Cyclic Progesterone Therapy for PCOS

Progesterone has anti-androgen benefits and can promote ovulation. That makes progesterone therapeutic for polycystic ovary syndrome, as described in my recent paper The central role of ovulatory disturbances in the etiology of androgenic polycystic ovary syndrome (PCOS)—Evidence for treatment with cyclic progesterone.

By “progesterone,” I mean real progesterone, also called body-identical progesterone or oral micronized progesterone (OMP), which is available as products such as Prometrium, Utrogestan, Teva, and Famenita, depending on your country. Progestins, on the other hand, are not progesterone and do not exert the same ovulation-promoting effect. And although some progestins (e.g. drospirenone) are anti-androgenic, others (e.g. levonorgestrel) are androgenic or testosterone-like and can worsen the androgen excess and insulin resistance of PCOS.

PCOS begins in the brain

Most evidence points to a “neuroendocrine” basis for PCOS, which means that dysfunction in the brain, or more specifically, in the hypothalamus, is the main cause of ovarian androgen excess. It works like this:

In a normal, healthy menstrual cycle, the hypothalamus releases pulses of GnRH (gonadotrophin-releasing hormone), first slowly, then more rapidly, and then slowly again after ovulation. In turn, those pulses stimulate pituitary hormones (FSH and LH) that coordinate ovulation and promote the healthy production of estrogen and progesterone.

A key feature of a healthy neuroendocrine system is progesterone’s beneficial slowing effect on GnRH pulsatility. In other words, progesterone (made by ovulation) exerts beneficial negative feedback on the hypothalamus, thereby lowering androgens and promoting future ovulation.

Normal neuroendocrine function of the hypothalamic-pituitary-ovarian (HPO) axis.
Normal GnRH pulsatility promotes ovulation and progesterone.

With PCOS, rapid GnRH pulses result in chronically elevated LH, androgen excess, insulin resistance, and ultimately, progesterone deficiency due to anovulation.

Neuroendocrine disturbance in PCOS
Abnormal or high GnRH pulsatility is associated with polycystic ovary syndrome.

Unfortunately, progesterone deficiency then promotes a vicious cycle of impaired feedback on the hypothalamus, leading to persistently rapid GnRH pulses and further anovulation.

👉🏽 Tip: High GnRH pulsatility is ultimately caused by a combination of genetics and epigenetics resulting from in-utero exposure to androgens and environmental toxins. High insulin or insulin resistance also contributes to high GnRH pulsatility.

Cyclic progesterone therapy to lower androgens

According to Professor Jerilynn Prior, “cyclic progesterone therapy is treatment with the natural progesterone hormone (oral micronized progesterone, Prometrium® or compounded in oil) in a way that mimics the normal pattern (14 days in the last half of the menstrual cycle) and amount (300 mg at bedtime).”

In our paper, Professor Prior and I explain the four mechanisms by which cyclic progesterone therapy can improve androgenic PCOS:

  • By inducing withdrawal bleeds, progesterone can prevent endometrial hyperplasia, atypia, and endometrial cancer. Tip: If cyclic progesterone does not induce a withdrawal bleed, it’s probably not PCOS.
  • By competing for the enzyme 5-alpha-reductase, progesterone reduces dihydrotestosterone (DHT), the active form of testosterone, thus relieving acne, hirsutism, and androgenic alopecia. This is the same enzyme that converts progesterone to the calming neurosteroid allopregnanolone, which is why progesterone is usually good for mood.
  • By increasing metabolic rate, progesterone can promote weight loss.

And most importantly:

  • Cyclic progesterone “addresses the central pathophysiology of androgenic PCOS by slowing the pulse frequency of both GnRH and LH to allow normal FSH and follicle growth and to promote normal reproductive cyclicity, ovulatory menstrual cycles, and fertility.”

By slowing GnRH pulsatility and lowering androgens, cyclic progesterone therapy can also help to improve insulin resistance.

How to take cyclic progesterone therapy

Many of my PCOS patients have had success with cyclic progesterone at a lower dose of 100 mg at bedtime. Taken cyclically two weeks on, two weeks off.

👉🏽 Tip: It’s best to take progesterone at bedtime because oral progesterone can be very sedating. Taking it during the day can cause grogginess and depression.

If cycles are irregular and anovulatory, the starting dose is two weeks on and two weeks off until regular ovulation can be established.

Once cycles become ovulatory, switch to taking progesterone only during the two weeks of the luteal phase (i.e. starting a day or two after ovulation). After six or more ovulatory cycles, you may be able to stop taking progesterone because you’re now making it.

To obtain oral micronised progesterone, you’ll need a prescription from your doctor. You could try saying:

“Could I please try a few months of Prometrium for PCOS? According to this Canadian endocrinology professor, progesterone can induce a withdrawal bleed and improve androgen symptoms.”

Show your doctor a printed copy of our paper The central role of ovulatory disturbances in the etiology of androgenic polycystic ovary syndrome (PCOS)—Evidence for treatment with cyclic progesterone and say you “would like to trial it for three months.” If your doctor is hesitant, offer to leave it with her and return for a second appointment. Email me for a PDF copy of the full paper.

Is progesterone safe?

Unlike progestins which are associated with mood side effects and an increased risk of breast cancer, body-identical progesterone is safe. For example, progesterone is usually beneficial for mood and sleep, and according to Professor Prior, natural progesterone may even help to reduce the risk of breast cancer.

As discussed in my “Guide to progesterone” blog post, cyclic progesterone therapy can also be helpful for perimenopause, heavy periods, endometriosis, adenomyosis, migraines, and premenstrual mood symptoms, including PMDD.

In conclusion, cyclic progesterone therapy is potentially beneficial for PCOS. It can be safely combined with other PCOS treatments, such as metformin, spironolactone, and inositol. Ask me in the comments.

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