Mild Ovarian Stimulation with Clomiphene Citrate

Overview

Ovarian stimulation holds an important place in the field of assisted reproductive technologies (ART).¹   In the recent decades, there have been noteworthy changes in the practice of ovarian stimulation, with a global trend being witnessed towards adoption of milder stimulation regimes for both IVF and IUI. While there is lack of consensus on the definition of mild ovarian stimulation (MOS), the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) consensus group suggests that “mild IVF” protocols are the ones in which the number of oocytes collected range from 2 to 7. This differs from “conventional IVF” wherein the aim is to retrieve 8 or more oocytes. Like this, MOS-IVF requires smaller doses of hormones for stimulation than a conventional protocol, making it far less aggressive.^2,3

Why Consider Mild Stimulation?

There are several advantages of MOS over standard IVF which provide a foundation for its consideration in assisted conception programs. Patient preference, decreased cost per fresh IVF cycle, low possibility of ovarian hyperstimulation syndrome (OHSS), and better pregnancy outcomes constitute the some of the main advantages.

• Patient preference is based on both comfort and cost of the protocol. When selecting an ovarian stimulation protocol, patient preference is given high importance. MOS may be a fairly good choice in certain patients who may fear the adverse effects associated with conventional controlled ovarian stimulation for IVF. As previously mentioned, MOS demands only small amounts of gonadotropins, unlike the standard protocol, and is therefore not as aggressive. This reduces not only patient,s discomfort, but also drives down the cost of the procedure, making MOS more patient-friendly.^3,4  
• The use of “mild IVF”, in addition greatly minimizes the risk of OHSS, which is a life endangering, high-cost complication of controlled ovarian hyperstimulation. Certain women, such as those with polycystic ovaries (PCO), are particularly predisposed to developing this complication. Some research papers have shown the risk of developing severe OHSS after a conventional ovarian stimulation to be about 6-9% for young women with PCO.⁴   To compare the safety of MOS with standard down-regulation protocol, a prospective, randomized study⁵   was conducted on 349 infertile patients at high risk of developing OHSS. The results revealed that lesser number of women in the MOS group (4.7%) had OHSS compared to standard protocol group (8.4%) (figure 1). The investigators concluded MOS to be a safer option in women contemplating IVF.

• In addition to the aforementioned advantages, MOS also results in reasonably good pregnancy outcomes. Although the number of oocytes collected by this approach is less, the quality of both oocyte and embryo is better than that achieved with the conventional protocol. Taking this notion a step further, Devroey et al reported that when MOS is used, the endometrial receptivity becomes better.⁶   In light of this, clinical outcomes yielded by MOS appear to be better than those achieved with the standard protocol. This was evidenced in a prospective, open, randomized study⁵   which demonstrated remarkably higher implantation rate (21.5 vs 14.5 %), pregnancy rate (37.7 vs 23.4 %), and delivery rate (32.8 vs 20.1 %) in MOS group than standard protocol group (figure 2).

Based on these data it is worthwhile to consider mild stimulation during ART programs.

Clomiphene citrate

Clomiphene citrate is a selective estrogen receptor modulator that stimulates endogenous FSH production and secretion by interrupting estrogen feedback to the hypothalamus and pituitary.⁷   A major therapeutic breakthrough in the management of anovulatory infertility probably in the early 1960s, is the introduction of clomiphene citrate.⁸   Clomiphene interestingly became very popular in a short period of time due to its effortless administration and minimal side effects.⁹   It is considered as the first line treatment for a majority of women with absent or irregular ovulation.¹⁰

Mechanism of action of clomiphene citrate

The mechanism of action of clomiphene includes the capability of interacting with estrogen-receptor Figure containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina and cervix. It also contends with estrogen for estrogen-receptor-binding sites delays replenishment of intracellular estrogen receptors. Clomiphene is known to initiate a series of endocrine events culminating in a pre-ovulatory gonadotropin surge and subsequent follicular rupture. The primary endocrine event includes an increase in the release of pituitary gonadotropin, which initiates steroidogenesis and folliculogenesis resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol.¹¹

Treatment with clomiphene citrate is known to increase GnRH frequency in ovulatory women. However, in anovulatory women with PCOS in whom the GnRH pulse frequency is already abnormally high, treatment with clomiphene citrate increases pulse amplitude but not frequency. In successful treatment cycles, the emergence and maturation occurs of one or more dominant follicles. Usually, the LH surge takes place 5-12 days after the last dose of clomiphene citrate.¹²

Pharmacology

Clomiphene citrate is a nonsteroidal triphenylethylene derivative which acts as a selective estrogen receptor modulator (SERM). It is racemic mixture of two different stereoisomers, enclomiphene (62%; originally known as cis-clomiphene) and zuclomiphene (38%; originally known as trans-clomiphene). Clomiphene exhibits both estrogenic agonist and antagonist properties. Moreover, it is the more potent isomer and the one responsible for ovulation-inducing actions. The two clomiphene isomers have been found to have mixed estrogenic and antiestrogenic effects, which may vary from one species to another. However, existing data suggest that both the estrogenic and antiestrogenic properties of clomiphene may participate in the initiation of ovulation.⁹

Mild Stimulation Protocols: Focus on the Benefits of Clomiphene Citrate

Mild stimulation protocols are based on the use of both oral and parenteral drugs since the pituitary is not downregulated. Three classes of drugs are commonly employed for MOS: Gonadotrophins (recombinant FSH, urinary FSH, urinary HMG), anti-estrogens (clomophene citrate), and aromatase inhibitors (letrozole). Letrozole was often used with gonadotrophins extensively in poor responders and patients requiring fertility preservation as it keeps the E2 levels low. However, presently letrozole is an off label drug and its use as an ovulation induction agent is banned due to concerns about teratogenecity.¹³   The fact that fewer oocytes are required in ARTs, opens the possibility of using unconventional stimulation regimes, such as clomiphene citrate.¹⁴  Clomiphene citrate is a simple and inexpensive, and has been used for over four decades for induction of ovulation in infertile women and for the treatment of ovulating infertile women.¹⁵   Its use in MOS has been shown to efficiently inhibit luteinizing hormone (LH) surge alone and with fairly good pregnancy outcomes in women undergoing IVF. Despite this, regular stimulation regimens do not consider inclusion of clomiphene due to the widely held view that it may adversely affect the endometrium. Some investigators have however, challenged this view demonstrating clomiphene to effectively suppress LH surge and limit the dose of gonadotropins thus driving down the costs and its negative impact on the endometrium and oocyte quality.¹⁶   Several reports in the literature endorse the benefits of clomiphene for mild stimulation. A large-scale case series¹⁷   demonstrated that with the use of clomiphenebased MOS protocols, a mature oocyte was retrieved in 68% of cycles for women aged 40-44 compared with 71% of women aged 30-34 years.

Mild stimulation protocol can involve clomiphene in combination with human menopausal gonadotropin (HMG), which yields better outcomes compared to HMG alone (46% vs. 25.9%) (figure 3).¹⁸   These findings were in congruity with another report¹⁹   which showed ovulation and pregnancy rate to be 82% and 21% respectively in women who underwent MOS using clomiphene in conjunction with hMG. Moreover, the average cost was much lower (one-third) than the hMG-only protocol.

The combination of clomiphene citrate with lower dose of hMG plus GnRH antagonist is more cost effective than the conventional ovarian stimulation in women with poor ovarian response, undergoing Intracytoplasmic Sperm Injection (ICSI). This was demonstrated in a randomized controlled study²⁰   which enrolled 70 women with a history of previous poor ovarian response undergoing controlled ovarian hyperstimulation (COH) for ICSI. The control group was randomized to receive a conventional mid-luteal long GnRH agonist treatment with HP HMG starting on day 2 of the cycle at a dose of 300 IU /day. Besides, in the study group, pre-treatment with luteal E2 supplementation was administrated followed by clomiphene citrate for 5 days, and 225 IU HP HMG and GnRH antagonist from cycle day 6 onward. The cost of ovarian stimulation per cycle worked out to be lesser with clomiphene citrate ovarian stimulation group in comparison to the conventional group. Similar results were demonstrated in another study²¹   which also showed that ovarian stimulation with clomiphene citrate is less expensive than the usual high dose of gonadotropins, in women with compromised ovarian reserve selected for in vitro fertilization.

However in a recent prospective cohort study²²  , a fixed dose protocol of clomiphene citrate at a dose of 100 mg/d from cycle days 3 to 7 in combination with low doses of gonadotropins and GnRH antagonist is found to reduce patient discomfort, risk, and treatment cost in mild stimulation protocol. The cumulative delivery rate with 100 mg dose of clomiphene citrate was reported to be 70%. Thus, this can be considered as a realistic option for good-prognosis of the patients undergoing IVF.

The efficacy of clomiphene for mild stimulation can be increased when its micronized form is used. Many drugs which are poorly water soluble show limited oral bioavailability. With micronization, both dissolution rate bioavailability can be enhanced. Moreover, improved digestive absorption and consequently better clinical efficacy have been reported with the use of micronized drugs. Based on these data, it appears logical to use the micronized form of clomiphene for ovarian stimulation. The benefits of micronizaton are summarized in box 1.^23,24

Future of MOS with clomiphene citrate

Several recent reports have described clomiphene citrate in combination with GnRH antagonist as a viable alternative to exogenous FSH in good-prognosis patients. Alterations in the revived clomiphene citrate protocols have given pregnancy rates per started cycle of 21-29%. In case of substantial reduction in treatment cost allowing its use in low-resource settings, oral compounds like clomiphene citrate alone is preferred with no luteal phase support.²⁵

Conclusion

Recently, a global trend has been witnessed towards adoption of MOS regimes for both IVF and IUI. MOSIVF requires smaller doses of hormones for stimulation than a conventional protocol, making it far less aggressive. Moreover, it has many other advantages including increased patient preference, decreased cost per fresh IVF cycle, low possibility of ovarian hyperstimulation syndrome (OHSS), and better pregnancy outcomes. Both oral and injectable agents can be used for stimulation since the pituitary is not down-regulated. Oral medications such as clomiphene citrate, either alone or in combination with gonadotropins have proved beneficial in women undergoing IVF.

References

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