Infertility

Second last post on endocrine pathophysiology!

Appreciate that the cause of infertility can be male, female or both and that our understanding of male infertility (unlike female infertility) is limited

Infertility, defined as the lack of conception after 1 year of frequent, unprotected intercourse, is actually a relatively common problem, affecting around 10-15% of couples. Around 20% of infertility is due to unknown causes, but of those that are known, around 40% is due to female factors, 40% due to male factors and 20% due to factors from both partners.

To understand infertility, it might first help to understand the workings of the reproductive system. Here are some posts that might help:

• Endocrinology of Reproduction part 1
• Endocrinology of Reproduction part 2
• Endocrinology of Reproduction part 3

Now onto the pathological stuff! Let's look at male infertility first, even though less is known about that.

There are structural causes for male fertility, as well as some possible environmental ones. Structural causes include a complete lack of the vas deferens, which might happen in some patients with cystic fibrosis. Some patients have varicose veins (varicocoele) in the spermatic cord, which causes pooling of blood and an increase in temperature in that area. (As you should probably know, sperm need to be at a slightly lower temperature in order to develop.) Undescended testes are also a problem.

Possible environmental causes include excessive heat and some chemical toxins, including drugs. Anabolic androgenic steroids can increase negative feedback on the pituitary and hypothalamus, resulting in hypogonadotropic-hypogonadism (i.e. a decline in gonadotropins leading to smaller gonads). Another drug that may cause infertility is an alopaecia (baldness) treatment called finasteride, which inhibits 5α-reductase (an enzyme that converts testosterone into dihydrotestosterone).

Semen analyses are sometimes used to diagnose infertility. Volume and viscosity of the semen, as well as density, motility and morphology of the sperm within, are examined to see if they fall into the normal range or not.

Since we don't know much about male infertility, we don't have many ways to treat it. Aside from encouraging patients to live a healthy lifestyle and crossing our fingers and hoping for the best, there's not really a lot we can do. There are, however, some technologies that we can use, such as intrauterine insemination of concentrated sperm (getting the semen, concentrating it and administering it into the uterus), IVF and intracytoplasmic sperm injection (ICSE- it's basically like IVF except you're taking a single sperm and injecting it straight into the egg).

Know the various causes of secondary amenorrhoea and be able to differentiate between ovulatory and structural causes
Be aware that female fertility declines long before menopause

Amenorrhoea, lack of menstruation, often goes hand in hand with anovulation (lack of ovulation) and hence female infertility. (However, not all amenorrhoea is anovulatory, as you shall soon see.) There are structural causes as well as immunologic ones (sometimes antibodies are formed against sperm or against the growing foetus). As mentioned above, fertility declines with age, especially from around age 35 onwards. This could be due to a variety of factors, such as older oocytes being "suboptimal" (more likely to have chromosome abnormalities, defective spindles, etc.), or simply from an increased likelihood of developing disorders within the reproductive tract.

Amenorrhoea can be divided into primary or secondary amenorrhoea. This division is a bit different from divisions of other endocrine disorders. In this case, primary amenorrhoea means that the patient has never had a menstrual period, whereas secondary amenorrhoea means that they used to have menstrual periods, but then stopped for some reason. Primary amenorrhoea might be caused by genetic disorders such as Turner syndrome (where the patient only has a single X chromosome), or by congenital disorders. Secondary amenorrhoea might be caused by CNS or pituitary tumours such as prolactinomas (prolactin has an inhibitory effect), inhibition of GnRH by stress, excessive exercise or otherwise, or by some kind of obstruction of the outflow tract. When obstruction is the issue, ovulation happens fine- it's just that the uterine lining can't get out because of the obstructions. Important obstructions to know about are leiomyoma (benign tumours of the myometrium) and Ashermann's syndrome (scarring of the uterine lining). Another issue may be blocked fallopian tubes, which usually occurs as a result of pelvic inflammatory disease.

Treatment of secondary amenorrhoea depends on the cause. In the case of leiomyomas and other tumours obstructing menstrual flow, surgical removal of the offending structure is often warranted. In the case of blocked fallopian tubes, surgical reanastomosis (cutting out the blocked bits and rejoining the good bits) may help. Some other medications may also be helpful: bromocriptine stops prolactin from exerting its inhibitory effects, as mentioned earlier, clomiphene can stimulate gonadotropin release by blocking negative feedback via oestrogen, and exogenous gonadotropins can also help. If the patient isn't worried about whether they can conceive or not, an oral contraceptive can be given to help maintain bone health (oestrogen is protective against osteoporosis).

Endometriosis

Endometriosis is another common problem that may affect fertility. Endometriosis is a condition where there is ectopic endometrium- that is, endometrium growing where it shouldn't be. This causes dysmenorrhoea (pain during menses) and dyspareunia (pain during intercourse). This can be treated by removing the stimulus for growth of the endometrium- that is, by preventing ovulation from occurring. This can be done by giving a GnRH agonist (sounds counter-intuitive, but this actually desensitises the GnRH receptor) or by giving an oral contraceptive. This, however, results in infertility. Sometimes the ectopic endometrium may be removed surgically.

Polycystic Ovary Syndrome (PCOS)

In PCOS, many follicles develop, appearing as a "string of pearls" on ultrasounds and other forms of imaging. Hardly any of these follicles develop fully, however, resulting in oligo-ovulation (few ovulations) or no ovulation. LH, FSH and androgen levels may all be elevated, and patients with the condition may develop insulin resistance (acanthosis nigricans). Due to the hyperandrogenism, patients with PCOS often have male-pattern body hair (so chest hair, beards etc.). It's not entirely sure what causes this, but a majority of patients with the syndrome (60%) are obese, so weight may be a factor.

Treatment for PCOS mainly consists of weight loss and a few different medications that may help with the symptoms. Even just a 5% decrease in body weight can help menstrual cycles return to normal. Clomiphene and aromatase inhibitors can stimulate FSH and thus ovulation, metformin can help with the diabetes as well as weight loss and menstrual cyclicity, and exogenous gonadotropins can also help stimulate ovulation. Alternatively oral contraceptives can be given to treat the hirsutism (excess body hair), but obviously this means that the patient will be unable to conceive. Oral contraceptives increase levels of sex-hormone binding protein (SHBG), which binds to androgen and stops it from causing excess hair growth.

Just one more post to go on this topic!