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HRT (Hormone Replacement Therapy) and DRIM (Drugs and Roentgen Induced Menopause) M. Luerti Dipartimento Materno Infantile U.O. di Ostetricia e Ginecologia - Presidio di Lodi ASL della Provincia di Lodi - Regione Lombardia - Italia HRT and DRIM Notwithstanding increasing epidemiological frequency of DRIM mainly because of diffusion of recent drugs: • Chemotherapies • GnRH analogues • Danazol • Gestrinone knowledge about this topic is rather lacking FACTORS AFFECTING DRIM • Disease motivating the induction of menopause • Ovarian failure inducing agent • Postmenopausal ageing in relation to the age at which menopause occurs DISEASES MOTIVATING THE INDUCTION OF MENOPAUSE Lymphomas Breast cancer Leukaemia Auto-immune diseases Soft tissue cancer Endometriosis Wilms tumor Uterine myomas Osteosarcoma Persistent menorrhagia Trophoblastic tumors Cardiovascular diseases PRIMITIVE DISEASE CAN EXACERBATE SOME SYMPTOMS Disease Cancer Symptoms Sexual life deterioration Anxiety Endometriosis Depression Sleeplessness Cardiovascular diseases Fatigue Anaemia Osteoporosis Dyspareunia FACTORS AFFECTING PROBABILITY OF OVARIAN FAILURE •Age of the patient •Duration of treatment •Dose •Fractionation of doses •Association of agents (polichemotherapy) FOLLICLE RESERVE IN WOMEN OF DIFFERENT AGES Age Birth 15-30 31-40 > 40 Average n. of primordial follicles Extreme limits 480.000 150.000 75.000 8.000 260.000-750.000 40.000-300.000 15.000-200.000 350-25.000 CHEMOTHERAPY AND OVARIAN CYTOTOXICITY Definite Probable *Chlorambucil *Cyclophosphamide *L-Phenylalanine Mustard *Nitrogen Mustard *Busulfan *Procarbazine *Doxorubicin *Vinblastine *Cytosine Arabinoside *Cisplatin *Nitrosureas *m-AMSA *Etoposide Unknown Unlikely *Bleomicin *Methotrexate *Fluorouracil *Mercaptopurine *Vincristine OVARIAN FAILURE INDUCING AGENTS Hormones Chemotherapy Radiotherapy Reversible Irreversible 53% irreversible under age 35 84% between ages 35-44 94% age 45 or older Reversible (< 250 r/ovary) Irreversible (> 250 r/ovary) OVARIAN FAILURE INDUCING AGENTS CAN EXACERBATE SOME CLIMATERIC SYMPTOMS Agent Chemotherapy Symptoms Fatigue Anaemia Hormonal therapy Radiotherapy Cardiovascular disease Osteoporosis Atrophy and dyspareunia POSTMENOPAUSAL AGEING The lower the age of induced menopause, the stronger the symptoms and higher the risk of long-term effects CONSEQUENCES OF SUDDEN OVARIAN FAILURE Surgical removal of both ovaries constitutes the better model to represent DRIM and its consequences on symptoms associated Evident increase of vaginal atrophy Evident decline of sexual activity CONSEQUENCES OF SUDDEN OVARIAN FAILURE The model based on surgical induction of menopause is the most important suitable and shows: •A higher osteoporotic risk • A higher cardiovascular risk • A net increase in the frequency of vaginal atrophy and decline of sexual activity CLIMATERIC SYNDROME IN DRIM The climateric syndrome in DRIM is more severe than in natural postmenopause, mainly due to increased intensity of psychoemotional complaints (nervousness, depression, insomnia and fatigue), largely due to the stress involved in DRIM LONG-TERM EFFECTS IN DRIM The risk of long-term effects in DRIM is higher than in natural postmenopause, mainly due to: •the action of ovarian failure inducing agent •postmenopausal ageing HRT and DRIM HRT should be useful in DRIM even more than in spontaneous menopause Unfortunately the intensity of the symptoms and consequences of DRIM is in contrast with the reluctance of the physician to treat patients RELUCTANCE OF THE PHYSICIAN: WHY? Is HRT contraindicated in DRIM? because of inducing agent? because of primitive illness? HRT and DRIM There are no contraindications to the use of HRT in DRIM in relation to ovarian failure inducing agent HRT IN PATIENTS TREATED FOR BREAST CANCER It is a general belief that HRT after breast cancer will increase the risk of developing recurrences, though there are no clear data available to support this suggestion RECURRENCES AFTER HRT IN PATIENTS TREATED FOR BREAST CANCER HRT NON HRT Eden, 1995 7% 17% Wren, 1995 9% 17% DiSaia,1996 14,6% 7,3% The National Cancer Institute of the United States, in 1996, initiated a randomised, prospective trial of HRT following treatment of breast cancer in women with Stage 1 and 2 disease. Inclusion criteria are: - disease free for 2 years with estrogen receptor negative disease - 10 years following a breast cancer with estrogen receptor status unknown RECURRENCES AND SURVIVAL AFTER HRT IN PATIENTS TREATED FOR ENDOMETRIAL CANCER Recurrences Chapman, 1996 Lee, 1990 Creasman, 1986 ERT NON ERT 3,2% 9,8% 0% 1,6% 2,1% 14,9% 6 years survival Creasman, 1986 93% 52% HRT IN PATIENTS TREATED FOR OVARIAN CANCER RR IC (95%) Mortality 0,73 0,44 – 1,20 Recurrences 0,90 0,52 – 1,54 From Eeles, 1991, modified HRT AND GYNECOLOGICAL CANCER from THE CANADIAN CONSENSUS CONFERENCE ON MENOPAUSE AND OSTEOPOROSIS, 1998 •Breast cancer: HRT may be offered after proper individual counselling •Endometrial cancer: HRT should not be withheld in treated Stage 1 or 2 Grade 1 or 2 •Ovarian cancer: HRT should not be withheld in these patients, after proper counselling •Cervical cancer: Several studies support the use of HRT in patients treated for squamous cell carcinoma of the cervix •Vaginal and vulvar cancers: There is no relevant published information indicating that HRT use has a negative effect on either squamous cell carcinoma of the vagina or the vulva HRT and OTHER CANCER from THE CANADIAN CONSENSUS CONFERENCE ON MENOPAUSE AND OSTEOPOROSIS, 1998 •Colo-rectal cancer: There are no data showing any change in risk associated with HRT in women who have been treated for colon cancer •Melanoma: cutaneous non-metastatic melanoma is not a contra-indication to the use of post-menopausal estrogen •Thyroid cancer: While it is recognized that, in post-menopausal women, well differentiated papillary and follicular carcinomas may be particularly aggressive, there is no evidence HRT after ENDOMETROSIS INDUCED MENOPAUSE from THE CANADIAN CONSENSUS CONFERENCE ON MENOPAUSE AND OSTEOPOROSIS, 1998 Combined estrogen and progestin replacement therapy in standard doses does not appear to cause regrowth of endometriosis in menopausal women, or in young women receiving estrogen-progestin “addback” therapy following medical oophorectomy with GnRH analogues. A small subgroup of women may experience recurrence of pain and other symptoms during unopposed estrogen therapy, particularly if residual disease remains following definitive surgery. There are anecdotal reports of endometrial cancer developing in residual endometriosis in women receiving unopposed estrogen following definitive surgery for endometriosis. This appears to be one of the few indications for progestin therapy following hysterectomy, either as part of a continuous-combined regimen or as progestin-only therapy. Available data do not allow a definitive answer to this question. HRT after FIBROIDS INDUCED MENOPAUSE from THE CANADIAN CONSENSUS CONFERENCE ON MENOPAUSE AND OSTEOPOROSIS, 1998 Uterine fibroids do not constitute a contra-indication to HRT, but it should be used with caution in women known to have fibroids. Although both estrogen and progestins can influence fibroid growth, the doses in conventional HRT regimens are usually not sufficient to cause enlargement of fibroids. However, rapid growth or abnormal bleeding (from a submucous fibroid) requires investigation and possibly surgical intervention. HRT and DRIM HRT DOESN’T APPEAR TO BE CONTRAINDICATED AND ADVISABLE IN MOST CASES OF DRIM HRT IN PATIENTS TREATED FOR BREAST AND ENDOMETRIAL CANCER It is recommended the use of a continuous combined estro-progestin therapy COMPLEMENTARY APPROACHES TO DRIM •Other medications Clonidine Bellergal® Topical estrogens High doses progestins Bisphosphonates SERMs •Diet and lifestyle •Phytoestrogens •Herbal remedies Cimicifuga racemosa Hypericum perforatum Ginkgo biloba Valeriana officinalis Evening Primrose Oil