However , subgroup analyses for the estrogen dose and the progestin type in relation to changes in SHBG levels did show significant differences : COCs containing second generation progestins and /or the lower estrogen doses ( 20–25 µg EE ) were found to have less impact on SHBG concentrations .
The current literature review and meta- analysis demonstrates that COCs decrease circulating levels of total T and free T and increase SBHG concentrations .
Due to the SHBG increase , free T levels decrease twice as much as total T. The estrogen dose and progestin type of the COC do not influence the decline of total and free T , but both affect SHBG .
BACKGROUND Combined oral contraceptives ( COCs ) reduce levels of and rogen , especially testosterone ( T ) , by inhibiting ovarian and adrenal and rogen synthesis and by increasing levels of sex hormone-binding globulin ( SHBG ) .
Although this suppressive effect has been investigated by numerous studies over many years , to our knowledge no systematic review concerning this issue had been performed .
Reproductive hormones and skeletal health in young women.
In young women , low estrogen levels complicate a wide variety of diseases , including premature ovarian failure , anorexia nervosa , athletic amenorrhea , prolactinoma , hypopituitarism , and chronic kidney disease . Hypoestrogenemia may also result from therapy with GnRH agonists , glucocorticosteroids , chemotherapy , and especially aromatase inhibitors . All of these situations are associated with bone loss , because estrogen chronically suppresses bone resorption . Several mechanisms are involved : 1 ) estrogen increases osteoclast apoptosis ; 2 ) by suppressing interleukins and proinflammatory cytokine expression in bone marrow cells , estrogen decreases the number of osteoclasts ; 3 ) by inhibiting the production of receptor activator of nuclear factor-κB lig and , estrogen reduces the number and activity of osteoclasts ; and 4 ) by increasing stromal cell/osteoblast cell expression of TGFβ , estrogen inhibits osteoclast activity . Estrogen also has some positive effects on bone formation by acting as a mitogen to cells early in the osteoblast line , reducing apoptosis of osteoblasts , and increasing expression of TGFβ , bone morphogenetic proteins , and IGF-I ( 1 ) . In these pathological conditions , the cause of the bone loss is frequently multifactorial . For example , women with anorexia nervosa also have low IGF levels . Nonspecific factors such as poor diet , reduced exercise , or chronic inflammation may further increase bone resorption . Low estrogen levels are also seen in healthy young women who are using depo-medroxyprogesterone acetate ( DMPA ) for contraception .  Bone loss is a side effect of this medication ( 2 ) . The bone mineral density ( BMD ) decreases at a more rapid rate during the first years of therapy and then continues to decrease at a slower rate ( 3 ) . After 5 yr , the loss is about 6 % ( 0.5 sd ) . The  DMPA effects are worse in teenagers ; combined results from four prospect i ve studies found an average loss of spine BMD of 3.1 % over 2 yr in  DMPA  users compared with a gain of 7.2 % in untreated controls ( 4 ) . A cross-sectional study in this issue by Walsh and colleagues ( 5 ) focused on the age of starting DMPA .  One group aged 18–25 started DMPA before age 20 , and another group aged 35–45 started after age 34 . Each group had matched controls . Importantly , the average use was 37 months in both groups . This avoids the confounding between age and duration of use , which is encountered in other studies . The BMD was significantly lower than controls when DMPA was started in teenagers but not when it was started after age 34 . Estrogen levels were lower in the DMPA users than the non-hormone users and were also lower in the younger women than in the older women . The authors concluded that estrogen levels mediated the effect of DMPA on bone markers because adding DMPA to a regression model reduced the correlation between markers and estrogen . These correlations were not very strong ( r = −0.17 between N-telopeptide and estradiol-treated ) , so this is a tenuous conclusion , but it is bolstered by the findings from two other studies that adding estrogen to DMPA abolishes the negative effect on the skeleton ( 6,7 ) . The age range of the older group of women is underrepresented in most of the previous studies of skeletal effects of DMPA . These results lead to several questions about basic bone biology . How are adolescent bones different from mature bones ? How does DMPA use compare to the natural state of low estrogen seen in healthy lactating women ? Is bone completely restored in these situations ? There are also important clinical questions about potential risk of fractures and the skeletal risks from other forms of contraception
However , subgroup analyses for the estrogen dose and the progestin type in relation to changes in SHBG levels did show significant differences : COCs containing second generation progestins and /or the lower estrogen doses ( 20–25 µg EE ) were found to have less impact on SHBG concentrations .
The current literature review and meta- analysis demonstrates that COCs decrease circulating levels of total T and free T and increase SBHG concentrations .
Due to the SHBG increase , free T levels decrease twice as much as total T. The estrogen dose and progestin type of the COC do not influence the decline of total and free T , but both affect SHBG .
BACKGROUND Combined oral contraceptives ( COCs ) reduce levels of and rogen , especially testosterone ( T ) , by inhibiting ovarian and adrenal and rogen synthesis and by increasing levels of sex hormone-binding globulin ( SHBG ) .
Although this suppressive effect has been investigated by numerous studies over many years , to our knowledge no systematic review concerning this issue had been performed .