Infertility
PCOS and infertility
Why it is difficult to get pregnant, and how the ovaries and the lining of the uterus can work in step again
Polycystic ovary syndrome (PCOS) is the most common hormonal cause of infertility in women. It accounts for most cases of absent ovulation. The 2023 international guideline also stresses the good news: with PCOS, pregnancy is usually possible, naturally or with help.
Infertility in PCOS does not have a single cause. Lack of ovulation is the best-known cause, but not the only one. PCOS also affects the quality of the egg, the lining of the uterus, implantation and the course of pregnancy. For this reason, the 2025 Italian guideline of SIRU and CECOS, which builds on the international guideline, recommends checking all criteria of PCOS in every woman who wants a child. Each criterion can affect the outlook and is important for counseling before and during pregnancy.
What is the normal path to ovulation?
In every cycle, a group of small follicles starts to grow. The hormone FSH from the pituitary gland selects one of them. This follicle keeps growing, produces estrogen and releases the egg at ovulation. It then becomes the corpus luteum and produces progesterone, which prepares the lining of the uterus for implantation. This process needs a fine balance between the brain, the ovary, the lining of the uterus and the metabolism.
Why does ovulation not happen?
The signal from the brain. In many women with PCOS, the hypothalamus sends its pulses faster than normal. As a result, the pituitary gland produces more LH and relatively little FSH. LH stimulates the cells of the ovary to produce androgens, and the relatively low FSH is not enough to select a follicle and let it mature.
Androgens in the ovary. In PCOS, the cells around the follicles produce more androgens. At first, androgens support the growth of many small follicles. This is why the ovary in PCOS has more follicles than usual. At the same time, however, they slow down further maturation. The follicles stop at a size of a few millimeters. These are the “cysts” seen on ultrasound. In reality, they are follicles that do not mature any further.
Insulin. Insulin resistance affects many women with PCOS, including women with a normal weight. The body produces more insulin. In the ovary, insulin acts like an amplifier of LH and increases androgen production even more. In the liver, insulin also lowers the binding protein SHBG. This raises the share of free, active androgens in the blood. Insulin and androgens strengthen each other.
AMH. The many small follicles produce a lot of anti-Müllerian hormone (AMH). In PCOS, AMH is often two to three times higher than usual. AMH makes the follicles less sensitive to FSH and blocks the conversion of androgens into estrogen. In this way, AMH itself helps to prevent the selection of a follicle. The Italian guideline recommends measuring AMH before stimulation, so that the doctor can recognize women with a higher risk of overstimulation, treatment failure or multiple pregnancy.
The result is a vicious circle: without the selection of a follicle there is no ovulation, without ovulation there is no progesterone, and without progesterone the hormone pattern with high LH and high androgens continues. Cycles become long, irregular or stop completely.
The vicious circle without ovulation
boosts the androgens
Is it only about ovulation?
Even when ovulation happens, for example after treatment, the environment in which the egg matures is often altered in PCOS. The fluid in the follicles contains more androgens, more insulin, more inflammatory substances and more oxidative stress. Studies show changes in the mitochondria, the “power plants” of the egg, and in its maturation. In IVF, women with PCOS often produce many eggs, but not all of them are mature and of good quality.
These changes are not the same in every woman. They are stronger in the forms with raised androgens and marked insulin resistance.
What happens to the lining of the uterus?
A large review by Palomba, Piltonen and Giudice (2021) shows that the lining of the uterus in PCOS does not change only because progesterone is missing. The lining responds less to progesterone, even when progesterone is present. Important molecules for implantation are reduced, and the transformation of the lining into the tissue that supports the pregnancy is disturbed. The lining itself can be insulin resistant and shows signs of mild chronic inflammation.
Without regular ovulation, the lining is also exposed to estrogen alone for long periods and is not shed regularly. This not only raises the risk of a thickened lining. It also makes the conditions for implantation worse. These changes explain why implantation can be more difficult in PCOS, even when a healthy embryo develops.
What role does weight play?
The international guideline gives a strong recommendation here: women with PCOS should know that a higher weight lowers pregnancy and birth rates after fertility treatment and raises the risk of miscarriage. Fat tissue is hormonally active. It produces estrogen and inflammatory substances, increases insulin resistance and disturbs the signals between the brain and the ovary. However, a higher weight is not the cause of PCOS. Slim women with PCOS also often have insulin resistance and the same ovulation problems.
At the same time, the guideline stresses that the doctor discusses weight only with the woman’s consent and without blame. Even a loss of 5-10% can bring ovulation back.
Is every form the same?
PCOS has four phenotypes. The classic forms with an irregular cycle and raised androgens usually have the strongest insulin resistance, the most marked changes in the egg and the lining of the uterus, and the greatest risks in pregnancy. Women with the form without raised androgens usually have a better outlook. For this reason, the phenotype helps the doctor to judge each woman’s chances and risks correctly.
Which other factors must not be missed?
PCOS does not protect against other causes of infertility. The Italian guideline recommends checking the male factor in every case. A semen analysis is therefore part of the assessment from the start. The doctor decides individually whether to check that the tubes are open, especially when their condition is unclear, for example when there has been no previous pregnancy. Before the diagnosis, the doctor rules out other conditions with a similar picture, such as thyroid disorders, raised prolactin or non-classic congenital adrenal hyperplasia. Functional hypothalamic amenorrhea can look like PCOS on ultrasound and can also occur together with it. More in the article “PCOS and functional hypothalamic amenorrhea”.
Age also matters. The high ovarian reserve in PCOS is an advantage, but it does not protect against the decline in egg quality with age. On top of this come emotional strain, a negative body image and changes in sexual life. These are more common in PCOS and make the path to a child even harder. More in the article “Pregnancy at an older age”.
How is the clinical form assessed hormonally?
Before any treatment, the doctor needs to know which form of PCOS a woman has and which mechanism is dominant. The assessment includes the pituitary hormones (LH and FSH), the androgens (total and free testosterone, SHBG, androstenedione, DHEA-S), AMH, the thyroid, prolactin and 17-hydroxyprogesterone. A glucose tolerance test with insulin measurement shows the metabolism. Measuring progesterone on the right day shows whether and when ovulation happens.
No single value means much on its own. Together with the cycle, weight, age and medical history, they show whether the main problem is the signal from the brain, the androgens, insulin or the lining of the uterus. The treatment follows from this picture.
How do the ovaries and the lining of the uterus work in step?
Ovulation alone is not enough. For a pregnancy, the maturation of the follicle, ovulation, progesterone production and the preparation of the lining must happen at the right time and in the right order. In PCOS, this timing is often lost. Ovulation can come late in the cycle, the luteal phase can be too weak, or the lining may not respond properly to progesterone.
For this reason, the doctor does not aim only for ovulation. The doctor first corrects the hormonal and metabolic balance, follows the cycle and, where needed, supports the luteal phase. The aim is for the ovaries and the lining of the uterus to work together again, so that the embryo finds a prepared lining when it reaches the uterus.
The importance of this timing is clearest in the form of PCOS with regular periods, the third phenotype. These women often ovulate, and yet pregnancy does not happen. The cause often lies in the second half of the cycle: in the quality of the egg, in the luteal phase and in the timing between the ovary and the lining of the uterus. As a result, fertilization or implantation may not take place. In these women, inducing ovulation alone is not enough. They need a targeted assessment of the second half of the cycle.
The ovaries and the lining of the uterus in step
Follicle maturation
FSH selects one follicle.
In PCOS: androgens, insulin and AMH slow down the selection.
Ovulation
The egg is released.
In PCOS: late, rare or not at all.
Luteal phase
Progesterone prepares the lining.
In PCOS: often too weak, also in the form with regular periods.
Implantation
The embryo finds a prepared lining.
In PCOS: the lining responds less to progesterone.
How is it treated?
The international guideline describes a clear path. It starts with preparation for pregnancy: weight, blood pressure, glucose tolerance test, smoking, alcohol, folic acid and mental health.
The first choice for inducing ovulation is letrozole, a tablet. In a large randomized trial in 750 women with PCOS (New England Journal of Medicine, 2014), the birth rate was about 28% with letrozole compared with 19% with clomiphene citrate. Metformin has a place as an addition in women with insulin resistance. The second choice is low-dose hormone injections with close monitoring, or laparoscopic surgery on the ovaries. The guideline still considers inositol and weight-loss medicines experimental for fertility.
What about IVF?
IVF is the third choice, when other treatments have not worked or when there are other factors, such as a problem with the tubes or the sperm. In PCOS, the ovaries often respond very strongly. This is why the risk of ovarian hyperstimulation is higher. Modern protocols, with a GnRH antagonist, triggering ovulation with a GnRH agonist and freezing all embryos, greatly reduce this risk.
The chances are good. In a randomized trial in 1,508 women with PCOS (New England Journal of Medicine, 2016), the transfer of frozen embryos led to a birth in about 49% of women, compared with 42% with the transfer of fresh embryos. Hyperstimulation fell from about 7% to 1%. Preeclampsia, however, was slightly more common after the transfer of frozen embryos. The preparation of the lining for the transfer therefore matters. Newer observational studies show more births when the transfer takes place in a cycle with induced ovulation rather than with hormones alone.
The article “PCOS and reproduction” describes miscarriage, risks in pregnancy, birth and breastfeeding in PCOS in detail.
The practice's approach
PCOS is one of the main areas of focus of the practice. The doctor starts with the hormonal assessment of the clinical form of PCOS, because each form has a different cause of infertility and needs a different treatment.
At the center of treatment is the timing between the ovaries and the lining of the uterus. The doctor corrects the hormonal and metabolic balance, so that ovulation and the preparation of the lining happen at the right time again. The choice of medicines depends on the form of PCOS and follows the 2023 international guideline and the latest data.
The aim of the practice is a pregnancy in the simplest possible way. When IVF is needed, the woman arrives at the fertility center with a complete hormonal picture and a better starting point.
Sources: Teede HJ et al., Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome, Human Reproduction 2023 (Monash University, ESHRE, ASRM). Palomba S et al., Diagnosis and management of infertility in patients with polycystic ovary syndrome (PCOS): guidelines from the Italian Society of Human Reproduction (SIRU) and CECOS Italy, Reproductive Biology and Endocrinology 2025. Palomba S, Piltonen TT, Giudice LC, Endometrial function in women with polycystic ovary syndrome: a comprehensive review, Human Reproduction Update 2021. Dewailly D et al., Interactions between androgens, FSH, anti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary, Human Reproduction Update 2016. Franks S et al., Follicle dynamics and anovulation in polycystic ovary syndrome, Human Reproduction Update 2008. Legro RS et al., Letrozole versus clomiphene for infertility in the polycystic ovary syndrome, New England Journal of Medicine 2014. Chen ZJ et al., Fresh versus frozen embryos for infertility in the polycystic ovary syndrome, New England Journal of Medicine 2016. Ovulation induction regimens are associated with a higher rate of livebirth after frozen single-blastocyst transfer among women with polycystic ovary syndrome (2022). WHO – Guideline for the prevention, diagnosis and treatment of infertility (2025).