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REVIEW

Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD B Frey Tirri1, P Häusermann2, H Bertz3, H Greinix4, A Lawitschka5, C-P Schwarze6, D Wolff7, JP Halter8, D Dörfler9 and R Moffat10,11 Despite similarities relevant age- and gender-specific issues exist in the care of patients after allogeneic hematopoietic SCT (HSCT). Female genital chronic GVHD (cGVHD) has been markedly underreported in the past but has a significant impact on the patients’ health and quality of life. Data on prevention and treatment of this complication are still limited. Here we present a comprehensive review summarizing the current knowledge, which was discussed during several meetings of the German, Austrian and Swiss Consensus Project on clinical practice in cGVHD. In this report, we provide recommendations for post-transplant gynecological care of cGVHD manifestations agreed upon by all participants. This includes guidelines for diagnosis, prevention, and therapeutic options and topical treatments in female patients with genital cGVHD and hormonal replacement treatment of premature ovarian failure for adult and pediatric patients and underlines the necessity for regular gynecological care and screening programs for women after HSCT. Bone Marrow Transplantation advance online publication, 27 October 2014; doi:10.1038/bmt.2014.242

INTRODUCTION Complications after allogeneic hematopoietic SCT (HSCT) are mainly due to adverse effects of cytotoxic treatment, acute and chronic GVHD (cGVHD), drug adverse effects or long-lasting immunodeficiency leading to prolonged susceptibility for opportunistic infections.1 To prevent permanent dysfunctions long-term follow-up programs for post-transplant patients have been developed which address age- and gender-specific characteristics.2 Despite many similarities, there are differences in clinical symptoms, prophylaxis and treatment of post-transplant complications between female and male patients. For example, hypogonadism due to premature gonadal failure is highly prevalent after intensive chemotherapy and TBI for conditioning in men and women. However, in women gonadal dysfunction is more pronounced and occurs more often and earlier after HSCT, and the recovery of gonadal function is less likely.3 This report focuses on some post-transplant issues, which are important to consider in female patients after allogeneic HSCT including cGVHD. Data on this consensus process have been presented at the German, Austrian and Swiss Consensus Conference on clinical practice in cGVHD held in Regensburg in 2009 and have been updated in a workshop held in Wiesbaden 2013. Updates were discussed during the cGvHD consortia meetings in 2011 and 2013. The consensus summarizes the currently available evidence for first-line, second-line and topical therapies in cGVHD and provides

practical guidelines for the use of supportive treatment modalities4,5 (summarized in Table 1). The evaluation of evidence and the subsequent recommendations were classified according to the rating system for ancillary therapy and supportive care published by Couriel in 2008 (ref. 27; Table 2). On the basis of the National Institutes of Health (NIH) Consensus recommendations for clinical research in cGVHD, the focus of this report was to provide updated and more detailed guidelines for the prevention and treatment of gender-specific problems associated with cGVHD in female patients in daily clinical routine. Strength of recommendation and evidence levels (Table 3) were based on a PubMed-based literature search with subsequent rating by an expert panel approval of the recommendations by all participants of the consensus process. Only English literature was considered. Abstracts from the Bone Marrow Transplantation Tandem meetings, the European Bone Marrow Transplantation meetings and the American Society of Hematology meetings were cited but not included in the evidence rating. Reference lists from the articles retrieved were also evaluated for relevant information. INCIDENCE AND RISK FACTORS FOR FEMALE GENITAL CGVHD The first report on female genital involvement of cGVHD was published in 1982.28 It took another 20 years until this problem became more widely recognized and discussed in the literature.29,30 Women rarely report genital symptoms to

1 Women’s Hospital, Cantonal Hospital Baselland, Bruderholz, Switzerland; 2Department of Dermatology, University Hospital Basel, Basel, Switzerland; 3Department of Hematology and Oncology, Albert Ludwigs-University Medical Center, Freiburg, Germany; 4Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria; 5St Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria; 6University Children’s Hospital Tuebingen, Tuebingen, Germany; 7Department of Medicine III, University of Regensburg, Regensburg, Germany; 8Department of Hematology, University Hospital Basel, Basel, Switzerland; 9Department of General Gynecology and Gynecological Oncology, Medical University of Vienna, Vienna, Austria; 10Clinic for Gynecological Endocrinology and Reproductive Medicine, University Hospital Basel, Basel, Switzerland and 11Fertisuisse, Center for Reproductive Medicine, Olten, Switzerland. Correspondence: Dr B Frey Tirri, Women’s Hospital, Cantonal Hospital Baselland, CH-4101 Bruderholz, Switzerland or Dr R Moffat, Clinic for Gynecological Endocrinology and Reproductive Medicine, University Hospital Basel, CH-4031 Basel, Switzerland. E-mail: [email protected] or [email protected] Received 30 December 2013; revised 5 September 2014; accepted 17 September 2014

Clinical guidelines for gynecologic care after HSCT B Frey Tirri et al

2 Table 1.

Summary of recommendations

Recommendation

Strength

Clinical assessment Asymptomatic women should be offered a gynecological examination once a year6 Symptomatic women should be referred to a gynecologist with experience in GVHD6 Pediatric patients: clinical assessment should be performed by an experienced pediatric gynecologist and includes Tanner staging, inspection of external genitalia and reevaluation every 3–6 months7

BIIa BIIIa AIIIb

Treatment Use of water only for genital hygiene is recommended. Perfumed lotions and soaps and tight underwear and clothes should be avoided8 In case of genital atrophy, use topical estrogen in the form of creams, capsules or estrogen-releasing rings even if the patient is using HT9 In case of genital cGVHD, achieve rapid control of inflammation with topical class IV corticosteroids10–12 Topical calcineurin inhibitors may be suitable for long-term treatment to reduce and replace topical corticosteroids. However, recent meta-analyses did not detect efficacy in patients with lichen planus13 and lichen sclerosus12 Regular intercourse, use of dilatators and surgery can improve vaginal narrowing14 Secondary malignancies of the female genital tract Regular gynecological examination including cervical cytology should be performed once a year15,16 If treatment of suspected genital cGVHD is not successful in a timely manner (6–8 weeks), biopsy of the lesion should be performed to avoid incorrect diagnosis, erroneous treatment and exclude malignancies15,17 Biopsy is recommended for all genital lesions suspicious for dysplasia or malignancy15 HPV vaccination may be offered to young women (12–26 years) after transplantation18

AIIIb BIb BIb CIb CIIIa BIIa AIIa BIIa BIIIa

Premature ovarian failure Women with POF under the age of 40 years should be offered systemic HT irrespective of symptoms if risk factors are inexistent19–21 BIIb until the median age of natural menopause at 51 years The risk for breast cancer after allogeneic HSCT is substantially increased after TBI or local chest radiotherapy.22,23 Early mammographic AIa screening starting at the age of 25 years or 8 years after radiation of the chest or TBI24–26 is therefore recommended Abbreviations: cGVHD = chronic GVHD; HT = hormone therapy; POF = premature ovarian failure.

Table 2.

Strength of recommendation

Category Definition A B C D E

Table 3.

Should always be offered Should generally be offered Evidence for efficacy is insufficient to support for or against, or evidence might not outweigh adverse consequences or cost of the approach. Optional Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never be offered

Quality of evidence supporting the recommendation

Quality of evidence Definition of evidence level I II III

Evidence from one or more properly randomized, controlled trial(s) Evidence from one or more well-designed clinical trial(s) without randomization, from cohort or case-controlled analytic studies (preferable from 41 center), or from multiple time series or dramatic results from uncontrolled experiments Evidence from opinions of respected authorities on the basis of clinical experience, descriptive studies or reports from expert committees

Qualifier for categories I–III a Evidence derived directly from study(s) in GVHD b Evidence derived indirectly from study(s) in analogous or other pertinent disease

their health care providers and rather neglect genital symptoms or sexual problems in the early course of the disease leading to a significant risk of underdiagnosis of genital cGVHD. On the other hand, health care providers might not specifically ask for genital symptoms. However, female genital cGVHD may lead to complications associated with pain, scarring and impairment of sexual life and therefore needs attention. Bone Marrow Transplantation (2014), 1 – 7

Currently, the actual incidence of female genital cGVHD is unknown. Initially it was estimated to be as low as 3% in BM recipients. However, recent publications mention incidence rates of up to 49% in a mixed population of BM and PBSC recipients.31 Systematic gynecological care detecting also milder forms, more frequent use of PBSC and better supportive care strategies for other post-transplant complications may explain the increase in frequency of cGVHD overall32 including female genital cGVHD. © 2014 Macmillan Publishers Limited

Clinical guidelines for gynecologic care after HSCT B Frey Tirri et al

3 Median time from HSCT to initial presentation of female genital cGVHD is between 7 to 10 months,29 but late onset more than 1 year after HSCT is not uncommon.10,31 Indeed, the exact time of onset often is unclear and both, patients and physicians, especially in sexually inactive patients, can delay detection of gynecological signs and symptoms. Isolated female genital cGVHD is rare but does occur.6,17 In 68% cases cGVHD affects the vulva, whereas in 26%, both vulva and vagina are involved.11 Vulvar cGVHD usually precedes vaginal cGVHD. In our experience, topical treatment of vulvar cGVHD does not prevent the development of vaginal manifestations. Often female genital cGVHD is associated with cGVHD manifestations in other organs, especially skin and other mucosal surfaces such as mouth, eyes and gastrointestinal tract, and may appear even a long time after the initial manifestation of cGVHD.27 This sequence of events underlines the need for regular gynecological care. Therefore, we recommend a gynecological examination once a year in asymptomatic women6 (BIIa). Symptomatic women should be referred to a gynecologist with experience in GVHD6 (BIIIa). The risk for female genital cGVHD seems to be higher after HSCT with PBSC compared with BM.33 Type of conditioning, donor, parity, age, GVHD prophylaxis or vaginal infection at the time of HSCT do not appear to have an impact on incidence of genital cGVHD.29,31 However, genital atrophy due to estrogen deficiency seems to be a confounding factor for female genital cGVHD.29 SYMPTOMS AND CLINICAL PRESENTATION OF GENITAL CGVHD Pain or burning, dysuria, a feeling of redness and swelling, perineal and perianal soreness, dryness and dyspareunia despite adequate systemic and/or topical hormone therapy (HT) are nonspecific symptoms of female genital cGVHD. Patients, who are sexually active, may recognize symptoms earlier. Female genital cGVHD causing complete vaginal obstruction resulting in hematocolpos or hematometra can manifest as cyclic pain and amenorrhea in women taking HT34,35 or as difficulty while voiding in case of vulvar adhesions. In 2005, NIH recommendations for diagnosing and staging of female genital cGVHD were published.36 According to these, lichen planus-like features and vaginal scarring or stenosis are diagnostic signs of genital cGVHD that do not require biopsy. Erosions, fissures and ulcers are distinctive signs requiring exclusion of infection, drug effects, malignancy or other causes. The NIH recommendations include a score (Table 4) on the basis of severity of symptoms and clinical signs, ranging from score 0 for asymptomatic women to score 3 for women with severe symptoms. The score published by Stratton10 (Table 5) grades female genital cGVHD on the basis of clinical signs but not symptoms. One of the limitations of the NIH recommendations is that genital atrophy caused by premature ovarian failure (POF) is a common finding and distinguishing atrophic vaginitis from mild female Table 4. Scoring for female genital chronic GVHD (cGVHD) according to NIH recommendations for diagnosis and staging of female genital cGVHD36 Score 0 No symptoms Score 1 Symptomatic with mild signs on exam and no effect on coitus and minimal discomfort with gynecologic exam Score 2 Symptomatic with moderate signs on exam and with mild dysparunia or discomfort with gynecologic exam Score 3 Symptomatic with advanced signs (stricture, labial agglutination or severe ulceration) and severe pain with coitus or inability to insert vaginal speculum

© 2014 Macmillan Publishers Limited

genital cGVHD is challenging. Second, reporting symptoms of dyspareunia and discomfort with gynecologic exam are subjective. Affected women usually have difficulties classifying the extent of pain perceived. Third, sexually inactive women may not report symptoms like dyspareunia but might have severe signs of female genital cGVHD. HISTOPATHOLOGY AND DIAGNOSIS Histological findings of female genital cGVHD are consistent with mucosal and skin manifestations in classic cGVHD,17,30,35 with signs of chronic and acute inflammation within the subepithelial stroma and epithelium, that is, vacuolar degeneration of the basal layer, apoptotic keratinocytes and superficial perivascular lymphohistiocytic infiltrates. According to NIH recommendations,36 biopsy is not required for diagnosis if lichen planus-like features or vaginal scarring or stenosis (diagnostic signs) are present. In case of vaginal erosions, fissures and ulcers (distinctive signs) biopsy may be required for diagnosing cGVHD, if cGVHD has not been confirmed at another organ manifestation. Shulman et al.17 recommend biopsy in suspected cGVHD to avoid incorrect diagnosis and erroneous treatment, but acknowledges that histopathologic examination has limitations. We prefer a trial of treatment after exclusion of infection, drug or allergic reactions and dysplasia in cases with distinctive signs (corresponding to moderate genital cGVHD in Stratton’s scoring). If the treatment is not successful in a timely manner (6–8 weeks), we perform a biopsy of the lesions to exclude malignancies15 (AIIa). DIFFERENTIAL DIAGNOSES Genital infections produce signs of inflammation such as redness and soreness as in mild cGVHD but typically cause vaginal discharge and alter vaginal pH. Leukocytes, clue cells or yeast can be identified by microscopy in wet mounts of vaginal fluid samples and cultures should be obtained to identify the pathogen. HSV and VZV infection typically cause vesicular and ulcerative lesions of the external genitalia. Viral culture and molecular assays are validated methods for direct diagnosis of HSV and other viral infections. Allergic reactions to topical remedies and sanitary products and eczema can cause vulvar erythema resembling cGVHD. Early stages of genital lichen sclerosus often cause erythema and edema that usually begin

Table 5. Severity scoring for female genital cGVHD disease according to Stratton10 Severity score Grade I (minimal)

Grade II (moderate)

Grade III (severe)

Findings on clinical examination Generalized erythema and edema of vulvar structures Patchy erythema of mucosa and glandular structures of vulvar vestibule Erythema around openings of vestibular (Bartholin’s and Skene’s) glands Grade I findings plus Erosions of mucosal surfaces of the vulva Fissures in vulvar folds (that is, interlabial sulci; fourchette) Grade II findings plus Agglutination of clitoral hood Introital stenosis Vaginal synechiae Hematocolpos or complete vaginal closure Fasciitis or spasticity of levator sling

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4 around the periclitoral hood accompanied by the typical porcelain-white lesions that are easily distinguishable from genital cGVHD.37 Genital lichen simplex chronicus is considered an atopic disorder caused by excessive scratching leading to lichenification of the vulva. The skin is leathery and thickened. Fissures can occur in severe cases.38 Intraepithelial dysplasia and squamous cell carcinoma, which is by far the most common cancer of the female genital tract, can be detected by visual inspection after application of acetic acid.39 Paget’s disease, melanoma and basal cell carcinoma are rare malignancies of the female genital tract. Biopsy is recommended for all lesions suspicious for dysplasia or malignancy. Burning, dryness, tenderness and pruritus are common symptoms of both genital cGVHD and genital atrophy due to estrogen deficiency. In both, sexual activity is often compromised and physical examination may be painful. Typical signs of mild cGVHD are generalized patchy erythema, edema of vulvar structures and reticulated leukoplakia. In contrast to cGVHD, atrophic epithelium is shiny, pale and frail and tends to bleed on contact. The vaginal pH is alkaline. Clinical signs of atrophic vaginitis are very similar to those of mild cGVHD.8 Atrophy often accompanies genital cGVHD but in contrast to cGVHD, local estrogen treatment alone is effective in these patients. TREATMENT Treatment of female genital cGvHD is based on the following principles: (1) Reduce mechanical or chemical irritation of the genital skin by using only warm water for genital hygiene. Avoid perfumed lotions, soaps and tight underwear and clothes8 (AIIIb). (2) Use topical estrogen in form of creams, capsules or estrogenreleasing rings even if the patient is using systemic HT9 (BIb). Topical estrogen treatment increases epithelial thickness and makes the vaginal epithelium more resilient. (3) Achieve control of GvHD-related inflammation with topical class IV corticosteroids (BIb). We suggest the use of clobetasol propionate (Dermovate) ointment once daily at bedtime for 4 weeks as first-line therapy in newly diagnosed cGVHD and in case of flare-ups. (4) Topical calcineurin inhibitors, such as tacrolimus (Protopic) and pimecrolimus (Elidel) may be suitable for long-term treatment to reduce and replace topical corticosteroids10–12 (CIb). However, recent meta-analyses did not detect efficacy in patients with lichen planus13 and lichen sclerosus.12 (5) Regular intercourse or use of dilators can prevent vaginal narrowing and stenosis14 (CIIIa). Prevention of vaginal stenosis is important to facilitate cervical cytology screening. On the basis of our experience, it is better to avoid intercourse, dilation or surgical lysis of synechiae when inflammation is acute because this may result in aggravation of inflammation. Patients hardly tolerate vaginal examination and dilation in this situation. Successful control of inflammation results in significant reduction of pain, redness and swelling, thus enabling gentle intercourse or use of dilators. Persistent vaginal synechiae in spite of intercourse or use of dilators are easily separated manually under anesthesia, incision is rarely necessary.40 However, recurrence of synechiae is common, especially after surgery. Therefore, we encourage patients to perform digital self-examinations several times a week. Regular intercourse, the use of dilators or estrogen-releasing rings (not available in all countries) can prevent recurrence as well. In our experience the patients appreciate if either their gynecologist provides the dilator set or if they can order it anonymously by internet. However, some patients might be reluctant to perform self-examinations or dilation. (6) Photodocumentation is an easy and painless way of monitoring response to treatment. Bone Marrow Transplantation (2014), 1 – 7

SECONDARY MALIGNANCIES OF THE FEMALE GENITAL TRACT AFTER HSCT Secondary solid tumors are a well-known severe post-transplant complication.24,41 Prolonged use of immunosuppressive drugs to treat cGVHD and severity of cGVHD are major risk factors for the development of human papillomavirus (HPV)-related dysplasia15 and squamous cell carcinoma of the female genital tract.42 We recommend performing regular gynecological examination including cervical cytology once a year15,16 (BIIa). In the case of suspicious genital lesions, colposcopy and biopsy are recommended (BIIa).15 Given the relevance of HPV infection in the pathogenesis of cervical cancer, HPV vaccination may be offered to young women after transplantation43,44 (BIIIa).The Advisory Committee on Immunization Practices recommends HPV vaccination for immunocompromised persons aged 12–26 years if they have not already received any or all vaccine doses.18 However, efficacy data are not yet available. POF, SEXUAL DYSFUNCTION AND FERTILITY ISSUES After allogeneic HSCT many women suffer from POF depending on conditioning regimen, pretransplant chemotherapy, the age at HSCT and post-transplant complications.45,46 Only a minority (o 5%) of these patients recover ovarian function after HSCT for a limited period of time before entering early menopause.47,48 Toxicity-reduced conditioning regimens applied in younger patients may reduce the incidence of POF but systematic review is currently pending.49 POF is associated with symptoms of estrogen deficiency, such as hot flushes, night sweats, mood disorders, sleep disorders, lack of concentration, arthralgia, impaired sexual function50 and loss of reproductive potential, all of which negatively impact quality of life.51,52 Lack of estrogen at an early age prevents the development of secondary sex characteristics, increases the risk for osteoporosis,53 cognitive impairment54 and cardiovascular disease55–58 that are frequently observed in women after HSCT.59,60 However, attributing these diseases to POF is difficult because their occurrence are influenced by other factors, such as the use of steroids, calcineurin inhibitors, selective serotonin receptor inhibitors and proton pump inhibitors, hyperlipidemia or vitamin D deficiency. Estrogen replacement significantly alleviates postmenopausal vasomotor symptoms,61 improves vaginal mucosal architecture9 and bone density,62 thus increasing quality of life. Women with POF under the age of 40 years should be offered systemic HT irrespective of symptoms until the median age of natural menopause at 51 years provided there are no contraindications, such as history of breast or endometrial cancer, thromboembolic disorders, cardiovascular disease, porphyria or severe liver disease (BIIb).19–21 Symptomatic women older than 40 years may benefit from HT as well. HT has been viewed negatively after publication of the results of the women’s health initiative.63 However, the results of the women’s health initiative may not be representative for young women with POF after high-dose chemotherapy. Benefits and risks of HT should be discussed individually with each patient preferably by a gynecological endocrinologist to prevent complications. The risk for breast cancer after allogeneic HSCT is substantially increased after TBI or local chest radiotherapy.22,23 Therefore, early mammography screening starting at the age of 25 years or 8 years after radiation of the chest or TBI16,25,26 (AIa) is recommended. In the absence of guidelines on the basis of randomized trials for women with chemotherapy-induced POF, transdermal (50 μg estradiol/24 h) or oral estrogen (2 mg estradiol) can be given. If the uterus is present, cyclic or continuous progesterone (for example, 170 μg norethisterone acetate/24 h by transdermal route or 0.5 mg norethisterone acetate per day by oral route) should be added. Alternatively, low-dose combined oral contraceptives may © 2014 Macmillan Publishers Limited

Clinical guidelines for gynecologic care after HSCT B Frey Tirri et al

5 be used for HT. To avoid menopausal symptoms during the 7-day hormone-free break, combined oral contraceptives can be given continuously. Women suffering from diminished libido, presumably due to estrogen and androgen deficiency, might benefit from testosterone therapy. Low-dose transdermal testosterone (300 μg/day) added to an estrogen/progesterone hormone therapy has been shown to improve hypoactive sexual desire disorder in surgically menopausal women.64 Reliable data on long-term safety and efficacy of treatments improving sexual dysfunction in women with chemotherapy-induced POF are lacking. Selective estrogen receptor modulators (for example, tamoxifen, raloxifene) preventing bone loss may be an option in women with POF after transplantation who prefer not to take estrogens or who have a high risk for breast cancer.65 Notably, selective estrogen receptor modulators can aggravate genital atrophy and vasomotor symptoms.66 There are no data to support the efficacy of phytoestrogens67 and black cohosh68 to relieve menopausal symptoms. Therefore, this treatment cannot be recommended as an alternative for HT. Selective serotonin receptor inhibitors alleviate vasomotor symptoms and improve sleep disorders and can be used instead of HT.69 Fertility is clearly impaired after HSCT and the reported overall conception rate is o1%.70 Some women achieve pregnancy and live birth even after high-dose chemotherapy and TBI and pregnancies are likely to have successful outcomes.71 In fact, pregnancies have been reported despite the presence of cGVHD, indicating that cGVHD and its therapy does not always impair fertility.70,71 Nonetheless, data on spontaneous and assisted conception are scarce. Women and girls facing HSCT should have fertility preservation counseling.72 PEDIATRIC ASPECTS Lesions of genital cGVHD in children and adolescents may be similar to those of adults but systematic reviews of incidence, risk factors, treatment and outcome of genital cGVHD in children and adolescents are lacking. Underdiagnosis may be higher because symptoms like genital irritation, dryness and pain are rarely mentioned by children. Young girls after HSCT are particularly vulnerable to vulvar or vaginal irritation and infection because of poor local immune system and thin genital epithelium due to the lack of estrogen. Frequent contact with irritants (bubble bath, wet wipes and soaps), the fact that the vaginal orifice is less well protected by the labia,73 its proximity to the anus and poor hygiene add to the risk of vulvovaginitis. Microbiological and viral findings may be A/B beta hemolytic Streptococcus, Staphylococcus aureus, Haemophilus influenzae, Escherichia coli, Enteroccus faecalis, Yersinia and Shigella and Pseudomonas aeruginosa, Chlamydia, Gardnerella, Mycoplasma hominis and Ureaplasma, Candida albicans (often) and glabrata, BK Virus, HSV 1/2, HPV, VZV, Pinworms (Enterobius vermicularis).74,75 Clinical assessment should be performed by an experienced pediatric gynecologist/endocrinologist and includes Tanner staging, inspection of external genitalia and reevaluation every 3–6 months7 (AIIIb). Appropriate patient history should include genital hygiene practices and previous treatments. Vaginal swabs for cultures and virus isolation should be taken from the lower vagina. Genital cGvHD lesions may be similar to those of adults. Late onset of symptoms such as vaginal obstruction causing hematocolpos at the time of menarche illustrates the importance of longterm follow-up. Underlying diseases like Fanconi anemia with higher risk of secondary malignancies have to be considered. Treatment recommendations follow those of adults. There are no data about absorption of topical drugs in children. In general, children and their parents should be instructed about proper genital hygiene, which includes the use of alcohol- and perfume-free toilet wipes, wiping from front to back after © 2014 Macmillan Publishers Limited

Table 6.

HT in pediatric patients for the induction of menarche

Time from onset

Drug

Month Month Month Month

Estradiol valerate 0.25 mg/day oral Estradiol valerate 0.50 mg/day oral Estradiol valerate 1.00 mg/day oral Estradiol valerate 1.50 mg/day oral, cyclic 3 weeks 1 week discontinued Combined therapy with Estradiol valerate/Dihydrogesteron

1–6 7–12 13–18 19–24

After month 25

Dose

urinating, frequently changing the diapers and avoiding constipation.76,77 In 70 percent of cases hypogonadism is a consequence of stem cell therapy in girls. This is predominantly due to damaged ovaries, resulting in primary hypergonadotropic hypogonadism. In some cases, central hypogonadotrophic hypogonadism can result from cranial radiation. Therefore a high percentage of girls will benefit from HT. Starting at age 8 pubertal status, growth and serum levels of luteinizing hormone, follicule stimulating hormone and estradiol of the girl should be evaluated every 6 months. Estrogen therapy for induction of puberty, maximizing growth and development of secondary sex characteristics should begin no later than age 15 and not before age 12 (refs 7,78; AIIIb). In pubertal girls, the starting dose of HT depends on the volume of the uterus and the Tanner stage. A possible treatment scheme is shown in Table 6. After the end of puberty, a short discontinuation of HT is encouraged to monitor if ovarian function has recovered. Once contraception is needed or desired, oral contraceptives can be given instead of HT. CONCLUSIONS Female genital cGVHD, secondary genital malignancies, POF and loss of fertility are frequent complications after HSCT. Genital symptoms are rarely reported spontaneously by patients. Therefore health care workers should ask patients for symptoms. Local corticosteroids are the mainstay of treatment of genital cGVHD. Careful surgical interventions may become necessary to improve severe forms of genital cGVHD. Women with genital cGVHD are at an increased risk of developing squamous cell carcinoma and need regular pap smears and meticulous examinations of suspicious genital lesions by experts. Almost all women will experience POF and infertility after HSCT. Estrogen/progesterone replacement should be considered for women younger than 40 years. Women between 40 and 50 years might benefit from HT depending on their individual risk for breast cancer and vascular complications. Women and girls facing HSCT should be offered fertility preservation counseling. More prospective studies are needed to improve our knowledge on genital cGVHD and POF. CONFLICT OF INTEREST The authors declare no conflict of interest.

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