Induction of Ovulation With Clomiphene Citrate: Mode of Action, Indications, Benefits, Limitations and Contraindications for its use

Clomiphene (Clomid, Serophene) is by far the most widely prescribed agent for the induction of human ovulation for women who do not ovulate, those with dysfunctional ovulation and women with ”unexplained” infertility. When used in young women (who have adequate ovarian reserve) with these problems the viable pregnancy rate is reported as being between 6% and 10% per cycle of treatment. Aside from conventional ovulation induction, clomiphene has been used in preparing women for intrauterine insemination and even for IVF. I personally rarely prescribe clomiphene because across the board, success rates are significantly lower than when gonadotropin therapy is used. The main reasons for clomiphene’s popularity is its low cost, simplicity of use and the low risk of dangerous complications such as severe ovarian hyperstimulation syndrome (OHSS).

Clomiphene treatment can be initiated at a dose of 50 mg (orally) daily for 5 days but it can be increased to as much as 200mg per day, starting on cycle 2, 3, 4, or 5. A spontaneous LH surge will usually follow within about 8-9 days of the last 50mg dosage. In some cases, 10,000U of hCG can be given as a trigger when there is at least one ovarian follicle of 18-20 mm in size. Routinely using the hCG trigger does tend to decrease pregnancy potential.

Clomiphene works by inducing ovulation through its “antiestrogen effect” which, by blocking estrogen receptors in an area of the brain known as the hypothalamus, tricks the brain into “thinking” that estrogen levels are low. In response, the hypothalamus prompts the pituitary gland to release an exaggerated amount of follicle-stimulating hormone (FSH), which in turn stimulates the growth and development of ovarian follicles, ultimately resulting in a surge in the release of pituitary LH. About 38-42 hours later, ovulation occurs from one or more of the larger follicles. As the follicles grow, they release more and more estrogen into the bloodstream, thus closing the feedback circle that the hypothalamus initiated in response to the anti-estrogen properties of Clomiphene.

There are several factors that need to be considered carefully before deciding to prescribe clomiphene to any woman:

  • Clomiphene citrate therapy is less effective than gonadotropin therapy and its efficacy declines with advancing age: Many infertile couples undergoing ovulation induction believe that the success rate using clomiphene citrate is equivalent to what we see in fertile couples trying to get pregnant on their own and to what is encountered when gonadotropins (Menopur/Follistim/Gonal-F and Puregon) are used. This is not the case. The truth is that the rate of conception with clomiphene therapy is actually about 30% lower than the natural fertility rate for normally ovulating women, and about 25% lower than when gonadotropin stimulation is used for ovarian stimulation in similar patients. Moreover, the discrepancy is further magnified with advancing maternal age, where in women under 35 years, the pregnancy rate with clomiphene treatment is about 10% per cycle, about 5% between 35 and 40 years and <2% for women in their early to mid-forties.
  • Clomiphene use should ideally be confined to younger women: Ideally the use of clomiphene should in my opinion be restricted to younger women (under 35 years) who have normal “ovarian reserve” (as assessed by basal blood FSH, and antimullerian hormone (AMH) levels). These are the women who are most likely to respond by producing multiple follicles. It is necessary that at least 3 sizeable follicles (>15mm) develop on clomiphene treatment, in order to override the “anti-estrogenic” effects of this drug and so insure adequate cervical mucus production as well as the development of a receptive endometrium.
  • Clomiphene should usually not be administered for more than 3 consecutive (back-to- back) cycles: If used back-to-back for more than 3 consecutive cycles, clomiphene is not only ineffective, but actually starts to function as a “relative” contraceptive! This is often is a shocking revelation to many women. Clomiphene’s anti-estrogenic effect is not confined to the hypothalamus. Any cells that have a high concentration of estrogen receptors will also be so affected. Needless to say, the cervical glands (that produce estrogenic mucus to facilitate sperm transport and the endometrial lining (endometrium) that thickens under the effect of estrogen are also highly vulnerable to a buildup of antiestrogen effects over successive back-to back cycles of clomiphene therapy. This why with >3 consecutive back-to back clomiphene cycles cervical mucus tends to thicken and dry up and the endometrium will thin, seriously reducing the likelihood of success. These anti-estrogenic manifestations require that following 3 back-to back clomiphene cycles of stimulation there be at  least 1 resting (non-clomiphene treated) cycle, before doing a 4th cycle.
  • Clomiphene should not be used in older women or in women who have diminished ovarian reserve (DOR): With clomiphene stimulation, the  release of pituitary FSH is always accompanied by the concomitant release of Luteinizing Hormone (LH). LH causes the ovary to produce male hormone (androgens) and testosterone. The production by the ovaries of a modest amount of testosterone would not present a problem. However, an excessive production of ovarian testosterone prejudices egg development and thus ultimately compromises embryo competency. Older women and women with DOR are the most vulnerable because they tend to have overgrowth of ovarian connective tissue (stroma/theca) which is the site where androgens are produced. The concentration of androgens is always much higher at the site of production (the ovaries) than in the peripheral blood (a dilution effect). Thus in older women and those with DOR, there will be excessive ovarian androgens that can compromise egg quality and thus ultimately reduce the chance of having a baby. The older the woman and/or the more severe the DOR, the greater this adverse effect is likely to be.
  • “Trapped” ovulation (LUF-Syndrome): About 20% of clomiphene cycles are associated with “trapped” ovulation (Luteinized Unruptured Follicle (LUF) Syndrome). This means that in spite of hormone changes suggesting that ovulation has occurred, the egg remains trapped in the ovary. Obviously this is not condusive to the establishment of a successful pregnancy.
  • Endometriosis is a “relative contraindication” to the use of clomiphene: Women with endometriosis (regardless of its severity) have” toxic factors” in their pelvic peritoneal fluid. Eggs, as they pass from the ovaries to the Fallopian tubes to reach the awaiting sperm, become exposed to these “toxins” which renders the egg envelopment (zona pellucida) resistant to sperm penetration. This reduces fertilization potential by a factor of at least 3 or 4. This means that if, in the absence of endometriosis, an egg has a 15% chance of being fertilized and thereupon resulting in a baby, that same egg, in a woman with endometriosis would have no more than a 5% chance. Thus, if the overall chance of a having a baby per year of actively trying is about 12% then the chance in a woman with mild endometriosis (of the same age) would probably be no more than 3-4%. This serves to explain why normally ovulating women with endometriosis and patent Fallopian tubes do not benefit significantly from intrauterine insemination, with or without the use of fertility drugs, or from surgery to remove endometriotic lesions (since many endometriotic deposits are non-pigmented, thus invisible to the naked eye and cannot be removed surgically). Only IVF improves the chance of a baby per month of trying.  Simply put…if a normally ovulating woman who has mild to moderate endometriosis conceives following IUI, surgery, or the use of fertility drugs, it is probably in spite of (rather than due) to such treatment.
  • Women with long gaps between menstruation are often not ideal candidates for clomiphene: Women who consistently have  >45 days between their periods will not respond well to clomiphene induction of ovulation and are better off going directly to injectable gonadotropins.
  • Multiple pregnancy: The incidence of multiple pregnancies with clomiphene induction of ovulation is about 5%. This is much lower than the 25% rate encountered when gonadotropins are given to women with absent or dysfunctional ovulation.

Clomiphene therapy is often used as a first line approach to inducing ovulation in women with irregular or absent ovulation such as in women with polycystic ovarian syndrome (PCOS). Its use in my opinion is best confined to women who menstruate/ovulate irregularly (but who bleed at least every 45 days), younger women, women who do not have tubal disease or endometriosis, women under 40 years of age (preferably <35Y), and women who do not have DOR . It should also be avoided when there is co-existing male factor infertility.  If pregnancy fails to occur after 3 consecutive cycles of clomiphene therapy, then in my opinion, it is time to move on to gonadotropin therapy, combined with IUI or IVF/ICSI depending on the underlying cause of the infertility.

4 Comments

Meenal

Hello dr. Sher
I am unable to conceive , doctors here refer it as unexplained infertility.
I have gone HSG , and the results were , bilateral tubal block , hence went for laproscopy in which left tube was patent and canulation done right tube. The results after laparoscopy was ” both tubes patent” .
After trying naturally for 7-8 months went on 3 cycles of clomiphene citrate and 3 cycles of letrosoule along with 3 cycle IUI .. still no result.
I have PCOD too. Kindly guide me what to do

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Dr. Geoffrey Sher

It is not possible to adfvise you authoritatively without talking to you.Consider calling my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com. You can also apply online at http://www.SherIVF.com.

Geoff Sher

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Rita

Hi dr Sher, I have a history of functional ovarian cysts, all of them resolved on their own, I’m planning for pregnancy (third try), I had a miscarriage in november, the question is for the future is this an absolute contraindication for any type of ovarian stimulation, in case I need this ?

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Dr. Geoffrey Sher

An ovarian cyst is any collection of fluid, surrounded by a very thin wall, within an ovary. An ovarian follicle that is larger than 22mm is termed a functional follicular cyst. They are non-malignant (benign) and harmless and in most cases, don’t even cause symptoms, however, in some cases, rapid distention of the cyst , or rupture with bleeding , can lead to sudden and severe pain and in some cases, a disruption in hormone balance leads to vaginal bleeding.

There are 2 varieties of “functional ovarian cysts:
1. Follicle Cysts: In menstruating women, a follicle containing the unfertilized egg will rupture during ovulation. If this does not occur, a follicular cyst of more than 2.5 cm diameter may result. These cysts develop in response to stimulation with follicle stimulating hormone that is either self-produced (by the woman’s own pituitary gland (endogenous) or is induced by agonists (e.g. Lupron/Decapeptyl/Buserelin) that sometimes propagate increased and sustained pituitary FSH release.
2. Corpus luteum cysts: These appear after ovulation or egg retrieval. The corpus luteum is the remnant of the follicle after the ovum has moved to the fallopian tubes. It usually degrades within 5-9 days. A corpus luteum of > 3 cm is regarded as being cystic.

A:Follicular cysts: These lesions have special relevance in women about to undergo controlled ovarian stimulation (COS) with gonadotropins for IVF where they can literally, “throw a spanner in the works”, causing a delay, postponement and sometimes even cancellation of the cycle of treatment.

Functional Ovarian cysts must be distinguished from “non-functional or cystic ovarian tumors”. By definition, “tumors are capable of independent growth. Thus “cystic ovarian tumors do not develop as a result of exposure to gonadotropin stimulation and it is this feature that distinguishes them from “functional” ovarian cysts.

Aside from sometimes causing pain and dysfunctional uterine bleeding, unruptured follicular cysts are usually relatively non-problematic. As stated above, in some cases, functional “cysts” undergo rapid distention (often as a result of a minor degree of bleeding inside the cyst itself). In such cases the woman will often experience a sharp or aching pain on one or other side of her lower abdomen and/or deep seated pain during intercourse. The cysts may even rupture, causing sudden lower abdominal pain that exacerbates and may even simulate an attack of acute appendicitis or a ruptured ectopic (tubular) pregnancy. While very unpleasant, a ruptured “functional cyst” seldom produces a degree of internal bleeding that warrants surgical intervention. The pain, typically is made worse by movement. It stabilizes within a number of days but subsides progressively to disappear within about four to seven days.

Whenever an ovarian cyst is detected (usually by ultrasound examination), the first consideration should be to determine whether it is a “functional cyst or a “cystic ovarian tumor”. The reason for this is that tumors are subject to a variety of complications such as twisting (torsion), hemorrhage, infection and even malignant change, all of which usually will require surgical intervention.

Gonadotropin releasing hormone agonists (GnRHa) such as Lupron, Buserelin, Nafarelin and Synarel, administered daily, starting a few days prior to menstruation, all elicit an initial and rapid, out-pouring (“surge”) in pituitary LH and FSH release. This “surge” lasts for a day or two. Then as the pituitary reservoir of FSH and LH becomes depleted, the blood FSH and LH levels fall rapidly reaching near undetectable blood levels within a day or two. At the same time, the declining FSH result in a drop in blood E2 concentration leading to a withdrawal bleed (menstruation). The progressive exhaustion of Pituitary FSH/LH along with the decline in blood E2, is referred to as ” down-regulation” The continued daily administration of GnRHa or its replacement (supplanting) with a GnRH antagonist (e.g. Ganirelix, Cetrotide or Orgalutron) results in blood LH concentrations being sustained at a very low level throughout the ensuing cycle of controlled ovarian hyperstimulation (COH) with gonadotropins, thereby optimizing follicular maturation and promoting E2 induced endometrial proliferation.

Functional follicular cysts resulting from controlled ovarian stimulation (COS), can occur regardless of whether down regulation with GnRHa (Lupron/Buserelin/Decapeptyl) is initiated in cases where the cycle of stimulation is launched with the woman coming off a BCP or when the agonist is initiated on day 20-23 (the mid luteal phase) of a natural cycle. When this happens it is due to the initial agonist-induced FSH “surge” sometimes so accelerating follicular growth that it leads to the development of one or more “functional follicular cysts”. These cysts release E2 and cause the blood E2 often to remain elevated (>70pg/ml). Depending on the extent of this effect, it sometimes leads to a delay in the onset of menstruation and thus also to deferment in the initiation of COS.

Failure of menstruation to commence within 4-7 days of initiating treatment with GnRHa suggestive of an underlying “functional ovarian cyst” and calls for an ultrasound examination to make the diagnosis. Once diagnosed, depending upon the number and size of cysts detected. There are two therapeutic options:
1) Wait for the cyst to absorb spontaneously and for menstruation to ensue: While it at first might seem that this approach of continuing GnRHa therapy in order to cause absorption of the cyst(s) within a week or two might be a good approach , it often has unintended consequences. First there is the real possibility that prolonged uninterrupted GnRHa therapy might blunt subsequent ovarian follicular response to gonadotropin therapy and second, if menstruation does not follow within 10-14 days, the cycle will usually need to be cancelled.
2) Immediate needle aspiration of the cyst(s) under local anesthesia. I personally favor needle aspiration, sooner rather than later in such cases. Menstruation will usually follow a successful aspiration within 2-4 days. Upon menstruation a blood E2 level is measured and as soon as it drops below 70pg/ml COS can be initiated.

B. Corpus Luteum cysts: As with follicular cysts, so at times do Corpus Luteum cysts also bleed, distend and cause fain. They often delay onset of spontaneous menstruation by a week or longer (Halban syndrome”.). In isolated cases, internal bleeding within the cyst substance causes pain, rapid enlargement of the lesion and by ultrasound examination reveals local areas of absorption causing it to appear as a “complex” cystic lesion that simulates a tumor, prompting surgical intervention. Sadly, there are countless cases where women have had an entire ovary removed due to this happening.

“Functional ovarian cysts” rarely present as a serious health hazard. In the vast majority of cases they spontaneously resolve within 2-4 weeks while “cystic tumors” will not. Accordingly, the persistence of any ovarian cyst that persists for longer than 4 weeks should raise suspicion of it being a tumor rather than with a “functional cyst”. Since ovarian tumors can be (or become) malignant, all ovarian cysts that persist for longer than 6 weeks (whether occurring in non-pregnant or pregnant women), should be considered for surgical removal and this should be followed by pathological analysis.

If you are interested in my advice or medical services, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com. You can also apply online at http://www.SherIVF.com.
Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoffrey Sher MD

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