• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. What is THE clinical sign of anovulation?

  • Oligomenorrhea
  • Defined as Cycle>35 days and <6 months

• #Clinicalpearl

  • Women with menstrual cycles of 35-45 may have intermittent spontaneous ovulation
  • More than 45- unlikely to have ovulation

• Q. What are lab tests for ovulatory dysfunction?

  • Lack of increase of basal body temperature by 5 degrees F
  • Midleuteal progesterone <2 ng/ml
  • Absence of ovarian follicles on TVS
  • Lack of LH surge on urinary LH monitoring

• Q. What are the three WHO classes of anovulation?

  • Class I- Hypogonadotropic hypogonadism
  • Class II- Normogonodotropic normogonadism with anovulation (e.g., PCOS)
  • Class III- Hypergonadotropic hypogonadism (e.g., Primary ovarian insufficiency)

• Q. Which are the four major causes of anovulation?

  • Hypothalamic amenorrhea
  • PCOS
  • Hyperprolactinemia
  • Primary ovarian insufficiency

• **Overview of approach **

• Q. Which hormone is a reliable indication of ovarian function?

  • Serum AMH (antimullerian hormone)

• Q. Which cells produce AMH?

  • Small pre-antral(<8 mm)
  • Or Early Antral follicles

• Q. What is the relation between AMH and IVF success?

  • Low AMH (<1ng/ml) - Less ovarian reserve- poor IVF success
  • Very high AMH- more risk of ovarian hyperstimulation syndrome

• Q. What are the goals of ovulation induction?

  • Monofollicular development and singleton pregnancy
  • Minimize risk of ovarian hyperstimulation syndrome
  • Maximize chances of pregnancy

• Q. Which type of patients have the highest risk of ovarian hyperstimulation?

  • PCOS patients

• Q. Which are the treatment of choice of each of the common causes of anovulation?

  • Hypothalamic amenorrhea  weight gain → if fails Pulsatile GnRH or Gonadotropins
  • PCOS- Clomiphene or Letrozole (Off label)
  • POI – advice IVF with donor oocyte
  • Hyperprolactinemia- dopamine agonist

• Q. Give the first, second, and third-line approach for ovulation induction in women with PCOS?

  • first-line weight loss
  • Second line- Clomiphene /letrozole +/- metformin
  • Third line- gonadotropins, ovarian drilling
  • Fourth line- IVF

• Ovulation Induction Agents

• **Clomiphene citrate ** (CC)

• Q. What is Clomiphene physiological?

  • It is a type of SERM (Selective estrogen receptor modulator)
  • It has part estrogenic and part antiestrogenic effect
  • It binds to estrogen receptors and competes with natural estrogen for the same

• Q. Can other SERMS like tamoxifen or raloxifene be used for ovulation induction?

  • Yes
  • But they are less successful

• Q. How is Clomiphene given?

  • It is given in a dose of 50 mg for five days on days 3 to 7 of menstrual Cycle
  • It is mainly used in PCOS patients

• Q. How is dose titration of CC done?

  • If ovulation does not occur with 50 mg, then the dose is increased to 100 mg in the next Cycle  this is the maximum dose
  • If ovulation occurs- the same dose is continued for 4-6 cycles

• Q. CC is used for a maximum of what number of cycles?

  • CC should not be used for more than 6-12 cycles; ASRM recommends no more than 12 cycles

• #Clinicalpearl

  • Generally, failure to conceive after six cycles of CC must trigger additional testing, including Hysterosaphnigography

• Q. When is a couple counseled for intercourse after giving CC?

  • LH surge typically occurs 5-12 days after stopping CC
  • Hence couple is counseled to have intercourse every day starting five days after the last dose of medication

• Q. How is LH surged diagnosed?

  • It can be diagnosed using a urinary LH kit
  • Brands are
    • Ovuline LH kit
    • i-Know kit
    • Ovutest kit

• Q. When does ovulation take place after LH surge?

  • Ovulation occurs about 14-48 hours after LH generally
  • Couples are advised that maximum fertility is for two days after LH surge is detected by the kit

• #Clinicalpearl

  • Clomiphene- days 3 to 7 of menstrual Cycle
  • LH surge occurs 5-12 days after stopping CC- can be monitored with urinary LH kit
  • Ovulation occurs 14-48 hours after LH surge

• Q. When does the rise in basal body temperature take place?

  • Occurs 1-5 days after LH surge (generally 1-4 days after ovulation)

• Q. What value of mid-luteal progesterone suggests ovulation?

  • More than 3 ng/ml (ideally >10 mg/ml) suggest ovulation

• Q. Is regular TVS monitoring required while on CC?

  • Some guidelines recommend regular TVS monitoring and HCG injection when the Follicle matures
  • It can be done if cost is not an issue
  • However, it is not required in all cases
  • It can be done in 1st Cycle to look for hyper-response

• Q. When is HCG injection given during ovulation induction?

  • Generally, PCOS women have adequate LH, so per se, HCG may not be required
  • However, some women have inadequate LH surge
  • In such women, TVS is done, and a single dose of HCG 5000-10,000 units is given when TVS shows follicular size >18 mm (mature Follicle)

• Q. How much time after HCG injection does ovulation occur?

  • 36-48 hours later

• Q. What are the success and risk parameters for Clomiphene?

  • Successful ovulation- 85%
  • Pregnancy rate of 40%
  • Twin pregnancy – 8 %
  • Triplet- 0.3%
  • OHSS – 1%
  • Miscarriage and ectopic pregnancy – not increased

• Q. How can multiple pregnancies be prevented?

  • By doing a TVS monitoring
  • Three or more Follicles >15 mm- stop ovulation induction and prescribe barrier contraception

• Q. What are the parameters that predict success?

  • Less free Testosterone
  • Oligomenorrhea as opposed to amenorrhea
  • Lower BMI
  • Lower ovarian volume

• Q. What is the mechanism of action of Clomiphene?

  • It blocks the effect of Estrogen on ER in the pituitary
  • Hence cutting off the negative feedback
  • This increases the FSH  produces ovulation

• Q. How does Clominphine produce hyperstimulation?

  • Clomiphene downregulates the ER
  • Because of this, even when the Clomiphene is stopped  because less ER estrogen cannot suppress the FSH till ER receptors are regenerated
  • Hence this can lead to hyperstimulation

• Q. What are the components of Clomiphene?

  • Combination of
  • Zu- clomiphene – 38%
  • En clomiphene- 62% - more potent antiestrogenic effect- primary effect in Ovulation induction

• Q. Do congenital malformations occur with Clomiphene?

  • No

• Q. Will patients having low estrogen respond to Clomiphene?

  • No
  • Estrogen is required for Clomiphene (CC)  to act
  • Hence women with PCOS do well with CC

• Q. When is CC preferred, and when is Letrozole chosen?

  • PCOS with
  • BMI <30 – CC
  • BMI > 30 – letrozole

• Q. Can it be given to hypogonadotropic hypogonadism women?

  • Though chances of response are less, some people give a trial of Clomiphene in hypo hypo patients before going for gonadotropins

• Q. Is it recommended for women with Premature ovarian insufficiency (POI)?

  • No

• **Adverse effects of Clomiphene **

• Q. Name some common side effects of CC?

  • Hot flashes
  • Abdominal distention
  • Nausea

• Q. What is done if there are ovarian cysts present on ultrasound?

  • CC is stopped if ovarian cysts are present on USG
  • Can be restarted once ovarian cysts disappear

• Q. Do visual symptoms occur after CC?

  • They have been reported
  • Exact reasons are not known
  • Some think it is because of retinal toxicity though not proven

• Q. Does it produce a luteal phase defect?

  • CC may produce iatrogenic Luteal phase defect in some patients
  • Giving HCG injection for ovulation followed by Progesterone support may have to be used

• Q. What is its effect on the endometrium?

  • May cause thinning of the endometrium

• Q. Does it increase cancer risk?

  • No

• Q. In which cases would you advice against intercourse for a patient on CC ?

  • In the first cycle a preovulatory scan is generally performed (10 days after starting CC)
  • If the patient has more than 3 follicles are present, it is generally advised to avoid intercourse

• **Metformin **

• Q. Can metformin cause ovulation?

  • It can reduce hyperinsulinemia
  • Whether it spontaneously causes ovulation  less likely
  • It is sometimes combined with Clomiphene, but results are mixed

• Q. Is metformin per se recommended for ovulation induction?

  • Endocrine Society is against its use for ovulation induction
  • It is only to be used for glucose intolerance in PCOS, according to the Endocrine society
  • Other societies are in favor of using metformin as an add on for ovulation induction

• **Letrozole (aromatase inhibitor)  **

• Q. How does Letrozole cause ovulation?

  • Reduce conversion of TestosteroneTestosterone to estrogen  reduces estrogen feedback to pituitary → increases FSH →induces ovulation

• Q. How does Letrozole compare to Clomiphene?

  • A meta-analysis of 9 trials have shown Letrozole to show a superior live birth rate compared to Clomiphene

• Q. Which subgroup of patients particularly does well with Letrozole?

  • Obese PCOS patients
  • Many experts suggest Letrozole as a drug of choice in Obese PCOS patients

• Q. What Does aromatase convert androstenedione to ?

  • Androstenadione → estrone
  • Testosterone → estradiol

• Q. Why does Letrozole produce fewer multiple pregnancies than CC?

  • As discussed previously, CC  causes depletion of ER → hence even after stopping, FSH levels remain high
  • Letrozole does not deplete ER, and hence once its work is done, the rest of ovarian follicles degenerate, estrogen increases→ , FSH falls

• Q. Why is Letrozole potentially teratogenic?

  • Because it can disrupt aromatase in the fetus

• Q. Why is letrozole and not anastrozole used for Ovulation Induction?

  • Because Letrozole is more effect Anastazole

• Q. How is Letrozole given?

  • It is given in a dose of 2.5 mg on day 3-7 of Cycle
  • If this dose does not work, increase the dose to 5 mg to 7.5 mg in the subsequent cycles

• Q. Enlist the differences between CC and Letrozole?

  • 

• Q. Is Letrozole better than CC as far as the live birth rate is concerned?

  • Yes – especially in the obese PCOS group
  • The non-obese group live birth rate is similar to CC

• Q. Do animal studies show teratogenicity?

  • Yes

• Q. What about human studies

  • Whatever studies were done in humans have not shown any more teratogenicity compared to CC

• **Dopamine agonist **

• Q. What is the indication for the use of Dopamine agonist in ovulation induction

  • It is helpful for ovulation induction in hyperprolactinemic women

• **PULSATILE GnRH **

• Q. What is the advantage of Pulsatile GnRH

  • It produces a controlled release of FSH and LH
  • Hence it shows a more negligible effect on Gonadotropin stimulation

• Q. In which patients are pulsatile GnRH preferred

  • In women with Hypogonadotropic hypogonadism

• Q. Can it be used in PCOS patients?

  • It can be used in PCOS patients
  • However, it seems less logical because PCOS patients often have increased LH production

• Q. Give the protocol for GnRH administration

  • It is injected using a pump
  • IV is preferred to subcutaneous
  • A pulse is given every 60-90 minThe dose is 2.5-5 mcg per pulse
  • It is continued till ovulation occurs
  • After, that GnRH is discontinued, and HCG is given for luteal support- it is given in the dose of 500 IU on days 7, 10, and 13 after ovulation

• Q. What is the success rate of Pulsatile GnRH?

  • 90% ovulation rate and 80% successful pregnancy

• Q. What are the brands of GnRH agonists

  • Factual
  • Lutrepulse
  • (Generic name is Gonadorelin)

• **Gonadotropin therapy **

• Q. What are the indications for gonadotropin therapy?

  • PCOS- when oral agents have a failure
  • Hypogonadotropic hypogonadism women

• Q. What are the various preparations of FSH?

  • HMG- crude preparation having 1:1 FSH and LH
  • uFSH- refined FSH preparation
  • rFSH- recombinant FSH

• #Clinicalpearl

  • The HCG and HMG are typically given IM
  • However, it can be given subcutaneously also

• Q. Which of the above is better?

  • Studies have shown similar results
  • However, rFSH preparations have less ovarian hyperstimulation

• Q. What is used to trigger ovulation?

  • HCG is used to trigger ovulation
  • It is given in a dose of 5000- 10,000 IU

• Q. What are the protocols used in ovulation induction?

  • High dose protocol- use FSH in a dose of 150 units directly  higher risk of hyperstimulation
  • Low dose, Step-up protocol- start with a lower amount of FSH and gradually up titrate – less risk of hyperstimulation
  • Low dose, step down a protocol

• Q. Describe the step-up protocol?

  • Start with FSH 37.5 to 50 units per day
  • Perform ultrasound monitoring and estrogen monitoring
  • If there is no progress after 14 days,  increase the dose by 37.5 units → dose is increased weekly by 37.5 to a maximum dose of 225 units/day
  • If the ovarian response is seen, then HCG is added to trigger ovulation

• Q. Describe the Step-down protocol?

  • Start with 150 units /day on 1st day of the menstrual Cycle
  • Monitor using TVS
  • If the dominant Follicle is >10 mm,  then reduce the dose to 112.5 units/day  x 3 days
  • Then reduce to 75 units/day after three days  → continue till HCG is given for trigger

• Q. How is monitoring done during this protocol?

  • Monitoring is done using TVS
  • Scans are done every 2-3 days during the late follicular phase

• Q. When is HCG given?

  • When there is sufficient maturation of a single follicle

• Q. What are the criteria for follicle maturity?

  • Follicle maturity is when Follicle diameter >18 mm and/or
  • Estrogen >200 pg/ml

• Q. When is induction protocol stopped to prevent hyperstimulation?

  • When three or more follicles are >15 mm – then stop the ovulation induction
  • Do not give HCG
  • Prescribe barrier contraceptive to prevent pregnancy

• Q. What is the advantage of Step up protocol over standard high dose?

  • Less ovulation hyperstimulation

• Q. What is the success rate of the step-up protocol?

  • 72%- ovulation induction
  • 45% - pregnancy rate

• Q. Which is the better Step Up or Step Down protocol?

  • Studies have shown mixed results
  • Step down protocol may be better as it is more physiological

• **Complications **

• Q. What is ovarian hyperstimulation syndrome?

  • It is a life-threatening complication
  • There is massive ovarian enlargement, third space fluid loss, hypovolemia, and thromboembolic phenomenon

• Q. What is a surgical option for women who fail with all the above measures?

  • Use laparoscopic ovarian diathermy (ovarian drilling)

• Q. Is there an increased risk of epithelial ovarian cancer in patients given pharmacological therapy for ovulation induction?

  • It was previously thought
  • But there is no convincing evidence for the same at present

• Q. Does it increase the risk of breast cancer?

  • No

• Q. Is there an increased risk of childhood deformities or teratogenicity?

  • At present little evidence for the same.