Fertility medication

The main techniques involving fertility medication in females are:

• Ovulation induction, with the aim of producing one or two ovulatory follicles for fertilization by sexual intercourse or artificial insemination
• Controlled ovarian hyperstimulation, which is generally part of in vitro fertilization, and the aim is generally to develop multiple follicles (optimally between 12 and 14 antral follicles measuring 2–8 mm in diameter),{{cite web |url= https://academic.oup.com/humrep/article/40/6/1127/8107877 |title= Randomized controlled trial to evaluate the impact of follicle priming on IVM outcomes in women with polycystic ovaries: CFA versus FSH-B |last= De Vos |first= Michel |date= April 7, 2025 |website= Stanford University Magazine |publisher= Human Reproduction, Volume 40, Issue 6, page 1127 |access-date= June 4, 2025 |quote=}} followed by transvaginal oocyte retrieval, co-incubation, followed by embryo transfer of a maximum of two embryos at a time.{{cite web | title = Fertility problems: assessment and treatment | url = http://guidance.nice.org.uk/CG156 | work = NICE clinical guideline CG156 | publisher = U.K. National Institute for Health and Care Excellence (NICE) | date = February 2013 }}
• Final maturation induction of follicles, also triggering a predictable time of ovulation.

{{Main|Gonadotropin-releasing hormone}}

Either gonadotropin-releasing hormone (GnRH) or any gonadotropin-releasing hormone agonist (such as Lupron) may be used in combination with luteinizing hormone (LH) using an infusion pump to simulate endogenous hormone production. GnRH stimulates the release of gonadotropins (LH and FSH) from the anterior pituitary in the body. This set of therapy is reserved for a subset of women with infertility and have produced ovulation rates of 90% and pregnancy rates of 80% or higher.{{medcn|date=August 2020}}

Antiestrogens inhibit the effects of estrogen, which include selective estrogen receptor modulators (SERM) and aromatase inhibitors.

File:Hypothalamic–pituitary–gonadal axis in females.png in females, with estrogen exerting mainly negative feedback on FSH secretion from the pituitary gland.]]

Clomiphene is a selective estrogen receptor modulator (SERM).{{cite journal |vauthors=Stute P, Birkhauser M |s2cid=23400904 |title=Selective estrogen receptor modulators (SERM)/Selektive Ostrogenrezeptormodulatoren (SERM). |journal=Gynakologische Endokrinologie |date=2015 |volume=13 |issue=2 |page=126 |doi=10.1007/s10304-015-0003-9 |url=http://doc.rero.ch/record/332590/files/10304_2015_Article_3.pdf }} It is the most widely used fertility drug.{{cite journal | vauthors = Fauser BC | title = Reproductive endocrinology: revisiting ovulation induction in PCOS | journal = Nature Reviews. Endocrinology | volume = 10 | issue = 12 | pages = 704–5 | date = December 2014 | pmid = 25178733 | doi = 10.1038/nrendo.2014.156 | s2cid = 8380091 }} Other medications in this class include tamoxifen and raloxifene, although both are not as effective as clomiphene and are thus less widely used for fertility purposes.{{cite journal | vauthors = Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L | title = A pharmacological review of selective oestrogen receptor modulators | journal = Human Reproduction Update | volume = 6 | issue = 3 | pages = 212–24 | date = 2000 | pmid = 10874566 | doi = 10.1093/humupd/6.3.212 | doi-access = free }} They are used in ovulation induction by inhibiting the negative feedback of estrogen at the hypothalamus. As the negative feedback of estrogen is inhibited, the hypothalamus secretes GnRh which in turn stimulates the anterior pituitary to secrete LH and FSH which help in ovulation. Between 60 and 85% of women, mostly with polycystic ovary syndrome (PCOS), ovulate successfully in response to clomiphene with a cumulative pregnancy rate of 30 to 40%.{{cite journal | vauthors = Dickey RP, Holtkamp DE | title = Development, pharmacology and clinical experience with clomiphene citrate | journal = Human Reproduction Update | volume = 2 | issue = 6 | pages = 483–506 | date = 1996 | pmid = 9111183 | doi = 10.1093/humupd/2.6.483 | doi-access = free }}{{cite journal | vauthors = Gorlitsky GA, Kase NG, Speroff L | title = Ovulation and pregnancy rates with clomiphene citrate | journal = Obstetrics and Gynecology | volume = 51 | issue = 3 | pages = 265–9 | date = March 1978 | pmid = 628527 | doi = 10.1097/00006250-197803000-00002 }}{{cite journal | vauthors = Gysler M, March CM, Mishell DR, Bailey EJ | title = A decade's experience with an individualized clomiphene treatment regimen including its effect on the postcoital test | journal = Fertility and Sterility | volume = 37 | issue = 2 | pages = 161–7 | date = February 1982 | pmid = 7060766 | doi = 10.1016/s0015-0282(16)46033-4 | doi-access = free }}

{{Main|Aromatase inhibitor}}

Although primarily used in breast cancer treatment, aromatase inhibitors (particularly generic letrozole) are also used in ovulation induction. Aromatase inhibitors are a common fertility treatment to treat women with PCOS. A meta-analysis analyzing live birth rates for women with PCOS treated with clomiphene compared to letrozole found that letrozole resulted in higher live birth rates.{{Cite journal |last1=Franik |first1=Sebastian |last2=Le |first2=Quang-Khoi |last3=Kremer |first3=Jan Am |last4=Kiesel |first4=Ludwig |last5=Farquhar |first5=Cindy |date=2022-09-27 |title=Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome |journal=The Cochrane Database of Systematic Reviews |volume=2022 |issue=9 |pages=CD010287 |doi=10.1002/14651858.CD010287.pub4 |issn=1469-493X |pmc=9514207 |pmid=36165742}} However, ovulation induction remains an off-label indication, which affects use.

{{Main|Gonadotropin preparations}}

Gonadotropins are protein hormones that stimulate the gonads (testes and ovaries). For medication, they can be extracted from urine in postmenopausal women or through genetic modification and bacterial recombination. Examples of recombinant FSH are Follistim and Gonal F, while Luveris is a recombinant LH. FSH and recombinant FSH analogues are mainly used for controlled ovarian hyperstimulation as well as ovulation induction.{{cite journal | vauthors = Conforti A, Esteves SC, Di Rella F, Strina I, De Rosa P, Fiorenza A, Zullo F, De Placido G, Alviggi C | display-authors = 6 | title = The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis | journal = Reproductive Biology and Endocrinology | volume = 17 | issue = 1 | pages = 18 | date = February 2019 | pmid = 30728019 | pmc = 6366097 | doi = 10.1186/s12958-019-0460-4 | doi-access = free }} There has been some controversy over the efficacy between extracted and recombinant FSH for ovulation induction; however, a meta-analysis of 14 trials among 1726 women found that there were no differences in clinical pregnancy or live birth outcomes.{{cite journal | vauthors = Weiss NS, Kostova E, Nahuis M, Mol BW, van der Veen F, van Wely M | title = Gonadotrophins for ovulation induction in women with polycystic ovary syndrome | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD010290 | date = January 2019 | issue = 1 | pmid = 30648738 | pmc = 6353048 | doi = 10.1002/14651858.CD010290.pub3 }}{{Update inline|reason=Updated version https://www.ncbi.nlm.nih.gov/pubmed/40193219|date = June 2025}}

Chemotherapy treatment in premenopausal women can compromise ovarian reserve and function, with gonadotoxic effects ranging from temporary to permanent infertility and premature ovarian failure (POF). Proposed mechanisms for chemotherapy-induced ovarian damage include apoptosis of growing follicles, fibrosis of stromal cells, and injury to blood vessels resulting in ischemia. First-line options for fertility preservation include embryo and oocyte preservation before starting chemotherapy, though these methods do not contribute to the preservation of gonadal function. GnRH agonist therapies have been associated with relatively low risk, time, and cost.{{cite journal | vauthors = Hickman LC, Llarena NC, Valentine LN, Liu X, Falcone T | title = Preservation of gonadal function in women undergoing chemotherapy: a systematic review and meta-analysis of the potential role for gonadotropin-releasing hormone agonists | journal = Journal of Assisted Reproduction and Genetics | volume = 35 | issue = 4 | pages = 571–581 | date = April 2018 | pmid = 29470701 | pmc = 5949114 | doi = 10.1007/s10815-018-1128-2 }} There is evidence that chemotherapy cotreatment with gonadotropin-releasing hormone (GnRH) can increase the probability of spontaneous menses and ovulation resumption. However, this cotreatment has not shown an improvement in pregnancy rates.{{cite journal | vauthors = Bedaiwy MA, Abou-Setta AM, Desai N, Hurd W, Starks D, El-Nashar SA, Al-Inany HG, Falcone T | display-authors = 6 | title = Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis | journal = Fertility and Sterility | volume = 95 | issue = 3 | pages = 906–14.e1–4 | date = March 2011 | pmid = 21145541 | doi = 10.1016/j.fertnstert.2010.11.017 | doi-access = free }}

{{Main|Human chorionic gonadotropin#Use as medication}}

Human chorionic gonadotropin (hCG), also known as the “hormone of pregnancy” is a hormone that is normally produced during pregnancy and plays an integral role throughout reproduction.{{cite journal | vauthors = Leão R, Esteves SC | title = Gonadotropin therapy in assisted reproduction: an evolutionary perspective from biologics to biotech | journal = Clinics | volume = 69 | issue = 4 | pages = 279–93 | date = 2014 | pmid = 24714837 | pmc = 3971356 | doi = 10.6061/clinics/2014(04)10 | type = Review }} It is crucial in maintaining pregnancy, from the stages of placentation to early embryo development. It is also used in assisted reproductive techniques as it can be used to replace LH in final maturation induction.

Although metformin has been used off-label to treat oligomenorrhea and ovarian hyperstimulation syndrome (OHSS) in women with PCOS, metformin is no longer recommended as infertility treatment per the American Society for Reproductive Medicine (ASRM) in 2017. Its use to treat anovulatory infertility was based on an association of insulin resistance in non-obese women with PCOS. While metformin may increase ovulation in women with PCOS, there is no evidence of increased pregnancy rates or live-birth rates, and the combination therapy of metformin and clomiphene citrate did not provide a significant benefit compared to clomiphene citrate alone. First-line therapy for ovulation induction in women with PCOS remains the anti-estrogen clomiphene citrate or the aromatase inhibitor letrozole.{{cite journal | vauthors = Penzias A, Bendikson K, Butts S, Coutifaris C, Falcone T, Fossum G, Gitlin S, Gracia C, Hansen K, La Barbera A, Mersereau J | display-authors = 6 | title = Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline | journal = Fertility and Sterility | volume = 108 | issue = 3 | pages = 426–441 | date = September 2017 | pmid = 28865539 | doi = 10.1016/j.fertnstert.2017.06.026 | doi-access = free }}

Treatment for oligospermia is centered around underlying causes, such as endocrine and systematic disorders that can cause hypogonadism.{{cite journal | vauthors = de Kretser DM | title = Male infertility | journal = Lancet | volume = 349 | issue = 9054 | pages = 787–90 | date = March 1997 | pmid = 9074589 | doi = 10.1016/s0140-6736(96)08341-9 | s2cid = 12928678 | type = Review }}

Typically, other assisted reproductive technologies are used. Although there is no FDA indication for use of aromatase inhibitors improving spermatogenesis, testolactone has been shown to be effective when compared to placebo.{{cite journal | vauthors = Ribeiro MA, Gameiro LF, Scarano WR, Briton-Jones C, Kapoor A, Rosa MB, El Dib R | title = Aromatase inhibitors in the treatment of oligozoospermic or azoospermic men: a systematic review of randomized controlled trials | journal = JBRA Assisted Reproduction | volume = 20 | issue = 2 | pages = 82–8 | date = May 2016 | pmid = 27244767 | doi = 10.5935/1518-0557.20160019 | type = Review | doi-access = free }}

Though there is no FDA indication for the use of clomiphene in male infertility, it has been prescribed since the 1960s. As of 2013, there is not substantial evidence to suggest that clomiphene can treat male infertility.{{cite journal | vauthors = Willets AE, Corbo JM, Brown JN | title = Clomiphene for the treatment of male infertility | journal = Reproductive Sciences | volume = 20 | issue = 7 | pages = 739–44 | date = July 2013 | pmid = 23202725 | doi = 10.1177/1933719112466304 | type = Review | s2cid = 206804686 }}

Combinations of vitamins and minerals, including selenium, co-enzyme Q10, L-carnitine, folic acid, zinc, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), have been shown to improve male infertility, but due to the low amounts of studies and participants, more clinical studies are needed.{{cite journal | vauthors = Buhling K, Schumacher A, Eulenburg CZ, Laakmann E | title = Influence of oral vitamin and mineral supplementation on male infertility: a meta-analysis and systematic review | journal = Reproductive Biomedicine Online | volume = 39 | issue = 2 | pages = 269–279 | date = August 2019 | pmid = 31160241 | doi = 10.1016/j.rbmo.2019.03.099 | doi-access = free }} Folate in combination with zinc supplementation was shown to have a statistically significant effect on sperm concentration and morphology when compared to placebo.{{cite journal | vauthors = Irani M, Amirian M, Sadeghi R, Lez JL, Latifnejad Roudsari R | title = The Effect of Folate and Folate Plus Zinc Supplementation on Endocrine Parameters and Sperm Characteristics in Sub-Fertile Men: A Systematic Review and Meta-Analysis | journal = Urology Journal | volume = 14 | issue = 5 | pages = 4069–4078 | date = August 2017 | pmid = 28853101 }} There is evidence suggesting a significant association between vitamin D serum concentrations and the quality of sperm in men, characterized by the sperm's motility and progress motility.{{cite journal | vauthors = Arab A, Hadi A, Moosavian SP, Askari G, Nasirian M | title = The association between serum vitamin D, fertility and semen quality: A systematic review and meta-analysis | journal = International Journal of Surgery | volume = 71 | pages = 101–109 | date = November 2019 | pmid = 31561004 | doi = 10.1016/j.ijsu.2019.09.025 | s2cid = 203580672 | doi-access = free }} Because the quality of men's sperm is influenced by genetics, results should be interpreted cautiously. There is little evidence that supplementation with antioxidants, such as pentoxifylline will increase male fertility.{{cite journal | vauthors = Smits RM, Mackenzie-Proctor R, Fleischer K, Showell MG | title = Antioxidants in fertility: impact on male and female reproductive outcomes | journal = Fertility and Sterility | volume = 110 | issue = 4 | pages = 578–580 | date = September 2018 | pmid = 30196940 | doi = 10.1016/j.fertnstert.2018.05.028 | doi-access = free }}{{cite journal | vauthors = Chehab M, Madala A, Trussell JC | title = On-label and off-label drugs used in the treatment of male infertility | journal = Fertility and Sterility | volume = 103 | issue = 3 | pages = 595–604 | date = March 2015 | pmid = 25660648 | doi = 10.1016/j.fertnstert.2014.12.122 | type = Review | doi-access = free }}

As of September 2017, mesenchymal stem cell therapy for infertility has been studied in animals, but has not entered clinical trials.{{cite journal | vauthors = Fazeli Z, Abedindo A, Omrani MD, Ghaderian SM | s2cid = 44236281 | title = Mesenchymal Stem Cells (MSCs) Therapy for Recovery of Fertility: a Systematic Review | journal = Stem Cell Reviews and Reports | volume = 14 | issue = 1 | pages = 1–12 | date = February 2018 | pmid = 28884412 | doi = 10.1007/s12015-017-9765-x }} Stem cells collected from bone marrow and umbilical cord have shown the most ability to rehabilitate fertility in animals, but more studies are needed to determine efficacy.

Since infertility increases the risk of ovarian cancer, fertility drugs have been used to combat this but the cancer risks are still not completely known.{{cite journal | vauthors = Rizzuto I, Behrens RF, Smith LA | title = Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | pages = CD008215 | date = June 2019 | issue = 6 | pmid = 31207666 | pmc = 6579663 | doi = 10.1002/14651858.cd008215.pub3 }} {{As of|2019|post=,}} there have been studies that have shown the risk of developing ovarian cancer is higher when taking fertility medications. However, due to the low number of studies, lack of follow-up time and other contribution factors, the risk is unclear. Most studies conducted have shown that fertility drugs do not increase the risk of other gynecologic cancers (cervical and endometrial) or other malignant cancers (thyroid, colon, melanoma, breast).{{cite journal | vauthors = Kroener L, Dumesic D, Al-Safi Z | title = Use of fertility medications and cancer risk: a review and update | journal = Current Opinion in Obstetrics & Gynecology | volume = 29 | issue = 4 | pages = 195–201 | date = August 2017 | pmid = 28538003 | pmc = 5551049 | doi = 10.1097/GCO.0000000000000370 }} The validity of these data may be affected by patient-reported biases, small subject numbers, and other confounding variables.

Children born to mothers who use fertility medication to induce ovulation are more than twice as likely to develop leukemia during their childhoods than other children.{{cite journal | vauthors = Rudant J, Amigou A, Orsi L, Althaus T, Leverger G, Baruchel A, Bertrand Y, Nelken B, Plat G, Michel G, Sirvent N, Chastagner P, Ducassou S, Rialland X, Hémon D, Clavel J | display-authors = 6 | title = Fertility treatments, congenital malformations, fetal loss, and childhood acute leukemia: the ESCALE study (SFCE) | journal = Pediatric Blood & Cancer | volume = 60 | issue = 2 | pages = 301–308 | date = February 2013 | pmid = 22610722 | doi = 10.1002/pbc.24192 | s2cid = 26010916 }}

Estrogen antagonists and gonadotropins may stimulate multiple follicles and other ovarian hormones leading to multiple birth and possible ovarian hyperstimulation syndrome (OHSS).{{cite journal |vauthors=Banker M, Garcia-Velasco JA |title=Revisiting ovarian hyper stimulation syndrome: Towards OHSS free clinic |journal=J Hum Reprod Sci |volume=8 |issue=1 |pages=13–7 |date=2015 |pmid=25838743 |pmc=4381376 |doi=10.4103/0974-1208.153120 |doi-access=free }} Development of OHSS is dependent on the administration of hCG and is mediated through vascular endothelial growth factor (VEGF). OHSS is characterized as enlargement of the ovaries.{{cite web |url= https://www.rcpi.ie/Portals/0/Document%20Repository/Institute%20of%20Obstetricians%20and%20Gynaecologists/National%20Clinical%20Guidelines/IOG_National%20Clinical%20Guidelines_Ovarian%20Hyperstimulation%20Syndrome_2012.pdf#:~:text=The%20occurrence%20of%20OHSS%20is%20dependent%20on%20the,duration%2C%20particularly%20in%20treatment%20cycles%20where%20conception%20occurs. |title= Clinical Practice Guideline: Ovarian Hyperstimulation Syndrome (OHSS) Diagnosis and Management |last= |first= |date= April 7, 2012 |website= Institute of Obstetricians and Gynaecologists, Royal College of Physicians of Ireland |publisher= |access-date= June 4, 2025 |quote=}}

Multiple birth is especially deleterious due to compounding risks including premature delivery and low birthweight, pre-eclampisa, and increased risk of neonatal mortality.{{cite web |url= https://www.reproductivefacts.org/news-and-publications/fact-sheets-and-infographics/medications-for-inducing-ovulation/ |title= Medications for Inducing Ovulation: A Guide for Parents |author= |date= 2016 |website= American Society for Reproductive Science |publisher= |access-date= May 27, 2025 |quote=}} While triplet births have been declining in ART, in 2022 multiple births remained over 45% of births from IVF in the USA.{{cite web |url= https://fertilityinstitute.com/understanding-the-risks-of-ivf-twins-and-multiples/ |title= Understanding The Risks Of IVF Twins And Multiples |author= |date= March 22, 2020 |website= The Fertility Institute Los Angeles |publisher= |access-date= May 27, 2025 |quote=}} However, there are limitations to measure, as 4% to 8% IVF clinics to do not report their data to the CDC.

In 2020, UK statistics showed that 11% of IVF pregnancies led to multiple births, compared to 1-2% of natural pregnancies.{{cite web |url= https://twinstrust.org/static/89af4d2a-49fe-4d23-bbcf8475f099762f/Key-stats-and-facts.pdf |title= Key statistics on multiple births |author= |date= |website= Twin Trust UK |publisher= |access-date= May 27, 2025 |quote=}} Australian figures in 2024 noted that multiple births after ART had halved in the last ten years, with only 2.7% births leading to twins or triplets.{{cite web |url= https://news.unsw.edu.au/en/rates-of-ivf-twins-and-triplets-hit-record-low-new-report |title= Rates of IVF twins and triplets hit record low: new report |author= |date= 13 September 2024 |website= University of New South Wales |publisher= |access-date= May 27, 2025 |quote=}}

Main reasons for discontinuation across all types of fertility treatment and treatment stage, are "postponement of treatment, physical and psychological burden and relational and personal problems".{{cite journal | vauthors = Gameiro S, Boivin J, Peronace L, Verhaak CM | title = Why do patients discontinue fertility treatment? A systematic review of reasons and predictors of discontinuation in fertility treatment | journal = Human Reproduction Update | volume = 18 | issue = 6 | pages = 652–69 | date = August 2012 | pmid = 22869759 | pmc = 3461967 | doi = 10.1093/humupd/dms031 }}

• Assisted reproductive technology
• Diethylstilbestrol

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{{Major Drug Groups}}

{{Pregnancy}}

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