Rebecca L. Glasera,b,∗, Constantine Dimitrakakisc,d
a b s t r a c t
Objectives: There is evidence that androgens are breast protective and that testosterone therapy treats
many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estrogen
and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated
with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women
treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy.
Study design: This is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study
investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency
treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anastrozole
(A), i.e., T + A implants. Breast cancer incidence was compared with that of historical controls
reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates,
and a representative, similar age group of our patients used as a ‘control’ group. The effect of adherence
to T therapy was also evaluated.
Results: Since March 2008, 1268 pre and post menopausal women have been enrolled in the study and
eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in
5642 person-years of follow up for an incidence of 142 cases per 100 000 person-years, substantially
less than the age-specific SEER incidence rates (293/100 000), placebo arm of Women’s Health Initiative
Study (300/100 000), never users of hormone therapy from the Million Women Study (325/100 000) and
our control group (390/100 000). Unlike adherence to estrogen therapy, adherence to T therapy further
decreased the incidence of breast cancer (73/100 000).
Conclusion: T and/or T + A, delivered subcutaneously as a pellet implant, reduced the incidence of breast
cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by maintaining
a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated,
T + A. This hormone therapy should be further investigated for the prevention and treatment of breast
cancer.
1. Introduction
Excluding skin cancer, breast cancer is the most common cancer
among women, with a lifetime risk of 1 in 8. It is well recognized
that estrogen and progestin therapy stimulates breast tissue and
increases the incidence of breast cancer. However, the long-term
effect of T therapy on the incidence of breast cancer has not been
previously documented in a prospective study. This is becoming
increasingly important as more research is being performed, and
more studies are being published on the benefits of T therapy in
women [1–7].
There is some concern about T and breast cancer risk. Although
some epidemiological studies have shown an increased incidence
of breast cancer associated with endogenous T levels [8–12], others
have not [13–16]. In addition, some studies have found T levels
to be protective [17,18]. Overall, the evidence from epidemiological
studies is conflicting. Furthermore, there are methodological
limitations, both for these studies, and for T assays, which have
been shown to be inaccurate in women.
Another concern is that T is the major substrate for estradiol and
therefore has a secondary ‘stimulatory’ effect at the estrogen receptor
(ER). Anastrozole (A), combined with T in a pellet implant, has
been shown to prevent aromatization and provides adequate levels
of T without elevating estradiol in breast cancer survivors [19,20].
Also, T has been shown to safely relieve side effects of aromatase
inhibitor therapy in cancer survivors [21,22].
T therapy is being increasingly prescribed, and its long-term
effect in the breast need to be further elucidated. The Testosterone
Implant Breast Cancer Prevention Study, i.e., ‘Dayton study’,
is a prospective, observational study that was specifically designed
to investigate the incidence of breast cancer in women treated
with subcutaneous T implants for symptoms of hormone deficiency.
This 5-year interim analysis addresses the incidence of
breast cancer in women treated with subcutaneous T, or T + A
without concurrent use of systemic estrogen or synthetic progestins.
2. Methods
2.1. Study design, setting, and participants
All patients enrolled in the study are part of an ongoing, 10-
year observational, longitudinal prospective IRB approved study,
investigating the incidence of breast cancer in women treated with
subcutaneous T implants. The study was approved in March of 2008
at which time recruitment was initiated. An interim analysis was
planned for year 5, March of 2013.
Pre and post menopausal patients participating in the study
were either self-referred or referred by their physician to the
clinic (RG) at the Millennium Wellness Center in Dayton, Ohio for
symptoms of relative androgen deficiency including hot flashes,
sweating, sleep disturbance, heart discomfort, depressive mood,
irritability, anxiety, pre-menstrual syndrome, fatigue, memory loss,
menstrual or migraine headaches, vaginal dryness, sexual problems,
urinary symptoms including incontinence, musculoskeletal
pain and bone loss. Female patients with no personal history of
breast cancer were asked to participate in this study. Study size
was not predetermined. All patients continuing T therapy were
invited to participate in the study. No patient was excluded from
participation based on age, prior hormone use, oral contraceptive
use, endometrial pathology, breast density, increased cancer
risk, menopausal status or body mass index (BMI). Mammography
and clinical breast exam were not protocol determined.
Screening mammograms were recommended, but not required,
prior to enrollment. As predetermined, patients with a single T
pellet insertion were not included in this analysis. Patients who
had received T implants prior to the IRB approval date were not
excluded from participation and were recruited to the study beginning
March 2008. An IRB approved, written informed consent was
obtained on all patients enrolled in the study. As per IRB protocol,
the incidence of breast cancer in our study population was to be
compared to historical controls as well as age specific Surveillance
Epidemiology and End Results (SEER) data.
Although a control group was not part of the original IRB
approved protocol, it was predetermined that patients receiving
only one pellet implant, i.e., 3 month of therapy, would not
be eligible for analysis. Such short-term hormone use would not
have a long-term affect on the incidence of breast cancer. This
group of 119 patients, enrolled and treated prior to 2010, was followed
prospectively as a ‘control’ group. As of January 2010, only
patients who continued T therapy (>1 insert) were enrolled in the
study.
2.2. Subcutaneous implants, the evolution of testosterone therapy
in clinical practice, testosterone combined with anastrozole
The T and T + A implants used in this clinical practice (RG) are
compounded by a pharmacy in Cincinnati, Ohio. They are composed
of non-micronized USP testosterone (T) and steric acid, or
non-micronized USP T, steric acid and USP anastrozole (A); compressed
with 2000 pounds of pressure using a standard pellet press
into 3.1 mm (diameter) cylinders; sealed in glass ampoules, and
sterilized at 20–25 psi of pressure at 121 ◦C (250 F) for 20–30 min.
The sterile implants are inserted into the subcutaneous tissue of
the upper gluteal area or lower abdomen through a 5 mm incision
using a disposable trocar kit.
This clinical practice (RG) has evolved over the past 6 years. Systemic
estrogen therapy was used in the majority of patients through
2008. However, it became evident that subcutaneous T was able to
treat symptoms in over 95% of patients, and the routine use of estrogen,
including estradiol (E2) implants, was discontinued. In this
practice, T implant dosing is weight based with an average starting
dose of 2–2.5 mg/kg and is adjusted based on clinical response; the
average interval for T pellet insertion is 13.8 ± 3.8 weeks [1,24].
We began using anastrozole (A), an aromatase inhibitor,
combined in the pellet implant in 2008; initially, to treat symptoms
of hormone deficiency in breast cancer survivors and men
on T implant therapy [19,20]. Subsequently, beginning early
2010, women who presented with signs or symptoms of hyperestrogenism,
obesity or increased risk for breast cancer were
offered A in combination with T as a pellet implant. We have
also found that pre-menopausal patients with symptoms of excess
estrogen including migraine headaches, dysfunctional uterine
bleeding, endometriosis, uterine fibroids, breast pain or severe premenstrual
syndrome, also benefit from the ‘low dose’ (compared
to 1 mg/day oral) A delivered subcutaneously with T. As previously
reported, current indications for aromatase inhibitor (AI) therapy
followed in this clinical practice are listed in Table 1 [20].
The amount of A in the pellet implant is 4 mg combined with
60 mg of T, which allows for consistent, simultaneous release of
both the T and A. Two implants, a total of 8 mg of A, has been shown
to prevent elevation of E2 in breast cancer survivors treated with
subcutaneous T [19]. We have subsequently found that 4 mg of A,
one T + A pellet, is able to prevent symptoms of excess estrogen
in many women without breast cancer. The T and T + A dosing is
based on clinical history, symptoms, clinical observation, weight,
amount of fatty tissue, T dose and laboratory evaluation. Often,
heavier, more obese patients require higher doses of both T and
A, Table 2.
2.3. Data analytics, patient follow up
From March of 2008 through February of 2010, all data were
entered into an excel format. In February 2010, a custom webbased
application using Microsoft Active Server Pages with a MySQL
database backend system was custom developed to prospectively
follow and track patients along with ‘person-days’ of therapy. Date
of the first T implant insertion, dose, and date of each subsequent
insertion along with patient identifiers were entered. The computer
program was programmed to identify women who had not
returned for therapy within a pre-set time frame of 240 days, the
maximum duration or exposure from T implant therapy as previously
determined, i.e., 2.5 times the average interval of insertion of
96 days [1]. Weekly ‘follow-up’ phone calls were performed by designated
research personnel. Any participant who was not seen for
240 days was contacted and breast cancer status was documented.
All patients no longer receiving therapy have agreed to contact the
office in the future for any subsequent diagnosis of breast cancer.
In addition, approaching year 5, additional phone calls were made
to patients no longer on T therapy.
2.4. Statistical methods
The incidence rates of breast cancer are reported as an unadjusted,
un-weighted value of newly diagnosed cases divided by the
sum of person-time of observation of the ‘at risk’ populations (ITT,
adherent and control).
Person-days of observation were calculated from the date of
first T pellet insertion for each participant up to the date of cancer
registration, the date of death, or the set date of 31 March 2013,
whichever came first. The computer program accurately and continually
tracks the number of person-days for patient and calculates
a running sum (cumulative total) across the group. Person-years
(p-y) are calculated by dividing person-days by 365.
The incidence of breast cancer was calculated per 100 000 p-y so
that our results could be compared to the incidence of breast cancer
in published historical controls, as has been done in other studies
[25], as well as age-group SEER published breast cancer incidence
rates for 2000–2009. Also, using SEER incidence rates, the expected
breast cancer incidence rate for our ITT group was calculated from
the age distribution of enrolled patients as of 31 March 2013. The
‘expected incidence’ is a weighted sum of the SEER incidence rates
with the weights corresponding to the proportion of the Dayton
study patients in each of the SEER age groups on March 31, 2013.
In order to investigate the effect of non-adherence on the
incidence of breast cancer, the computer was programmed to
calculate person-days of compliance or adherence to therapy. Nonadherence
was defined as, and calculated at, 240 days after the last
T pellet insertion (per individual patient) at which time the persondays
no longer accrued. The effect of non-adherence was conducted
by recalculating adherent p-y of therapy (as described above) and
incidence of breast cancer after censoring events that occurred in
women who had inconsistent T insertions at >8 month intervals
or events that happened within the first 8 months after starting
therapy.
In addition, bootstrapping, a method of estimating the sampling
distribution of the estimates, was used to confirm the significance
of these results [26]. Bootstrap sampling distributions of the ITT
group and the adherent group were constructed to determine if
there were important differences in breast cancer incidence rates
between the two groups. In addition, bootstrapping distribution
was performed on our ‘control’ group of patients not receiving T
therapy. Bootstrap calculations were performed using the Bootstrap
R (S-plus) functions (boot), R package version 1.3-9.
3. Results
3.1. Patient demographics, accrual
Patient demographics are shown in Table 3. As of 31 March
2013, interim analysis study year 5, 1388 patients were accrued to
the Dayton study with 1268 patients having received more than
one pellet implant and eligible for analysis, i.e., Intent to treat
(ITT) group. There were 119 eligible ‘control’ patients and one
non-eligible patient, being recently inadvertently enrolled at first
implant. The mean age at first T pellet insertion was 52.2 ± 8.7 years.
The mean age of the 119 ‘control’ patients was 53.5 ± 9.3 years.
Patients were not at an increased (or decreased) risk for breast cancer,
in regards to risk factors such as family history, or hormonal
and reproductive factors, shown in Table 3.
The majority of patients (62%) were accrued to the study within
the first year. Over 85% of patients were accrued by study year 2,
90% by year 3, and 96% by year 4. Only 4% of patients were accrued
between 1 March 2012 and 1 March 2013. The mean number of
years since first T implant was 4.6 ± 1.3 years; the median was
4.7 ± 1.7 years. The maximum duration of T therapy was 7.36 years,
which includes women who received their first T implant prior to
study accrual. Since the study remained open for accrual through
31 March 2013, the minimum duration of therapy was 0.28 years.
The percent of female patients (without breast cancer) treated
with the combination T + A implant has increased from approximately
11% in 2010, to 30% January through July 2011, and to 62% 1
December 2012 through 1 March 2013; with half of those patients
currently being treated with the 4 mg A dose, Table 2.
3.2. Person-years: Intent to treat, adherence to therapy, ‘control’
As of 31 March 2013, there were 2,059,144 days of follow up,
equating to 5642 p-y of observation in the ITT group of patients.
There have been 1,508,476 days, or 4133 p-y of adherent follow up,
as defined above. In addition, there have been 187,365 days, or 513
p-y of follow up in the 119 patients followed as ‘controls’.
3.3. Breast cancer incidence and characteristics
Breast cancers were verified by obtaining the pathology report
from biopsy and definitive surgery. As of 31 March 2013, 8 cases of
invasive breast cancer have been diagnosed in 1268 women (0.63%)
treated with T implant therapy in 5642 p-y of follow-up, resulting
in an incidence of 142 cases per 100 000 p-y, Table 4.
Patient data, prior therapy and tumor characteristics are presented
in Table 5. The mean age at diagnosis was 56.3 ± 8.0 years.
Seven patients were postmenopausal with 5 of these 7 having surgical
menopause. Seven of 8 patients had been on systemic estrogen
in the past and 3 of those 7 had been treated with E2 implants.
Although this study is reporting on the incidence of breast cancer
in patients treated with T alone, these patients were included in
the results as they had been off estrogen therapy for at least 1 year.
Interestingly, the four patients age 52 years of age and younger, had
a lower BMI (20.1 ± 1.1) compared to the four patients 55 years
of age and older (27.5 ± 4.1). Baseline serum T levels were available
in 5 of the 8 patients diagnosed with cancer, and were lower
compared to baseline T in our general population (13.6 ± 6.3 vs.
19.0 ± 12.8 ng/dl). A 6th patient had a salivary T level below the
lower limit for females. Patient 2 had been on E2 and T implants by
another physician since 2005 and screening labs were not available.
Three patients (no. 1, 4 and 8) diagnosed with breast cancer had
been treated consistently with T implants for at least 8 months
prior to diagnosis, i.e., adherent to therapy. Only one patient (no.
8) had been consistently treated with T + A combination therapy
prior to diagnosis. Patient 6 had been consistently treated for 2
years, but was non-adherent for 11 months prior to the diagnosis
of a 4 mm invasive cancer. She has continued to be treated with
T + A implant therapy along with oral anastrozole. Patient 3 (premenopausal)
was treated with T implants for fewer than 8 months
prior to her diagnosis. She has continued therapy with T + A combination
implants, initially with Tamoxifen, which was changed to
anastrozole after menopause. Patient 2 had been non-adherent to
T therapy and was diagnosed with an aggressive hormone receptor
negative tumor. Patient 5 had a single T implant prior to being diagnosed
with breast cancer one month later. Patient 7 had received
3 implants between April and September 2010 and had been off T
therapy for over 2 years prior to diagnosis.
One additional patient, a 55 year-old postmenopausal female,
has been diagnosed with an 8 mm non-high grade (non-invasive)
ductal carcinoma in situ, which was treated with a lumpectomy
alone. The patient continued T therapy and is currently treated with
the combination T + A implants.
3.4. Tumor characteristics
Six of 8 tumors were Stage 1, small (<2 cm), node negative, estrogen
receptor (ER) positive infiltrating ductal carcinomas; five of
these 6 were HER2 negative. One ER positive patient (no. 8) who had
lymph node involvement, had a small, <0.5 mm infiltrating lobular
carcinoma. One tumor was an aggressive, 5 cm, node positive, triple
negative (i.e., ER negative, PR negative, HER2 negative) invasive
cancer, Table 5.
3.5. Effect of adherence to T therapy
3 breast cancers (events) were diagnosed in women (patients
1, 4, and 8) who were adherent to therapy (predetermined as consistent
therapy at ≤8 month intervals, event diagnosed >8 months
after initiating T therapy) in 4133 p-y, which equates to an incidence
of 73 per 100 000 p-y. Although patient 6 had been off
therapy for 11 months prior to diagnosis, if she were re-classified
as ‘adherent’, the incidence would be 97 per 100 000 person-years,
still significantly less than the ITT group, 142 per 100 000.
There have been 2 cases of breast cancers diagnosed in the 119
‘control’ patients, both diagnosed 18 months or longer after their
single T pellet insert. This equates to an incidence of 390/100 000
p-y, which is substantially greater than the 142/100 000 for the
ITT. The percent of breast cancer cases diagnosed was significantly
higher in the ‘control’ group (1.68%) compared to ITT group (0.63%).
Comparison of bootstrap sampling distribution of the incidence
of breast cancer revealed a significantly (P < 0.001) lower incidence
of breast cancer in the T adherent population compared to the ITT
group as well as the calculated expected SEER incidence rate based
on the age distribution, further supporting that T and T + A therapy
reduces the incidence of breast cancer, Fig. 1. In addition, breast
cancer occurrence for the ‘control’ group was significantly higher
than either the adherent group or the ITT group (P < 0.001).
3.6. Adverse drug events, side effects of therapy
We have previously measured T levels in a representative
subgroup of patients from this population and have shown that
pharmacologic doses of subcutaneous T (55–240 mg), as evidenced
by serum levels on therapy, are necessary to produce a physiologic
effect. Serum T levels measured at ‘week 4’ (299.36 ± 107.34 ng/dl),
and when symptoms returned (171.43 ± 73.01 ng/dl), were severalfold
higher compared to levels of endogenous T. Despite
pharmacologic serum levels, there have been no reported adverse
drug events attributed to T therapy other than expected androgenic
side effects, which are reversible with lowering T dose. As previously
reported, the majority of patients studied (92%) reported a
slight or moderate increase in facial hair; however, no patient discontinued
therapy because of this. Interestingly, 63% of patients
who reported scalp hair thinning prior to T therapy, reported hair
re-growth on therapy [23]. 51% of patients reported a mild or moderate
increase in acne, and 52% (including patients with an increase
in acne) reported improved appearance of the skin. In addition,
there have been no adverse drug events related to subcutaneous A.
The amount of A released over an average of 100 days is approximately
0.04–0.08 mg per day, compared to 1 mg orally per day.
The only reported side effect from the 8 mg dose of A has been hot
flashes, which resolve with lowering the dose of A to 4 mg (one
implant) or treating the patient with T alone, no A.
4. Discussion
In the past 7 years, over 16 000 T pellet insertions have been
performed in 1388 pre and postmenopausal women followed on
protocol since 1 March 2008. We have previously reported on the
benefits and safety of T therapy, T dosing and levels on therapy,
as well as efficacy of A combined with T [1,2,19,20,23]. Our current
data evidence that an average T dose of 2.0–2.5 mg/kg (range
55–240 mg), delivered subcutaneously with or without 4.0–8.0 mg
of A at approximately 3 month intervals, has resulted in a reduction
in the incidence of breast cancer.
The 5-year interim analysis of the Dayton study resulted in
a ratio of 142 breast cancer events per 100 000 p-y, which is
remarkably lower when compared to all previous studies concerning
hormonal treatments, Table 4. Even in comparison to
the placebo group of the Women’s Health Initiative Randomized
Trial (300/100 000) and never users from Million Women Study
(325/100 000), there was a reduced incidence of breast cancer with
T therapy used in the Dayton study [27–29].
We also demonstrated a reduced incidence of breast cancer with
T and T + A in comparison to the Adelaide Study (238/100 000),
which previously reported a reduced incidence of breast cancer
with T-use in combination with conventional hormone therapy
[25].
In addition, the Dayton study showed a reduced incidence of
breast cancer compared with age-specific SEER incidence rates for
both the younger age group, i.e., 50–54 y (234/100 000) and the
current age comparable (at time of analysis) group, i.e., 55–59 y
(292/100 000) [30,31]. Notably, the incidence rate for our ITT group
(142/100 000) was approximately half of the calculated expected
SEER incidence rate (276 ± 6.81/100 000) based on the age distribution
of Dayton study participants. Even more significant, women
who were adherent to T or T + A therapy had over a 3.5-fold reduction
in the expected incidence rate of breast cancer.
These outcomes, which indicate a beneficial effect of T and T + A
in the breast, were not unexpected. There is sufficient biological
and clinical data indicating that androgens have a protective role in
breast tissue. Although some epidemiological studies show an association
between increased serum androgen levels and higher breast
cancer incidence, others do not; and many of these studies fail to
isolate T from the circulating estrogens or account for local aromatization
to estrogens [8–18]. In addition, they do not address the
known insulin-inflammation-cancer connection; insulin stimulation
of T production; or the insulin stimulated increase in aromatase
activity, including locally in the breast; all of which would contribute
to increased cancer risk [32–36].
Most importantly, association does not infer causation [37],
and a ‘cause and effect’ interpretation of inconsistent epidemiologic
data conflicts with the known biological effect of T in the
breast. Although a few studies report both a proliferative and
antiproliferative affect of T in breast cancer cell lines [38,39], the
abundance of evidence supports that T’s direct effect via androgen
receptors (AR) is anti-prolific, pro-apoptotic, and inhibits breast
cancer cell growth [40–46]. In addition, clinical studies in primates
and humans, including long-term studies in female to male
transgender patients, as well as clinical observations, support the
protective role of T in the breast [47–51]. Androgens, including T
pellet implants, have been used to successfully treat breast cancer
in the past as well as symptoms of menopause in breast cancer survivors
[52–55]. Androgen receptor status in breast cancer has been
shown to be prognostic; evidencing smaller tumor sizes, lower histological
grade, better prognosis and increased disease free survival
[56–61].
A limitation of the study was a lack of a matched control
group from the onset of the study. However, we prospectively followed
patients receiving a single T insert, i.e., limited, 3-month
exposure to therapy, as a ‘control’ group. Although our ‘control’
group was small (n = 119), these patients were representative of
the same population, presented with similar symptoms and were
similar in age. We demonstrated a reduced incidence of breast cancer
in both our adherent group (73/100 000 p-y) as well as our
ITT group (142/100 000 p-y) in comparison to our ‘control’ group
(390/100 000 p-y).
Of note is the discordant effect of ‘adherence to
estrogen–progestin (E/P) therapy’ compared to ‘adherence to
T therapy’ on outcome. We have shown that adherence to T
therapy has the converse outcome on breast cancer incidence,
i.e., decreased events (signifying a protective effect), compared to
adherence with E/P therapy, i.e., increased events [27].
A possible argument regarding the low breast cancer incidence
reported in our study is that our patient population was
at low risk for breast cancer. Indeed, there was no specific criterion
excluding or including high-risk women. In the Dayton study,
women enrolled were seeking therapy for symptoms of hormone
deficiency; thus, our population was comparable to populations
included in the historical hormone therapy trials mentioned above.
Our mean age at the time of analysis, 56.6 y, compares with the
mean age of other studies at recruitment/screening and evaluation,
and age specific SEER data. Although our mean age at the time of
recruitment was slightly lower, the younger pre/peri-menopausal
women who enrolled in the study presented with symptoms of
estrogen excess and androgen deficiency, possibly putting them at
an increased risk for breast cancer. Regarding additional risk factors
for breast cancer, our incidence of family history was comparable
to other studies, as was mean age at menarche, first birth, and
menopause [27,29].
Currently, patients at highest risk for increased aromatization
are being increasingly identified and treated with A delivered
simultaneously with T in the combination implant. We did not
begin using the combination implant in this population until early
2010, implying that the reduction in breast cancer reported at year
5, is likely a result of T’s effect at the AR rather than primarily
aromatase inhibition. With the addition of low dose aromatase
inhibitor (AI) therapy in high-risk women, the favorable balance
of T to E ratio may be further restored and it is possible that a further
reduction in the incidence breast cancer will be demonstrated
in the future.
A critique of our practice is the use of low dose, subcutaneous
AI in some pre/perimenopausal patients. Although AI are not indicated
for therapy in premenopausal breast cancer patients, it is
not because they are ineffective; but rather, with oral AI therapy
total suppression of estradiol in this subgroup could ‘potentially’
increase gonadotropin releasing hormone, and secondarily stimulate
the ovary to re-produce estrogen via ovarian-pituitary negative
feedback mechanism [62]. Although a discussion of AI therapy in
pre-menopausal patients is beyond the scope of this paper, our
interventions were based on the previously successful use of AI
to treat breast and gynecologic diseases where pathological tissues
overexpress aromatase and increase local production of estrogens
[63]. We have found that low dose A (0.04–0.08 mg/d) combined
with T, delivered subcutaneously, effectively treats these conditions
without adverse effects, or alteration of menstrual cycles.
The favorable effect of T in the breast is further supported by
the lack of recurrence in our breast cancer survivors treated with
subcutaneous T or T + A [19]. This observation represents the preliminary
result of an ongoing trial designed to assess T treatment
role in breast cancer survivors. We are also examining the effect of
neoadjuvant, intra-mammary (peritumoral) T + A implants in invasive
breast cancers, and demonstrating a rapid clinical response of
tumors to this therapy (report under publication).
It is possible that continuous, subcutaneous T + A could help prevent
breast cancer in high-risk women, and recurrences in breast
cancer survivors. In addition to providing consistent therapeutic
levels of T and A, the subcutaneous delivery route also allows
both T and A to bypass the liver, avoiding the ‘first pass effect’
and thus eliminating the increased risk of blood clots, pulmonary
embolism and deep venous thrombosis. It also increases efficacy
and decreases side effects, including gastrointestinal side effects of
oral therapy.
Testosterone is critical to both physical and mental health in
women. However, patients differ in their ability to aromatize T to
E2. Caution should be used in treating patients with clinical evidence
increased aromatase activity and consideration should be
given to the addition of AI therapy.
5. Conclusion
Continuous T and T + A, delivered as a subcutaneous implant,
seems to represent safe and effective therapy in treating hormonal
symptoms in both pre and postmenopausal women. In this study,
safety is verified by the significant decline in breast cancer incidence.
We demonstrated that subcutaneous T, and subsequently,
T + A, has a protective effect in the breast, and prevented cancer
occurrence in some cases. Our findings are consistent with the
known favorable biological effect of T on the breast tissue via the
AR, as well as data from previously reported preclinical and clinical
studies. Our results refute the ‘cause and effect interpretation’ of
epidemiological studies demonstrating an association of endogenous
testosterone levels with breast cancer. Further studies should
be done on subcutaneous T, and the combination of T + A, for the
possible prevention and therapy of breast cancer.
Study details
Glaser, R (PI) and Dimitrakakis, C (PI). Testosterone Implants and
the Incidence of Breast Cancer: TIBCaP 0108 (Testosterone Implant
Breast Cancer Prevention Trial 0108). IRB Approved 21 March
2008, continued through March 2013. Atrium Medical Center, Premier
Health Partners, One Medical Center Drive, Middletown, Ohio
45005. Registered through the Office for Human Research Protections
(OHRP).
As of March 2013, no additional patients will be accrued to this
study. Patients may continue to be accrued under a central institutional
review board (Wright State University IRB) study, SC# 509,
‘Testosterone Implants and the Incidence of Breast Cancer’, Number:
FWA00002427.
Contributors
RG and CD contributed equally to the research, design of the
study, analyzing the data, writing and editing the manuscript. RG
recruited participants. Both authors approved the final manuscript.
Competing interest
Neither author (RG, CD) has any competing interests.
Funding
None was secured for the study or the writing of this manuscript.
Acknowledgments
Anne York, York Data Analysis, PO 31375, Seattle, WA, 98103,
USA performed the statistical analyses, including the ‘bootstrapping’
of the sampling distribution and SEER data analysis. She
reviewed and approved the manuscript for statistical accuracy.
We would like to express gratitude and appreciation to Jennifer
Dichito, D. Kathy Boomershine, Roxanne Smith, Joan Royce
and Katherine Glaser Koehler.
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