“The Diag­no­sis and Mana­ge­ment of Pri­mary Hypothyroidism” 

vs.

Post Thy­roid Deficiencies

by Eric K. Pritchard, M.Sc. and Sheila Turner

The sta­te­ment “The Diag­no­sis and Mana­ge­ment of Pri­mary Hypothy­roi­dism” by the Royal College of Phy­si­cians pre­sents very serious health­care pro­blems for those patients with the post thy­roid defi­cien­cies of defi­cient periphe­ral meta­bo­lism or defi­cient hor­mone recep­tion by the periphe­ral cells. Nomi­nally, there should not be a con­flict because this sta­te­ment claims to address pri­mary hypothy­roi­dism only. Howe­ver, some of the sta­te­ments in conc­lu­sion have a far grea­ter breadth. They can only be inter­pre­ted to inc­lude post thy­roid defi­cien­cies with the unmis­ta­ka­ble prosc­rip­tion of all triio­dothy­ro­nine (T3) hor­mone repla­ce­ments. These repla­ce­ments are neces­sary for the lives and well-being of the post thy­roid defi­cient patient, and now, victim. 

There is a real con­flict bet­ween the vision, pur­pose, and objec­ti­ves of the Royal College of Phy­si­cians (RCP) and the diag­no­sis and treat­ment of post thy­roid defi­cien­cies. The clai­med highest medi­cal stan­dards fail to ack­now­ledge, diag­nose, and treat post thy­roid defi­cien­cies. Rather their stan­dard pro­mo­tes chro­nic suf­fe­ring for the vic­tims of these defi­cien­cies. In fact, for these vic­tims, the Royal College of Phy­si­cians has tur­ned the calen­dar back more than a cen­tury to do what medi­cine did then – nothing. King Henry VIII would be sorely disap­poin­ted in this por­tion of his legacy.

Ini­tially, the RCP sta­te­ment gives the thyroxine-resistant, post thy­roid defi­cient patient real hope. First, the RCP dec­la­red that their sta­te­ment was only on pri­mary hypothy­roi­dism, a defi­ciency of the thy­roid gland. Second, the RCP sta­ted that those with con­ti­nuing symp­toms of hypothy­roi­dism in spite of “nor­mal” levels of the thy­roid sti­mu­la­ting hor­mone (TSH) and thy­ro­xine (T4), should be inves­ti­ga­ted for non-thyroid sour­ces of their symp­toms. Since the periphe­ral meta­bo­lism sites are hos­ted by major organs, the hope was for medi­cine to finally be free to threat and miti­gate the other­wise chro­nic symp­toms of post thy­roid defi­cien­cies – defi­cient periphe­ral meta­bo­lism and defi­cient periphe­ral cellu­lar hor­mone reception.

Howe­ver, all hopes for high medi­cal stan­dards or any ratio­nal stan­dard for post thy­roid were dashed in the conc­lu­sion. Here, the Royal College of Phy­si­cians retur­ned to the pre-20th Cen­tury lack of appro­priate the­rapy with their prohi­bi­tion against any thy­roid hor­mone the­rapy for con­ti­nuing symp­toms of hypothyroidism. 

This situa­tion demands a com­pa­ri­son bet­ween the objec­ti­ves of the Royal College of Phy­si­cians with the post thy­roid defi­cient patients’ reality.

Vision, Pur­pose, and Objec­tive of the Royal College of Physicians

The Rea­lity of the Post Thy­roid Defi­cient Patient

Edu­ca­ted to the Highest Medi­cal Standards

The medi­cal science (see the annex) of the post thy­roid etio­lo­gies of the symp­toms of hypothy­roi­dism, circa 1970, is sys­te­ma­ti­cally igno­red and dis­mis­sed. [2 – 4]

Lea­ding Role in Deli­ve­ring High Qua­lity Patient Care

The patients are igno­red in favor of labo­ra­tory assays. When the “sub­jec­tive” patient pre­sen­ta­tion con­flicts with the “objec­tive” blood test, the test results take pre­ce­dence – the source of the con­flict is not inves­ti­ga­ted – it could be that the test is impro­per or impro­perly inter­pre­ted as thy­roid func­tion tests are for post thy­roid deficiencies.

Lea­ding Role in Deli­ve­ring High Qua­lity Patient Care – 

Con­ti­nued

The medi­cal care of the post thy­roid defi­cient patient is essen­tially no care. The presc­rip­tion by the Royal College of Phy­si­cian for these vic­tims is chro­nic suf­fe­ring and inc­rea­sed sus­cep­ti­bi­lity to disease, espe­cially life’s great killers, dia­be­tes and heart disease. [5 – 16]

The Royal College of Phy­si­cians is not lea­ding the way towards high qua­lity patient care but follo­wing the impro­per, unethi­cal care of post thy­roid defi­cient patients requi­red by other medi­cal asso­cia­tions, Bri­tish [17 – 19] and Ame­ri­can [20 – 25]

Lea­ding Role in Deli­ve­ring High Qua­lity Patient Care – 

Con­ti­nued

The Royal College of Phy­si­cians sta­te­ment on the diag­no­sis and mana­ge­ment of pri­mary hypothy­roi­dism is not logi­cally con­sis­tent. It also does not adhere to lin­guis­tic stan­dards of care set in the 17th Cen­tury and does not adhere to pro­to­cols for autho­ring medi­cal prac­tice gui­de­li­nes set forth by the Ame­ri­can Asso­cia­tion of Cli­ni­cal Endoc­ri­no­lo­gists [26] and others.

If this sta­te­ment on the diag­no­sis and main­te­nance of pri­mary hypothy­roi­dism were exa­mi­ned as stu­dies on medi­cal prac­tice gui­de­li­nes [27 – 29] would do, it would be jud­ged a fai­lure, pro­bably an abject failure. 

Cham­pio­ning the Values of the Medi­cal Profession

The medi­cal care presc­ri­bed by the Royal College of Phy­si­cians for the post thy­roid defi­cient patient vio­late nume­rous stan­dards of medi­cal ethics. Briefly they are the following:

Pro­vide a Good Stan­dard of Prac­tice and Care. Keep Your Pro­fes­sio­nal Know­ledge and Skills up to Date. The UK Gene­ral Medi­cal Coun­cil (2006)

Make the Care of Your Patient Your First Con­cern The UK Gene­ral Medi­cal Coun­cil (2006) 

Be Honest and Open and Act With Inte­grity. The UK Gene­ral Medi­cal Coun­cil (2006)

In the treat­ment of a patient, where pro­ven prophy­lac­tic, diag­nos­tic and the­ra­peu­tic methods do not exist or have been inef­fec­tive, the phy­si­cian, with infor­med con­sent from the patient, must be free to use unpro­ven or new prophy­lac­tic, diag­nos­tic and the­ra­peu­tic mea­su­res, if in the physician’s jud­ge­ment it offers hope of saving life, re-establishing health or alle­via­ting suf­fe­ring. Where pos­si­ble, these mea­su­res should be made the object of research, desig­ned to eva­luate their safety and effi­cacy. In all cases, new infor­ma­tion should be recor­ded and, where appro­priate, published. The other rele­vant gui­de­li­nes of this Dec­la­ra­tion should be follo­wed. (World Medi­cal Asso­cia­tion — Hel­sinki, 1964)

Impro­ving Stan­dards of Cli­ni­cal Practice

The cli­ni­cal prac­tice presc­ri­bed by the Royal College of Phy­si­cians for the post thy­roid defi­cient patient igno­res medi­cal science, the dif­fe­ren­tial diag­nos­tic pro­to­col, and evi­dence based medicine.

Impro­ving Stan­dards of Cli­ni­cal Practice – 

Con­ti­nued

Medi­cal science has ack­now­led­ged the exis­tence of the post thy­roid ope­ra­tions upon thy­roid hor­mo­nes – the con­ver­sion of the rela­ti­vely inac­tive pro-hormone, thy­ro­xine (T4), to the active hor­mone, triio­dothy­ro­nine (T3) and the recep­tion of T3 by the periphe­ral cells for the use in their nuc­lei. But these are not inc­lu­ded in any dif­fe­ren­tial diag­nos­tic expres­sed or implied. The evi­dence prof­fe­red by this medi­cal science must be con­si­de­red as part of cli­ni­cal prac­tice. Howe­ver, the rou­tine thy­roid labo­ra­tory assays do not exa­mine post thy­roid beha­vior. And the Royal College of Phy­si­cians has effec­ti­vely ban­ned all other poten­tial tests. This is con­trary to the wis­dom of sys­tem tes­ting, which demands tes­ting before and after every major function.

Even more basi­cally, the Royal College of Phy­si­cians is effec­ti­vely cove­ring up the short­falls of medi­cine for the post thy­roid defi­cient patient in the fog of impre­cise lan­guage which con­fu­ses these issues by desc­ri­bing phy­sio­lo­gi­cally dif­fe­rent issues by the same names and terms. [30]

Pro­mo­ting Patient-Centered Care

The care of post thy­roid defi­cient patients is dis­tinctly not cen­te­red on the patient. It is, howe­ver, cen­te­red upon one or more quite unpro­fes­sio­nal human frail­ties, such as igno­rance or impro­per dis­mis­sal of rela­tive medi­cal science.

The impro­per diag­no­sis of “func­tio­nal soma­to­form disor­ders” unfairly bla­mes the patients’ ima­gi­na­tions for their trea­ta­ble phy­si­cal defi­cien­cies. [31] The impro­per bla­ming of ina­de­quate medi­cine with “nons­pe­ci­fic symp­toms” also unfairly con­demns the patient to life-long chro­nic suf­fe­ring. [4]

If the Royal College of Phy­si­cian sta­te­ment were truly patient cen­te­red it would not prosc­ribe the the­ra­pies that have been pro­ven neces­sary in so many patients and are neces­sary in so many more. A study dis­co­ve­red of those trea­ted for hypothy­roi­dism, 13% were dis­sa­tis­fied with their medi­cal treat­ment and care [32] and worse. [33] These high dis­sa­tis­fac­tion rates are neither caring nor professional.

Sup­por­ting Phy­si­cians in their Prac­tice of Medicine

The Royal College of Phy­si­cians, by issuing the sub­ject sta­te­ment, has joi­ned other pro­fes­sio­nal socie­ties in for­cing a pro­fes­sio­nal dilemma upon phy­si­cians: Treat post thy­roid defi­cient patients ethi­cally and scien­ti­fi­cally and face the wrath of the Gene­ral Medi­cal Coun­cil. Or not trea­ting the patient pro­perly or ethi­cally. Either way, this is hardly being sup­por­tive of the prac­tice of medi­cine in the niche of post thy­roid defi­cien­cies. [30]

The Royal College is set­ting a stan­dard of care in the post thy­roid defi­ciency niche which is unrea­so­nably below the poten­tial demons­tra­ted by medi­cal science.

Pro­vide Lea­dership on Health and Health­care Issues

The Royal College of Phy­si­cians in sup­port of various endoc­ri­no­logy asso­cia­tions rela­tive to the know­ledge, diag­nos­tics, and health­care for the post thy­roid defi­cient patient has not lead but retrea­ted from modern medi­cal science, embra­ced the impre­cise lan­guage of this niche of medi­cal prac­tice, and crea­ted the basis for enfor­ce­ment for vir­tually tor­tu­ring of the post thy­roid defi­cient patient. This is dis­tinctly not health­care leadership.

Conc­lu­sion

The Royal College of Phy­si­cians began correctly by sta­ying within the title’s limit to pri­mary hypothy­roi­dism. Notably, con­ti­nuing symp­toms of hypothy­roi­dism (or its mimics) are sub­ject now for further medi­cal inves­ti­ga­tion for non-thyroid cau­ses. But then in the conc­lu­sion, for the vic­tims of hypothyroidism’s mimics, this is taken by the prosc­rip­tion of any thy­roid hor­mone repla­ce­ment for con­ti­nuing symp­toms in spite of poten­tial non-thyroid, post thy­roid cau­ses. This prosc­rip­tion is unfoun­ded in medi­cal science.

There are pro­po­nents for desic­ca­ted thy­roid, old [7] and new. [5,6] One study stands out in its giving lives back to patients. [34] Doc­tors Bai­sier, Her­toghe, and Eeckhaut trea­ted 40 fai­lu­res of the endoc­ri­no­logy esta­blish­ment with desic­ca­ted thy­roid with good results. And there are many more, for exam­ple. [35 – 39]

End­no­tes and References

  1. The Royal College of Phy­si­cians, The Diag­no­sis and Mana­ge­ment of Pri­mary Hypothy­roi­dism, Novem­ber 2008, Endor­sed by the Royal College of Gene­ral Prac­ti­tio­ners made on behalf of nume­rous endoc­ri­no­logy associations

  2. Gos­sel, TA, Endoc­ri­no­logy Con­ti­nuing Edu­ca­tion acc­re­di­ted by the Acc­re­di­ta­tion Coun­cil for Con­ti­nuing Medi­cal Edu­ca­tion (ACCME), 2005

  3. Gar­ber JR, Hypothy­roi­dism — Tal­king Points 2006, AACE

  4. “Wilson’s Syn­drome,” Ame­ri­can Thy­roid Asso­cia­tion, Nov 1999 upda­ted May 2005

  5. Starr, Mark MD, Hypothy­roi­dism Type 2, Mark Starr Trust, Colum­bia, MO, 2005

  6. Lowe JC, The Meta­bo­lic Treat­ment of Fibrom­yal­gia, McDo­well Publishing Com­pany, 2000

  7. Bar­nes, B MD, Hypothy­roi­dism: The Unsus­pec­ted Ill­ness, Har­per & Row, 1976, pgs 142 – 144, 178 – 181

  8. Ame­ri­can Thy­roid Asso­cia­tion, Hypothy­roi­dism, ©2005, a patient brochure avai­la­ble at the ATA web­site: www.thyroid.org

  9. Hypothy­roi­dism, a publi­ca­tion by the Ame­ri­can Asso­cia­tion of Cli­ni­cal Endoc­ri­no­lo­gists and sup­por­ted by Abbott Labo­ra­to­ries. 2006 & 2008. www.thyroidawareness.com

  10. Nikoo MH, Car­dio­vas­cu­lar Mani­fes­ta­tions of Hypothy­roi­dism, Shi­raz E-Medical J, 2(1) http://www.sums.ac.ir/semj/vol2/jan2001/hypothy&heart.htm

  11. Hak AE, Pols HAP, Vis­ser, TJ, et al., Low Thy­roid Func­tion Without Symp­toms as a Risk Indi­ca­tor for Heart Disease in Older Women, Ann of Intern Med, 15 Feb 2000, 132(4):270 – 278

  12. Camacho PM, Dwar­ka­nathan AA, Sick Euthy­roid Syn­drome, Post­gra­duate Medi­cine , April 1999, 105(4)

  13. Cana­ris GJ, Mano­witz NR, Mayor G, Ridg­way EC, The Colo­rado Thy­roid Disease Pre­va­lence Study, Arch Intern Med, Feb 28, 2000, 160(4)

  14. Thy­roid Pro­blems Inc­rease Risk of Heart Disease and Death, Ame­ri­can Thy­roid Asso­cia­tion, Oct 1, 2004

  15. Kvetny J, Held­gaard PE, Bladb­jerg EM, and Gram J, Subc­li­ni­cal Hypothy­roi­dism is Asso­cia­ted with a Low-Grade Inflam­ma­tion, Inc­rea­sed Trigly­ce­ride Levels, and Pre­dicts Car­dio­vas­cu­lar Disease in Males Below 50 Years, Clin Endoc­ri­nol, August 2004, 61(2):232

  16. Ier­vasi G, Pin­gi­tore A, Landi P., et al., Low-T3 Syn­drome –  A Strong Prog­nos­tic Pre­dic­tor of Death in Patients With Heart Disease, Clin Phy­siol Inst, Ame­ri­can Heart Asso­cia­tion ©2003

  17. Hypothy­roi­dism  – Cli­ni­cal Fea­tu­res and Treat­ment, a publi­ca­tion of the Bri­tish Thy­roid Asso­cia­tion, www.british-thyroid-association.org/guidelines.htm

  18. Van­der­pump MPJ, Ahl­quist JAO, Franklyn JA, et al., Con­sen­sus Sta­te­ment for Good Prac­tice and Audit Mea­su­res in the Mana­ge­ment of Hypothy­roi­dism and Hyperthy­roi­dism, BMJ, August 1996

  19. UK Gui­de­li­nes for the Use of Thy­roid Func­tion Tests, The Asso­cia­tion for Cli­ni­cal Bioche­mistry, Bri­tish Thy­roid Asso­cia­tion, Bri­tish Thy­roid Foun­da­tion, 2006, www.british-thyroid-association.org/guidelines.htm

  20. Bas­kin HJ, MD, Medi­cal Gui­de­li­nes for Cli­ni­cal Prac­tice for the Eva­lua­tion and Treat­ment of Hyperthy­roi­dism and Hypothy­roi­dism, Am Assoc Clin Endoc­ri­nol, 2002, Rev 2006

  21. Levy EG, Ridg­way EC, War­tofsky L, Algo­rithms for Diag­no­sis and Mana­ge­ment of Thy­roid Disor­ders, www.thyroidtoday.com 2004.

  22. The Ame­ri­can Thy­roid Asso­cia­tion pro­vi­des links to seve­ral hypothy­roi­dism rela­ted gui­de­li­nes: “Use of Labo­ra­tory Tests in Thy­roid Disor­ders,” “Treat­ment Gui­de­li­nes for Patients with Hyperthy­roi­dism and Hypothy­roi­dism,” and “Gui­de­li­nes for Detec­tion of Thy­roid Dysfunction.”

  23. Levy EG, Hypothy­roi­dism Treat­ment Fai­lure: Dif­fe­ren­tial Diag­no­sis, www.thyroidtoday.com 2004.

  24. Gar­ber JR, Hen­nes­sey JV, Lie­ber­man JA, Morris CM, Tal­bert RI, Mana­ging the Cha­llen­ges of Hypothy­roi­dism, Sup­ple­ment to J of Fam Pract, 2006, www.jponline.com

  25. Kaplan MM, Cli­ni­cal Pers­pec­ti­ves in the Diag­no­sis of Thy­roid Disease, Clin Chem, 1999, 45:8(B) 1377 – 1383

  26. Mecha­nic JI, Ber­man DA, Braith­waite SS, Palumbo PJ, Ame­ri­can Asso­cia­tion of Cli­ni­cal Endoc­ri­no­lo­gists Pro­to­col for Stan­dar­di­zed Pro­duc­tion of Cli­ni­cal Prac­tice Gui­de­li­nes, Endocr Pract, 2004, 10(4), Par­ti­cu­larly Table 4

  27. Sha­ney­felt TM, Mayo-Smith MF, Roth­wangl, J, Are Gui­de­li­nes Follo­wing Gui­de­li­nes?, JAMA, May 26, 1999., 281(20)

  28. Gri­lli R, Magrini N, Penna A, Mura G, Libe­rati A, Prac­tice Gui­de­li­nes Deve­lo­ped by Spe­cialty Socie­ties: The Need For a Cri­ti­cal Apprai­sal, Lan­cet, Jan 8, 2000.

  29. Bur­gers JS, Fer­vers B, Haugh M, Brou­wers M, Brow­man G, Clu­zeau PFA, Inter­na­ti­nal Assess­ment of the Qua­lity of Cli­ni­cal Prac­tice Gui­de­li­nes in Onco­logy Using the Apprai­sal of Gui­de­li­nes and Research and Eva­lua­tion Ins­tru­ment, J Clin Oncol, May 15, 2004, 22(10)

  30. Pritchard EK, “The Lin­guis­tic Etio­lo­gies of Thyroxine-Resistant Hypothy­roi­dism,” Thy­roid Science www.thyroidscience.com – click on “debate.”

  31. Weet­man AP, Whose Thy­roid Hor­mone Repla­ce­ment is it Any­way? Clin Endoc­ri­nol, 2006;64(3):231 – 233

  32. Sara­va­nan P, Chau F, Roberts N, Vedhara K, Green­wood R, Dayan CM, 2002, Psycho­lo­gi­cal Well-Being in Patients on “Ade­quate” Doses of L-Thyroxine Results of a Large, Con­tro­lled Community-Based Ques­tion­naire Study, Cli­ni­cal Endoc­ri­no­logy, 2002, 57: 577 – 585

  33. Tur­ner S, Hypothy­roi­dism Patient Sur­vey Results, Thy­roid Patient Advocacy-UK, http://www.tpa-uk.org/tpauk_survey.pdf

  34. Bai­sier, WV, Her­toghe, J., Eeckhaut, W., Thy­roid Insuf­fi­ciency? Is Thy­ro­xine the Only Valua­ble Drug?, J Nutr and Envi­ron Med, Sep­tem­ber 2001, 11(3):159 – 166

  35. Gaby AR, Sub-Laboratory Hypothy­roi­dism and the Empi­ri­cal use of Armour® Thy­roid, Alt Med Rev, 2004, 9(2)

  36. Danzi S and Klein I, Poten­tial Uses of T3 in the Treat­ment of Human Disease, Clin Cor­ners­tone, 2005, 7(S2): S9-S15

  37. Bune­va­cius, R MD PhD, Kaca­na­vi­cius, G MD PhD, Zalin­ki­ne­vi­cius, R MD, Prange, A MD, Effects of Thy­ro­xine as Com­pa­red with Thy­ro­xine plus Triio­dothy­ro­nine in Patients with Hypothy­roi­dism, NEJM, Feb 11, 1999, 340:424 – 429

  38. Bente C, Appelhof EF, Ellie MW, et al., Com­bi­ned The­rapy with Levothy­ro­xine and Liothy­ro­nine in Two Ratios, Com­pa­red with Levothy­ro­xine Monothe­rapy in Pri­mary Hypothy­roi­dism: a Double-Blind, Ran­do­mi­zed, Con­tro­lled Cli­ni­cal Trial, J Clin Endoc­ri­nol Meta­bol, 90(5):2666 – 2674.

  39. Her­toghe T, Lo Cas­cio A., Her­toghe J. Con­si­de­ra­ble impro­ve­ment of hypothy­roid symp­toms with two com­bi­ned T3–T4 medi­ca­tion in patients still symp­to­ma­tic with thy­ro­xine treat­ment alone. Anti-Aging Medi­cine, Ed. Ger­man Society of Anti-Aging Medicine-Verlag 2003– 2004; 32 – 43

Annex – Miles­to­nes in the His­tory of Thy­roid Rela­ted Discoveries

Circa

Event

1786

Asso­cia­tion bet­ween hyperthy­roid state and chan­ges in heart and eyes noted

1820

Iodide the­rapy used in Europe to treat goi­ters [Marine & Kimball]

1871

Cre­ti­nism described

1874

Myxe­dema (Gull’s disease) desc­ri­bed [Gull]

1883

Myxe­dema dis­co­ve­red after thy­roi­dec­tomy [Kocher]

1891

Thy­roid extract the­rapy for myxe­dema [Murray]

1895

Effect of thy­roid on con­tro­lling meta­bo­lic rate discovered

1912

Hashimoto’s disease described

1914

Thy­roid hor­mone dis­co­ve­red and crys­ta­lli­zed [Kendall]

1926

Struc­ture deter­mi­na­tion of thy­ro­xine (T4) [Harring­ton]

1952

Iden­ti­fi­ca­tion of triio­dothy­ro­nine (T3), the much more active thyroid-related hor­mone [Gross & Pitt-Rivers]

The thyroid-only hypothy­roi­dism para­digm became entrenched.

1950’s

Hypothyroidism-like malady that only res­ponds to T3

1958

First synthe­tic thy­ro­xine, Synth­roid®, mar­ke­ted without patent protection.

Some patients using synthe­tic thy­ro­xine con­ti­nue to exhi­bit symp­toms in spite of being assa­yed as “normal.”

1963

Thy­ro­tro­pin (TSH) purified

1960’s

Thy­ro­tro­pin (thy­roid sti­mu­la­ting hor­mone) assay deve­lo­ped [Uti­ger & Odell]

1967

Iden­ti­fies patients with resis­tance to T4, but res­pond to T3 [Refetoff]

1967

Resis­tance to thy­roid hor­mone recep­tion found [Refe­toff, Dewind, & DeGroot]

1970

Evi­dence that cir­cu­la­ting T3 was deri­ved lar­gely from periphe­ral mono­deio­di­na­tion (con­ver­sion) of T4 [Bra­ver­man, Ing­bar, & Sterling]

Medi­cal science now knows that there are post-thyroid cau­ses of hypothy­roi­dism –  but they are igno­red in prac­tice – medi­cal science is trum­ped by the esta­blished hypothy­roi­dism paradigm.

1971

Thy­ro­tro­pin immu­noas­says for diag­no­sis of hypothyroidism

1972

Iden­ti­fi­ca­tion of T3–bin­ding recep­tors in tissue

1990

Demons­tra­tions that point muta­tions in the thyroid-hormone recep­tor accoun­ted for hor­mone resistance

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