hrt (hormone replacement therapy) and drim (drugs and roentgen induced menopause) m. luerti...
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HRT(Hormone Replacement Therapy)
and
DRIM(Drugs and Roentgen Induced Menopause)
M. LuertiDipartimento Materno Infantile
U.O. di Ostetricia e Ginecologia - Presidio di Lodi
ASL della Provincia di Lodi - Regione Lombardia - Italia
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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
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FACTORS AFFECTING DRIM
• Disease motivating the induction of menopause
• Ovarian failure inducing agent
• Postmenopausal ageing in relation to the age at which menopause occurs
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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
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PRIMITIVE DISEASE CAN EXACERBATE SOME SYMPTOMS
Disease Symptoms
Cancer Sexual life deterioration
Anxiety
Endometriosis Depression
Sleeplessness
Cardiovascular diseases Fatigue
Anaemia
Osteoporosis
Dyspareunia
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FACTORS AFFECTING PROBABILITY OF OVARIAN FAILURE
•Age of the patient
•Duration of treatment
•Dose
•Fractionation of doses
•Association of agents (polichemotherapy)
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FOLLICLE RESERVE IN WOMEN OF DIFFERENT AGES
Age Average n. of primordial Extreme limits
follicles
Birth 480.000 260.000-750.000
15-30 150.000 40.000-300.000
31-40 75.000 15.000-200.000
> 40 8.000 350-25.000
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CHEMOTHERAPY AND OVARIAN CYTOTOXICITY
Definite Probable*Chlorambucil *Doxorubicin*Cyclophosphamide *Vinblastine*L-Phenylalanine Mustard *Cytosine Arabinoside*Nitrogen Mustard *Cisplatin*Busulfan *Nitrosureas*Procarbazine *m-AMSA
*Etoposide
Unknown Unlikely*Bleomicin *Methotrexate
*Fluorouracil*Mercaptopurine*Vincristine
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OVARIAN FAILURE INDUCING AGENTS
ReversibleHormones
Irreversible
53% irreversible under age 35Chemotherapy 84% between ages 35-44
94% age 45 or older
Reversible (< 250 r/ovary)Radiotherapy
Irreversible (> 250 r/ovary)
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OVARIAN FAILURE INDUCING AGENTS CAN EXACERBATE SOME CLIMATERIC SYMPTOMS
Agent Symptoms
FatigueChemotherapy
Anaemia
Hormonal therapyCardiovascular disease
Radiotherapy Osteoporosis
Atrophy and dyspareunia
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POSTMENOPAUSAL AGEING
The lower the age of induced
menopause, the stronger the
symptoms and higher the risk of
long-term effects
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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
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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
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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
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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
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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
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RELUCTANCE OF THE PHYSICIAN: WHY?
Is HRT contraindicated in DRIM?because of inducing agent?
because of primitive illness?
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HRT and DRIM
There are no contraindications to the use of HRT in DRIM in
relation to ovarian failure inducing agent
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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
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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%
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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
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RECURRENCES AND SURVIVAL AFTER HRT IN PATIENTS TREATED FOR ENDOMETRIAL CANCER
Recurrences
ERT NON ERT
Chapman, 1996 3,2% 9,8%
Lee, 1990 0% 1,6%
Creasman, 1986 2,1% 14,9%
6 years survival
Creasman, 1986 93% 52%
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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
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HRT AND GYNECOLOGICAL CANCERfrom 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
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HRT and OTHER CANCERfrom 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
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HRT after ENDOMETROSIS INDUCED MENOPAUSEfrom 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.
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HRT after FIBROIDS INDUCED MENOPAUSEfrom 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.
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HRT and DRIM
HRT DOESN’T APPEAR TO
BE CONTRAINDICATED
AND ADVISABLE IN MOST
CASES OF DRIM
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HRT IN PATIENTS TREATED FOR BREAST AND ENDOMETRIAL CANCER
It is recommended the use of
a continuous combined
estro-progestin therapy
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COMPLEMENTARY APPROACHES TO DRIM
•Other medicationsClonidineBellergal®Topical estrogensHigh doses progestinsBisphosphonatesSERMs
•Diet and lifestyle
•Phytoestrogens
•Herbal remediesCimicifuga racemosaHypericum perforatumGinkgo bilobaValeriana officinalisEvening Primrose Oil