Understanding Hormones, Medications, Fertility Drugs

October 5, 2018

After working in the field of fertility for over a decade and freezing my own eggs twice, I’m often asked about the hormones and shots involved with fertility treatments. There are a lot of medications your doctor can prescribe. Fertility drugs work by causing your body to release hormones that trigger or regulate ovulation — the release of an egg from your ovary. Here is a break down of the basics ones that are most commonly prescribed and what actually happens when you ovulate.

Ovulation is the process by which a mature follicle bursts and releases an egg. The egg is then picked up and goes down the fallopian tube(s). This event marks the transition from the follicular phase of the menstrual cycle into the luteal phase. Refer to the post about ovulation to learn more about how to predict your cycle better. https://eggsperience.com/predicting-your-ovulation/

Controlled ovarian hyperstimulation (COH) is an integral part of many infertility treatments because the development of a single follicle with a good egg, or the development of multiple follicles, improves pregnancy rates. There are numerous ways (protocols) for controlled ovarian hyperstimulation to be carried out.

The most widespread protocols involve the use of fertility drugs like Gonadotropins (Follistim, Gonal F, Fertinex, Pergonal, Humegon, Repronex) and Clomiphene Citrate (Clomid, Serophene). The basic steps in these generalized protocols are explained below. As you can tell, generic drug compounds are often referred to by their trade names as well.

Before outlining the drug therapy protocols, the table below offers a brief synopsis of the names and types of fertility drugs that are most commonly used for controlled ovarian hyperstimulation. If you are trying conceive now or attempting to have a natural pregnancy often times your physician will prescribe enhancing medications to help you ovulate or time your cycle for natural conception.

CLOMID OR SEROPHENE

Clomiphene citrate (Clomid) has been used for more than 40 years. Clomid is a pill that you take by mouth. Your doctor may prescribe it if you’re not ovulating normally. Clomid and Serophene, the brand names of clomiphene, are known as estrogen-blocking drugs. They cause the hypothalamus and pituitary gland, located in your brain, to release hormones called GnRH (gonadotropin-releasing hormone), FSH (follicle-stimulating hormone) and LH (luteinizing hormone).

These hormones trigger your ovaries to make eggs. These drugs are often used along with other fertility methods like assisted reproductive techniques or artificial insemination. It is competitive inhibitor of estradiol. It blocks estrogen receptors in a part of the brain called the hypothalamus, which causes the hypothalamus to signal the pituitary gland to release more FSH (follicle stimulating hormone) and LH (luteinizing hormone) into the bloodstream. The increased levels of FSH lead to the development of the follicle and egg which secretes more estrogen into the bloodstream.

About a week after ingestion of the last clomiphene tablet, the hypothalamus receptors are no longer blocked and thus trigger an LH surge in response to the artificially elevated levels of estrogen in the blood. As you can see from the picture above, the LH surge triggers ovulation approximately 14 days before the end of the cycle (on cycle day 14 in a 28 day cycle, day 21 in a 35 day cycle). If ovulation does not occur as expected, the standard 50mg dosage can be increased based on the discretion of the physician.

If pregnancy has not been achieved after increased dosage, the reproductive endocrinologist may recommend adding hCG (human chorionic gonadotropin) to “imitate” the LH surge. As a patient, there are potential side effects to clomiphene therapy that your physician will advise you about- the most common are hot flashes, breast tenderness, and mood swings. The chance for multiple pregnancies during this therapy is approximately 10% for twins and 1% for triplets. Clomiphene is often used as a first treatment to help stimulate ovulatory production. Because of its lower cost, lower multiple pregnancy rate, and its ease of use, clomiphene is often indicated before use of gonadotropins.

LUPRON

Gonadotropin-releasing hormone agonist (GnRH agonist), such as Lupron, Synarel, and Zoladex. If you are freezing your eggs or going through a fresh fertility cycle like IVF or IUI then different protocols are given and the injectable hormones below are often used during this treatment. When starting a fertility cycle, the injectable hormones start on the second or third day of your period and then continues with the dosing for about 7 to 12 days. The shots are given just beneath the skin so like your belly or stomach region, upper arm or thigh.

GnRH agonists can be given starting either in the luteal phase around cycle day 21 as shown above, or in the early follicular phase just after the menstrual period has begun (“flare”). Both protocols prevent premature ovulation. The follicular phase (“flare”) start may occasionally appear to be more effective in women who respond poorly to the gonadotropins. Different investigators have reported varied results with these two treatment protocols, but the luteal phase start (“long suppression”) is much more commonly used.

AGONIST DRUGS: FOLLICLE-STIMULATING HORMONE (FSH)

Follicle-stimulating hormone (FSH) such as Bravelle, Fertinex, Follistim, and Gonal-F are drugs that trigger the growth of eggs in your ovaries. Most physicians will issue and prescribe two main drugs Follistim and Gonal-F. They are made by two different pharmaceutical companies. Follistim is a product of Merck USA. Gonal-F is a product of EMD Serono. Common IVF drugs include Gonadotropins (which stimulate ovaries) that go under the medication names “Follistim”, “Gonal-F”, “Bravelle”, and “Menopur”;

Follicle stimulating hormone is one of the gonadotrophic hormones, the other being luteinising hormone. Both are released by the pituitary gland into the bloodstream. Follicle stimulating hormone is one of the hormones essential to pubertal development and the function of women’s ovaries and men’s testes. In women, this hormone stimulates the growth of ovarian follicles in the ovary before the release of an egg from one follicle at ovulation. It also increases oestradiol production. In men, follicle stimulating hormone acts on the Sertoli cells of the testes to stimulate sperm production (spermatogenesis).

COMBO FSH AND LH HORMONES: HUMAN MENOPAUSAL GONADOTROPIN (hMG)

Human menopausal gonadotropin (hMG), such as Menopur, Metrodin, Pergonal, and Repronex. This drug combines FSH and LH (luteinizing hormone). The main drug Menopur is a product of Ferring Pharmaceuticals. It can be an added drug in your cycle along with Follistim or Gonal-F.

A hormone used to stimulate the development of multiple follicles. Injectable human menopausal gonadotropin, also known as menotropin (brand names: Humegon, Pergonal, Repronex), is a purified preparation of the naturally occurring hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These medications stimulate the ovaries to develop many follicles and mature eggs. If your pituitary does not release FSH and LH properly, hMG can be given to stimulate the production of eggs. Studies show that about 90% of women on hMG will ovulate and 40% will conceive when the tubes are patent, the sperm count is adequate, and the ovary has normal reserve. Formulations of hMG intended for intramuscular injection (an injection into muscle) must not be administered subcutaneously (into fat), and vice versa. If you are administering this medication at home, your doctor will give you detailed instructions on how to mix the solution and give yourself the injection. Do not inject menotropins if you are not sure how. Side effects may include: allergic reactions, ovarian enlargement and discomfort, hyperstimulation syndrome, multiple gestation, abdominal pain, and headaches. Discomfort and bruising may occur at the injection site. Monitoring with ultrasounds and blood tests minimizes the risk of complications.

ANTAGONIST DRUGS: GONADOTROPIN-RELEASING HORMONE

Gonadotropin-releasing hormone antagonist (GnRH antagonist), such as Antagon and Cetrotide or Ganirelix. GnRH-antagoinists (prevent premature ovulation) which include the meds “Ganirelix” and “Cetrotide.”

GONADOTROPINS WITH GnRH AGONISTS

If clomiphene treatment is not successful or if you are preparing to undergo a cycle of ART treatment (ie: IVF or GIFT) your Reproductive Endocrinologist may prescribe gonadotropins that contain both follicle stimulating hormone (FSH) and luteinizing hormone (LH), or FSH alone. Brand names for these drugs include Pergonal, Humegon, and Repronex or recombinant technology produced gonadotropins such as Follistim and Gonal-F.

Unlike clomiphene treatment, gonadotropins act directly on the ovaries and are often prescribed in order to stimulate the development of multiple eggs during IVF or GIFT cycles. Gonadotropin treatment requires a series of injections and more intensive monitoring than clomiphene and is much more expensive.

Most physicians feel that before gonadotropin treatment is started, all other infertility factors should be investigated by a complete infertility study often including laparoscopy. Multiple pregnancies can occur in approximately 20-40% of gonadotropin induced cycles. Of this percentage about three fourths are twins, while one fourth is triplets or more.

Due to the higher risk associated with gonadotropin treatment, patients will receive intensive monitoring and consultation about their options.There are potentially serious side effects– the most significant besides multiple pregnancy is ovarian hyperstimulation syndrome. Although rare, this condition causes the ovaries to be painfully sensitive to pressure due to swelling, and can result in complications that require hospitalization and bed rest.

More serious complications can occur, and they should be discussed with your physician before starting gonadotropin treatment. GIFT and IVF procedures regularly utilize gonadotropin therapy to stimulate the ovaries to produce multiple eggs. These eggs are retrieved through a small needle which is placed through the top of the vagina when the woman is under conscious sedation anesthesia.This graphic outlines the major steps in gonadotropin treatment as a part of an IVF/GIFT cycle.

Oral contraceptives may be given in the month prior to treatment to limit development of small ovarian cysts. Most doctors start gonadotropin treatments on day 2, 3 or 4 of the menstrual cycle (where day one is the first day of actual bleeding). The treatment involves a series of subcutaneous injections in the upper leg or buttocks, followed by monitoring of blood estradiol (the most potent estrogen) levels and ultrasound evaluation of follicle development.

If satisfactory blood estradiol level and follicle development occur then the physician will trigger ovulation with an injection of hCG (see above). GnRH agonists are prescribed for nearly all patients during gonadotropin therapy for IVF or GIFT to prevent premature ovulation. GnRH agonists such as Lupron and Synarel are synthetic imitators of GnRH which normally stimulates the pituitary gland to produce FSH and LH. However, when a patient is treated with GnRH agonists, the pituitary intially increases its production of FSH and LH, but then stops FSH and LH production due to “downregulation”. Thus GnRH agonists serve to suppress the ovaries and provide the physician with greater control over controlled ovarian hyperstimulation.

HUMAN CHORIONIC GONADOTROPIN (hCG) or “TRIGGER SHOT”

Human chorionic gonadotropin (hCG) includes brands like such as Novarel, Ovidrel, Pregnyl, and Profasi. This medication is usually used along with other fertility drugs to trigger your ovaries to release an egg. These shots are usually injected into the muscle like buttocks. HCG (makes eggs mature) which include the meds “Profasi”, “Novarel”, “Ovidrel,” and “Pregnyl”;

GONADOTROPIN-RELEASING HORMONE (GnRH) GROWTH HORMONE

Gonadotropin-releasing hormone (GnRH), such as Factrel and Lutrepulse. This hormone triggers the release of FSH and LH from your pituitary gland, but it’s rarely prescribed in the U.S.

PROGESTERONE

Progesterone is the hormone which supports development of the uterine lining (endometrium) in the luteal phase and prepares the endometrium for the embryo to implant. Progesterone supplementation is sometimes used with clomiphene and/or gonadotropins, and almost always used when GnRH agonists are used. Progesterone can be delivered by intramuscular injection or by vaginal suppositories. However vaginal suppositories may not provide adequate blood leves of progesterone. Oral progesterone is also available, but most clinicians feel it does not supply consistently adequate levels of progesterone to the blood stream to be used with ART cycles.

DRUG DISCOUNT PROGRAMS TO REVIEW

Discount programs include Compassionate Care; Compassionate Corps (for veterans and spouses of veterans); First Steps; New Life Agency Fertility Pharmacy Care Card; and Heart + Savings through Ferring Fertility. Rebates and coupons are generally available to everyone, but there may be time constraints for when you can submit, and you may not be able to combine with discount programs. Other rebate programs like IVF Greenlight Ferring medical discount program and Go Direct to Savings Coupons for Follistim manufacturer discounts, but usually require insurance with pharmacy benefits that are just under covered.

General Tips and Price Breakdown

–Most regular pharmacies (CVS, Walgreens, RiteAid, etc) will not carry specialty infertility drugs.
–There are many infertility drug specialty pharmacies (often they have their prices listed online and they offer free or overnight shipping).
–Ask your doctor to find out which pharmacy they are networked with.
–There are a number of much cheaper specialty pharmacies located outside of the United States. (med prices are so high because the US has a free market and drug companies set drug prices)
–Many infertility med speciality pharmacies in the UK, Europe, and Israel have websites and will send meds to US patients with a valid prescription. Note that shipping from overseas usually means a long wait time (in some cases 2-3 weeks) and people have reported issues with meds being stopped in customs.
–Check with your insurance company and employer plans for coverage or Flex Savings programs.
–Ask your clinic to give you the physical prescriptions to price shop at brick and mortar places (most pharmacies will NOT run a price check with your insurance card unless they have an actual prescription; in the USA to do so is insurance fraud). But don’t assume that your RE has all the information about drug pricing.
–For some meds (like Clomid and Femara) check with your Costco/Sam’s Club. At Costco, (with or without a memerbership) the pharmacy for example will sell Femara for $2.00 versus the over $100 that CVS quotes.
–Different specialty pharmacies work with different drug companies, so some pharmacies will have better prices on certain meds. (Example: Metro Drugs in NY is a Design Rx pharmacy and has low prices on Follistim but much higher prices on Gonal-F verses Freedom Fertility and Mandell)
–You may get a price break if you are a cash paying patient.