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Hormonal Contraceptives: Adverse Effects, P5


Anticonceptivos hormonales; Contraceptifs Hormonaux; Hormonale Kontrazeptiva

Effects on the musculoskeletal system.

BONE DENSITY. Combined oral contraceptives are generally considered not to have a detrimental effect on bone mineral density but study results have been inconsistent and any clinical significance unclear. However, overall, combined oral contraceptives appear not to affect bone mineral density or biochemical markers of bone turnover.

Reviews of studies in different age groups have found that bone mineral density in healthy premenopausal women does not appear to be significantly affected. However, there is limited evidence that adolescents and young women (less than 23 years of age) using oral combined contraceptives have a lower bone mineral density than non-users it is unclear whether contraceptives might prevent young women from reaching their peak bone mass and put them at increased risk of osteoporosis later in life. There is some evidence of a positive effect on bone mineral density in perimenopausal and postmenopausal women taking combined oral contraceptives, but past use in postmenopausal women appeared to have no effect. Although bone mineral density is used as an indicator of fracture risk, the true effects of combined oral contraceptives on this clinical outcome are unclear there is a particular lack of data in older women, in whom osteoporotic fractures are most common.

There is stronger evidence that bone mineral density is reduced in current users of the depot progestogen-only contraceptive, medroxyprogesterone acetate. Recovery occurs after stopping treatment, but it is still unclear whether adult women can regain baseline bone mineral density levels, and whether adolescents can reach peak bone mass. There is also a lack of data on the clinical outcome of fracture in both current and former users of all ages.

As adolescence is an age at which bone mineral density is normally increasing there is some concern about the possible long-term effects of medroxyprogesterone. The UK CSM has advised that in adolescents it should only be used if other methods of contraception are unsuitable or unacceptable, and that there should be a re-evaluation of risks and benefits for women of all ages who wish to continue use beyond 2 years. The FDA has also advised that, for all women, medroxyprogesterone should only be used as a long-term contraceptive, giving an example of more than 2 years, if other contraceptive methods are inadequate. In contrast, however, WHO advises that there should be no restriction, including duration of use, on the use of medroxyprogesterone in women aged 18 to 45 who are otherwise eligible to use it in adolescents and women over 45, the advantages generally outweigh the theoretical risks of fracture, but because of limited data on long-term use the overall risks and benefits should be reconsidered over time with the individual user. Others offer similar recommendations in support, pointing out that further research is needed.

There is some evidence that oestrogen supplementation may reduce or prevent the reduction in bone mineral density caused by medroxyprogesterone acetate. Although such supplementation could be considered in medroxyprogesterone users who have osteopenia or are at high risk, the optimal dose, route, and extent of benefit has not been established.

RHEUMATOID ARTHRITIS. There have been rare reports of arthritis or arthropathies attributed to oral contraceptives, and some large studies have investigated the incidence of rheumatoid arthritis in oral contraceptive users. A negative association between the use of oral contraceptives and the development of rheumatoid arthritis has been reported in some studies thus giving rise to the suggestion that oral contraceptive use may, in fact, have some sort of protective role. These findings were not, however, substantiated by a recent, large, long-term cohort study which found no association, either beneficial or detrimental, between the use of oral contraceptives and the later development of rheumatoid arthritis. An earlier meta-analysis also found no conclusive evidence of a protective effect of oral contraceptives on rheumatoid arthritis risk. There is limited information about the effect of oral contraceptives on pre-existing rheumatoid arthritis. One study found that there was no significant influence on the progression of the disease, but there was a trend towards less radiographic joint damage and disability with long-term oral contraceptive use.

Effects on the nervous system. Headache is reported as a common adverse effect and frequent reason for stopping combined oral contraceptives. However, a systematic review found that although study results could not be pooled, there was no strong evidence associating combined oral contraceptive use with headache. There may have been an increase in headache in the early cycles, but this tended to improve with continued use for most women there was no effect on headache activity and some actually reported improvement. Headache also appeared to be associated with oestrogen withdrawal during the tablet-free week of the cycle, but there was no evidence that headache was improved by changing to a preparation with a lower dose of oestrogen. However, some women appeared to be at higher risk, such as those with a strong personal or family history of troublesome headaches, particularly migraine. Combined oral contraceptives are not contra-indicated in women with non-migrainous headache, but they should be used with caution or avoided in women with migraine because of the increased risk of stroke (see Migraine, under Precautions, below).

Chorea has been reported in women using combined oral contraceptives. Reviews of the literature have reported the onset of chorea to range from 1 week to 11 months, with an average of 3 months, and resolution of symptoms after stopping the contraceptive to occur after 1 week to 5 months or an average of 5 weeks. The mechanism of this effect is unclear. Some cases occurred in patients with no history of neurological disease, but others had a history of rheumatic fever, often with Sydenham chorea, or chorea gravidarum, chorea secondary to other conditions, or congenital heart disease. There is some evidence that chorea could be mediated by the production of antiphospholipid antibodies, as either a primary antiphospholipid syndrome or secondary to SLE. It has been suggested that the production of these antibodies could be aggravated by the oestrogen component of combined oral contraceptives In another case report it was suggested that the presence of anti-basal ganglia antibodies might have played a role in the development of chorea by making the basal ganglia more susceptible to the effects of the oestrogen component of an oral contraceptive.

It is generally advised that combined oral contraceptives should be used with caution or avoided in women with antiphospholipid antibodies because they are at increased risk of venous throm-boembolism, see Cardiovascular Disease, under Precautions, below.

Effects on the pancreas. There have been reports of pancreatitis secondary to hyper lip idaemia associated with the use of combined oral contraceptives.

Effects on the skin. Oral contraceptives may cause chloasma, and those containing androgenic progestogens may cause or aggravate acne and hirsutism. More rarely, oral contraceptives have been implicated in photosensitivity reactions and photosensitivity associated with drug-induced lupus erythematosus. A survey of people using UVA sunbeds at commercial premises in the UK revealed that the prevalence of pruritus, nausea, and skin rashes as adverse reactions to sunbed use was higher in women taking oral contraceptives than in women receiving no medication. There has been a report of hidradenitis suppurativa, a condition resulting in the recurrence of boils at the axillary apocrine sweat glands, anogenital region, and breasts, occurring in 7 women using oral contraceptives. Sweet’s syndrome (acute febrile neutrophilic dermatosis) has been described very rarely with hormonal contraceptives. In one case, the reaction started 10 days after beginning a combined oral contraceptive and resolved after stopping the contraceptive and treating with oral and topical corticosteroids. The woman reported that a similar reaction had occurred 6 months earlier with a different combined oral contraceptive. Sweet’s syndrome has also occurred 1 month after insertion of a levonorgestrel IUD the condition was controlled with corticosteroids, but only resolved completely after removal of the IUD. For mention of the refuted association between oral contraceptives and malignant melanoma, see Skin under Carcinogenic ity above. Autoimmune progesterone dermatitis has been reported in women with a history of oral contraceptive use.

Effects on the uterus. The Oxford Family Planning Association study found that the risk of developing uterine leiomyomas (uterine fibroids) was reduced by the use of oral contraceptives by about 17% with each 5 years of oral contraceptive use. This was not thought to be due to selective prescribing. The authors hypothesised that unopposed oestrogen may be a risk factor for uterine fibroids, and that the reduced risk with oral contraceptives might be analogous to the reduction in endometrial carcinoma seen with these drugs (see above). Other studies’ have also reported a reduced risk of uterine leiomyomas in current users of oral contraceptives, while past users have a risk similar to that in women who have never used oral contraceptives. However, one study did suggest that in women who had first used oral contraceptives at an early age (13 to 16 years) there was a modestly elevated risk. Another case-control study involving 390 women with leiomyomas failed to find a protective (or detrimental) effect with oral contraceptive use. A further cohort study also found no association between oral contraceptive use and leiomyoma formation, but did report a reduced risk with current use of medroxyprogesterone acetate depot injection.

Pelvic inflammatory disease. It has been suggested that oral contraceptives protect against pelvic inflammatory disease. However, although oral contraceptives are thought to reduce the risk of developing acute pelvic inflammatory disease, higher rates of infection of the lower genital tract by Chlamydia trachomatis, and, more tentatively, Neisseria gonorrhoeae, have been reported. Other studies have suggested that oral contraceptive use is associated with reduced symptom severity, but absence of symptoms is not the same as absence of disease: oral contraceptives might reduce the inflammatory reaction to infection, resulting in unrecognised disease and subsequent complications such as tubal infertility and ectopic pregnancy. There is evidence that users of older oral contraceptives containing more than 50 micrograms of oestrogen may have been at increased risk of tubal infertility, particularly if first used before 20 years of age. No increased risk, or an active decrease in risk (depending on age at first use) was reported for formulations containing 50 micrograms or less of oestrogen, which are now favoured. The possible effects of depot medroxyprogesterone acetate have also been examined and one study suggested that it was associated with an increase in cervical chlamydial and gonococcal infections. However, confounding factors in this study such as sexual practices, a history of infection, and the background pool of infectivity in sexual partners, have been highlighted and cast doubt on a true causal relationship between medroxyprogesterone acetate and risk of infection.

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