In women, the most common adverse effects of<unk>  are acne, changes in menstrual flow, drowsiness, and can cause birth defects if taken by pregnant women. Other common side effects include breast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain. Lowered libido has been reported as a side effect of<unk>  in women. DMPA can affect menstrual bleeding. After a year of use, 55% of women experience amenorrhea (missed periods); after two years, the rate rises to 68%. In the first months of use "irregular or unpredictable bleeding or spotting, or, rarely, heavy or continuous bleeding" was reported.<unk>  does not appear to be associated with vitamin B12 deficiency. Data on weight gain with DMPA likewise are inconsistent. At high doses for the treatment of breast cancer,<unk>  can cause weight gain and can worsen diabetes mellitus and edema (particularly of the face). Adverse effects peak at five weeks, and are reduced with lower doses. Less frequent effects may include thrombosis (though it is not clear if this is truly a risk, it cannot be ruled out), painful urination, headache, nausea, and vomiting. When used as a form of androgen deprivation therapy in men, more frequent complaints include reduced libido, impotence, reduced ejaculate volume, and within three days, chemical castration. At extremely high doses (used to treat cancer, not for contraception)<unk>  may cause adrenal suppression and may interfere with carbohydrate metabolism, but does not cause diabetes. When used as a form of injected birth control, there is a delayed return of fertility. The average return to fertility is 9 to 10 months after the last injection, taking longer for overweight or obese women. By 18 months after the last injection, fertility is the same as that in former users of other contraceptive methods. Fetuses exposed to progestogens have demonstrated higher rates of genital abnormalities, low birth weight, and increased ectopic pregnancy particularly when<unk>  is used as an injected form of long-term birth control. A study of accidental pregnancies among poor women in Thailand found that infants who had been exposed to DMPA during pregnancy had a higher risk of low birth weight and an 80% greater-than-usual chance of dying in the first year of life. Mood changes There have been concerns about a possible risk of depression and mood changes with progestins like<unk> , and this has led to reluctance of some clinicians and women to use them. However, contrary to widely-held beliefs, most research suggests that progestins do not cause adverse psychological effects such as depression or anxiety. A 2018 systematic review of the relationship between progestin-based contraception and depression included three large studies of DMPA and reported no association between DMPA and depression. According to a 2003 review of DMPA, the majority of published clinical studies indicate that DMPA is not associated with depression, and the overall data support the notion that the medication does not significantly affect mood. In the largest study to have assessed the relationship between<unk>  and depression to date, in which over 3,900 women were treated with DMPA for up to 7 years, the incidence of depression was infrequent at 1.5% and the discontinuation rate due to depression was 0.5%. This study did not include baseline data on depression, and due to the incidence of depression in the study, the FDA required package labeling for DMPA stating that women with depression should be observed carefully and that DMPA should be discontinued if depression recurs. A subsequent study of 495 women treated with DMPA over the course of 1 year found that the mean depression score slightly decreased in the whole group of continuing users from 7.4 to 6.7 (by 9.5%) and decreased in the quintile of that group with the highest depression scores at baseline from 15.4 to 9.5 (by 38%). Based on the results of this study and others, a consensus began emerging that DMPA does not in fact increase the risk of depression nor worsen the severity of pre-existing depression. Similarly to the case of DMPA for hormonal contraception, the Heart and Estrogen/Progestin Replacement Study (HERS), a study of 2,763 postmenopausal women treated with 0.625 mg/day oral CEEs plus 2.5 mg/day oral<unk>  or placebo for 36 months as a method of menopausal hormone therapy, found no change in depressive symptoms. However, some small studies have reported that progestins like<unk>  might counteract beneficial effects of estrogens against depression. Long-term effects The Women's Health Initiative investigated the use of a combination of oral CEEs and<unk>  compared to placebo. The study was prematurely terminated when previously unexpected risks were discovered, specifically the finding that though the all-cause mortality was not affected by the hormone therapy, the benefits of menopausal hormone therapy (reduced risk of hip fracture, colorectal and endometrial cancer and all other causes of death) were offset by increased risk of coronary heart disease, breast cancer, strokes and pulmonary embolism. When combined with CEEs,<unk>  has been associated with an increased risk of breast cancer, dementia, and thrombus in the eye. In combination with estrogens in general,<unk>  may increase the risk of cardiovascular disease, with a stronger association when used by postmenopausal women also taking CEEs. It was because of these unexpected interactions that the Women's Health Initiative study was ended early due to the extra risks of menopausal hormone therapy, resulting in a dramatic decrease in both new and renewal prescriptions for hormone therapy. Long-term studies of users of DMPA have found slight or no increased overall risk of breast cancer. However, the study population did show a slightly increased risk of breast cancer in recent users (DMPA use in the last four years) under age 35, similar to that seen with the use of combined oral contraceptive pills. Blood clots DMPA has been associated in multiple studies with a higher risk of venous thromboembolism (VTE) when used as a form of progestogen-only birth control in premenopausal women. The increase in incidence of VTE ranges from 2.2-fold to 3.6-fold. Elevated risk of VTE with DMPA is unexpected, as DMPA has little or no effect on coagulation and fibrinolytic factors, and progestogens by themselves normally do not increase the risk of thrombosis. It has been argued that the higher incidence with DMPA has reflected preferential prescription of DMPA to women considered to be at an increased risk of VTE. Alternatively, it is possible that<unk>  may be an exception among progestins in terms of VTE risk. A 2018 meta-analysis reported that<unk>  was associated with a 2.8-fold higher risk of VTE than other progestins. It is possible that the glucocorticoid activity of<unk>  may increase the risk of VTE. Bone density DMPA may cause reduced bone density in premenopausal women and in men when used without an estrogen, particularly at high doses, though this appears to be reversible to a normal level even after years of use. On 17 November 2004, the United States Food and Drug Administration put a black box warning on the label, indicating that there were potential adverse effects of loss of bone mineral density. While it causes temporary bone loss, most women fully regain their bone density after discontinuing use. The World Health Organization (WHO) recommends that the use not be restricted. The American College of Obstetricians and Gynecologists notes that the potential adverse effects on BMD be balanced against the known negative effects of unintended pregnancy using other birth control methods or no method, particularly among adolescents. Three studies have suggested that bone loss is reversible after the discontinuation of DMPA. Other studies have suggested that the effect of DMPA use on postmenopausal bone density is minimal, perhaps because DMPA users experience less bone loss at menopause. Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density. The FDA recommends that DMPA not be used for longer than two years, unless there is no viable alternative method of contraception, due to concerns over bone loss. However, a 2008 Committee Opinion from the American Congress of Obstetricians and Gynecologists (ACOG) advises healthcare providers that concerns about bone mineral density loss should neither prevent the prescription of or continuation of DMPA beyond two years of use. HIV risk There is uncertainty regarding the risk of HIV acquisition among DMPA users; some observational studies suggest an increased risk of HIV acquisition among women using DMPA, while others do not. The World Health Organization issued statements in February 2012 and July 2014 saying the data did not warrant changing their recommendation of no restriction – Medical Eligibility for Contraception (MEC) category 1 – on the use of DMPA in women at high risk for HIV. Two meta-analyses of observational studies in sub-Saharan Africa were published in January 2015. They found a 1.4- to 1.5-fold increase risk of HIV acquisition for DMPA users relative to no hormonal contraceptive use. In January 2015, the Faculty of Sexual & Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists
Medroxyprogesterone acetate
Hydroxyprogesterone acetate
Desoxymethyltestosterone
Retroprogesterone
Gestodene
Lipoidal estradiol
Hydroxyprogesterone caproate
Cloxestradiol acetate