April 24, 2023
Ovarian Stimulation in the Treatment of Infertility: A Review
By Ioana Pencea
Director’s Note: During National Infertility Awareness Week, we are featuring an article comparing various options available for ovulation induction, including clomiphene citrate, aromatase inhibitors, metformin, and gonadotropins. Ioana Pencea, a former FACTS elective participant, summarized information published in the Textbook of Assisted Reproductive Techniques. Given the prevalence of infertility caused by anovulation, these medications may benefit couples struggling to conceive, particularly when combined with charting with fertility awareness-based methods (FABMs) as a cost-effective way to gain insight into a woman’s menstrual cycle and health.
Introduction
Infertility is common, affecting an estimated 15% of couples. Anovulation is a frequent cause of infertility. Signs include irregular periods, a period that is lighter or heavier than usual, the lack of a period, and difficulty achieving pregnancy. For women who track their cycles by charting with fertility awareness-based methods (FABMs), changes in cycle length or the lack of a mucus peak day may indicate anovulation. Causes of anovulation include hormonal birth control, being underweight or overweight, excessive exercise, excessive stress, and most commonly, polycystic ovary syndrome (PCOS).
“Anovulation is a frequent cause of infertility.”
Women experiencing infertility due to anovulation may undergo ovarian stimulation treatment. Yet, attempts should be made to first identify and treat underlying causes of anovulation, including hormonal imbalances as seen with PCOS. Through cycle tracking with various FABMs, women and couples can work with FABM trained clinicians to identify and treat such underlying causes and, if necessary, use medications for ovulation induction to increase the likelihood of a successful pregnancy.
Medications that act on various parts of the hypothalamic-pituitary-ovarian (HPO) axis can be used to induce ovulation. Gonadotropin releasing hormone (GnRH) secreted from the hypothalamus acts on the anterior pituitary to stimulate secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH). These hormones then act on the ovaries to induce follicle growth and ovulation, and to trigger secretion of estradiol and progesterone. In turn, estradiol and progesterone can have a negative feedback effect, reducing production of FSH and LH.
“Medications that act on various parts of the hypothalamic-pituitary-ovarian (HPO) axis can be used to induce ovulation.”
Options for Ovulation Induction
Clomiphene citrate
Clomiphene citrate is used as a first-line treatment for anovulation. Clomiphene citrate is given for 5 days, beginning on day 5 of the menstrual cycle. As a selective estrogen receptor modulator, it reduces the negative feedback effect from estrogen. This results in an increase in LH and FSH release and subsequent follicular maturation and rupture. Side effects can include hot flashes, abdominal distension, bloating, breast discomfort, nausea and vomiting, visual impairment, and headache. Treatment also comes with a slight increase in the risk of ovarian cancer.
Aromatase inhibitors
For women who don’t respond to clomiphene citrate, aromatase inhibitors have been shown to be equally effective at inducing ovulation, particularly in women with PCOS. Aromatase inhibitors can be given from day 3 to day 7 of the menstrual cycle. Third-generation aromatase inhibitors, including letrozole, anastrozole, and vorozole, are most commonly used. Aromatase is needed to synthesize estrogen; thus, inhibition of aromatase results in lower serum estradiol. This increases LH and FSH and has a similar effect as clomiphene citrate. Side effects include bone pain, hot flashes, back pain, nausea, and dyspnea.
Metformin
In women with PCOS, metformin has also been shown to increase ovulation. Metformin is an oral antihyperglycemic agent and works by increasing insulin sensitivity. While it is not completely clear how metformin improves ovulation, insulin is known to play a role in healthy ovulation and implantation. Increasing sensitivity to insulin likely increases the likelihood of a healthy ovulation event. Metformin has been shown to be especially helpful for women with PCOS when combined with clomiphene citrate. While pregnancy rates in women taking metformin have been shown to be comparable to women taking only clomiphene citrate, women taking metformin have a lower rate of miscarriages and subsequently, a higher live birth rate. Side effects of metformin can include diarrhea, nausea and vomiting, asthenia, indigestion, abdominal discomfort, and headache.
“While it is not completely clear how metformin improves ovulation, insulin is known to play a role in healthy ovulation and implantation.
Gonadotropins
A more direct method of ovarian stimulation involves the use of synthesized gonadotropins. Human menopausal gonadotropin (hMG) can be purified to act as FSH. Recombinant human FSH (r-hFSH) can also be given to stimulate growth of follicles. Human chorionic gonadotropin (hCG) can be used as a surrogate for an LH surge, triggering ovulation. When preovulatory follicles are present, this results in granulosa cell luteinization as well as follicle rupture 36-40 hours later. Side effects of these injections can include pain and allergic reactions at the injection site. While these methods can be effective, there is an increased chance of high-risk multiple pregnancies.
GnRH agonists
Finally, gonadotropin-releasing hormone agonists can trigger ovulation. Leuprolide, which is given continuously to suppress hormones for conditions such as endometriosis, can be given in two doses, 12 hours apart. This medication works like GnRH, increasing gonadotropin release and causing ovulation. This option is commonly used for egg retrieval during in vitro fertilization (IVF). This treatment results in low estrogen and can cause symptoms associated with low estrogen, including hot flashes, decreased libido, impotence, vaginal dryness, and emotional instability.
Given the prevalence of infertility caused by anovulation, these medications may be useful options for couples struggling to conceive. However, it is important to diagnose and treat underlying causes of anovulation before pursuing such treatment. Additionally, human chorionic gonadotropin (hCG) may be used as an injection to trigger ovulation either alone or in combination with the other medications, but this option was not specifically addressed in this textbook chapter.
References
[1] Shoham, Z. “Drugs Used for Ovarian Stimulation: Clomiphene Citrate, Aromatase Inhibitors, Metformin, Gonadotropins, Gonadotropin-Releasing Hormone Analogs, and Recombinant Gonadotropins.” Textbook of Assisted Reproductive Techniques, Volume Two: Clinical Perspectives (2012).
[2] https://www.osmosis.org/answers/anovulatory-cycle/
[3] https://www.singlecare.com/blog/news/infertility-statistics/
About the Author
Ioana Pencea
Ioana Pencea is a fourth-year medical student at the Philadelphia College of Osteopathic Medicine, Georgia Campus. She earned a Master’s degree in Public Health from Emory University. Ioana recently participated in the FACTS elective and became interested in learning about FABMs to be able to effectively counsel future patients interested in these methods.
