Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by irregular menstrual cycles, excess androgen levels, and polycystic ovaries. PCOS affects approximately 5-10% of reproductive-aged women and is one of the leading causes of infertility. There are several treatment options available for managing PCOS, including lifestyle changes, birth control pills, and metformin. In some cases, injections may be recommended to help regulate the menstrual cycle and induce ovulation. The two main types of injections used for PCOS are gonadotropins and GnRH agonists.
Gonadotropins
Gonadotropins are injectable fertility medications that contain follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which directly stimulate the ovaries. The three types of gonadotropin injections used for PCOS are:
– Human menopausal gonadotropins (hMG): extracted from the urine of postmenopausal women. Brand names include Menopur, Repronex.
– Recombinant FSH (rFSH): synthesized in a lab using recombinant DNA technology. Brand names include Gonal-F, Follistim.
– Human chorionic gonadotropin (hCG): derived from the urine of pregnant women. Brand name is Ovidrel.
Gonadotropins are commonly used for ovulation induction in women with PCOS who have not ovulated or responded to first-line treatments like clomiphene citrate. The gonadotropins stimulate the growth and maturation of ovarian follicles to trigger ovulation.
A typical gonadotropin protocol involves daily injectable doses of FSH, starting within the first few days of menstruation. Serial monitoring of follicular development is done using ultrasound and blood tests. When follicles reach an appropriate size, hCG is injected to induce ovulation. Timing of intercourse or intrauterine insemination (IUI) is planned accordingly.
Potential side effects of gonadotropins include ovarian hyperstimulation syndrome (OHSS), multiple pregnancies, and local injection site reactions. Risk of multiples is reduced by careful monitoring and limiting the number of mature follicles prior to hCG trigger.
GnRH Agonists
Gonadotropin-releasing hormone (GnRH) agonists are synthetic hormones that initially stimulate the pituitary gland but ultimately downregulate and suppress gonadotropin (FSH and LH) secretion. This leads to prevention of premature LH surges and ovulation.
Examples of GnRH agonists used for PCOS include leuprolide acetate (Lupron), nafarelin acetate (Synarel), and goserelin acetate (Zoladex). They are available as daily injections or longer-acting monthly or 3-monthly depot injections.
GnRH agonists can be used before starting gonadotropins to suppress endogenous LH and FSH secretion. This “pituitary downregulation” allows for better control of the stimulation cycle. They may also be used to trigger final oocyte maturation instead of hCG.
Side effects of GnRH agonists include menopausal symptoms like hot flashes, vaginal dryness, headache, and bone loss. Use is therefore time-limited to avoid long-term complications. Add-back therapy with estrogen and progesterone helps reduce side effects.
Choosing Between Gonadotropins and GnRH Agonists
The choice between gonadotropins and GnRH agonists depends on several factors:
– **Patient history** – Gonadotropins are preferred as first-line for ovulation induction in PCOS. GnRH agonists may be used for pituitary suppression in patients who have failed previous gonadotropin cycles.
– **Cost** – Gonadotropin injections tend to be much more expensive compared to GnRH agonists. Insurance coverage varies.
– **Monitoring** – Gonadotropin cycles require intensive ultrasound and blood work monitoring. GnRH agonist cycles require less monitoring.
– **Side effects** – Both classes have side effects. Gonadotropins have higher risk of OHSS and multiples. GnRH agonists cause more menopausal symptoms.
– **Efficacy** – When combined with IUI, both result in reasonably good ovulation, pregnancy, and live birth rates. Gonadotropins may have a slight edge for patients with PCOS.
– **Availability** – Gonadotropins may not be available or affordable in some regions. Long-acting GnRH agonist depot injections allow for ovulation induction in remote areas.
The reproductive endocrinologist will take all these factors into account when designing a treatment plan. The lowest doses and shortest duration is used to minimize complications.
Effectiveness of Gonadotropins and GnRH Agonists for PCOS
Multiple studies have demonstrated gonadotropins and GnRH agonists, used alone or together, are effective for ovulation induction in anovulatory women with PCOS:
– In a 2018 Cochrane review of 27 trials, gonadotropins were associated with higher live birth rates (28%) compared to clomiphene citrate (23%) for PCOS.
– A meta-analysis in Reproductive Biomedicine Online found gonadotropin + IUI cycles in PCOS had a pooled ovulation rate of 74.3% and pregnancy rate of 28.1% per patient.
– A study in Seminars in Reproductive Medicine reported ovulation rates per cycle of 60-85% and pregnancy rates of 30-40% using gonadotropins in PCOS.
– GnRH agonists combined with gonadotropins achieved ovulation rates of 60-85% and pregnancy rates approaching 50% per cycle in PCOS patients according to an analysis in Human Reproduction Update.
– One randomized trial found similar ovulation rates with GnRH agonist and hCG trigger for gonadotropin ovulation induction cycles in clomiphene-resistant PCOS.
While gonadotropins tend to be used more commonly, GnRH agonists provide a lower cost alternative that may be preferred in some scenarios like low resource settings or for patients who require minimal monitoring or have failed gonadotropin therapy.
Protocols
There are several standard protocols using gonadotropin and GnRH agonist injections for ovulation induction in PCOS:
Gonadotropin Only Protocol
– Start gonadotropin injections (FSH +/- LH) within 3-5 days of menstrual bleeding
– Use ultrasound and estradiol levels to monitor follicle growth
– When the lead follicle reaches ~18 mm, give hCG trigger injection
– Timed intercourse or IUI 34-36 hours after trigger
GnRH Agonist Downregulation Protocol
– Start GnRH agonist in mid-luteal phase for 7-14 days to suppress pituitary
– Once downregulated, begin gonadotropin stimulation
– When follicles mature, use GnRH agonist to trigger instead of hCG
– Timed intercourse/IUI
GnRH Agonist Only Protocol
– Start GnRH agonist injections in follicular phase
– Continue for 6-8 weeks to induce ovarian quiescence
– Then stop GnRH agonist to stimulate follicular development
– Monitor with ultrasound +/- estrogen levels
– Timed intercourse when ovulation predicted
GnRH Antagonist Protocol
– Begin gonadotropin injections on cycle day 2-3
– When lead follicle is 14-16 mm, add GnRH antagonist to prevent premature LH surge
– Continue gonadotropins till appropriate maturation, then trigger with hCG
– Timed IUI
The reproductive endocrinologist selects the ideal protocol based on the patient’s history and ovulatory response. Serial monitoring allows for adjusting gonadotropin doses to minimize risk of hyperstimulation while optimizing the chance of ovulation.
Preparations Available
The gonadotropin and GnRH agonist injections used for ovulation induction in PCOS patients are available in the following preparations:
Gonadotropins
| Generic Name | Brand Names | Formulations |
|---|---|---|
| Human menopausal gonadotropin (hMG) | Menopur, Repronex | Vials containing FSH + LH activity |
| Recombinant FSH (rFSH) | Gonal-F, Follistim | Vials, pens, prefilled syringes with FSH only |
| Human chorionic gonadotropin (hCG) | Ovidrel, Novarel, Pregnyl | Vials, prefilled syringes |
– Administered as subcutaneous injections daily during stimulation phase.
– Doses adjusted based on ovarian response.
– hCG given as one injection to trigger ovulation when mature follicle reached.
GnRH Agonists
| Generic Name | Brand Names | Formulations |
|---|---|---|
| Leuprolide acetate | Lupron | Daily injections, 1-month & 3-month depots |
| Goserelin acetate | Zoladex | 1-month & 3-month depots |
| Nafarelin acetate | Synarel | Daily nasal spray |
– Daily or monthly injections given during downregulation and ovulation triggering phase.
– Nasal spray taken daily for 1-2 months to suppress ovulation.
– Depot injections preferred to improve compliance over daily dosing.
How to Administer Injections
Gonadotropin and GnRH agonist injections should be administered subcutaneously, i.e. into the fatty tissue layer between the skin and muscle. Follow these steps for proper injection technique:
1. Wash hands thoroughly with soap and water.
2. Prepare supplies – medications, syringes and needles based on your prescribed doses.
3. Select an injection site. Common sites are the lower abdomen below the navel, upper thighs, or upper arms. Vary sites daily.
4. Clean injection site with alcohol pad in a circular motion and let it air dry.
5. For vials, draw up prescribed amount of medication. For pre-filled syringes, just attach needle.
6. Pinch about 1 inch of skin and subcutaneous tissue.
7. Insert needle fully at 45-90° angle.
8. Inject medication slowly and steadily. Take 5-10 seconds.
9. Remove needle and apply pressure with gauze for 10-15 seconds.
10. Dispose syringe/needle safely in sharps container.
11. Keep a written record of dates and times of injections.
12. Contact your provider if you experience any reactions or have issues.
Proper injection technique is vital to maximize medication effects and avoid complications like infection, bruising or irritation. Many fertility clinics also provide injection training. Videos online can be helpful learning resources as well.
Cost and Insurance Coverage
Gonadotropin and GnRH agonist injections can be quite expensive. Some approximate costs are:
– FSH injections: $80-200 per vial
– hCG trigger shot: $100-200
– GnRH agonist daily injections: $100-300 per month
– GnRH agonist depot shot: $500-1,000 per injection
– IUI procedure: $300-1,000 per cycle
– Monitoring: $200-500 per cycle
The total cost per ovulation induction cycle with gonadotropins averages $3000-$5000 but can be much higher depending on the types and doses of medications used and degree of monitoring needed.
GnRH agonist cycles tend to be lower cost, in the range of $1000-$2000 per cycle.
Insurance coverage varies widely. Many plans cover a portion of medically necessary fertility treatments, but patients still end up paying significant out-of-pocket costs. Discuss your coverage with your insurance provider.
Some ways to reduce costs include using generic injectables when possible, having monitoring done at low-cost clinics, and using financial assistance programs offered by drug manufacturers and specialty pharmacies.
Side Effects and Risks
The potential side effects and risks with gonadotropin and GnRH agonist injections include:
– Ovarian hyperstimulation syndrome (OHSS) – Serious complication from high response causing enlarged ovaries and fluid buildup. Strict monitoring and trigger criteria minimize risk.
– Multiple pregnancy – Twins or higher order multiples may occur. Generally aim for 1-2 mature follicles before trigger.
– Local injection reaction – Temporary redness, swelling, bruising at injection site.
– Hypersensitivity reaction – Very rare allergic reaction to medications.
– Infection at injection site
– Bone loss with prolonged GnRH agonist use
– Headaches, menopausal symptoms from GnRH agonists
OHSS and multiples are most concerning and highlight the need for close monitoring. Overall, these injectable medications are well-tolerated under proper provider supervision.
Monitoring Requirements
Close monitoring is essential when using gonadotropin and GnRH agonist injections to minimize risks like OHSS and multiple pregnancy. Monitoring includes:
– **Transvaginal ultrasound** starting within 1-3 days of menstrual period to check ovaries at baseline, then every 1-3 days during gonadotropin stimulation to track follicular development. Assesses number and size of developing follicles.
– **Blood tests** for estradiol levels, conducted alongside ultrasounds to help assess response. May check other hormone levels like LH, progesterone and AMH.
– **Endometrial thickness** measurement by ultrasound to ensure adequate lining growth.
– Ultrasound monitoring continues until lead follicles reach 16-18 mm and estradiol levels indicate approaching ovulation.
– After hCG trigger, one ultrasound may be done to confirm ovulation occurred.
– If GnRH agonist is used, less intensive monitoring may be adequate after initial suppression confirmed.
Frequency of monitoring can often be reduced for subsequent cycles once patient’s response is known. Monitoring prevents adverse outcomes like multifetal gestation, ensures proper timing of trigger and intercourse/IUI.
When to Use These Injections
Gonadotropin and GnRH agonist injections are commonly used for ovulation induction in the following populations of women with PCOS:
– Those who do not ovulate or respond to oral ovulation induction agents like clomiphene citrate.
– Those undergoing intrauterine insemination (IUI) cycles in order to achieve multiple follicle development.
– Those undergoing in vitro fertilization (IVF) treatment to stimulate follicle growth before egg retrieval.
– Previous history of successful ovulation or pregnancy using these injections.
– Those with clomiphene failure/resistance or other ovulatory dysfunction along with PCOS.
– Those desiring minimal medication exposure and monitoring may elect to try GnRH agonist alone.
– Those with Irregular menses desiring more regular menstrual cyclicity.
The decision when to pursue injectable treatment requires balancing effectiveness with costs, monitoring burden, and risks like OHSS. In PCOS patients <35 yo, gonadotropins with IUI provides an intermediate step before considering IVF.
Conclusion
Gonadotropins and GnRH agonists play an integral role in ovulation induction regimens for infertile women with PCOS. Gonadotropins like FSH, often combined with GnRH analogs for optimal timing, directly stimulate follicle development in anovulatory patients. Though injectable treatment increases costs, monitoring needs, and risks compared to oral medications, the higher ovulation rates and ability to time intercourse or IUI leads to improved pregnancy outcomes in this population. Close provider supervision and adherence to medication protocols helps reduce adverse effects like OHSS and multiple gestation. For PCOS patients who require injectable therapy, gonadotropins and GnRH agonists used alone or together provide safe, effective options for achieving ovulation and conception.
