OVULATORY DYSFUNCTION IN INFERTILITY AND IT’S MANAGEMENT
Transcript of OVULATORY DYSFUNCTION IN INFERTILITY AND IT’S MANAGEMENT
Hormone Therapy Review of Options
Assoc.Prof.Pawin Puapornpong.
Faculty of Medicine
Srinakharinwirot University
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Assoc.Prof.Pawin Puapornpong. 2
Why Hormone Replacement Therapy?
With a marked increase in longevity, women now spend
1/3 rd of their lives in the post-menopausal period. It is
estimated that 1/3 rd of total female population are in
menopause. Therefore they would have to cope with the
post menopausal syndrome and face the consequences
.HRT relieves the well known symptoms of post
menopausal syndrome .Again women are now asking for
a quality life after menopause. So HRT is a hot topic in
this era as it is no more for symptomatic management for
PMS, but for the total management from prophylactic to
curative .
Assoc.Prof.Pawin Puapornpong. 3
Since estrogen deficiency is a major cause
of the long-term complications of the
menopause, estrogen replacement is the
rational treatment to address the cause of
the problems after menopause .But as there
are limitations of estrogen therapy as HRT,
some other drugs are also used besides
estrogen
What is hormone replacement therapy?
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Oral: - Conjugated equine estrogen (CEE): 0.625 mg (Estrone
Sulphate + equilin sulphate +17 d dihydro equilin)
Estradiol valerate (1, 2, 4 mg).
Estrial succinate (1, 2 mg).
Transdermal (estradiol): - Patches: 25 micro gm, 50 micro gm / 24 hour twice
weekly.
Gel : 75 micro gm / 24 hours daily.
Sub cutaneous implant (estradiol): - 25 / 50 / 100 mg. 6 monthly.
Vaginal: cream.
1. Estrogens
DRUGS USED IN HRT
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DRUGS USED IN HRT
Oral route –. Norgestrol: 150 mg /day.
Micronised progesterone: 200 mg /day.
Dydrogesterone: 20 mg / day.
Medroxy progesterone acetate: 10mg/day.
Norethisterone acetate : 0.7 – 2.5 mg/ day.
Hormone releasing intra uterine system –. Levonorgestrel: 20 mcg / day.
Progestasert: 65mcg / day.
Vaginal - natural progesterone gel / pessary.
Transdermal - sequential / continuous patch.
2. Progestins:
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DRUGS USED IN HRT
Synthetic steroid, tissue specific HRT
2 hydroxy metabolites are estrogenic
D 4 isomer binds to progesterone & androgen receptors
Addition of progesterone not required
3. Tibolone
4. Androgen
• Oral Tablets
• Implants-Pellets of 100 mg testosterone
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DRUGS USED IN HRT Regimens
Estrogen alone: in post hysterectomy cases
E + P
Cyclic sequential: E on day 1-25; P on day 14 –25 (for
climacteric patients with intact uterus )
Continuous sequential: E daily; P for 12 days at 16
days interval (for post menopausal patients with intact
uterus)
Continuous combined: E + P taken daily
Progesterone alone: cyclic / continuous
Estrogen + Progesterone + Androgen
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Vasomotor symptoms: Hot flushes & night sweats resulting from hyperactivity of
mid brain-hypothalamic-pituitary axis & characteristic of
climacteric are relieved by HRT
Sleep disturbances: Early morning awakening and inability to get back to
sleep is a frequent complaint in postmenopausal
women. Estrogen receptors are present in Reticular
Activation System, preoptic area, and hypothalamus.
Estrogen replacement improves sleep by acting at
these sites.
Benefits of HRT
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Mood & psychological changes:
Estrogen replacement appears to have a direct mental
tonic effect on the cognitive functions even in the
absence of vasomotor symptoms .It over comes anxiety,
over sensitivity, tearfulness, irritability, aggression.
However if progesterone is also given, it may reduce the
beneficial effects of estrogen on libido & mood.
Benefits of HRT
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Benefits of HRT
Atrophy of genital tract leading to vaginal dryness & postmenopausal
bleeding from atrophic vaginitis / atrophic
endometrium respond to estrogen therapy.
Dyspareunea
due to vaginal dryness is not a problem in
menopause, but it is a problem during climacteric.
Loss of libido
also responds to estrogen replacement. Some also
get benefit from testosterone.
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Benefits of HRT
Urinary symptoms: Incontinence –Urethral abnormality, Detrussor
instability, Overflow Incontinence
Frequency, Urgency, Dysuria
Difficulty in voiding
Estrogen may produce considerable improvement in
these symptoms by increasing
Epithelial thickness, vascularity, closing pressure of urethra
Adrenergic receptor in bladder urethral muscle
Collagen content of connective tissue
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Benefits of HRT
Bone & skeleton: Post menopausal women, due to increased bone
resorption, exceeding the rate of new bone formation.
Loose 30% of their total bone mass. It leads to
osteoporosis, and fracture may occur with minimal /
trivial trauma.
Estrogens cause stimulation of C cells of thyroid
resulting in increased level of calcitonin, which causes
inhibition of osteoclastic bone resorption.
Progesterone has synergistic action, as it binds
competitively with glucocorticoid receptors in bone, thus
inhibiting the resorbing effect of cortisone.
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Benefits of HRT
Cardiovascular system : In menopause as there is increased level of plasma
total cholesterol & LDL and decreased level of HDL, leading to atherosclerosis, there is increase in cardiovascular diseases.
Skin, hair, body fat : In postmenopausal women there is decrease in
content of collagen in skin .So the skin becomes wrinkled. Estrogen increases the collagen content .It also prevents varicose ulceration.
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Benefits of HRT
Neuroprotection: It reduces the risk of Alzheimer’s disease by
reducing amyloid protein & cholinergic dysfunction
in brain.
It enhances the proliferation of neuronal cell
population within the hippocampus.
It regulates the synaptic neurotransmission &
increases nerve growth factor. Thus it enhances
neuroplasticity, memory, and cognition.
It delays the onset of Parkinson’s disease by its
action on dopaminergic system in midbrain.
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Benefits of HRT
Other effects: Estrogen prevents tooth loss & periodontal disease.
There is substantial decrease in the risk of fatal colon cancer.
There is reduction in age related macular degeneration,cataract and severe nuclear sclerosis.
In diabetic women there is improvement in glycemic control.
Less risk of Osteoarthritis:.
Alleviates the worsening symptoms of multiple sclerosis.
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Specific actions of TIBOLONE
Tibolone comes closest to being the ideal product for long term HRT because of the specific actions. Brain: - enhances mood, libido.
Heart: -beneficial effects on CVS.
Breast: -lower incidence of breast tenderness and no effect on mammography.
Endometrium: -no proliferation.
Urogenital symptoms:- improved.
Bone: -prevents bone loss.
It induces amenorrhoea.
Thus it is a menstruation free HRT, which is most
welcome to most women, with an intact uterus.
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RISKS OF HRT
Continuous use of estrogen can cause endometrial hyperplasia, leading to endometrial carcinoma. Addition of progesterone reduces this risk as it
inhibits DNA synthesis,
reduces the no. of estrogen receptors,
stimulates the enzyme 17alpha dehydrogenase, which converts E2 to E1.
Tibolone does not stimulate the endometrium as it exhibits progestogenic & androgenic activities in endometrial tissue.
Endometrial risk:
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RISKS OF HRT
There is increased incidence of breast carcinoma
with long-term use of estrogen.
Progestogen has no protective effect .
So annual breast examination including
mammography is necessary.
Tibolone & its metabolites are very potent inhibitors
of stimulants of breast tumors.
Breast neoplasia:
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RISKS OF HRT
Unopposed estrogen therapy may cause
endometroid tumor. So patients need annual
pelvic examination.
Ovarian neoplasia
Venous thromboembolic disease
There is little risk of venous thromboembolism
with conventional HRT.
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Advantages.
Easy to take & cheap.
Good control due to short ½ life.
Disadvantages.
High dose required.
Wide variation in absorption & metabolism during its first pass
through intestine, liver.
High incidence of minor side effects.
E2: E1 remains same.
Increase in free cholesterol pool in hepatic cells.
Increases serum triglycerides, worsens glucose tolerance & insulin
resistance
Advantages & Disadvantages of each preparation: -
ESTROGEN: ORAL -
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Advantages.
Stable compound due to ethinyl group,
Minimal dose required 10 –20 microgram.
Disadvantages.
Passes unchanged to liver, greater metabolic effects on liver results in increased risk of venous & arterial thrombosis,
Suppression of F.S.H. & Urinary calcium excretion.
Relatively increased incidence of breast carcinoma.
Stimulates: hepatic production of renin substrate & angiotensinogen with risk of hypertension, vasoconstriction, platelet aggregation
Advantages & Disadvantages of each preparation: -
ESTROGEN: ORAL - ETHINYL ESTRADIOL
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Very potent, not subject to enzymatic metabolism,
low plasma clearance.
Stored in fat & released slowly. But in higher doses
(1.25 mg /day) this may cause increased plasma
level of renin substrate like EE.
Advantages & Disadvantages of each preparation: -
ESTROGEN: ORAL - CEE.
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Short acting as it has only short retention time in the
nuclei of endometrial cells .No endometrial
proliferation.
Cyclic progesterone administration is not required.
Postmenopausal withdrawal bleeding do not occur.
Particularly effective in the treatment of urogenital
symptoms.
Advantages & Disadvantages of each preparation: -
ESTROGEN: ORAL - Estriol
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Low dose, pure estradiol.
Avoids intestine & liver metabolism.
Physiological E2: E1.
Reduces serum triglyceride & insulin resistance.
No adverse effect on biliary cholesterol saturation index & biliary salt composition.
But more expensive, not well tolerated in warm climates, skin reaction may occur.
Variable absorption.
Advantages & Disadvantages of each preparation: -
ESTROGEN: TRANSDERMAL
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Pure estradiol, 6 monthly insertion, high level of
estradiol in blood.
Avoids first pass effects, physiological E2: E1 ratio,
better response in severe osteoporosis.
But needs surgical procedure, unable to control
absorption, risk of supraphysiological blood levels,
difficult to remove pellet, prolonged release of
estradiol.
Advantages & Disadvantages of each preparation: -
ESTROGEN: IMPLANTS
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Given with / without combination of systemic
therapy to the older women having urogenital
symptoms. Natural estrogen preparation avoids
significant systemic absorption.
Advantages & Disadvantages of each preparation: -
ESTROGEN: VAGINAL CREAM
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SPECIAL SITUATIONS
Hypertension:- non oral estrogens are of choice
Thromboembolism:- Transdermal route is preferable
Gallbladder disease: - non-oral route
Side effects: change to non-oral
Poor response: may be due to inadequate absorption from intestine / transdermally: - Implant is beneficial
Lactose intolerance: - lactose present in oral preparation, so non-oral route is of choice
Choice Of Preparation
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INDICATIONS FOR STARTING HRT
1) Women having climacteric symptoms and urogenital symptom
2) All asymptomatic high-risk women having Premature menopause (surgical / spontaneous)
Established osteoporosis on x-ray /B.M.D. Measurements
Family history of osteoporosis
Thin, small sedentary women
Poor diet, excess alcohol
Corticosteroid & other medications
High urinary calcium / creatinine
Low plasma estradiol
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Contraindications of conventional HRT
Known / suspected breast cancer
Estrogen dependent neoplasia
Undiagnosed abnormal genital bleeding
Active thrombophlebitis
Abnormal liver function tests
Malignant melanoma
Known / suspected pregnancy
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SPECIFIC INDICATIONS OF TIBOLONE
Breast cancer risk
Breast cancer treated
Family history
Low parity / nulliparity
Racial factor
Endometrial cancer risk
Past H/O endometriosis / fibroid
Patients with NIDDM
Patients with hypertriglyceridemia & H/O
thromboembolic phenomena
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Adverse effects of Progestins & their management
Bleeding problems: heavy / prolonged bleeding on
sequential therapy – Select more androgenic type
progestogen (LNG & Norethisterone).
Physical side effects: edema, weight gain, bloating,
migraine - Spironolactone 25 mg O.D. In the last week.
Acne, greasy skin - progestogen having no androgenic
effect.
Head ache - adding a mild diuretic / androgen.
Psychological: fatigue, depression, irritability, anxiety, and
forgetfulness - switch from oral to non oral treatment.
Women having CVS disease / DM: natural progesterone /
less androgenic derivative of progesterone is ideal.
32 Assoc.Prof.Pawin Puapornpong.