So, infertility and endocrinopathies. Nothing to disclose. So, infertility is a disease of the reproductive system characterized by inability to conceive after 12 months of regular unprotected intercourse. One of six people worldwide will experience infertility. Research indicate that 80% of the couples with a female partner under the age of 40 are likely to conceive within 12 months. So, as an endocrinologist, what is our role? A lot of our patient will have a pre-existing condition like hypothyroidism, hyperthyroidism, hyperprolactinoma, and our responsibility will be optimizing their treatment before and during pregnancy. We will see patient with amenorrhea, irregular menses, delayed puberty, azospermia, and we affiliate as well with a program of assisted reproductive technology. So, what is the referral guidelines? Actually, the recommendation depends on female age and the duration of infertility. So, usually for a female partner, if the age is below 35, we refer after 12 months of trying to conceive without success. If the age is 35 to 40, we refer after six months. But when the age is above 40, we refer immediately for evaluation and treatment. So, there is a special consideration, of course. Referral may be earlier for women and men depending on the condition, like for female with irregular cycle, polycystic ovary, endometriosis, recurrent pregnancy loss. For male, previous testicular surgery, chemotherapy, non-genetic disorder. So, a 32-year-old female and a 34-year-old male partner have been trying to conceive for the last two years. The female has a history of irregular menstrual cycle, hercitism, obesity, and she was diagnosed with a polycystic ovarian syndrome. Her partner has oligospermia with a sperm count of nine million per mL and 30% motility discovered incidentally during workup. So, what is the causes of infertility? Actually, female infertility, we find that ovulatory dysfunction, tubular factor like indigestion, tubular factor like endometriosis, inflammatory bowel disease, inflammatory, sorry, pelvic disease, and age-related decline in ovarian reserve for female. For male infertility, sperm production issues, varicocele and genetics. And of course, we have the combined factor, male and male factors in like 10 to 20% of the cases. So, female infertility. We'll talk about normal ovarian function. Usually, oocytes are laid down in the female fetus by 20 weeks gestation, and there is a continual oocyte loss occurs from 20 weeks gestation and going onward, and at puberty, the oocytes begin to mature for reproduction and one oocyte is produced each cycle. So again, the oocyte quality and quantity will decline with age, and the risk of miscarriages is increased and as well, the risk of fetus anomalies. So, this is an interesting observational study to talk about like fetus and the oocytes. So, around seven million oocytes are laid down in the fetus female, and at birth, this number will decline to around million, and this will continue to decline with age until menopause, and we can see that it's varied between female. So, now, let's start talking about ovarian reserve testing. Ovarian reserve testing is like very common, and it's a good predictor of response to stimulation in a fertility treatment, but it's a poor predictor of chance of natural conception. Female with irregular menses and low ovarian reserve has pretty much same chances of conception with each cycle, and here is the question. Is it a good predictor of time left? Is it a good predictor of time left? Currently, many women are testing their ovarian reserve, but it often provides a false reassurance as it only measures the quantity, not the quality of the egg, and doesn't assess the quality, and we need to discourage the practice of checking AMH without a proper counseling or without fertility counseling. So, what is the ovarian reserve testing? We use the anti-Mullerian hormone check. It's a dimeric glycoprotein, and this excellent predictor of primary oocyte pool, minimal cycle variability, and usually the normal range is between one to three nanogram per milliliter. Another ovarian reserve testing is the antral follicular count, and antral follicular count is the number of the follicle in both ovaries typically measured via ultrasound, vaginal ultrasound, and normal range usually is between six and 10. Now, starting with a classification of anovulation, we'll start talking about hypogonadotrophic hypogonadism with a low FSH, LH, and estradiol. So, hypogonadotrophic hypogonadism could be congenital, a genetic mutation, including Kalman syndrome, and it may come later in life during adulthood, like we will see a female developing later in life due to a lot of factors like weight loss, stress, medical condition like prolactinomas, drugs, iron overload, renal failure, and immunological disease. So, I choose the function of hypothalamic amenorrhea because it's relatively common, particularly among women of reproductive age. It's caused by low body fat, excessive exercise, and caloric restriction. It's affecting fertility. Usually, BMI is not a good predictor because athletes tend to have a normal BMI, but it's mainly related to a low body fat, and the low body fat is the key for diagnosis. Usually, we need to address the underlying cause of this and encourage weight gain, reduce exercise, and recovery may take two to three years, and this is very important because if the female is 22 and 23 and we encourage weight gain, she can restore the ovulatory and fertility within the age of 25, 26, but if she is 32, 33, and we need to wait another two years, it's better to, we will use the ovulation induction by gonadotropin, but again, we need to make sure that we achieve a good body fat because low pregnancy outcome with a low body fat will still risk. Again, for normal gonadotrophic hypogonadism, it's a normal FSHLH estradiol and the high AMH. Usually, we see it in polycystic ovarian syndrome. So, polycystic ovarian syndrome, as well, is the most common hormonal disorder among women with reproductive age. We still use the same criteria since 2003, the Rotterdam criteria, the two out of three. Actually, I will talk about the ovulation induction in polycystic ovary and the first-line treatment is litrazole, like 2.5 to five milligram for five days from the first to sixth day of the cycle. Usually, higher pregnancy rate, a lower multiple pregnancy versus clomiphene. Again, clomiphene citrate is used, as well, and it's less effective than litrazole and the higher risk of multiple pregnancy. Metformin's still questionable. It's still in the guidelines, but a low evidence. Second-line treatment, so if we fail to achieve like pregnancy with the first line, we will start, we talk about gonadotropin treatment and ovulation will happen in 80% of the female and pregnancy rate's 50%. It has a lower risk of ovarian hyperstimulation syndrome. Ovarian drilling is another stimulation that we use. It has the same as gonadotropin, but it will be effective only for 12 months and there is a surgical risk, of course. The last choice is like assisted reproductive technology, like IVF and ICSI. Going to the third classification is hypergonadotrophic hypogonadism, high FSHLH with a low estradiol and AMH. Actually, this is a result of oocyte depletion. It's a devastating diagnosis. We really need to make sure before giving the patient this diagnosis and definitely counseling is very important. It's like the chances of pregnancy usually with the egg donation and there are a lot of legality behind this, different between each country. Now, we'll go to male fertility. So, male infertility is one of 20 men are subfertile. About 60% of the cases, we will not find a cause for that. Diagnosis is essential, although minority is treatable. 50% of assisted reproductive technology involve, solve, or contribute to a male factor. Of course, pre-consumption counseling and planning, we need to talk about obesity, smoking, exogenous testosterone, and anabolic steroids. As Dr. Tariq mentioned, the excessive alcohol and occupational exposure. And the common investigation that we check usually FSH, testosterone, prolactin, semen analysis. We may do a testicular ultrasound, karyotyping, genetic testing. Testicular ultrasound, karyotyping, genetic testing, and testicular biopsy. So, semen analysis is important, but it's only a rough guide to fertility. If we have a poor result, we need to repeat in six weeks. And we need always to make sure that sperm analysis is a test for sperm count, not the sperm function. So, this is the WHO references values for a normal female, sorry, for the semen analysis. Now, we will talk about FSH. Usually, FSH reflect the state of sperm production. So, in obstruction, we will find a normal FSH, normal testosterone with adospermia. Spermatogenic failure will be associated with a high FSH level, low testosterone, of course, and oligospermia. And if it's secondary to pituitary involvement, so the FSH will be low with a low testosterone level. So, now, what is the normal level of FSH? The cutoff is usually interesting, because if we look at the reference range, we will find it's different between centers, between labs. We need to have a kind of idea what is the normal level. So, this is an interesting observational study on 147 men, 124 of them are healthy and age between 21 and 35. And the consensus references of serum FSH was 1.3 to 8.4. And then, they consider like anything above 8.4 is a kind of abnormal. So, I will talk about this patient, 28-year-old male. Male has a primary infertility. He's easily fatigued, his wife is 27. And had a regular cycle. Semen analysis is 4 mL with azoospermia. On physical examination, he had a normal habitus, well-viralized, normal penis crotum. The testicular size is 3 mL. So, FSH and LH apparently high. Testosterone level is on a low normal value, 250 nanogram per deciliter. So, the karyotype testing is for XSF, Kleinfelter Syndrome. So now, hypergonadotrophic hypogonadism, spermatogenic failure, we see it in Kleinfelter Syndrome. Y dilation, chemo radiotherapy, vascular mumps, or chitis. And it could be idiopathic. There are many new gene causation with a recent publication. So, the number of diagnoses of gene was almost double to 21 gene. Application of this procedure in a routine diagnostic will significantly improve the diagnostic fields and clinical workup. As a result, indicate the success rate of the testicular sperm extraction. Again, it's recommended to perform genetic testing for any male with a sperm count of less than 10 million per mL. Genetic testing has an implication of the success of the ICSI and help to predict the risk of miscarriages and the likelihood of the live birth with disability. So, in our case, with the Kleinfelter Syndrome, what is the couple option? They came to us for, like, infertility. So, the only option for them is the testicular sperm extraction. It's a surgical procedure, micro-dissection, testicular sperm extraction. They isolate, like, overmatured spermatoids, and they use it for intracetoplasmic sperm injection. Of course, testosterone treatment is contraindicated, and it's reversible after six months. In Kleinfelter Syndrome, they find that there is a stem cell niche with a normal karyotype, and that the risk of offspring carrying this gene mutation is low. It's not the same for Y chromosomes, because for Y chromosome deletion, we know that all male will carry the gene, the all offspring. And it's very important to know exactly what is the micro-deletion happen in the Y chromosomes, because the likelihood of live birth and disability, the risk of miscarriages, is different between different micro-deletion. Now, hypogonadotrophic hypogonadism. It's a primary to pituitary hypofunction, like Kalman Syndrome is one of these cases. And it could be secondary, like surgery, radiation. And usually, we use the beta-RCG, and later, the FSH, for three weeks. And this procedure may take up to two years, especially with the Kalman, and the cases that have a very low level of FSH and H from the beginning. It's not the same scenario for secondary causes, because usually, for secondary, the stimulation may happen in a shorter duration. Now, the use of serums and the clomiphene, it's not FDA-approved, actually. And there is limited data about it. And better not to delay the effective treatment of fertility by gonadotrophin and assisted reproductive technology. And in summary, the time of referral of fertility is very important. Both partners should be undergoing evaluation. And the implementation of preconception lifestyle modification, including weight loss, increased exercise, and cessation of smoking, and assessing the ovarian reserve, consider referral for genetic evaluation and counseling. Thank you.

infertility

endocrinologists

ovarian reserve

IVF

genetic counseling