Tag: Anti-Oestrogens

Anti-Oestrogens

Anti-Oestrogens


Introduction:

  • The drugs which antagonize oestrogens at the receptor level are clomiphene and tamoxifen

Clomiphene Citrate:

  • Nonsteroidal compound related to diethylstilbestrol (DES)

Mixture of two isomers:

  • zuclomiphene(Cis 38%)+enclomiphene citrate(trans 63%)

Mode of Action:

  • DOC in induction of ovulation.
  • Starting on the second day of the cycle and given for 5 days

Blocks the negative feedback of  oestrogen at hypothalamus by binding estrogen receptor

GnRH release

LH & FSH secretion 

  • Exerts anti-E action on the endometrium and cervical mucus & decrease in the fertility rate.
  • E2 level starts increasing 5–6 days after stopping drug and induces maturity of the Graafian follicle & ovulation with LH surge.
Indications:

Anovulatory infertility.

  • Polycystic ovarian syndrome
  • In in vitro fertilization:Gamete intrafallopian transfer (GIFT) technique and assisted reproduction therapy(ART).
  • Stein- leventhal syndrome
  • 25 mg orally for 25 days each month for 3 to 6 months to stimulate spermatogenesis(used for male infertility with oligozoospermia)
Contraindications
  • Ovarian cyst—the cyst can increase in size.
  • Chronic liver disease, because it is metabolized in the liver.
  • Scotoma.
Side Effects
  • Ovarian enlargement
  • Hot flushes, sweating due to oestrogen deficiency
  • Osteoporosis
  • Nausea, vomiting
  • Visual disturbances, blurring,scotoma
  • Headache, dizziness
  • Urticaria
  • Hair loss
  • Weight gain
  • Anti-oestrogenic effect on cervical mucus and endometrium
  • CLPD
  • Ovarian Hyperstimulation Syndrome(OHSS)
  • Neural tube defect
  • Multiple ovulation and multiple pregnancy(6-10%)
  • Abortion rate 25 to 40%
  • Ovarian  malignancy( treatment is extended beyond 1 year)
  • Premature ovarian failure
  • Gynaecomastia
  • Increase Incidence of unruptured luteinized follicle
Letrozole:
  • Nonsteroidal aromatase inhibitor
  • Induce ovulation
  • Prevents conversion of androstenedione to oestrone

Advantages over clomiphene:

  • Better pregnancy rate:no anti-oestrogenic action on the endometrium & cervix
  • Induces mono-follicular stimulation, adequate LH surge and avoids multiple pregnancy
  • Better implantation
  • No hyperstimulation syndrome
  • Cause drowsiness and liver dysfunction.
Tamoxifen:
  • Nonsteroidal anti-oestrogenic drug
  • selective estrogen receptor modulator (SERM).
  • Acts by binding to and reducing the availability of oestrogen receptors.

Dosage:

  • 10–20 mg twice daily for less than 5 yrs

Uses:

  • Advanced breast cancer in postmenopausal women:BRCA1 and BRCA2 gene positive women
  • PCOD.

Side effects:

  • Hot flushes, vaginal dryness (anti-E2 action)
  • Endometrial hyperplasia, polyp
  • Endometrial carcinoma and sarcoma
  • Hyperglyceridaemia,
  • Deep venous thrombosis
  • Ischaemic heart disease
  • Retinopathy, Cataract

Precautions:

  • Monitor endometrial growth
  • Women receiving Tamoxifen should be periodically screened with Endometrial sampling

 Ormeloxifene (Centchroman)

  • Nonsteroidal anti-oestrogen developed for its contraceptive potential.
  • Weekly nonsteroidal pill
  • Antioestrogen activity on endometrium
  • Does not inhibit ovulation and exerts contraceptive effect on implantation.
Exam Question
 
  • Antihormonal substance used to induce ovulation clomiphene citrate
  • Anovulatory infertility can be treated by clomiphene
  • Clomiphene citrate is indicated in stein- leventhal syndrome
  • Clomiphene causes hyperstimulation 
  • Drugs used for ovulation induction  Clomiphene citrate & Tamoxifen
  • Clomiphene citrate is  Anti estrogen
  • The most serious complication of clomiphene therapy for induction of ovulation is Hyperstimulation syndrome
  • Tamoxifen is Non steroidal antioestrogenic
  • Long term tamoxifen therapy may cause Endometrium Ca
  • In Clomiphene citrate Risk of multiple pregnancy is 6-10%
  • Clomiphene citrate can also be used for male infertility with oligozoospermia
  • Gynaecomastia is caused by Clomiphene citrate
  • Mechanism of action of Clomiphene Citrate is Binds estrogen receptors and prevents negative feed back at hypothalamus
  • Side effects of clomiphene citrate include Multiple pregnancy, Increase risk of ovarian ca & Multiple polycystic ovary
  • Women receiving Tamoxifen should be periodically screened with Endometrial sampling
  • Use of tamoxifen in carcinoma of breast patients shows Endometrial hyperplasia,Thromboembolic events, Endometrial Carcinoma & cataract
  • Tamoxifene is SERM
  • Letrozole belongs to Aromatse inhibitors
  • Drug useful in breast cancer is Tamoxifen
Don’t Forget to Solve all the previous Year Question asked on Anti-Oestrogens

Anti-Oestrogens

Anti-Oestrogens

Q. 1

Antihormonal substance used to induce ovulation :

 A

Mifepristone

 B

Clomiphene citrate

 C

Tamoxifen

 D

Raloxifen

Q. 1

Antihormonal substance used to induce ovulation :

 A

Mifepristone

 B

Clomiphene citrate

 C

Tamoxifen

 D

Raloxifen

Ans. B

Explanation:

 

Ans. is b i.e. Clomiphene citrate            

1. Clomiphene citrate is the initial treatment for most anovulatory infertile women. It is chemically similar to tamoxifen Clomiphene is a non steroidal triphenylethylene derivative which demonstrates both estrogen agonist and antagonist properties (predominant).

It is the agent of choice for women with oligomenorrhea or amenorrhea having sufficient ovarian function to maintain estrogen at a serum level of 40pg/ml.

Patient selection :

  • Normal gonadotropic° normoprolactinemic° patients with normal cycle with absent or infrequent ovulation.°
  • PCOS°                                                                                        
  • Post pill amenorrhea.°

Dose :

  • Initial dose of 25 to 50mg° is given daily from D2 – D 5.
  • Ovulation is expected to occur about 5 – 7 days after the last day of therapy.
  • If ovulation doesnot occur, dose is increased in 50mg steps to a maximum of 250mg daily. (Although doses > 100 mg /day are not approved by FDA).
  • Therapy is in given for 4-6 cycles.

Clomiphene will be successful in inducing ovulation in about 70% of women, with ovaries producing estrogen

Switch over from clomiphene to more aggressive therapy is done when :

  • There is no response to clomiphene° (even with 100 mg / day dosing).
  • There is ovulatory response to clomiphene but no pregnancy° (following 3 to 6 months of ovulatory response to clomiphene).
  • Patients with pituitary insufficiency°

These patients usually respond to Gonadotropins.

Note : Letrozole – 2.5mg (non steroidal aromatase inhibitor) is found superior to clomiphene.

2. Gonadotropin therapy :

Prerequisite for Gonadotropin therapy : Ovarian reserve must be present. The Gonadotropins used are

  • Human menopausal Gonodotropin :

— It is a formulation containing equal amounts of FSH and LH (751U each).

— It is prepared from hormones obtained from urine of postmenopausal women.

  • HCG is required as an ovulatory trigger.
  • FSH : purified urinary FSH and Recombinant FSH are also available.

3. Gonadotropin releasing hormone :

Pulsatile GnRH : If other methods have failed then pulsatile GnRH is needed in patients with anovulation and

hypothalamic insufficiency.

Other drugs which can be used to for ovulation :

  1. Bromocriptine/Cabergoline : Are used to to treat anovulation caused by increase in serum prolactin level.

Corticosteroids : Use to treat anovulation due to congenital adrenal hyperplasia.

Also know :

Mangement of unilateral proximal tubal block :

Hysteroscopic cannulation or microsurgical tubo cornual anastomosis (if any periadenaxal adhesions are also present).

Management of distal tubal block :

Best is IVF.

Surgical procedures like fimbrioplasty (lysis of fimbrial adhesions or dilatation of fimbrial stenosis) or neosalpingostomy may be done.

Management of distal tubal block by hydrosalperix

First laparoscopic salpingectomy followed by IVF

Management of Bipolar tubal obstruction i.e. both proximal and distal tubal obstruction. Best is IVF

Extra Edge :

Lets quickly revise the tests for tubal patency.

Tests for tubal patency :

  • Rubins test : Outdated°
  • Hysterosalpingography : screening procedure.°
  • Hystero contrastosonography
  • Laparoscopy : Best technique for diagnosis of tubal and peritoneal pathology.°
  • Selective salpingography and falloscopy For evaluation of proximal tube obstruction. By falloscopy : tubal ostia and intra tubal architecture can also be seen.

Time for performing tubal patency tests : D6-D 11 of the cycle.


 


Q. 2

Treatment for Cervical infertility can be all except:

 A

Condom for 3 month

 B

IUI

 C

Gamete Intrafallopian transfer

 D

Clomiphene citrate

Q. 2

Treatment for Cervical infertility can be all except:

 A

Condom for 3 month

 B

IUI

 C

Gamete Intrafallopian transfer

 D

Clomiphene citrate

Ans. D

Explanation:

Ans. is d i.e. Clominphene citrate

Cervical factor infertility can be due to abnormal or deficient mucus due to :                

  1.  Infection
  2. Prior cervical surgery
  3. Use of antiestrogens (eg clomiphene citrate) for ovulation induction (so clomiphene is a cause of cervical factor infertility rather than management)
  4. Sperm antibodies

The treatment of cervical factor thus depends on the cause :

  • If it is due to chronic cervicult / infection – Treatment of infection by antibiotics is the cure.
  • If is due to decreased mucus vis volume – Treatment includes short term supplementation with exogenous estrogen

like ethinyl estradiol and use of mucolytic expectorant like guaifenesin. However, their value has not been

confirmed.

  • If it is due to antisperm antibodies. Treatment options include :

Use of condom or diaphragm as a barrier method for 3 months. During this period, the antibodies will

disappear and conception may occur then.

–  Corticosteroids given to female partner can also help in getting rid of these antibodies.

intrauterine insemination at the time of ovulation (most acceptable method for cervical factor infertility) or GIFT (Gamete intrafallopian transfer) are very useful techniques in such cases.

IUI is the best method for treating cervical factor infertility and unexplained infertility. So many clinicians forgo cervical mucus testing and proceed directly to IUI treatment in absence of tubal disease.


Q. 3

Which of the following pairs are correctly matched:

  1. Endometriosis                      Danazol
  2. Endometrial carcinoma       Oestrogen
  3. Anovulatory infertility         Clomiphene
  4. Prolactinoma                       Alpha-Bromocriptine

Select the correct answer using the codes given be­low :

 A

1.2,3 and 4

 B

1.3 and 4

 C

2. 3 and 4

 D

1 and 2

Q. 3

Which of the following pairs are correctly matched:

  1. Endometriosis                      Danazol
  2. Endometrial carcinoma       Oestrogen
  3. Anovulatory infertility         Clomiphene
  4. Prolactinoma                       Alpha-Bromocriptine

Select the correct answer using the codes given be­low :

 A

1.2,3 and 4

 B

1.3 and 4

 C

2. 3 and 4

 D

1 and 2

Ans. B

Explanation:

1.3 and 4


Q. 4

Which of the following is not indicated in menorrhagia :

 A

NSAID’s

 B

Clomiphene

 C

Norethesterone

 D

Tranexamic acid

Q. 4

Which of the following is not indicated in menorrhagia :

 A

NSAID’s

 B

Clomiphene

 C

Norethesterone

 D

Tranexamic acid

Ans. B

Explanation:

Ans. is b i.e. Clomiphene

Clomiphene is mainly indicated in anovulatory infertility and PCOD.

Medical management of menorrhagia :

  • NSAID’s or prostaglandin synthetase inhibitors
  • Hormones : — Progesterones  — Combined OCP

— Danazol  — Gestrinone, GnRH agonist

— Mifepristone (In Menorrhagia due to fibroids)

  • Antifibrinolytic drugs : Act by inhibiting plasminogen activators, reducing the accelerated fibrinolytic activity found in menorrhagic women.e.g. : Tranexamic acid
  • Ethamsylate : Acts by decreasing capillary fragility.
  • GnRH agonist : They induce down regulation of pituitary with an initial agonist phase followed by down regulation causing hypoestrogenism which results in amenorrhea in 90% cases.
  • SERM-Ormeloxiphene:lt is an antagonist to uterine and breast tissue by its antiestrogenic effects and agonist to bone and CVS.
  • Seasonale-It is a new drug with estrogen & progesterone combined.lt is given daily for 84 days & a gap of 6 days is given after that during which menstruation occurs.



Q. 5

Clomiphene citrate is indicated in :

 A

Stein – Leventhal syndrome

 B

Ovarian cyst

 C

Asherman’s syndrome

 D

Carcinoma endometrium

Q. 5

Clomiphene citrate is indicated in :

 A

Stein – Leventhal syndrome

 B

Ovarian cyst

 C

Asherman’s syndrome

 D

Carcinoma endometrium

Ans. A

Explanation:

Ans. is a i.e Stein leventhal Syndrome

Clomiphene citrate is the first line intervention for medical induction of ovulation in PCOS patients. (Stein leventhal syndrome). It is a weak synthetic estrogen but it mimics the activity of an estrogen antagonist when given at pharmacological doses.

Prerequisite : A functional hypothalamic pituitary ovarian axis is required for appropriate clomiphene citrate activity.

Mechanism of action :

Results : 80-85% treated women ovulate and 40% conceive after the use of Clomiphene.

Regimes :

  • Ovulation is then documented using home urine LH kits or by follicular monitoring.
  • Ovulation testing should begin on Day 12 or Day 13 and continued daily till results are positive. If it is successful, ovulation occurs 7-12 days after the last day of treatment and coitus should be timed accordingly.

Traditional                                                              Recent

Clomiphene 50mg/day given from             Clomiphene 50mg/day given from

D-5 to Day 9 of the cycle.                          132-D5 of the cycle.

  • If it fails : clomiphene is increased by 25 mg each cycle to a maximum of 150 mg/day.
  • It is the agent of choice for women with oligomenorrhea or amenorrhea having sufficient ovarian function to maintain estrogen at serum level of 40pg/ml.

Indications :

  • Anovulatory infertility in case of PCOS. Chiari frommel syndrome.
  • Amenorrhea and Anovulation following the use of OCP’s (Post pill amenorrhea).
  • In vitro fertilization, GIFT technique and Assisted Reproduction Technique.
  • In men to stimulate spermatogenesis.

Contraindications : • Impaired liver function

  • Ovarian cyst
  • Scotoma.

Side effects : Polycystic ovaries, multiple pregnancy, hotflushes, gastric upset, vertigo, allergic dermatitis, visual disturbances, scotoma, hyperstimulation syndrome, T Risk of ovarian malignancy (if used for >1 yr), premature ovarian failure.



Q. 6

True about Clomiphene citrate

 A

Commonly causes hyperstimulation

 B

Used tor ovulation induction

 C

Multiple prognanci€s seen in 3-8% cases

 D

All are correct options

Q. 6

True about Clomiphene citrate

 A

Commonly causes hyperstimulation

 B

Used tor ovulation induction

 C

Multiple prognanci€s seen in 3-8% cases

 D

All are correct options

Ans. D

Explanation:

Ans. is a, b and c i.e. All are correct options

Clomiphene citrate is the most commonly used drug for ovulation induction.

it is the usual first choice for ovulation induction in most patients because of its relative safety, efficacy, route of administration and relative low cost.”

The two most common complications of ovulation induction with clomiphene are : multiple pregnancy and ovariar, hyperstimulation syndrome.

As far as incidence of multiple pregnancies is concerend.

Novak 14/e. p 1064 says ‑

“Incidence of multiple pregnancies ranges from 6.25 to 12.3%.

But according to COGDT 10/e p 923 says ‑

“The incidence of twin gestation is 8% and triplets or higher order multiple pregnancies is < 1%." Jeffcoates 7/e, p 105 says ‑

“Pregnancy occurs in 40 – 50% of women following treatment and even though the dosage is carefully monitored, 5-10% of the conceptions are multiple. –

So, I am taking option ‘c’ correct.


Q. 7

Drugs used for ovulation induction :

 A

Clomiphene citrate

 B

Danazol

 C

Tamoxifen

 D

Option A and C both

Q. 7

Drugs used for ovulation induction :

 A

Clomiphene citrate

 B

Danazol

 C

Tamoxifen

 D

Option A and C both

Ans. D

Explanation:

Ans. is a and c i.e. Clomiphene citrate; and Tamoxifen

Drugs used for

  • Clomiphene                                                                        • Chlorpromazine

(given 50mg daily OD from D2-D5 upto max. 150my/day)                 • Reserpine

  • Tamoxifen                                                                           • Busulfan

(given 10mg BD from Day 2- Day 6 upto max. of 40mg daily)            • Vinca alkaloid

  • Corticosteroid (Cortisone)                                                        • Bleomycin

useful in infertility d/t Congenital, adrenal hyperplasia,                     • Cytosine arabinoside

Addison’s disease                                                                        • Hydroxyurea

  • Dexamethasone                                                                  • Electroconvulsive therapy

In patients of hirsutism (Dexamethasone + clomiphene                   • Estrogens/OCP’s

0.5mg at bed time), given good response                                       • Androgens

  • Gonadotrophins                                                                    • Danazol

useful in cases where ovulation is arrested d/t failure in the production of gonadotrophins by the HPO axis

Available preparation : HMG (has 75U of FSH & LH each) Purified urinary FSH

Recombinant FSH

Recombinant HCG

Recombinant LH

  • GnRH (In cases where anovulation occurs d/t hypothalamic inhibition with anterior pituitary intact), GnRH analogues are used to induce ovulation.
  • Bromocriptine It does not Specifically induce ovulation but is DOC for those women with dysmenorrhea / infertility associated with hyperprolactinemia.

Q. 8

Clomiphene citrate is :

 A

Anti-androgen

 B

Synthetic steroid

 C

Anti estrogen

 D

GnRH analogue

Q. 8

Clomiphene citrate is :

 A

Anti-androgen

 B

Synthetic steroid

 C

Anti estrogen

 D

GnRH analogue

Ans. C

Explanation:

Ans. is c i.e. Antiestrogen

Clomiphene is an antiestrogen.

Category                                                            Drug

Antiestrogen                                                      Clomiphene, Tamoxifen

Antiprogesterone                                                 Mifepristone

Testosterone (Androgen derivative)                       Danazol, Gestrinone

Antiandrogen                                                       Cyproterone acetate, Spironolactone, Flutamide,Finasteride


Q. 9

The most serious complication of clomiphene therapy for induction of ovulation is :

 A

Bone marrow depression

 B

Hyperstimulation syndrome

 C

Secondary amenorrhea

 D

Multiple pregnancy

Q. 9

The most serious complication of clomiphene therapy for induction of ovulation is :

 A

Bone marrow depression

 B

Hyperstimulation syndrome

 C

Secondary amenorrhea

 D

Multiple pregnancy

Ans. B

Explanation:

Ans. is b i.e. Hyperstimulation syndrome

Hyperstimulation syndrome is the most dreaded complication of Clomiphene.

Hyperstimulation Syndrome :

  • Results from ovulation induction in infertility cases.
  • It is more common with FSH / LH therapy than with Clomiphene and pulsatile GnRH therapy°.
  • Raised LH in PCOD is responsible for hyperstimulation, and HCG should not be included in the therapy in such cases. HCG administration increases the risk.

Complications of OHSS :

  • Vascular : cerebrovascular accidents, thromboembolic phenomenon, DVT.
  • Coagulopathy
  • Liver dysfunction
  • ARDS due to ascites / hydrothorax
  • Renal failure due to hypovolemia
  • Gastrointestinal
  • Torsion and hemorrhage in ovarian cyst

Treatment : IV fluids for hypovolemia

  • Glucocorticoids
  • Anticoagulants
  • Diuretics for pulmonary edema
  • Dopamine improves renal blood flow, oliguria and prevents renal failure.

Q. 10

Tamoxifen is :

 A

Non steroidal antiprogesterone

 B

Non steroidal antioestrogenic

 C

Synthetic progestogen norethindrone

 D

Competitive inhibitor of the 5alpha-reductase 

Q. 10

Tamoxifen is :

 A

Non steroidal antiprogesterone

 B

Non steroidal antioestrogenic

 C

Synthetic progestogen norethindrone

 D

Competitive inhibitor of the 5alpha-reductase 

Ans. B

Explanation:

Non steroidal antioestrogenic


Q. 11

Long term tamoxifen therapy may cause :

 A

Endometrium Ca

 B

Ovary Ca

 C

Cervix Ca

 D

Vagina Ca

Q. 11

Long term tamoxifen therapy may cause :

 A

Endometrium Ca

 B

Ovary Ca

 C

Cervix Ca

 D

Vagina Ca

Ans. A

Explanation:

Ans. is a i.e. Endometrium cancer

Long term Tamoxifen therapy is a predisposing factor for Endometrial hyperplasia and cancers. For more details, refer answer 6

Also know :

Malignancies caused by Long Term Tamoxifen therapy :

  • Carcinoma endometrium – it is the most common carcinoma associated with it.
  • Uterine sarcoma.
  • Rarely liver cancer with long term high dose.

Non Malignant effects of Tamoxifen on uterus :

  • Endometrial hyperplasia
  • Endometriosis
  • Fibroid uterus
  • Ovarian cysts
  • Menstrual irregularities or Amenorrhea.



Q. 12

True about clomiphene citrate all except ‑

 A

Enclomiphene has antiestrogenic affect

 B

Chance of pregnancy is three fold as compared to placebo

 C

Risk of multiple pregnancy is 6-10%

 D

It can also be used for male infertility with oligozoospermia

Q. 12

True about clomiphene citrate all except ‑

 A

Enclomiphene has antiestrogenic affect

 B

Chance of pregnancy is three fold as compared to placebo

 C

Risk of multiple pregnancy is 6-10%

 D

It can also be used for male infertility with oligozoospermia

Ans. B

Explanation:

Chance of pregnancy is 3 fold compared to placebo [Ref: Katzung 10 /e p. 673; KDT 6th/e p. 303, Goodman Gillman 6thIe p. 1556, 1555]


Q. 13

Gynaecomastia is caused by

 A

Clomiphene citrate

 B

Tamoxifen

 C

Spironolactone

 D

Testosterone

Q. 13

Gynaecomastia is caused by

 A

Clomiphene citrate

 B

Tamoxifen

 C

Spironolactone

 D

Testosterone

Ans. A

Explanation:

Clomiphene; ‘c’ i.e., Spironolactone [Ref: Harrison 161h/e p 2192]

 

Causes of Gynaecomastia

Digitalis

•    Spironolactone

Ethionamide

•    Ketoconazole

Estrogens

•    Calcium antagonists

INH

•    Griseofulvin

Reserpine

•    Methyldopa

Cimetidine

•    Phenytoin

Cyproterone acetate

•    Flutamide

Clomiphene

•    Goserelin

  • Gynaecomastia occurs as a result of imbalance between estrogens which stimulate breast tissue and androgens which counteract these effects.

The gvnaecomastia causing drugs can be categorized into :

  • The first type are drugs that act exactly like estrogens, such as diethylstilbestrol, birth control pills, digitalis, and estrogen containing cosmetics.
  • The second type is drugs that enhance endogenous estrogen formation such as gonadotropins and clomiphene.
  • The third type is drugs that inhibit testosterone synthesis and action such as spimnolactone, ketoconazole, metronidazole and cimetidine.
  • The final type is drugs that act by unknown mechanisms such as isoniazid, methyldopa, captopril, tricyclic antidepressants, diazepam and heroin.

Also know,

  • Testosterone also causes Gynacconiastia

Q. 14

Mechanism of action of Clomiphene Citrate is:

 A

Binds to estrogen receptors and causes negative feedback at hypothalamus

 B

Binds estrogen receptors and prevents negative feed back at hypothalamus

 C

Binds to progesterone receptors

 D

Progesterone agonist

Q. 14

Mechanism of action of Clomiphene Citrate is:

 A

Binds to estrogen receptors and causes negative feedback at hypothalamus

 B

Binds estrogen receptors and prevents negative feed back at hypothalamus

 C

Binds to progesterone receptors

 D

Progesterone agonist

Ans. B

Explanation:

Clomiphene citrate binds to both Estrogen receptors (ER a and B) and acts as a pure estrogen antagonist, in all human tissues.

It induces the Gn secretion in women by blocking estrogenic feedback inhibition of pituitary which inturn increases the amount of LH and FSH released at each secretory pulse and results in ovulation.

Ref: KDT, 6th Edition, Page 303 ; Essentials of Medical Pharmacology By K D Tripathi, 4th Edition, Page 278


Q. 15

A patient treated for infertility with clomiphene citrate presents with sudden onset of abdominal pain and distension with ascites. Most probable diagnosis is:

 A

Uterine rupture

 B

Ectopic pregnancy rupture

 C

Multifetal pregnancy

 D

Hyperstimulation syndrome

Q. 15

A patient treated for infertility with clomiphene citrate presents with sudden onset of abdominal pain and distension with ascites. Most probable diagnosis is:

 A

Uterine rupture

 B

Ectopic pregnancy rupture

 C

Multifetal pregnancy

 D

Hyperstimulation syndrome

Ans. D

Explanation:

Ovarian hyperstimulation syndrome (OHSS) is a clinical symptom complex associated with ovarian enlargement resulting from exogenous gonadotropin therapy.

Symptoms may include abdominal pain and distension, ascites, gastrointestinal problems, respiratory compromise, oliguria, hemoconcentration, and thromboembolism.

Predisposing factors for OHSS include,

  • Multifollicular ovaries such as with PCOS
  • Young age
  • High estradiol levels during ovulation induction
  • Pregnancy

Ref: Hoffman B.L., Schorge J.O., Schaffer J.I., Halvorson L.M., Bradshaw K.D.,Cunningham F.G., Calver L.E. (2012). Chapter 20. Treatment of the Infertile Couple. In B.L. Hoffman, J.O. Schorge, J.I. Schaffer, L.M. Halvorson, K.D. Bradshaw, F.G. Cunningham, L.E. Calver (Eds), Williams Gynecology, 2e.


Q. 16

Which of the following drug is an antihormonal substance used to induce ovulation?

 A

Raloxifen

 B

Tamoxifen

 C

Mefiprestone

 D

Clomiphene citrate

Q. 16

Which of the following drug is an antihormonal substance used to induce ovulation?

 A

Raloxifen

 B

Tamoxifen

 C

Mefiprestone

 D

Clomiphene citrate

Ans. D

Explanation:

Clomiphene citrate is a nonsteroidal estrogen antagonist that increases FSH and LH levels by blocking estrogen negative feedback at the hypothalamus.

Clomiphene citrate is approved by the FDA, as an ovulation-inducing drug. It is given orally in dosages of 50 to 100 mg/d for 5 days on a monthly basis to induce ovulation in infertile women.

Ref: Textbook of gynecology by D C Dutta 4th Edition, Page 486-7.


Q. 17

Side effects of clomiphene citrate include all, EXCEPT:

 A

Multiple pregnancy

 B

Increase risk of ovarian ca

 C

Multiple polycystic ovary

 D

Teratogenic effect on offsprings

Q. 17

Side effects of clomiphene citrate include all, EXCEPT:

 A

Multiple pregnancy

 B

Increase risk of ovarian ca

 C

Multiple polycystic ovary

 D

Teratogenic effect on offsprings

Ans. D

Explanation:

There is no evidence of teratogenicity observed in humans when the drug used to induce ovulation.

Clomiphene increases gonadotropin secretion and stimulates ovulation.
It increases the amplitude of LH and FSH pulses without changing pulse frequency.
It acts largely at the pituitary level to block inhibitory actions of estrogen on gonadotropin release from the gland and causing the hypothalamus to release larger amounts of GnRH per pulse.
 
Side effects of clomiphene include;
  • Multiple gestation
  • Ovarian hyperstimulation syndrome (OHSS)
  • Ovarian cysts
  • Hot flashes
  • Blurred vision
  • Risk of ovarian cancer
Ref: Levin E.R., Hammes S.R. (2011). Chapter 40. Estrogens and Progestins. In L.L. Brunton, B.A. Chabner, B.C. Knollmann (Eds), Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12e.

Q. 18

Women receiving Tamoxifen should be periodically screened with –

 A

Mammography

 B

PAP smear

 C

Ca-125 level

 D

Endometrial sampling

Q. 18

Women receiving Tamoxifen should be periodically screened with –

 A

Mammography

 B

PAP smear

 C

Ca-125 level

 D

Endometrial sampling

Ans. D

Explanation:

Ans. is ‘d’ i.e., Endometrial sampling

Tamoxifen is a selective estrogen receptor modulator (SERM).

o It increases the risk of endometrial carcinoma —) Women receiving tamoxifen should be periodically screened with endometrial sampling.


Q. 19

Use of tamoxifen in carcinoma of breast patients does not lead to the following side effects ‑

 A

Thromboembolic events

 B

Endometrial Carcinoma

 C

Cataract

 D

Cancer in opposite breast

Q. 19

Use of tamoxifen in carcinoma of breast patients does not lead to the following side effects ‑

 A

Thromboembolic events

 B

Endometrial Carcinoma

 C

Cataract

 D

Cancer in opposite breast

Ans. D

Explanation:

Ans is ‘d’ i.e. Cancer in opposite breast 

Adverse effects of Tamoxifen: ‑

(a)       Hot flushes, nausea vomiting (most common side effects)*

(b)       Menstrual irregularities, vaginal bleeding, discharge, pruritis vulvae & dermatitis

(c)       Endometrial cancer

(d)       Thromboembolism

(e)       Cataracts

(f)      Retinal deposits & decreased visual acuity

Benefits of Tamoxifen: ‑

(a)     Estrogen receptor positive breast cancer: used in both pre and postmenopausal women.

(b)       it appears to increase bone density (slows the development of osteoporosis in postmenopausal women) favourably affect lipid and lipoprotein profiles.


Q. 20

Tamoxifene ‑

 A

SSRI

 B

SERM

 C

SNRI

 D

DNRI

Q. 20

Tamoxifene ‑

 A

SSRI

 B

SERM

 C

SNRI

 D

DNRI

Ans. B

Explanation:

Ans. is `b’ i.e., SERM

Tamoxifen is a selective estrogen receptor modulator (SERM).


Q. 21

Letrozole belongs to which group?

 A

SERM

 B

SERD

 C

LHRH analogues

 D

Aromatse inhibitors

Q. 21

Letrozole belongs to which group?

 A

SERM

 B

SERD

 C

LHRH analogues

 D

Aromatse inhibitors

Ans. D

Explanation:

Ans. is ‘d’ i.e., Aromatase inhibitors

Aromatase inhibitors

  • Aromatase inhibitors are drugs which inhibit the enzyme Aromatase.
  • Aromatase is an enzyme responsible for the conversion of testosterone (androgens) to estrogens.
  • This conversion of androgens to estrogens occur in several tissues including ovary, adrenal cortex, peripheral tissues.
  • Inhibition of Aromatase leads to decrease in estrogen level.
  • Aromatase inhibitors prevent the conversion of androgens to estrogens only in postmenopausal women, not in premenopausal women.
  • In premenopausal women, as the level of estrogens decrease it activates the pituitary hypothalamic axis. Activation of pituitary hypothalamic axis leads to increased secretion of pituitary gonadotropins. The pituitary gonadotropins inturn increase the secretion of estrogens. Thus the estrogen level returns back to their normal level.
  • On the other hand aromatase inhibitors effectively decrease the secretion of estrogen in postmenopausal women.
  • In postmenopausal women, the production of estrogen from androgens occurs, only in extraovarian sites such as peripheral tissues where the conversion of androgens to estrogens is blocked by aromatase inhibitors.
  • Use of aromatase inhibitors
  • Aromatase inhibitors are used in the t/t of Hormone receptor positive breast carcinomas in postmenopausal women. They are not effective in premenopausal women.
  • How are Aromatase inhibitors useful in Breast carcinomas ?
  • In breast carcinomas, estrogen delivers growth signals to the hormone receptors. The hormone receptors upon receiving the growth signals, cause the proliferation of tumor cells.
  • After the inhibition by aromatase inhibitors, estrogen level decreases, this leads to lesser delivery of growth signals and in turn lesser proliferation of tumor cells.
  • Aromatase inhibitors are of two types :
  • Type I (steroidal) aromatase inhibitor – They cause irreversible inhibition of aromatase, e.g. Exmestane, formestane.
  • Type II (non-steroidal) aromatase inhibitor – They cause reversible inhibition of aromatase e.g. Anastrazole, Letrozole, vorozale.
  • Above classification is based on chemical structure (steroidal or non-steroidal) and type of inhibition (reversible or irreversible). Based on the evolution the aromatase inibitors arc:
  1. First generation → Aminoglotethimide
  2. Second generation → Steroidal type I (Example, formestane), non-steroidal type II (Anastrazole, Letrozole, Vorozole, fadrozole)
  • Side effects – Hot flushes, nausea, diarrhoea, dyspepsia, thinning of hair and Joint Pain (Arthralgia) and increased risk of fracture.
  • There is no endometrial proliferation (no risk of endometrial carcinoma), no risk of venous thromboembolism and no deterioration of lipid profile.

Remember

  • Anastrozole and letrozole are nonsteroidol compound, while exemestane is steroidol. o Exemestane also has weak androgenic activity.
  • Anastrozole is more potent than letrozole.
  • First generation aromatase inhibitors → Aminoglutethimide.
  • Second generation aromatase inhibitors → Letrozole, anastrozole, fadrozole and exemestone.

Q. 22

Tamoxifen causes ‑

 A

Osteoporosis

 B

Endometrial hyperplasia

 C

Ovarian cancer

 D

Decreased triglyceride level

Q. 22

Tamoxifen causes ‑

 A

Osteoporosis

 B

Endometrial hyperplasia

 C

Ovarian cancer

 D

Decreased triglyceride level

Ans. B

Explanation:

Ans. is ‘b’ i.e., Endometrial hyperplasia


Q. 23

All are side effects of clomiphene citrate except ‑

 A

Ovarian cysts

 B

Hot flushes

 C

Breast soreness

 D

Amenorrhea

Q. 23

All are side effects of clomiphene citrate except ‑

 A

Ovarian cysts

 B

Hot flushes

 C

Breast soreness

 D

Amenorrhea

Ans. D

Explanation:

Ans. is `d’ i.e., Amenorrhea 

Clomiphene citrate

  • It is a nonsteroidal compound.
  • It is binds to both estrogen receptor a & (ERa and ER13)
  • It acts as a pure estrogen antagonist in all human tissues.
  • Induces gonadotropin secretion (LH, FSH) by blocking estrogenic feedback inhibition on pitutary (not on hypothalamus).
  • In response to increased LH/FSH ovaries enlarge and ovulation occurs.
  • Antagonism of peripheral actions of estrogen results in hot flushes.
  • The chief use of clomiphene is in sterlity due to failure of ovulation – Addition of menotropins or chorionic gonadotropin improves the success rate.
  • Other uses are to aid in vitro fertilization and oligospermia (male infertilty).
  • Adverse effects → Polycystic ovarian disease (hyperstimulation syndrome), multiple pregnancy, hot flushes are main.
  • There is increase risk of ovarian tumor
  • Side effects of clomiphene→ Polycystic ovary, hyperstimulation syndrome, hot flush, multiple pregnancy, alopecia, vertigo, allergic dermatitis, gastric upset and increased risk of ovarian tumor.

Q. 24

Drug useful in breast cancer is ‑

 A

Tamoxifen

 B

Cyproterone

 C

Testosterone

 D

Chlorambucil

Q. 24

Drug useful in breast cancer is ‑

 A

Tamoxifen

 B

Cyproterone

 C

Testosterone

 D

Chlorambucil

Ans. A

Explanation:

Ans. is ‘a’ i.e., Tamoxifen

Pharmacotherapv of breast cancer

  • Many breast carcinomas possess estrogen receptors  Estrogen promotes their growth.
  • Drugs which decrease the action of estrogen on breast CA by one or other mechanisms, can be used in breast CA. Drugs used in Breast cancer
  • Selective estrogen receptor modulators (SERMs) – Tamoxifen, Tromifene.
  • Selective estrogen receptor down regulators (SERDs) – Fulvestrant
  • Aromatase inhibitors – Letrozole, anastrozole, exemestone
  • LHRH (GnRh) analogues
  • Aminoglutethemide
  • High doses progesterones – Megastrol acetate.


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