Ovulation induction is the stimulation of

ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...

by medication. It is usually used in the sense of stimulation of the development of

ovarian follicles An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with th ...

Ovulation Problems and Infertility: Treatment of ovulation problems with Clomid and other fertility drugs.
Advanced Fertility Center of Chicago. Gurnee & Crystal Lake, Illinois. Retrieved on Mars 7, 2010Flinders reproductive medicine > Ovulation Induction
Retrieved on Mars 7, 2010 to reverse

anovulation Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulat ...

oligoovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized ...

Scope

The term ''ovulation induction'' can potentially also be used for: *

Final maturation induction Induction of final maturation of oocytes is a procedure that is usually performed as part of controlled ovarian hyperstimulation to render the oocytes fully developed and thereby resulting in optimal pregnancy chances. It is basically a replacemen ...

, in the sense of triggering ''oocyte release'' from relatively mature ovarian follicles during late

follicular phase The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle (or, in primates for example, the menstrual cycle) during which follicles in the ovary mature from primary follicle to a fully ...

. In any case, ovarian stimulation (in the sense of stimulating the development of oocytes) is often used in conjunction with triggering oocyte release, such as for proper timing of

artificial insemination Artificial insemination is the deliberate introduction of sperm into a female's cervix or uterine cavity for the purpose of achieving a pregnancy through in vivo fertilization by means other than sexual intercourse. It is a fertility treatment ...

. *

Controlled ovarian hyperstimulation Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval (egg coll ...

(stimulating the development of multiple follicles of the ovaries in one single cycle), has also appeared in the scope of ovulation induction.IVF.com > Ovulation Induction
Retrieved on Mars 7, 2010 Controlled ovarian hyperstimulation is generally part of

in vitro fertilization In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...

, and the aim is generally to develop multiple follicles (optimally between 11 and 14 antral follicles measuring 2–8 mm in diameter),Antral Follicle Counts, Resting Follicles, Ovarian Volume and Ovarian Reserve. Testing of egg supply and predicting response to ovarian stimulation drugs
Advanced Fertility Center of Chicago. Retrieved on October 2, 2009 followed by

transvaginal oocyte retrieval Transvaginal oocyte retrieval (TVOR), also referred to as oocyte retrieval (OCR), is a technique used in in vitro fertilization (IVF) in order to remove oocytes from the ovary of a woman, enabling fertilization outside the body. Transvaginal oocyte ...

, co-incubation, followed by

embryo transfer Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus of a female with the intent to establish a pregnancy. This technique (which is often used in connection with in vitro fertilizat ...

of a maximum of two embryos at a time.Fertility: assessment and treatment for people with fertility problems
NICE clinical guideline CG156 - Issued: February 2013 *Also, where

or oligovulation is secondary to another disease, the treatment for the underlying disease can be regarded as ovulation induction, by indirectly resulting in ovulation. However, this article focuses on medical ovarian stimulation, during early to mid-

, without subsequent

, with the aim of developing one or two ovulatory follicles (the maximum number before recommending

sexual abstinence Sexual abstinence or sexual restraint is the practice of refraining from some or all aspects of sexual activity for medical, psychological, legal, social, financial, philosophical, moral, or religious reasons. Sexual abstinence is distinct from a ...

Indications

Ovulation induction helps reversing

or oligoovulation, that is, helping women who do not ovulate on their own regularly, such as those with

polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and n ...

(PCOS).

Regimen alternatives

Hypothalamic–pituitary–gonadal axis in females

The main alternatives for ovulation induction medications are: *

Antiestrogen Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or i ...

, causing an inhibition of the

negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...

of estrogen on the

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypop ...

, resulting in an increase in secretion of

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

. Medications in use for this effect are mainly

clomifene citrate Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course ...

and

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...

(both being

selective estrogen-receptor modulator Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists a ...

s), as well as

letrozole Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer. It was patented in 1986 and approved for medical use in 1996. In 2020, it was the 257th most commo ...

(an

aromatase inhibitor Aromatase inhibitors (AIs) are a class of medication, drugs used in the treatment of breast cancer in menopause, postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when suppleme ...

. *

Follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

, directly stimulating the ovaries. In women with

, it may be an alternative after 7 to 12 attempted cycles of antiestrogens (as evidenced by clomifene citrate), since the latter ones are less expensive and more easy to control.

Antiestrogens

Clomifene citrate

Clomifene citrate Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course ...

(or clomid) is the medication which is most commonly used to treat anovulation. It is a

, affecting the

hypothalamic–pituitary–gonadal axis The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–ovarian/testicular axis) refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single e ...

to respond as if there was an estrogen deficit in the body, in effect increasing the production of

. It is relatively easy and convenient to use. Clomifene appears to inhibit

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of th ...

s in

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...

, thereby inhibiting

of estrogen on production of follicle-stimulating hormone.DrugBank > Clomifene
Updated on April 19, 2011 It may also result in direct stimulation of the hypothalamic-pituitary axis. It also has an effect on

cervical mucus The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...

quality and uterine mucosa, which might affect sperm penetration and survival, hence its early administration during the

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eg ...

. Clomifene citrate is a very efficient ovulation inductor, and has a success rate of 67%. Nevertheless, it only has a 37% success rate in inducing pregnancy. This difference may be due to the anti-estrogenic effect which clomifene citrate has on the

endometrium The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional lay ...

, uterine blood flow, as well as the resulting decrease in the motility of the

fallopian tubes The fallopian tubes, also known as uterine tubes, oviducts or salpinges (singular salpinx), are paired tubes in the human female that stretch from the uterus to the ovaries. The fallopian tubes are part of the female reproductive system. In ...

and the maturation of the

oocytes An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female g ...

Letrozole

Letrozole Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer. It was patented in 1986 and approved for medical use in 1996. In 2020, it was the 257th most commo ...

has been used for ovarian stimulation by fertility doctors since 2001 because it has fewer side-effects than

clomiphene Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a cours ...

and less chance of multiple gestation. A study of 150 babies following treatment with letrozole or letrozole and follicle-stimulating hormone presented at the

American Society of Reproductive Medicine The American Society for Reproductive Medicine (ASRM) is a nonprofit, multidisciplinary organization for advancement of the science and practice of reproductive medicine. The society has its headquarters in Washington, D.C and its administrati ...

2005 Conference found no difference in overall abnormalities but did find a significantly higher rate of locomotor and cardiac abnormalities among the group having taken letrozole compared to natural conception. A larger, follow-up study with 911 babies compared those born following treatment with letrozole to those born following treatment with clomiphene. That study also found no significant difference in the rate of overall abnormalities, but found that congenital cardiac anomalies was significantly higher in the clomiphene group compared to the letrozole group. Dosage is generally 2.5 to 7.5 mg daily over 5 days. A higher dose of up to 12.5 mg per day results in increased follicular growth and a higher number of predicted ovulations, without a detrimental effect on endometrial thickness, and is considered in those who do not respond adequately to a lower dose.

Tamoxifen

Tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...

affects estrogen receptors in a similar fashion as clomifene citrate. It is often used in the prevention and treatment of

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

. It can therefore also be used to treat patients that have a reaction to clomifene citrate.

Follicle-stimulating hormone

Preparations of follicle-stimulating hormone mainly include those derived from the urine of menopausal women, as well as recombinant preparations. The recombinant preparations are more pure and more easily administered, but they are more expensive. The urinary preparations are equally effective and less expensive, but are not as convenient to administer as they are available in vials versus injection pens.

Gonadotropin-releasing hormone pump

The

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...

pump is used to release doses in a pulsatile fashion. This hormone is synthesised by the

and induces the secretion of follicle-stimulating hormone by the pituitary gland. Gonadotropin-releasing hormone must be delivered in a pulsatile fashion to imitate the random secretion of the hypothalamus in order to stimulate the pituitary into secreting

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (Gn ...

and follicle-stimulating hormone. The gonadotropin-releasing hormone pump is the size of a cigarette box and has a small catheter. Unlike other treatments, using the gonadotropin-releasing hormone pump usually does not result in multiple pregnancies. Filicori from the University of Bologna suggests that this might be because gonadotrophins are absent when the treatment is initiated, and therefore the hormones released by the pituitary (luteinizing hormone and follicle-stimulating hormone) can still take part in the retro-control of gonadotrophin secretion, mimicking the natural cycle. This treatment can also be used for underweight and/or

anorexic Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by underweight, low weight, Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thi ...

patients; it has also been used in certain cases of hyperprolactimenia.

National and regional usage

In the Nordic countries, letrozole is practically the standard initial regimen used for ovulation induction, since no formulation of clomifene is registered for use there. India banned the usage of letrozole in 2011, citing potential risks to infants. In 2012, an Indian parliamentary committee said that the drug controller office colluded with letrozole's makers to approve the drug for infertility in India.

Technique

Although there are many possible additional diagnostic and interventional techniques, protocols for ovulation induction generally consist of: *Determining the first day of the last menstruation, which is termed day 1. In case of

amenorrhea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of mense ...

, a period can be induced by intake of an oral

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a '' synthetic'' progestogen. Pro ...

for 10 days. *Daily administration of the ovulation induction regimen, starting on day 3, 4, or 5, and it is usually taken for 5 days. * Sexual intercourse or

by the time of

Ultrasonography

During ovulation induction, it is recommended to start at a low dose and

monitor Monitor or monitor may refer to: Places * Monitor, Alberta * Monitor, Indiana, town in the United States * Monitor, Kentucky * Monitor, Oregon, unincorporated community in the United States * Monitor, Washington * Monitor, Logan County, West ...

the ovarian response with

transvaginal ultrasound Vaginal ultrasonography is a medical ultrasonography that applies an ultrasound transducer (or "probe") in the vagina to visualize organs within the pelvic cavity. It is also called transvaginal ultrasonography because the ultrasound waves go ''a ...

, including discernment of the number of developing follicles. Initial exam is most commonly started 4–6 days after last pill. Serial transvaginal ultrasound can reveal the size and number of developing follicles. It can also provide presumptive evidence of ovulation such as sudden collapse of the preovulatory follicle, and an increase in fluid volume in the

rectouterine pouch The rectouterine pouch (recto-uterine pouch), pouch of Douglas, or rectovaginal pouch is the extension of the peritoneum between the rectum and the posterior wall of the uterus in the human female. Its anterior boundary is formed by the posterior ...

. After ovulation, it may reveal signs of luteinization such as loss of clearly defined follicular margins and appearance of internal echoes.

Supernumerary follicles

A cycle with supernumerary follicles is usually defined as one where there are more than two follicles >16 mm in diameter. It is generally recommended to have such cycles cancelled because of the risk of

multiple pregnancy A multiple birth is the culmination of one multiple pregnancy, wherein the mother gives birth to two or more babies. A term most applicable to vertebrate species, multiple births occur in most kinds of mammals, with varying frequencies. Such bi ...

(see also the " Risks and side effects" section below). In cancelled cycles, the woman or couple should be warned of the risks in case of supernumerary follicles, and should avoid sexual intercourse or use contraception until the next menstruation. Induction of final maturation (such as done with hCG) may need to be withheld because of increased risk of

ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS) is a medical condition that can occur in some women who take fertility medication to stimulate egg growth, and in other women in very rare cases. Most cases are mild, but rarely the condition is severe and ...

. The starting dose of the inducing drug should be reduced in the next cycle. Alternatives to cancelling a cycle are mainly: *Aspiration of supernumerary follicles until one or two remain. *Converting the protocol to

IVF In vitro fertilisation (IVF) is a process of fertilisation where an ovum, egg is combined with spermatozoon, sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's Ovulation cycle, ovulatory process, remo ...

treatment with

of up to two embryos only. * Selective fetal reduction. This alternative confers a high risk of complications. *Proceeding with any multiple pregnancy without fetal reduction, with the ensuing risk of complications. This alternative is not recommended.

Lab tests

The following

laboratory A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratory services are provided in a variety of settings: physici ...

tests may be used to monitor induced cycles: *Serum

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

levels, starting 4–6 days after last pill *Adequacy of luteinizing hormone surge

LH surge Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...

by urine tests 3 to 4 days after last clomifene pill *Post-coital test 1–3 days before ovulation to check whether there are at least 5 progressive sperm per HPF *Mid-luteal progesterone, with at least 10 ng/ml 7–9 days after ovulation being regarded as adequate.

Final maturation induction

and release, such as by human chorionic gonadotropin (HCG or hCG) or recombinant luteinizing hormone, results in a predictable time of ovulation, with the interval from drug administration to ovulation depending on the type of drug. This avails for sexual intercourse or

intrauterine insemination Artificial insemination is the deliberate introduction of sperm into a female's cervix or uterine cavity for the purpose of achieving a pregnancy through in vivo fertilization by means other than sexual intercourse. It is a fertility treatment ...

to conveniently be scheduled at ovulation, the most likely time to achieve pregnancy.IVF.com > Ovulation Induction
Retrieved on Mars 7, 2010 As evidenced by clomifene-induced cycles, however, triggering oocyte release has been shown to decrease pregnancy chances compared to frequent monitoring with LH surge tests. Therefore, in such cases, triggering oocyte release is best reserved for women who require intrauterine insemination and in whom luteinizing hormone monitoring proves difficult or unreliable. It may also be used when luteinizing hormone monitoring has no shown an luteinizing hormone surge by cycle day 18 (where cycle day 1 is the first day of the preceding menstruation) and there is an

ovarian follicle An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with t ...

of over 20 mm in size.Clomiphene Citrate, Clomid
. By Robert B. McWilliams. The Center for Reproduction and Women's Health Care, Houston, Texas. Retrieved May 2014

Repeat cycles

Ovulation induction can be repeated every

. For clomifene, the dosage may be increased by 50-mg increments in subsequent cycles until ovulation is achieved.Medications for Inducing Ovulation
from

American Society for Reproductive Medicine The American Society for Reproductive Medicine (ASRM) is a nonprofit, multidisciplinary organization for advancement of the science and practice of reproductive medicine. The society has its headquarters in Washington, D.C and its administrat ...

. Revised 2012. However, at a dosage of 200 mg, further increments are unlikely to increase pregnancy chances. It is not recommended by the manufacturer of clomifene to use it for more than 6 consecutive cycles. In women with

, 7 - 12 attempted cycles of pituitary feedback regimens (as evidenced by clomifene citrate) are recommended before switching to gonadotrophins, since the latter ones are more expensive and less easy to control. It is no longer recommended to perform an ultrasound examination to exclude any significant residual ovarian enlargement before each new treatment cycle.

Risks and side effects

Ultrasound and regular hormone checks mitigate risks throughout the process. However, there are still some risks with the procedure.

Ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS) is a medical condition that can occur in some women who take fertility medication to stimulate egg growth, and in other women in very rare cases. Most cases are mild, but rarely the condition is severe and ...

occurs in 5-10% of cases.Ovulation Induction Risks and Overview
/ref> Symptoms depend on whether the case is mild, moderate, or severe, and can range from bloating and nausea, through to shortness of breathe, pleural effusion, and excessive weight gain (more than 2 pounds per day).

Multiple pregnancy

There is also the risk that more than one egg is produced, leading to twins or triplets. Women with

may be particularly at risk. Multiple pregnancy occurs in approximately 15-20% of cases following cycles induced with gonadotrophins such as human menopausal gonadotropin and follicle-stimulating hormone.Hong Kong College of Obstetricians and Gynaecologists > Guidelines for use of gonadotrophins- revised
. Number 1. April 2003. The risks associated with

are much higher than singleton pregnancy; incidence of perinatal death is seven times higher in triplet births and five times higher in twin births than the risks associated with a singleton pregnancy. It is therefore important to adapt the treatment to each individual patient. If more than one or two ovulatory follicles are detected on ultrasonography,

is recommended.

Alternatives

In vitro fertilization In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...

, including

controlled ovarian hyperstimulation Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval (egg coll ...

. *

In vitro maturation In vitro maturation (IVM) is the technique of letting the contents of ovarian follicles and the oocytes inside mature '' in vitro''. It can be offered to women with infertility problems, combined with In Vitro Fertilization (IVF), offering women p ...

is letting

s mature

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...

, and this technique can potentially be an alternative both to anovulation reversal and oocyte release triggering. Rather, oocytes can mature outside the body, such as prior to IVF. Hence, no (or at least a lower dose of) gonadotropins have to be injected in the body. However, there still isn't enough evidence to prove the effectiveness and security of the technique.

References

{{Reproductive health Fertility medicine Assisted reproductive technology