Induction of ovulation: measures are

  1. General
  2. Drugs
  3. Surgery

General:

*psychotherapy to improve the emotional causes, if any

*Reduction of weight in obesity as in PCOS cases is essential to have a good response of drug therapy for induction. This facilitates spontaneous ovulation.

Drugs:

*CLOMIFENE CITRATE

*LETROZOLE

*HMG (humegon,pergonal)

*FSH

*HCG

*GnRH

CORRECTION OF BIOCHEMICAL ABNORMALITY

*Hyperinsulinemia-metformin

*Androgen excess-dexamethasone 0.5mg daily for 10days from D1 to till ovulation.

*Prolactin raised-bromocriptine

SUBSTITUTION THERAPHY

*Hypothyroidism-thyroxin

*Diabetes mellitus-Antidiabetic drugs

Objectives for monitoring for induction of ovulation:

To select time for pre ovulatory administration of HCG , to prevent OHSS, to select time for intercourse or artificial insemination, to select time for ovum retrieval in IVF.

MONITORING DURING OVULATION INDUCTION:

For diagnosis of ovulation in a Ivf Center in Chennai, BBT and cervical mucus study and serial estimation of E2 and ultrasonic measurement of growing follicle (folliculometry).

Clomiphene citrate: CC is simple, safe and cost effective, it is a mixture of enclomifene and zuclomifene in 3:2 ratio. Initial dose-50mg daily between day2 and day 5 for 5 days. Dose is increased in 50mg steps to a maximum of 250 mg daily. Half-life 5 days. Therapy for 6 cycles is generally given. If CC therapy fails following 6-8cycles, FSH and hCG therapy is recommended.

Patient selection: normogonadotropic-normoprolactinemic patients who are having normal cycles with absent or infrequent ovulation, PCOS cases with oligomenorrhea or amenorrhea. The estradiol level should be >40pg per ml, hypothalamic amenorrhea following stress or pill use.

CC is anti-estrogenic as well as weakly estrogenic. It blocks the estrogen receptors in the hypothalamus. This results in increased GnRH pulse amplitude causing increased gonadotropin secretion from the pituitary. Antiestrogenic effects are seen on the endometrium and cervical mucus .Side effects are hot flushes, nausea, vomiting, headache, visual symptoms, and ovarian hyper stimulation (rare). Ovarian hyper stimulation syndrome (OHSS) occurs in 5-10% of cases. Symptoms depend on whether the case is mild, moderate, or severe, and can range from bloating and nausea, through to shortness of breath, pleural effusion, and excessive weight gain (more than 2 pounds per day).

COUPLE INSTRUCTION: couple is advised to have sexual intercourse daily or on alternate days beginning 5-7days after the last dose of CC

LETROZOLE: It is a nonsteroidal aromatase inhibitor. It inhibits the enzyme aromatase in the granulosa cells of ovarian follicles. It suppresses estrogen synthesis. Dose 2.5mg given from from D3-D7.It has no peripheral anti estrogenic effects on the endometrium and cervical mucus like CC. Half-life is 48-50hrs.prolonged clomiphene and letrozole therapy beyond 8months can cause estrogen deficiency with menopausal symptoms of hot flushes and osteoporosis (reversible).It is contraindicated in severe hepatic dysfunction. However, it is banned by the government of India for use in infertility.

FSH is a medication with follicle stimulation hormone while HMG is a medication with a combination of FSH and LH (luteinizing hormone). Both medications are often used together in a single cycle while in some instances one or the other form is more appropriate. They are medications used for stimulation of egg development in women who do not ovulate spontaneously, who fail to ovulate or to conceive with clomiphene citrate, or who ovulate extremely irregularly. It is also used to super-ovulate, to increase the number of eggs developed in a single cycle in women who already ovulate. Due to the variability in response, the dosage varies from individual to individual. Each patient and cycle must be individualized.

FSH and hMG are more potent super-ovulation medications than oral medications such as clomiphene citrate. Hence the risks are higher for severe ovarian hyper-stimulation syndrome and high order multiple pregnancies. Some form of monitoring of the ovarian response is necessary to avoid such complications. A combination of blood estrogen measurement (E2) and ultrasound is the best approach at the present time. These fertility medications can be used with both intrauterine insemination (IUI) and in vitro fertilization (IVF).

FSH and HMG are available only in an injectable form. Self-administered injection techniques are taught in a special injection instruction class given by the nursing staff at the Family Fertility Centre in Chennai. There are also links to injection videos in our website under Resources.

HCG: Human Chorionic Gonadotropin (Novarel®, Pregnyl ®or Ovidrel®)

HCG is a hormone that helps with the final maturation of the eggs and triggers the ovaries to release the mature eggs (ovulation). It also stimulates the corpus luteum to secrete progesterone to prepare the lining of the uterus for implantation of the fertilized egg. Ovulation (follicle rupture) usually occurs about 40-46 hours after the HCG is given. HCG is self-administered as an injection.

GONADOTROPINS:

GnRH: Pulsatile GnRH treatment stimulates physiologic levels of pituitary gonadotropin secretion.so development of follicular growth, selection, recruitment and ovulation occurs as in normal menstrual cycle. Indicated in women with hypothalamic amenorrhea, hypogonadotropic hypogonadism ,hyperprolactinemia conditions. GnRH is administered IV or SC.

GnRH Analogues: GnRH agonist (buserline, nafarlin) is given SC or intranasally either maintaining a short or long protocol. It is used for down regulation of pituitary gland by desensitization of pituitary GnRH receptors.it usually produce stimulation of gonadotropin secretion known as flare effect. This effects last for about 2-3 weeks. GnRH antagonists can block the pituitary GnRH receptors completely without any flare effect. Contraindications of gonadotropins therapy includes primary ovarian failure with raised serum FSH, uncontrolled thyroid and adrenal dysfunction, sex hormone dependent tumor in the body, pituitary tumor, and ovarian cysts.

Follicular monitoring

Follicular monitoring or follicular study is a vital component of IUI and IVF assessment and timing. It basically employs a simple technique for assessing ovarian follicles at regular intervals and documenting the pathway to ovulation.

Physiology

Journey to ovulation begins during late luteal phase of prior menstrual cycle, when certain 2-5 mm sized healthy follicles form a population, from which dominant follicles is to be selected for next cycle This process is called ‘recruitment’. Usual number of such follicles may be 3-11, which goes on decreasing with advancing age 1.

During Day 1-5 of the menstrual cycle, a second process of ‘follicular selection’ begins, when among all recruited follicles, certain growing follicles of size 5-10 mm are selected, while rest of the follicles regress or become atretic.

During Day 5-7 of the menstrual cycle, a process of ‘dominance’ begins, when a certain follicle of 10 mm size takes the control and becomes dominant. This also suppresses the growth of the rest of the selected follicles, and in a way, is destined to ovulate. This follicle starts growing at rate of 2-3 mm a day and reaches 17-27 mm size just prior to ovulation 2. One important learning point in this regard is, “largest follicle on day 3 of the cycle, may or may not be a dominant follicle in the end. Process of dominance begins late, when suddenly a certain underdog follicle starts growing faster and suppresses others to become dominant”.

Almost nearing ovulation, rapid follicle growth takes place, and follicle starts protruding from the ovarian cortex, attains a crenated border, and it literally explodes to release the ovum, along with some antral fluid.

Ultrasound monitoring: general

Transvaginal ultrasound is preferred and usually mandatory modality for monitoring follicles. Ultrasound monitoring may begin on day 3 of the cycle, to assess a baseline size, as well as exclude if any cyst remains from previous hyper stimulation or otherwise. It’s important to count the number of existing follicles, document two/three dimensions of each follicles, and also comment on shape (round/oval/rectangular/triangular), echogenicity (echogenic/hypoechoic/anechoic) and antral edges (smooth/intermediate/rough) if possible.

As the study progresses on day 7, we should start guessing the ovulatory dominant follicle i.e. dominant follicle which is destined to ovulate. Basically, there are three varieties of eligible follicles:

  • Atretic dominant follicle: This follicle is usually largest follicle on day 3, but it is not destined to ovulate. It has an irregular shape, rough edges, and may be little echogenic.
  • Ovulatory dominant follicle: This follicle is typically round, with smooth borders, and usually hypoechoic.
  • An ovulatory-luteinizing dominant follicle: This dominant follicle grows at a good pace but fails to ovulate, and later becomes a cyst or luteinizes. These are also round and smooth, however anechoic. This subtle recognition of echogenicity difference between hypoechoic and anechoic follicle can help determine whether a follicle is growing to ovulate.

Once the follicle reaches 16 mm size, a daily monitoring of follicle is recommended.

Next step is documentation of ovulation. Ovulation is sonographically determined by the following sonographic signs:

  • follicle suddenly disappears or regresses in size
  • irregular margins
  • intra-follicular echoes. Follicle suddenly becomes more echogenic
  • free fluid in the pouch of Douglas
  • increased perifollicular blood flow velocities, on doppler
  • Ultrasound monitoring in induced cycles, and predicting success of IVF

Most of the IVF studies in any Best Ivf Centre in Chennai are conducted after induction of ovaries with help of ovulation inducing agents like Clomiphene citrate. In such induced cycle, primary determinants of success are:

  • Ovarian volume
  • Antral follicle number
  • Ovarian stromal blood flow

Ovarian volume is easy to measure, although not a good predictor of IVF outcome. Now, it is documented, that a low ovarian volume does not always lead to anovulatory cycle. But, it is important to recognize a polycystic ovarian pattern and differentiate it from post-induction multicystic ovaries. Follicles arranged in the periphery forming a ‘necklace sign’, echogenic stroma, and more than 10 follicles of less than 9 mm size, signify a polycystic pattern in induced cycle. While, follicles in the center as well as the periphery, are seen in normal induced multicystic ovaries 4.

Antral follicle number of less than three 5, usually signify possible failure of assisted reproductive therapy (ART).

Ovarian stromal blood flow has been recommended as a good predictor of ART success. Increased peak systolic velocity (>10 cm/sec) is one of such parameters which has been advocated.

When to administer gonadotropins?

Although, it is a matter of choice, based on experience of individual IVF specialists, there are certain parameters which may be considered. Minimal criteria 6 suggested is a follicle size of at least 15 mm, and serum estradiol level of 0.49 nmol/L. Better prospects are at follicle size of 18 mm, and serum estradiol level of 0.91 nmol/L.

Random hCG administration should be avoided 3, to prevent a risk of ovarian hyperstimulation syndrome (OHSS).

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