Ovulation Induction (OI)

Hormones under the control of the hypothalamus, the pituitary gland and the ovaries regulate the female reproductive cycle. If this basic control system does not work correctly, ovulation will be disturbed or absent. Ovulatory disorders are characterized by anovulation (complete failure to ovulate) or infrequent and/or irregular ovulation.

The WHO has adopted a treatment-orientated classification of anovulating patients:
Group I patients have hypothalamic-pituitary failure. They are amenorrheic and lack both follicle stimulating hormone (FSH) and luteinizing hormone (LH).

Group II patients have hypothalamic-pituitary dysfunction and present with a variety of cycle disorders including amenorrhoea, oligomenorrhoea and luteal phase deficiencies. About 97% of anovulatory patients fall into this group, including polycystic ovarian disease (PCOD, a condition commonly characterized by hirsutism, obesity, menstrual abnormalities, infertility, and enlarged ovaries; thought to reflect excessive androgen secretion of ovarian origin), which is thought to be the most common cause of ovarian dysfunction.

Ovulation induction (OI) aims to correct hormonal imbalances, allowing where possible, mono-ovulation to occur. More than 80% of infertile women without anatomical disorders are treated successfully with fertility agents that promote the growth and development of ovarian follicles via the stimulation of FSH and LH.

Ovulation induction should be performed only when there is an access to ovarian ultrasound monitoring. This will increase the success rate & at the same time prevent adverse effects.


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With folliculogenesis taking place with the ovulation induction drugs, with follicular growth the antrum which is the only thing seen on ultrasound increases in size and the oocyte also develops and matures during the process.

Agents most commonly used for Ovulation Induction are:

Clomiphene citrate, acting on the hypothalamus to increase the release of gonadotropin releasing hormone (GnRH), which, in turn, stimulates the pituitary gland to release FSH and LH; It should not be taken for more than 12 months. If taken for more than 12 months there is an increased risk of ovarian carcinoma.


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Letrazole, acts at hypothamopituitary levels increasing FSH & LH secretion by decreasing the estrogen production by inhibiting the enzyme aromatase which is required for the conversion of androgens to estrogens in granulose and theca cells. It also acts locally in the ovaries where it increases the sensitivity of follicles to FSH & LH. It also increases the blood flow to the uterus & increases the endometrial thickness.


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Gonadotropins FSH and LH acting directly on the ovary, promoting follicular development and hCG triggers maturation and ovulation of the oocyte after follicular stimulation.

In WHO Group I patients, gonadotropin therapy with both FSH and LH is required for follicular development and ovulation. WHO Group II patients may respond to clomiphene citrate. FSH treatment is normally reserved for those who do not respond to clomiphene.

OI is usually combined with timed intercourse or with artificial insemination (also called intrauterine insemination - IUI) in order to increase the probability of successful fertilization. If conception has not taken place after approximately three to five cycles with clomiphene citrate and a further three to five cycles with gonadotropin treatment, the patient may be referred for ART. The number of clomiphene citrate/gonadotropin treatment courses is related to the type of infertility, the result of the investigations and reimbursement schemes practiced in each individual country.

FSH is effective in ovarian stimulation. Human chorionic gonadotropin (hCG) injections are used in conjunction with FSH to provoke egg release (hCG is given to mimic the natural LH surge). A frequent adjunct to FSH therapy is synthetic luteinizing hormone releasing hormone (LHRH) analogues which work by suppressing the ovaries. In their suppressed state, the ovaries are more receptive to FSH therapy and higher quality eggs are produced as a result. This is particularly useful for women with PCOD not responding to FSH alone.

Bromocriptine is a useful agent in the treatment of hyperprolactinemia, a condition where there is excess of the hormone prolactin in the blood. This condition results in the suppression of GnRH release contributing to anovulation.

GnRh agonist – One could use either the ultrashort, short or long protocol
Ultrashort protocol – 500 mcg/day from D1 or 2 for 3 days
Short protocol – 250 - 300 mcg/day from D2 till hCG injection
Long protocol -GnRHa 500 - 600 mcg/day from D 21 of previous cycle till menstruation
Dose reduced to 200 - 300 mcg per day till hCG injection
hMG/FSH from D 2 of MC if E2 < 35 pg/ml
USG - Absence of follicles more than 5 mm
Endometrial echo < 6 mm
Increase/decrease by 75-150 IU after D 7 depending on E2 levels & follicular growth at USG till follicle 16 –18 mm


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GnRh antagonist ( Ganirelix, orgalutran, Antagon)
Dose and Time of administration

GT 150 – 225 IU Day 2 till follicular diameter 18-20 mm
Antagonist 0.25 mg SC from Day 7 till hCG injection
hCG at follicular diameter of 18-20 mm/E2 300pg/ml/per follicle
Flexible protocol- here administration of antagonist is
individualized given when follicles reach a diameter of 13-14 mm

Risks of Ovulation Induction
CC/Letrazole

  • Vasomotor symptoms
  • Visual symptoms
  • Headache
  • Nausea / vomiting
  • Abdominal distention
  • Ovarian enlargement / cyst
  • Multiple gestation
  • NO risk of malformations

Gonadotropins

  • Multiple gestation
  • OHSS (~1%)

Abnormal response to controlled ovarian stimulation

  • Premature lutenisation
  • Endogenous surge
  • Poor response
  • Hyperstimulation

Premature lutenisation

  • Premature & suboptimal LH surge
  • Progesterone production but no ovulation
  • Oocyte maturation without follicular rupture
  • Poor quality oocytes & embryos
  • Endometrium out of phase
  • Reduces implantation rate

LUF

Insufficient strength of LH surge to induce follicular rupture but sufficient to induce oocyte maturation
Endogenous LH surge

  • Compromised oocytes & embryo quality
    - result of exposure to inappropriate LH levels
  • Requires extensive endocrine monitoring
  • Prevented with use of GnRha
  • Poor response
  • Causes
    • Idiopathic
    • Ovarian failure
    • Antibodies to exogenous GTS
  • Treatment
    • Modified stimulation protocols
    • Growth hormone augmentation
    • Pituitary down regulation – GnRha/OC

Ovarian hyperstimulation syndrome

Excessive response to ovulation induction
Predisposing factors

  • Small and thin patients
  • PCOD
  • High dose of GT early in follicular phase

Pathogenesis of OHSS dependent on ovarian renin-angiotensin system

Grades of OHSS

A.Mild: B. Moderate: C. Severe:
E2 levels 1500 pg/ml
10 follicles at USG
No luteal phase complications
E2 levels 3000 pg/ml
Luteal phase problem of painful
ovaries and ascities < 1.5 lts
E2 levels > 3000 pg/ml
Large ovarian cyst
Ascities > 1.5 lts
Intravascular volume depletion
Electrolyte imbalance
Coagulopathy
Hydrothorax

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In the presence of impending Ovarian hyperstimulation, cryopreservation of Embryos for replacement in latter cycles done.

Treatment

  • Strict I/O chart
  • Check urea, electrolytes, osmolarity of plasma,& urine, clotting parameters, LFT
  • Serial USG
  • Correction of circulatory and electrolyte imbalance, replace plasma proteins
  • 100 mg hydrocortisone IV at admission followed by Prednisilone 5 mg 6 hrly & then dose tapered
  • Anticoagulants if evidence of thromboembolism
  • Aspiration of ascitic fluid
  • Surgery if evidence of hemorrhage, torsion, rupture, or ectopic pregnancy

Cancellation of ovarian stimulation cycles
Definite Indication

  • Poor follicular growth
  • E2 levels < 100 pg/ml on day 5 – 6

Possible Indication

  • Adenexal cyst secondary to GnRha
  • Endogenous LH surge
  • Steady decline in E2 levels
  • E2 < 750 pg/ml on day of hCG

Luteal Phase Support is given after oocyte collection in IVF/ICSI or after ovulation in IUI or timed intercourse cycles till pregnancy test & continued for 12 weeks if pregnancy is established.
It is used to support the uterine lining or endometrium.

The drugs used for luteal phase support are as follows

hCG 1000 – 2000 IU every 3 days from 4th day of ovulation/OR (4, 7, 10,13)
Progesterone 400 mcg pessaries or pure progesterone 50 –100 mg IM daily from day of ovulation/OR for 16 – 17 days
hCG+Progesterone Progesterone IM or vaginally for 5 days with hCG day 4 onwards every 3 days for 4 doses

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Dr. Patil’s Fertility and Endoscopy Clinic

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