Another one from the archives. This one is an article in the July 2014 JFPRHC explaining the physiology behind PCOS and our treatments, by W. Colin Duncan, clinical fellow and consultant in reproductive medicine at the University of Edinburgh. It’s complicated, but helpful enough that I’ve been keeping it around until I had time to summarise it for this blog.
The production of androgens and oestrogens
Androgens are produced from cholesterol in two places in the body:
- The thecal cells of the ovarian follicle, under the stimulation of LH
- The adrenal glands
Normally these produce roughly equivalent amounts of androgen.
There are two other important players we need to know about in this situation:
- SHBG acts as a ‘sponge’ to mop up any excess circulating androgen. Hence, a deficiency in SHBG will mean that excess androgen levels aren’t dealt with and remain high.
- Insulin potentiates the action of LH on thecal cells, meaning that the LH will be more effective in inducing androgen production. Higher levels of circulating insulin are therefore associated with higher levels of androgen production.
So, three things that can lead to increased androgen production are:
- Increased LH
- Decreased SHBG
- Increased insulin
Oestrogens are, in their turn, produced from androgens. The androgen –> oestrogen conversion is carried out by aromatase, in the granulosa cell layer of the ovarian follicle, under the stimulation of FSH. (OK, I just gave myself a Cluedo flashback. It was… the FSH, with the aromatase, in the granulosa cells!) Oestrogen then inhibits FSH secretion in a negative feedback loop. (That bit will come in later, so remember it.)
(The thecal cell layer is the outer layer and the granulosa cell layer is the inner layer, but that doesn’t seem terribly important from the point of view of what goes on hormonally.)
So… why is this important?
Because androgen inhibits the growth of larger antral follicles but stimulates the growth of smaller antral follicles in the ovary. Therefore, excess androgen is going to stimulate an ovary to develop multiple small follicles that don’t spontaneously progress – in other words, it’s going to turn it into a polycystic ovary. This has been seen in rhesus monkeys treated with exogenous androgens, and in women with conditions causing pathological increase of endogenous androgens (androgen-secreting tumours and late-onset CAH).
So, the three situations listed above that produce increased androgen production can each contribute to the development of PCOS. In addition, a vicious circle can develop with the increased insulin secretion, as insulin causes weight gain, weight gain causes increased insulin resistance, increased insulin resistance causes increased insulin secretion… and hence causes greater amounts of circulating insulin, which causes weight gain. And weight and SHBG production are inversely related, so all that weight gain causes decrease in circulating SHBG and contributes to the symptoms.
But all this, of course, also gives us our clues about how to solve it. Because, if we can:
- Decrease LH, and/or
- Increase SHBG, and/or
- Decrease circulating insulin…
then we can decrease the amount of androgen in the system, and hence improve the symptoms of PCOS.
How can we do this?
Decreasing LH can be done with the COC (which decreases both gonadotrophins). Note that the progestogens in older COCs tend to be more androgenic in nature, so for obvious reasons the newer ones are preferred. Cyproterone has anti-androgenic effects, so using co-cyprindiol as the COC can be particularly helpful with androgenic symptoms, as it doesn’t just block ovarian androgen production but also inhibits the androgens being produced in the adrenal gland.
(This, of course, doesn’t help when the problem is that pregnancy is desired – that situation is discussed below.)
Increasing SHBG can be done, as you will have gathered from above, by losing weight – which will have the double advantage of improving insulin resistance and thereby also decreasing circulating insulin. This, of course, is why weight reduction is such a key part of improving PCOS symptoms. Note that exercise will improve PCOS symptoms even in the absence of weight loss symptoms.
Decreasing circulating insulin can, as above, be done by losing weight/increasing exercise/eating appropriately. The other way to improve it, of course, is by increasing insulin sensitivity with metformin treatment. Women seem to vary in how they respond to this, but it can improve symptoms of PCOS.
What about fertility?
The goal of fertility treatment, in this case, is to increase FSH levels so that more androgens get converted into oestrogens. As stated above, oestrogens inhibit FSH secretion, so oestrogen antagonists will increase it – and that’s how clomifene works. However, oestrogen is obviously needed for endometrial secretion, as well as to stimulate the mid-cycle surge of LH that triggers ovulation, which is why clomifene is only given at the beginning of the cycle.
If clomifene isn’t effective, the next step is to try injections to raise FSH directly. However, all those partly-developed but arrested follicles in the ovary can still develop if stimulated with FSH, so women with PCOS are at increased risk of ovarian hyperstimulation syndrome as a complication of FSH treatment.
The article also mentioned letrozole, which is an aromatase inhibitor and hence will reduce the amount of initial oestrogen production and raise the FSH level (so… you reduce oestrogen production in order to ultimately increase it? Negative feedback loops can get complicated). It didn’t go into any details about how this might be deployed.
And don’t forget endometrial protection
Remember that those anovulatory cycles are leaving women exposed to unopposed oestrogen – as well as being a long-term risk, this can cause prolonged heavy bleeding in the short term. Amenorrhoeic women with PCOS need some kind of endometrial protection:
- The COC obviously does the trick
- LNG-IUS is an option
- If women aren’t on either of these, it’s worth inducing three or four withdrawal bleeds a year. This can be done with oral MPA 10 mg twice daily for 7 days or once daily for 10 days; the bleed should occur a few days after stopping treatment. (If the bleed is particularly heavy, try giving the treatment more often so that there’s less chance for the endometrium to build up.) This would, I suppose, be useful in women who don’t want to be using contraception.
The COC, particularly one containing cyproterone, may deal with this. If not, look at options such as topical eflornithine or laser therapy. (The article didn’t mention any other options such as spironolactone.)