PCOS symptoms and contraception: A wrench in the works.

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 and 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.

How to distinguish 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.

The NIH Consensus Report urged renaming and establishment of assessment and diagnostic criteria of PCOS (1).

Close to 5 million American women & 1.4 million Canadian women suffer from one form of PCOS (1,2,5,6). It is 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 ovaries (1,6).

These can present in four phenotypic combinations:(1,2,3,6)

1. HA + Anovulation and No cysts
2. HA + Cysts  and Ovulatory cycles
3. Anovulation + Cysts and 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 (1,2,3,7). A broad diagnosis that affects a broad range of systems leaves us with little to discern causes.

Defining each of these criterion 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, 2-8 mm cysts arranged in a necklace pattern (3,9,10). The clinical presentation has progressed over the years and the dimensions of the diagnostic cysts are less clear. Biochemically the understanding of PCOM is that Gonadotropic Releasing Hormone (GnRH) increases the release of LH over FSH which stimulates follicular theca cell activity and hypertrophy of theca cells is present on histology – though this indistinguishable on ultrasound (3,6,8,9). 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 DHT.12These androgens cause the acne, balding & unwanted hair often reported with PCOS (3,12,13)

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 androgens(8,9). In this light, it seems that insulin affects steroid hormones more significantly than the reverse relationship (8).

Insulin resistance, LH dominance & hyperthecosis are 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 (14) The use of high dose Ethinyl Estradiol (EE) (150ug per day) was effective in completely suppressing GnRH and thus prevented ovulation (14,15).

The original COC cycle length was designed to mirror the average menstruating female’s cycle, helping to normalize the transition to hormonal contraception (14). The cycle was set to 21 days of hormones with a 7-day hormone free interval (HFI) (14,15,16) The schedule was based on nothing more than average menstrual cycle precedent (16).

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 ug (14,15,16,17). 20ug is the lowest possible concentration to effectively suppress Follicle Stimulating Hormone (FSH)(17). 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 consumption is crucial. The hormones metabolize within 24 hours and as a result on day 22 hormone suppression is effectively removed (5,7,10,15,16,17). In the pre-1975 pills, EE levels sustained for first 5 days of the HFI, enough to maintain follicle suppression while creating a withdrawal bleed (14,16) In post-1975 pills, no pill was higher than 50ug of EE. For harm reduction and side effects, currently most pill prescriptions contain 20-35 ug of EE per day (15,17), 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 (5,7,10,15,16,17). Estradiol & FSH return to regular menstruation levels and can continue to increase from day 4 to day 12, even after EE is reinitiated (5,7,10,15,16,17). If pre-contraception ovulation dates were before day 14, FSH will rebound more rapidly (18). 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? (5,7,15,16,17)

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 ovulation.

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

After 7 days the exogenous hormones are reintroduced which may or may not effectively suppress Luteinizing Hormone (LH). Depending on the follicular maturation stage the follicle may:

• atrophy
• ovulate or
• remain as a functional ovarian cyst (10,15,16,17).
  • These cysts are considered normal within a reproductive age group, and resorption generally occurs within 2-3 months (10,15,16,17). Functional ovarian cysts may not cause pain or known pathology, but do release hormones and have higher incidence 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 of women may have functional ovarian cysts 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 formation (17,19).

Luteinized Unruptured Follicle cysts (LUF): Follicles that reach pre-ovulatory diameters, fail to ovulate and become luteinized, either through granulosa cell luteinization (more commonly) or theca cell luteinization (17,19).

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

The formation of these types of cysts in LDE COC users could shed light on the cause of one 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 SHBG (4,5,6,20,21) and certain progestins are competitive agonists for androgen receptors (4,6). COCs suppress GnRH thereby shutting down ovarian production of estradiol and progesterone (14,15). For these reasons, LDE COCs are a common, effective first line prescription to manage PCOS, or PCOS-like symptoms (4,6,10).

In the catch-22 that is medicine, COCs also increase insulin resistance (22). The circulating insulin triggers testosterone release from theca cells into the blood stream – aggravating the long term consequences of insulin resistance in PCOS. Compounding on itself, as a female’s insulin resistance rises, the negative impact of COCs on metabolism worsens (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 respond to increased FSH & estradiol flux with follicular growth (5,7,10,15,16,17,19). When exogenous hormones are re-established 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 dosing schedule is feeding 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 is exacerbating 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 a 21/7 cycle (15,16,19). 

Continuous cycling may seem foreign, but if there is no menstrual cycle nor 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 (15,16).

Where to go from here:

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 new onset of hyperandrogenism, functional cysts and unknown ovulatory function could be classified within the PCOS spectrum – but 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 re-establish ovarian function. For some patients this is not an option. For some, the symptoms have already appeared and removal of hormonal suppression may worsen symptoms for an unpredictable amount of time.

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

1. Re-establish regular cycling.

2. Initiate complete hormone suppression, or

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.

References:

1. National Institutes of Health. Executive Summary. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome. Dec 3-5, 2012.

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. Opinion piece. Human Reproduction 2007;22(2):317-322

5. Bachmann, G, Kopacz, S. Drospirenone/ethinyl estradiol 3mg/20ug (24/4 day regimen): hormonal contraceptive choices – use of a fourth generation progestin.Patient Preference and Adherence. 2009;3:259-264.

6. Richardson, MR. Current perspectives in Polycystic Ovary Syndrome. American Family Physician. 2003;68(4):697-704.

7. Sulak, PJ. Elimination and alteration of the hormone-free-interval: reasons and methods. The Female Patient (supp). 2006; 1-6.

8. Dunaif A. Insulin Resistance and the Polycystic Ovary Syndrome: Mechanisms and Implications for Pathogenesis. Endocrine Reviews 1997;18(6):774-800.

9. Ehrmann, DA. Polycystic Ovary Syndrome. N Engl J Med 352;1223-36.

10. ESHRE Capri Workshop Group. Ovarian and endometrial function during hormonal contraception. Human Reproduction. 2001;16(7):1527-1535.

11. Jenkins, JM. The development and influence of functional ovarian cysts during in vitro fertilisation cycles. J Brit Fert Soc. 1996;1(2):132-136.

12. 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):5907-13.

13. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS) Fertility and Sterility 2012; 97(1):28 – 38 e25.

14. Christin-Maitre S. History of oral contraceptive drugs and their use worldwide. BestPract Res Clin Endocrinol Metab 2013;27(1):3-12.

15. Wright, LP, Johnson, JV. Evaluation of extended and continuous use oral contraceptives. Therapeutics and Clin Risk Management. 2008;4(5):905-911.

16. Blake, J, Giesbrecht, E, Soares, CN. Evolving strategies in the dosing of oral contraceptives. The Can J of CME. 2009;21(9):35-40.

17. Baerwald, AR, Pierson, RA. Ovarian follicular development during the use of oral contraception: A review. J. Obstet gynaecol Can. 2004;26(1):19-24.

18. Duijkers, IJM, Verhoeven, CHJ, Dieben, TOM, & Klipping, C. Follicular growth during contraceptive pill or vaginal ring treatment depends on the day of ovulation in the pretreatment cycle. Human Reproduction 2004;19(11):2674-2679.

19. Hoogland HJ, Skouby SO. Ultrasound evaluation of ovarian activity under oral contraceptives. Contraception 1993;47:583–90.

20. Thorneycroft IH, Stanczyk FZ, Bradshaw KD, Ballagh SA, Nichols M, Weber ME. Effect of low-dose oral contraceptives on androgenic markers and acne. Contraception1999;60(5):255-62.

21. Van der Vange N, Blankenstein MA, Kloosteboer HJ, Haspels AA, Thijssen JH. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception1990; 41(4):345-52.

22. Sondheimer, S. Metabolic effects of the birth control pill. Clin Obstet Gynecol 1981;24(3):927-41.