Balanced Hormone Therapy and Breast Cancer

Can hormone therapy be safely used in breast cancer survivors?

 

Introduction

High levels of estrogen and long periods of unopposed estrogen are thought to be a risk factor for breast cancer. Testosterone balances the action of estrogen, prevents proliferation of breast tissue and has been shown to lower the risk of breast cancer. Vaginal estrogen therapy, in particular vaginal estriol, does not increase the risk of breast cancer. Progesterone has not been associated with an increase in breast cancer, unlike the synthetic progestins.

Breast Tissue, Testosterone and Pellet Implants

Testosterone has been used to treat patients with advanced breast cancer and has been used (as a hormone implant) as part of endocrine therapy in breast cancer survivors [1, 2, 12].

Clinical evidence supports that testosterone is breast protective [4-8]. Androgens are known
to inhibit breast cancer in almost every breast cell line via the androgen receptor [13-15].
Adrenal androgens have been shown to counteract the growth stimulatory affects of estrogen
on breast cancer cells [16]. Non-oral testosterone, including testosterone delivered by pellet
implant, has been shown to prevent breast proliferation, decrease estrogen receptor alpha and
prevent the stimulation of breast tissue from estrogen/progestin therapy. [17-20]. Breast
density is inversely associated with testosterone levels. Testosterone, delivered by pellet
implant has also been shown to lower the risk of breast cancer when given with estrogen and
estrogen/progestin therapy [11, 21]. Long-term follow up data supports the safety of
testosterone, delivered by pellet implant.

Estradiol delivered by pellet implant has been shown to increase the risk of breast cancer
equivalent to oral and topical estrogens [9]. However, when used in combination with
testosterone implants, even high doses of estradiol did not increase the risk of breast cancer in
up to 22-year follow-up [11]. Even in patients with a history of breast cancer, estrogen did not
increase the risk of recurrence when used with testosterone implants [12].

Testosterone has been used successfully to treat breast cancer patients [2, 22]. It is highly
unlikely that non-oral testosterone would have any long-term negative effect on breast tissue
unlike oral synthetic methyl-testosterone [23, 99].

Testosterone, delivered by pellet implant does not raise serum levels estradiol [24, 25] when
given with estrogen. However, a 200 mg. testosterone pellet implant alone, demonstrated a
non statistically significant rise in estradiol [24]. Oral, synthetic methyl-testosterone is
converted to 17-α methyl-estradiol by aromatase [26], which is found in large quantities in the
fatty tissue of the GI tract. 17-α methyl-estradiol is stimulatory to the breast tissue, binding
strongly to ER alpha [26, 27]. This, along with the combined use of ethinyl-estradiol
(Estratest®), may explain the increased incidence of breast cancer with the synthetic, oral
methyl-testosterone [23]. Methyl testosterone may also act as an endocrine disrupter by
preventing testosterone from binding to the androgen receptor.

Although some retrospective, epidemiologic/statistical studies using inaccurate methodologies
to measure testosterone (RIA), have shown an increased incidence of breast cancer
‘associated’ with elevated testosterone levels, other studies have show a decreased risk or no
difference [28, 30]. It has been clearly established that testosterone, measured by RIA is
inaccurate in women and should not be relied on [28-32]. Higher levels of testosterone are
associated with higher levels of estrogen. After adjusting for estrogen levels, androgens had a
negligible impact on breast cancer risk [97,98]. In addition, women with polycystic ovarian
syndrome and elevated testosterone levels do not have an increased risk of breast cancer (RR
0.52) [33, 34].

Recent data (under publication*) has shown that newly diagnosed breast cancer patients have
lower salivary testosterone levels compared to controls. Also, women with higher testosterone
levels have higher estradiol levels.

Androgens (testosterone and DHT) have been reported to ‘stimulate breast cells’. However,
in these studies it was pharmacologic doses of testosterone (up to >100 times physiologic
levels) that stimulated breast cancer cells via the estrogen receptor [35, 102, 103].
Physiologic doses of testosterone and DHT inhibit growth of breast cancer cells via the
androgen receptor [13-16].

Estriol, Progesterone and Vaginal Delivery of Hormones

Vaginal delivery of hormones, including estriol, estradiol, estrone, progesterone and
testosterone, has been well established in the literature. It has been shown in multiple studies
that hormones administered vaginally are absorbed systemically, bypass hepatic metabolism
and are biologically active [36-47]. It has also been shown that hormones applied to the
mucous membranes are more readily absorbed than hormones applied to the skin [48-51].
Testosterone, applied to the mucous membranes of the labia, has been shown to be absorbed
and have systemic effects [50, 52]. Hormones applied vaginally achieve higher plasma levels
than if taken orally and the vaginal route appears to be more adequate than the oral one for
hormone replacement therapy [51].

Symptomatic relief of genital urinary symptoms as well as systemic climacteric symptoms
with vaginally administered hormones has been described and is dose dependent [46, 53-55].

The long-term safety of vaginal estrogen therapy has been established in the literature.
Multiple large studies, including the Million Women’s Study and Fournier’s E3N French
Cohort study, have repeatedly shown that vaginal estriol does not increase the risk of breast
cancer (RR 0.67-0.70) [9, 68-74]. There is no data to the contrary. Vaginal estriol use in
breast cancer patients does not increase the risk of recurrence (RR 0.57) or death [69,70].
Estriol has a low binding affinity for ERα and does not stimulate breast tissue or increase
breast density [62, 78-81]. Vaginal estriol, used in the correct doses, does not increase the risk
of endometrial hyperplasia or uterine cancer [56-58, 67]. Unlike oral estriol, vaginal estriol
has been shown to increase bone density [56, 59]. There is no accumulation of hormones or
metabolites with vaginal estrogen or progesterone therapy [45, 51, 57, 60-62].

Vaginal progesterone has preferential distribution to the uterus and protects the uterine lining
[75-77]. Unlike the oral synthetic progestins, vaginal progesterone does not negate the
beneficial effects of estrogen on the heart and enhances the effect of estrogen on exercise
induced myocardial ischemia [47].

In Fournier’s E3N French prospective, cohort study, progesterone did not increase the
risk breast cancer (RR 0.9) like the synthetic progestins (RR 1.4) [71,72].

Progesterone, the bio-identical molecule, has been shown to decrease or have no effect breast
proliferation [18, 95, 96]. It is highly unlikely that vaginal progesterone would have a
negative effect on breast tissue. Progesterone, applied vaginally, has a high local effect on the
endometrium without systemic side effects (bloating, sedation, persistent hot flashes) due to
high plasma progesterone levels and metabolites [61-64, 76, 77]. Vaginal administration of
progesterone is preferred in patients with cardiovascular disease, liver disease or hepatic
overload [65].

Cancer cells are known to over-express insulin receptors [100]. A diet of whole foods with
limited refined carbohydrates may lower the risk of cancer. Hyperinsulinemia has been
associated with a higher incidence of breast cancer, increased recurrence of disease and
increased mortality. Synthetic progestins increase insulin receptor content and insulin
stimulation of growth in human breast cancer cells [101].

Hormone Replacement Therapy in breast cancer survivors

In the past, a history of breast cancer has been a relative contraindication to ‘Hormone
Replacement Therapy’ in women. This approach has continued, despite a lack of data to
support the position. Hormone replacement therapy (HRT) most often refers to estrogen,
with or without synthetic progestins to protect the uterine lining. The addition of
synthetic progestins traditionally are employed in conjunction with estrogen to modulate the
proliferative effect estrogen has on the uterine lining as protection against endometrial cancer.

The majority of studies investigating hormone replacement therapy in breast cancer patients
show lower cancer recurrence rates (RR 0.72) as well as, significantly lower mortality rates in
treated patients (RR 0.18) [69, 70, 82-94].

The HABITS trial, a large, prospective clinical trial on the safety of HRT after breast
cancer, showed an increase in the recurrence of breast cancer in women taking estrogen,
estrogen/progestin therapy [91]. However, the patient selection, as well as, the HRT
regimens in the HABITS trial were so variable that one cannot determine whether or not there
were subgroups of breast cancer survivors who could take HRT without risk of recurrence of
breast cancer. The majority of women in the HABITS trial were treated with synthetic
progestins, which have consistently been shown to increase the risk of breast cancer. When
the use of synthetic progestins was limited in the prospective ’sister’ trial completed in
Stockholm, the risk of cancer recurrence was not increased (RR 0.82) [92]. In addition, the
Stockholm trial showed the risk of death from all causes was not increased with HRT (RR
0.5). The Stockholm trial did have a slightly higher per-cent of patients treated with
tamoxifen.

Balanced Hormone Therapy for Breast Cancer Survivors

Breast cancer survivors treated with hormone therapy should notify their oncologist. The
patient’s oncologist must be in agreement with therapy.

Patients should acknowledge the possibility of recurrence with or without hormone therapy.
The Habits and Stockholm trials along with other data (Meurer 02) should be reviewed with
the patient. Opinions by uninformed physicians should be questioned. Unsubstantiated
‘Clinical Guidelines’ should be labeled as such.

Pre and Post Implant Testing and Evaluation

The patient’s physician will determine what testing is needed to best treat their patient.
Testosterone pellet therapy is indicated for symptoms of testosterone deficiency (fatigue,
decreased libido, memory loss, lack of motivation, depression, anxiety, insomnia, aches,
pains, hot flashes etc.). A free testosterone in the lower third of normal, or low total
testosterone may be helpful for diagnosing testosterone deficiency.

If a patient is on a testosterone implant, it is recommended that a CBC, estradiol and FSH be
obtained annually. Testosterone levels fluctuate and have little or no clinical significance.
Although historical studies (Thom, Davis) have shown that testosterone implants do not
elevate serum estradiol levels, these studies were done in conjunction with estradiol implants.
Testosterone can convert to estradiol via aromatase. Breast cancer survivors, not on an
aromatase inhibitor as part of their therapy, may be placed on anastozole 1mg, ½ pill twice
weekly to prevent the conversion of testosterone to estradiol. This dose lowers estradiol
levels and is not prescribed as therapy for breast cancer.

Options for Therapy for Breast Cancer Survivors

1. Testosterone pellet implant alone 75-150 mg implanted every 3-5 months
2. Testosterone pellet implant with vaginal estriol 0.5 mg and progesterone 25 mg (added temporarily for severe vaginal  dryness)
a. Testosterone pellet implant 75-150 mg implanted every 3-5 months
b. Vaginal Estriol 2 mg, Progesterone 100mg per cc of cream base dosed 0.25 mg 2-3 times weekly as needed for severe vaginal dryness and urinary urgency.
3. Vaginal Estriol 0.5 mg, Progesterone 25 mg and Testosterone 0.5 mg (minimal systemic symptoms)
a. Vaginal Estriol 2 mg, Progesterone 100 mg, Testosterone 2 mg per cc of cream dosed 0.25 mg daily for 14 days then 2 3 times weekly.
Anastrozole (Arimidex®) 0.5 mg twice weekly may be prescribed depending on a
physician’s decision of ‘risk vs. benefit’. A thin patient with low body fat and low risk of
recurrent disease may benefit from additional estrogen. Estrogen receptor status may play a
role in this decision.

References
1. Loeser A. Mammary Carcinoma, Response to implantation of male hormone and
progesterone. Lancet 1941; Dec 6: pp 698-700
2. Greenblatt R, Suran R. Indications for Hormonal Pellets in the Therapy of Endocrine
and Gynecic Disorders. Am. J. Obst. & Gynaec 1949; Feb 37 (2): 249-301.
3. Greenblatt R, Bryner J, Estradiol Pellet Implantation in the Management of
Menopause. The Journal of Reproductive Medicine 1977: 18 (6): 307-316.
4. Ando S, DeAmicis F, Rago V, Carpino A, Maggiolini M, Panno M, Lanzino M.
Breast cancer: from estrogen to androgen receptor. Mol Cellular Endocrin 2002; 193:
121-28.
5. Ortmann J, Prifti S, Bohlmann M, Rehberger-Schneider S, Strowitzki T, Rabe T.
Testosterone and 5 alpha-dihydrotestosterone inhibit in vitro growth of human breast
cancer cell lines. Gynecol Endocrinol 2002; 16: 113-20.
6. Lapointe J, Fournier A, Richard V, Labrie C. Androgens down-regulate bcl-2
protooncogene expression in ZR-75-1 human breast cancer cells. Endocrin 1999; 140
(1): 1416-21.
7. Kandouz M, Lombet A, Perrot J, Jacob D, Carvajal S, Kazem A, et al.
Proapototic effects of antiestrogens, progestins and androgen in breast cancer
cells. J Steroid Biochem Mol Biol 1999; 69: 463-71.
8. Birrell S, Butler L, Harris J, Buchanan G, Tilley W. Disruption of androgen
receptor signaling by synthetic progestins may increase the risk of developing
breast cancer. The FASEB Journal 2007; 2 (21) 1-9.
9. Million Women Study Collaborators. Breast cancer and hormone-replacement
therapy in the Million Women Study. Lancet 2003; 362: 419-27.
10. Davelaar E, Gerretesen G, Relyveld J. Geen toename van het aantal
mammacarcinomen bij súbcutaan estradiolgeb. Ned Tijdschr Geneeskd 1991;
135, 613-15
11. Gambrell D, Natrajan P. Moderate dosage estrogen-androgen therapy
improves continuation rates in postmenopausal women; impact of the WHI
reports. Climacteric 2006; 9; 224-33.
12. Natrajan P, Gambrell D. Estrogen replacement therapy in patients with early
breast cancer. Am J Obstet Gynecol 2002; 187 (2): 289-94.
13. Ortmann J, Prifti S, Bohlmann M, Rehberger-Schneider S, Strowitzki T, Rabe T.
Testosterone and 5 alpha-dihydrotestosterone inhibit in vitro growth of human breast
cancer cell lines. Gynecol Endocrinol 2002; 16: 113-20.
14. Szelei J, Jimenez J, Soto A, Luizzi F, Sonnenschein C. Androgen-induced
inhigition of proliferation in Human Breast Cancer MCF7 cells transfectd with
androgen receptor. Endocrinology 1997; 138 (4): 1406-12.
15. Hackenberg R, Schulz K-D. Androgen Receptor Mediated Growth Control of
Breast Cancer and Endometrial cancer modulated by anti-androgens- and
androgen-like steroids. J. Steroid Biochem Molec Biol; 56 (1-6):113-17.
16. Boccuzzi G, Brignardello E, DiMonaco M, Gatto V, Leonardi L, Pissini A,
Gallo M. 5-En-androstene-3β, 17β-diol inhibits the growth of MCF-7 breast
cancer cells when oestrogen receptors are blocked by oestradiol. Br. J. Cancer
1994; 70: 1035-39.
17. Zhou J, Ng S, Adesanya-Famuiya O, Anderson K, Bondy C. Testosterone inhibits
estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor
expression. FASEB J 2000: 14: 1725-30.
18. Dimitrakakis C, Zhou J, Wang J, Belanger A, LaBrie F, Cheng C, Powell D, Bondy
C. A physiologic role for testosterone in limiting estrogenic stimulation of the breast.
Menopause 2003; 10 (4) 292-92.
19. Hofling M, Hirschberg Q, Skoog L, Tani E, Hagerstrom T, vonSchoultz B.
Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in
postmenopausal women. Menopause 2007; 14 (2): 1-8.
20. Slagter M, Gooren L, Scorilas A, Petraki C, Diamandis E. Effects of lont-term
androgen administratin on breast tissue of female-to-male transsexuals. Journal
of Histochemistry & Cytochemistry 2006; 54 (8): 905-10.
21. Dimitrakakis C., Jones R, Liu A, Bondy C. Breast cancer incidence in
postmenopausal women using testosterone in addition to usual hormone therapy.
Menopause 2004; 11 (5): 531-35.
22. Testosterone Monograph. Clinical Pharmacology 2000.
23. Tamimi R, Hankinson S, Chen W, Rosner B, Colditz G. Combined estrogen and
testosterone use and risk of breast cancer in postmenopausal women. Arch Intern
Med 2006; 166: 1483-88.
24. Thom M, Collins W, Studd J. Hormonal profiles in postmenopausal women
after therapy with subcutaneous implants. British Journal of Obstetrics and
Gynaecoloty 1981; 88: 426-33.
25. Davis S, Walker K, Strauss B. Effects of estradiol with and without
testosterone on body composition and relationships with lipids in
postmenopausal women. Menopause 2000; 7 (6): 395-401.
26. deGoyer M, Oppers-Tiemissen H, Leysen D, verheul H, Kloosterboer J.
Tibolone is not converted by human aromatase to 7α-methyl -17α-
ethynlestradiol (7α-MEE): Analysis with sensitive bioassays for estrogens and
androgens and with LC-MSMS. Steroids 2003; 68: 235-43.
27. Kuhl H. Personal communication.
28. LaBrie F, Luu-The V, Labrie C, Belanger A, Simard J, Lin S-X, Pelletier G.
Endocrine and intracrine sources of androgens in Women: Inhibition of breast
cancer and other roles of androgens and their precurson
dehydroepiandrosterone. Endocrine Reviews 2003; 24 (2): 152-82.
29. Bachmann G, Bancroft J, Braunstein G, Burger H, Davis S, et al. Female
androgen insufficiency: the Princeton consensus statement on definition,
classification, and assessment. Fertility and Sterility; 77 (4): 660-65.
30. Somboonporn W, Davis S. Testosterone effects on the breast: Implications for
testosterone therapy for women. Endocrine Reviews 2004; 25 (3): 374-88.
31. Rivera-Woll L, Papalia M, Davis S, Burger H. Androgen insufficiency in
women: diagnostic and therapeutic implications. Human Reproduction Update
2004; 10 (5): 421-32.
32. Stanczyk F, Lee J, Santen R. Standardization of steroin hormone assays: Why,
How, and When? Cancer Epidemiol Biomarkers Prev 2007; 16 (9): 1713-1719.
33. Anderson K, Sellers T, Chen P-L, Rich S, Hong C-P, Folsom A. Association of
Stein-Leventhal Syndrome with the incidence of postmenopausal breast carcinoma in
a large prospective study of women in Iowa. Cancer 1997; 79 (3); 494-99.
34. Gammon M, Thompson D. Polycystic ovaries and the risk of breast cancer.
American Journal of Epidemiology 1991; 134 (8): 818-24.
35. Zava D, McGuire W. Androgen action through estrogen receptor in a human breast
cancer cell line. Endocrinology 1978; 103: 624-31.
36. Schiff I, Tulchinsky D, Ryan K. Vaginal absorption of estrone and 17β-estradiol.
Fertility and Sterility 1977; 28;10, pp 1063-66
37. Schiff I, Wentworth B, Koos B, Ryan K, Tulchinsky D. Effect of estriol
administration on the hypogonadal woman. Fertility and Sterility 1978; 30:3, pp 278-
82
38. Punnonen R, Vilska S, Grőnroos M, Rauramo L. The vaginal absorption of
oestrogens in post-menopausal women. Maturitas 1980; 2:4, pp 321-26
39. Heimer G, Englund D. Estriol: absorption after long-term vaginal treatment and
gastrointestinal absorption as influenced by a meal. Acta Obstet Gynecol Scand
1984; 63:6, pp 563-67
40. Heimer G, Englund D. Plasma oestriol following vaginal administration: morning
versus evening insertion and influence of food. Maturitas 1986; 8, pp 239-43
41. Mattson L, Cullberg G. Vaginal absorption of two estriol preparations. A
comparative study in postmenopausal women. Acta Obstet Gynecol Scand. 1983; 62:
5, pp 393-96
42. Cedars M, Judd H. Nonoral routes of estrogen administration. The Menopause 1987;
14:1 pp 269-98
43. Carlstrőm K, Pschera H, Lunnell N. Serum levels of oestrogens, progesterone,
follicle-stimulating hormone and sex-hormone-binding globulin during simultaneous
vaginal administration of 17 beta-oestradiol and progesterone in the pre- and postmenopause.
Maturitas 1988; 10, pp 307-16
44. Suh-Burgmann E, Sivret J. Duska L, Carmen M, Seiden M. Long-term
administration of intravaginal dehydroepiandrosterone on regression of low-grade
cervical dysplasia-a pilot study. Gynecol Obstet Invest 2003; 55, pp 25-31
45. Keller PJ, Riedmann R, Fischer M, Gerber C. Oestrogens, gonadotropins and
prolactin after intra-vaginal administration of oestriol in post-menopausal women.
Maturitas 1981; 3, pp 47-53
46. Rigg LA, Hermann H, Yen SS. Absorption of estrogens from vaginal creams. N Engl
J Med 1978; 298, pp 195-97
47. Rosano G, Webb C, Chierchia S, Morgani G, Gabraele M, Sarrel P, Ziegler D,
Collins P. Natural progesterone, but not medroxyprogesterone acetate, enhances the
beneficial effect of estrogen on exercise-induced myocardial ischemia in
postmenopausal women. J Am Col Card 2000; 36:7, pp 2154-59
48. Oriba H, Bucks D, Maibach H. Percutaneous absorption of hydrocortisone and
testosterone on the vulva and forearm: effect of the menopause and site. Br J Derm
1996; 134, pp 229-233
49. Corbo D, Liu JC, Chien Y. Drug absorption through mucosal membranes: effect of
mucosal route and penetrant hydrophilicity. Pharmaceutical Research 1989; 6:10, pp
848-52
50. Friedrich E, Kalra P. Serum Levels of Sex Hormone in Vulvar Lichen Sclerosus, and
the Effect of Topical Testosterone. The N Engl J Med 1981; 310, pp 488-91
51. Nahoul K, Dehennin L, Jondet M, Roger M. Profiles of plasma estrogens,
progesterone and their metabolites after oral or vaginal administration of estradiol or
progesterone. Maturitas 1993;16, pp 185-202
52. Zeisler E, Bancher-Todesca D, Sator M, Schneider B, Gitsch G. Short-term effects of
topical testosterone in vulvar lichen sclerosis. Obstet.Gynecol 1997; 89(2): 297-99
53. Mandel F, Geola F, Meldrum D, Lu J, Eggena P, Sambhi M, Hershmann J, Judd H.
Biological effects of various doses of vaginally administered conjugated equine
estrogens in postmenopausal women. J Clin Endo Met 1983; 57:1, pp 133-39
54. Bottiglione F, Volpe A, Esposito G, Aloysio D. Transvaginal estriol administration
in postmenopausal women: a double blind comparative study of two different doses.
Maturitas 1995; 22, pp 227-32
55. Schiff I, Tulchinsky D, Ryan K, Kadner S, Levitz M. Plasma estriol and its
conjugates following oral and vaginal administration of estriol to postmenopausal
women: Correlations with gonadotropin levels. Am. J. Obstet. Gynecol. 1980; 138:8,
pp.1137-41
56. Blum M. Benefits of vaginal estriol cream combined with clonidine HCl for
menopausal syndrome treatment. Clin Exp Obst Gyn 1985; 12 (1-2): 1-2.
57. Fink RS, Collins W, Papadaki L, O’Reilly B, Ginsburg J. Vaginal oestriol: Effective
menopausal therapy not associated with endometrial hyperplasia. J Gynaec
Endocrinol 1985; 1: 1-11.
58. Weiderpass E, Baron J, Adami H, Magnusson C, Lindgren A, Bergstrom R, Correia
N, Persson I. Low-potency oestrogen and risk of endometrial cancer: a case-control
study. Lancet 1999; 353: 1824-28.
59. Michaelsson K, Baron J, Farahmand B, Ljunghall S. Use of low potency estrogens
does not reduce the risk of hip fractures. Bone 2002: 30 (4): 613-18.
60. Trevoux R, Van der Velden W, Popovic D. Ovestin vaginal cream and suppositiories
for the treatment of menopausal vaginal atrophy. Reproduction 1982; 6: 101-6.
61. Levy T, Yairi Y, Bar-Hava I, Shalev J, Orvieto R, Ben-Rafael Z. Pharmacokinetics
of the progesterone-containing vaginal table and its use in assisted reproduction.
Steroids 2000; 65: 645-49.
62. Kuhl H. Pharmacology of estrogens and progestogens: influence of different routes
of administration. Climacteric 2005; 8: 3-63.
63. Ficicioglu C, Gurbuz B, Tasdemir S, Yalti S, Canova H. High local endometrial
effect of vaginal progesterone gel. Gynecol Endocrinol 2004; 18: 240-243.
64. deLignieres B, Dennerstein L, Backstrom T. Influence of route of administration on
progesterone metabolism. Maturitas 1995; 21: 251-57.
65. Jaaskelainen a, Shaerer E, deZiegler D. Vaginal progesterone in menopause: long
term acceptability of a new therapeutic option for physiological progesterone
replacement. Maturitas 1997; OFC: 57.
66. Ando S, DeAmicis F, Rago V, Carpino A, Maggiolini M, Panno M, Lanzino M.
Breast cancer: from estrogen to androgen receptor. Mol Cellular Endocrin 2002; 193:
121-28.
67. Vooijs, GP, Geurts TBP. Review of the endometrial safety during intravaginal
treatment with estriol. Obstet Gynecol 1995; 62: 101-06
68. Bergkivist L, Adami H, Persson I, Hoover R, Schairer C. The risk of breast cancer
after estrogen and estrogen-progestin replacement. NEJM 1985; 321 (5): 293-97
69. Dew J, Eden J, Beller E, Magarey C, Schwartz P, Crea P, Wren B. A cohort study of
hormone replacement therapy given to women previously treated for breast cancer.
Climacteric 1998; 1: 137-42.
70. Dew J, Wren B, Eden J. A cohort study of topical vaginal estrogen therapy in women
previously treated for breast cancer. Climacteric 2003; 6: 45-52
71. Fournier A, Berrino F, Riboli E, Avenel V. Clavel-Chapelon F. Breast cancer risk in
relation to different types of hormone replacement therapy in the E3N-EPIC cohort.
Int. J. Cancer 2004; 114: 448-54.
72. Fournier A, Berrino F, Clavel-Chapelon F.Unequal risks for breast cancer associated
with different hormone replacement therapies; results from the E3N cohort study.
Breast Cancer Res Treat 2007; DOI 10.1007/s10549-007-9523-x
73. Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women
using estrogen-only therapy. Obstet Gynecol 2006; 108 (6): 1354-60.
74. Rosenberg L, Magnusson C, Lindstrom E, Wedren S, Hall P, Dickman P.
Menopausal hormone therapy and other breast cancer risk factors in relation to the
risk of different histological subtypes of breast cancer: a case-control study. Breast
Cancer Research 2006; 8 (1).
75. Ross D, Cooper A, Pryse-Davies J, Bergeron C, Collins W, Whitehead M.
Randomized, double-blind, dose-ranging study of the endometrial effects of a vaginal
progesterone gel in estrogen-treated postmenopausal women. Am J Obstet. Gynecol.
1997; 177:4, pp 937-41
76. Cicinelli E, Cignarelli M, Sabatelli S. Romano F, Schonauer L, Padovano R, Einer-
Jensen N. Plasma concentrations of progesterone are higher in the uterine artery than
in the radial artery after vaginal administration of micronized progesterone in an oilbased
solution to postmenopausal women. Fertility and Sterility 1998; 69:3, 471-73
77. Levine H, Watson N, Comparison of the pharmacokinetics of Crinone 8%
administered vaginally versus Prometrium administered orally in postmenopausal
women. Fertility and Sterility 2000; 73:3 pp 516-21
78. Bergink E, Kloosterboer J, van der Vies J. Oestrogen Binding Proteins in the
Female Genital Tract. J Steroid Biochem 1984: 20; 48 pp 1057-60.
79. Valdiva 00
80. Takahashi 00
81. Minaguchi 96
82. Guidozzi 99
83. Disaia 00
84. O’Meara 01
85. Peters 01
86. Durna 02
87. Decker 03
88. Durna 04
89. Vassilopoulou-Sellin 99
90. Martunen 01
91. Holmberg L, Anderson H. HABITS (hormonal replacement therapy after
breast cancer-is it safe?), a randomized comparison: trial stopped. Lancet 2004.
363: Feb; 453-55.
92. Von Schultz E, Rutqvisat L. Menopausal Hormone Therapy After Breast
Cancer: The Stockholm Randomized Trial. J Natl Cancer Inst 2005: 97 pp 533-
35.
93. Meurer L, Lena S. Cancer recurrence and mortality in women using hormone
replacement therapy after breast cancer: Meta-analysis. The Journal of Family
Practice 2002; 51:2 pp 1056-62.
94. Col N, Kim H, Chlebowski R. Menopausal hormone therapy after breast
cancer: a met-analysis and critical appraisal of the evidence. Breast Cancer
Research 2005; 7:4 pp 535-40.
95. Chang K-J, Fournier S, Lee T, deLignieres B, Linares-Cruz G. Influences of
percutaneous administration of estradiol and progesterone on human breast epithelial
cell cycle in vivo. Fertility and Sterility 1995; 83:4 pp 785-91.
96. Plu-Bureau G, Le M, Thalabard J, Sitruk-Ware R, Mauvais-Jarvis P. Percutaneous
progesterone use and risk of breast cancer: Results from a French cohort study of
premenopaual women with benign breast disease. Cancer Detection and Prevention
1999; 24:4 pp 290-96.
97. Key, Endogenous Hormones and Breast Cancer Collaborative Group. Body Mass
Index, Serum Sex Hormones, and Breast Cancer Risk in Postmenopausal Women.
Journal of the National Cancer Institute 2003; 95:16 pp. 1218-26.
98. Thomas H, Key T, Allen D, Moore J, Dowsett M, Fentiman I, Wang D. A prospective
study of endogenous serum hormone concentrations and breast cancer risk in
premenopausal women on the island of Guernsey. British Journal of Cancer 1997;
75:7 pp. 1075-79.
99. Ness R, Albano J, McTiernan A, Cauley J. Influence of Estrogen Plus Testosterone
Supplementation on Breast Cancer. Archives of Internal Medicine 2009; 169:1 pp.
41-46.
100.Papa V, Belfiore A. Insulin receptors in breast cancer: Biological and clinical role.
J. Endocrinol. Invest. 1996; 19: pp. 324-33.
101. Papa v, Reese C, Brunetti A, Vigneri R, Siiteri P, Goldfine I. Progestins increase
insulin receptor content and insulin stimulation of growth in human breast carcinoma
cells. Cancer Research 1990; 50: pp. 7858-62.
102. Marugo M, Bernasconti D, Miglietta L, Fazzuli L, Ravera F, Cassulo S, Gordano G.
Effects of dihyrotestosterone and hydroxyflutamide on androgen receptors in cultured
human breast cancer cells (EVSA-T). J. Steroid Biochem. Molec. Biol 1992; 42:5 pp.
547-54.
103. Hackenburg R, Hofmann J, Hölzel F, Schulz K-D. Stimulatory effects of androgen
and antiandrogen on the in vitro proliferation of human mammary carcinoma cells.
Cancer Research Clinical Oncology 1998; 114 pp 593-601.
* Dimitrakakis, Bondy, Glaser