Oxytocin is a peptide hormone produced in the hypothalamus and it is best known for its role in labor and lactation. Topical treatment with oxytocin appears to improve vaginal atrophy in postmenopausal women.
Oxytocin is available as a vaginal gel in doses ranging from 100-400IU per ml.
Oxytocin is a nano-peptide (nine amino acids) hormone secreted by the posterior pituitary. Oxytocin acts both peripherally and in the brain. Oxytocin is secreted by both males and females during orgasm and many consider it as the hormone of desire, social recognition and bonding.
Estrogen is known to increase the number of oxytocin receptors and to increase the release of oxytocin; this was demonstrated by Burbach and colleagues1 who studied the effect of 17β-estradiol on the activity of the oxytocin gene promoter, in vivo oxytocin messenger RNA and peptide levels in rats and reached this conclusion. Mohr and Schmitz2 also showed that the rat oxytocin gene harbors two functional estrogen-responsive elements near the transcription initiation site, one of which is conserved in the respective gene in humans, while Mitchell and colleagues3 studied plasma concentration levels in six women throughout the complete menstrual cycle and found a significant elevation in circulating oxytocin concentration associated with peak levels of luteinizing hormone which is known to be stimulated by estrogen.
Oxytocin improves cell growth depending on time and dose, and this is different to the effect of hormonal therapy. Also, oxytocin receptor expression was increased as well as caveolin-1, and hence cell proliferation4.
Some studies have found that oxytocin actually counteracts the development of some types of cancers, such as breast cancer, endometrial cancer, ovarian cancer and colon cancer. The mechanisms involved in these effects are induced via different pathways to those involved in the promotion of growth in normal cells. Kallak and Uvnäs-Moberg5 found that oxytocin stimulates cell proliferation, in vivo and in vitro, supporting the role of oxytocin signaling in cell proliferation.
These findings suggest that an increase in cell proliferation is one of the mechanisms of action by which local oxytocin increases vaginal thickness and relieves vaginal symptoms in postmenopausal vaginal atrophy.
Oxytocin also increases the rate of wound healing, mucosal blood flow and transport of nutrients as well as stimulation of secretion of several growth factors and induction of mitosis in several cell types5,6
Administration of oxytocin to the nasal musocsa resulted in an increase in oxytocin plasma levels from 20.8 ± 5.9 pg/mL at baseline to 41.1 ± 19.9 pg/mL after 15 minutes (P=.02) and 35.1 ± 16.4 pg/mL after 30 minutes (P=.07). After placebo administration, oxytocin plasma levels remained unaltered from baseline levels of 20.0 ± 3.2 pg/mL to 20.0 ± 5.2 pg/mL after 15 minutes and 20.7 ± 5.6 pg/mL after 30 minutes (repeated measures ANOVA, P<.001, between groups)
Oxytocinase, a glycoprotein aminopeptidase that is capable of degrading oxytocin, is produced during pregnancy and is present in the plasma. There is little or no degradation of oxytocin in nonpregnant women and men. Oxytocin is rapidly removed from plasma by the liver and kidneys, with only small amounts being excreted unchanged in the urine.
Jonasson and co-workers7 conducted a 7-day pilot study involving 20 patients equally divided into two groups and found 70% (seven out of ten cases) normalization of the vaginal epithelium on examination in the oxytocin group (p = 0.003), and a difference approaching significance in the morphological appearance of the vaginal mucosa as compared to the placebo group (p = 0.07);
Al-Saqi and co-workers8 conducted a double-blind, randomized, controlled trial to test the effectiveness on postmenopausal vaginal atrophy of vaginal oxytocin gel in two different concentrations, 400 IU (24 cases of which 17 cases completed the study), and 100 IU (24 cases of which 23 cases completed the study), versus placebo (16 cases of which 14 cases completed the study), for 7 weeks. In their study, women had increased superficial cells and maturation value of the vagina, in addition to a significant improvement in symptoms with the 400 IU dose (53% of women had improvement and this was highly significant compared with placebo), while the lower dose (100 IU) was more effective for pH, dyspareunia and the scores of vaginal atrophy by histological evaluation.
Al-Saqi and colleagues9 conducted a larger double-blind, randomized, controlled trial involving 68 patients divided into 33 patients receiving 600 IU vagitocin gel and 35 receiving placebo daily in the first 2 weeks, and then twice weekly for another 10 weeks. All cases were followed up for four to five visits by vaginal smears at each visit and vaginal biopsy in 20 of the women both pre- and post-treatment.
They found an increase in the proportion of superficial vaginal cells in the first 2 weeks (p = 0.04), a high difference in the maturation value in the first 12 weeks (p = 0.01), and a significant reduction in the scores of atrophy according to the histological parameter at 12 weeks (p < 0.04), all in favor of the vagitocin group. Based on their findings, they concluded that daily vagitocin administration improved vaginal atrophy both cytologically and histologically; the treatment was less effective when the vagitocin was used twice weekly
Torkey10 conducted a randomized controlled trial to test the effectiveness of topical oxytocin gel to improve vaginal atrophy in postmenopausal women. A total of 140 postmenopausal women presenting with vaginal atrophy and who satisfied the inclusion and exclusion criteria were randomized into two groups each of 70 patients; they received intravaginal oxytocin gel or placebo gel for 30 days. Serum estrogen level, visual, colposcopic and histological vaginal examination were performed before and after treatment. Forty-seven out of 70 women in the oxytocin gel group improved after treatment and none in the placebo group (p = 0.001). Forty-five participants in the oxytocin group and seven in the placebo group reported relief of dyspareunia (p = 0.001). Thirty-four participants in the oxytocin group and seven in the placebo group reported relief of soreness (p = 0.001). Torkey concluded that Oxytocin gel is useful in the restoration of the vaginal epithelium in cases of postmenopausal atrophic vaginitis.
Torkey10 also showed that the level of serum estrogen was not elevated after treatment with oxytocin vaginal gel, indicating that the mechanism of improved vaginal mucosa is not related to estradiol but oxytocin, and there were no side-effects for the applied treatments. Jonasson and colleagues7 also showed no significant difference in the circulating estradiol level in both groups. Thus, the effect of oxytocin is most likely exerted locally in the vagina and does not seem to be mediated by estrogen.
Oxytocin gel has been shown to be useful in the restoration of the vaginal epithelium in cases of postmenopausal atrophic vaginitis.10
100IU-400U Gel PV daily x 7-12 weeks, followed by a gradual reduction, based on symptom relief, until a maintenance dosage of 3-4 X weekly is achieved.
No specific maximum dosage limit recommendations are available. Dosage regimens of oxytocin depend upon the patient’s age, sex, weight, and condition being treated, product chosen, and the prescribing clinician’s judgment. Therefore, doses may vary widely and must be carefully individualized.
The common exclusion criteria in oxytocin studies are pregnancy, breastfeeding, severe medical/psychiatric illnesses, known allergies to ingredients of medication, excessive smoking or drinking, and other medication intake with associated reduction of sexual function. Oxytocin may possess antidiuretic effects, and prolonged use can increase the possibility of an antidiuretic effect.
Based on the study by Torkey10 et al, side effects are minimal to nonexistent.
Oxytocin presents a potential occupational hazard to men and women actively trying to conceive and women who are pregnant or may become pregnant, and are breast feeding, due to presence of the drug in breast milk.
Endogenous oxytocin is involved in the process of lactation and therefore, oxytocin has been used in mothers having difficulty with engorgement and breast feeding. Because several small studies have failed to show a beneficial effect, oxytocin is not used for this indication. Oxytocin is excreted in breast milk, but is not expected to have adverse effects in the infant.
Specific guidelines for dosage adjustments in renal and hepatic impairments are not available; it appears that no dosage adjustments are needed.
- Burbach JPH, Adan RAH, Van Tol HHM, et al. Regulation of the rat oxytocin gene by estradiol. J Neuroendocrinol 1990;2:633–9
- Mohr E, Schmitz E. Functional characterization of estrogen and glucocorticoid responsive elements in the rat oxytocin gene. Brain Res Mol Brain Res 1991;9:293–8
- Mitchell MD, Haynes PF, Anderson AB, et al. Plasma oxytocin concentration during the menstrual cycle. Eur J Obstet Gynaecol Reprod Biol 1982;12:195–200
- Jonasson AF, Markusson D. A pharmacokinetic study of vaginally and intravenously administered oxytocin in postmenopausal women with vaginal atrophy. Phase II Trial, Peptonic Medical. adisinsight.springer.com. 2017
- Kallak TK, Uvnäs-Moberg K. Oxytocin stimulates cell proliferation in vaginal cell line Vk2E6E7. Post Reprod Health 2017;23:6–12
- Uvnäs-Moberg K, Petersson M. Oxytocin, a mediator of anti-stress, well-being, social interaction, growth and healing. Z Psychosom Med Psychother 2005;51:57–80
- Jonasson AF, Edwall L, Uvnas-Moberg K. Topical oxytocin reverses vaginal atrophy in postmenopausal women: a double-blind randomized pilot study. Menopause Int 2011;17:120–5
- Al-Saqi SH, Uvnäs-Moberg K, Jonasson AF. Intravaginally applied oxytocin improves post-menopausal vaginal atrophy. Post Reprod Health 2015;21:88–97
- Al-Saqi SH, Jonasson AF, Naessen T, Uvnas-Moberg K. Oxytocin improves cytological and histological profiles of vaginal atrophy in postmenopausal women. Post Reprod Health 2016;22:25–33
- H. A. Torky, A. Taha, H. Marie, E. El-Desouky, O. Raslan, A. A. Moussa, A. M. Ahmad, A. Abo-Louz, S. Zaki, T. Fares & A. Eesa (2018) Role of topical oxytocin in improving vaginal atrophy in postmenopausal women: a randomized, controlled trial, Climacteric, 21:2, 174-178
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