For normal ovulation to occur, a sequence of signals between the ovary, the hypothalamus (an area at the base of the brain) and the pituitary gland initiates the release of follicle stimulating hormone (FSH) from the pituitary. The FSH hormone stimulates the growth of eggs within the ovary until they are ready for ovulation. At this point, a second hormone – Luteinizing Hormone (LH) – is released by the pituitary gland, triggering ovulation 24-36 hours later.

The site of ovulation becomes the Corpus Luteum. It produces progesterone hormone which prepares the lining of the uterus for embryo implantation. Low levels of progesterone are associated with failure of the embryo to implant and with an increased risk of a miscarriage.

In a typical menstrual cycle, only one egg develops in response to low levels of the naturally occurring FSH hormone. During In Vitro Fertilization (IVF), supra-physiologic amounts of FSH hormone are injected into the patient and stimulate the ovary to produce multiple eggs.

What are the causes of ovulation disorders?

Any disruption of the hormonal signals regulating healthy egg development may cause infertility. Ovulation problems can present in several ways. Sometimes a woman has no menses at all (amenorrhea). At other times she may only ovulate sporadically reducing her chances for pregnancy. Once your doctor identifies the cause for the ovulation problem, proper treatment results in excellent pregnancy rates.

Ovulation disorders are most commonly associated with the following conditions:

  • Polycystic Ovary Disease (PCOS) - characterized by irregular cycles, obesity and increased male hormone levels.
  • Thyroid hormone abnormality.
  • High pituitary prolactin hormone level.
  • Luteal Phase Defect (LPD) is associated with low progesterone hormone level after ovulation. When the progesterone level is low, the uterine lining may not be adequately nurtured to receive the embryo, resulting in implantation failure or a miscarriage. Progesterone level is typically measured 6-8 days after ovulation. A progesterone level lower than 10ng/ml is suggestive of luteal phase defect.
  • Stress, excessive exercise, and smoking.

Evaluation of ovulation disorders

  1. Menstrual history.
  2. Blood tests for AMH, FSH, LH, Estrogen, Thyroid Stimulating Hormone (TSH) and Prolactin levels.
  3. Pelvic ultrasound.
  4. Blood test for progesterone level.

Treatment of ovulation disorders

  • Clomiphene citrate (Clomid, Serophene) is indicated in patients who are not ovulating regularly, or those with (PCOS). The treatment can restore normal ovulation in about 80% of the patients. In those that do ovulate, about 30% will conceive after three or four treatment cycles. 85 % of all pregnancies with Clomiphene occur within the first 3-4 ovulatory cycles. There is little benefit in continuing treatment with Clomid much longer and Injectable ovulation medications or IVF should be considered instead.
    In some patients with PCOS adding an Insulin blocker (Metformin) to Clomid can improve the ovulatory response, increase the pregnancy rate and decrease the rate of miscarriage.
    In other patients with PCOS, high level of the adrenal male hormone DHEAS (Dehydroepiandrosterone Sulfate) can disrupt ovulation. Adding Prednisone to Clomiphene lowers that hormone level and helps restore normal ovulation.

  • Thyroid medication is usually recommended when the problem is low thyroid hormone levels.
  • When the prolactin level is high, treatment with prolactin lowering medication, such as, Parlodel or Dostinex is advised.
  • Progesterone supplementation after ovulation may be recommended when luteal phase defect is the problem.
  • Life style modification, such as cessation of smoking, maintaining normal body weight, acupuncture, yoga, meditation and biofeedback, can reduce stress and help improve the ovulation process.

How does Clomid works?

Clomid works by lowering a woman’s estrogen level, which triggers the pituitary gland to release more of the follicle stimulating hormone (FSH). The end result is healthier egg development and release of the egg in a timely fashion.

How is Clomiphene treatment monitored?

Typically a pelvic ultrasound is performed 3-5 days after beginning your period. This is done to make sure that there are no large ovarian cysts present. A pregnancy test is also performed to make sure you are not pregnant.

Clomid is taken daily for 5 days beginning 3-5 days after the onset of menses. An ultrasound is often performed on day 13 of cycle to check on the developing eggs (fig. 2) and to make sure that the lining of the uterus is thick enough to support embryo implantation (fig. 3).

The egg is microscopic and can not be seen on ultrasound. We can tell when the egg is ready for ovulation by measuring the size of the follicle containing the egg. When the follicle size is greater than 16-18 mm, an HCG injection is given to trigger the ovulation which is expected to occur 36-40 hours later.

  
fig. 1fig. 2fig. 3

What are the side effects of Clomiphene treatment?

Side effects attributed to the medication occur in less than 10% of patients and include hot flashes, breast tenderness, enlarged ovaries and mild abdominal pain. There is an increased incidence of twins (7%) if more than one egg is released, but higher order pregnancy (triplets) is rare.

You are not a good candidate for Clomiphene treatment if:

  • You are over the age of 40.
  • You have an undetectable or very low level of FSH. In this case, you are unlikely to ovulate with Clomiphene, and injectable gonadotropin therapy or IVF may be advised.
  • You do not get a period with Provera – indicating that you have a very low estrogen level and are highly unlikely to respond to Clomid. Treatment with injectable ovulation inducing medications may be recommended instead.
  • You have high FSH or low AMH levels consistent with diminished ovarian reserve. The ovaries are resistant to any ovarian stimulation protocol and donor egg IVF may be advised.
  • You have other fertility factors (tubal factor, fibroids, severe endometriosis or severe male factor).

What to do when Clomiphene treatment is not successful?

When treatment with Clomiphene Citrate fails to restore ovulation or if you have low pituitary FSH level, you may be considered
for Gonadotropin therapy. The treatment is often combined with intrauterine insemination utilizing your partner’s sperm. With this treatment, you can expect to receive daily injections of fertility medication such as Gonal F, Follistim or Menopur for about 10 days. The medications are self injected into the skin with a pen-like instrument equipped with a very small needle.

What are the risks of ovulation induction treatment?

As with any medical treatment, there are some risks specific to fertility medications. The most serious complications of ovulation induction occur with gonadotropin injection therapy.

  • Multiple pregnancy – (mostly twins) occur in approximately 20% of ovulation induction cycles utilizing gonadotropin injections. Careful monitoring of the developing eggs by ultrasound and blood tests can lower the risk of multiple pregnancies. When a triplet or higher order pregnancy occurs, reducing the pregnancy to twins (Selective Reduction) may be considered.
  • Cycle cancellation – Gonadotropin injections are discontinued and ovulation is prevented when there are too many eggs developing. Cycle cancellation prevents the dangers of high order pregnancy. An alternative to cycle cancellation is to convert the treatment to In Vitro Fertilization (IVF). Following egg retrieval, only 1-2 embryos are transferred, thus, preventing high order pregnancy.
  • Ovarian Hyperstimulation Syndrome (OHSS) – is a potentially life threatening complication resulting from over stimulation of the ovaries, requiring hospitalization and aggressive treatment. The condition is associated with ovarian enlargement, torsion (twisting) of the ovaries, weight gain, accumulation of abdominal fluid, decrease of blood volume and low blood pressure. OHSS may occur even with mild stimulation. Fortunately, the severe form of Ovarian Hyperstimulation Syndrome is uncommon, occurring in less than 1% of patients.

How to measure the ovarian reserve?

In older women, problems with ovulation may result from normal” aging” of their eggs. When a woman’s eggs are depleted, women stop having periods altogether (menopause). Some women may experience menopause at younger age (Premature Ovarian Failure). The status of the ovaries (ovarian reserve) can be determined by ultrasound egg count (AFC) and blood tests for Follicle Stimulating Hormone (FSH), estradiol and Anti Mullerian Hormone (AMH) on day 3 of the menstrual cycle.

What to do if you have Diminished Ovarian Reserve (DOR)?

If you have been told that you have Diminished Ovarian Reserve, IVF should be considered as soon as possible. For patients with extremely poor ovarian reserve, treatment with ovulation-inducing medications or IVF utilizing their own eggs is unlikely to be successful. In Vitro Fertilization (IVF) with donated eggs from younger women or adoption should be considered instead. Delivery rates for donor egg IVF exceed 50%.