Polycystic Ovarian Syndrome (PCOS) and Infertility
Polycystic Ovarian Syndrome (PCOS) occurs in 5-10% of women of reproductive age. The condition is characterized by abnormal ovarian function (irregular or absent periods, abnormal or absent ovulation and infertility), androgenicity (increased body hair or hirsutism, acne) and increased body weight/body mass index or BMI. The ovaries of women with PCOS characteristically contain multiple micro-cysts often arranged like a “string of pearls” immediately below the ovarian surface (capsule), interspersed by an overgrowth of ovarian connective tissue (stroma).
PCOS women often have a family history of diabetes and demonstrable insulin resistance (evidenced by high blood insulin levels and an abnormal 2-hour glucose tolerance test). This underlying diabetic profile could play a role in the development of PCOS and contribute to the development of obesity, an abnormal blood lipid profile, and a predisposition to coronary vascular disease. Women with PCOS are also slightly more at risk of developing uterine, ovarian and possibly also breast cancer in later life and accordingly should be evaluated for these conditions on a more frequent basis than non-PCOS women.
Most women with PCOS either do not ovulate at all or they ovulate irregularly. As a consequence, they usually experience delayed, absent or irregular menstruation. In addition, an inordinately high percentage of the eggs produced by PCOS women following ovulation induction tend to be chromosomally abnormal (aneuploid). Rather than being due to an intrinsic egg defect or being inherent in PCOS women, the poor egg quality is more than likely the result of overexposure to male hormones (predominantly testosterone) produced by the ovarian stroma. These two factors (ovulation dysfunction and poor egg quality) are the main reasons for the poor reproductive performance (infertility and an increased miscarriage rate) in PCOS women.
PCOS patients are also at an inordinate risk of severely over-responding to injectable fertility drugs such as Follistim, Puregon, Bravelle, Gonal F and Menopur. In such cases a very large number of ovarian follicles are formed and blood estrogen levels go sky high. In some cases this can lead to life endangering complications. When this happens, the condition is referred to as severe ovarian hyperstimulation syndrome (OHSS). In addition, PCOS women receiving fertility agents followed by the “hCG trigger” shot, they often release several eggs at a time (i.e multiple ovulation). This can lead to about a 40 % chance of a multiple pregnancy and a 10-20% chance of high order multiples (i.e. triplets or greater) with often devastating consequences.
Varieties of Polycystic Ovarian Syndrome:
1) Hypothalamic-pituitary-PCOS: This is the commonest form of PCOS. It is often genetically transmitted and is characteristically associated with uncharacteristically high blood Luteinizing Hormone (LH) levels. In such cases the LH is usually much higher than the Follicle Stimulating Hormone (FSH) level. In non PCOS women, the FSH is usually higher than the LH concentration. PCOS is also associated with high-normal blood androgen (male) hormone concentrations e.g. androstenedione, testosterone and dehydroepiandrosterone – (DHEA). Hypothalamic-pituitary-ovarian PCOS is commonly associated with insulin resistance (in about 40%-50% of cases).
2) Adrenal PCOS: Here, the excess of androgen (male) hormones is derived from overactive adrenal glands rather than from overactive ovaries. Blood levels of testosterone and/or androstenedione are raised, but with this variety of PCOS, characteristically the blood level of dehydroepiandrosterone (DHEAS), only produced only by the adrenals is also raised, thereby clinching the diagnosis.
3) PCOS associated with severe pelvic adhesive disease: here the multiple ovarian cysts are thought to be due to prolonged ovarian engorgement with blood the result of severe pelvic adhesions. The condition is sometimes seen with severe endometriosis, chronic pelvic inflammatory disease and/or extensive pelvic surgery: In contrast with ovarian or adrenal PCOS, these women tend not to hyperstimulate with fertility drugs. In contrast they are often even “poor responders”.
Treatment of infertility due to associated ovulation dysfunction:
Hypothalamic-pituitary-/ovarian PCOS:Ovulation induction [with or without intrauterine insemination (IUI) is often successful in establishing pregnancies in PCOS women. However, it has one significant draw back, namely that it is associated with an inordinately high risk of multiple pregnancies (often triplets or greater). IVF, by allowing purposeful limitation of the number of embryos reaching the uterus, prevents this risk and at the same time is several times more effective than IUI in resulting in pregnancy. It is in my opinion that IVF represents the treatment of choice (see below).
The oral diabetes medication, Glucophage (syn. Metformin) administered to PCOS women who have hyperinsylinism will within 3 months of startingtreatment result in a significant drop in blood insulin and a 40% reduction of the blood testosterone level. This can lead to an improvement in ovulatory function, and es a degree of suppression of androgenous symptoms and signs.
- “Ovarian drilling”: In this process multiple holes are made in the ovarian surface, ostensibly to drain the micro-cysts. Unfortunately this is usually wishful thinking because if there is any benefit at all, it will certainly be very short lived.
- Ovarian Wedge resection: This traditional surgical “approach” designed to remove androgen hormone producing tissue fro the ovaries often at times result in reinstatement of regular ovulation and can result in pregnancies. However it notoriously also often results ibn the development of extensive post-surgical adhesions adding an anatomical barrier to fertility to an existing ovulatory dysfunction.
- Adrenal PCOS: This form of PCOS is often successfully treated with cortisone-like steroids such as prednisone or dexamethasone to reducing the realease of male hormones by the adrenal glands. Over a period of several weeks, regular spontaneous ovulation often is reinstated. In some cases the additional use of fertility drugs will be needed.
- PCOS due to Pelvic Adhesive Disease: This is an atypical variety of the condition because unlike other varieties of PCOS it is often associated with reduced ovarian reserve, a raised FSH blood level and a reduced response to fertility drugs. In such cases, high dosages of gonadotropins (FSH-dominant) with “estrogen priming” will be needed to induce appropriate follicle growth. Neither steroids nor Metformin are helpful in most such cases.
Severe Ovarian Hyperstimulation Syndrome (OHSS):
As stated above, there is an inordinate propensity for women with PCOS to hyper-respond to gonadotropin fertility drugs and in the process produce large numbers of ovarian follicles and dangerously high blood estrogen (estradiol) concentrations. If left unchecked, this can lead to OHSS, a potentially life endangering condition.
So, the onset of OHSS is signaled by the development of a large number of ovarian follicles (usually, > 25 in number) accompanied by rapidly rising plasma estradiol (E2) levels, often exceeding 3,000 pg/ml within 7 or 8 days of initiating ovarian stimulation. The E2 level will usually peak above 6,000 pg/ml prior to hCG administration (In fact I have often encountered blood E2 levels rising to more than double this level). When the E2 rises above 6,000 pg/ml, the risk of OHSS occurring (with life-endangering complications) is above 80%.
Symptoms and signs of OHSS include: abdominal distention due to excessive fluid accumulation in the abdominal cavity (i.e. ascites), fluid in the chest cavity (i.ehydrothorax), rapid weight gain (of a pound or more per day) due to tissue fluid retention, abdominal pain, lower back ache, nausea, diarrhea, vomiting, visual disturbances, a rapidly declining urine output, vascular collapse and failure of blood to clot resulting in severe bruising (echymosis) etimes frank bleeding and multiple organ failure. These symptoms and signs usually start developing even before pregnancy is diagnosed.
Once pregnancy occurs, the OHSS condition will rapidly worsen progressively over a period of 3-5 weeks whereupon it will suddenly resolve spontaneously over a few days. If no pregnancy occurs the condition is self-limiting with symptoms and signs usually all disappearing spontaneously within 10-12 days of the “hCG trigger” shot.
When the amount of fluid collecting in the abdominal cavity gets so severe as to make breathing difficult or it causes a lot of discomfort, some or all of the fluid can readily and safely be drained through sterile needle introduced into the abdominal cavity (usually via the vagina), thereby improving the situation significantly. Fluid drainage might have to be repeated intermittently.
In all cases of OHSS, the ovaries will invariably become markedly enlarged. Unless the ovary twists on its axis, cutting off the blood supply (ovarian torsion) the ovarian enlargement is temporary and somewhat inconsequential. Ovarian torsion is fortunately an extremely rare complication of OHSS, but when it occurs, it represents a surgical emergency.
It is important to know that because the symptoms and signs of OHSS are aggravated by rising hCG levels, such patients should never be given additional hCG injections.
Does PCOS cause poor egg/embryo quality?
It is undeniable that women with PCOS undergoing IVF commonly produce a disproportionate number of poor quality eggs with reduced fertilization potential and which upon fertilization can produce embryos with poor developmental potential. However, rather than being due to the eggs of PCOS women having an intrinsic defect, such poor embryo quality is much more likely to be the consequence of excessive local varian production of androgen hormones, aggravated by severe ovarian hyperstimulation.
Increased androgen hormone production can be limited through the selective use of customized low-gonadotropin dose ovarian stimulation protocols. This will reduce exposure of developing follicles (and the eggs they harbor) to excessive ovarian androgens. Such protocols should be designed to suppress the woman’s LH production throughout the duration of ovarian stimulation with gonadotropins. This in turn will reduce androgen hormone release by the ovarian stroma. At the same time, administration of high LH-containing gonadotropins such (e.g. Menopur) should kept to a minimum. Finally those women at imminent risk of developing OHSS must be treated by “prolonged coasting” (see below).
In the past, even a threat of the dreaded development of OHSS often prompted the treating physician to abruptly cancel the cycle or prematurely administer the “hCG trigger” in an attempt to arrest the process and so limit the risk to the patient. But, while premature administration of hCG does abruptly arrest progression of follicle growth, there is always the risk that if hCG is given too prematurely the eggs might not have have had sufficient time to develop adequately beforehand. In such cases, very premature administration of the “hCG trigger” will increase the risk of numerical egg chromosomal abnormalities (aneuploidy) and thereby set the scene for poor embryo quality.
In women with PCOS, the connective tissue that surrounds the follicles (ovarian stroma) is often characteristically overgrown (stromal hyperplasia). It is this stroma that produces androgen hormones (mainly testosterone) in response to LH stimulation. PCOS women who often have elevated blood LH concentration are thus predisposed to have excessive production of androgen hormones (mainly testosterone) and as a result, compromised egg/can also impair endometrial response to estrogen.leading to poor endometrial thickening (often seen in association with ovarian stimulation of PCOS women).
The obvious remedy to such adverse effects on egg/embryo and endometrial development is to prescribe a stimulation protocol that regulates and limits ovarian over-exposure to LH and at the same time allows sufficient time for the follicles/eggs to develop optimally, prior to administering the “hCG trigger” shot. It is in regard to the latter, that the precise timing for initiating “Prolonged Coasting” (PC) becomes a critical consideration.
What is Prolonged Coasting and how does it work?
In the early 90’s, we were the first to report on “prolonged coasting” (PC), a novel approach that helps to protect egg quality while preventing the development of OHSS. PC has since gained universal acceptance as a method of choice for preventing OHSS.
Prolonged coasting involves withholding gonadotropin therapy while continuing the administration of the GnRHa and then waiting until the plasma estradiol concentration drops low enough to insure that the woman is out of danger. Only then is the “hCG trigger” initiated. In such cases, the correct application of PC will prevent severe OHSS, regardless of the number of prior developed follicles or the number of eggs retrieved.
Some have suggested that PC leads to poor quality eggs that upon being fertilized produce poor quality embryos. This, is not so! PC itself is not a cause of poor egg quality unless the timing with which the “coasting” process is implemented is wrong. If PC is initiated too early, follicle growth and development may stop. If started too late, the follicles will become over-ripe (often cystic) leading to poor quality eggs/embryos. Thus, precise timing of the initiation of PC is critical.
Prolonged coasting virtually eliminates the risk of OHSS. When properly implemented, it will not significantly compromise egg development and maturation. Because of this, it prevents canceled IVF cycles and with it, “canceled dreams”.