1. Compounded Testosterone Therapy in women
27 June, 2019
Rebecca L. Glaser, M.D.
Assistant Clinical Professor, Wright State University, Boonshoft School of Medicine, Department of Surgery

2. Outline Critical role of testosterone (T) Necessity
Safety and efficacy T implant therapy
Data on testosterone implants (PK)
Hormone levels (controversies)
The industry
Issues and controversies
Estradiol pellets, PK studies

3. “Difference of opinion leads to enquiry, and enquiry to truth;
and that, I am sure, is the ultimate and sincere object of us both.”
Thomas Jefferson 1815
Thomas Jefferson to P. H. Wendover, 1815

4. background
Critical role of testosterone

5. Sex drive and libido
‘Low T’

6. Lean muscle mass, strength, co-ordination, confidence (both sexes)
T known effect
ALTERNATE image: Physical perfection
DRGG National Champion 200 fly

7. Androgen Receptors Every organ system in both sexes
M. N. DIEUDONNE ´ , R. PECQUERY, A. BOUMEDIENE, M. C. LENEVEU, AND Y. GIUDICELLI. Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids the American Physiological Society
Kimura NORIKO, Mizokami ATSUSHI, Oonuma TETSUTAROU, Sasano HIRONOBU, Nagura HIROSHI. Immunocytochemical localization of androgen receptor with polyclonal antibody in paraffin-embedded human tissues. Journal of Histochemistry & Cytochemistry. 1993;41:
Takeda H. Immunohistochemical localization of androgen receptors with mono-and polyclonal antibodies to androgen receptor. 1990
Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are expressed in a variety of human tissues. Molecular and cellular endocrinology. 1996;120:51-57
Quigley CA, Bellis AD, Marschke KB, El-Awady MK, Wilson EM, French FS. Androgen Receptor Defects: Historical, Clinical, and Molecular Perspectives*. Endocrine reviews. 1995;16:
Richards M. Hidden in Plain Sight: A Real Solution to the Diseases of Aging and the Imploding Medicare System
Päivi Pihlajamaa, Biswajyoti Sahu, and Olli A. Jänne. Determinants of Receptor- and Tissue-Specific Actions in Androgen Signaling by the Endocrine Society
Merja Blӓuer, Annikki Vaalaski, Seija Liisa Pauli. Location of Androgen Receptor in Human Skin. J Invest Dermatol 97: , 1991
R. S. Calandra, K. Purvis, O. Naess, A. Attramadol, O. Djoseland, V. Hansson. Androgen receptors in the rat adrenal gland. Journal of Steroid Biochemistry Volume 9, Issue 10, October 1978, Pages
Chawnshang Chang, Shuyuan Yeh, Soo Ok Lee, and Ta-min Chang. Androgen Receptor (AR) Pathophysiological Roles in Androgen Related Diseases in Skin, Metabolism Syndrome, Bone/Muscle and Neuron/Immune Systems: Lessons Learned from Mice Lacking AR in Specific Cells. Nuclear Receptor Signaling 2013
Patrick M. Azcarate, Vincent D. Venincasa, William Feuer et all. Androgen Deficiency and Dry Eye Syndrome in the Aging Male. Investigative Ophthalmology & Visual Science, 2014
T. T. Schug, R. Abagyan, B. Blumberg, T. J. Collins, D. Crews, P. L. DeFur, S. M. Dickerson, T. M. Edwards, A. C. Gore, L. J. Guillette,j T. Hayes, J. J. Heindel, A. Moores, H. B. Patisaul, T. L. Tal, K. A. Thayer, L. N. Vandenberg, J. C. Warner, C. S. Watson, F. S. vom Saal, R. T. Zoeller, K. P. O’Brien and J. P. Myers. Designing endocrine disruption out of the next generation of chemicals. Green Chem., 2013, 15, 181
Dennis Lubahn, David R. Joseph, Patrick M. Sullivan, Huntington F. Willard, Frank S. French, Elizabeth M. Wilson. Cloning of Human Androgen Receptor Complementary DNA and Localization to the X Chromosome, 1988
Takahiro Matsumoto, Matomo Sakari, Maiko Okada, Atsushi Yokoyama, Sayuri Takahashi, Alexander Kouzmenko, and Shigeaki Kato. The Androgen Receptor in Health and Disease. Annu. Rev. Physiol :
CYNTHIA A. HEINLEIN AND CHAWNSHANG CHANG. The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions. Molecular Endocrinology 16: 2181–2187, 2002
S. Yu. Kalinchenko, I. A. Tyuzikov, Yu. A. Tishova, L. O. Vorslov. Testosterone Functions in Women. Part 1: General and Age-Specific Endocrine and Other Physiological Functions of Testosterone in Women. Gynecology Endocrinology No. 14 (115) / 2015
J.A. Stanleya, M.M. Aruldhasa, M. Chandrasekaranc, R. Neelamohana, E. Suthagara, K. Annapoornaa, S. Sharmilaa, J. Jayakumarc, G. Jayaramanb, N. Srinivasana, S.K. Banud. Androgen receptor expression in human thyroid cancer tissues: A potential mechanism underlying the gender bias in the incidence of thyroid cancers. Journal of Steroid Biochemistry & Molecular Biology 130, 105– 124, 2012
PETER J. SHERIDAN, HENRY C. McGILL, JR, JEAN C. LISSITZKY, and PIERRE M. MARTIN. The Primate Thyroid Gland Contains Receptors for Androgens. Endocrinology 115: 2154–2159, 1984
E. O. ABU, A. HORNER, V. KUSEC, J. T. TRIFFITT, AND J. E. COMPSTON. The Localization of Androgen Receptors in Human Bone. J Clin Endocrinol Metab 82: 3493–3497, 1997
P. J. RIEKKINEN, and MIKKO NIEMI. Androgen-Dependent Salivary Gland Protease in the Rat. Endodrinology 83: 1224, 1968
Wickham LA , Gao J, Toda I, Rocha EM, Ono M, Sullivan DA. Identification of androgen, estrogen and progesterone receptor mRNAs in the eye. Acta Ophthalmol Scand. 2000
Williams, Michelle D. MD; Roberts, Dianna PhD; Blumenschein, George R. Jr MD; Temam, Stephane MD; Kies, Merrill S. MD; Rosenthal, David I. MD; Weber, Randal S. MD; El-Naggar, Adel K. MD, PhD. Differential Expression of Hormonal and Growth Factor Receptors in Salivary Duct Carcinomas: Biologic Significance and Potential Role in Therapeutic Stratification of Patients. American Journal of Surgical Pathology, 2007
Intira Sriprasert,MD, Dwight W. Warren, PhD, Austin K. Mircheff, PhD, and Frank Z. Stanczyk, PhD. Dry eye in postmenopausal women: a hormonal disorder. Menopause: The Journal of The North American Menopause Society, 2015
Elizabeth A. Townsend, Virginia M. Miller, and Y. S. Prakash. Sex Differences and Sex Steroids in Lung Health and Disease. Endocrine Reviews 33: 1–47, 2012
Y.S. Prakash, Venkatachalem Sathish, and Elizabeth A. Townsend. Sex Steroid Signaling in the Airway. Springer International Publishing Switzerland 2014
Ulrich Kaiser, Jürgen Hofmann, Margret Schilli et all. Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer. International Journal of Cancer, 1996
C. Vermeulen-Meiners, J. Poortman, M. Nabuurs and J. H. H. Thijssen. The endogenous concentration and subcellular distribution of androgens in normal human premenopausal endometrium, myometrium and vagina. Gynecological Endocrinology, Vol. 2, No. 2 , Pages , 1988
Malcolm B. Hodgins Senior Lecturer, Rosemary C. Spike Research Fellow, Rona M. Mackie Professor, Allan B. MacLean Senior Lecturer. An immunohistochemical study of androgen, oestrogen and progesterone receptors in the vulva and vagina. British Journal of Obstetrics and Gynaecology, Vol. 105, pp , 1998
S. J. WEIL, K. VENDOLA, J. ZHOU, O. O. ADESANYA, J. WANG, J. OKAFOR, AND C. A. BONDY. Androgen Receptor Gene Expression in the Primate Ovary: Cellular Localization, Regulation, and Functional Correlations. J Clin Endocrinol Metab 83: 2479–2485, 1998
Veronica Torres-Estay, Daniela V Carreno, Ignacio F San Francisco, Paula Sotomayor, Alejandro S Godoy, and Gary J Smith. Androgen receptor in human endothelial cells. Journal of Endocrinology, 224, R131–R137, 2015
Mark Richards. A Real Solution to the Diseases of Aging and the Imploding Medicare System
Hen Prizant, Norbert Gleicher and Aritro Sen. Androgen actions in the ovary: balance is key. Journal of Endocrinology, 222, R141–R151, 2014
Yuanjie Niu, Saleh Altuwaijri, Kuo-Pao Lai, Chun-Te Wu, William A. Ricke, Edward M. Messing, Jorge Yao, Shuyuan Yeh, and Chawnshang Chang. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. PNAS, 2008
Luis M Montano, Julia Espinoza, Edgar Flores-Soto, Jaime Chavez and Mercedes Perusquıa. Androgens are bronchoactive drugs that act by relaxing airway smooth muscleandpreventingbronchospasm. Journal of Endocrinology, 222, 1–13, 2014
DONG KUN LEE AND CHAWNSHANG CHANG. ENDOCRINE MECHANISMS OF DISEASE Expression and Degradation of Androgen Receptor: Mechanism and Clinical Implication. The Journal of Clinical Endocrinology & Metabolism, 2008
Yasumasa Ikeda, Ken-ichi Aihara, Sumiko Yoshida, Masashi Akaike and Toshio Matsumoto. Effects of androgens on cardiovascular remodeling. Journal of Endocrinology 2012
Susan R Davis, Sarah Wahlin-Jacobsen. Testosterone in women—the clinical signifi cance. Lancet Diabetes Endocrinol 2015
Chawnshang Chang, Alan Saltzman, Shuyuan Yeh et all. Critical Reviews in Eukaryotic Gene Expression, 1995
Hepper PG, Shannon EA and Dornan JC. Sex differences in fetal mouth movements. Lancet, 1997
Pelletier G. Localization of androgen and estrogen receptors in rat and primate tissues. Histol Histopathol 2000
Beato M, Klug J. Steroid hormone receptors: an update. Hum Reprod Update 2000
Cloke B, Huhtinen K, Fusi L, Kajihara T, Yliheikkila M, Ho KK, Teklenburg G, Lavery S, Jones MC, Trew G et al. The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium. Endocrinology 2008
Handelsman DJ. Androgen physiology, pharmacology and abuse. In: De Groot LJ, Jameson JL (eds). Endocrinology, 6th edn. Philadelphia: Elsevier Saunders, 2009
Kumar RC, Thakur MK. Androgen receptor mRNA is inversely regulated by testosterone and estradiol in adult mouse brain. Neurobiol Aging 2004
Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome—a review. J Pediatr Adolesc Gynecol 2008
Pelletier G, Luu-The V, Li S, Labrie F. Localization and estrogenic regulation of androgen receptor mRNA expression in the mouse uterus and vagina. J Endocrinol 2004
Sar M, Lubahn DB, French FS, Wilson EM. Immunohistochemical localization of the androgen receptor in rat and human tissues. Endocrinology 1990
Yeh S, Tsai MY, Xu Q, Mu XM, Lardy H, Huang KE, Lin H, Yeh SD, Altuwaijri S, Zhou X et al. Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proc Natl Acad Sci USA 2002
Zoppi S, Marcelli M, Deslypere JP, Griffin JE, Wilson JD, McPhaul MJ. Amino acid substitutions in the DNA-binding domain of the human androgen receptor are a frequent cause of receptor-binding positive androgen resistance. Mol Endocrinol 1992
R.A. Campbell, P. Bhat- Nakshatri, N.M. Patel, D. Constantinidou, S. Ali, H. Nakshatri, Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance, J. Biol. Chem. 2001
T.E. Hickey, J.L. Robinson, J.S. Carroll, Tilley W.D. Minireview, The androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene, Mol. Endocrinol. 2012
P. Kabos, J. Finlay- Schultz, C. Li, E. Kline, C. Finlayson, J. Wisell, et al., Patient-derived luminal breast cancer xenografts retain hormone receptor heteroge- neity and help define unique estrogen-dependent gene signatures, Breast Cancer Res. Treat. 2012
V. Panet-Raymond, B. Gottlieb, L.K. Beitel, L. Pinsky, M.A. Trifiro, Interactions between androgen and estrogen receptors and the effects on their trans-activational properties, Mol. Cell. Endocrinol. 2000

8. Every organ system in both sexes
T function at the AR
Every organ system in both sexes
M. N. DIEUDONNE ´ , R. PECQUERY, A. BOUMEDIENE, M. C. LENEVEU, AND Y. GIUDICELLI. Androgen receptors in human preadipocytes and adipocytes: regional specificities and regulation by sex steroids the American Physiological Society
Kimura NORIKO, Mizokami ATSUSHI, Oonuma TETSUTAROU, Sasano HIRONOBU, Nagura HIROSHI. Immunocytochemical localization of androgen receptor with polyclonal antibody in paraffin-embedded human tissues. Journal of Histochemistry & Cytochemistry. 1993;41:
Takeda H. Immunohistochemical localization of androgen receptors with mono-and polyclonal antibodies to androgen receptor. 1990
Wilson CM, McPhaul MJ. A and B forms of the androgen receptor are expressed in a variety of human tissues. Molecular and cellular endocrinology. 1996;120:51-57
Quigley CA, Bellis AD, Marschke KB, El-Awady MK, Wilson EM, French FS. Androgen Receptor Defects: Historical, Clinical, and Molecular Perspectives*. Endocrine reviews. 1995;16:
Richards M. Hidden in Plain Sight: A Real Solution to the Diseases of Aging and the Imploding Medicare System
Päivi Pihlajamaa, Biswajyoti Sahu, and Olli A. Jänne. Determinants of Receptor- and Tissue-Specific Actions in Androgen Signaling by the Endocrine Society
Merja Blӓuer, Annikki Vaalaski, Seija Liisa Pauli. Location of Androgen Receptor in Human Skin. J Invest Dermatol 97: , 1991
R. S. Calandra, K. Purvis, O. Naess, A. Attramadol, O. Djoseland, V. Hansson. Androgen receptors in the rat adrenal gland. Journal of Steroid Biochemistry Volume 9, Issue 10, October 1978, Pages
Chawnshang Chang, Shuyuan Yeh, Soo Ok Lee, and Ta-min Chang. Androgen Receptor (AR) Pathophysiological Roles in Androgen Related Diseases in Skin, Metabolism Syndrome, Bone/Muscle and Neuron/Immune Systems: Lessons Learned from Mice Lacking AR in Specific Cells. Nuclear Receptor Signaling 2013
Patrick M. Azcarate, Vincent D. Venincasa, William Feuer et all. Androgen Deficiency and Dry Eye Syndrome in the Aging Male. Investigative Ophthalmology & Visual Science, 2014
T. T. Schug, R. Abagyan, B. Blumberg, T. J. Collins, D. Crews, P. L. DeFur, S. M. Dickerson, T. M. Edwards, A. C. Gore, L. J. Guillette,j T. Hayes, J. J. Heindel, A. Moores, H. B. Patisaul, T. L. Tal, K. A. Thayer, L. N. Vandenberg, J. C. Warner, C. S. Watson, F. S. vom Saal, R. T. Zoeller, K. P. O’Brien and J. P. Myers. Designing endocrine disruption out of the next generation of chemicals. Green Chem., 2013, 15, 181
Dennis Lubahn, David R. Joseph, Patrick M. Sullivan, Huntington F. Willard, Frank S. French, Elizabeth M. Wilson. Cloning of Human Androgen Receptor Complementary DNA and Localization to the X Chromosome, 1988
Takahiro Matsumoto, Matomo Sakari, Maiko Okada, Atsushi Yokoyama, Sayuri Takahashi, Alexander Kouzmenko, and Shigeaki Kato. The Androgen Receptor in Health and Disease. Annu. Rev. Physiol :
CYNTHIA A. HEINLEIN AND CHAWNSHANG CHANG. The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions. Molecular Endocrinology 16: 2181–2187, 2002
S. Yu. Kalinchenko, I. A. Tyuzikov, Yu. A. Tishova, L. O. Vorslov. Testosterone Functions in Women. Part 1: General and Age-Specific Endocrine and Other Physiological Functions of Testosterone in Women. Gynecology Endocrinology No. 14 (115) / 2015
J.A. Stanleya, M.M. Aruldhasa, M. Chandrasekaranc, R. Neelamohana, E. Suthagara, K. Annapoornaa, S. Sharmilaa, J. Jayakumarc, G. Jayaramanb, N. Srinivasana, S.K. Banud. Androgen receptor expression in human thyroid cancer tissues: A potential mechanism underlying the gender bias in the incidence of thyroid cancers. Journal of Steroid Biochemistry & Molecular Biology 130, 105– 124, 2012
PETER J. SHERIDAN, HENRY C. McGILL, JR, JEAN C. LISSITZKY, and PIERRE M. MARTIN. The Primate Thyroid Gland Contains Receptors for Androgens. Endocrinology 115: 2154–2159, 1984
E. O. ABU, A. HORNER, V. KUSEC, J. T. TRIFFITT, AND J. E. COMPSTON. The Localization of Androgen Receptors in Human Bone. J Clin Endocrinol Metab 82: 3493–3497, 1997
P. J. RIEKKINEN, and MIKKO NIEMI. Androgen-Dependent Salivary Gland Protease in the Rat. Endodrinology 83: 1224, 1968
Wickham LA , Gao J, Toda I, Rocha EM, Ono M, Sullivan DA. Identification of androgen, estrogen and progesterone receptor mRNAs in the eye. Acta Ophthalmol Scand. 2000
Williams, Michelle D. MD; Roberts, Dianna PhD; Blumenschein, George R. Jr MD; Temam, Stephane MD; Kies, Merrill S. MD; Rosenthal, David I. MD; Weber, Randal S. MD; El-Naggar, Adel K. MD, PhD. Differential Expression of Hormonal and Growth Factor Receptors in Salivary Duct Carcinomas: Biologic Significance and Potential Role in Therapeutic Stratification of Patients. American Journal of Surgical Pathology, 2007
Intira Sriprasert,MD, Dwight W. Warren, PhD, Austin K. Mircheff, PhD, and Frank Z. Stanczyk, PhD. Dry eye in postmenopausal women: a hormonal disorder. Menopause: The Journal of The North American Menopause Society, 2015
Elizabeth A. Townsend, Virginia M. Miller, and Y. S. Prakash. Sex Differences and Sex Steroids in Lung Health and Disease. Endocrine Reviews 33: 1–47, 2012
Y.S. Prakash, Venkatachalem Sathish, and Elizabeth A. Townsend. Sex Steroid Signaling in the Airway. Springer International Publishing Switzerland 2014
Ulrich Kaiser, Jürgen Hofmann, Margret Schilli et all. Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer. International Journal of Cancer, 1996
C. Vermeulen-Meiners, J. Poortman, M. Nabuurs and J. H. H. Thijssen. The endogenous concentration and subcellular distribution of androgens in normal human premenopausal endometrium, myometrium and vagina. Gynecological Endocrinology, Vol. 2, No. 2 , Pages , 1988
Malcolm B. Hodgins Senior Lecturer, Rosemary C. Spike Research Fellow, Rona M. Mackie Professor, Allan B. MacLean Senior Lecturer. An immunohistochemical study of androgen, oestrogen and progesterone receptors in the vulva and vagina. British Journal of Obstetrics and Gynaecology, Vol. 105, pp , 1998
S. J. WEIL, K. VENDOLA, J. ZHOU, O. O. ADESANYA, J. WANG, J. OKAFOR, AND C. A. BONDY. Androgen Receptor Gene Expression in the Primate Ovary: Cellular Localization, Regulation, and Functional Correlations. J Clin Endocrinol Metab 83: 2479–2485, 1998
Veronica Torres-Estay, Daniela V Carreno, Ignacio F San Francisco, Paula Sotomayor, Alejandro S Godoy, and Gary J Smith. Androgen receptor in human endothelial cells. Journal of Endocrinology, 224, R131–R137, 2015
Mark Richards. A Real Solution to the Diseases of Aging and the Imploding Medicare System
Hen Prizant, Norbert Gleicher and Aritro Sen. Androgen actions in the ovary: balance is key. Journal of Endocrinology, 222, R141–R151, 2014
Yuanjie Niu, Saleh Altuwaijri, Kuo-Pao Lai, Chun-Te Wu, William A. Ricke, Edward M. Messing, Jorge Yao, Shuyuan Yeh, and Chawnshang Chang. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. PNAS, 2008
Luis M Montano, Julia Espinoza, Edgar Flores-Soto, Jaime Chavez and Mercedes Perusquıa. Androgens are bronchoactive drugs that act by relaxing airway smooth muscleandpreventingbronchospasm. Journal of Endocrinology, 222, 1–13, 2014
DONG KUN LEE AND CHAWNSHANG CHANG. ENDOCRINE MECHANISMS OF DISEASE Expression and Degradation of Androgen Receptor: Mechanism and Clinical Implication. The Journal of Clinical Endocrinology & Metabolism, 2008
Yasumasa Ikeda, Ken-ichi Aihara, Sumiko Yoshida, Masashi Akaike and Toshio Matsumoto. Effects of androgens on cardiovascular remodeling. Journal of Endocrinology 2012
Susan R Davis, Sarah Wahlin-Jacobsen. Testosterone in women—the clinical signifi cance. Lancet Diabetes Endocrinol 2015
Chawnshang Chang, Alan Saltzman, Shuyuan Yeh et all. Critical Reviews in Eukaryotic Gene Expression, 1995
Hepper PG, Shannon EA and Dornan JC. Sex differences in fetal mouth movements. Lancet, 1997
Pelletier G. Localization of androgen and estrogen receptors in rat and primate tissues. Histol Histopathol 2000
Beato M, Klug J. Steroid hormone receptors: an update. Hum Reprod Update 2000
Cloke B, Huhtinen K, Fusi L, Kajihara T, Yliheikkila M, Ho KK, Teklenburg G, Lavery S, Jones MC, Trew G et al. The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium. Endocrinology 2008
Handelsman DJ. Androgen physiology, pharmacology and abuse. In: De Groot LJ, Jameson JL (eds). Endocrinology, 6th edn. Philadelphia: Elsevier Saunders, 2009
Kumar RC, Thakur MK. Androgen receptor mRNA is inversely regulated by testosterone and estradiol in adult mouse brain. Neurobiol Aging 2004
Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome—a review. J Pediatr Adolesc Gynecol 2008
Pelletier G, Luu-The V, Li S, Labrie F. Localization and estrogenic regulation of androgen receptor mRNA expression in the mouse uterus and vagina. J Endocrinol 2004
Sar M, Lubahn DB, French FS, Wilson EM. Immunohistochemical localization of the androgen receptor in rat and human tissues. Endocrinology 1990
Yeh S, Tsai MY, Xu Q, Mu XM, Lardy H, Huang KE, Lin H, Yeh SD, Altuwaijri S, Zhou X et al. Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proc Natl Acad Sci USA 2002
Zoppi S, Marcelli M, Deslypere JP, Griffin JE, Wilson JD, McPhaul MJ. Amino acid substitutions in the DNA-binding domain of the human androgen receptor are a frequent cause of receptor-binding positive androgen resistance. Mol Endocrinol 1992
R.A. Campbell, P. Bhat- Nakshatri, N.M. Patel, D. Constantinidou, S. Ali, H. Nakshatri, Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance, J. Biol. Chem. 2001
T.E. Hickey, J.L. Robinson, J.S. Carroll, Tilley W.D. Minireview, The androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene, Mol. Endocrinol. 2012
P. Kabos, J. Finlay- Schultz, C. Li, E. Kline, C. Finlayson, J. Wisell, et al., Patient-derived luminal breast cancer xenografts retain hormone receptor heteroge- neity and help define unique estrogen-dependent gene signatures, Breast Cancer Res. Treat. 2012
V. Panet-Raymond, B. Gottlieb, L.K. Beitel, L. Pinsky, M.A. Trifiro, Interactions between androgen and estrogen receptors and the effects on their trans-activational properties, Mol. Cell. Endocrinol. 2000

9. Testosterone (T) Most abundant active hormone in both sexes
Direct effect at the androgen receptor (AR)
Peripheral conversion of T is major source of estrogen in men and postmenopausal women
Longscope C. Adrenal and gonadal androgen secretion in normal female. J Clin Endocrinol Metab. 1986;15:
Burger HG. Androgen production in women. Fertility and sterility. 2002;77:3-5.
Labrie F. All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause. The Journal of steroid biochemistry and molecular biology. 2015;145:
AR

10. Testosterone > Estradiol levels
Throughout the entire female lifespan
Dimitrakakis. Androgens and the mammary gland. Fertility and Sterility 2002
Entire lifespan T > E2
Dimitrakakis 02

11. Adrenal androgens, pro-hormones Major source of T at the cellular level (75% of T)≅
Androstenedione
Reference Range
Adult Male
18-30 Years ng/dL
31-50 Years ng/dL
Adult Female 
Follicular ng/dL
Luteal ng/dL
DHEA
Reference Range
Adult Male
ng/dL
Adult Female
ng/dL
Important to understand when ‘levels on therapy’ are discussed
Significance

12. Androgens decline with age

13. Testosterone Peaks in women in their twenties Gradual decline
Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab. 2005;90:
Dimitrakakis C, Zhou J, Bondy CA. Androgens and mammary growth and neoplasia. Fertility and sterility. 2002;77:26-33.
Davison 05

14. Androstenedione (A4) 17B-HSD (T) Aromatase (E1)
IMPORTANT! A4 men = women. Direct precursor for T. Declines with age.
Significantly impacts testosterone activity at the cellular level
17B-HSD (T)
Aromatase (E1)

15. DHEA(S) 3B-HSD (A4)17B-HSD (T) 17B-HSD (Adiol)3B-HSD (T)
Make sure this is understood. DHEA also declines with age and is a source of T. Thousands times more DHEA > T
3B-HSD (A4)17B-HSD (T)
17B-HSD (Adiol)3B-HSD (T)

16. Labrie 17
Serum testosterone is not a valid marker of androgenic activity in women
...it is not surprising that despite long series of prospective and case-control cohort studies performed during the last 30 years, a correlation between serum testosterone and any clinical condition believed to be under androgenic control in women has remained elusive.
Controversial guidelines
Labrie F, Martel C, Bélanger A, Pelletier G. Androgens in women are essentially made from DHEA in each peripheral tissue according to intracrinology. The Journal of steroid biochemistry and molecular biology. 2017;168:9-18.

17. TRT: Serum T + DHEA(S) + Androstenedione
T at AR T
DHEA(S) A4
Men ≈ Women
30-40% 75% Locally
Endogenous
serum T
levels
(≈ 25%)
> x T T
>5 x T T
T’s affect at the cellular level
Stanczyk 03
IN postmenopausal women more than 75% of T (local/active) is synthesized from androgen precursors (versus 30-40% in men)
circulating androgens might be more important for maintaining localestrogen levels in extragonadal sites than are circulating estrogens.
Glaser R, Kalantaridou S, Dimitrakakis C. Testosterone implants in women: pharmacological dosing for a physiologic effect. Maturitas. 2013;74:
TRT (pellet), T levels delivered by the implant must replace T, A4, and DHEA at the cellular level. Androstenedione
Reference Range
Adult Male
18-30 Years ng/dL
31-50 Years ng/dL
51-60 Years ng/dL
Adult Female
Follicular ng/dL
Luteal ng/dL
Postmenopausal  20-75 ng/dL
DHEA
Adult
Male
ng/dL
Female
ng/dL
Intra and extracellular AR
Physiologic Effect

18. Symptoms of androgen deficiency Men and Women (pre and post menopausal)
Physical fatigue, exhaustion
Bone loss
Muscle wasting
Fat accumulation
Thin, dry skin, wrinkles, brittle hair and nails
Chronic pain, muscle aches, stiffness

19. Symptoms of androgen deficiency
Urinary incontinence, frequency, urgency
BPH
Vaginal atrophy
Decreased sex drive and libido
Impotence (decreased performance)

20. Symptoms of androgen deficiency
Dysphoric mood
Depression, anxiety, irritability, loss of confidence
Sleep disturbance, insomnia
Vasomotor instability (hot flashes)
Cognitive changes, decreased mental focus
Memory loss
Increased inflammation
Inflammation: implications in many diseases

21. Age associated diseases, T beneficial effect
Obesity
Coronary artery disease, CHF
Pulmonary disease, asthma, COPD
Insulin resistance, diabetes, metabolic syndrome
Cancer (immune function)
Neurological diseases, dementia
Osteoporosis, sarcopenia
References available upon request

22. Necessity
There is no FDA approved USP testosterone product for women in the United States

23. Compounded vaginal cream
Testosterone with estriol (E3)
Testosterone, estriol, and progesterone
Testosterone (+ P)
Initially began using in breast cancer patients for urogenital symptoms over 20 years ago
Non BCA patients
Vaginal dryness, urinary urgency, frequency, painful sex, etc.
Systemic symptoms
DATA
Glaser RL, Zava DT, Wurtzbacher D. Pilot study: absorption and efficacy of multiple hormones delivered in a single cream applied to the mucous membranes of the labia and vagina.
Gynecologic and obstetric investigation. 2008;66:
Article submitted to NAS committee on BHRT
Vaginal superior systemic absorption versus skin

24. USP Estriol (E3) Low binding affinity for myometrium and breast
High binding affinity in bladder and vagina
Vaginal estriol does not increase the risk or recurrence of breast cancer
Does not accumulate
OTC in Europe
Only available in compounded preparations in the US
Lack of data on the efficacy of topical estriol (skin)
Bergink 84
Dew 03
Kuhl 05
Low RBA

25. Affordable care Prices from GoodRx.com (23 June 2019) and WIP
*Excludes $6.95 shipping from WIP
Intrarosa (Endoceuticals)

26. Compounded T pellets, 80 years
1937 US both sexes
-Therapy for BCA
Compressed T powder
1972 FDA approved 75 mg T pellet, Testopel®
50, 100, and 200 mg T pellets Europe and Australia
Implants used in women (US) are compounded
Compounded formulations
T +Anastrozole (AI)
T + Finasteride
No bioequivalence testing

27. Greenblatt AJOG
…implantation of hard compressed pellets of crystalline steroids resulted in a slow and more physiologic absorption of the hormone
“…endogenous mechanism of hormonal secretion is more nearly approached and the physiologic action of the hormone more closely imitated.”
Greenblatt RB, Suran RR. Indications for hormonal pellets in the therapy of endocrine and gynecic disorders. American journal of obstetrics and gynecology. 1949;57:294

28. Indications for T pellets - 70 years
Menopausal symptoms in whom estrogen therapy has proved unsatisfactory or is contraindicated
Prevent uterine bleeding
Endometriosis
Fibroids
Nocturia
Low libido
Carcinoma of the breast
Addison’s disease
Anorexia
Greenblatt RB, Suran RR. Indications for hormonal pellets in the therapy of endocrine and gynecic disorders. American journal of obstetrics and gynecology. 1949;57:294

29. Breast cancer patients
It would be impossible to adequately treat breast cancer survivors without compounded formulations
Compounded vaginal testosterone + estriol cream + progesterone
T + anastrozole (an aromatase inhibitor) combination implant (2009)
DATA presented at ASCO 2010
‘The combination of testosterone with anastrozole, delivered subcutaneously, provides therapeutic levels of testosterone without elevating estradiol levels’.
Over 2,400 inserts
ASCO American Society of Clinical Oncology Breast Cancer Symposium

30. Significant

31. PK study. Glaser original data
T and E2 levels measured over time
T + AI prevents elevated E2 throughout the entire cycle

32. ASCO Breast cancer symposium 2014
Efficacy of subcutaneous T on symptoms in BCA patients
Validated QoL questionnaire (MRS)
Prospective study
BCA patients (Stage 0-4)
Compounded Testosterone + Anastrozole (A) implants
Documented therapeutic T levels on therapy
Glaser R, Dimitrakakis C. Efficacy of subcutaneous testosterone on menopausal symptoms in breast cancer survivors. J Clin Oncol 32, 2014 (suppl 26; abstract 109)
American Society of Clinical Oncology
N=72
IRB approved study

33. ASCO 2014 No ADE No disease recurrence
Glaser R, Dimitrakakis C. Efficacy of subcutaneous testosterone on menopausal symptoms in breast cancer survivors. J Clin Oncol 32, 2014 (suppl 26; abstract 109

34. Summary of distribution of severity scores pre and post therapy
Summary of distribution of severity scores pre and post therapy. P < in all symptom categories.
SS improvement in MRS total score and all 3 sub-scores

35. Quality of Life

36. 60 yo metastatic BCA 5/2015  62 yo met BCA since 2012
2015 Celexa, Ativan, Vicodin, Ambien, Supplements, Xeloda
Weak fragile severe pain bone pain from met disease (red arrow) 

37. On T + L implant therapy 11/2017 (Off Vicodin, Ativan, Ambien)
240 mg T 12 L 6F
Remains on Xeloda
Disease regression
Bone pain significantly improved

38. Quality of life Thriving 3.5 years T + L Compounded implants:
T 240 mg + Letrozole 12 mg
Finasteride 6 mg
TRT 11/2015
240 mg T 12 L 6F
Remains on Xeloda
Patient permission granted to use image

39. Survival
This patient wouldn’t be alive….

40. Therapy for breast cancer
Glaser RL, Dimitrakakis C. Rapid response of breast cancer to neoadjuvant intramammary testosterone-anastrozole therapy: neoadjuvant hormone therapy in breast cancer. Menopause (New York, NY). 2014;21:673.

41. 82 y. o. patient (180 mg T + 12 mg A) 31 May 2013 (3
82 y.o. patient (180 mg T + 12 mg A) 31 May 2013 (3.7 cm ) July 2013 (2.0 cm )
82 yo female with palpable infiltrating lobular carcinoma, palpable nodes
ER, PR positive, AR positive
Treated with Intra mammary testosterone 180 mg mg anastrozole

42. 19 weeks 31 May October 2013

43. T + Letrozole implant Side effects from chemotherapy
51 yo female diagnosed with 3.3 cm IDC
To receive pre-op chemotherapy
Testosterone (180 mg) + Letrozole (8 mg) implants
- 43% reduction in tumor at day 41, prior to starting CTX
- Complete pathological response
No long term effects (cardiac or neurological) from CTX
Glaser, R. L., York, A. E., and Dimitrakakis, C Subcutaneous testosterone-letrozole therapy before and concurrent with neoadjuvant breast chemotherapy: clinical response and therapeutic implications. Menopause. 24, 7,
Expected complete pathological response < 40%

44. Cost
<1% cost of CTX
>200,000 ($217,700)
>100,000 ($106,590)
$230 includes office visit, insertion procedure, review labs, and medical care for 3 months.

45. Research & Data
Efficacy and safety

46. In vitro dissolution studies
…continuous, zero-order release of the inventive T + A implant (T:A at a ratio of 15:1) was identical to the release of the T only implants (110 mg T and 85 mg T) and the Testopel® implant, and continued for more than 1400 minutes.

47. Efficacy in women Testosterone implants alone (no estrogen) N=300
Glaser R, York AE, Dimitrakakis C. Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS). Maturitas. 2011;68:
Testosterone implants alone (no estrogen)
N=300
108 premenopausal (35.3%)
IRB approved study 10-year incidence of BCA

48. Indications: T implants N=300 women, pre and post meno
Validated questionnaire MRS (Menopause Rating Scale)

49. Glaser, York, Dimitrakakis 2011
N=300
P < all 11 symptom categories
Glaser, York, Dimitrakakis 2011

50. Migraine headaches-testosterone implants
Glaser R, Dimitrakakis C, Trimble N, Martin V. Testosterone pellet implants and migraine headaches: a pilot study. Maturitas. 2012;71:

51. Voice changes
Prospectively followed 10 women treated with T pellet implants for one year
Mean T pellet dose mg
Measured fundamental frequencies at baseline, 3, 6, and 12 months
No change in fundamental frequency among subjects
FACT: There is no evidence that SQ testosterone therapy causes hoarseness or irreversible vocal cord changes in women
Glaser R, York A, Dimitrakakis C. Effect of testosterone therapy on the female voice. Climacteric. 2016;19:2;198.
Climacteric 2016, Vol. 19,No. 2,
Glaser R, York A, Dimitrakakis C. Effect of testosterone therapy on the female voice. Climacteric. 2016;19:2;198.

52. Box-whisker plot of fundamental frequency (F0) of all subjects at baseline, 3 months, 6 months and 12 months during subcutaneous testosterone therapy by context (Average, Conversation, Paragraph, and Sentence); the mid-line is the median, the boxes enclose data from the 25th percentile to the 75th percentile.

53. T is not excreted in breast milk
Testosterone, delivered by a subcutaneous pellet implant was effective in relieving symptoms of testosterone deficiency and was not measurably increased in breast milk or measurable in infant serum.
International Congress on Steroidal Hormones and Hormones & Cancer, Quebec City, Canada (September 2008)

54. Long term safety T implants
Glaser R, Dimitrakakis C. 58 BENEFICIAL EFFECTS OF SUBCUTANEOUS TESTOSTERONE THERAPY ON LIPID PROFILES IN WOMEN. Maturitas. 2012;71:S41.
Glaser RL, Dimitrakakis C. Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: a prospective, observational study. Maturitas. 2013;76:
Glaser, R. L., York, A. E., and Dimitrakakis, C Abstract #1435/Poster presentation. Reduced incidence of breast cancer with testosterone implant therapy: a 10-year cohort study San Antonio Breast Cancer Symposium , December: P
Over 60% reduction in the incidence of breast cancer
Higher levels of testosterone were associated with higher levels of HDL, lower levels of VLDL and lower levels of TG.

55. Safety of higher ‘male’ doses of T
mg doses of T used to treat BCA patient
Supra-physiologic doses in female to male transgender patients have been demonstrated to be safe
de Blok CJM, Wiepjes CM, Nota NM et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ. 2019;365:l1652.
Lamar CP, Rezek PR: Testosterone pellet implants for advanced breast carcinomatosis in the female; preliminary report. Journal of the American Geriatrics Society 1958, 6:
Segaloff: Hormone Therapy of Breast Cancer. Cancer treatment reviews 1975, 2:
Traish, A. M. and Gooren, L. J Safety of physiological testosterone therapy in women: Lessons from female‐to‐male transsexuals (FMT) treated with pharmacological testosterone therapy. The Journal of Sexual Medicine. 7, 11, DOI= /j x.
Streed CG, Harfouch O, Marvel F, Blumenthal RS, Martin SS, Mukherjee M. Cardiovascular Disease Among Transgender Adults Receiving Hormone Therapy: A Narrative Review. Ann Intern Med. 2017;167:

56. Research: Alliance cancer trial A221102
National double-blind randomized trial
Compounded combination T + A pellets
Compounded topical cream
Results under publication
Leon-Ferre, R, Le-Rademacher, J, Terstriep,S, Glaser, R. et.al Abstract #1434/Poster presentation. A randomized, double-blind, placebo-controlled trial of testosterone (T) for aromatase inhibitor-induced arthralgias (AIA) in postmenopausal women: Alliance A San Antonio Breast Cancer Symposium , December: P
Patients on T+AI pellets reported significantly less nausea (p=0.02), fatigue (p=0.04), mood swings (p=0.03), hand/feet swelling (p<0.01), stress urinary incontinence (p=0.04), and changes in skin appearance, texture or tone (p<0.01) compared to patients on Placebo pellets.

57. Pharmacokinetic studies
Glaser R, Kalantaridou S, Dimitrakakis C. Testosterone implants in women: pharmacological dosing for a physiologic effect. Maturitas. 2013;74:
Safety and efficacy of current T doses
Therapeutic levels on therapy
Controversial ES guideline recommendation (not based on evidence)
“… resulting in a mid-normal premenopausal value in a reference assay to avoid pharmacological T administration.”
Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline JCEM 2014
Strong recommendation based on no or lack of evidence.

58. Pharmacologic dosing for a physiologic effect
Female study T implants
Dose mg, range mg
Results
Week 4 levels (n=154), ng/dl
4-6 x endogenous range, 44/72 ng/dl
Symptoms returned (n=261), ng/dl
2-3 x endogenous range
Subset: Quest lab (n=154)
TT 185 ng/dl ( 2-45 ng/dl), fT 19 pg/ml ( pg/ml)
No ADE
Glaser, R., Kalantaridou, S., and Dimitrakakis, C Testosterone implants in women: pharmacological dosing for a physiologic effect. Maturitas. 74, 2,
Glaser, R., Kalantaridou, S., and Dimitrakakis, C Testosterone implants in women: pharmacological dosing for a physiologic effect. Maturitas. 74, 2,
Glaser, R. L Testosterone, anastrozole and venous thrombosis. Maturitas. 103, 91.
153 of these 261 patients had both free and total testosterone
performed by a single lab (Quest) at the ‘end’ of their pellet implantation.
The mean total T in this group was °æ
74.6 ng/dl
(range 47–461, CV 40.4%), over 4 times the upper limit of normal
for endogenous production (reference range total T: 2–45 ng/dl).
The mean free T level was °æ pg/ml (range 1.1–74.8,
CV 61.2%). The average free T prior to re-implantation was over
3 times the upper limits of normal for endogenous production (reference
range free T: 0.1–6.4 pg/ml).

59. Basic physiology 3B-HSD (A4)17B-HSD (T) 17B-HSD (Adiol)3B-HSD (T)
Make sure this is understood. DHEA also declines with age and is a source of T. Thousands times more DHEA > T
3B-HSD (A4)17B-HSD (T)
17B-HSD (Adiol)3B-HSD (T)

60. T at AR T Physiologic Effect
T replacement at the end organ (cellular level) Serum T + DHEA(S) + Androstenedione
T at AR T
DHEA(S) A4
Men ≈ Women
30-40% 75% Locally
Endogenous
serum T
levels
(≈ 25%)
> x T T
>5 x T T
Stanczyk 03
IN postmenopausal women more than 75% of T (local/active) is synthesized from androgen precursors (versus 30-40% in men)
circulating androgens might be more important for maintaining localestrogen levels in extragonadal sites than are circulating estrogens.
Glaser R, Kalantaridou S, Dimitrakakis C. Testosterone implants in women: pharmacological dosing for a physiologic effect. Maturitas. 2013;74:
TRT (pellet), T levels delivered by the implant must replace T, A4, and DHEA at the cellular level. Androstenedione
Reference Range
Adult Male
18-30 Years ng/dL
31-50 Years ng/dL
51-60 Years ng/dL
Adult Female
Follicular ng/dL
Luteal ng/dL
Postmenopausal  20-75 ng/dL
DHEA
Adult
Male
ng/dL
Female
ng/dL
Intra and extracellular AR
Physiologic Effect

61. Data FACT: Symptoms returned T levels 171 + 73 ng/dl
Levels on therapy apply only to the SQ implant
Basic physiology
Serum T levels reflect the contribution of androgen precursors to T available at the end organ
FACT: Symptoms returned T levels ng/dl
TT 185 ng/dl ( 2-45 ng/dl), fT 19 pg/ml ( pg/ml)
FACT: NO ADE in over 10-years of therapy

62. Male data on compounded implants
Glaser, R. L Testosterone, anastrozole, and venous thrombosis. Maturitas. 103, 91. Presented at EMAS Amsterdam 2017
SC T + A implant therapy does not increase and may lower the occurrence of venous thrombotic events.
Subcutaneous Testosterone Anastrozole Therapy in Men: Rationale, Dosing, and Levels on Therapy (Under publication IJPC 2019)
Low-dose anastrozole released from the combination implant maintained low estradiol levels throughout the implant cycle and prevented clinical side effects attributed to excess estrogen.

63. Myths and misconceptions
Glaser R, Dimitrakakis C. Testosterone therapy in women: Myths and misconceptions. Maturitas. 2013;74:
There is no data…. The biggest myth of all
80 years of data

64. conclusion
Compounded testosterone use in women 2019

65. Conclusion T is critical for health, and well-being
The gradual decline of T associated with aging is responsible for many of the adverse signs and symptoms of aging including mental and physical deterioration
TRT must be done with adequate doses
Clinical effect (benefits) vs. adverse events (risks)
-Not serum levels on therapy
Labrie, F., Bélanger, A., Cusan, L., Gomez, J.-L., and Candas, B Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. The Journal of Clinical Endocrinology & Metabolism. 82, 8,
Labrie F, Martel C, Bélanger A, Pelletier G. Androgens in women are essentially made from DHEA in each peripheral tissue according to intracrinology. The Journal of steroid biochemistry and molecular biology. 2017;168:9-18.
Glaser R, Kalantaridou S, Dimitrakakis C. Testosterone implants in women: pharmacological dosing for a physiologic effect. Maturitas. 2013;74:
Parker Jr, C. R., Slayden, S. M., Azziz, R., Crabbe, S. L., Hines, G. A., Boots, L. R., and Bae, S Effects of Aging on Adrenal Function in the Human: Responsiveness and Sensitivity of Adrenal Androgens and Cortisol to Adrenocorticotropin in Premenopausal and Postmenopausal Women 1. The Journal of Clinical Endocrinology & Metabolism. 85, 1,
Davison, S. L., Bell, R., Donath, S., Montalto, J. G., and Davis, S. R Androgen levels in adult females: changes with age, menopause, and oophorectomy. The Journal of Clinical Endocrinology & Metabolism. 90, 7,

66. Compounded hormones
Compounded hormones are critical to the care of millions of breast cancer patients in whom estrogen therapy is contraindicated
Compounded T + AI (anastrozole/letrozole) implants have been shown to treat breast cancers and improve QoL in breast cancer survivors
Maintain therapeutic T levels without raising estradiol levels
Compounded T + A implants prevent side effects of of excess estrogen in male and female patients

67. Compounded testosterone
Compounded testosterone implants have been safely used in women for over 80 years
Subcutaneous testosterone is clinically effective
Data exists on the safety, efficacy, and pharmacokinetics of compounded subcutaneous testosterone implants
There is a demand (over 80 years)
Supply: FDA approval in women????
There will still be a need for compounding!
Dosing
Inactive ingredients
Combination formulations

68. The Art of Medicine
Fildes captures so well: the sacred bond between doctor and patient.
HIDE CAPTION
A doctor tends to a mortally ill child in Sir Luke Fildes’s 1891 painting ‘The Doctor.’ Art Resource, NY

69. Hormone levels
To measure or not to measure

70. Critics of compounded BHRT
Under-dosing or overdosing
Can occur with compounded BHRT or conventional HT
Measuring levels on therapy is controversial
Ranges on (T) therapy are controversial but data supports efficacy and safety
Equivalence studies
No two patients absorb, distribute, metabolize, or excrete any medication the same
Sood R, Warndahl RA, Schroeder DR et al. Bioidentical compounded hormones: a pharmacokinetic evaluation in a randomized clinical trial. Maturitas. 2013;74:

71. Clinical decision vs. labs
Hormone levels fluctuate and are unreliable.
Standard of care: an individual patient should be treated based on his/her symptoms, response to therapy, as well as the benefits and risks of therapy.
An individual’s physical comfort may not be related to their absolute hormone levels.
Sherif K, Sherif K. Medical Association Guidelines, Post-2002/Women’s Health Initiative Findings. Hormone Therapy: A Clinical Handbook. 2013;21-3
Most important slide in the presentation

72. Known Testosterone’s effect is dose dependent
Huang G, Basaria S, Travison TG et al. Testosterone dose-response relationships in hysterectomized women with and without oophorectomy: effects on sexual function, body composition, muscle performance and physical function in a randomized trial. Menopause (New York, NY) 21:612-23, 2014.
Glaser R, York AE, Dimitrakakis C. Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS). Maturitas 68: , 2011.

73. Controversy: T levels on therapy (ES)
“Clinicians should maintain serum T levels during treatment in the mid-normal range for healthy young men”.
“… resulting in a mid-normal premenopausal value in a reference assay to avoid pharmacological T administration.”
NO EVIDENCE that this is effective therapy or that higher levels are associated with ADE
Do not specify method of delivery
No data that supports that statement ES statements
T effect is dose dependent even anti-hypertensive
Perusquía M, Herrera N, Ferrer M, Stallone JN. Antihypertensive effects of androgens in conscious, spontaneously hypertensive rats. The Journal of steroid biochemistry and molecular biology. 2017;167:

74. The data disagrees
Physiology disagrees

75. Clinically effect dose, No ADE

76. Weight/BMI and levels on therapy Week 1 levels women (preliminary data), Male data
Levels on therapy affected by weight/BMI
Women < 130 pounds have higher levels on therapy despite lower (weight based) dosing
Wt < ng/dl (mean dose 165 mg)
Wt > ng/dl (mean dose 213 mg)
Similar results in male patients (under publication IJPC)
The mean T level when symptoms return in men with a BMI <25 is ng/dl compared to (BMI 25-<30), ng/dl (BMI 30-<35), and ng/dl (BMI >35).
Midrange when symptoms return

77. Comparing apples to oranges.
Paul Cezanne 1895 Still life with Apples and Oranges
Cannot practically be compared. Incommensurable Ranges on therapy
False analogy

78. Micromanaging T levels
Reliability
Inter-individual variation
Intra-individual variation
_____________________________________
Therapy should be based on clinical effect and therapeutic response (benefits) vs. side effects (risks)
Inadequate doses are ineffective
231 vs. 310 ng/dl 79ng/dl

79. Mean T level 190.8 + 80 ng/dl (range 83-368, CV 41.9%) Zava, Glaser
Inter-individual variation
N=12
Twelve female patients all received 100 mg T implant
Normal range upper limit ng/dl
Similar results published 40 years ago.
Mean T level ng/dl (range , CV 41.9%) Zava, Glaser

80. Method of testing
Note: all but one patient remained in normal ranges. Patient 2, has highest serum levels on T.
End organ effect.
Mean pg/ml (range 17-86, CV 43.8%). Ref pg/ml (Zava, Glaser)

81. Single female patient tested over 26 h
Intra-individual variation
Single female patient tested over 26 h
Varies by over 200 ng/dl
Mean T level ng/dl (range , CV 25%) Zava, Glaser

82. ACOG Committee Opinion No. 532
Hormone level testing
(However) individualized testing in only indicated when a narrow therapeutic window exists for a drug or drug class
Steroid hormones… do not meet these criteria and thus do not require individualized testing.
August 2012 reaffirmed 2018
Compounded Bioidentical Menopausal Hormone Therapy

83. ACOG Hormone level testing cont.
If treatment is initiated for symptom control, subjective improvement in symptoms is the therapeutic end point, and there is no need to assess hormone levels.
Hormone therapy should not be titrated to hormone levels.
AGREED!

84. Compounded Bioidentical Hormones in Endocrinology Practice: An Endocrine Society Scientific Statement JCEM 2016
… there is no evidence that monitoring compounded HT with serial salivary or blood testing is effective, except in the case of thyroid hormone.
Compounded Bioidentical Hormones in Endocrinology Practice: An Endocrine Society Scientific Statement
Nanette Santoro, Glenn D. Braunstein, Cherie L. Butts, Kathryn A. Martin, Michael McDermott, and JoAnn V. Pinkerton
J Clin Endocrinol Metab, April 2016, 101(4):1318–1343

85. Idiom*
We continue to recommend against making a diagnosis of androgen deficiency syndrome in healthy women because there is a lack of a well-defined syndrome, and data correlating androgen levels with specific signs or symptoms are unavailable.
Versus
…recommend that HT be individualized on the basis of symptoms (not hormone levels)
*Idiom- Speaking/maintaining contradictory positions or beliefs, often self-serving
Androgen Therapy in Women: A Reappraisal:
An Endocrine Society Clinical Practice Guideline JCEM 2014
Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline JCEM 2014
Strong recommendation based on no or lack of evidence.

86. Labrie 17
Serum testosterone is not a valid marker of androgenic activity in women
...it is not surprising that despite long series of prospective and case-control cohort studies performed during the last 30 years, a correlation between serum testosterone and any clinical condition believed to be under androgenic control in women has remained elusive.
Labrie F, Martel C, Bélanger A, Pelletier G. Androgens in women are essentially made from DHEA in each peripheral tissue according to intracrinology. The Journal of steroid biochemistry and molecular biology. 2017;168:9-18.

87. Recommend testing for T JCEM 2014
5.2 If a woman is to be given a trial of T therapy, we suggest checking baseline T level and the use of an approved non-oral preparation for women (such as a transdermal patch, gel, or cream) if such a treatment is available
5.3 We suggest monitoring T levels 3–6 weeks after initiation of therapy and every 6 months thereafter to assess for patient overuse or signs of androgen excess
No evidence
Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline JCEM 2014
Strong recommendation based on no or lack of evidence.

88. Confused???
…baseline hormone measurements to replace “abnormal” hormone deficiencies has no basis in medical practice.
…HT be individualized on the basis of symptoms (not hormone levels) for menopausal women using HT with estrogen and/or progestin, or androgen.

89. Convictions are more dangerous enemies of truths than lies.
Friedrich Nietzsche

90. The industry
Specialty societies and COI

91. Cost FDA approved formulations versus compounded formulations
Bijuva TherapeuticsMD

92. Specialty societies (funded)
ES, NAMS, ACOG, IMS
Opinions
Guidelines
Journals
COI
KOL
Meetings
Presentations

93. Competition
Most articles, guidelines, and opinions expressing concern over compounded BHRT are sponsored by pharmaceutical companies (specialty societies)
Published in ‘Society’ Journals
Physician authors with COI
Ghost authors or paid marketing authors (e.g. Precise publications, LLC)
Pinkerton JV, Constantine GD. Compounded non-FDA-approved menopausal hormone therapy prescriptions have increased: results of a pharmacy survey. Menopause. 2016;23:
Santoro N, Braunstein GD, Butts CL, Martin KA, McDermott M, Pinkerton JV. Compounded Bioidentical Hormones in Endocrinology Practice: An Endocrine Society Scientific Statement. J Clin Endocrinol Metab. 2016;101:
Stanczyk FZ, Niu C, Azen C, Mirkin S, Amadio JM. Determination of estradiol and progesterone content in capsules and creams from compounding pharmacies. Menopause. 2019

94. COI Compounded hormones ES 2016 JCEM
Disclosure Summary: N.S. received grant support from Bayer, Inc and stock options from Menogenix; G.D.B. worked on the editorial staff at Merck, participated in a mock Food and Drug Administration meeting with Amgen, and worked as a consultant at Allergan; C.L.B. was employed at Biogen; K.A.M. and M.M. has nothing to declare; and J.V.P. received consultant fees from Pfizer, Noven Pharmaceuticals, Novo Nordisk, TherapeuticsMD, and Shionogi (paid directly to the University of Virginia),and received research grants from TherapeuticsMD and Endoceutics (paid directly to the University of Virginia).
2016
Compounded Bioidentical Hormones in Endocrinology Practice: An Endocrine Society Scientific Statement
J Clin Endocrinol Metab, April 2016, 101(4):1318–1343
Addressed in 22 June 2019 statement R Glaser

95. 2013 The following JCEM Editors reported relevant financial relationships:
The Editor-in-Chief, Leonard Wartofsky, M.D., is a Consultant for Asurogen, Genzyme, and IBSA, and is on the Speaker's Bureau for Genzyme. Kenneth Burman, M.D., is a Consultant for Medscape and UpToDate; a Reviewer for the Endocrine Fellows Foundation; and has received Institutional Grants for Research from Amgen, Eisei, and Pfizer. Samuel Dagogo-Jack, M.D., is a Consultant for Merck and Novo Nordisk; a Grantee for the American Diabetes Association, AstraZeneca, Boehringer Ingelheim, National Institutes of Health, and Novo Nordisk; and a Grant Reviewer for the American Diabetes Association and National Institutes of Health. Silvio Inzucchi, M.D., is a Consultant/Advisor for Boehringer Ingelheim, Genentech, Janssen, Merck, and Takeda; has DSMB Activity with Amgen, Esai, and Gilead; and receives CME support from Abbott, Amylin, Boeringher-Ingelheim, Merck, and Takeda. Kieren Mather, M.D., received an Investigator-initiated Grant from Novo Nordisk. Lynnette Nieman, M.D., is an Author/Editor for UpToDate, and receives Research Support from HRA-Pharmaceutical.

96. ES Corporate Liaison Board Members
Abbott Diabetes Care Inc.
AbbVie Inc.
Akcea Therapeutics
Amgen Inc.
Ascendis Pharma Inc.
AstraZeneca
Boehringer Ingelheim Pharmaceuticals, Inc.
Dexcom, Inc.
Insulet Corporation
Janssen Pharmaceuticals, Inc.
Lilly USA, LLC
Medtronic Diabetes
Merck & Co., Inc.
Merck-Pfizer Diabetes Collaboration
Novo Nordisk Inc.
Pfizer, Inc.
Sandoz
Sanofi
Shire International GmbH
Therapeutics MD, Inc.
Wyeth subsided- And guess who funded this firing squad disguised as a “discussion panel”?
You got it — Pfizer. NAMS 2015
In fact, 41% of hormone users reported choosing compounded products — often referred to as bioidenticals — over those approved by the US Food and Drug Administration (FDA).
NAMS officials and a panel of discussants spent an hour decrying the practice of prescribing "unsafe and unapproved" compounded hormones during a plenary, supported by a grant from Pfizer, here at the 2015 Annual Meeting.

97. ‘Classic faux-advocacy’
The Hormone Health Network offers a variety of programs and services to reach the public with important hormone-related information. Its strategies involve dissemination and promotion directly to consumers, physicians and consumer media. HHN welcomes the opportunity to collaborate with corporations, patient support groups, government agencies, and non-profit organizations to expand the reach of important health messages in creative ways.
ES website

98. Articles
Funding/support: TherapeuticsMD sponsored the study and provided support for final manuscript editing by Dominique Verlaan, PhD, CMPP (Precise Publications, LLC).
Financial disclosure/conflicts of interest: Dr Stanczyk consults for Agile Therapeutics, Mithra, and TherapeuticsMD. Chunying Niu has no conflicts of interest. Colleen Azen consults for TherapeuticsMD. Dr Mirkin is an employee of TherapeuticsMD with stock/stock options. Ms Amadio is an employee of TherapeuticsMD with stock/stock options.
2019 by The North American Menopause Society (Menopause)
Determination of estradiol and progesterone content in capsules and creams from compounding pharmacies
Vol. 26, No. 9, pp DOI: /GME by The North American Menopause Society
Precise Publications is a medical communications company specializing in writing results from clinical trials for publication and presentation, and providing medical and scientific content you can trust.

99. 2019 NAMS CORPORATE LIAISON COUNCIL
Amag Pharmaceuticals USA (View company website)
Amgen USA (View company website)
Ansh Labs (View company website)
Astellas Pharma
Duchesnay
EndoCeutics, Inc. (vaginal DHEA)
Pfizer Inc. (View company website)
Pharmavite LLC
Procter & Gamble Ventures
Radius Health (View company website)
TherapeuticsMD (View company website) (bio-identical E2 P)

100. Disclaimer omitted 2016 version
Published Online October 3, 2006 DISCLAIMER: Clinical Practice Guidelines are developed to be of assistance to endocrinologists by providing guidance and recommendations for particular areas of practice. The Guidelines should not be considered inclusive of all proper approaches or methods, or exclusive of others. The Guidelines cannot guarantee any specific outcome, nor do they establish a standard of care. The Guidelines are not intended to dictate the treatment of a particular patient. Treatment decisions must be made based on the independent judgment of healthcare providers and each patient’s individual circumstances.
ES guidelines

102. Compounding BHRT
Issues and controversies

103. Compounding False claims of superiority, proprietary pellets
Some pharmacies compound formulations without testing
Anastrozole alone implant
Omit autoclaving pellet, which heat fuses the implant and slows release. BUT, this has been dictated by some state boards of pharmacy.
Have not done dissolution testing
Gamma radiation may be acceptable
The FDA approved pellet is autoclaved and the process has worked for over 80 years.

104. Testing omitted

105. Against the routine use of estradiol pellets
Not a compounding issue
Physician decision
Not needed
T is the major source of estradiol at the cellular level
Continuous T provides adequate estradiol in the majority of women
Complications
Another speaker mentioned estradiol pellets

106. Estradiol pellet Estradiol can accumulate
Prolonged stimulation of the uterine lining (prolonged bleeding)
Increased risk of breast with higher doses MWS 03
Not removable (Treat with Tamoxifen)
No evidence to support dosing to suppress FSH
No evidence to support ‘minimum’ serum levels of E2
Most physicians prescribe lower doses of E2 (6-15 mg)
Limited data, safer
Estra pellet FDA approved for shipping overseas
Collaborators MWS. Breast cancer and hormone-replacement therapy in the Million Women Study. The Lancet. 2003;362:

107. Data does exist (Studd 94)
327 pmol/L = pg/ml ( )

108. References PK compounded estradiol implants
Stanczyk FZ, Shoupe D, Nunez V, Macias-Gonzales P, Vijod MA, Lobo RA. A randomized comparison of nonoral estradiol delivery in postmenopausal women. Am J Obstet Gynecol. 1988;159: Lobo RA, March CM, Goebelsmann U, Krauss RM, Mishell DR. Subdermal estradiol pellets following hysterectomy and oophorectomy. Effect upon serum estrone, estradiol, luteinizing hormone, follicle-stimulating hormone, corticosteroid binding globulin-binding capacity, testosterone-estradiol binding globulin-binding capacity, lipids, and hot flushes. Am J Obstet Gynecol. 1980;138: Studd JW, Holland EF, Leather AT, Smith RN. The dose-response of percutaneous oestradiol implants on the skeletons of postmenopausal women. Br J Obstet Gynaecol. 1994;101:

109. Comparison-equivalence
Studd 94

110. Randomized trial Compounded OMP 100 mg vs. Prometrium (100 mg)
Serum progesterone levels were comparable in conventional vs. compounded groups
Prometrium #30, $ with coupon
Generic #30, $22.75 with coupon
Compounded #30, $39.50
Topical BiEst, estradiol levels were not equivalent to the patch
Sood R, Warndahl RA, Schroeder DR et al. Bioidentical compounded hormones: a pharmacokinetic evaluation in a randomized clinical trial. Maturitas. 2013;74:
Sood R, Warndahl RA, Schroeder DR et al. Bioidentical compounded hormones: a pharmacokinetic evaluation in a randomized clinical trial. Maturitas. 2013;74:
GoodRx 6/26/19 pricing WIP

111. Critics of cBHRT Under-dosing or overdosing
Can occur with compounded BHRT or conventional HT
Measuring levels on therapy is controversial
Ranges on (T) therapy are controversial but data supports efficacy and safety
Equivalence
No two patients absorb, distribute, metabolize, or excrete any medication the same
Standard of care: an individual patient should be treated based on his/her symptoms, response to therapy, as well as the benefits and risks of therapy
Sood R, Warndahl RA, Schroeder DR et al. Bioidentical compounded hormones: a pharmacokinetic evaluation in a randomized clinical trial. Maturitas. 2013;74:

112. BHRT ‘movement’ Popularity Marketing Hype and claims
Micromanaging dosing based on repetitive testing
No data
Self appointed experts and their methodology
Data often only case presentations
Unsubstantiated claims of superiority
Unsubstantiated criticism of other therapies (blogs etc.)
Lack of data on some preparations
Safety is not an issue (excluding higher doses of estradiol)

113. Separate ‘compounding’ from ‘BHRT movement’
Ideology is here to stay
Individualized therapy
Listening to the patient
Bio-similar formulations (advantage)
There will always be a need for compounded BHRT

114. As for the right way, the correct way, and the only way,
You have your way.
I have my way.
As for the right way, the correct way, and the only way,
it does not exist.
Friedrich Nietzsche