether our results can be extrapolated for synthetic progestins, which might have significant implication on the indications for their use.

Hormonal contraception and risk of endometrial cancer: a systematic review

More than 15 case-control studies and at least four large cohort studies demonstrated a decrease in the risk of endometrial cancer of about 50% for ever use of combined oral contraceptives (COCs). In most of these studies, this protective effect persisted for more than 10-15-20 years after cessation of the COC. An increasing protective effect with longer duration of COC use has been found in most studies. The beneficial effect was independent of the composition of COC, i.e. dosage and type of progestogen, combined with ethinyl estradiol 30-50 μg/day. COCs with higher progestogen potency seem to be somewhat more effective. Nonhormonal uterine devices have also been found to be strongly protective; however, data on oral or injectable progestogen-only preparations (POPs) including the levonorgestrel-releasing intrauterine system (LNG-IUS) are still rare, but also suggest similar protective action. COCs, POPs, as well as LNG-IUS can effectively reduce endometrial hyperplasia but should only be used in exceptional cases in patients with or after endometrial cancer. In contrast to nonhormonal IUS, systemic side effects cannot be excluded with LNG-IUS, but they are certainly rare, as the main effect has decreased the endometrial estrogen response because of the high endometrial tissue levels of LNG.

New once-a-month injectable contraceptives, with particular reference to Cyclofem®/Cyclo-Provera TM

Once-a-month injectable contraceptives containing a progestogen and an estrogen have been developed that disrupt vaginal bleeding patterns less than the widely used progestogen-only preparations. Pharmacokinetic studies were undertaken of dosages and ratios of the progestogens and the respective estrogens. In Phase III clinical trials, annual pregnancy rates were below 0.4% for Mesigyna® (norethisterone enanthate/estradiol valerate, Schering AG, Berlin, Germany) and below 0.2% for Cyclofem® (MPA/E2C) (medroxyprogesterone acetate/estradiol cypionate, Aplicaciones Farmaceuticas, SA, Mexico and PT Tunggal, Indonesia). More than two-thirds of women had predictable, regular cycles, and discontinuation due to bleeding-related problems occurred less than half as often as with progestogen-only injectables. With MPA/E2C, return to fertility is similar to that observed with other hormonal or intrauterine methods, and both products have little effect on lipids or hemostasis. Introductory trials of MPA/E2C in 12 000 women with 100 000 woman-months of experience confirmed the high efficacy of the product in routine use. The use of Cyclofem in a non-reusable injection device, Uniject® (Becton Dickinson, Franklin Lakes, NJ) is discussed. Once-a-month hormonal contraceptives have been shown to provide a safe contraceptive option for all women and an alternative for women who wish to use injectable formulations that cause less disruption in vaginal bleeding and minimal side effects.

Effects of progestogens on haemostasis.

Epidemiological data suggested an involvement of the progestogen component in the pathomechanism of venous and arterial diseases during intake of oral contraceptives. The influence of progestogens on haemostasis parameters depend on type and dose of the progestogen, the presence of an estrogen, the route of application, and the duration of use. Treatment of women with progestogen-only preparations caused only minor effects on coagulation and fibrinolysis. Similarly, during hormone replacement therapy with natural estrogens, the additional application of progestogens induced no unfavourable changes on haemostasis. In contrast, the use of ovulation inhibitors resulted in an acceleration of coagulation and fibrinolysis. This is primarily induced by the marked action of ethinylestradiol on hepatic and vascular function. Progestogens with androgenic properties may counteract the estrogen-induced changes in the hepatic synthesis of platelet aggregation and readiness for coagulation. Estrogen and progesterone receptors are localized in endothelial and smooth muscle cells of the vessel wall, but there are differences in the response of veins and arteries to sex steroids. Estrogens and progestogens may influence collagen and elastin synthesis, and the release of vasoactive compounds and of factors controlling fibrinolysis from endothelium. In veins, progestogens may increase distensibility and capacitance resulting in a decreased blood flow. In predisposed women, this may lead to venous stasis and thrombosis. In arteries, progestogens may act as vasoconstrictors, and may enhance vasospasms at sites of injured endothelium which finally may lead to ischemic diseases.

Prescribing Oral Contraceptives

The combined oral contraceptive pill is the most popular method of contraception worldwide, with modern low-dose formulations significantly improving tolerability. Breakthrough bleeding is the most significant adverse event associated with the low-dose combined oral contraceptives. Monophasic, biphasic, triphasic and progestogen-only preparations are available, and the choice of formulation should be tailored to best suit the patient. Any areas of uncertainty or concern that the patient has should be addressed, and the patient should be clearly informed of how to use the oral contraceptive effectively, the likely initial adverse effects and what to do if a pill is missed.

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-Koln 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.

The Effects of Hormonal Contraceptives on Lactation: Current Findings, Methodological Considerations, and Future Prorities

Findings and shortcomings of several articles which review clinical studies of lactation are discussed, and the main recommendations for family planning programs that have emerged from them are summarized. The basic recommendation has been that hormonal preparations containing estrogen should be avoided during either the early or the entire period of lactation. The largest number of studies have considered milk yield and establishment and maintenance of lactation; aspects of these studies discussed in this article include cultural and social factors; sample characteristics and size; use of control groups, placebos, and double blind design; the hormone preparations used; timing of hormone administration; duration of treatment and observation; indicator of milk yield; basis for comparison and analytical measures; and other influences. Despite the number and diversity of variables involved and the pitfalls in studying them, the balance of evidence appears to support the conclusion that preparations containing estrogen are more often implicated in suppression of lactation than are progestogen-only preparations. Most reviews which consider milk quality conclude that evidence is conflicting but that any adverse affects are trivial, although the need for further research is noted, particularly concerning the effects of possible changes in milk composition on the infant. Very little research has been reported on the transfer of steroids to the infant via breastmilk. Future research should include thorough evaluation of existing studies; further research into physiological aspects of lactation and hormonal contraception; review of existing data on lactation problems from family planning programs; and clinical studies that correct or avoid the methodological shortcomings of earlier research.

The clinical use of monthly injectable contraceptive preparations.

The clinical use of monthly injectable contraceptive preparations is reviewed. The preparations include estrogen-progestogen combinations progestogen only and estrogen only. Clinical trials of monthly injectables were done with: 1) Deladroxate - 150 mg dihydroxyprogesterone (Algestone) acetophenide (DHPA) + 10 mg estradiol enanthate (EE) in 1 ml oil: 2) Cycle-Provera - depot medroxyprogesterone acetophenide + 10 mg estradiol-3- Benzoate 17beta butyrate; acetate (DMPA) + estradiol cypionate; 3) Unimens - 150 mg 16-17 dihydroxyprogesterone 4) Gravibinon - 250 mg 17alpha-OH progesterone (250 mg) caproate + 5 mg estradiol valerate; 5) 50-70 norethisterone enanthate (Net En) and 5-10 mg estradiol unducelate; 6) 25 mg norgestrel and 5 mg estradiol hexahydrobenzoate; 7) Czechoslovakian injectables; 8) progestogen-only preparations; and 9) estrogen only. The rate of continuation with the use of injectable contraceptives compares favorably with that of IUDs and pills. Most studies show a carryover cumulative effect to subsequent cycles. There is a tendency toward a significant dropout rate following 12 months of use and a delay in return to fertility. The main advantage of monthly injectables is a better cycle control that with the ones used for longer periods.

Low-oestrogen oral contraceptives.

I was surprised to read in your leading article on this subject (November 20, p. 1216) the statement that''pharmaceutical companies seem to be preferring 17alpha-hydroxyprogesterone derivatives in oral contraceptives.'' The last surviving product on the British market containing 1 of this variety of progestogen (megestorl acetate) disappeared when Volidan was withdrawn in 1975. The 22 combined pills (containing 50 mcg of estrogen or less) and the 4 progestogen-only preparations currently available in this country all rely on 19-nortestosterone derivatives. Of these, norgestrel has no inherent estrogenicity and yet when as little as .15 mg is combined with only 30 mcg of ethinyl estradiol it provides the degree of reliability quoted in your article. Editors's note: Our leading article was, perhaps, misleading on this point. Certainly all the combined oral contraceptives currently available in Britain use 19-nortestosterone derivatives for their progestogen component - and there are good commercial and clinical reasons for that choice. However, a switch to 17alpha-hydroxyprogesterone derivatives would make it easier to calculate the estrogen content of contraceptives without having to make allowance for a variable amount of metabolic conversion from nortestosterone. There is, we believe, a resurgence of interest in that alternative, though no new formulations are yet on trial.

Oral contraception and platelet aggregation.

93 British women using various oral contraceptives daily were compared with 89 normal and pregnant controls to determine the effect of contraceptives on platelet aggregation. The 93 test subjects were subdivided as follows: 1) 14 used conventional high-dose estrogen-progestogen combinations; 2) 14 used the conventional low-dose Norinyl-1 preparation; 3) 18 used Ortho-Novin a preparation containing twice the hormone dose of Norinyl-1 i.e. 2 mg of norethisterone and .1 mg of mestraniol; 4) 32 used .5 mg of chlormadinone acetate (pure progestogen); and 15 changed to pure progestogen from combined conventional preparations. A slightly modified Chandlers tube technique showed platelet aggregation to be significantly more accelerated in the pregnant controls than in normal controls or any test group. Platelet aggregation was significantly accelerated in the high- and low-dose groups although a comparison of the two low-dose groups failed to show a significant dose-dependent difference between them. The progestogen group without prior experience showed no significant change at 6 months; but there was a significant acceleration normalized after 1 month and remaining normal at 6 months in subjects who had previously used conventional preparations. A follow-up study showed that the progestogen-only preparations caused a significantly smaller acceleration than the combined preparations after 2 years of use and therefore may offer a lesser risk of thrombosis.