Dr. Goodyear

The RRs were 0.95 (0.54, 1.67) under 55 years

1.35 (0.77, 2.38) at 55–59

1.29 (0.71, 2.35) at 60–64,

1.35 (0.44, 4.18) at 65–69, 1.62

3.43 (1.54, 7.66) at 75 years and older

The adjusted post/pre RR for PDE5I across all ages was 1.08

For TT prescription, in men under age 65 years, the RR was 2.90 (1.49, 5.62) for those with a history of heart disease and 0.90 (0.61, 1.34) for those without

In men aged 65 year and older, the RR was 2.16 (0.92, 5.10) for those with a history of heart disease and 2.21 (1.09, 4.45) for those without.

Among men aged 65 years and older, we observed a two-fold increase in the risk of MI in the 90 days after filling an initial TT prescription

Among younger men with a history of heart disease, we observed a two to three-fold increased risk of MI in the 90 days following an initial TT prescription and no excess risk in younger men without such a history

Among older men, the two-fold increased risk was associated with TT prescription regardless of cardiovascular disease history

our own findings appear consistent with a higher frequency of thrombotic events following TT prescription among men with more extensive coronary vascular disease.

Our findings are consistent with a recent meta-analysis of placebo-controlled randomized trials of testosterone therapy lasting 12 or more weeks among mainly older men, which reported that testosterone therapy increased the risk of adverse cardiovascular-related events (OR = 1.54, 95%CI:1.09, 2.18), as well as serious adverse cardiovascular-related events (OR = 1.61, 95%CI:1.01, 2.56) which included myocardial infarction along with other conditions

This association appeared unrelated to average baseline testosterone level (p = 0.70) but varied by source of funding (p = 0.03), with a stronger summary effect in a meta-analysis of studies not funded by the pharmaceutical industry (OR = 2.06, 95%CI:1.34, 3.17) compared with studies funded by the pharmaceutical industry

the evidence supports an association between testosterone therapy and risk of serious, adverse cardiovascular-related events–including non-fatal myocardial infarction–in men

there is some evidence that low endogenous testosterone levels may also be positively associated with cardiovascular events

effects of endogenous and exogenous testosterone may differ. Exogenous testosterone (TT) is associated with physiologic changes that predispose to clotting and thrombotic disorders including increased blood pressure [18], polycythemia [19], reductions in HDL cholesterol [18], [20], and hyperviscosity of the blood and platelet aggregation. [20]–[23]; TT also increases circulating estrogens [24], [25] which may play a role in the observed excess of adverse cardiovascular-related events, given that estrogen therapy has been associated with this excess in both men and women

did not include information on the serologic or diagnostic indications for treatment.

no association between PDE5I prescriptions and the risk of MI

Recently TT has been increasing extraordinarily rapidly, including among younger men and among those without hormone measurement

5αR2 has been found predominantly in androgen-dependent organs, such as epididymis and prostate

The 5α-pregnanes:4-pregnenes ratio was about 8-fold higher in tumorous than in nontumorous breast tissue after an 8-hour incubation with [14C]progesterone

Studies with breast cell lines, showing that 5α-pregnanes stimulate proliferation and decrease attachment of cells

both tissue and breast cell line studies suggest that an elevated level of progesterone 5α-reductase activity may be an indicator of breast tumorigenesis, regardless of presence or absence of ER and/or PR

5αR1 is the main isoform expressed in human breast carcinomas [29] and that 5αR2 may not be associated with risk of breast cancer

the differences in 5α-pregnane production between the cells is due primarily to a difference in 5αR1 expression

As in the case of 5α-reductase activity, the presence or absence of ER and PR do not appear to be related to 5α-reductase expression.

the conversion of progesterone to the cancer promoting 5α-pregnanes is significantly higher in the human tumorigenic breast cell lines

lthough both 5αR1 and 5αR2 are expressed by these cells, the elevated 5α-reductase activity appears to be the result of significantly greater expression of 5αR1

Changes in progesterone metabolizing enzyme expression (resulting in enzyme activity changes) may be responsible for promoting breast cancer progression due to increased production of tumor-promoting 5α-pregnanes and decreased production of anti-cancer 20α – and 3α-4-pregnenes

Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors

Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions

The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress

hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions.

a large proportion (about 30% to 60%) of breast tumors are ER and/or PR negative

about 90% of normal proliferating breast epithelial cells are receptor negative

Our previous in vitro studies had shown that breast tissues and cell lines readily convert progesterone to 5α-pregnanes, such as 5αP, and delta-4-pregnenes, such as 3αHP (Figure ​(Figure1),1), and that tumorous breast tissues [15] and tumorigenic breast cell lines [16] produce higher levels of 5αP and lower levels of 3αHP than do normal breast tissues and nontumorigenic cell lines

The progesterone metabolism studies suggested that increases in 5αP and decreases in 3αHP production accompany the shift toward breast cell neoplasia and tumorigenicity

In vitro studies on five different human breast cell lines showed that cell proliferation and detachment are significantly increased by 5αP and decreased by 3αHP

the prevailing theory of hormonal regulation of breast cancer, as well as hormone-based therapies, revolves around estrogen and/or progesterone and ER/PR-positive breast cells and tumors.

Not only do these "receptor-negative" breast cancers fail to benefit from current hormonal therapies, but they also generally exhibit more-aggressive biologic behaviors and poorer prognosis than the receptor-positive ones

The results of the studies reported here show for the first time that the progesterone metabolites, 5αP and 3αHP, act as hormones that regulate ER/PR-negative breast tumor formation, growth, and regression

The onset of the ER/PR-negative human breast cell tumors in mice was considerably accelerated, and the growth significantly stimulated, by just one or two applications of 5αP

In contrast, 3αHP retarded onset of tumor formation, suppressed tumor growth, and inhibited or regressed existing 5αP-induced tumors

When both hormones were administered simultaneously, the effects of one were abrogated by the effects of the other.

The 5αPR and 3αHPR (which are associated with the plasma membranes of both ER/PR-positive [19] and ER/PR-negative [29] cells) are distinct from each other and from known ER, PR, androgen, and corticosteroid receptors, and lack affinity for other steroids, such as progesterone, estrogen, androgens, corticosteroids, and other progesterone metabolites

Levels of 5αPR are upregulated by 5αP itself and estradiol, and downregulated by 3αHP in both ER/PR-positive and -negative cells

ndications are that 5αP acts via the surface receptor-linked mitogen-activated protein kinase (MAPK; Erk1/2) pathway; 5αP significantly stimulates activation of Erk1/2 [30], increases the Bcl-2/Bax expression ratio [18] and actin depolymerization [31], and decreases expression of actin and adhesion plaque-associated vinculin [31], resulting in decreased apoptosis and increased mitosis and cell detachment

3αHP appears to suppress protein kinase C (PKC), phospholipase C (PLC), Ca2+ mobilization (unpublished observations), and the Bcl-2/Bax expression ratio [18], and increases expression of the cell-cycle inhibitor p21 [18], resulting in increased apoptosis and decreased proliferation and detachment of breast cell lines.

serum from mice with tumors had significantly more 5αP than 3αHP

the tumors, which on average had about threefold higher concentrations of 5αP than the respective sera, and >10-fold higher 5αP than 3αHP levels

Previous in vitro metabolism studies showed that human breast tumor tissues convert significantly more progesterone to 5α-pregnanes like 5αP and less to 4-pregnenes like 3αHP than do paired normal (nontumorous) tissues

Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines

breast carcinomas are able to synthesize progesterone

The current findings, along with the previous in vitro studies, suggest that the relative concentrations of 5αP and 3αHP in the breast microenvironment constitute important autocrine/paracrine determinants not only for tumorigenesis but also for potential regression of tumors and the maintenance of normalcy of ER/PR-negative breast cells/tissues.

Evidence presented here shows that a high concentration of 5αP, relative to 3αHP in the microenvironment, promotes initiation and growth of tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy

5α-reductase and 5αPR levels are upregulated by 5αP

in the 3αHP-treated mice, the elevated 3αHP levels, relative to 5αP, in the microenvironment could have opposed progression to xenograft neoplasia by its inherent anticancer actions and the suppression of 5αP synthesis and 5αPR expression

the opposing actions of the progesterone metabolites also appear to exert some control over the estrogen-regulated effects on breast cancer by their ability to modulate ER numbers in ER-positive cells

because both ER/PR-negative and ER/PR-positive, as well as normal and tumorigenic human breast cell lines, have been shown to respond to 5αP and 3αHP in vitro, it is suggested that these endogenously produced progesterone metabolites may also play regulatory hormonal roles in ER/PR-positive breast cancers, as well as in the maintenance of normalcy in nontumorous breast tissues.

The in vivo data provide further evidence that progesterone metabolites, such as 5αP and 3αHP, deserve to be considered as active hormones in their own right, rather than inactive waste products