Anovulation and Ovulation Induction

During a normal menstrual cycle an egg is released from the ovary at the time of ovulation. Released eggs become fertilised by sperm in one of the Fallopian tubes to make an embryo, which them implants in the womb resulting in pregnancy. Failure to release an egg (known as anovulation) therefore causes infertility. Anovulation is responsible for around 20-30% of cases of infertility.

What is ovulation induction?

Ovulation induction refers to interventions aimed at bringing about the release of an egg in women who do not ovulate. There are different methods for inducing ovulation. The particular method used depends on the underlying reason for anovulation. Ovulation induction should not be confused with superovulation, which refers to the use of drugs to induce more than one egg to be released in women who already ovulate.

How does ovulation come about?

Ovulation depends on hormones produced in two neighbouring regions located at the base of the brain known as the hypothalamus and the pituitary gland. Gonadotrophin releasing hormone (GnRH) produced by the hypothalamus acts on the pituitary causing it to release the hormone, FSH. FSH travels in the blood stream to the ovary and causes the development of follicles (which contain eggs) within the ovary. These growing follicles produce oestrogen. Rising oestrogen levels from ovarian follicles then cause the pituitary to release a surge of the hormone, LH, which acts on the lead follicle to bring about the release of its egg (ovulation). For more information on ovarian follicles, see my section on the Menstrual Cycle.

What are the causes of anovulation?

Any problem that affects either the production, or coordinated action, of GnRH, FSH and LH will prevent ovulation.

PCOS is the commonest cause for anovulation accounting for around 80% of cases. In PCOS, the hormones GnRH, LH, FSH and oestrogen are being produced, and follicles containing eggs are present in the ovary, but there is lack of coordination amongst them. Due to this lack of coordination, a lead follicle does not develop to the advanced stage required for ovulation. Although women with PCOS often do not release eggs, ironically, their ovaries typically contain very high numbers of eggs.

Very high levels of the hormone, prolactin, can cause anovulation by blocking the production of GnRH. Like FSH and LH (which are called gonadotrophins), prolactin is produced by the pituitary gland. Prolactin is responsible for breast milk production in pregnancy. High levels of prolactin are often caused by a very small tumour in the pituitary (known as a microadenoma) but can also be caused by some medications such as antipsychotics and some antihypertensives. In other cases, the cause for high prolactin levels are unknown.

Stress and low body weight:
GnRH production can also become disrupted by having a very low bodyweight with low levels of body fat or by psychological stress. This is referred to as hypothalamic amenorrhoea.

Kallmann syndrome:
Some individuals are unable to produce GnRH from birth. This condition is often associated with loss of the sense of smell and is known as Kallmann syndrome.

Lack of FSH and LH:
In rare cases, anovulation is due to an inborn lack of FSH and LH as in congenital hypopituitarism.
Loss of the ability to produce FSH and LH can also be due to a brain tumour.
Loss of FSH and LH may also happen after giving birth if the delivery was associated with very heavy blood loss. The resulting low blood flow starves the pituitary gland of oxygen causing it to become damaged. This condition is known as Sheehan’s syndrome.

What treatments can be used for inducing ovulation?

Since PCOS is by far the commonest cause of anovulation, most treatments are geared towards inducing ovulation in women with PCOS.

Lifestyle change and weight loss:
A very important intervention in overweight anovulatory women with PCOS is lifestyle change aimed at losing weight. In some cases, weight loss alone is enough to correct the hormonal imbalance in PCOS and bring about ovulation.

Recent international PCOS guidelines recommend that the first line medical treatment for inducing ovulation should be letrozole (Femara). Letrozole belongs to a family of drugs known as aromatase inhibitors, which are best known for treating hormonally-responsive breast cancer. By blocking oestrogen production, letrozole tricks the body into producing more FSH, which causes follicle growth and leads to ovulation. Letrozole is taken in tablet form for 5 days with ovulation expected to occur around 6-8 days after the last tablet.

Clomiphene citrate:
The most widely used ovulation induction agent is clomiphene citrate (Clomid). Clomiphene causes an increase in the body’s own FSH levels to promote follicle development. It is taken in tablet form for 5 days with ovulation expected to occur around 6-8 days after the last tablet.

Metformin (Glucophage) helps the body to use insulin more effectively and is used to treat diabetes. This benefits some women with PCOS since with PCOS, there is often resistance to the action of insulin. Metformin is less effective than either letrozole or clomiphene for inducing ovulation.

FSH injections:
If oral medications fail, the next step is to directly administer FSH. FSH is administered daily by injection under the skin (subcutaneous). Compared with oral medications, there is a higher risk of causing too many follicles to develop with FSH injections so this treatment requires very close monitoring.

Laparoscopic ovarian “drilling”:
Another option for increasing ovulation, and the sensitivity of ovaries to ovulation induction drugs, is ovarian “drilling”. This is a surgical procedure typically performed via laparoscopy in which small holes are drilled in the ovarian surface using electricity delivered by a surgical point electrode.

Other treatment options:
Treatment for other causes of anovulation should target the underlying defect. In cases of hyperprolactinaemia, ovulation induction can be brought about by reducing prolactin levels using drugs such as bromocriptine (Parlodel) and cabergoline (Dostinex). Pituitary tumours producing prolactin may need to be surgically removed, especially if they are large and associated with visual disturbances.
In cases of hypothalamic amenorrhoea associated with low body weight, restoration of weight into the normal range can be effective, but may not be easy to achieve. In these and other cases where FSH and LH are lacking, both of these hormones (or an equivalent) can be administered by injection under the skin. In some countries, GnRH is a treatment option and is administered using a pump system that automatically delivers GnRH under the skin at a pre-determined rate.

What monitoring do I need during ovulation induction?

It is important when a drug is first used that the ovarian response is monitored to ensure it is appropriate and importantly, that it is not excessive. An excessive response that induces too many follicles to develop and leads to too many eggs being released is risky as it could lead to multiple pregnancies like triplets and quadruplets that pose risks of prematurity to the babies.

During treatment with oral agents such as letrozole and clomiphene, it is advisable that monitoring be performed for at least the first one or two cycles. This will not only check that a response is occurring, it will also confirm that it is not excessive. Monitoring is achieved using transvaginal ultrasound scanning to monitor follicle development. Scanning is usually combined with blood tests for measuring hormone levels that will enable the timing of ovulation, and of the right time for sexual intercourse, to be calculated. A blood test for progesterone levels can confirm whether ovulation occurred, but because it is performed around 1 week after ovulation, serum progesterone levels cannot be used to advise on timing of intercourse.

When using FSH injections for inducing ovulation, ultrasound scan monitoring is always required.

In cases of treatment for hyperprolactinaemia (usually with drugs), prolactin levels in the blood are monitored to ensure that they are returning to the normal range. As prolactin levels normalise, patients will find that their menstrual cycles are becoming more regular, which would be an indication that ovulation has resumed.

How can I tell whether I am ovulating?

Period regularity:
One of the best signs about whether or not you are ovulating is period regularity. Women who have regular periods, every 28-35 days, and don’t skip months, are almost always found to be ovulating. Conversely, women with periods longer than 6 weeks apart are not ovulating regularly.

Blood progesterone measurements:
A simple test for ovulation is a blood test for measuring progesterone. In order for this test to be reliable, it is critically important that it is done at the correct time in the cycle. Progesterone is produced by the follicle after the egg is released and its levels peak around 7 days after ovulation and around 7 days prior to the next period.

This means that for a 28-day cycle, progesterone should be measured on Day 21 (with Day 1 being the first day of the bleed), but for a 35-day cycle, it should be measured on Day 28 (measuring progesterone on Day 21 of a 35-day cycle will detect low progesterone levels and erroneously lead to the conclusion that ovulation is not occurring). If cycle length is more variable, another approach is to measure serial progesterone levels, starting on Day-21 and then weekly thereafter until the next bleed starts. In this way, any progesterone rise associated with ovulation will be detected.

Ovulation kits:
These kits detect the presence of LH in the urine. Note, however, that although ovulation usually follows the LH surge, this is not always guaranteed, so these kits do not actually test for ovulation. Since ovulation is preceded by the LH surge from the pituitary, the rise in LH in the blood filters through into the urine at high enough levels to be detected by the kit. Occasionally, in some women, kits may not produce a reliable result, either because the urine is too dilute or because the design of the kit is not able to identify their unique structure of LH.

Ultrasound scanning:
Ultrasound scanning can be used to track development of the lead follicle. When combined with blood tests, it is a very accurate way for confirming that ovulation is occurring. A range of other information can be obtained by scanning. See my section on the Menstrual Cycle and Ovulation Tracking for more information.

How can I find out which form of anovulation I might have?

This will require a systematic evaluation by a specialist trained in Reproductive Endocrinology to determine which of the above mentioned conditions is responsible for anovulation. Diagnosis is not always straightforward (e.g. for diagnosing hypothalamic amenorrhoea) and requires highly specialised expertise in Reproductive Endocrinology in combination with blood tests for measuring the levels of a range of hormones.

For details on making the diagnosis of PCOS, see my section on PCOS.

Investigating for hyperprolactinaemia involves measuring the levels of active prolactin in the blood. This will need to take into account the levels of inactive circulating prolactin (or macroprolactin). Other relevant investigations could include MRI scanning of the brain if a pituitary tumour is suspected.