Fertility medication


Fertility medication, better known as fertility drugs, are drugs which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are currently very few fertility medication options available for men.
Agents that enhance ovarian activity can be classified as either gonadotropin releasing hormone, estrogen antagonists or gonadotropins. Patients should be involved in treatment decision making which involve four major factors: efficacy, burden of treatment, safety, and financial costs.

Female

Main techniques

The main techniques involving fertility medication in females are:
The treatment of ovulatory dysfunction is based on the underlying cause of anovulation, which is categorized into three different groups per WHO guidelines. Most fertility treatment approaches target class 2 patients.
WHO Class Type of anovulation
Class 1: Hypogonadotropic hypogonadal anovulation Low serum follicle stimulating hormone concentrations and low serum estradiol concentrations from decreased hypothalamic secretion of gonadotropic-releasing hormone or lack of pituitary response.
Class 2: Normogonadotropic normoestrogenic anovulation FSH secretion during the follicular phase of the ovulation cycle is abnormal. This is commonly seen in women with polycystic ovary syndrome.
Class 3: Hypergonadotropic hypoestrogenic anovulation Premature ovarian failure due to early menopause and/or ovarian resistance.

Gonadotropin-releasing hormone

Either gonadotropin-releasing hormone or any gonadotropin-releasing hormone agonist may be used in combination with luteinizing hormone using an infusion pump to simulate endogenous hormone production. GnRH stimulates the release of gonadotropins from the anterior pituitary in the body. This set of therapy is reserved for class 1 patients and have produced ovulation rates of 90% and pregnancy rates of 80% or higher.

Antiestrogens

s inhibit the effects of estrogen, which include selective estrogen receptor modulators and aromatase inhibitors.
in females, with estrogen exerting mainly negative feedback on FSH secretion from the pituitary gland.

Selective estrogen receptor modulators (SERM)

is a selective estrogen receptor modulator. It is the most widely used fertility drug. 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. 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. 60 to 85% of women, mostly with PCOS, ovulate successfully in response to clomiphene with a cumulative pregnancy rate of 30 to 40%.

Aromatase inhibitors

Although primarily a breast cancer treatment, aromatase inhibitors are also used in ovulation induction. Aromatase inhibitors will decrease the amount of testosterone and androstenedione converted to estradiol and estrone, respectively. Less estradiol circulating in the body will decrease the negative feedback at the pituitary and result in sustained FSH secretion. More FSH will be available to stimulate the ovary and mature multiple follicles for ovulation. This is a common fertility treatment to treat women with PCOS. Letrozole has been seen to exhibit fewer adverse effects than clomiphene and 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. However, ovulation induction remains an off-label indication which affects patient use.

Gonadotropins

are protein hormones that stimulate the gonads. 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. 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. There is evidence that chemotherapy cotreatment with gonadotropin-releasing hormone 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, 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 through to early embryo development. hCG is also used in assisted reproductive techniques as it can be used to replace LH in final maturation induction.

Male

Treatment for oligospermia is centered around underlying causes, such as endocrine and systematic disorders that can cause hypogonadism. Though there is no FDA indication for the use of Clomiphene in male infertility, it has been prescribed since the 1960s and has been shown to have consistent results in increasing sperm concentrations. However despite this potential benefit, there is still not enough substantial evidence to suggest that Clomiphene can treat male infertility. Typically, other assisted reproductive technologies are used. Although there is also no FDA indication for use of aromatase inhibitors improving spermatogenesis, testolactone has been shown to be effective when compared to placebo. Varying combination of certain vitamins and minerals, including: selenium, co-enzyme Q10, L-carnitine, folic acid, zinc, eicosapentaenoic acid, and docosahexaenoic acid, have also been shown to improve male infertility, but due to the low amounts of studies and participants, more clinical studies are needed.

Adverse effects

Cancer

The use of fertility drugs is highly correlated with other ovarian cancer risk factors which complicates the direct contribution of the fertility drugs to ovarian cancer. Numerous studies indicate the risk of developing ovarian cancer as a result of fertility drugs is insignificant, but long-term exposure to fertility drugs may require further studies to determine their role in ovarian tumors and other health risks. In a review of fertility medications and cancer risk, they found that most studies conducted thus far have shown that fertility drugs also do not increase the risk of other gynecologic cancers or other malignant cancers. However, the validity of these data may be affected by patient-reported biases, small subject numbers, and other confounding variables.

Ovarian hyperstimulation syndrome (OHSS)

Estrogen antagonists and gonadotropins may stimulate multiple follicles and other ovarian hormones leading to multiple birth and possible ovarian hyperstimulation syndrome. Development of OHSS is dependent on the administration of hCG and is mediated through vascular endothelial growth factor. OHSS is characterized as cystic 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, multiple births remain over 50% of births from IVF. However, there are limitations to measure, as 4% to 8% IVF clinics to do not report their data to the CDC.

Fertility treatment discontinuation

In a systematic review across 22 studies, they found that the 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". Though these reasons are valid, albeit vague, much more research will need to be conducted to accurately detail the causal relationship behind discontinuation and treatment.