Graft-versus-Host Disease: Genitals
Presenter: Oluwatosin Goje, MD, MSCR, FACOG, Cleveland Clinic
Presentation is 37 minutes long, followed by 16 minutes of Q&A
Summary: Graft-versus-host disease (GVHD) often affects the genitals in patients who undergo a stem cell transplant using cells from a donor (allogeneic transplant). Genital GVHD can cause pain and can interfere with sexual intimacy. Learn how to detect and treat genital GVHD in both men and women.
- An estimated one-half of patients transplanted with stem cells from a donor experience sexual difficulties after transplant. Men will usually return to pre-transplant functioning two to-three years after transplant. Women are less likely to return to pre-transplant sexual functioning.
- Potential sexual problems after transplant include decreased sexual desire; genital GVHD; hormonal dysfunction, especially in young women; erectile dysfunction in men; difficult or painful sexual intercourse; and infertility in couples that still desire childbirth.
- Early recognition and treatment of genital GVHD is important. Treatment does not change GVHD but can halt its progression.
(04:46): Total body irradiation, graft-versus-host disease, certain medications and psychological stress can contribute to sexual difficulties after transplant.
(06:14): Graft-versus-host disease (GVHD) can cause scarring and pain in women, and abnormal ejaculation in men. Interventions for genital GVHD may include lubrication, vaginal vitamin E with hyaluronic acid, dilators, and topical estrogen.
(10:26): Women diagnosed with genital GVHD should have lifelong follow-up and treatment.
(10:57): The psychological and psychosocial impact of genital GVHD is enormous and can lead to depression, anxiety, especially with intercourse, feelings of inadequacy with partners, and body image issues, especially with patients who have severe GVHD.
(12:05): Vulvovaginal GVHD in women, if left untreated, can cause inflammation, fibrosis and narrowing or closing of the vagina.
(13:29): The prevalence of genital GVHD in women is under-reported. Estimates range from 24% to 69%.
(14:23): Symptoms of vaginal GVHD include itching, burning and dryness, loss of elasticity, painful intercourse, pain with urination and abnormal discharge of swelling in the vagina.
(27:10): Vaginal rehabilitation or intercourse twice a week is recommended to prevent adhesion and vaginal stenosis caused by genital GVHD in women.
(33:49): Sexual difficulties after transplant is a couple’s problem that partners should work on together.
(34:18): Symptoms of genital GVHD in men include a decreased desire to have sex, redness or rash on the penis, ulcers on the penis, inflammation, inability to ejaculate, and narrowing of the urethra.
Transcript of Presentation:
(00:01): [Becky Dame]: Introduction of Speaker. Welcome to the workshop, Graft-versus-Host Disease: Genitals. My name is Becky Dame, and I will be your moderator for this workshop.
It is my pleasure to introduce today's speaker, Dr. Oluwatosin Goje. Dr. Goje is an associate professor of obstetrics, gynecology, and reproductive biology at Cleveland Clinic's Lerner College of Medicine of Case Western Reserve University. She is the medical director of the Cleveland Clinic for Infant and Maternal Health and a staff member at Cleveland Clinic's Women's Health Institute Center for Specialized Women's Health. Dr. Goje specializes in treating patients with reproductive infectious diseases and non-infectious diseases of the vulva and vagina. Please join me today in welcoming Dr. Goje.
(00:56): [Dr. Oluwatosin Goje]: Thank you for that warm welcome. Good morning, good afternoon, good evening, wherever you are. I'm certain that we will have a great interactive session this afternoon.
(01:10): Learning Objectives. At the conclusion of this workshop, we should all understand who is at risk of developing genital GVHD after transplant, the signs and symptoms of genital GVHD in both men and women, and the treatment options for genital GVHD, including pharmacologic and nonpharmacologic therapy for men and women.
(01:38): I am a storyteller, because I believe we are not just medical record figures or Social Security numbers, we're humans. A 46-year-old woman diagnosed with Acute Myeloid Leukemia (AML), married and a mother of five children, underwent a stem cell transplant with donor cells in 2008. Since the transplant, she's suffered with GVHD in her eyes, intestine, the vulva, and the vagina.
(02:14): According to Ms. A, genital GVHD has caused dryness and pain that prevented her from having a normal sex life, as well as emotional problems and frustration. She was treated with steroid cream and cyclosporine cream that she inserted into the vagina every night. She was advised to use vaginal dilators in addition to the creams, to treat scarring that may have occurred during the GVHD . After a year, her genital GVHD symptoms were significantly decreased, and her sexual relationship was restored.
(02:51): "I'm finally healthy inside and out. I'm a healthy and confident wife, mother, daughter, and friend," says Mrs. A. This happy ending is what we hope for each of our patients and that's why this is an important conversation that is dear to my heart.
(03:14): Potential sexual problems after transplant include decreased sexual desire; genital GVHD ; hormonal dysfunction, especially in young women; erectile dysfunction in men; difficult or painful sexual intercourse; and infertility in couples that still desire childbirth. What are the potential sexual problems after transplant? It is important that these potential problems be discussed before transplant, and patients should be referred to the appropriate specialist before transplant. Potential problems include decreased sexual desire; genital GVHD ; hormonal dysfunction, especially in young women; erectile dysfunction in men; difficult or painful sexual intercourse; and infertility in couples that still desire childbirth.
(03:54): Discussing, diagnosing, and treating sexual problems following transplant is vital. There was a study that showed if you don't ask the patient, the patient might not discuss sexual problems after transplant at all. In the past, I've heard patients say, "Oh, I'm just grateful to be alive, so I never mentioned it to my doctors, and my doctors never asked me."
(04:15): This culture must change. We need to ask patients about problems encountered following transplant; few people talk about it. It's a difficult and uncomfortable discussion to have. Many patients have estrogen deficiency or testosterone deficiency; Young women have premature ovarian failure, which is defined as early menopause before the age of 40, and of course, chronic genital GVHD .
(04:46): Total body irradiation, graft-versus-host disease, certain medications, and psychological stress can contribute to sexual difficulties after transplant. What are the general risk factors for sexual problems after transplant, and what are the main culprits? Some patients have total body irradiation, some have GVHD following transplant. In some patients, it's medication and drug interactions or a chronic medical problem that is compounded by transplant, and of course, psychological distress.
(05:11): When we study them, total body irradiation leads to gonadal failure. I had a patient who, at age 28, had premature ovarian failure, and did not talk to anyone about it until she saw a survivor nurse who helped with some education. This can lead to decreased sexual desire or arousal, orgasm disorder, discomfort with intercourse, and ureteral dysfunction in men.
(05:43): Sexual problems caused by hormonal issues can be addressed with medication. These are conditions that can often be remediated. There are hormonal replacements for young women with premature ovarian failure. We can start them on either birth control pills or hormone replacement therapy, depending at what stage they come to the clinic.
(06:05): The same goes for erectile dysfunction in men. There are medications and management of stress and biofeedback, that can be tried.
(06:14): Graft-versus-host disease (GVHD ) can cause scarring and pain in women, and abnormal ejaculation in men. GVHD leads to a lot of performance stress, because there's a lot of scarring, which we will discuss. There's often pain with intercourse that adds to performance stress, as well as abnormal ejaculation in the male partner, intercourse often becomes impossible, and some women just give up.
(06:33): Interventions for genital GVHD may include lubrication, vaginal vitamin E with hyaluronic acid, dilators and topical estrogen. There are many possible interventions. Patients can use lubrication during intercourse. For my patients, I go step-by step. They can use a water or silicone-based lubricator. If that does not work, we can compound vaginal vitamin E with hyaluronic acid. With most patients, you see the light on their face, like "Hyaluronic acid, like what we use for our face?" I say, "Yes, it can be compounded as a vaginal formulation." Of course, there are vaginal dilators. Some patients can use topical vaginal estrogen, a ring, a cream, a suppository, or vaginal DHEA for patients that cannot use estrogen.
(07:20): For medication-related problems, we consider reducing the dose and/or trying alternative medication for them. If the risk factor is a chronic medical problem, treatment of underlying medical problems is important.
(07:37): I have a 40-something-year-old patient, a leukemia survivor who is doing great, but she reacts adversely to some medications because she also has mental health disorders for which she takes medication. We had a discussion, virtually, with all her providers, to see which medications would be better suited for her, knowing that she has some underlying medical problems.
(08:05): For psychological stress, patients can benefit from sex therapy, pelvic floor therapy, Reiki, yoga, and/or biofeedback therapy, which may be present in their locality.
(08:23): An estimated one-half of patients transplanted with stem cells from a donor (allogeneic transplant) experience impaired sexual function. Genital Chronic GVHD is quite prevalent, although we don't have the exact figures. Half of patients transplanted with stem cells from a donor experience impaired sexual function following transplant. This develops primarily during the first year; some studies show seven months post-transplant up to three years post-transplant. On average, most people develop genital GVHD in the latter half of the first-year post-transplant.
(09:00): We must have good surveillance for patients as they follow up with us post-transplant. Sexual problems are usually under-reported. People don't talk about this issue. Female prevalence is 24.9% to 69%. This is probably due to a lack of reliable reporting. The median time is seven to 10 months for female patients. Data is seriously lacking in male patients; one shows a median time of about 5.9 years in male patients.
(09:35): Men will usually return to pre-transplant functioning in two- to-three years. Women are less likely to return to pre-transplant sexual functioning. Early detection and treatment is important. In our practice, I prefer that patients have a gynecologic evaluation before transplant. After transplant, they should have another evaluation and be followed up yearly. If they develop GVHD, they should be followed up three months after initiation of treatment, then every six months. We can then progress to annual appointments, depending on how they're responding to treatment. Early treatment of genital GVHD may halt its progress so that it does not progress to severe genital GVHD . Men will usually return to pre-transplant functioning in two- to-three years. Women are less likely to return to pre-transplant sexual functioning.
(10:26): Women diagnosed with genital GVHD should have a lifelong follow-up and treatment. As a gynecologist and a vaginal specialist, I can tell you that women just get tired of the whole follow-up, and that's where advocacy comes in. That's where teams, like the survivorship clinic, come in to encourage those patients to continue with the treatment. Because when they don't continue with treatment, there may be reversal of the gains.
(10:57): The psychological and psychosocial impact of GVHD is enormous. It takes a heavy psychological toll on women, from the inability to discuss it, to having providers that have no understanding of what is going on. It can often lead to depression, anxiety, especially with intercourse, feeling of inadequacy with their partners, and body image issues, especially with patients who have severe GVHD. It impacts their relationship with their partners. My patients say words like, "My partner is patient, my partner understands, but I'd love to do more. I'd love to be intimate." So, it strains relationships.
(11:43): There's distorted body image, which leads to decreased sexual desire. And there's that perception that they're less desirable, just because of the change in the anatomy of the female genitalia or male genitalia. There's a reduction in the quality and quantity of sexual activity, and of course, impaired sexual function.
(12:05) Vulvovaginal GVHD in women, if left untreated, can cause inflammation and fibrosis and narrowing or closing of the vagina. Let's hone down to genital GVHD in women. Genital GVHD in women, or vulvovaginal GVHD, is the most common cause of symptoms post-transplant in the vulva and vagina, even in children. Untreated inflammation and fibrosis, which shows up as scarring in the vulva and vagina, may lead to total vaginal narrowing and closing of the vagina.
(12:36): As I said earlier, I'm a storyteller, and my patients are the best. Sometimes, when I see advanced GVHD, I ask, "tell me the story. What happened?" And it's usually, "I just was dealing with other things, and nobody said anything." So, it's important we advocate and we ask our patients, because it significantly impacts the quality of life and interferes with sexual intimacy.
(13:05): Early detection and treatment of genital GVHD reduces pain by healing the eroded mucus membranes in the vagina. Some of these pictures might be a bit overwhelming for some since they are medical pictures.
(13:29): The prevalence of genital GVHD in women is under-reported; there is a wide range from 24% to 69%; that may be underestimated or under-reported.
(13:43): In these tables, you'll see Spinelli and Zantomio and Chung, and a few other researchers who have looked at genital GVHD . The number of patients they had was not a large population, except for Spinelli, but you can see the median age of the patients. They're young women, and you see the donor type. What this table tells us is that addressing genital GVHD is crucial, especially looking at the age of the patients. They are young women, in the prime of their lives.
(14:23): Symptoms of vaginal GVHD include itching, burning and dryness, loss of elasticity, painful intercourse, pain with urination and abnormal discharge of swelling in the vagina. This pie chart shows the most common symptoms that women reported in the study of 27 patients. The majority, 10, reported itching; this is where misdiagnosis or underdiagnosis can come in. Because vaginal itching could be from an allergy, contact dermatitis, or from a yeast infection. This patient presents with a symptom that has a lot of other differential diagnoses, which could lead to delay. I always tell my residents, "If a patient complains of itching, and you've prescribed over-the-counter Miconazole or other anti-itch treatments, you need to bring the patient in for examination. It might not be a yeast infection." I have a topic titled "Not Every Itch is Yeast."
(15:16): Vaginal itching, burning, and dryness are number one. The formation of white lines, scarring, and adhesions, which is closure of the vagina, is also common.
(15:27): Loss of elasticity in the vagina is devastating and common, when patients ask "Why am I in pain?" The vagina is supposed to be very elastic, enough to push out a 10-pound baby. It becomes so rigid that any form of stretching can make it crack and bleed. Patients complain about post-intercourse bleeding, or even just bleeding after exercise, due to the loss of elasticity.
(15:52): Over time, there's narrowing of the vaginal canal. I had one patient tell me, "My partner said he can't get in. Did I leave a tampon or something in there?" So, I examined her and I said, "There's nothing in there. It's just that the vagina, over time, has become like a very narrow tube. Because it's lost elasticity, it's no longer pliable and soft and stretchy."
(16:20): Patients often have more than one symptom: painful intercourse, pain with urinating because the vagina is related to the base of the bladder, abnormal discharge and swelling of the vagina. It's important that they're evaluated to see what is happening.
(16:41): In this slide, you can see a lot of redness/irritation as well as a small ulcer; you can see that this is a mild disease state. The area is called the vestibule, which is the inner part of the vulva. This will cause pain with penetration at intercourse.
(17:12): The urethra, where we urinate from; when that acidic urine comes into contact with this ulcer, it causes burning. I tell my patients, if they are experiencing burning in conjunction with or even without urination, she should get a urinalysis. Regardless of the test results, it is important that we validate this symptom and examine our patient.
(17:47): There can also be extension of the problem, as depicted in this slide. If not treated, it continues to worsen; you can note that it's already starting on the other side. So, this is mild genital chronic GVHD, diffuse redness and swelling of the vulva with some reticulation here, a little less. If it persists, what happens is it progresses.
(18:11): One patient has a small ulceration and, over time, she has narrowing of the vaginal opening. You will notice the V-shape of the clitoral area. With progressive disease, it gradually shuts down; It's called agglutination. Thus, the clitoral area is stuck together, for lack of a better phrase. It's agglutinated, and slowly, the opening of the vagina gets smaller. This is vaginal narrowing and introital narrowing…the opening of the vagina, which leads to the vaginal canal.
(18:55): Here is picture from a different patient. You can see this is where the clitoris was, slowly closing. You'll hear us use the term, sclerosis fibrosis. If you look at her normal skin, this area is getting very white, because it's getting sclerotic. This patient, conversely, has what we call fissures, moderate to severe fissures, like someone took a small knife and just cut the sides of the vulva. And all of these things can cause irritation in our patients.
(19:33): What do we do to help? Health-care providers must ask questions of their patients. If those questions are not asked, I recommend you speak up and say, "I have these symptoms."
(19:48): Early recognition and treatment of genital GVHD is important. If the health-care provider is not trained in female genitalia, a gynecologic consultation should be requested for those patients. In order to have uniformity of how we diagnose GVHD, whether you're in Oklahoma or in the United Kingdom, we need to all be speaking the same language. The National Institutes of Health (NIH) came up with clinical scoring of genital chronic GVHD .
(20:26): A score of zero is assigned when patients are asymptomatic. A score of one is assigned when you have mild signs, which has no effect on coitus, with just minimal discomfort. That would be a patient with just the beginning of an ulcer. A score of two, when patients are symptomatic; they have moderate signs like adhesion causing pain with intercourse called dyspareunia, and/or pain with gynecologic exam. A score of three is assigned to patients who have advanced disease, like the inability to put in a speculum. For some of these patients, I request a pediatric or a newborn speculum. Often, even with that, you can't do a thorough exam. For one of my patients, I could not see the cervix because the whole area was stenotic; meaning it was closed.
(21:20): Treatment does not change graft-versus-host disease. What it does is halt the progression. It's not common to have reversal without surgery. Even when we have reversal from surgery, if it's not actively managed medically, it's going to return to status quo.
(21:47): When we talk about treatment for genital GVHD, we want to start by correcting any estrogen deficiency, because that is what starts most of the symptoms we have. We correct estrogen deficiency by using vaginal estrogen, we also add highly potent topical steroids. Clobetasol propionate ointment 0.05% is what is commonly used in the United States. For patients who cannot tolerate clobetasol or have failed clobetasol, tacrolimus ointment or cyclosporine ointment can be used in addition to clobetasol or alone; that is for treatment of the vulva.
(22:31): For problems concerning the vagina, it is a bit more complicated, because most patients who have vaginal symptoms also have vulva symptoms. Intravaginal estrogen, whether as a suppository or as a cream, intravaginal steroids is often used. Many times, the intravaginal steroid has to be compounded. Tacrolimus cream or suppositories can be used also.
(22:57): Patients should be encouraged to dilate. They can be purchased at many drug stores, on-line, or at some cancer centers. Dilation is important to avoid vaginal narrowing, vaginal stricture, and vaginal stenosis. If patients are in a relationship, we encourage them to have intercourse at least twice a week, because either intercourse or dilation helps to break filmy adhesions before they become fibrotic, which can lead to surgical intervention. Patients with vaginal stenosis/synechiae, fibrosis, in addition to everything we've talked about, may be a candidate for surgical intervention for lysis or reconstruction.
(23:51): At every point, patients should be surveilled. For women younger than the age of 40, their blood tests for follicle-stimulating hormone (FSH) should be checked. If the diagnosis of premature ovarian failure is made, they should be started on hormone replacement. Patients who are not sexually active should be encouraged to dilate, even if they don't have fissures.
(24:19): Avoiding irritating over-the-counter feminine products is important, because many times the vagina, even when there are no symptoms, is fragile. Use of irritating over-the-counter vaginal products aggravates the vagina. I always recommend a simple emollient, whether it is olive oil, coconut oil, Aquaphor, or something that is simple and hypoallergenic.
(24:48): Because itching is the most reported symptom, patients with itching should be tested for infection. The fact that a patient has genital GVHD does not exclude or rule out yeast infection or bacterial vaginosis that could also cause itching. Patients with genital GVHD have a higher risk of reactivation of the human papilloma virus, and secondary malignancy screening should be done. Post-transplant, they should receive annual pap smears and then the test scan be spaced out over the years, depending on how stable they are.
(25:33): My recommendations for monitoring are that we start genital exams at three to six months after transplant or sooner if the patient is symptomatic, and then we can move to annually. Always consider gynecologic exam at a minimum of three months with patients that have active GVHD as things can change quickly. Cervical cytology, pap smear with HPV annually. And if the patient is young and meets the age criteria of 45, consider HPV vaccine after consulting the oncologist. At any time when a patient who has stable regimen reports a flare-up, please bring them back and consider infection or an allergic or irritant contact dermatitis that can also present like GVHD .
(26:24): Should you avoid penetrative sex while you have genital GVHD ? The answer is ‘no’. You can have penetrative sex if you're comfortable. Patients will also ask, "Can I have sex when I'm using the topical estrogen or the vaginal DHEA?" The answer is ‘yes.’ These are very low-dose products that should not affect your partner.
(26:48): Some patients will also use 2% to 5% topical lidocaine at the opening of the vagina prior to intercourse, just to prevent pain. Most patients will use a pea-sized amount of the topical lidocaine about 15 to 20 minutes before intercourse to help with penetration.
(27:10): Vaginal rehabilitation or intercourse twice a week is recommended to prevent adhesion, vaginal stenosis. Having a vaginal exam can also help. And that's why when patients have active GVHD, we recommend they have follow-up visits at least every three months until the initial treatment has given some relief of the symptoms.
(27:39): Topical steroids are used for women with genital GVHD and are readily available in the United States For patients with vaginal involvement, we tend to use steroids first unless there's a contraindication to steroids. Hydrocortisone acetate is a rectal suppository. We use it as a vaginal suppository in our patients since it's already pre-formulated, is usually paid for by insurance, and is available across the country. Hydrocortisone as a 10% foam or gel must be compounded, and not every community has a compounding pharmacy; we don't want to delay treatment.
(28:29): If the patient cannot tolerate steroids, we can use intravaginal clindamycin 2%, or we could use tacrolimus, as I mentioned earlier, as a vaginal suppository. Topical clobetasol is what we use for vulva involvement, twice daily for six weeks, then daily for six weeks, and then we taper down to three times weekly.
(28:58): There is no evidence that using a small amount of topical steroid twice a week for a year, to treat genial GVHD will cause thinning of the skin. Patients often ask about steroid-use causing thinning of the skin. There is no evidence that using a small amount of topical steroid, about a pea-size, twice a week for a year, will cause thinning of the skin. There are studies from New Zealand and Australia in patients with other vulva dermatoses, in which even children have tolerated it.
(29:22): The concern is when people use a lot of topical steroids for a prolonged period of time. A patient who needs steroids every day for a year should be reexamined. Most likely the medication is not effective. Vaginal DHEA can be compounded, or it can be obtained as a generic formulation from a pharmacy and is used the same way. The compounded medication has a higher dose of DHEA, a hormone produced by the body's adrenal glands. The formulary is called INTRAROSA, which is a man-made version of DHEA, and has a reduced strength. However, not every community has a compounding pharmacy and not every insurance will pay for the formulary. It depends on what is available.
(30:16): This table shows different regimen for patients. You can see, estrogen was given twice a week and continued with that dosage up to week 23. Tacrolimus was every other day and clobetasol was every other day. It was then tapered to twice a week, then once a week. The same regimen was prescribed with vaginal dilators. It's not set in stone; what is important is that patients use this medication for an appropriate period of time and not just for a week or two.
(30:53): Maintain patency (opening) of the vagina by preventing adhesions and vaginal stenosis. In non-sexually active patients, dilators should still be encouraged. It helps with scarring and narrowing.
(31:09): I recently had a patient come in for a follow-up appointment. In 2020 she had surgery, and she was doing well. However, she had stopped using steroids and vaginal estrogen after surgery. According to my patient, "I was doing well after surgery, and I regressed. I stopped using vaginal estrogen and clobetasol." She was back to where she had started. She's experiencing vaginal narrowing and adhesion; she's not interested in surgery again. We're going to try self-dilation starting from the smaller size, coating the dilator with some clobetasol and estrogen, and trying to do it every night, and then taper down to twice a week after six weeks.
(32:02): For patients that have moderate to severe GVHD, instead of using a vaginal suppository to apply a steroid, a vaginal ring might be better since the vaginal ring also helps to keep the vaginal canal patent, and is inserted and switched out every three months. In addition to the vaginal ring, the patient should also continue to coat their dilators with either topical estrogen or DHEA every time they dilate.
(32:36): Pelvic floor therapy can be very important. It helps empower the patient. Sometimes patients have heard negative things about pelvic floor therapy, and they don't want to consult a therapist. I always encourage them to do so.
(33:00): Biofeedback can also be important; It also helps to empower patients. Consulting a sex therapist or a family health therapist is also important. Behavioral health therapist, mental health therapist, any help that we can give to support our patients, should always be advocated.
(33:20): To improve sexual health, in addition to reaching out to a therapist, you should talk to your gynecologist. Sometimes patients are prescribed vaginal estrogen, and because of the bad rap it has in the media, they don't use it. Talk to your gynecologist about your hormone therapy because it helps to improve lubrication. And if you don't want to use hormone therapy, talk about hyaluronic acid or vitamin E that can be compounded for you.
(33:49): Sexual problems after transplant is a couple’s problem that partners should work on together. Also, talk to your partner about your difficulties. This is a couple’s problem, and the couples should go together. Keep intimacy alive. I have patients who say, "We don't have penetrative sex, but Dr. Goje, we are happy. We have other sexual encounters. We have other things to do. We just don't have penile-vaginal penetrative sex. But that keeps intimacy going and alive."
(34:18): Symptoms of genital GVHD in men include a decreased desire to have sex, redness or rash on the penis, ulcers on the penis, inflammation, inability to ejaculate, and narrowing of the urethra. In the next few minutes, I will discuss genital GVHD in men; very little is documented. The biggest study for men was from Simon Mueller. The symptoms are a decreased desire to have sex, redness or rash on the penis, ulcers on the penis, inflammation, inability to ejaculate, and narrowing of the urethra.
(34:51): These are pictures from Mueller, et al. You can see sclerosis, which is the whiteness. There's changing skin color of the head of the penis. There's some redness with white lines, and of course, there's difficulty or pain retracting the foreskin in uncircumcised men because of scarring and adhesions.
(35:16): Treatment is the same. Once or twice daily high-potency steroid ointment. If they cannot tolerate topical clobetasol and they have genital lichen sclerosis-like presentation, they may benefit from tacrolimus, which is a topical calcineurin inhibitor. Circumcision in case of tight foreskin is also advocated.
(35:40): Testosterone replacement therapy is appropriate for patients with low testosterone and should be discussed with your health-care provider. If you can't discuss it with your provider, you can send a message to your survivorship team to ask questions.
(36:01): Early recognition of genital GVHD in men is important, and a urologic consultation should be requested by all patients even when there are no symptoms. We should not wait for symptoms before we request a urologic consultation for our patients.
(36:18): What are my key points today? Check frequently for symptoms of genital GVHD . If you have symptoms that may be genital GVHD, request a gynecologic or urologic referral. Wash with warm water and soap. Avoid over-the-counter products that may cause allergies, since they can irritate the fragile skin, and avoid perfumed products. Wear loose cotton or cotton-lined undergarments and change them after swimming and athletic activities. And always request supportive therapy. Thank you very much.
Question & Answer Session
(36:57): [Becky Dame]: Thank you, Dr. Goje, for this excellent presentation. We will now begin the question-and-answer session. Our first question is how to know if vaginal itching and burning is vaginal GVHD or skin GVHD ?
(37:30): [Dr. Oluwatosin Goje]: The first thing I ask my female patient is if you are itching or if it's just a sensation. Is it the groin, the labia, or the vulva, or is it inside the vagina? Take a mirror or ask your partner to take pictures and note where the skin changes are. If you don't see any skin changes on the labia, you part the lips; if you don’t see anything, it's most likely in the vagina. As a patient, you can't really see inside your vagina; you need a provider to look at it.
(38:11): [Becky Dame]: To your knowledge, are there specialists for vaginal GVHD ?
(38:18): [Dr. Oluwatosin Goje]: There are not specialists trained just in vaginal GVHD, but there are specialists who are trained in vaginal disorders. That is where I come from. They're providers who have gotten extra training from, perhaps, the International Society for the Study of Vulvovaginal Disease (ISSVD) or from other societies and are interested in this work.
(38:52): [Becky Dame] What hormone replacement should I use? This patient is currently using a vaginal cream insert, Replens®, for atrophy and dryness, and periodically use an oral over-the-counter estrogen.
(39:14): [Dr. Oluwatosin Goje]: Depending on her age and her symptoms and based on evidence that if she became postmenopausal from her procedures before age 40, she should be on hormone replacement therapy, meaning estrogen and progesterone, because it also has other benefits for her general well-being. That is one.
(39:38): Two, if she's not a candidate for that, then she should use vaginal estrogen. Replens is a moisturizer, but if we have dryness from GVHD with that stricture and tightening, that is not enough. She will need some vaginal estrogen or a vaginal DHEA. She just needs to consult with her oncologist to decide which is best for her.
(40:11):[Becky Dame]: Does GVHD of the vagina ever clear up or is it an ongoing problem?
(40:21): [Dr. Oluwatosin Goje]: It can improve; I've seen patients get almost 80 to 90% better. I've seen patients that were so stenotic that I could not see their cervix, and by the end of one year they had opened enough for us to see the cervix; it just takes diligence. I have not seen anyone go back to pre-transplant function, like when they were in their 30s, but pain goes away, lubrication gets better, and some are able to have intercourse with their partner.
(40:57):[ Becky Dame]: Did you mention estrogen cream on the dilators themselves? If so, how often should they do this, and what they should be using with a lubricant?
(41:09): [Dr. Oluwatosin Goje]: I recommend using vaginal estrogen twice a week. The evidence for vaginal estrogen was to use one gram, and most of the tubes come with a graduated applicator. One gram daily for two weeks and then twice a week. So, for dilation, for the day you are using your dilator, instead of just inserting estrogen, use it on the dilator. So, let's say a seven-day regimen. Every night, get some Aquaphor, some coconut oil or some olive oil to coat your dilator and dilate. But for the two nights that you use your estrogen, use the estrogen on the dilator. The same thing if you're using a compounded hydrocortisone cream in the vagina twice a week, the days you use it, don't insert, use it on the dilator. Because it will stick and coat the vagina better than when you just put it in.
(42:20): [Becky Dame]: You had mentioned earlier receiving pelvic physical therapy, and some people are asking when that should be added to the treatment regimen?
(42:31): [ Dr. Oluwatosin Goje]: The moment you start to have pain, and you have used your vaginal creams or dilator for at least a month, you should start pelvic therapy. Most women shy away from pelvic therapy because it's invasive of their privacy, and they think it's going to result in more pain. I tell my patients, "If you can dilate yourself and you're not hurting or bleeding, then you are ready for pelvic floor therapy. If you've started your creams to help with lubrication, you are ready for pelvic floor." I don't start pelvic floor first, and then say dilate after a month. Use those steps first, then pelvic floor maybe within a month or two, depending on how comfortable the patient is.
(43:24): [Becky Dame]: Do you have a protocol on following women post-transplant for early diagnosis of graft-versus-host disease and treatment guidelines after diagnosis?
(43:36): [Dr. Oluwatosin Goje]: My protocol is not from any research, but from my patients. After transplant, they should have a well-woman exam every six months, since there is increased risk of HPV and premature ovarian failure. They should have that well-woman exam covering everything from testing to questions. If they are symptom-free, they should be seen in six months.
(44:03): I see patients every six months for a year or two. And if they're doing well, then I see them annually. For patients who are symptomatic, who I start on medication, I want to see them three months after starting the medication. I want to make sure that the regimen we've put together of twice-a-week hydrocortisone/ twice-a-week estrogen is working. After the three-months visit, if they're better, I will move them to six months visit for a year or two. If they keep improving, I see them once a year; it's a lifelong follow-up of once a year.
(44:42): [Becky Dame]: Do you have a recommendation for women who can't use estrogen-based products because of a history of breast cancer? This question is in regard to not experiencing dryness, just soreness.
(44:57): [Dr. Oluwatosin Goje]: Yes. With a patient who is experiencing soreness, I first ask is this soreness, burning, or pain? If it's burning or painful, they can use vaginal gabapentin. Vaginal gabapentin can be compounded as a 4% or 6% insert for the vagina. Gabapentin is a medication used for pain. I try to go with the vaginal path, since it has less side effects, if it's pain.
(45:26): If it's soreness, pelvic floor therapy will help with muscle relaxation. Sometimes there are other medications that can be compounded as a muscle relaxer for the vagina, like baclofen. These are all non-hormonal. But to keep the area lubricated, which is important, they can use the Replens. They can use other over the counter or they can compound hyaluronic acid just like we use it for the face, or vitamin E as a vaginal cream. Those are non-hormonal.
(46:06): [Becky Dame]: How can you distinguish between lichen sclerosus, lichen planus, and GVHD of the vulva?
(46:18): [Dr. Oluwatosin Goje]: It's not a straightforward answer. Many times, patients have been referred to me for genital GVHD . And after examination and looking at the gradient, it's not genital GVHD, but atrophic vaginitis from lack of hormones, which could be also a side effect of transplant.
(46:39): Lichen sclerosus has three clear stigmata. Over time, lichen sclerosus has agglutination of the clitoral hood. With lichen sclerosus, you lose the labia minora. Lichen sclerosus has what we call a figure of eight pattern, where the hypopigmentation or lichening of the skin covers the entire clitoral area, and the vagina narrows down and covers the anal opening. And then there's what we call the cellophane paper or crinkled skin appearance, where the skin looks like someone squeezed a newspaper, and then tried to flatten it out.
(47:26): There are classic stigmata of lichen sclerosus. It does have itching associated with it. It could be in a woman who is having atrophic vaginitis. Lichen planus, on the other hand, is a bit different. Lichen planus tends to have multiple sides. Lichen sclerosus tends to be in the vulva only. Lichen planus could be in the vagina, the mouth, or in the vulva. I've seen patients whose first diagnosis of lichen planus was diagnosed by the dentist.
(47:59): Lichen planus does not cause fibrosis or sclerosis; it causes more degradation, like someone took a knife and scraped off a layer of the skin. The area is red and looks very fragile to touch; it can bleed just from contact. If lichens planus extends into the vagina, patients have copious yellow-green discharge, because of that inflammation that is also happening in the vagina.
(48:34): With GVHD, you grade it. Rarely do you have GVHD being as aggressive as you see with the copious discharge in lichen planus. However, they're all treated, to a large extent, the same way… estrogen or DHEA, steroids or tacrolimus.
(48:59): [Becky Dame]: What, if any, medical procedures, can be done for extreme tightness of the vagina, other than dilators, hormone inserts, and the extra lubrication? Those didn't work for this individual.
(49:18): [Dr. Oluwatosin Goje]: Surgery. There are urologic surgeons, gynecologic surgeons, and pelvic floor surgeons, who are dedicated to doing this, not just for GVHD but for other conditions, such as patients who had vaginal radiation for cervical cancer. They also present with stricture.
(49:49): [Becky Dame]: What can be done to correct vaginal atrophy?
(49:56): [Dr. Oluwatosin Goje]: The best treatment for vaginal atrophy is to use hormones. Whether it's vaginal estrogen or DHEA. DHEA, which I have seen in my breast cancer patients, is accepted by their oncologist, I think is dehydroepiandrosterone. Before I prescribe a vaginal hormone, I reach out to the patient’s oncologist. For my breast cancer patients, many of them have been candidates for DHEA if they're not candidates for vaginal estrogen. Osphena®, an oral medication, is also a good choice for moderate to severe vaginal atrophy. These are the things that will be most effective. Everything else will just be a lubricant or a palliative.
(50:58): [Becky Dame]: Is complete loss of libido a side effect of the chemotherapy and radiation treatments involved with the transplant?
(51:10): [Dr. Oluwatosin Goje]: No. It's a side effect of many things. It can originate from body irradiation or chronic medical conditions like diabetes or hypertension, in addition to transplant. It could be from medications that patients take for cancer or for comorbidities. It's not just transplants that cause loss of libido; there are other factors involved. For example, it may be accentuated in a patient who had a bone marrow transplant in addition to uncontrolled diabetes.
(51:52): [Becky Dame]: This is a very sensitive question. When do you recommend starting to monitor pediatric and adolescent patients and how often?
(52:12): [Dr. Oluwatosin Goje]: This is a sensitive question; I take care of children and it can be a very emotional subject. I rarely want young children to have examinations. When I send them to a pediatric gynecologist or a pediatrician who specializes in children with that condition, questions should be asked first. The best way to monitor the children is to understand the baseline questions and to ask questions; only examine them when it's absolutely necessary.
(52:52): [Becky Dame]: Thank you. On behalf of the BMT InfoNet and our partners, I'd like to thank you for this very helpful presentation. And thank you to the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way.This article is in these categories: