Selective Estrogen Receptor Modulators (SERMs)

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.

Serial ultrasound

Ans. is b i.e. Tibolone 

Friends this is the most often asked question on endometriosis. It is worth while to know a few details on this topic.

Emperical treatment : is for pain presumed to be due to endometriosis. (in absence of definitive diagnosis) and includes :— Counselling

—            Analgesia

—            Nutritional therapy

—            Progestin or OCP’s

Analgesia : Studies have shown NSAID’s except niflumic acid are more effective in chronic pain relief due to endometriosis or dysmenorrhea suspected to be due to endometriosis.

Hormonal medical treatment :

Basis of management : Since estrogen is known to stimulate the growth of endometriosis, hormonal therapy has been designed to suppress estrogen synthesis, thereby inducing atrophy of ectopic endometrial implants or interrupting the cycle of stimulation and bleeding.

Indication : — Mild pelvic endometriosis in young women.°

— Treatment of residual and recurrent disease following conservative surgery.

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.

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.

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.

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.

Ans. is c i.e. Reduces the incidence of venous thrombosis       

Raloxifene increases the incidence of venous thrombosis.

About Raloxifene :

• Raloxifene is a Selective Estrogen Receptor Modulator (SERM)°.
• SERM are compounds that act as both estrogen agonist and antagonists depending on the tissue.
• Raloxifene exercises estrogen like action on both bones and lipids without stimulating the breast or endometrium.
• Reduces the risk of fracture by 50%, specially vertebra by increasing bone mineral density by 2 – 3%.

It causes 10% reduction in total and low density lipoprotein and raises HDL.

• It does not raise the level of Triglycerides.

• Cardioprotective in long term.

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

Hyperstimulation syndrome

Cervical carcinoma

Non steroidal antioestrogenic

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.

Ans. is c i.e. It is a synthetic hormone

Centchroman :

• It is a synthetic NON-STEROIDAL (ormiloxifene) contraceptive.
• A tablet of 30 mg started on 1st day of menstruation and taken twice weekly for 12 weeks, and weekly thereafter (t1/2 – 170 hrs).

• Mechanism of action :

–   it prevents implantation through endometrial changes and does not inhibit ovulation.

–  increases transport of zygote through the fallopian tube.

– It accelerates blastocyst formation.

• Developed by CDRI, Lucknow and released in India by 2 trade names Saheli and Centron.
• Exhibits strong anti-estrogenic and a weak estrogenic actions peripherally at receptor level.
• It is not teratogenic or carcinogenic, exerts no pharmacological effect on other organs. The only side effect
  noted is prolonged cycles and oligomenorrhea in 8% cases. This is due to prolonged proliferative cases.
• Pregnancy rate is (1-4 )/100 women years.
• Return of fertility is within 6 months of stopping the drug.
• The drug can also be used as a post coital pill, given in 60 mg dose within 24 hours of coitus, 2 tablets repeated after 12 hours with a failure rate of 1%.
• Side effects – headache, nausea, vomiting, gain in weight, does not protect against HIV and STD, Prolonged cycles (due to prolonged proliferative phase) and oligomenorrhea (in 8% cases). There is some delay in return of fertility.
• Contraindications :

1. During first 6 months of lactation
2. PCOD, hepatic dysfunction, Kidney disease, TB

Non-Contraceptive use :

Because of its potent anti estrogenic activity – It is being tried in :

• DUB
• Endometrial hyperplasia
• Endometriosis
• Breast cancer

It is used as HRT because of its weak estrogenic property

Safe in liver disease

Failure is 10 per 100 women years

Raloxifene [Ref: K.D.T. 6/e 305; Harrison 17/c 2405; Katzung 11/e 716]

• Traditionally hormone replacement therapy with estrogen was being used to prevent/treat osteoporosis in postmenopausal worsen.
• HRT has been shown to reduce the risk of osteoporosis in women.
• But long term use of estrogen leads to range of adverse effect including cardiovascular disease, stroke, pulmonary emboli and invasive breast cancer.
• These serious adverse effect made to look for other options.

Selective estrogen receptor modulators

• These are class of compounds that act on estrogen receptors.
• Their characteristic feature is that they do not have pure agonist or antagonistic action on estrogen receptors. – Their selective action distinguishes these substances _.from pure receptor agonist or antagonist.

– SERMS are “selective” that means SERMS block estrogen in some tissues and activate estrogen action in  others.

– All the SERMS bind to the estrogen receptor but each agent produces a unique receptor drug conformation.

– As a result specific coactivator or co-oppressor proteins are bound to the receptor resulting in differential effects. Two SERMS are currently being used

• Raloxifens        For the t/t and prevention of osteoporosis
• Tamoxifen —> For the t/t and prevention of Breast Ca
• The _.first SERM to reach the market was Tamoxifen which blocks the stimulative effect of estrogen on breast tissue and is used in breast cancer.
• Raloxifene is the second SERM to be approved by the FDA.
• Raloxifens has been approved for the tit and prevention of osteoporosis in postmenopausal women.
• Raloxifens acts like estrogen on bone and helps to build and maintain bone density.

– Raloxifen has been shown in clinical trials to increase bone density in the spine and hip and to reduce the risk of spinal fractures in women with osteoporosis.

• While it acts like estrogen on bone, it blocks the action of estrogen on breast and uterus.

– This profile makes it very useful for the t/t of osteoporosis because Raloxifene provides the bone benefits of estrogen without increasing the risk for estrogen related breast and uterine cancers.

Raloxifene in Breast cancer

• Due to its antiestrogenic effect on breast, Raloxifene has been shown to reduce the risk of invasive breast cancer in women who are taking it for osteoporosis.
• Raloxifene reduces the risk of breast cancer by 50-70% in both low risk and high risk postmenopausal women.
• The national cancer institute U.S.A. funded the STUDY OF TAMOXIFEN AND RALOXIFEN (STAR) a clinical trial comparing raloxtfens with tamoxifen in preventing breast cancer, in postmenopausal women who are at increased risk of developing the disease.
• The study found that tamoxifen and Raloxifen are equally effective in reducing invasive breast cancer risk in postmenopausal women who are at increased risk of the disease.
• The study also _.found out that women who took raloxifen had fewer uterine cancer and_.fewer blood clots than women who took tamoxifen. However, Raloxifen did not decrease the risk of noninvasive breast Ca.
• On September 14 2007, the US. food and drug administration announced approval of raloxifens for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive cancer.

Enclomiphene is anti-estrogenic [Re Katzung 10 ^th/e p 673; KDT 6 ^this p 303, Goodman Gillman 6 ^tiVe p 1556, 1555]

• Clotnifene is structurally related to stilbestrol,
• It is a weak estrogen agonist having less activity than natural estrogens, so that its ocupation of receptors results in antagonism.

Clomiphene acts as an antiestrogen.

It has two isomers

Zuclomiphene (cis clomiphene)                 Weak estrogen agonist

– Enclomiphene (trans clomiphene)            Potent antagonist of estrogen.

• Clomiphene binds to both the estrogen receptors ccand 13 It acts as pure estrogen antagonist in all human tissues.
• Antagonists of estrogen receptor are used to induce gonadotropin release in anovulatory fertility.
• Normally estrogen exerts negative feedback on the production of LH and FSH.

– This _.feedback effect seems to operate mainly on the anterior pituitary gland directly but they also operate on the hypothalamus to decrease secretion of GnRh.

– Clomiphene blocks hypothalamic estrogen receptors so that the negative feedback of natural estrogens is prevented and the pituitary responds by increased secretion of gonadotropin.

• In response to increased LH/FSH, ovaries enlarge and ovulation occurs.
• This is the basis for clomiphene’s major pharmacological use?

To induce ovulation in women with a functional hypothalamic-hypophyseal ovarian system and adequate endogenous estrogen production.

Clinical use of Clomiphene

• Treatment of disorders of ovulation.

Usually a single ovulation is induced by a single course of therapy, and the patient must be treated repeatedly untily the pregnancy is achieved, since normal ovulatory function does not usually resume.

The drug is of no value in patients with ovarian or pitutary failure.

• Oligospermia                     

— Clomiphene increases gonadotropin secretion in men also and promotes spermatogenesis. Thus it is prescribed even for male infertility.

Adverse effects

• Hot flushes due to estrogen blocks.
• Polycystic ovaries
• Multiple pregnancy (incidence is 6-10%),
• Increased risk of ovarian tumor.

The answer is still not clear. Let see each option one by one.

Option ‘a’  (i.e.,Enclomiphene is anti-estrogenic)

There is no doubt regarding this one. – Enclomiphene is an anti-estrogen.

Option ‘^lb’  (i.e.,Pregnancy rate is 3 times as compared to placebo)

• From whatever 1 have gathered, this option seems true.
• The odd ratio for pregnancy in clomiphene citrates is 3.4 when compared to placebo.

Here are some excerpts from medical journals

• “A recent metaanalysis of four randomized placebo controlled studies state that clomiphene showed odds ratio for ovulation- 6.82 and for pregnancy- 3.42 as compared to placebo.”
• “Approximately 75-80% of patients with PCOS will ovulate after clomiphene citrate (Homburg, 2005; Messinis, 2005). Although there appears to he discrepancy between ovulation and pregnancy rates, life-table analysis of the largest and most reliable studies indicates a conception rate of up to 22% per cycle in those ovulating on clomiphene citrate (Hammond et al., 1983; Kousta et al., 1997,- Etikemans et al., 2003)”.
• “The estimate for pregnancy per cycle with clomiphene versus no treatment for oligo-ovulation, is 3.4 (95% CI 1.23, 9.48) (Hughes et al., 1997)”.

Option `d’  (i.e.,it has been shown to increase _,fertility in oligospermic males in randomized controlled trials.)

• Clontiphette citrate is commonly prescribed in male infertility to treat oligospermia,
• Despite its common use, its efficacy has not been firmly established.
• There have been several clinical trials confirming the efficacy of clomiphene in oligospermia.
• But the largest randomized controlled trial undertaken by WHO in 19.92 failed to demonstrate the efficacy of clomiphene in oligospermia.
• However, most of the subsequent trials though smaller in size, established the beneficial role of clomiphene in oligospennia.

An article from http://www.medscape.com states;

Antiestrogens in male infertility (clomiphene)

“The logic underlying the use of antiestrogens lies in their ability to favorably alter the intrinsic HPG honnone axis. The most popular of these drugs is clomiphene citrate, a selective estrogen receptor modulator. By reducing hypothalamic and pituitary sensitivity to estrogens, antiestrogens increase pituitary output of LH and FSH, thus stimulating both testosterone production and spennatogenesis. Despite at least 20 clinical trials with clomiphene citrate for male infertility in the last 30 years, there is still debate about the value of antiestrogens for male infertility. A WHO study of 190 couples found clomiphene to have no significant effect on pregnancy rates or semen characteristics, while an older Cochrane meta-analysis of ten controlled studies involving 738 men showed beneficial hormonal effects, but no effect on pregnancy rates. However, there is emerging literature to suggest that clomiphene citrate may play an important role in a subgroup of infertile patients to overcome acquired hypogonadotropic hypogonadism at the pituitary level due to prolactinoma, sickle cell disease, diabetes mellitus and thalassetnias. Other selective estrogen receptor modulator drugs, including tamoxifen citrate, act in a similar fashion to clomiphene citrate”.

Option ‘c’ (i.e.,Incidence of twins is 5-6%)

• The incidence of twin pregnancy mentioned in the option is not far off from the actual incidence.
• “The incidence of twin pregnancy with clomiphene ranges from minimum 6% to maximum 10%”.
• Still, we can consider this one incorrect.

Oestrogen (partial agonist)

SERM’s (Selective Estrogen Receptor Modulators) has increased risk of developing deep vein thrombosis. The incidence rate is same as in the patients treated with estrogen replacement therapy.

Ref: Richard Finkel, Michelle Alexia Clark, Pamela C. Champe, Luigi X. Cubeddu (2009), Chapter 25, “Estrogens and Androgens”, In the book, “Pharmacology”, 4th Edition, Lippincott Williams and Wilkins Publications, United States Page 302

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

Clomiphene is an antiestrogen. These compounds are distinguished from the Selective estrogen receptor modulators(SERMs) in that they are pure antagonists in all tissues studied.

Clomiphene citrate is a potent anti-estrogen that primarily is used for treatment of anovulation in the setting of an intact hypothalamic—pituitary axis and adequate estrogen production (e.g., PCOS). By inhibiting the negative feedback effects of estrogen at hypothalamic and pituitary levels, clomiphene increases follicle-stimulating hormone (FSH) levels—typically by ~50%—and thereby enhances follicular maturation.

Clomiphene s approved for the treatment of infertility in anovulatory women.

Clomiphene increases gonadotropin secretion and stimulates ovulation.

It increases the amplitude of LH and FSH pulses without changing pulse frequency.

This suggests that the drug is acting largely at the pituitary level to block inhibitory actions of estrogen on gonadotropin release from the gland and/or is somehow causing the hypothalamus to release larger amounts of GnRH per pulse.

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.

Fulvestrant: is an estrogen receptor antagonist that downregulates the estrogen receptor and has no agonist effects.

Fulvestrant competitively inhibits binding of oestradiol to the estrogen receptor (ER), with a binding affinity that is 89% that of oestradiol. Reduces the number of estrogen receptor.

Good to know:

It is approved for the treatment of metastatic breast cancer in postmenopausal women who have failed antiestrogen therapy. Given once in a month as a intramusclar injection.

Ref: Goodman & Gillman’s Pharmacological Basis of Therapeutics’ 12th Edition, Page 1759, 1760.

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.

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.

Although clomiphene is effective in inducing ovulation in perhaps 75% of women, successful pregnancy ensues in only 40-50% of those who ovulate.

 This has been attributed to clomiphene’s inhibition of estrogen action on the endometrium, resulting in an environment that is not optimal for fertilization and/or implantation.

Ref: Schimmer B.P., Parker K.L. (2011). Chapter 66. Contraception and Pharmacotherapy of Obstetrical and Gynecological Disorders. In L.L. Brunton, B.A. Chabner, B.C. Knollmann (Eds), Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12e.

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

• Multiple gestation
• Ovarian hyperstimulation syndrome (OHSS)
• Ovarian cysts
• Hot flashes
• Blurred vision
• Risk of ovarian cancer

Centchroman is a synthetic non steroidal contraceptive and has oestrogen antagonistic effect. It prevents implantation through endometrial changes. Fertility returns within 6 months of stoppage of drugs. It has no teratogenic, carcinogenic or mutagenic effects. It has long plasma half life.

Oral contraceptives will not predispose to Endometrial Ca.

Ref: Current Obs and Gynae Diagnosis and Treatment, 9th Edition, Page 916 ; Shaw’s Textbook of Gynaecology, 12th Edition, Pages 302-3

• Clomiphene citrate is a racemic mixture of enclomiphene & zuclomiphene.
• Clomiphene citrate is a triphenylethylene; its two isomers, zuclomiphene (cis-clomiphene) and enclomiphene (trans-clomiphene), are a weak estrogen agonist and a potent antagonist, respectively.
• The incidence of multiple pregnancies is approximately 10%.
• Although clomiphene is effective in inducing ovulation in perhaps 75% of women, successful pregnancy ensues in only 40-50% of those who ovulate.
• Clomiphene also may be used to evaluate the male reproductive system because testosterone feedback on the hypothalamus and pituitary is mediated to a large degree by estrogens formed from aromatization of the androgen. 
• Enclomiphene is a more potent anti-oestrogenic isomer and the one primarily responsible for the ovulation-inducing actions of clomiphene citrate.
• Intrauterine insemination and clomiphene citrate increase pregnancy rate 3 times as compared to placebo.
• Incidence of twin pregnancy following clomiphene citrate ovulation induction is 10%, while that of triplets is 1%.
• A randomized control study showed that use of clomiphene has improved sperm motility and percent of normal forms but has not established an increased fertility.
• Indications of clomiphene: Ovulation induction To aid invitro fertilization when given with gonadotrophins In oligozoospermia: it increases gonadotrophin secretion and promotes spermatogenesis and testosterone secretion Adverse effects of clomiphene: Polycystic ovaries Multiple pregnancy Hot flushes Gastric upset Increased risk of ovarian tumor

Clomiphene therapy

Ans. is ‘b’ i.e., Raloxifen

• “Raloxifene does not relieve vasomotor symptoms of menopause, rather hot flushes may be induced in some women.             
  
• Hot fluses and other vasomotor symptoms respond to estrogen.
• Tibolone has both estrogenic and progestational properties .
• Tibolone suppresses menopausal symptoms and lowers the the raised gonadotropin levels –
  
• Isoflavones (genistein) have estrogenic effect (Goodman & Gillman 
• So they can suppress vasomotor symptoms.
• Estrogen can be produced from androgen by the action of aromatase. Selected women may be treated with low dose methyltestosterone, which is available in combination with conjugated estrogen.

Ans. is ‘b’ i.e., Antiestrogen

o It acts as a pure estrogen antagonist in all human tissues.

Ans. is ‘b’ i.e., Binds estrogen receptors & prevents negative feed back at hypothalamus

o Induces gonadotropin secretion (LH, FSH) by blocking estrogenic feedback inhibition on hypothalamus.

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.

Ans is ‘c’ i.e. Slower acting, safer and less effective than SERM

Fulvestrant

• It is a selective estrogen receptor downregulator (SERD) or pure antiestrogen/pure estrogen antagonist. o Fulverstrant is thought to have an improved safety profile, faster onset and longer duration of action than the SERMs due to its pure ER antagonistic activity.

o Fulvestrant is used to treat post menopausal women with metastatic breast cancer that expresses the estrogen receptor (hormone receptor positive) and is used when first line treatments (e.g. tamoxifen or an aromatase inhibitor) have failed.

Therapeutic uses

o Fulverstrant typically is administered as a 250-gm intramuscular injection of monthly intervals.

o It is used in post-menopausal women as antiestrogen theraphy of hormone receptor — positive metastatic breast cancer after progression on first – line antiestrogen theraphy such as tamoxifen or aromatase inhibitors.

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.

Ans. is ‘a’ i.e., Tamoxifen 

• Hormonal drug therapy for breast cancer targets estrogen receptor positive breast cancer. It aims at blocking the action of estrogen on estrogen receptor positive breast cells.
• The hormonal therapy of choice for breast cancer in premenopausal women is Tamoxifen.
• Tamoxifen belongs to class of drugs known as “Selective Estrogen Receptor Modulator”.
• Tamoxifen binds to the estrogen receptors on tumours and blocks the effect of estrogen on these cells.
• Tamoxifen is only effective in treating estrogen receptor positive breast cancers.

– Therefore the tumour’s hormone receptor status should be determined before deciding on treatment option for breast cancer.

• Tamoxifen is used to treat patients with early stage breast cancer as well as those with metastatic breast cancer

Adjuvant therapy with Tamoxifen

–  Chemotherapy after primary t/t to increase the chance of cure.

It helps in preventing the recurrence and also helps to prevent the development of new cancers in the other breast. When used as adjuvant chemotherapy it is usually taken for 5 years. When taken for 5 years if reduces the chance of the original breast cancer coming back in the same breast or elsewhere. It also reduces the risk of developing secondary primary cancer.

Metastatic cancer therapy with Tamoxifen

–  As a treatment for metastatic breast cancer, the drug slows or stops the growth of cancer cells that are present in the body.

Patient with metastatic breast cancer may have to take tamoxifen for varying lengths of time.

Ans. is `b’ i.e., SERM

Tamoxifen is a selective estrogen receptor modulator (SERM).

Ans. is ‘a’ i.e., 30 mg

Cetchroman (Saheli)

• Ormeloxifene, research product of Central Drug Research Institute, Lucknow, India.
• It is a potent non – steroidal compound with potent anti – estrogenic and weak estrogenic properties. It is taken orally (30 mg) twice a week for first three months then once a week.
• It works primarily by preventing implantation of fertilized ovum. It does not inhibit ovulation.
• It is avoided in PCOD, with liver and kidney diseases and in tuberculosis. There may be a tendency of oligomenorrhoea.
• The failure rate is 1 – 4/100 woman years of use. Failure rate is less with increased doses. It is devoid of any significant adverse metabolic effect.
• This may also be used as a emergency contraceptive.

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

Ans. d. Tamoxifen

“Tamoxifen was first synthesized in 1966 and initially developed as on oral contraceptive but instead was found to induce ovulation and proved to have anti proliferative effect on estrogen-dependent breast cancer. Tamoxifen is a competitive inhibitor of estradiol, binding to the estrogen receptor. It has become a standard agent as a result of its anti-cancer activity and good tolerability profile. Tamoxifen is prescribed for the prevention of breast cancer in high-risk patients, for the adjuvant therapy of early stage breast cancer, and for the therapy of advanced breast cancer. It also prevents development of breast cancer in woman at high risk based on a strong family history, prior non-malignant breast pathology, or inheritance

Tamoxifen

• Tamoxifen is a standard hormonal treatment of breast cancer in both premenopausal and postmenopausal womene
• Tamoxifen is effective in Estrogen Receptor (ER) positive breast carcinoma but some ER negative tumors also respond to tamoxifene.
• Tamoxifen is approved for primary prophylaxis of breast cancer in high risk womene
• If reduces the recurrence rate of breast cancer in ipsilateral as well contralateral breaste Tamoxifen is associated with reduced risk of cancer in the contralateral breast°.
• Dose: 10 mg BD X 5-yearse
• While tamoxifen blocks estrogen receptors on the breast, it stimulates these receptors in the uterus (because tamoxifen is a partial against of ER), may lead to endometrial hyperplasia and endometrial cancere
• Potent antagonist in breast carcinoma cells, blood vessels and at some peripheral sites^Qo

Partial agonist in the uterus, bone, liver and pituitarye

Adverse Effects of Tamoxifen

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.