Fertility medications, also known as fertility drugs, are medications which enhance reproductive

fertility Fertility in colloquial terms refers the ability to have offspring. In demographic contexts, fertility refers to the actual production of offspring, rather than the physical capability to reproduce, which is termed fecundity. The fertility rate ...

. For women, fertility medication is used to stimulate follicle development of the

ovary The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/ oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are end ...

. There are very few fertility medication options available for men. Agents that enhance ovarian activity can be classified as either gonadotropin releasing hormone,

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.gonadotropins. Treatment decision-making involves four major factors: efficacy, burden of treatment (such as frequency of injections and office visits), safety, and financial costs.

Female

Main techniques

The main techniques involving fertility medication in females are: * Ovulation induction, with the aim of producing one or two ovulatory follicles for

fertilization Fertilisation or fertilization (see American and British English spelling differences#-ise, -ize (-isation, -ization), spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give ...

sexual intercourse Sexual intercourse (also coitus or copulation) is a sexual activity typically involving the insertion of the Erection, erect male Human penis, penis inside the female vagina and followed by Pelvic thrust, thrusting motions for sexual pleasure ...

artificial insemination Artificial insemination is the deliberate introduction of sperm into a female's cervix or uterine cavity for the purpose of achieving a pregnancy through in vivo fertilization by means other than sexual intercourse. It is a fertility treatment ...

* Controlled ovarian hyperstimulation, which is generally part of

in vitro fertilization In vitro fertilisation (IVF) is a process of fertilisation in which an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating the ovulatory process, then removing an ovum or ova (egg or eggs) from ...

, and the aim is generally to develop multiple follicles (optimally between 12 and 14 antral follicles measuring 2–8 mm in diameter), followed by transvaginal oocyte retrieval, co-incubation, followed by

embryo transfer Embryo transfer refers to a step in the process of assisted reproduction in which embryos are placed into the uterus of a female with the intent to establish a pregnancy. This technique - which is often used in connection with in vitro fertili ...

of a maximum of two embryos at a time. * Final maturation induction of follicles, also triggering a predictable time of ovulation.

Gonadotropin-releasing hormone

Either

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and rele ...

(GnRH) or any gonadotropin-releasing hormone agonist (such as Lupron) may be used in combination with

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...

(LH) using an infusion pump to simulate endogenous hormone production.

GnRH Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...

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.

Antiestrogens

Antiestrogens inhibit the effects of

, which include selective estrogen receptor modulators ( SERM) and aromatase inhibitors.

Selective estrogen receptor modulators

Clomiphene Clomifene, also known as clomiphene, is a medication used to treat infertility in women who anovulation, do not ovulate, including those with polycystic ovary syndrome. It is taken by mouth. Common side effects include pelvic pain and hot f ...

is a

selective estrogen receptor modulator Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists (e.g., full agonists and silent ...

(SERM). It is the most widely used fertility drug. Other medications in this class include

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...

and raloxifene, although both are not as effective as clomiphene and are thus less widely used for fertility purposes. 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 Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...

(PCOS), ovulate successfully in response to clomiphene with a cumulative pregnancy rate of 30 to 40%.

Aromatase inhibitors

Although primarily used in breast cancer treatment, aromatase inhibitors (particularly generic

letrozole Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer for post-menopausal women. It was patented in 1986 and approved for medical use in 1996. In 2021, ...

) are also used in ovulation induction. Aromatase inhibitors are a common fertility treatment to treat women with PCOS. A

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

analyzing live birth rates for women with PCOS treated with clomiphene compared to letrozole found that letrozole resulted in higher live birth rates. However, ovulation induction remains an

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...

indication, which affects use.

Gonadotropins

Gonadotropins are protein hormones that stimulate the

gonads A gonad, sex gland, or reproductive gland is a mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, ...

(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. 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. 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 Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

of growing follicles,

fibrosis Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...

of stromal cells, and injury to

blood vessels Blood vessels are the tubular structures of a circulatory system that transport blood throughout many animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the tissues of a body. They also take waste an ...

resulting in

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...

. 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. 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.

Human chorionic gonadotropin

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. 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.

Other medications

Although

metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, ...

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.

Male

Treatment for oligospermia is centered around underlying causes, such as endocrine and systematic disorders that can cause hypogonadism. 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. Though there is no FDA indication for the use of

clomiphene Clomifene, also known as clomiphene, is a medication used to treat infertility in women who anovulation, do not ovulate, including those with polycystic ovary syndrome. It is taken by mouth. Common side effects include pelvic pain and hot f ...

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. 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. Folate in combination with zinc supplementation was shown to have a statistically significant effect on sperm concentration and morphology when compared to placebo. 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. 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. As of September 2017,

mesenchymal stem cell Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are multipotent stromal cells that can Cellular differentiation, differentiate into a variety of cell types, including osteoblasts (bone cells), ...

therapy for infertility has been studied in animals, but has not entered clinical trials. 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.

Adverse effects

Cancer

Since infertility increases the risk of

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...

, fertility drugs have been used to combat this but the cancer risks are still not completely known. 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 The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...

) or other malignant cancers (

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...

, colon,

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

). The validity of these data may be affected by patient-reported biases, small subject numbers, and other

confounding In causal inference, a confounder is a variable that influences both the dependent variable and independent variable, causing a spurious association. Confounding is a causal concept, and as such, cannot be described in terms of correlatio ...

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.

Ovarian hyperstimulation syndrome

Estrogen antagonists and gonadotropins may stimulate multiple follicles and other ovarian hormones leading to

multiple birth A multiple birth is the culmination of a multiple pregnancy, wherein the mother gives birth to two or more babies. A term most applicable to vertebrate species, multiple births occur in most kinds of mammals, with varying frequencies. Such births ...

and possible

ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS) is a medical condition that can occur in some women who take fertility medication to stimulate egg growth, and in other women in sporadic cases. Most cases are mild, but rarely the condition is severe and c ...

(OHSS). Development of OHSS is dependent on the administration of hCG and is mediated through

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

(VEGF). OHSS is characterized as enlargement of the ovaries. Multiple birth is especially deleterious due to compounding risks including premature delivery and low birthweight, pre-eclampisa, and increased risk of neonatal mortality. While triplet births have been declining in ART, in 2022 multiple births remained over 45% of births from IVF in the USA. However, there are limitations to measure, as 4% to 8% IVF clinics to do not report their data to the

CDC The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services (HHS), and is headquartered in Atlanta, ...

. In 2020, UK statistics showed that 11% of IVF pregnancies led to multiple births, compared to 1-2% of natural pregnancies. 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.

Discontinuation

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".

References

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