Hormone Therapy For Fertility

Introduction

Infertility is defined as the inability to conceive a child with your partner after one year or more of trying. This condition affects not only individuals assigned female at birth (AFAB) but also those assigned male at birth (AMAB). It is a common condition, affecting 186 million people worldwide, or 1 in every 7 couples in developed countries.

In many cases, infertility is attributed to hormonal imbalances, abnormal levels of one or more hormones in the bloodstream. These imbalances can result from several factors, including hormones being secreted at the wrong time, improper hormonal interactions, or the body's inability to respond appropriately to their effects. If hormonal imbalances occur, conception and pregnancy can be difficult.

While these imbalances can affect both AMABs and AFABs, they are a leading cause of infertility in AFAB individuals. Therefore, hormonal treatment is most often used to treat infertility in this group. Hormone treatments primarily work by stimulating egg maturation and ovulation, and by helping the AFAB body prepare for pregnancy.¹

Hormones and fertility

Many hormones are involved in reproduction and fertility. Some of these hormones are produced by the gonads, which are the ovaries in AFABs and the testes in AMABs. These hormones include oestrogen, progesterone, anti-Müllerian hormone (AMH), and testosterone. Additionally, there are secondary hormones important for reproduction that are produced by the pituitary glands, such as luteinising hormone (LH), follicle-stimulating hormone (FSH), prolactin, and human chorionic gonadotropin (hCG). Any imbalance in one or more of these hormones can lead to infertility. 

Oestrogen

Oestrogen is one of the two primary sex hormones found in AFABs. It is responsible for secondary sex characteristics (such as breasts and hips), menstruation, pregnancy, and menopause. AFABs with low oestrogen levels tend to have less frequent menstrual periods, which can affect their ability to get pregnant. Although AFABs have the highest levels of oestrogen, AMABs also produce it in smaller amounts. High oestrogen levels in AMABs can lead to infertility and erectile dysfunction.

Progesterone

Progesterone is also produced by AFABs and, along with oestrogen, plays a key role in the reproductive system. In AFABs, progesterone is produced by the corpus luteum, a temporary endocrine gland that forms after ovulation, or by the placenta if pregnancy occurs. The main function of progesterone is to prepare the lining of your uterus for a potential pregnancy. If pregnancy does not occur, the uterine lining sheds during menstruation, allowing your body to start a new ovulation cycle. However, if conception occurs, progesterone levels increase to support the pregnancy.

Low progesterone levels in AFABs can affect fertility by causing abnormal menstrual cycles and by not providing the right environment for a fertilised egg to develop. Additionally, AFABs with low progesterone have an increased risk of miscarriage, as this hormone is essential for maintaining a pregnancy.

Anti-müllerian hormone (AMH)

AMH is essential in fetal development during pregnancy. This hormone assists in the reproductive development of a male fetus by preventing the formation of female reproductive organs. AMH is produced by AMABs throughout their lives and by AFABs from puberty until menopause. In AFABs, cells inside the ovarian follicles produce AMH. The levels of AMH correspond to the number of eggs in your ovaries, also known as the ovarian reserve. Higher AMH levels indicate more eggs and a higher ovarian reserve, while lower levels suggest fewer eggs and a lower ovarian reserve.²

In AFABs, low levels of AMH are often associated with primary ovarian insufficiency (POI), while high levels can be indicative of polycystic ovarian syndrome (PCOS). In AMABs, low levels of AMH can lead to abnormal development of the reproductive system, resulting in a low or absent sperm count.

Testosterone

This hormone plays a key role in the development of male characteristics in AMABs during puberty and is pivotal for sperm production. Low testosterone levels in AMABs can lead to lower libido, poor erections, and a low sperm count, thereby causing infertility. 

Testosterone is produced in both testicles or ovaries, however, testosterone levels are naturally much higher in people AMABs than in AFABs.

Luteinising hormone (LH) and follicle-stimulating hormone (FSH)

LH and FSH are produced by both AMABs and AFABs. In AFABs, they act in synergy to stimulate the growth of the follicle (a small sac which contains the developing egg) and regulate ovulation (the release of the mature egg from the ovary into the fallopian tube). In AMABs, they are essential for the initiation and support of spermatogenesis (the production of sperm) in the testes. Imbalances in these hormones often lead to problems in ovulation or sperm production and therefore negatively impact fertility.³

Prolactin

Prolactin is a hormone responsible for lactation (milk production) and breast tissue development and contributes to numerous bodily processes. Normally, prolactin levels are low in AMABs, non-lactating, and non-pregnant individuals. However, they are typically elevated in pregnant or breastfeeding individuals to stimulate milk production and regulate menstrual cycles by suppressing ovulation.

High levels of prolactin (hyperprolactinemia) in AFABs can result in difficulty getting pregnant due to irregular ovulation or anovulation (lack of ovulation). In AMABs, high levels of prolactin can lead to sexual dysfunction and infertility.^4,5

Human chorionic gonadotropin (hCG)

HCG is a hormone produced by the placenta during pregnancy to support the development and maintenance of the early stages of pregnancy. It helps thicken your uterine lining to support a growing embryo and signals the body to stop menstruation. HCG levels rise after conception and continue to increase until about 10 weeks into pregnancy, after which they decline for the remainder of the pregnancy. Healthcare providers typically measure hCG levels in your urine or blood around 10 to 11 days after conception (when a sperm fertilises an egg) to confirm pregnancy.

In addition to its role in pregnancy, hCG is also an important hormone in AMABs. It assists the testes in producing testosterone, which is key for sperm formation.⁶

Common causes of hormonal imbalances that lead to infertility

Polycystic ovary syndrome (PCOS)

It is a common condition that occurs when your ovaries produce high levels of androgens (sex hormones like testosterone that are normally produced in small amounts in AFAB). High levels of androgens affect your menstrual cycle and cause excess acne, hair growth, and infertility.

Hypothalamic dysfunction

The hypothalamus is the central command centre for hormonal regulation in your body. When it is dysregulated, it can affect your hormone levels and, therefore, cause infertility, decreased sex drive, erectile dysfunction, breastfeeding problems, and other issues.⁷

Thyroid disorders

The thyroid is a gland that produces important hormones involved in reproduction. However, thyroid dysfunction can result in anovulatory cycles, high levels of prolactin, and other sex hormone imbalances.⁸

Male factor infertility

Male factor infertility is often caused when a person's AMAB is not producing enough healthy sperm. It can also result from conditions like cystic fibrosis or a blockage in the genital tract. Unlike female infertility, the exact cause of male infertility is often unknown. Therefore, common treatments include artificial insemination, in vitro fertilisation (IVF), or intracytoplasmic sperm injection. If hormonal imbalances are the cause, hormonal therapy such as gonadotropin therapy can be used as treatment.

Hormonal therapy

How hormone therapy works

Hormone therapy for infertility attempts to regulate the level of hormones to restore fertility and increase the chances to conceive. The treatment received depends on various factors, such as your age, how long you have been trying to conceive without success and your personal preferences. There are different treatments for infertility, ranging from medication to surgery, as well as using sophisticated techniques to help you get pregnant.

Hormonal medications for individuals AFAB

Fertility medications are usually prescribed when you have ovulation disorders that negatively impact your fertility. These medications stimulate ovulation by acting like the natural hormones (FSH and LH) that trigger the development and release of an egg. Here are some of these medications:

• Clomiphene citrate, an oral medication indicated to treat anovulatory by stimulating your ovaries to produce eggs⁹
• Letrozole (Femara) is used to induce ovulation in AFAB with anovulatory infertility. It acts similarly to clomiphene by increasing the release of FSH to stimulate ovulation¹⁰
• Gonadotropins, an injected treatment to stimulate your ovary to produce multiple eggs. Some gonadotropin medications involve hMG (Menopur) and FSH (Follistim, Gonal-F, Bravelle)
• Metformin is a medicine primarily used to treat type 2 diabetes. It is also used to treat PCOS by improving insulin resistance, thereby increasing the likelihood of ovulation. This treatment is used for AFABs whose suspected cause of infertility is insulin resistance¹¹
• Bromocriptine is often used to treat infertility caused by hyperprolactinemia (excess production of prolactin by the pituitary gland). It is also used to treat menstrual problems (like amenorrhea)

Risks of fertility treatments in individuals AFAB

Like all medications, using fertility treatment medications comes with risks. Some of these risks include:

Multiple pregnancies

Some medications focus on increasing the number of released eggs, thus increasing your chance of conceiving multiple babies. Although the increased risk for oral medications like clomiphene or letrozole is 10%, injected medications like gonadotropins can increase your risk up to 30%. Therefore, it is important to regulate and monitor the number of fertilised eggs, as carrying more fetuses increases health risks for you and your babies.

Some of the risks that might affect your babies include: 

• Premature labour
• Low birth weight 
• Developmental problems later in life

Other risks that might affect your health include:

• A higher risk of developing gestational hypertension (high blood pressure)
• Anaemia (iron deficiency)
• Caesarian delivery
• Postpartum haemorrhage (increased risk of bleeding after giving birth)

Ovarian hyperstimulation syndrome (OHSS)

Injecting a medication that stimulates ovulation can induce ovarian hyperstimulation syndrome, which is characterised by ovary inflammation, abdominal pain, nausea, diarrhoea, and vomiting. This condition is very rare and typically resolves without treatment.

Long-term risk of ovarian tumour

While fertility treatments are generally safe and carry few (if any) long-term risks, some studies have found a correlation between AFABs taking fertility treatments for periods longer than 12 months without conceiving and an increased risk of ovarian tumours later in life.¹² However, it is worth noting that this association is controversial, as AFABs who have never been pregnant already have a higher risk of ovarian tumours. Therefore, further research is necessary to determine whether this association is due to the underlying fertility issue or the medications used to treat it.

Medical treatment for individuals AMAB 

As explained earlier, most AMAB infertility is caused by a low sperm count, unhealthy sperm, or a blockage impeding the delivery of sperm. Unlike AFAB infertility, most AMAB infertility is idiopathic (the underlying reasons are unknown), and conception is often achieved by other methods. If your infertility is attributed to hormonal imbalances, treatments will aim at optimising testosterone levels, increasing FSH, and normalising the testosterone-oestrogen level ratio. 

Here are some of these treatments:^13,14

• Clomiphene citrate, similar to the AFAB treatment, acts as an oestrogen receptor blocker that stimulates your body to produce more FSH and LH, which help in sperm production
• HcG involves an intramuscular or subcutaneous injection used to stimulate sperm production by adjusting FSH and LH levels and increasing testicular levels of testosterone
•  Anastrozole assists in balancing the oestrogen-testosterone ratio by reducing your body's levels of oestrogen

Adverse effects of hormonal treatment for fertility in AMAB

•  Injection site pain
• Gynecomastia (growth of tissue inside the breast glands)
• Hyperglycemia (high blood sugar)
• Headache
• Gastrointestinal distress
• Hair loss
• Decreased libido
• Elevated liver enzymes (reversible)¹⁴

Importance of monitoring

If you are undertaking hormone therapy for fertility, it is crucial to be monitored by your doctor. This ensures the effectiveness of the treatment, your safety, minimisation of potential risks and side effects, and adjustment of the therapy as needed to optimise the chances of achieving a successful pregnancy.

Summary

Infertility is defined as the inability to conceive after one year of trying with your partner and can affect both AMABs and AFABs. While infertility can have various causes, hormonal imbalances (abnormal levels of hormones) play an important role in its development. Hormonal treatments are the main therapy for infertility in AFAB, as the causes of infertility are often identifiable.

In contrast, for AMAB, where the causes of infertility are frequently unknown, hormonal treatments may not be as common. However, the mode of action of hormonal therapies is similar in both AMAB and AFAB, as they aim to restore egg or sperm development, release the egg, and prepare the body to accommodate a pregnancy.

Although fertility treatments are considered safe, hormonal therapies can have adverse effects, such as an increased risk of multiple pregnancies and ovarian hyperstimulation syndrome for AFAB; and high blood sugar, gynecomastia, hair loss, and elevated liver enzymes in AMAB. To ensure their safety and effectiveness, close monitoring by healthcare professionals is essential when taking hormonal therapy.