ovulatory dysfunction in infertility and itâ€™s management

Hormone Therapy Review of Options

Assoc.Prof.Pawin Puapornpong.

Faculty of Medicine

Srinakharinwirot University

1

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 .


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?


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


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:


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


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


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


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


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.


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


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.


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.


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.


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.


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.


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:


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:


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.


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 -


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


ESTROGEN: ORAL - ETHINYL ESTRADIOL


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.


ESTROGEN: ORAL - CEE.


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.


ESTROGEN: ORAL - Estriol


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.


ESTROGEN: TRANSDERMAL


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.


ESTROGEN: IMPLANTS


Given with / without combination of systemic

therapy to the older women having urogenital

symptoms. Natural estrogen preparation avoids

significant systemic absorption.


ESTROGEN: VAGINAL CREAM


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


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


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


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


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.

ovulatory dysfunction in infertility and itâ€™s management

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