Year : 2012 | Volume
: 3 | Issue : 3 | Page : 95--98
Does Gonadotropin Releasing Hormone Agonists plus add-back therapy bring an aurora to orthodontic treatment?
Jiang Lingyong1, Wang Chao2, Wu Yuqiong1, Zhang Peng1, Fang Bing1,
1 Department of Oral and Maxillofacial Surgery, Centre of Craniofacial Orthodontics Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, PR China
2 Department of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fu Dan University, Shanghai, PR China
Department of Oral and Maxillofacial Surgery, Centre of Craniofacial Orthodontics, Ninth People«SQ»s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key, Laboratory of Stomatology, Shanghai
Introduction: Obviously, long therapy time of orthodontic treatment and a number of its adverse effects, such as pain, root resorption, enamel demineralization, periodontal disease, are the main reasons of complaints from patients. It is the first thing for an orthodontist to shorten the period of treatment and decrease the complications of orthodontic treatment as much as possible. The Hypothesis: We hypothesis Gonadotropin Releasing Hormone Agonists (GnRHa) and add-back therapy can create the «DQ»therapeutic window«DQ», namely, the appropriate estrogen level and assuage the adverse effects of estrogen deficiency which should be avoided as much as possible. Evaluation of the Hypothesis: It is generally acknowledged that estrogen has direct regulating role in bone metabolism by acting on osteoblasts and osteoclasts. Estrogen deficiency can increase the rate of orthodontic tooth movement and also bring about some adverse effects. The appropriate estrogen level, which we call the «DQ»therapeutic window«DQ» in orthodontic treatment, can speed up the orthodontic tooth movement and eliminate the adverse effects as far as possible. GnRHa can be the maker of estrogen deficiency; meanwhile, add-back therapy can remove the adverse effects by estrogen deficiency. So, we believe that GnRHa plus add-back therapy could be a new adjuvant method of orthodontic treatment and be good for orthodontists and patients.
|How to cite this article:|
Lingyong J, Chao W, Yuqiong W, Peng Z, Bing F. Does Gonadotropin Releasing Hormone Agonists plus add-back therapy bring an aurora to orthodontic treatment?.Dent Hypotheses 2012;3:95-98
|How to cite this URL:|
Lingyong J, Chao W, Yuqiong W, Peng Z, Bing F. Does Gonadotropin Releasing Hormone Agonists plus add-back therapy bring an aurora to orthodontic treatment?. Dent Hypotheses [serial online] 2012 [cited 2020 Sep 27 ];3:95-98
Available from: http://www.dentalhypotheses.com/text.asp?2012/3/3/95/103915
To be an orthodontist, what is the most important thing to do when patients complain the long therapy time and a number of adverse effects, such as pain, root resorption, enamel demineralization, periodontal disease, and even give up the treatment. Obviously, how to shorten the time is the key. The shorter of the treatment time is, the little adverse effects are, the more patients stick to the treatment. That is the reasons all of orthodontists are investigating a shortened duration of treatment for patients.
Orthodontic Tooth Movement
Orthodontic tooth movement (OTM) is the result of bone remodeling at the interface with the periodontal ligament (PDL). Bone remodeling starts with resorption, in which the osteoclasts orchestrate. Osteoclasts break down bone by dissolving mineral and resorbing the matrix that osteoblasts have formed. After bone resorption, the bone formation begins consequently, which the osteoblasts administrate. During remodeling, the formation and resorption are more closely coupled at the same site. Whenever a tooth is subjected to an orthodontic force, it results in areas of pressure and tension. The alveolar bone is resorbed at the pressure side whenever the root causes compression of the periodontal ligament for a certain length of time. New alveolar bone is deposited at the tension side whenever there is stretching force acting on the periodontal ligament fibers. This is the simplest and the most widely accepted theory.
Although the theory is simple, the biologic processes of OTM is very complicated, involving in the reactions of both periodontal cells and extracellular matrix to orthodontic force application, the activities of both osteoblasts and osteoclasts, the processes of bone resorption and bone formation, and various factors, such as steroid hormones, dietary calcium and so on. ,, Among these aspects osteoblasts and osteoclasts are the focus of studies on OTM since they are in charge of bone formation and resorption.
Influences of Estrogen in Osteoblasts and Osteoclasts
It was in 1941 that Albright et al. first suggested a strong link between the decrease of estrogen levels and the onset of postmenopausal osteoporosis.  Since this first report, many studies had been conducted to assess the role of estrogen in osteocyteshomeostasis. When estrogen receptors had been identified in cultured human osteoblasts,  it was believed that estrogen has direct regulating role in bone metabolism. Up to now, it is generally acknowledged that so a certain amount of estrogen maintain the bone metastasis by acting on osteoblasts and osteoclasts.
It is evidenced that estrogen can increase the activities of osteoblasts in favor of bone formation through regulating the alkaline phosphatase (ALP) activity, osteoprotegerin (OPG) and so on. ,,, On the other hand, estrogen can inhibit the activities of osteoclasts to prevent bone resorption. Low estrogen levels can increase the activities of osteoclasts and the rate of bone turnover by regulating the levels of interleukin-1 and -6, tumor necrosis factor-alpha (TNF-a), receptor activator of nuclear factor kappa-B ligand (RANKL), macrophage colony-stimulating factor (M-CSF) and up-regulate T cell activity. ,,
Therefore, it was proven that estrogen can effect orthodontic tooth movement by regulate the activities of osteoblasts and osteoclasts and the rate of bone turnover.
Influences of Estrogen Deficiency on Orthodontic Tooth Movement
A study focused on the rate of buccal movement of molars induced by a force of 12.5 cN during the normal estrous cycle in rats. It was found that the rate of OTM was inversely related to the estrogen serum level.  There was an other study looked into the effect of ovariectomy on buccal movement of rat molars induced by a force of 10 cN showed a significant increase in the rate of OTM was established,  and the author also pointed out that a negative balance of bone metabolism could be exaggerated by accelerated bone metabolism induced by tooth movement, and osteopenia in alveolar bone might be a consequence. Seher observed that estrogen deficiency increased orthodontic tooth movement but also decreased the count of osteoblasts, and presented that although estrogen deficiency may help achieve a rapid correction, it may negatively affect the maintenance of this correction, that means, it may increase the relapse rate. 
These experimental results, proved estrogen deficiency accelerated tooth movement, almost derived from the osteoporosis animal models built by ovariectomy. That implicates the estrogen levels were as low as the menopausal level, which is usually 10 to 30 pg/mL. Moreover, according to the experimental results, oariectomy induced osteopenia and increased the indices of bone resorption and formation in the rat tibia as early as 14 days after surgery, and the maximal increase in the femur occurred up to a few months post-ovariectomy.  The effect of increased the mineral appositional rate and mineral formation rate on bone formation in alveolar bone by ovariectomy were found at 14 days post-ovariectomy. 
From above, estrogen deficiency can increase the rate of OTM, and the degree and duration of estrogen deficiency is the two key factors influencing the rate of OTM, although estrogen deficiency can bring about some adverse effects.
Here it comes, for the effects of estrogen deficiency on OTM, how to make the estrogen deficiency status? How to control exactly the degree and duration of estrogen deficiency? How to eliminate the consequent adverse effects causing by estrogen deficiency? That is resource of our hypothesis. We believe that using the appropriate estrogen level to speed up the OTM and eliminate the adverse effects as far as possible is absolutely a breach to solve that big problem above. The appropriate estrogen level is equal to the "therapeutic window" in orthodontic treatment, like in endometriosis treatment. Gonadotropin Releasing Hormone Agonists (GnRHa) can be the maker of estrogen deficiency, and add-back therapy can remove the adverse effects by estrogen deficiency. So, the combination GnRHa and add-back therapy can create the "therapeutic window". GnRHa plus add-back therapy, which is recommended to be the therapeutic standard reference for medical treatment of endometriosis, could be also suggested to the orthodontic patients for shorting the treatment time and consolidate curative effect.
Evaluation of the Hypothesis
GnRHa, the Maker for the Estrogen Deficiency
GnRH, a decapeptide, is released into the capillaries of the hypophyseal-portal circulation in a pulsatile fashion. It binds to specific receptors selectively on the anterior pituitary gonadotrophic cells, and activates intracellular signaling pathways that regulate both the production and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).  GnRHa, agonists and antagonists of GnRH, have been synthesized over the past 30 years. GnRHa have a greater affinity for the receptor than the native decapeptide, and produce a state of inhibition of secretion of gonadotropins and gonadal steroids. The ultimate effect of GnRHa is to determine a estrogen deficiency condition resembling the menopause or ovarievtomy.  In addition, GnRHa is safe, effective and generally well tolerated by most women,  because GnRHa has been recommended for treating endometriosis for many years.
GnRHa, Add-Back Therapy and "Therapeutic Window"
As said above, GnRHa can make the serum estrogen deficient level; unfortunately, estrogen deficiency by GnRHa at the same time brings about some unexpected effects, such as hot flushes, emotional lability, insomnia, and vaginal dryness. So, it need to add a low-dose continuous estrogen and interrupted progestin that is called add-back therapy, when symptoms of estrogen deficiency occur during treatment. ,
Estrogen concentration approximately in range of 30 to 45 pg/mL could be associated with no growth of endometriotic lesions and minimal changes in other tissues and organs, such bone. However, estrogen concentrations in the range of 10 to 20 pg/mL result in the loss of trabecular bone mineral, vasomotor symptoms, and so on.  So, it is usually the estrogen level needs to be controlled in range of 30 to 45 pg/mL with GnRHa plus add-back therapy by examining blood samples. The estrogen levels with range of 30 to45 pg/mL were named "therapeutic window" in endometriosis treatment.
"Therapeutic Window" in Orthodontic Treatment
OTM depends on the bone formation regulating by osteoblasts in tension side and resorption by osteoblasts in pressure side, of course, the curative effects of orthodontic treatment rely on the conditions of bone formation and resorption. Rapid OTM, maintenance of correct occlusion and minimal adverse effects are the ideal goals of orthodontic treatment. Since estrogen can act on both osteoblasts and osteoblasts, it is possible to regulate the estrogen levels to get the goals. Only focusing on the estrogen deficiency may neglect the importances of estrogen for health is inadvisable. Specifically, estrogen deficiency do can increase the rate of OTM which could help to short the time of treatment, but, during the orthodontic treatment estrogen deficiency can inhibit the activities of osteoblasts and hamper the bone formation which is also important for orthodontic treatment, and give us systenic symptoms of autonomic instability and psychological symptoms are regarded as components of the menopausal syndrome, those are not what we want. So, orthodontic treatment also needs the "Therapeutic window" if we want to decrease the estrogen levels to speed up the OTM and eliminate the adverse effects by estrogen deficiency.
Which estrogen level is the "Therapeutic window" in orthodontic treatment? Is it, like for endometriosis treatment, the range of 30 to 45 pg/mL too? We believe someday we can find the more precise "Therapeutic window" through more and more researches.
The work supported by the National natural science Foundation of China (30901698, 10972142) and Science and Technology Commission of Shanghai (08411961600).
|1||Masella RS, Meister M. Current concepts in the biology of orthodontic tooth movement. Am J Orthod Dentofacial Orthop 2006;129:458-68.|
|2||Meikle MC. The tissue, cellular, and molecular regulation of orthodontic tooth movement: 100 years after Carl Sandstedt. Eur J Orthod 2006;28:221-40.|
|3||Krishnan V, Davidovitch Z. Cellular, molecular, and tissue-level reactions to orthodontic force. Am J Orthod Dentofacial Orthop 2006;129:469 e1-32.|
|4||Albright FS, Richardson AM. Postmenopausal osteoporosis. JAMA 1941;116:2465-74.|
|5||Gray TK, Flynn TC, Gray KM, Nabell LM. 17 beta-estradiol acts directly on the clonal osteoblastic cell line UMR106. Proc Natl Acad Sci U S A 1987;84:6267-71.|
|6||Delaney MF. Strategies for the prevention and treatment of osteoporosis during early postmenopause. Am J Obstet Gynecol 2006;194 (2 Suppl):S12-23.|
|7||Coetzee M, Kruger MC. Osteoprotegerin-receptor activator of nuclear factor-kappaB ligand ratio: A new approach to osteoporosis treatment? South Med J 2004;97:506-11.|
|8||Ramaswamy B, Shapiro CL. Osteopenia and osteoporosis in women with breast cancer. Semin Oncol 2003;30:763-75.|
|9||Zhou Y, Fu Y, Li JP, Qi LY. The role of estrogen in osteogenetic cytokine expression in human periodontal ligament cells. Int J Periodontics Restorative Dent 2009;29:507-13.|
|10||D'Amelio P, Grimaldi A, Di Bella S, Brianza SZ, Cristofaro MA, Tamone C, et al. Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: A key mechanism in osteoporosis. Bone 2008;43:92-100.|
|11||Bodine PV, Harris HA, Komm BS. Suppression of ligand-dependent estrogen receptor activity by bone-resorbing cytokines in human osteoblasts. Endocrinology 1999;140:2439-51.|
|12||Haruyama N, Igarashi K, Saeki S, Otsuka-Isoya M, Shinoda H, Mitani H. Estrous-cycle-dependent variation in orthodontic tooth movement. J Dent Res 2002;81:406-10.|
|13||Yamashiro T, Takano-Yamamoto T. Influences of ovariectomy on experimental tooth movement in the rat. J Dent Res 2001;80:1858-61.|
|14||Arslan SG, Arslan H, Ketani A, Hamamci O. Effects of estrogen deficiency on tooth movement after force application: An experimental study in ovariectomized rats. Acta Odontol Scand 2007;65:319-23.|
|15||Wronski TJ, Cintron M, Doherty AL, Dann LM. Estrogen treatment prevents osteopenia and depresses bone turnover in ovariectomized rats. Endocrinology 1988;123:681-6.|
|16||Hsieh YD, Devlin H, McCord F. The effect of ovariectomy on the healing tooth socket of the rat. Arch Oral Biol 1995;40:529-31.|
|17||Janssens RM, Brus L, Cahill DJ, Huirne JA, Schoemaker J, Lambalk CB. Direct ovarian effects and safety aspects of GnRH agonists and antagonists. Hum Reprod Update 2000;6:505-18.|
|18||Guillemin R. Hypothalamic hormones a.k.a. hypothalamic releasing factors. J Endocrinol 2005;184:11-28.|
|19||Irahara M, Uemura H, Yasui T, Kinoshita H, Yamada M, Tezuka M, et al. Efficacy of every-other-day administration of conjugated equine estrogen and medroxyprogesterone acetate on gonadotropin-releasing hormone agonists treatment in women with endometriosis. Gynecol Obstet Invest 2001;52:217-22.|
|20||Vercellini P, Somigliana E, Vigano P, Abbiati A, Daguati R, Crosignani PG. Endometriosis: Current and future medical therapies. Best Pract Res Clin Obstet Gynaecol 2008;22:275-306.|
|21||Barbieri RL. Hormone treatment of endometriosis: The estrogen threshold hypothesis. Am J Obstet Gynecol 1992;166:740-5.|