PCOS and Contraception: A Wrench in the Works

Thara Vayali, BSc, MA, ND

Polycystic Ovary Syndrome (PCOS) is also referred to as Anovulatory Androgen Excess, and a yet-to-be-determined name under development.1 This diagnosis of exclusion has thrown its net far and wide; as such, the assessment is fuzzy, the treatments are disheartening, and prognosis is confusing.2,3 Fundamentally, we are dealing with a broad-ranging female endocrine error syndrome that is increasing in incidence.1,2,4,5 As naturopathic physicians, we often see patients that fall into these sweeping diagnoses; there is no definitive box to fit within, so patients arrive forlorn and hoping for help from alternative medicine. If we can deconstruct the overarching diagnosis into its varied syndromes, we may be able to treat the wide range of root causes individually or – better yet – circumvent the preventable factors. To do this effectively, we must assess and treat the different patterns of female endocrine abnormalities as separate diagnoses. One pattern, which I think is worth spending time on, is the distinct effect of Low-Dose Estrogen (LDE) Combined Oral Contraceptives (COCs) on ovarian follicle growth, insulin sensitivity, and androgen release. The dosing schedule for LDE COCs may be creating symptoms that lie within the PCOS spectrum. This unexpected consequence can throw a wrench into the modern woman’s health plan. A realistic solution may be surprisingly simple.

Distinguishing Patterns in PCOS:

“The current name focuses on a criterion – ovarian cysts – which is neither necessary nor sufficient to diagnose the syndrome.”

(NIH Consensus Report, 2012)

In 2012, the NIH Consensus Report urged renaming and establishment of assessment and diagnostic criteria of PCOS.1

Close to 5 million American women and 1.4 million Canadian women suffer from one form of PCOS, the most common endocrine disorder in reproductive females.1,2,5,6 The current diagnosis of PCOS defines that 2 of 3 criteria are met: Anovulation, Hyperandrogenemia/Hyperandrogenism (HA), and/or several cysts on the ovaries.1,6

These can present in 4 possible phenotypic combinations1-3,6:

  1. HA + Anovulation + No cysts
  2. HA + Cysts + Ovulatory cycles
  3. Anovulation + Cysts + Normal androgen presentation
  4. Anovulation + Cysts + HA

The collection of symptoms is also associated with obesity, cardiovascular disease, non-insulin-dependent diabetes mellitus, and hormone-related cancers.1-3,7 A broad diagnosis that affects a broad range of systems leaves us with little to discern causes.

Defining each of these criteria is in a developing and unfinished state. The unanswered questions surround what parameters are appropriate for varying life stages, ethnicities, migration patterns, and compounding lifestyle factors.3,6,8

Originally, PCO morphology (PCOM) was described as a “string of pearls” >10, 2 to 8-mm cysts arranged in a necklace pattern.3,9,10 The clinical presentation has progressed over the years, and the dimensions of these diagnostic cysts are less clear. Biochemically, the understanding of PCOM is that gonadotropin-releasing hormone (GnRH) increases the release of luteinizing hormone (LH) relative to follicle-stimulating hormone (FSH), which stimulates follicular theca cell activity; hypertrophy of theca cells is present on histology, though this indistinguishable on ultrasound.3,6-9 Currently, ovarian volume >10 cm3, regardless of cyst morphology, is enough to diagnose PCOM.2,3

Findings suggest that a high insulin level is the common determinant of all phenotypes of PCOS.6,9 Insulin and LH work synergistically, causing the release of androgens from theca cells.8,9 In addition, insulin enhances the conversion of testosterone to dihydrotestosterone (DHT).11 These androgens cause the acne, balding, and unwanted hair often reported with PCOS.3,11,12

Insulin resistance is seen in PCOS patients in the absence of obesity or cystic ovaries, and is unaffected by changes in androgen levels.8 However, hepatic production of sex-hormone binding globulin (SHBG) protein is regulated by insulin (ie, when insulin levels are high, SHBG decreases, allowing for higher circulating free androgens.8,9 In this light, it seems that insulin affects steroid hormones more significantly than the reverse relationship.8

Insulin resistance, LH dominance, and hyperthecosis represent the root of this androgenic, anovulatory, ovarian cystic syndrome that affects women of all ages. Discovering why these issues are occurring – for the patient in front of us – is where our work lies.

Changes in Contraception

In 1960, the first oral contraceptive was introduced to the public.13 The use of high-dose ethinyl estradiol (EE) (150 µg per day) was effective in completely suppressing GnRH, and thus prevented ovulation.13,14

The original COC cycle-length was designed to mirror the average menstruating female’s cycle, helping to normalize the transition to hormonal contraception.13 The cycle was set to 21 days of hormones, with a 7-day hormone-free interval (HFI).13-15 The schedule was based on nothing more than the average menstrual cycle precedent.15

Fast-forward 50 years, and the playing field has altered significantly. In 1975, the first LDE pill was approved, with the doses of EE significantly reduced to 20-50 µg.13-16 A dose of 20 µg is the lowest possible concentration that effectively suppresses FSH.16 This change of focus and dosage failed to take into account the impact of a 7-day HFI on endogenous hormones.

In LDE COCs, timing of ingestion is crucial. The hormones metabolize within 24 hours; as a result, hormone suppression is effectively removed by Day 22.5,7,10,14-16 In the pre-1975 pills, EE levels were sustained for first 5 days of the HFI – enough to maintain follicle suppression while creating a withdrawal bleed.13,15 In post-1975 pills, no pill was higher than 50 µg of EE. To reduce harm and minimize side effects, currently most pill prescriptions contain 20-35 µg of EE per day.14,16 Yet, the HFI remains the same. In the 7-day HFI, as EE doses drop, FSH is no longer suppressed and endogenous hormones rebound like a reperfusion, with a significant surge of FSH on Day 4.5,7,10,14-16 Estradiol and FSH return to regular menstruation levels and can continue to increase from Day 4 to Day 12, even after EE is reinitiated.5,7,10,14-16 If pre-contraception ovulation dates were before Day 14, FSH will rebound more rapidly.17 If the FSH surge is inhibited, LDE COCs can maintain the complete hormonal suppression required for contraception.

What is the impact of this endogenous hormonal rebound? 5,7,14-16

  1. Increase in menstrual-like symptoms – breast tenderness, headache, bloating, pelvic pain, cramping
  2. Continued follicular development – increased risk of functional ovarian cysts and escape (unexpected) ovulation

The longer the HFI, the greater the growth of follicles during the HFI.10 In LDE COC users, the majority of follicles that develop are large enough to respond to ovulatory triggers.10

After the 7-day HFI, the exogenous hormones are reintroduced, which may or may not effectively suppress LH. Depending on the follicular maturation stage, the follicle may atrophy, ovulate, or remain as a functional ovarian cyst.10,14-16 These cysts are considered normal within a reproductive age group, and resorption generally occurs within 2-3 months.10,14-16 Functional ovarian cysts may not cause pain or known pathology, but do release hormones, and there is a higher incidence of these cysts when a long HFI and LDE are coupled.10

Though the true incidence of cysts is unknown, in the 1980s, women using COCs had fewer functional cysts recorded than in more recent years, where 40-50% of women have functional ovarian cysts detected on ultrasound.3,10

Two forms of functional ovarian cysts are relevant to LDE COC use:

  • Follicular cysts: Disordered folliculogenesis and maturation without rupture may cause follicle cyst formation16,18
  • Luteinized Unruptured Follicle (LUF) cysts: Follicles that reach pre-ovulatory diameters, fail to ovulate and become luteinized, either through granulosa cell luteinization (more commonly) or theca cell luteinization16,18

With FSH release and LH suppression, follicular cysts are the most likely to form. When FSH and LH have been elevated for more than 4 days and follicles are enlarged, LUF cysts are likely. While the mechanism of LDE COCs purposefully aims for temporary infertility, these cysts are inadvertently induced and have the potential to increase ovarian volume and increase circulating androgens; all 3 criteria of PCOS may be filled but not recognized.

The formation of these types of cysts in LDE COC users could shed light on cause within 1 region on the PCOS spectrum.

How Do LDE, 21/7 COCs Impact PCOS-like Symptoms?

Within this historical medical context, there are some females whose symptoms fall within the incomplete criteria of PCOS. They are suffering from uncertain ovulation, weight gain, acne, hair growth, hair loss, mood swings, and/or pelvic pain – indicative of hyperandrogenism and female hormone dysfunction.

EE in COCs lowers circulating testosterone by increasing SHBG4,5,6,19,20 and certain progestins are competitive agonists for androgen receptors.4,6 COCs suppress GnRH, thereby shutting down ovarian production of estradiol and progesterone.13,14 For these reasons, LDE COCs are a common, effective first-line prescription for managing PCOS, or PCOS-like symptoms.4,6,10

In the catch-22 that is medicine, COCs also increase insulin resistance.21 The circulating insulin triggers testosterone release from theca cells into the bloodstream, aggravating the long-term consequences of insulin resistance in PCOS. Compounding on itself, as female’s insulin resistance rises, the negative impact of COCs on metabolism increases.4

Layering these factors with a 21/7 schedule, the situation becomes dire. As described above, LDE is able to suppress GnRH response for just 24 hours. The 7-day HFI allows the ovaries to respond to increased FSH and estradiol flux with follicular growth.5,7,10,14-16,18 When exogenous hormones are reestablished on Day 8 (or later if pills are missed), ovulation may still occur in response to an unrelenting LH level, the large follicles could resorb, or potentially remain and develop into functional cysts. Some of these cysts could develop into follicular or theca cysts, creating a morphology that would not have developed if exogenous hormones were managed properly.

There is a wrench in the works!

Though LDE COCs can be an effective symptomatic solution, the usual dosing schedule feeds the problem.4

If PCOS-like symptoms are arising after long-term use of LDE COCs, a practitioner must consider the possibility that the 7-day HFI exacerbated a situation of functional cysts, induced insulin resistance, and triggered androgen release. The follicular flux is less likely in a 24/4 cycle or continuous suppression, than in a 21/7 cycle.14,15,18

Continuous cycling may seem foreign, but if there is no menstrual cycle or corpus luteum shedding, the timing of withdrawal bleeding is arbitrary. Post-contraception fertility and reported side effects are unchanged when comparing continuous cycling to classic 21/7 dosing.14,15

Putting It All Together

If the classic string-of-pearls cysts are found before COC-use initiation, COCs almost always decrease cyst size, and most are completely resorbed in prolonged treatment, though cysts reappear on cessation of COCs.6,10

With all other presentations, the answers are less clear. By distilling the symptom pattern and gathering a clear hormone history, our specific target may be easier to find.

A female on LDE COCs, presenting with a new onset of hyperandrogenism, functional cysts, and unknown ovulatory function, could be classified within the PCOS spectrum; however, her root cause and treatment are different than what might be assumed for classic PCOS.

Removing exogenous hormonal influences would be the most direct way to clear the slate and reestablish ovarian function. For some patients this is not an option. For example, if the symptoms have already appeared, removal of hormonal suppression may worsen symptoms for an unpredictable amount of time.

The best method of care offers 3 options based on a patient’s preference and practicality:

  1. Reestablish regular cycling
  2. Initiate complete hormone suppression
  3. Minimize follicular maturation by shortening the HFI from 7 days to 4 or less

With this alternate schedule, the chance of hormonal rebound is lowered and, along with it, ovarian tissue is protected from gonadotropin surges. If our goal is to reduce harm and assist our patients, we can treat the cause by working with the prescription they already have.

Though I’m a proponent of menstruation, I advocate that it is better to have no cycle, than half a cycle.

Once the root cause is managed, only then can we begin to effectively treat the symptoms through regulating insulin and hormones through the diet, lifestyle, and herbal prescriptions that we know so well. First, let’s reach in and use the wrench fix to the works.


Thara Vayali, B.Sc, MA, ND, is a graduate from the University of British Columbia (Nutritional Sciences), Royal Roads University (Environmental Communications), and the Boucher Institute of Naturopathic Medicine. She practices in Vancouver, BC, and is the creator of Change: Natural Medicine. Her clinical focus is on gastrointestinal, immune, and endocrine health. As a speaker, teacher and researcher, her passion is translating high-quality information into an understandable format.

References

  1. National Institutes of Health. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome. Executive Summary. Dec 3-5, 2012. NIH Web site. https://prevention.nih.gov/docs/programs/pcos/FinalReport.pdf. Accessed May 15, 2014.
  2. Lujan ME, Chizen DR, Pierson RA. Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies. J Obstet Gynaecol Can. 2008;30(8):671-679.
  3. Balen A, Michelmore K. What is polycystic ovary syndrome: Are national views important? Human Reprod. 2002;17(9):2219-2227.
  4. Nader S, Diamanti-Kandarakis E. Polycystic ovary syndrome, oral contraceptives and metabolic issues: new perspectives and a unifying hypothesis. Hum Reprod. 2007;22(2):317-322
  5. Bachmann G, Kopacz S. Drospirenone/ethinyl estradiol 3 mg/20 mug (24/4 day regimen): hormonal contraceptive choices – use of a fourth generation progestin. Patient Prefer Adherence. 2009;3:259-264.
  6. Richardson MR. Current perspectives in polycystic ovary syndrome. Am Fam Physician. 2003;68(4):697-704.
  7. Sulak PJ. Elimination and Alteration of the Hormone-free Interval: Reasons and Methods. The Female Patient (supp). Nov, 2006. http://www.femalepatient.com/PDF/031110001s.pdf. Accessed May 15, 2014.
  8. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanisms and implications for pathogenesis. Endocr Rev. 1997;18(6):774-800.
  9. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352(12):1223-1236.
  10. ESHRE Capri Workshop Group. Ovarian and endometrial function during hormonal contraception. Hum Reprod. 2001;16(7):1527-1535.
  11. Tsilchorozidou T, Honour JW, Conway GS. Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. J Clin Endocrinol Metab. 2003;88(12):5907-5913.
  12. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28-38.e25.
  13. Christin-Maitre S. History of oral contraceptive drugs and their use worldwide. Best Pract Res Clin Endocrinol Metab. 2013;27(1):3-12.
  14. Wright KP, Johnson JV. Evaluation of extended and continuous use oral contraceptives. Ther Clin Risk Manag. 2008;4(5):905-911.
  15. Blake J, Giesbrecht E, Soares CN. Evolving Strategies in the Dosing of Oral Contraceptives. The Can J of CME. 2009;21(9):35-40. http://www.stacommunications.com/journals/cme/2009/09-Sep-09/WNiCRCME.pdf. Accessed May 15, 2014.
  16. Baerwald AR, Pierson RA. Ovarian follicular development during the use of oral contraception: A review. J Obstet Gynaecol Can. 2004;26(1):19-24.
  17. Duijkers IJ, Verhoeven CH, Dieben TO, Klipping C. Follicular growth during contraceptive pill or vaginal ring treatment depends on the day of ovulation in the pretreatment cycle. Hum Reprod. 2004;19(11):2674-2679.
  18. Hoogland HJ, Skouby SO. Ultrasound evaluation of ovarian activity under oral contraceptives. 1993;47(6):583-590.
  19. Thorneycroft IH, Stanczyk FZ, Bradshaw KD, et al. Effect of low-dose oral contraceptives on androgenic markers and acne. 1999;60(5):255-262.
  20. Van der Vange N, Blankenstein MA, Kloosteboer HJ, et al. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. 1990; 41(4):345-352.
  21. Sondheimer S. Metabolic effects of the birth control pill. Clin Obstet Gynecol. 1981;24(3):927-941.
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