Important Legal Disclaimer: This is an off-label use of botulinum toxin; no results are ever guaranteed (no therapy works every time). If considered, it should only be done by a physician who has been properly trained and certified to do the procedure and only after considering all other options, including the option to do nothing, and only after a signed consent that includes the fact that results may vary and are unpredictable for a new, off-label therapy and includes all the usual contraindications and possible side effects of botulinum toxin.
->Download the original research for the Clitoxin™ procedure with relevant references<–
->Where this lecture was recorded: the March 2024 meeting of the International Society of Cosmetic Gynecology
Summary of Mechanism of Action…
After Injecting botulinum neurotoxin (BoNT) into the clitoris, it is thought that (1) it is taken up by endocytosis and then migrates by axonal transport to the ganglion embedded in the wall of the vagina; (2) these ganglia then signal (through afferent autonomic nerves in the inferior hypogastric plexus) to trigger the hypothalamus (where the arousal center resides); (3) the activated hypothalamus triggers (through efferents going back to the genitalia and to the cerebral cortex) arousal, desire, and lubrication, and facilitate orgasm, combining to increase sexual satisfaction in the woman. This is in addition to the neovascularization, neurogenesis, and local vasodilation triggered by the BoNT. These effects can be amplified when the BoNT is combined with the regenerative properties of platelet-rich plasma. Here’s the original research by Runels and Runnels supporting these ideas (click to read).
References: start with the references in the original research for Clitoxin™ (click to read), then read the following references for a better understanding
- Botulinum Toxin used in the Corpus Cavernosum for Men (Clitoxin® is botulinum toxin injected into the corpus cavernosum of women)
- Botulinum Toxin: Neuronal Transport
- Botulinum Toxin Mechanism of Action with Migraine (gives clues to how the central effects of botulinum toxin would change libido and orgasm
- Regenerative Effects of Botulinum Toxin
- Guidelines with Off-Label Prescriptions (at least 21% of all prescriptions written) and why some well-proven therapies will never get FDA approval (and it’s not the fault of the FDA).
- A Quick Review of Why We Need an FDA-Approved Version of Testosterone for Women (but likely will never have one because of the “orphan” nature of the situation…see the references under off-label prescriptions)
- The O-Shot® and Clitorally-Injected PRP for Improved Sexual Function in Women
- The Placebo Effect in Studies of Female Sexual Function
- Why Saline is Not a Placebo in Regenerative Tissue Studies
- Why the Method of PRP Preparation Matters (added to the botulinum toxin, increased the effectiveness of Clitoxin™ by 50%)
- More about the phrase “lizard brain” and why normal function is needed even in the modern homosapien
Botulinum Toxin used in the Corpus Cavernosum for Men (Clitoxin® is botulinum toxin injected into the corpus cavernosum of women)
1.
Habashy E, Köhler TS. Botox for Erectile Dysfunction. The Journal of Sexual Medicine. 2022;19(7):1061-1063. doi:10.1016/j.jsxm.2022.03.216
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Porter DM. Botox: the new Viagra? It’s one way to treat erectile dysfunction.https://www.thetimes.co.uk/article/botox-could-help-men-beat-erectile-dysfunction-here-s-what-to-know-8x2vvt9c7. Accessed November 8, 2022.
3.
Morris JL, Jobling P, Gibbins IL. Botulinum neurotoxin A attenuates release of norepinephrine but not NPY from vasoconstrictor neurons. American Journal of Physiology-Heart and Circulatory Physiology. 2002;283(6):H2627-H2635. doi:10.1152/ajpheart.00477.2002
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Giuliano F, Denys P, Joussain C. Effectiveness and Safety of Intracavernosal IncobotulinumtoxinA (Xeomin®) 100 U as an Add-on Therapy to Standard Pharmacological Treatment for Difficult-to-Treat Erectile Dysfunction: A Case Series. Toxins. 2022;14(4):286. doi:10.3390/toxins14040286
5.
Phan K, Younessi S, Dubin D, Lin MJ, Khorasani H. Emerging off‐label esthetic uses of botulinum toxin in dermatology. Dermatologic Therapy. 2022;35(1). doi:10.1111/dth.15205
6.
Shehri ZG, Alkhouri I, Hajeer MY, Haddad I, Abu Hawa MH. Evaluation of the Efficacy of Low-Dose Botulinum Toxin Injection Into the Masseter Muscle for the Treatment of Nocturnal Bruxism: A Randomized Controlled Clinical Trial. Cureus. Published online December 4, 2022. doi:10.7759/cureus.32180
7.
Emura F, Peura D. Interview with Barry J. Marshall. Winner of the Nobel Prize in Medicine for the Discovery of Helicobacter pylori. :8.
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El-Shaer W, Ghanem H, Diab T, Abo-Taleb A, Kandeel W. Intra-cavernous injection of BOTOX® (50 and 100 Units) for treatment of vasculogenic erectile dysfunction: Randomized controlled trial. Andrology. 2021;9(4):1166-1175. doi:10.1111/andr.13010
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Giuliano F, Denys P, Joussain C. Safety and Effectiveness of Repeated Botulinum Toxin A Intracavernosal Injections in Men with Erectile Dysfunction Unresponsive to Approved Pharmacological Treatments: Real-World Observational Data. Toxins. 2023;15(6):382. doi:10.3390/toxins15060382
10.
Abdelrahman IFS, Raheem AA, Elkhiat Y, Aburahma AA, Abdel-Raheem T, Ghanem H. Safety and efficacy of botulinum neurotoxin in the treatment of erectile dysfunction refractory to phosphodiesterase inhibitors: Results of a randomized controlled trial. Andrology. 2022;10(2):254-261. doi:10.1111/andr.13104
11.
Giuliano F, Joussain C, Denys P. Safety and Efficacy of Intracavernosal Injections of AbobotulinumtoxinA (Dysport®) as Add on Therapy to Phosphosdiesterase Type 5 Inhibitors or Prostaglandin E1 for Erectile Dysfunction—Case Studies. Toxins. 2019;11(5):283. doi:10.3390/toxins11050283
Botulinum Toxin: Neuronal Transport
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2.
Ramachandran R, Yaksh TL. Therapeutic use of botulinum toxin in migraine: mechanisms of action. Br J Pharmacol. 2014;171(18):4177-4192. doi:10.1111/bph.12763
Botulinum Toxin Mechanism of Action with Migraine (gives clues to how the central effects of botulinum toxin would change libido and orgasm
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Argyriou AA, Mitsikostas DD, Mantovani E, Vikelis M, Tamburin S. Beyond chronic migraine: a systematic review and expert opinion on the off-label use of botulinum neurotoxin type-A in other primary headache disorders. Expert Review of Neurotherapeutics. 2021;21(8):923-944. doi:10.1080/14737175.2021.1958677
2.
Escher CM, Paracka L, Dressler D, Kollewe K. Botulinum toxin in the management of chronic migraine: clinical evidence and experience. Ther Adv Neurol Disord. 2017;10(2):127-135. doi:10.1177/1756285616677005
3.
Wang SJ. Comorbidities of migraine. Front Neur. 2010;4. doi:10.3389/fneur.2010.00016
4.
FDA official recomendations regarding Botox. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2011/103000s5236lbl.pdf
5.
Minen MT, Begasse De Dhaem O, Kroon Van Diest A, et al. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016;87(7):741-749. doi:10.1136/jnnp-2015-312233
6.
Chan TLH. OnabotulinumtoxinA Improves Quality of Life in Chronic Migraine: The PREDICT Study. Can J Neurol Sci. 2022;49(4):477-478. doi:10.1017/cjn.2021.159
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Zandieh A, Cutrer FM. OnabotulinumtoxinA in chronic migraine: is the response dose dependent? BMC Neurol. 2022;22(1):218. doi:10.1186/s12883-022-02742-x
8.
Ramachandran R, Yaksh TL. Therapeutic use of botulinum toxin in migraine: mechanisms of action. Br J Pharmacol. 2014;171(18):4177-4192. doi:10.1111/bph.12763
Regenerative Effects of Botulinum Toxin
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Franz CK, Puritz A, Jordan LA, et al. Botulinum Toxin Conditioning Enhances Motor Axon Regeneration in Mouse and Human Preclinical Models. Neurorehabil Neural Repair. 2018;32(8):735-745. doi:10.1177/1545968318790020
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Zhibo X, Miaobo Z. Botulinum toxin type A affects cell cycle distribution of fibroblasts derived from hypertrophic scar. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2008;61(9):1128-1129. doi:10.1016/j.bjps.2008.05.003
3.
Kasyanju Carrero LM, Ma W, Liu H, Yin X, Zhou B. Botulinum toxin type A for the treatment and prevention of hypertrophic scars and keloids: Updated review. J Cosmet Dermatol. 2019;18(1):10-15. doi:10.1111/jocd.12828
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Chernoff G. Combining topical dermal infused exosomes with injected calcium hydroxylapatite for enhanced tissue biostimulation. J of Cosmetic Dermatology. 2023;22(S1):15-27. doi:10.1111/jocd.15695
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Wang YX, Wang Y, Zhang Q, Zhang RD. Current Research of Botulinum Toxin Type A in Prevention and Treatment on Pathological Scars. Dermatol Surg. 2023;49(5S):S34-S40. doi:10.1097/DSS.0000000000003770
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Bushnell JY, Cates LN, Hyde JE, Hofstetter CP, Yang CC, Khaing ZZ. Early Detrusor Application of Botulinum Toxin A Results in Reduced Bladder Hypertrophy and Fibrosis after Spinal Cord Injury in a Rodent Model. Toxins. 2022;14(11):777. doi:10.3390/toxins14110777
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Rahman SHA, Mohamed MS, Hamed AM. Efficacy and safety of Nd:YAG laser alone compared with combined Nd:YAG laser with intralesional steroid or botulinum toxin A in the treatment of hypertrophic scars. Lasers Med Sci. 2021;36(4):837-842. doi:10.1007/s10103-020-03120-0
8.
Disphanurat W, Viarasilpa W, Thienpaitoon P. Efficacy of Botulinum Toxin A for Scar Prevention After Breast Augmentation: A Randomized Double-Blind Intraindividual Controlled Trial. Dermatol Surg. 2021;47(12):1573-1578. doi:10.1097/DSS.0000000000003198
9.
Matak, Bölcskei, Bach-Rojecky, Helyes. Mechanisms of Botulinum Toxin Type A Action on Pain. Toxins. 2019;11(8):459. doi:10.3390/toxins11080459
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Aru RG, Songcharoen SJ, Seals SR, Arnold PB, Hester RL. Microcirculatory Effects of Botulinum Toxin A in the Rat: Acute and Chronic Vasodilation. Annals of Plastic Surgery. 2017;79(1):82-85. doi:10.1097/SAP.0000000000001054
11.
Koo HS, Yoon MJ, Hong SH, et al. Non-invasive Intrauterine Administration of Botulinum Toxin A Enhances Endometrial Angiogenesis and Improves the Rates of Embryo Implantation. Reprod Sci. 2021;28(6):1671-1687. doi:10.1007/s43032-021-00496-4
12.
Lewandowski M, Świerczewska Z, Barańska-Rybak W. Off-Label Use of Botulinum Toxin in Dermatology—Current State of the Art. Molecules. 2022;27(10):3143. doi:10.3390/molecules27103143
Guidelines with Off-Label Prescriptions (at least 21% of all prescriptions written) and why some well-proven therapies will never get FDA approval (and it’s not the fault of the FDA).
1.
Radley DC, Finkelstein SN, Stafford RS. Off-label Prescribing Among Office-Based Physicians. Arch Intern Med. 2006;166(9):1021. doi:10.1001/archinte.166.9.1021
2.
Van Norman GA. Off-Label Use vs Off-Label Marketing of Drugs. JACC Basic Transl Sci. 2023;8(2):224-233. doi:10.1016/j.jacbts.2022.12.011
More about the “lizard brain” that is activated when botulinum toxin migrates to the ganglion to then activate the midhypothalamus<–
A Quick Review of Why We Need an FDA-Approved Version of Testosterone for Women (but likely will never have one because of the “orphan” nature of the situation…see the references under off-label prescriptions)
1.
Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women’s Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. The Journal of Sexual Medicine. 2021;18(5):849-867. doi:10.1016/j.jsxm.2020.10.009
The O-Shot® and Clitorally-Injected PRP for Improved Sexual Function in Women
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Runels C. A Pilot Study of the Effect of Localized Injections of Autologous Platelet Rich Plasma (PRP) for the Treatment of Female Sexual Dysfunction. J Women’s Health Care. 2014;03(04). doi:10.4172/2167-0420.1000169
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Wiśniewska-Ślepaczuk K, Pieczykolan A, Grzesik-Gąsior J, Wdowiak A. A Review of Aesthetic Gynecologic Procedures for Women. Plastic Surgical Nursing. 2021;41(4):191-202. doi:10.1097/PSN.0000000000000400
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4.
Castellani D, Valloni A, Piccirilli A, Paradiso Galatioto G, Vicentini C. An innovative approach to treating vaginal mesh exposure after abdominal sacral colpopexy: endoscopic resection of mesh and platelet-rich plasma; initial experience in three women. Int Urogynecol J. 2017;28(2):325-327. doi:10.1007/s00192-016-3154-x
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Callewaert G, Da Cunha MMCM, Sindhwani N, Sampaolesi M, Albersen M, Deprest J. Cell-based secondary prevention of childbirth-induced pelvic floor trauma. Nat Rev Urol. 2017;14(6):373-385. doi:10.1038/nrurol.2017.42
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Oshiro T, Kimura R, Izumi K, Ashikari A, Saito S, Miyazato M. Changes in urethral smooth muscle and external urethral sphincter function with age in rats. Physiological Reports. 2021;8(24):e14643. doi:10.14814/phy2.14643
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Saleh DM, Abdelghani R. Clinical evaluation of autologous platelet rich plasma injection in postmenopausal vulvovaginal atrophy: A pilot study. Journal of Cosmetic Dermatology. n/a(n/a). doi:10.1111/jocd.14873
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O’Connor E, Riogh AN an, Karavitakis M, Monagas S, Nambiar A. Diagnosis and Non-Surgical Management of Urinary Incontinence – A Literature Review with Recommendations for Practice. IJGM. 2021;14:4555-4565. doi:10.2147/IJGM.S289314
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Parizzi NG, Rubini OÁ, Almeida SHM de, Ireno LC, Tashiro RM, Carvalho VHT de. Effect of platelet-rich plasma on polypropylene meshes implanted in the rabbit vagina: histological analysis. International braz j urol : official journal of the Brazilian Society of Urology. 43(4):746-752. doi:10.1590/S1677-5538.IBJU.2016.0177
11.
Jhang JF, Jiang YH, Hsu YH, et al. Improved Urothelial Cell Proliferation, Cytoskeleton and Barrier Function Protein Expression in the Patients With Interstitial Cystitis/Bladder Pain Syndrome After Intravesical Platelet-Rich Plasma Injection. Int Neurourol J. 2022;26(Suppl 1):S57-67. doi:10.5213/inj.2142100.050
12.
Casabona F, Gasparini G, Cozzani E, et al. Improvement in quality of life and sexual function in patients affected by vulvar lichen sclerosus treated with combined autologous platelet-rich plasma and fat grafting. Eur J Dermatol. 2023;33(3):249-254. doi:10.1684/ejd.2023.4480
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Zubieta M, Carr RL, Drake MJ, Bø K. Influence of voluntary pelvic floor muscle contraction and pelvic floor muscle training on urethral closure pressures: a systematic literature review. Int Urogynecol J. 2016;27(5):687-696. doi:10.1007/s00192-015-2856-9
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Zheng Z. Materials Selection for the Injection into Vaginal Wall for Treatment of Vaginal Atrophy. Published online 2021:11.
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Jhang JF, Wu SY, Lin TY, Kuo HC. Repeated intravesical injections of platelet-rich plasma are effective in the treatment of interstitial cystitis: a case control pilot study. LUTS: Lower Urinary Tract Symptoms. 2019;11(2):O42-O47. doi:10.1111/luts.12212
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24
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The Placebo Effect in Studies of Female Sexual Function
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Why Saline is Not a Placebo in Regenerative Tissue Studies
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Why the Method of PRP Preparation Matters (added to the botulinum toxin, increased the effectiveness of Clitoxin™ by 50%)
1.
Kao DS, Zhang SW, Vap AR. A Systematic Review on the Effect of Common Medications on Platelet Count and Function: Which Medications Should Be Stopped Before Getting a Platelet-Rich Plasma Injection? Orthopaedic Journal of Sports Medicine. 2022;10(4):232596712210888. doi:10.1177/23259671221088820
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Smith OJ, Talaat S, Tomouk T, Jell G, Mosahebi A. An Evaluation of the Effect of Activation Methods on the Release of Growth Factors from Platelet-Rich Plasma. Plastic and Reconstructive Surgery. 2022;149(2):404-411. doi:10.1097/PRS.0000000000008772
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Fermín TM, Calcei JG, Della Vedova F, et al. Review of dohan eherenfest et al. (2009) on “classification of platelet concentrates: from pure platelet-rich plasma (p-prp) to leucocyte- and platelet-rich fibrin (l-prf).” Journal of ISAKOS. Published online August 2023:S205977542300545X. doi:10.1016/j.jisako.2023.07.010
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Ulasli AM, Ozturk GT, Cakir B, Celik GE, Bakir F. The effect of the anticoagulant on the cellular composition and growth factor content of platelet-rich plasma. Cell Tissue Bank. Published online August 28, 2021. doi:10.1007/s10561-021-09952-6
More about the phrase “lizard brain” and why normal function is needed even in modern homosapiens: the reptilian brain, also known as the lizard brain (click here & here for more about your lizard brain), is made up of primitive brain structures that date back to dinosaurs. It controls vital functions such as breathing, heart rate, body temperature, balance, and the desire for sex and orgasm. The reptilian brain includes the brainstem, cerebellum, and basal ganglia.