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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