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Pharmacotherapy for Individuals with PCOS

by , | June 29, 2024 | Articles, Hormone Health

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PCOS has often been viewed or treated as a gynecologic condition, however it is now being better understood as a condition that involves the endocrine system and is both a gynecologic and metabolic condition. To be formally diagnosed with PCOS, individuals must present with two of the three categories of signs and symptoms: hyperandrogenism (high testosterone levels leading to symptoms such as facial hair and acne), polycystic ovaries, or oligo- anovulation (periods that are >35 days apart)[1]. Individuals with a PCOS diagnosis can make impactful changes through nutritional, supplemental, and lifestyle interventions. Medical interventions may be necessary. This needs to be discussed with your medical provider and through the lens of your specific condition and symptoms. This article will focus on pharmacological approaches that can be utilized for those with PCOS.

Combined Oral Contraceptives (COC) (used to protect the endometrium and reduce testosterone)

For women who have hyperandrogenism or infrequent menstrual cycles, COCs are often a first line intervention and are most commonly used as a long-term treatment for those with PCOS. It is important to note that the COCs commonly prescribed are comprised of estrogen and synthetic progestins. Some progestins can be more androgenic (have testosterone-like effect) while others are less so. In our clinical practice, we carefully select less androgenic progestins for individuals with elevated testosterone levels.

Progestins in OCPs with higher levels of androgenic activity include: Norgestrel and Levonorgestrel

Progestins in OCPs with mid-range of androgenic activity are: Norethindrone and Norethindrone acetate.

Progestins in OCPs with lower levels of androgenic activity include: Norgestimate, Desogestrel, and Drospirenone

Some of the benefits of using COCs for those with PCOS are:

  • Helping to normalize and regulate menstrual cycles[2]
  • Protecting the endometrium from unopposed estrogen[3]
  • Lowering androgens[4]
  • Decreasing luteinizing hormone[5]
  • Increasing sex hormone binding globulin[6]
  • Suppressing the hypothalamic pituitary ovarian axis[7]

Progestin only, or Progesterone Only Treatment (used to protect the endometrium)

As an alternative option, some physicians may prescribe cyclical oral micronized progesterone instead. This type of progesterone is also referred to as bioidentical and is available as the FDA approved medication Prometrium (oral micronized progesterone). Some believe that synthetic progestins and bioidentical progesterone affect ovulation differently, and cyclical oral micronized progesterone may be more ovulation-promoting. [8] Our team has not been able to identify research supporting this statement, however, in clinical setting, we have observed that some individuals can come off cyclical progesterone and resume normal cycles. This result, however, can be due to multiple interventions.

When prescribed, cyclical progesterone is typically prescribed in the following manner:

  • Take one dose between 200-300mg at nighttime as it can make people tired or groggy.[9]
  • Take for two weeks on and then two weeks off (if cycles are irregular).
  • Once your cycle is regular it is best to take progesterone during the luteal phase of the menstrual cycle.[10] The luteal phase occurs after ovulation, and for a 28-day cycle, the luteal phase would occur after day 14 (ovulation day) until day 28.
  • Cyclical progesterone is NOT used as birth control.
  • Always consult with your physician about the best option for hormonal therapy and dosing for you. Note that certain individuals may have contraindications to being on hormone therapy.

Another option is medroxyprogesterone acetate 10-14 days every 1-2 months (does not confer protection from pregnancy). Progestin-only pill can be prescribed and taken daily (not in a cyclical fashion), or progestin-releasing IUD can be used, if birth control is desired and there is a contraindication for estrogen.

Spironolactone (primarily prescribed for hirsutism and acne)

Spironolactone is primarily utilized in instances of hyperandrogenism causing hirsutism (male pattern hair growth) and acne. Spironolactone is considered a mineralocorticoid receptor antagonist, meaning it can bind to both progesterone and androgen receptors in the body.[11] The reason spironolactone is often used in the treatment of acne is because it may reduce sebum production by binding to androgen receptors.[12] The effectiveness of using spironolactone to treat hyperandrogenism has been shown, in addition to data showing it may have positive effects on lipid profiles and glucose metabolism.[13] In some instances, using spironolactone in conjunction with metformin has shown to reduce BMI and lower total testosterone. [14]

Metformin (primarily prescribed for the management of diabetes)

Metformin is an anti-diabetic agent that is primarily used when managing diabetes, trying to prevent the development of diabetes, and in individuals with PCOS.[15] It is important to note that Metformin is not recommended for weight loss or for individuals with normal glucose tolerance. Metformin helps to enhance insulin sensitivity, reduce intestinal absorption of glucose and decrease glucose production in the liver with the overall goal of lowering blood glucose levels. [16] The exact role of Metformin in the treatment of ovulation disorders in women with PCOS is unclear. It is important to note that using Metformin alone is not recommended for the treatment of anovulation (lack of ovulation). [17] In fertility treatment, metformin may be recommended for women who are or become resistant to Clomiphene and some individuals may benefit from the use of both Clomiphene and Metformin.[18]

Clomiphene and Letrozole (primarily prescribed for ovulation induction and fertility treatment)

Letrozole and Clomiphene are considered first-line treatments for ovulation induction in women with PCOS who are planning a pregnancy. Both are SERMs, or selective estrogen receptor modulators, that are used primarily in instances of anovulatory (when a woman is not ovulating) or oligo-ovulatory (when a women’s ovulation is very infrequent) infertility.[19] Clomiphene and Letrozole function by binding to estrogen receptors leading to both an estrogenic and anti-estrogenic effect. It is important to note they can also increase LH, FSH, and testosterone levels. [20]

Letrozole is now suggested as a preferential choice for oligo-ovulatory women with PCOS over Clomiphene.[21] Letrozole was found superior to Clomiphene when looking at both pregnancy rates as well as live birth rates.[22] It is important to speak with your doctor about the appropriate dosing, timing and duration when using either of these SERMs.[23]

To maximize the efficacy and safety of the pharmacologic therapies outlined here, we strongly advise undergoing thorough bloodwork analysis under the care of a primary care provider, gynecologist, integrative medicine provider, endocrinologist, or fertility specialist. Subsequently, engage in a discussion with your doctor to interpret the results and develop a personalized treatment plan to establish precise dosages, optimal timings, and the ideal duration for these interventions. Furthermore, it is important to consider the potential synergies of integrating nutritional, supplemental, and lifestyle interventions, as part of your treatment plan.

References

  1. Christ JP, Cedars MI. Current Guidelines for Diagnosing PCOS. Diagnostics (Basel). 2023 Mar 15;13(6):1113. doi: 10.3390/diagnostics13061113. PMID: 36980421; PMCID: PMC10047373. ↑
  2. Reed BG, Carr BR. The Normal Menstrual Cycle and the Control of Ovulation. [Updated 2018 Aug 5]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279054/ ↑
  3. Yang, S., Thiel, K. W., & Leslie, K. K. (2011). Progesterone: the ultimate endometrial tumor suppressor. Trends in endocrinology and metabolism: TEM, 22(4), 145–152. https://doi.org/10.1016/j.tem.2011.01.005 ↑
  4. Shah, D., Patil, M., & National PCOS Working Group (2018). Consensus Statement on the Use of Oral Contraceptive Pills in Polycystic Ovarian Syndrome Women in India. Journal of human reproductive sciences, 11(2), 96–118. https://doi.org/10.4103/jhrs.JHRS_72_18 ↑
  5. Shah, D., Patil, M., & National PCOS Working Group (2018). Consensus Statement on the Use of Oral Contraceptive Pills in Polycystic Ovarian Syndrome Women in India. Journal of human reproductive sciences, 11(2), 96–118. https://doi.org/10.4103/jhrs.JHRS_72_18 ↑
  6. El Hayek, S., Bitar, L., Hamdar, L. H., Mirza, F. G., & Daoud, G. (2016). Poly Cystic Ovarian Syndrome: An Updated Overview. Frontiers in physiology, 7, 124. https://doi.org/10.3389/fphys.2016.00124 ↑
  7. El Hayek, S., Bitar, L., Hamdar, L. H., Mirza, F. G., & Daoud, G. (2016). Poly Cystic Ovarian Syndrome: An Updated Overview. Frontiers in physiology, 7, 124. https://doi.org/10.3389/fphys.2016.00124 ↑
  8. Briden, L. (2024, January 10). Cyclic progesterone therapy for PCOS. Lara Briden – The Period Revolutionary . https://www.larabriden.com/cyclic-progesterone-therapy-for-pcos/#:~:text=Cyclic%20progesterone%20%E2%80%9Caddresses%20the%20central,menstrual%20cycles%2C%20and%20fertility.%E2%80%9D ↑
  9. Prior, J. (2018, December 5). Cyclic Progesterone Therapy. The Centre for Menstrual Cycle and Ovulation Research. https://www.cemcor.ubc.ca/resources/cyclic-progesterone-therapy ↑
  10. Briden, L. (2024, January 10). Cyclic progesterone therapy for PCOS. Lara Briden – The Period Revolutionary . https://www.larabriden.com/cyclic-progesterone-therapy-for-pcos/#:~:text=Cyclic%20progesterone%20%E2%80%9Caddresses%20the%20central,menstrual%20cycles%2C%20and%20fertility.%E2%80%9D ↑
  11. Patibandla S, Heaton J, Kyaw H. Spironolactone. [Updated 2023 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554421/ ↑
  12. Layton, A. M., Eady, E. A., Whitehouse, H., Del Rosso, J. Q., Fedorowicz, Z., & van Zuuren, E. J. (2017). Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review. American journal of clinical dermatology, 18(2), 169–191. https://doi.org/10.1007/s40257-016-0245-x ↑
  13. Rani, N., Kumar, P., Mishra, A. K., Sankuratri, B. Y. V., Sethi, S., Gelada, K., & Tiwari, H. (2021). Efficacy of Spironolactone in Adult Acne in Polycystic Ovary Syndrome Patients an Original Research. Journal of pharmacy & bioallied sciences, 13(Suppl 2), S1659–S1663. https://doi.org/10.4103/jpbs.jpbs_391_21 ↑
  14. Zeng, H., Zhang, Y., Huang, S., Wu, J., Ren, W., Zhou, L., Huang, L., & Ye, Y. (2023). Metformin combined with spironolactone vs. metformin alone in polycystic ovary syndrome: a meta-analysis. Frontiers in endocrinology, 14, 1223768. https://doi.org/10.3389/fendo.2023.1223768 ↑
  15. Corcoran C, Jacobs TF. Metformin. [Updated 2023 Aug 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK518983/ ↑
  16. Corcoran C, Jacobs TF. Metformin. [Updated 2023 Aug 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK518983/ ↑
  17. Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org, & Practice Committee of the American Society for Reproductive Medicine (2017). Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertility and sterility, 108(3), 426–441. https://doi.org/10.1016/j.fertnstert.2017.06.026 ↑
  18. Johnson N. P. (2014). Metformin use in women with polycystic ovary syndrome. Annals of translational medicine, 2(6), 56. https://doi.org/10.3978/j.issn.2305-5839.2014.04.15 ↑
  19. Mbi Feh MK, Patel P, Wadhwa R. Clomiphene. [Updated 2024 Jan 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559292/ ↑
  20. Mbi Feh MK, Patel P, Wadhwa R. Clomiphene. [Updated 2024 Jan 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559292/ ↑
  21. Sakar MN, Oglak SC. Letrozole is superior to clomiphene citrate in ovulation induction in patients with polycystic ovary syndrome. Pak J Med Sci. 2020 Nov-Dec;36(7):1460-1465. doi: 10.12669/pjms.36.7.3345. PMID: 33235557; PMCID: PMC7674913. ↑
  22. Franik S, Le QK, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2022 Sep 27;9(9):CD010287. doi: 10.1002/14651858.CD010287.pub4. PMID: 36165742; PMCID: PMC9514207. ↑
  23. Guang, H. J., Li, F., & Shi, J. (2018). Letrozole for patients with polycystic ovary syndrome: A retrospective study. Medicine, 97(44), e13038. https://doi.org/10.1097/MD.0000000000013038Uptodate.com ↑

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