Understanding Ovarian Hyperstimulation Syndrome (OHSS)
Ovarian Hyperstimulation Syndrome (OHSS) is an iatrogenic complication of controlled ovarian stimulation, representing an excessive response to the hormone medications used in fertility treatments, particularly in vitro fertilization (IVF) [1.2.1, 1.6.5]. In this condition, the ovaries swell and become painful [1.2.2]. The core issue is an abnormal reaction by ovarian blood vessels to high levels of hormones, especially human chorionic gonadotropin (hCG), causing them to leak fluid [1.2.2]. This fluid can accumulate in the abdomen and, in severe cases, the chest, leading to a range of symptoms from mild bloating to life-threatening complications like blood clots and kidney failure [1.2.1, 1.7.1]. While mild OHSS is common, affecting up to a third of IVF patients, the severe form occurs in about 1% of cases [1.2.4, 1.3.3]. The syndrome's development is closely tied to the administration of specific medications designed to stimulate egg development.
Primary Medications Causing OHSS
The medications most likely to cause OHSS are injectable hormones used to stimulate the ovaries [1.2.2].
Injectable Gonadotropins
Injectable gonadotropins are the class of drugs most frequently associated with OHSS [1.2.1, 1.3.2]. These medications contain follicle-stimulating hormone (FSH) or a combination of FSH and luteinizing hormone (LH). They work by directly stimulating the ovaries to produce multiple eggs. Examples of these drugs include Gonal-F, Bemfola, Menopur, and Luveris [1.3.2]. The risk of OHSS increases with higher doses of gonadotropins and in women who have a very robust response, developing a large number of follicles [1.5.1, 1.6.2].
Human Chorionic Gonadotropin (hCG) Trigger Shot
The administration of hCG, often called a "trigger shot" (e.g., Ovidrel), plays a crucial role in the development of OHSS [1.2.2, 1.3.4]. This injection is used to induce the final maturation of the eggs and prepare them for ovulation or retrieval. However, hCG has a long half-life and can excessively stimulate the ovaries, especially when many follicles have developed [1.8.4, 1.11.4]. The abnormal vascular response that defines OHSS, where blood vessels become leaky, typically begins within a week after the hCG injection [1.2.2, 1.9.1]. If a pregnancy occurs during the treatment cycle, the body's own production of hCG can worsen the syndrome or make it last longer [1.2.1, 1.2.2].
Other Medications and Contributing Factors
While injectable hormones pose the highest risk, other medications used in fertility treatments can also, though less commonly, contribute to OHSS.
- Oral Medications: Oral fertility drugs like clomiphene citrate (Clomid) are less likely to cause OHSS than injectable medications [1.2.2]. The incidence of OHSS with clomiphene is less than 1% [1.4.1]. Letrozole, another oral medication, also has a very low risk [1.10.2].
- GnRH Agonists and Antagonists: Gonadotropin-releasing hormone (GnRH) analogues are used to prevent premature ovulation during an IVF cycle. Studies have shown that using a GnRH antagonist protocol is associated with a lower risk of severe OHSS compared to a long GnRH agonist protocol [1.11.3, 1.11.4]. Furthermore, using a GnRH agonist (like Lupron) instead of hCG as the trigger shot can significantly reduce or even eliminate the risk of OHSS [1.2.2, 1.9.3].
Comparison of Fertility Drugs and OHSS Risk
| Medication Type | Brand Examples | Mechanism of Action | OHSS Risk Level |
|---|---|---|---|
| Injectable Gonadotropins | Gonal-F, Menopur, Follistim | Directly stimulate ovaries to produce multiple follicles. | High [1.2.1, 1.3.2] |
| hCG Trigger Shot | Ovidrel, Pregnyl, Novarel | Induces final egg maturation; has a strong, prolonged stimulating effect. | High (Key trigger for OHSS) [1.2.2, 1.9.1] |
| Oral Ovulation Inducers | Clomid (Clomiphene), Femara (Letrozole) | Indirectly stimulate ovulation by affecting hormone feedback loops. | Low [1.2.2, 1.4.1] |
| GnRH Agonist Trigger | Lupron (Leuprolide) | Induces a natural, shorter LH surge to trigger maturation. | Very Low (Used as a preventive strategy) [1.2.2, 1.6.3] |
| GnRH Antagonists | Cetrotide, Ganirelix | Prevent premature ovulation during stimulation. | Lower than GnRH Agonist protocols [1.11.3, 1.11.4] |
Prevention and Management
Recognizing the medications that cause OHSS allows for several preventive strategies. A physician may adjust medication by using the lowest possible dose of gonadotropins to achieve a response [1.2.2]. For high-risk patients, such as those with Polycystic Ovary Syndrome (PCOS) or a high follicle count, several strategies are employed [1.2.4, 1.5.1]. One of the most effective methods is to avoid the hCG trigger shot altogether and instead use a GnRH agonist like leuprolide (Lupron) to trigger ovulation [1.6.3]. Another key strategy is the "freeze-all" approach, where all resulting embryos are cryopreserved for a future transfer, allowing the body to recover and avoiding the endogenous hCG rise from a potential pregnancy [1.2.2, 1.6.3]. Other medications, such as cabergoline or letrozole, may also be prescribed to help reduce fluid accumulation and lower the risk [1.2.1, 1.5.5].
Conclusion
Ovarian Hyperstimulation Syndrome is a direct consequence of the powerful medications used to control and enhance fertility. The primary drivers of OHSS are injectable gonadotropins that stimulate the ovaries and the hCG trigger shot that finalizes egg maturation. While oral medications like clomiphene pose a much lower risk, they are not entirely exempt. Fortunately, advances in pharmacology and treatment protocols, such as the use of GnRH antagonist cycles, GnRH agonist triggers, and freeze-all strategies, have provided clinicians with effective tools to significantly mitigate the risk of this serious complication, making fertility treatment safer for patients.
For further reading, visit: Ovarian Hyperstimulation Syndrome (OHSS) - ReproductiveFacts.org [1.2.1]
