Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. [1] These multiple follicles can be taken out by oocyte retrieval (egg collection) for use in in vitro fertilisation (IVF), or be given time to ovulate, resulting in superovulation which is the ovulation of a larger-than-normal number of eggs, [2] generally in the sense of at least two. When ovulated follicles are fertilised in vivo, whether by natural or artificial insemination, there is a very high risk of a multiple pregnancy.
In this article, unless otherwise specified, hyperstimulation will refer to hyperstimulation as part of IVF. In contrast, ovulation induction is ovarian stimulation without subsequent IVF, with the aim of developing one or two
ovulatory follicles. [3]
Response predictors determine the protocol for ovulation suppression as well as dosage of medication used for hyperstimulation. Response prediction based on ovarian reserve confers substantially higher live birth rates, lower total costs and more safety. [4]
It is commonly agreed not to exclude anyone from their first IVF attempt only on the basis of poor results on response predictors, as the accuracy of these tests can be poor for the prediction of pregnancy. [5]
The response to gonadotropins may be roughly approximated by antral follicle count (AFC), estimated by vaginal ultrasound, which in turn reflects how many primordial follicles there are in reserve in the ovary. [6]
The definition of "poor ovarian response" is the retrieval of less than 4 oocytes following a standard hyperstimulation protocol, that is, following maximal stimulation. [5] [note 1] On the other hand, the term "hyper response" refers to the retrieval of more than 15 or 20 oocytes following a standard hyperstimulation protocol. [5] The cut-offs used to predict poor responders versus normal versus hyper-responders upon vaginal ultrasonography vary in the literature, with that of likely poor response varying between an AFC under 3 and under 12, largely resulting from various definitions of the size follicles to be called antral ones. [5]
The following table defines antral follicles as those about 2–8 mm in diameter: [6]
Antral follicle count | Classification [6] | Approximate expected response [6] | Risks [6] | Pregnancy rates [6] | Recommendation [6] |
---|---|---|---|---|---|
Less than 4 | Extremely low | Very poor or none | Cancelled cycle expected | 0–7% with 1 oocyte [7] | Not attempt IVF |
4-7 | Low | Possibly/probably poor response | Higher than average rate of IVF cycle cancellation | 15% [7] | High doses of gonadotropin likely |
8-10 | Reduced | Lower than average | Higher than average rate of IVF cycle cancellation | Slightly reduced [6] | |
11-14 | Normal (but intermediate) | Sometimes low, but usually adequate | Slight increased risk for IVF cycle cancellation | Slightly reduced compared to the "best" group [6] | |
15-30 | Normal (good) | Excellent | Very low risk for IVF cycle cancellation. Some risk for ovarian overstimulation | Best overall as a group [6] with approx. 35% [7] | Low doses of gonadotropins |
More than 30 | High | Likely high | Overstimulation and ovarian hyperstimulation syndrome | Very good overall as a group, but potential egg quality issues [6] | Low doses of gonadotropins |
The incidence of poor ovarian response in IVF ranges from 10 to 20%. [5] Older poor responders have a lower range of pregnancy rates compared with younger ones (1.5–12.7 versus 13.0–35%, respectively). [7] Also, the other way around, there is a lower prevalence of poor responders among young women compared to those of advancing age, with 50% of women aged 43–44 years being poor responders. [5]
In most patients, injectable gonadotropin preparations are used, usually FSH preparations. The clinical choice of gonadotrophin should depend on availability, convenience and costs. [14] [ needs update ] The optimal dosage is mainly a trade-off between the pregnancy rate and risk of ovarian hyperstimulation syndrome. [13] A meta-analysis came to the result that the optimal daily recombinant FSH stimulation dose is 150 IU/day in presumed normal responders younger than 39 years undergoing IVF. [15] Compared with higher doses, this dose is associated with a slightly lower oocyte yield, but similar pregnancy rates and embryo cryopreservation rates. [15] For women predicted to have a poor response, there may not be any benefit to start at a higher FSH dosage than 150 IU per day. [5]
When used in medium dosage, a long-acting FSH preparation has the same outcome in regard to live birth rate and risk of ovarian hyperstimulation syndrome as compared to daily FSH. A long-acting FSH preparation may cause decreased live birth rates compared to daily FSH when using low dosages (60 to 120 μg of corifollitropin alfa). [16]
Recombinant FSH (rFSH) appears to be equally effective in terms of live birth rate compared to any of the other types of gonadotropin preparations irrespective of the protocol used for ovulation suppression. [14]
Typically, approximately 8–12 days of injections are necessary. [17]
Administering recombinant hCG in addition to an FSH-preparation has no significant beneficial effect. [18] The hCG is the FSH extracted from the urine in menopausical women.
Clomifene, in addition to gonadotropins, may make little or no difference to the live birth rate but may lower the probability of ovarian hyperstimulation syndrome. [19] A systematic review showed that using clomifene citrate in addition to low dose gonadotropin (in a GnRH antagonist protocol as described in the following section) resulted in a trend towards better pregnancy rates and a greater number of oocytes retrieved when compared with a standard high-dose FSH regime. [20] Such a protocol avails for using lower dosages of FSH-preparations, conferring lower costs per cycle, being particularly useful in cases where cost is a major limiting factor. [20]
Recombinant luteinizing hormone (rLH) in addition to FSH probably increases pregnancy rates, but it is not certain if the live birth rate is also increased. [21] Using low dose human chorionic gonadotropin (hCG) to replace FSH during the late follicular phase in women undergoing hyperstimulation as part of IVF may make little or no difference to pregnancy rates, and possibly leads to in an equivalent number of oocytes retrieved, but with less expenditure of FSH. [22] Before ovarian stimulation with antagonist protocols, pretreatment with combined oral contraceptive pills probably reduces the rate of live birth or ongoing pregnancy, while it is uncertain whether pretreatment with progesterone only has any effect on live birth or ongoing pregnancy rates. [23] For other stimulation protocols, the evidence around pretreatment with combined oral contraceptives and progesterone only is uncertain. [23]
Findings are conflicting, but metformin treatment as a complement in IVF cycles may reduce the risk of ovarian hyperstimulation syndrome and increase live birth rates. [24]
When used in conjunction with in vitro fertilization (IVF), controlled ovarian hyperstimulation confers a need to avoid spontaneous ovulation, since oocyte retrieval of the mature egg from the fallopian tube or uterus is much harder than from the ovarian follicle. The main regimens to achieve ovulation suppression are:
Regarding pregnancy rate, choosing GnRH agonist protocol for a cycle is approximately as efficient as choosing GnRH antagonist protocol. [5] [14] Still, the two protocols differ on a number of aspects:
Thus, in short, a GnRH antagonist protocol may be harder to schedule timewise but has shorter cycle lengths and less (or even eliminated) risk of ovarian hyperstimulation syndrome.
GnRH antagonist protocol has overall better results for expected poor and hyper-responders; A study of these protocols in women undergoing their first IVF and having a poor predicted response (by an AMH level below 5 pmol/L by DSL assay), using the GnRH antagonist protocol was associated with a substantial drop in cycle cancellation (odds ratio 0.20) and required fewer days of gonadotrophin stimulation (10 days versus 14 days) compared to GnRH agonist protocol. [5] Using GnRH antagonist protocol in high responders has been associated with significantly higher clinical pregnancy rates (62 versus 32%). [5]
The pregnancy rate is probably higher with long-course GnRH protocols compared to short or ultra-short GnRH agonist protocols. [23] There is no evidence that stopping or reducing GnRH agonist administration at the start of gonadotropin administration results in a decrease in pregnancy rate. [14]
There is a concomitant monitoring, including frequently checking the estradiol level and, by means of gynecologic ultrasonography, follicular growth. A Cochrane review (updated in 2021) found no difference between cycle monitoring by ultrasound (TVUS) plus serum estradiol compared to monitoring by ultrasound only relative to pregnancy rates and the incidence of ovarian hyperstimulation syndrome (OHSS). [29]
Tracking or supervising the maturation of follicles is performed in order to timely schedule oocyte retrieval. Two-dimensional ultrasound is conventionally used. Automated follicle tracking does not appear to improve the clinical outcome of assisted reproduction treatment. [30]
When used in conjunction with IVF, ovarian hyperstimulation may be followed by final maturation of oocytes, using human chorionic gonadotropin (hCG), or a GnRH agonist if a GnRH antagonist protocol is used for ovulation suppression. A transvaginal oocyte retrieval is then performed just prior to when the follicles would rupture.
It is uncertain if coasting, which is ovarian hyperstimulation without induction of final maturation, reduces the risk of OHSS. [23]
Perhaps the greatest risk associated with controlled ovarian hyperstimulation is ovarian hyperstimulation syndrome (OHSS). OHSS occurs when, following a "trigger" injection for final oocyte maturation, excessive VEGF production by numerous follicles acts systemically. This can result in a shift of fluid from the bloodstream to "third spaces", including the belly and the space around the lungs. This can make it difficult and painful to breathe or move, and in extremely rare cases can be fatal. Severe cases often require hospitalization, removal of fluid from the abdomen, and replacement of fluid in the blood. OHSS is most prevalent in very high responders, almost always those with more than 20 developing ovarian follicles, who are triggered with hCG. One means of greatly reducing OHSS risk is to trigger with GnRH agonist instead of hCG. This results in a surge of LH from the pituitary, the same hormone that matures the eggs in natural cycles. LH has a much shorter half-life than hCG, so that nearly all of the LH is cleared by the time of egg collection, or about 36 hours after trigger. Any developing signs of OHSS will typically vanish at that point. However, in rare cases, severe OHSS can continue to develop. Reduced success rates have been reported in fresh embryo transfers when the agonist trigger is used without hCG, so that most centers will freeze all embryos in cycles triggered only with the agonist.
Ovarian hyperstimulation does not seem to be associated with an elevated risk of cervical cancer, nor with ovarian cancer or endometrial cancer when neutralizing the confounder of infertility itself. [31] Also, it does not seem to impact increased risk for breast cancer. [32]
Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and after the follicular phase. Ovulation is stimulated by an increase in luteinizing hormone (LH). The ovarian follicles rupture and release the secondary oocyte ovarian cells.
Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.
Ovarian hyperstimulation syndrome (OHSS) is a medical condition that can occur in some women who take fertility medication to stimulate egg growth, and in other women in sporadic cases. Most cases are mild, but rarely the condition is severe and can lead to serious illness or even death.
Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.
In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an immature oocyte. Folliculogenesis describes the progression of a number of small primordial follicles into large preovulatory follicles that occurs in part during the menstrual cycle.
The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.
A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.
Gonadotropin-releasing hormone antagonists are a class of medications that antagonize the gonadotropin-releasing hormone receptor and thus the action of gonadotropin-releasing hormone (GnRH). They are used in the treatment of prostate cancer, endometriosis, uterine fibroids, female infertility in assisted reproduction, and for other indications.
Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.
Oocyte cryopreservation is a procedure to preserve a woman's eggs (oocytes). The technique is often used to delay pregnancy. At the time pregnancy is desired, the eggs can be thawed, fertilized, and transferred to the uterus as embryos. Many studies have suggested infertility problems as germ cell deterioration related to aging. The procedure's success rate varies according to the woman's age, health, and genetic factors. The first human birth of oocyte cryopreservation was reported in 1986.
An antral or secondary follicle, also known as Graafian follicle and tertiary follicle, is an ovarian follicle during a certain latter stage of folliculogenesis.
In vitro maturation (IVM) is the technique of letting the contents of ovarian follicles and the oocytes inside mature in vitro. It can be offered to women with infertility problems, combined with In Vitro Fertilization (IVF), offering women pregnancy without ovarian stimulation.
Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure may represent a continuum of premature ovarian senescence. It is usually accompanied by high FSH levels.
Fertility preservation is the effort to help cancer patients retain their fertility, or ability to procreate. Research into how cancer, ageing and other health conditions effect reproductive health and preservation options are growing. Specifically sparked in part by the increase in the survival rate of cancer patients.
Natural Cycle In Vitro Fertilization (IVF) is an assisted reproductive technique designed to closely mimic a woman's natural menstrual cycle. In traditional IVF, a woman's ovaries are stimulated with fertility medications to produce multiple eggs, which are then retrieved and fertilized outside the body. A natural cycle IVF, on the other hand, works with the woman's natural hormonal fluctuations and ovulation cycle.
Infertility in polycystic ovary disease (PCOS) is a hormonal imbalance in women that is thought to be one of the leading causes of female infertility. Polycystic ovary syndrome causes more than 75% of cases of anovulatory infertility.
Luteal support is the administration of medication, generally progesterone, progestins, hCG or GnRH agonists, to increase the success rate of implantation and early embryogenesis, thereby complementing and/or supporting the function of the corpus luteum. It can be combined with for example in vitro fertilization and ovulation induction.
Induction of final maturation of oocytes is a procedure that is usually performed as part of controlled ovarian hyperstimulation to render the oocytes fully developed and thereby resulting in optimal pregnancy chances. It is basically a replacement for the luteinizing hormone (LH) surge whose effects include final maturation in natural menstrual cycles.
Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.
Female fertility agents are medications that improve female’s ability to conceive pregnancy. These agents are prescribed for infertile female who fails to conceive pregnancy after 1-year of regular and unprotected sexual intercourse. The following will cover the advancements of female fertility agents, major causes of female infertility. Next, it emphasizes on common female fertility agents in terms of their mechanism of action, side effects, fetal consideration and clinical application and ended up by the introduction of supplements and herbal medicines for female infertility.