Trig­ge­ring ovu­la­tion: Hor­mone tre­at­ment with clo­mi­phene

Hor­monal sti­mu­la­tion

Hor­monal sti­mu­la­tion is one of the many the­ra­pies de­si­gned to ad­dress hor­monal im­ba­lance as a cause of fe­male in­fer­ti­lity.

In this ar­ticle we dis­cuss what clo­mi­phene is, how and when it is used and what side ef­fects it can have. We also look at al­ter­na­tives, such as le­tro­zole, which are used in me­di­cine for hor­mone tre­at­ments among other things.

Im­portant ad­vance: The choice of pre­pa­ra­tion for hor­mone tre­at­ments al­ways de­pend on the type of dis­order and in­di­vi­dual fac­tors, which is why a prior dia­gnosis by a doctor is im­portant. Doc­tors adapt the the­rapy ac­cor­dingly to each pa­tient and de­cide on a par­ti­cular type of tre­at­ment with sui­table me­di­ca­tion.

What is clo­mi­phene?

Clo­mi­phene is one of the ac­tive sub­s­tances pre­scribed to women for ova­rian sti­mu­la­tion to trigger ovu­la­tion if they do not ovu­late or ovu­late ir­re­gu­larly. It can be used for hor­monal tre­at­ments of the fe­male cycle to trigger egg ma­tu­ra­tion on the ova­ries. Ho­wever, there are other drugs bes­ides clo­mi­phene that are pre­scribed for this pur­pose, espe­ci­ally for PCOS. The aro­ma­tase in­hi­bitor le­tro­zole is now a common al­ter­na­tive.

When is clo­mi­phene used?

The ac­tive in­gre­dient clo­mi­phene is used in fer­ti­lity tre­at­ments. Women who want to have children and who have been trying un­suc­cessfully for se­veral months to be­come pregnant du­ring their fer­tile phase should have their doctor ex­amine them and find out about pos­sible forms of the­rapy. Hor­monal tre­at­ments with clo­mi­phene may be an op­tion to in­duce ovu­la­tion in women with ova­rian dis­func­tion. Ova­rian dis­func­tion is when there is no ovu­la­tion or ir­re­gular ovu­la­tion [1], when there are pro­blems with the ma­tu­ra­tion of the fol­licles (egg sacs) or dis­or­ders of the corpus lu­teum phase.

There are pre­re­qui­sites for clo­mi­phene tre­at­ment [2] [3]:

• Ex­clu­sion of pregnancy
• Proven func­tional pro­blems of the cycle
• To­le­rance of the in­gre­di­ents
• Ex­clu­sion of tu­mours, liver di­se­ases, ova­rian cysts (ex­cep­tion: PCOS -> tre­at­ment only under strict me­dical ob­ser­va­tion)
• Avo­id­ance of al­cohol, drugs and ni­co­tine

How does clo­mi­phene work?

It is as­sumed that clo­mi­phene in­hi­bits the oes­trogen re­cep­tors and leads to the re­lease of go­na­do­tro­pins (such as FSH and LH). The hor­mones re­leased sti­mu­late fol­licle ma­tu­ra­tion and lead to ovu­la­tion [7]. Re­le­vant steps of the cycle are shown in the fol­lo­wing dia­gram. Hor­monal sti­mu­la­tion is sup­posed to help with ir­re­gular or ab­normal cy­cles. Ho­wever, clo­mi­phene does not work for every pro­blem that af­fects ovu­la­tion and is most ef­fec­tive for PCOS as a cause. So far, le­tro­zole has been found to be more ef­fec­tive for PCOS.

Clo­mi­phene: Do­sage, costs and suc­cess rate

Clo­mi­phene should al­ways be taken exactly as pre­scribed by a doctor. The do­sage and du­ra­tion of the­rapy are de­ter­mined in­di­vi­du­ally. Un­less other­wise pre­scribed by the doctor, clo­mi­phene tre­at­ment is often started on the fifth day after the start of the pe­riod. In the be­gin­ning, 1 ta­blet (50 mg) is usually taken once a day for 5 days. Women who have not had their pe­riod for a long time can usually start the the­rapy at any given time after con­sul­ta­tion [2]. The do­sage can be higher or lower for you if your doctor pre­scribes a dif­fe­rent amount for you.

Clo­mi­phene costs

The cost of clo­mi­phene ta­blets can vary de­pen­ding on the pro­vider and country. As it is a pre­scrip­tion me­di­cine, it can only be bought in (on­line) phar­macies with a valid pre­scrip­tion. Clo­mi­phene is usually sold in ta­blet form with 25–50 mg of ac­tive in­gre­dient. The average price is curr­ently around 20€ — 35€ for a pack of 10 50 mg ta­blets (as of 22.01.2020, data sub­ject to ch­ange).

Suc­cess rate

The suc­cess rate of clo­mi­phene tre­at­ment is usually quite high: ac­cor­ding to stu­dies, women with ovu­la­tion pro­blems have up to a 70–80% chance of ovu­la­tion [4] [5]. The chances of sub­se­quently be­co­ming pregnant are around 30–40% [6] [8].

The role of age
As you pro­bably al­ready know, a wo­man’s fer­ti­lity is in­fluenced by se­veral fac­tors. One of the big­gest fac­tors is age. For women over the age of 35, clo­mi­phene can only be hel­pful if there is a suf­fi­cient supply of eggs to begin with. If the supply of available eggs is too low, the drug may not be suc­cessful [6].

Spe­cial case of PCOS: clo­mi­phene vs. le­tro­zole

As an al­ter­na­tive the­rapy for PCOS pa­ti­ents, le­tro­zole is said to have a “more fa­vourable side-ef­fect pro­file”. Fur­ther­more, sin­gular fol­li­cular ma­tu­ra­tion usually oc­curs, which means a slightly lower rate of mul­tiple pregnan­cies overall [10].

Ac­cor­ding to the of­fi­cial in­ter­na­tional PCOS re­com­men­da­tion gui­de­line, the pro­ba­bi­lity of mul­tiple pregnan­cies in women with po­ly­cy­stic ovary syn­drome is lower with le­tro­zole than with clo­mi­phene [11].

The rate of twin pregnan­cies could be com­pared bet­ween the clo­mi­phene and le­tro­zole groups in a study. The rate of twin pregnan­cies in pantin women on clo­mi­phene was slightly higher (7.4%) than in those on le­tro­zole (3.4%) [10].

Le­tro­zole and clo­mi­phene are con­sidered first-line drugs for in­du­cing ovu­la­tion in women with PCOS.
In Ger­many, the drug le­tro­zole has so far only been ap­proved for the tre­at­ment of breast cancer. It is the­r­e­fore used “off-label” for fer­ti­lity tre­at­ments [11].

With women af­fected by PCOS, the pro­ba­bi­lity of trig­ge­ring ovu­la­tion is higher with le­tro­zole than with clo­mi­phene. Ho­wever, there is still no evi­dence that le­tro­zole is more ef­fec­tive for women wi­t­hout PCOS.

PCOS pa­ti­ents with a higher pregnancy rate (per pa­tient and per cycle) were other­wise ob­served with le­tro­zole tre­at­ments com­pared to clo­mi­phene [11]. The live birth rate was also higher in the le­tro­zole group than in the clo­mi­phene group [10] [11].

Gen­a­do­tro­pins can be used as “se­cond-line the­rapy” if clo­mi­phene or le­tro­zole could not achieve the de­sired re­sult [11].

If the at­tempt to in­duce ovu­la­tion has not been suc­cessful, the third op­tion is as­sisted re­pro­duc­tion by IVF or ICSI, for ex­ample [11].

Side ef­fects of clo­mi­phene

Du­ring clo­mi­phene tre­at­ment, more than 1 in 10 women may ex­pe­ri­ence flus­hing, hot flushes and en­lar­ge­ment of the ova­ries [2]. Other side ef­fects may occur in rare cases, but can be found on the re­le­vant leaf­lets or from your doctor. In ad­di­tion, tre­at­ment with clo­mi­phene can lead to so-called “ova­rian hy­per­sti­mu­la­tion syn­drome”.

When ta­king clo­mi­phene, there is an in­creased pro­ba­bi­lity of mul­tiple pregnan­cies (6–8%) [1] [8].

Pro­blems with mul­tiple pregnan­cies
The rate of mul­tiple pregnan­cies is lower with tre­at­ments with the aro­ma­tase in­hi­bitor le­tro­zole com­pared to clo­mi­phene [10].

The pro­blem with mul­tiple pregnan­cies du­ring pregnancy is the risks of pre­ma­tu­rity, in­creased risk of pre­ma­ture death and so-called “in­trau­te­rine growth rest­ric­tion”, which means that the foetus does not reach its ge­netic growth po­ten­tial.

For pregnant women, mul­tiple pregnan­cies are also as­so­ciated with in­creased cases of va­rious, in­creased risks. The­r­e­fore, me­dical gui­dance and su­per­vi­sion is im­portant to avoid com­pli­ca­tions.

Con­clu­sion

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