Atrophic vaginitis: Difference between revisions
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====Pathogenesis==== | ====Pathogenesis==== | ||
The pathogenesis of atrophic vaginitis is due to decreased estrogen levels. Estrogen is a vasoactive hormone, which increases blood flow and maintain vaginal lubrication through fluid transudation from blood vessels.<ref name="pmid27472999">{{cite journal |vauthors=Gandhi J, Chen A, Dagur G, Suh Y, Smith N, Cali B, Khan SA |title=Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management |journal=Am. J. Obstet. Gynecol. |volume= |issue= |pages= |year=2016 |pmid=27472999 |doi=10.1016/j.ajog.2016.07.045 |url=}}</ref> The following are the manifestations of decreased estrogen levels:<ref name="pmid27472999">{{cite journal |vauthors=Gandhi J, Chen A, Dagur G, Suh Y, Smith N, Cali B, Khan SA |title=Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management |journal=Am. J. Obstet. Gynecol. |volume= |issue= |pages= |year=2016 |pmid=27472999 |doi=10.1016/j.ajog.2016.07.045 |url=}}</ref><ref name="pmid20042564">{{cite journal |vauthors=Mac Bride MB, Rhodes DJ, Shuster LT |title=Vulvovaginal atrophy |journal=Mayo Clin. Proc. |volume=85 |issue=1 |pages=87–94 |year=2010 |pmid=20042564 |pmc=2800285 |doi=10.4065/mcp.2009.0413 |url=}}</ref><ref name="pmid9332260">{{cite journal |vauthors=Pandit L, Ouslander JG |title=Postmenopausal vaginal atrophy and atrophic vaginitis |journal=Am. J. Med. Sci. |volume=314 |issue=4 |pages=228–31 |year=1997 |pmid=9332260 |doi= |url=}}</ref> | The pathogenesis of atrophic vaginitis is due to decreased estrogen levels. Estrogen is a vasoactive hormone, which increases blood flow and maintain vaginal lubrication through fluid transudation from blood vessels.<ref name="pmid27472999">{{cite journal |vauthors=Gandhi J, Chen A, Dagur G, Suh Y, Smith N, Cali B, Khan SA |title=Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management |journal=Am. J. Obstet. Gynecol. |volume= |issue= |pages= |year=2016 |pmid=27472999 |doi=10.1016/j.ajog.2016.07.045 |url=}}</ref> The following are the manifestations of decreased estrogen levels:<ref name="pmid27472999">{{cite journal |vauthors=Gandhi J, Chen A, Dagur G, Suh Y, Smith N, Cali B, Khan SA |title=Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management |journal=Am. J. Obstet. Gynecol. |volume= |issue= |pages= |year=2016 |pmid=27472999 |doi=10.1016/j.ajog.2016.07.045 |url=}}</ref><ref name="pmid20042564">{{cite journal |vauthors=Mac Bride MB, Rhodes DJ, Shuster LT |title=Vulvovaginal atrophy |journal=Mayo Clin. Proc. |volume=85 |issue=1 |pages=87–94 |year=2010 |pmid=20042564 |pmc=2800285 |doi=10.4065/mcp.2009.0413 |url=}}</ref><ref name="pmid9332260">{{cite journal |vauthors=Pandit L, Ouslander JG |title=Postmenopausal vaginal atrophy and atrophic vaginitis |journal=Am. J. Med. Sci. |volume=314 |issue=4 |pages=228–31 |year=1997 |pmid=9332260 |doi= |url=}}</ref> | ||
*A hypoestrogenic state, such as that seen in menopause | *A hypoestrogenic state, such as that seen in menopause causes breakdown of collagen and elastic fibres in the vagina resulting in vaginal epithelium to lose its rugae to become thin and pale or erythematous with fine petechial hemorrhages and a narrow and shortened vagina. | ||
*Decreased glycogen content within the epithelium due to decreased thickness leads to less glycogen content available for the [[lactobacilli]] to utilize and turn it into [[lactic acid]]. As a result, the vaginal pH rises with a resultant overgrowth of other bacteria, such as [[group B streptococci]], [[Staphylococci]] and diptheroids resulting in recurrent vaginal infections and [[UTI]]. | *Decreased glycogen content within the epithelium due to decreased thickness leads to less glycogen content available for the [[lactobacilli]] to utilize and turn it into [[lactic acid]]. As a result, the vaginal pH rises with a resultant overgrowth of other bacteria, such as [[group B streptococci]], [[Staphylococci]] and diptheroids resulting in recurrent vaginal infections and [[UTI]]. | ||
Revision as of 17:59, 11 January 2017
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]
Synonyms and keywords: Atrophic vulvovaginitis; vaginal atrophy; urogenital atrophy; genitourinary syndrome of menopause
Overview
Historical Perspective
Classification
Pathophysiology
Pathogenesis
The pathogenesis of atrophic vaginitis is due to decreased estrogen levels. Estrogen is a vasoactive hormone, which increases blood flow and maintain vaginal lubrication through fluid transudation from blood vessels.[1] The following are the manifestations of decreased estrogen levels:[1][2][3]
- A hypoestrogenic state, such as that seen in menopause causes breakdown of collagen and elastic fibres in the vagina resulting in vaginal epithelium to lose its rugae to become thin and pale or erythematous with fine petechial hemorrhages and a narrow and shortened vagina.
- Decreased glycogen content within the epithelium due to decreased thickness leads to less glycogen content available for the lactobacilli to utilize and turn it into lactic acid. As a result, the vaginal pH rises with a resultant overgrowth of other bacteria, such as group B streptococci, Staphylococci and diptheroids resulting in recurrent vaginal infections and UTI.
Genetics
There are no genetic factors associated with atrophic vaginitis.
Gross Pathology
Gross pathology findings in atrophic vaginitis include:[4]
- Vaginal dryness
- Loss of vaginal rugae
- Changes in vaginal mucosa: pallor and friability or redness and petechiae of the mucosa
Microscopic Pathology
Cytology of the vaginal cells show an increase in the parabasal cells and decreased superficial cells.
Associated Conditions
Causes
Atrophic vaginitis is caused by any condition that may lead to decreased circulating estrogen levels. A hypoestrogenic state may be due to ovarian failure or other causes:[1]
- Ovarian failure: this category includes menopause, premature ovarian failure, bilateral oophorectomy, chemotherapy and radiation
- Other causes: elevated prolactin levels, due to lactation or pituitary adenoma, or medications that have an anti-estrogenic effect
Ovarian Failure | Other causes |
---|---|
Menopause | Elevated Prolactin Postpartum |
Premature Ovarian Failure
Bilateral oophorectomy |
Pituitary Adenoma |
Chemotherapy and Radiation | Medication with anti-estrogenic effect |
Epidemiology and Demographics
- Atrophic vaginitis is often an underdiagnosed condition, because many women are embarrassed to discuss their symptoms. Some others think of the symptoms associated with atrophic vaginitis as a process of natural aging.[1]
- Based on self-reported symptoms of vaginal dryness, the prevalence of atrophic vaginitis ranged from 4% to 47%, depending on the stage of menopause (early or late menopause).[2]
Risk Factors
The risk factors associated with vaginal atrophy are related to decreased estrogen levels, which can be due to menopause (most common cause) or other causes that may lead to hypoestrogenism or vaginal atrophy. These include:[1]
- Menopause (most common cause)
- Bilateral oophorectomy
- Premature ovarian failure
- Decreased ovarian function, due to chemotherapy or radiation
- Medications with an anti-estrogenic side effect:
- Tamoxifen
- Danazol
- Medroxyprogesterone acetate
- GnRH agonsists: leuprolide, nafarelin, goserelin
- GnRH antagonists: ganirelix
- Elevated prolactin levels during lactation
- Sexual abstinence
- Vaginal nulliparity
- Smoking
- Alcohol abuse
- Lack of exercise
Screening
There are no screening recommendations for atrophic vaginitis.[5]
Differentiating atrophic vaginitis from other diseases
Atrophic vaginitis must be differentiated from other disease processes that may present with similar symptoms. These can be divided into 4 categories:[2] [1]
- Vaginal infections: Candida vulvovaginitis, bacterial vaginosis and trichomoniasis
- Vulvovaginal dermatoses: lichen sclerosus, lichen planus and lichen simplex chronicus
- Cancer and precancerous lesions: vulvar intraepithelial neoplasia, vulvar cancer and extramammary Paget disease
- Others: foreign body, sexual trauma and contact irritants
The following is a list of differential diagnosis for Atrophic Vaginits: [6][7][8][9][10]
Disease | Findings |
---|---|
Atrophic vaginitis |
|
Trichomoniasis |
|
Bacterial Vaginosis |
|
Candida Vulvovaginitis |
|
Lichen Sclerosus |
|
Lichen Planus |
|
Lichen simplex chronicus |
|
Contact dermatitis |
|
Vulvar intraepithelial neoplasm | |
Vulvar Cancer |
|
Extramammary Paget disease |
Natural History, Complications and Prognosis
Natural History
Complications
Complications of atrophic vaginitis include:[1][21]
- Stress urinary incontinence
- Urge incontinence
- Pelvic organ prolapse
- Recurrent urinary tract infections
- Sexual dysfunction
Prognosis
Diagnosis
History and Symptoms
Symptoms of atrophic vaginitis can be divided into three categories:[1][2][3]
- External genital symptoms:
- Vaginal dryness
- Vaginal irritation
- Vaginal itching
- Vaginal discharge
- Sexual symptoms:
- Painful sexual intercourse (dyspareunia)
- Postcoital bleeding
- Loss of bleeding
- Loss of arousal
- Pelvic pain
- Urological symptoms:
- Burning on urination (dysuria)
- Urinary frequency
- Urinary urgency
- Nocturia
- Urinary incontinence
- Recurrent urinary tract infections (UTI)
Physical Examination
Physical examination in women with atrophic vaginitis includes a general inspection of the external genitalia, as well as a speculum examination of the internal genitalia.[3][8]
- Physical examination in women with atrophic vaginitis begins with inspection of the external genitalia. Findings include decreased elasticity of the skin, sparsity of pubic hair, dryness of the labia and/or fusion of the labia minora.
- Gynecologic examination is carried using a small speculum to avoid damage to the atrophic vaginal or vulvar tissue. Vaginal epithelium may be atrophic and appear pale, smooth and shiny. Other findings include increased friability, inflamed epithelium with patchy erythema and petechiae.
- Other findings may include: pelvic organ prolapse, such as cystocele and/or rectocele, urethral polyps or eversion of the urethral mucosa.
Laboratory Findings
CT
MRI
Ultrasound
An ultrasound of the uterus may demonstrate thinning of the endometrium lining to 4-5mm.
Other Diagnostic Studies
Treatment
Medical Therapy
Atrophic vaginitis is a chronic condition which mandates continuous treatment. The choice of therapy is based on the severity of the symptoms and associated factors such as history of harmone dependent cancer.
- In patients with mild symptoms lubricants are helpful to relieve symptoms.
- In patients with moderate to severe symptoms topical estrogen or oral estrogen therapy is encouraged.
- In patients with history of hormone dependent cancer, topical estrogen or other treatment modalities can be used, however endometrial surveillance is advised.
The following table is the description of available options for the treatment of Atrophic vaginitis[22]:
Treatment Modality | Improvement in symptoms | Advantages | Limitations |
---|---|---|---|
Topical Estrogen[23][2][24]
(Creams and Estradiol releasing vaginal rings) |
|
| |
Oral Estrogen Therapy |
In addition to the changes with topical estrogen other actions include:
|
Treats menopausal symptoms like hot flashes |
|
Selective estrogen receptor modulator
Ospemifene[28] |
|
Less than 1% risk of developing endometrial hyperplasia after treatment for 52weeks[29] | Increased risk of venous thromboembolism |
Laser Therapy |
|
Lack of longterm evidence on efficacy and safety[33]
| |
Tibolone
Synthetic steriod |
|
|
Lack of longterm evidence on efficacy
Increases recurrence risk of breast cancer in patients with history of breast cancer Vaginal spotting and bleeding[36] |
Oxytocin | Oxytocin gel improves vaginal secretions and epithelial thickness and pH[37][38] | No endometrial hyperplasia | No longterm evidence[39] |
Intravaginal dehydroepiandrosterone | Improves vaginal epithelium thickness and secretions[40][41] | None | Lacks longterm studies |
Moisturizers and lubricants[42] | Polymers adhere to the epithelial and mucin improving vaginal lubrication | Temporary relief for patients with mild symptoms | Doesnt reverse atrophic changes |
Assessment of Response to treatment
- Atrophic vaginitis being a chronic disease continuous therapy is recommended. Response to treatment is assessed by the following:
- Vaginal Maturation Index(VMI)
- Vaginal pH assessment
Primary Prevention
Secondary Prevention
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Gandhi J, Chen A, Dagur G, Suh Y, Smith N, Cali B, Khan SA (2016). "Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management". Am. J. Obstet. Gynecol. doi:10.1016/j.ajog.2016.07.045. PMID 27472999.
- ↑ 2.0 2.1 2.2 2.3 2.4 Mac Bride MB, Rhodes DJ, Shuster LT (2010). "Vulvovaginal atrophy". Mayo Clin. Proc. 85 (1): 87–94. doi:10.4065/mcp.2009.0413. PMC 2800285. PMID 20042564.
- ↑ 3.0 3.1 3.2 Pandit L, Ouslander JG (1997). "Postmenopausal vaginal atrophy and atrophic vaginitis". Am. J. Med. Sci. 314 (4): 228–31. PMID 9332260.
- ↑ Wysocki S, Kingsberg S, Krychman M (2014). "Management of Vaginal Atrophy: Implications from the REVIVE Survey". Clin Med Insights Reprod Health. 8: 23–30. doi:10.4137/CMRH.S14498. PMC 4071759. PMID 24987271.
- ↑ U.S. Preventive Services Task Force https://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=atrophic+vaginitis. Accessed on Oct. 24, 2016
- ↑ Guerrero A, Venkatesan A (2015). "Inflammatory Vulvar Dermatoses". Clin Obstet Gynecol. 58 (3): 464–75. doi:10.1097/GRF.0000000000000125. PMID 26125955.
- ↑ Centers for Disease Control and Prevention. 2015 Sexually Transmitted Diseases Treatment Guidelines. Bacterial Vaginosis. http://www.cdc.gov/std/tg2015/bv.htm Accessed on October 13, 2016
- ↑ 8.0 8.1 Bachmann GA, Nevadunsky NS (2000). "Diagnosis and treatment of atrophic vaginitis". Am Fam Physician. 61 (10): 3090–6. PMID 10839558.
- ↑ Krieger JN, Tam MR, Stevens CE, Nielsen IO, Hale J, Kiviat NB; et al. (1988). "Diagnosis of trichomoniasis. Comparison of conventional wet-mount examination with cytologic studies, cultures, and monoclonal antibody staining of direct specimens". JAMA. 259 (8): 1223–7. PMID 2448502.
- ↑ Eckert LO, Hawes SE, Stevens CE, Koutsky LA, Eschenbach DA, Holmes KK (1998). "Vulvovaginal candidiasis: clinical manifestations, risk factors, management algorithm". Obstet Gynecol. 92 (5): 757–65. PMID 9794664.
- ↑ Zendell K, Edwards L (2013). "Lichen sclerosus with vaginal involvement: report of 2 cases and review of the literature". JAMA Dermatol. 149 (10): 1199–202. doi:10.1001/jamadermatol.2013.4885. PMID 23925660.
- ↑ McPherson T, Cooper S (2010). "Vulval lichen sclerosus and lichen planus". Dermatol Ther. 23 (5): 523–32. doi:10.1111/j.1529-8019.2010.01355.x. PMID 20868406.
- ↑ Thorstensen KA, Birenbaum DL (2012). "Recognition and management of vulvar dermatologic conditions: lichen sclerosus, lichen planus, and lichen simplex chronicus". J Midwifery Womens Health. 57 (3): 260–75. doi:10.1111/j.1542-2011.2012.00175.x. PMID 22594865.
- ↑ Harper J, Zirwas M (2015). "Allergic contact dermatitis of the vagina and perineum: causes, incidence of, and differentiating factors". Clin Obstet Gynecol. 58 (1): 153–7. doi:10.1097/GRF.0000000000000094. PMID 25608257.
- ↑ Preti M, Igidbashian S, Costa S, Cristoforoni P, Mariani L, Origoni M; et al. (2015). "VIN usual type-from the past to the future". Ecancermedicalscience. 9: 531. doi:10.3332/ecancer.2015.531. PMC 4431399. PMID 25987900.
- ↑ Nelson EL, Bogliatto F, Stockdale CK (2015). "Vulvar Intraepithelial Neoplasia (VIN) and Condylomata". Clin Obstet Gynecol. 58 (3): 512–25. doi:10.1097/GRF.0000000000000132. PMID 26133495.
- ↑ Reyes MC, Cooper K (2014). "An update on vulvar intraepithelial neoplasia: terminology and a practical approach to diagnosis". J Clin Pathol. 67 (4): 290–4. doi:10.1136/jclinpath-2013-202117. PMID 24399036.
- ↑ Chokoeva AA, Tchernev G, Castelli E, Orlando E, Verma SB, Grebe M; et al. (2015). "Vulvar cancer: a review for dermatologists". Wien Med Wochenschr. 165 (7–8): 164–77. doi:10.1007/s10354-015-0354-9. PMID 25930015.
- ↑ van der Linden, M.; Meeuwis, K.A.P.; Bulten, J.; Bosse, T.; van Poelgeest, M.I.E.; de Hullu, J.A. (2016). "Paget disease of the vulva". Critical Reviews in Oncology/Hematology. 101: 60–74. doi:10.1016/j.critrevonc.2016.03.008. ISSN 1040-8428.
- ↑ Lopes Filho LL, Lopes IM, Lopes LR, Enokihara MM, Michalany AO, Matsunaga N (2015). "Mammary and extramammary Paget's disease". An Bras Dermatol. 90 (2): 225–31. doi:10.1590/abd1806-4841.20153189. PMC 4371672. PMID 25830993.
- ↑ Woods NF, Mitchell ES (2005). "Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women's lives". Am. J. Med. 118 Suppl 12B: 14–24. doi:10.1016/j.amjmed.2005.09.031. PMID 16414323.
- ↑ Domoney C (2014). "Treatment of vaginal atrophy". Womens Health (Lond). 10 (2): 191–200. doi:10.2217/whe.14.9. PMID 24601810.
- ↑ North American Menopause Society (2007). "The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society". Menopause. 14 (3 Pt 1): 355–69, quiz 370-1. doi:10.1097/gme.0b013e31805170eb. PMID 17438512.
- ↑ Holmgren PA, Lindskog M, von Schoultz B (1989). "Vaginal rings for continuous low-dose release of oestradiol in the treatment of urogenital atrophy". Maturitas. 11 (1): 55–63. PMID 2498619.
- ↑ Palacios, Santiago; CasteloBranco, Camil; Currie, Heather; Mijatovic, Velja; Nappi, Rossella E.; Simon, James; Rees, Margaret (2015). "Update on management of genitourinary syndrome of menopause: A practical guide". Maturitas. 82 (3): 308–313. doi:10.1016/j.maturitas.2015.07.020. ISSN 0378-5122.
- ↑ Suckling J, Lethaby A, Kennedy R (2006). "Local oestrogen for vaginal atrophy in postmenopausal women". Cochrane Database Syst Rev (4): CD001500. doi:10.1002/14651858.CD001500.pub2. PMID 17054136.
- ↑ Willhite, Laurie A.; O'Connell, Mary Beth (2001). "Urogenital Atrophy: Prevention and Treatment". Pharmacotherapy: Official Journal of the American College of Clinical Pharmacy. 21 (4): 464–480. doi:10.1592/phco.21.5.464.34486. ISSN 0277-0008.
- ↑ McLendon AN, Clinard VB, Woodis CB (2014). "Ospemifene for the treatment of vulvovaginal atrophy and dyspareunia in postmenopausal women". Pharmacotherapy. 34 (10): 1050–60. doi:10.1002/phar.1465. PMID 25052122.
- ↑ Wurz GT, Kao CJ, DeGregorio MW (2014). "Safety and efficacy of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy due to menopause". Clin Interv Aging. 9: 1939–50. doi:10.2147/CIA.S73753. PMC 4235480. PMID 25419123.
- ↑ Athanasiou S, Pitsouni E, Antonopoulou S, Zacharakis D, Salvatore S, Falagas ME; et al. (2016). "The effect of microablative fractional CO2 laser on vaginal flora of postmenopausal women". Climacteric. 19 (5): 512–8. doi:10.1080/13697137.2016.1212006. PMID 27558459.
- ↑ Pitsouni E, Grigoriadis T, Tsiveleka A, Zacharakis D, Salvatore S, Athanasiou S (2016). "Microablative fractional CO2-laser therapy and the genitourinary syndrome of menopause: An observational study". Maturitas. 94: 131–136. doi:10.1016/j.maturitas.2016.09.012. PMID 27823733.
- ↑ Salvatore S, Nappi RE, Parma M, Chionna R, Lagona F, Zerbinati N; et al. (2015). "Sexual function after fractional microablative CO₂ laser in women with vulvovaginal atrophy". Climacteric. 18 (2): 219–25. doi:10.3109/13697137.2014.975197. PMID 25333211.
- ↑ Hutchinson-Colas J, Segal S (2015). "Genitourinary syndrome of menopause and the use of laser therapy". Maturitas. 82 (4): 342–5. doi:10.1016/j.maturitas.2015.08.001. PMID 26323234.
- ↑ Botsis D, Kassanos D, Kalogirou D, Antoniou G, Vitoratos N, Karakitsos P (1997). "Vaginal ultrasound of the endometrium in postmenopausal women with symptoms of urogenital atrophy on low-dose estrogen or tibolone treatment: a comparison". Maturitas. 26 (1): 57–62. PMID 9032748.
- ↑ Szlendak-Sauer K, Wierzba W, Radowicki S (2008). "[The influence of a tibolone therapy on endometrium in postmenopausal women]". Ginekol Pol. 79 (11): 758–61. PMID 19140498.
- ↑ Formoso G, Perrone E, Maltoni S, Balduzzi S, Wilkinson J, Basevi V; et al. (2016). "Short-term and long-term effects of tibolone in postmenopausal women". Cochrane Database Syst Rev. 10: CD008536. doi:10.1002/14651858.CD008536.pub3. PMID 27733017.
- ↑ Al-Saqi, S. H.; Uvnas-Moberg, K.; Jonasson, A. F. (2015). "Intravaginally applied oxytocin improves post-menopausal vaginal atrophy". Post Reproductive Health. 21 (3): 88–97. doi:10.1177/2053369115577328. ISSN 2053-3691.
- ↑ Al-Saqi SH, Jonasson AF, Naessén T, Uvnäs-Moberg K (2016). "Oxytocin improves cytological and histological profiles of vaginal atrophy in postmenopausal women". Post Reprod Health. 22 (1): 25–33. doi:10.1177/2053369116629042. PMID 26883689.
- ↑ Jonasson AF, Edwall L, Uvnäs-Moberg K (2011). "Topical oxytocin reverses vaginal atrophy in postmenopausal women: a double-blind randomized pilot study". Menopause Int. 17 (4): 120–5. doi:10.1258/mi.2011.011030. PMID 22120944.
- ↑ Labrie F, Archer DF, Koltun W, Vachon A, Young D, Frenette L; et al. (2016). "Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause". Menopause. 23 (3): 243–56. doi:10.1097/GME.0000000000000571. PMID 26731686.
- ↑ Archer DF (2015). "Dehydroepiandrosterone intra vaginal administration for the management of postmenopausal vulvovaginal atrophy". J Steroid Biochem Mol Biol. 145: 139–43. doi:10.1016/j.jsbmb.2014.09.003. PMID 25201455.
- ↑ Edwards D, Panay N (2016). "Treating vulvovaginal atrophy/genitourinary syndrome of menopause: how important is vaginal lubricant and moisturizer composition?". Climacteric. 19 (2): 151–61. doi:10.3109/13697137.2015.1124259. PMC 4819835. PMID 26707589.